Systemic Pathology — MCQs

Q: An investigator is studying the immunologic response to a Staphylococcus aureus toxin in a mouse model. Fourteen days after injecting mice with this toxin, he isolates antibodies against neutrophil proteinase 3 in their sera. A patient with high concentrations of these antibodies would most likely present with which of the following clinical features?

Nasal mucosal ulcerations and hematuria. ***Nasal mucosal ulcerations and hematuria*** - Antibodies against **neutrophil proteinase 3 (PR3-ANCA)** are characteristic of **granulomatosis with polyangiitis (GPA)**, previously known as Wegener's granulomatosis. - GPA classically involves the **upper and lower respiratory tracts** (e.g., nasal ulcerations, sinusitis, pulmonary nodules) and the **kidneys** (e.g., glomerulonephritis leading to hematuria), and can also involve the eyes, skin, and joints. *Migratory thrombophlebitis and digital ulcers* - **Migratory thrombophlebitis (Trousseau's sign)** is associated with **adenocarcinomas**, particularly pancreatic cancer, and not directly with PR3-ANCA. - **Digital ulcers** can be seen in various conditions like systemic sclerosis or vasculitis, but are not specific for GPA's primary presentation. *Genital ulcers and anterior uveitis* - **Genital ulcers** and **anterior uveitis** are hallmarks of **Behçet's disease**, a systemic vasculitis not typically associated with PR3-ANCA. - Behçet's disease is characterized by recurrent oral and genital ulcers, ocular inflammation, and skin lesions. *Polyneuropathy and melena* - **Polyneuropathy** can be seen in various conditions, including some vasculitides (e.g., polyarteritis nodosa), but is not a primary or most characteristic feature of GPA. - **Melena (black, tarry stools)** indicates upper gastrointestinal bleeding, which is not a typical presentation of GPA. *Visual impairment and jaw claudication* - **Visual impairment** and **jaw claudication** (pain in the jaw after chewing) are classic symptoms of **giant cell arteritis (temporal arteritis)**. - Giant cell arteritis is a large-vessel vasculitis, distinctly different from the small-vessel vasculitis associated with PR3-ANCA.

Q: Two hours after undergoing allogeneic kidney transplantation for polycystic kidney disease, a 14-year-old girl has lower abdominal pain. Examination shows tenderness to palpation in the area the donor kidney was placed. Ultrasound of the donor kidney shows diffuse tissue edema. Serum creatinine begins to increase and dialysis is initiated. Which of the following is the most likely cause of this patient's symptoms?

Preformed antibodies against class I HLA molecules. ***Preformed antibodies against class I HLA molecules*** - This scenario describes **hyperacute rejection**, a rapid and severe immune response occurring minutes to hours post-transplant. - It is mediated by **preformed antibodies** (often anti-HLA antibodies) in the recipient's circulation that bind to donor antigens, leading to complement activation, endothelial damage, and graft thrombosis. *Immune complex deposition in donor tissue* - This mechanism is characteristic of **Type III hypersensitivity** reactions, which are not typically involved in hyperacute rejection. - Immune complex deposition is more common in conditions like **lupus nephritis** or **post-streptococcal glomerulonephritis**, not immediate graft failure. *T-lymphocyte activation by donor HLA peptides* - This describes the mechanism of **acute cellular rejection**, which is mediated by host T-lymphocytes recognizing donor HLA antigens. - Acute rejection typically occurs days to weeks or months after transplantation, not within hours. *Irreversible intimal fibrosis and obstruction of vessels* - This process is characteristic of **chronic rejection**, which develops months to years after transplantation. - Chronic rejection is a slow, progressive decline in graft function due to vascular damage, fibrosis, and ultimately graft failure. *Proliferation of donor T lymphocytes* - Proliferation of donor T lymphocytes is not a mechanism of transplant rejection but rather relevant to **graft-versus-host disease (GVHD)**. - GVHD occurs when immunocompetent T-cells in the donor tissue (e.g., bone marrow transplant) attack recipient tissues.

Q: A 41-year-old African American woman presents to her primary care physician with a 3-week history of lower extremity edema and shortness of breath. She says that she has also noticed that she gets fatigued more easily and has been gaining weight. Her past medical history is significant for sickle cell disease and HIV infection for which she is currently taking combination therapy. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia, and urinalysis demonstrates 4+ protein. Which of the following would most likely be seen on kidney biopsy in this patient?

Segmental scarring. ***Segmental scarring*** - The patient's history of **HIV infection**, symptoms of **nephrotic syndrome** (edema, weight gain, fatigue, hypoalbuminemia, 4+ proteinuria), and African American ethnicity are highly suggestive of **HIV-associated nephropathy (HIVAN)**. - HIVAN is a form of **collapsing focal segmental glomerulosclerosis (FSGS)**, a condition characterized by **segmental scarring** and collapse of the glomerular tuft. In HIVAN, this scarring is severe and progressive. *Birefringence under polarized light* - This finding is characteristic of **amyloidosis**, where protein deposits (amyloid) accumulate in tissues and exhibit apple-green birefringence under Congo red stain and polarized light. - While amyloidosis can cause nephrotic syndrome, it is not the most common kidney pathology in an HIV-positive patient with these specific features. *Subepithelial deposits* - **Subepithelial deposits** with a characteristic "spike and dome" appearance on electron microscopy are pathognomonic for **membranous glomerulonephritis**. - This type of glomerulonephritis is not typically associated with HIV infection, nor does it typically present with the rapidly progressive decline seen in HIVAN. *Expansion of the mesangium* - **Mesangial expansion** is a common feature in several glomerular diseases, including **diabetic nephropathy** and early-stage IgA nephropathy. - While it can be present in some forms of FSGS, it is not the primary or most characteristic finding for HIVAN, which is better described by collapsing glomeruli and segmental scarring. *Normal glomeruli* - Given the patient's profound **proteinuria (4+)**, hypoalbuminemia, and symptoms of **nephrotic syndrome**, it is highly unlikely that the glomeruli would appear normal on biopsy. - Normal glomeruli would not explain the significant kidney dysfunction and proteinuria observed in this patient.

Q: A 34-year-old woman comes to the physician because of recent fatigue and weakness that is exacerbated by cross-country skiing. Four weeks ago, she was diagnosed with pneumonia; sputum cultures on Eaton agar showed organisms that lacked a cell wall. Physical examination shows conjunctival pallor and cyanosis of the fingertips. Both lungs are clear to auscultation. Which of the following findings is most likely to confirm the diagnosis?

Erythrocytes coated with autoantibodies. ***Erythrocytes coated with autoantibodies*** - The patient's history of **pneumonia caused by *Mycoplasma pneumoniae*** (lacked a cell wall, grew on Eaton agar) is a classic trigger for **cold agglutinin hemolytic anemia**. - **Cold agglutinins** are autoantibodies (typically IgM) that bind to red blood cells at colder temperatures, causing **hemolysis** and symptoms like cyanosis of the fingertips and fatigue due to anemia. *Erythrocytes with denatured hemoglobin inclusions* - These inclusions, known as **Heinz bodies**, are characteristic of **G6PD deficiency** or other conditions causing **oxidative stress**. - While they cause hemolytic anemia, the context of *Mycoplasma pneumoniae* infection points away from this diagnosis. *Neutrophils with hypersegmented nuclei* - **Hypersegmented neutrophils** are a hallmark feature of **megaloblastic anemias**, such as those caused by **vitamin B12 deficiency** or **folate deficiency**. - These anemias present with fatigue and weakness, but the history of *Mycoplasma* pneumonia and cyanosis of the fingertips are not typical features. *Microcytic, hypochromic erythrocytes* - This morphology is characteristic of **iron deficiency anemia** or **thalassemia**. - While fatigue and weakness are symptoms, cyanosis of the fingertips and the recent *Mycoplasma* infection do not align with these diagnoses. *Erythrocytes with basophilic granules* - **Basophilic stippling** (basophilic granules) in red blood cells is typically seen in **lead poisoning** or **thalassemia**. - This finding also does not fit the clinical picture of *Mycoplasma pneumoniae*-induced cold agglutinin hemolytic anemia.

A 7-year-old girl is brought to her pediatrician by her mother because of puffiness under both eyes in the morning. The mother reports that the child has just recovered from a seasonal influenza infection a few days ago. Vital signs include: temperature 37°C (98.6°F), blood pressure 100/67 mm Hg, and pulse 95/min. On examination, there is facial edema and bilateral 2+ pitting edema over the legs. Laboratory results are shown: Serum albumin 2.1 g/dL Serum triglycerides 200 mg/dL Serum cholesterol 250 mg/dL Urine dipstick 4+ protein Which of the following casts are more likely to be present in this patient’s urine?

A 6-year-old girl comes with her parents to the physician's office to initiate care with a new physician. The patient was recently adopted and her parents do not know her birth history; however, she has had some issues with fatigue. They were told by the adoption agency that the patient has required blood transfusions for "low blood count" in the past but they are not aware of the reason for these transfusions. Her temperature is 37.8°C (99.8°F), blood pressure is 110/84 mmHg, and pulse is 95/min. Physical examination is notable for conjunctival pallor, pale skin, and mild splenomegaly. A complete blood count is taken in the office with the following results: Hemoglobin: 6.8 g/dL Leukocyte count: 5,000/mm^3 Platelet count: 190,000/mm^3 Peripheral smear shows spherocytes and further analysis reveals rigid red blood cells. The most likely cause of this patient's symptoms has which of the following modes of inheritance?

An investigator is studying the immunologic response to a Staphylococcus aureus toxin in a mouse model. Fourteen days after injecting mice with this toxin, he isolates antibodies against neutrophil proteinase 3 in their sera. A patient with high concentrations of these antibodies would most likely present with which of the following clinical features?

An 8-year-old boy has a known genetic condition in which the substitution of thymine for adenine in the 6th codon of the beta globin gene leads to a single-point substitution mutation that results in the production of the amino acid valine in place of glutamic acid. The patient comes to the clinic regularly for blood transfusions. What is the most likely laboratory finding that can be observed in this patient?

A 31-year-old man comes to the emergency department for acute tearing chest pain that radiates to the back. Despite appropriate therapy, the patient dies. Autopsy shows an increase in mucoid extracellular matrix and loss of smooth muscle cell nuclei in the media of large arteries. Which of the following additional findings is most likely in this patient?

Two hours after undergoing allogeneic kidney transplantation for polycystic kidney disease, a 14-year-old girl has lower abdominal pain. Examination shows tenderness to palpation in the area the donor kidney was placed. Ultrasound of the donor kidney shows diffuse tissue edema. Serum creatinine begins to increase and dialysis is initiated. Which of the following is the most likely cause of this patient's symptoms?

A 41-year-old African American woman presents to her primary care physician with a 3-week history of lower extremity edema and shortness of breath. She says that she has also noticed that she gets fatigued more easily and has been gaining weight. Her past medical history is significant for sickle cell disease and HIV infection for which she is currently taking combination therapy. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia, and urinalysis demonstrates 4+ protein. Which of the following would most likely be seen on kidney biopsy in this patient?

A 34-year-old woman with beta-thalassemia major is brought to the physician because of a 2-month history of fatigue, darkening of her skin, and pain in her ankle joints. She has also had increased thirst and frequent urination for 2 weeks. She receives approximately 5 blood transfusions every year; her last transfusion was 3 months ago. Physical examination shows hyperpigmented skin, scleral icterus, pale mucous membranes, and a liver span of 17 cm. Which of the following serum findings is most likely in this patient?

A 3-year-old boy is brought to the physician for evaluation of pallor and increasing lethargy for 3 days. Six days ago, he experienced abdominal pain, vomiting, and bloody diarrhea that have since resolved. The family returned from a road trip to Mexico 4-weeks ago. His temperature is 38.8°C (101.8°F), pulse is 128/min, respirations are 30/min, and blood pressure is 96/60 mm Hg. Examination shows pale conjunctivae and scleral icterus. The abdomen is soft, nontender, and nondistended. Bowel sounds are hyperactive. Laboratory studies show: Hemoglobin 7.8 g/dL Mean corpuscular volume 92 μm3 Leukocyte count 18,500/mm3 Platelet count 45,000/mm3 Prothrombin time 12 sec Partial thromboplastin time 34 sec Serum Urea nitrogen 32 mg/dL Creatinine 1.8 mg/dL Bilirubin Total 2.0 mg/dL Direct 0.1 mg/dL Lactate dehydrogenase 1685 U/L A peripheral blood smear shows schistocytes. Which of the following is the most likely mechanism of this patient's presentation?

Q10

A 34-year-old woman comes to the physician because of recent fatigue and weakness that is exacerbated by cross-country skiing. Four weeks ago, she was diagnosed with pneumonia; sputum cultures on Eaton agar showed organisms that lacked a cell wall. Physical examination shows conjunctival pallor and cyanosis of the fingertips. Both lungs are clear to auscultation. Which of the following findings is most likely to confirm the diagnosis?

Systemic Pathology US Medical PG Practice Questions and MCQs

Question 1: A 7-year-old girl is brought to her pediatrician by her mother because of puffiness under both eyes in the morning. The mother reports that the child has just recovered from a seasonal influenza infection a few days ago. Vital signs include: temperature 37°C (98.6°F), blood pressure 100/67 mm Hg, and pulse 95/min. On examination, there is facial edema and bilateral 2+ pitting edema over the legs. Laboratory results are shown: Serum albumin 2.1 g/dL Serum triglycerides 200 mg/dL Serum cholesterol 250 mg/dL Urine dipstick 4+ protein Which of the following casts are more likely to be present in this patient’s urine?

A. Waxy casts
B. Fatty casts (Correct Answer)
C. Red cell casts
D. Granular casts
E. White cell casts

Explanation: ***Fatty casts*** - The patient's presentation with **facial edema**, **pitting edema**, **hypoalbuminemia**, **hyperlipidemia** (increased triglycerides and cholesterol), and **heavy proteinuria** (4+ protein on urine dipstick) is highly suggestive of **nephrotic syndrome**. - **Fatty casts** are pathognomonic for **nephrotic syndrome** because they are formed from renal tubular epithelial cells that have absorbed filtered lipids (cholesterol, triglycerides) and subsequently desquamated. *Waxy casts* - **Waxy casts** are typically associated with **chronic kidney disease** and indicate severe, longstanding tubular atrophy and dilation, often seen in end-stage renal disease. - While they can be present in nephrotic syndrome if the kidney damage is severe and chronic, they are not the most characteristic cast *specifically* for the acute onset and hyperlipidemia seen here. *Red cell casts* - **Red cell casts** are indicative of **glomerulonephritis** (nephritic syndrome), where red blood cells leak through damaged glomerular capillaries into the renal tubules. - This patient's presentation is characterized by **heavy proteinuria** and **edema** (nephrotic syndrome), without signs such as hematuria or hypertension that would typically suggest a nephritic picture. *Granular casts* - **Granular casts** are formed from degenerated cellular casts (e.g., granular breakdown products of renal tubular epithelial cells) or aggregated plasma proteins, and are non-specific indicators of **kidney damage** or **acute tubular necrosis**. - While they can be seen in various kidney diseases, including nephrotic syndrome, they are not as specific as fatty casts for the constellation of symptoms presented. *White cell casts* - **White cell casts** are typically associated with **pyelonephritis** (kidney infection) or **interstitial nephritis**, indicating inflammation within the renal tubules or interstitium. - There is no clinical or laboratory evidence of infection or inflammation suggesting pyelonephritis in this patient.

Question 2: A 6-year-old girl comes with her parents to the physician's office to initiate care with a new physician. The patient was recently adopted and her parents do not know her birth history; however, she has had some issues with fatigue. They were told by the adoption agency that the patient has required blood transfusions for "low blood count" in the past but they are not aware of the reason for these transfusions. Her temperature is 37.8°C (99.8°F), blood pressure is 110/84 mmHg, and pulse is 95/min. Physical examination is notable for conjunctival pallor, pale skin, and mild splenomegaly. A complete blood count is taken in the office with the following results: Hemoglobin: 6.8 g/dL Leukocyte count: 5,000/mm^3 Platelet count: 190,000/mm^3 Peripheral smear shows spherocytes and further analysis reveals rigid red blood cells. The most likely cause of this patient's symptoms has which of the following modes of inheritance?

A. Autosomal recessive
B. Autosomal dominant (Correct Answer)
C. Mitochondrial inheritance
D. X-linked dominant
E. X-linked recessive

Explanation: ***Autosomal dominant*** - The clinical picture of severe **anemia** requiring transfusions, **splenomegaly**, and peripheral smear findings of **spherocytes** and rigid red blood cells is highly suggestive of **hereditary spherocytosis**. - **Hereditary spherocytosis** is caused by defects in red blood cell membrane proteins (e.g., spectrin, ankyrin), and the **most common mode of inheritance** for this condition is **autosomal dominant** (approximately 75% of cases). *Autosomal recessive* - While approximately **25%** of hereditary spherocytosis cases result from **autosomal recessive inheritance** or de novo mutations, the majority (~75%) follow an autosomal dominant pattern. - The severity of presentation alone does not distinguish between inheritance patterns; both can present with severe anemia requiring transfusions. - Other common red blood cell disorders, such as **sickle cell anemia** and **beta-thalassemia**, are autosomal recessive, but their characteristic findings (e.g., sickle cells, target cells) are not described here. *Mitochondrial inheritance* - **Mitochondrial disorders** primarily affect organs with high energy demands (e.g., muscles, brain) and do not typically cause isolated hemolytic anemia with spherocytes. - This mode of inheritance involves genes located in the **mitochondrial DNA** and is passed down exclusively from the mother. *X-linked dominant* - **X-linked dominant** disorders affect both males and females (though often more severely in males) and do not fit the typical presentation or known genetic basis of hereditary spherocytosis. - Examples include **Rett syndrome** and **incontinentia pigmenti**. *X-linked recessive* - **X-linked recessive** disorders, such as **G6PD deficiency** or **hemophilia**, are more common in males and have distinct clinical and laboratory features that do not match the patient's presentation of hereditary spherocytosis. - While **G6PD deficiency** can cause hemolytic anemia, it is typically triggered by oxidative stress and does not primarily involve spherocytes or chronic splenomegaly in the same manner.

Question 3: An investigator is studying the immunologic response to a Staphylococcus aureus toxin in a mouse model. Fourteen days after injecting mice with this toxin, he isolates antibodies against neutrophil proteinase 3 in their sera. A patient with high concentrations of these antibodies would most likely present with which of the following clinical features?

A. Migratory thrombophlebitis and digital ulcers
B. Genital ulcers and anterior uveitis
C. Polyneuropathy and melena
D. Visual impairment and jaw claudication
E. Nasal mucosal ulcerations and hematuria (Correct Answer)

Explanation: ***Nasal mucosal ulcerations and hematuria*** - Antibodies against **neutrophil proteinase 3 (PR3-ANCA)** are characteristic of **granulomatosis with polyangiitis (GPA)**, previously known as Wegener's granulomatosis. - GPA classically involves the **upper and lower respiratory tracts** (e.g., nasal ulcerations, sinusitis, pulmonary nodules) and the **kidneys** (e.g., glomerulonephritis leading to hematuria), and can also involve the eyes, skin, and joints. *Migratory thrombophlebitis and digital ulcers* - **Migratory thrombophlebitis (Trousseau's sign)** is associated with **adenocarcinomas**, particularly pancreatic cancer, and not directly with PR3-ANCA. - **Digital ulcers** can be seen in various conditions like systemic sclerosis or vasculitis, but are not specific for GPA's primary presentation. *Genital ulcers and anterior uveitis* - **Genital ulcers** and **anterior uveitis** are hallmarks of **Behçet's disease**, a systemic vasculitis not typically associated with PR3-ANCA. - Behçet's disease is characterized by recurrent oral and genital ulcers, ocular inflammation, and skin lesions. *Polyneuropathy and melena* - **Polyneuropathy** can be seen in various conditions, including some vasculitides (e.g., polyarteritis nodosa), but is not a primary or most characteristic feature of GPA. - **Melena (black, tarry stools)** indicates upper gastrointestinal bleeding, which is not a typical presentation of GPA. *Visual impairment and jaw claudication* - **Visual impairment** and **jaw claudication** (pain in the jaw after chewing) are classic symptoms of **giant cell arteritis (temporal arteritis)**. - Giant cell arteritis is a large-vessel vasculitis, distinctly different from the small-vessel vasculitis associated with PR3-ANCA.

Question 4: An 8-year-old boy has a known genetic condition in which the substitution of thymine for adenine in the 6th codon of the beta globin gene leads to a single-point substitution mutation that results in the production of the amino acid valine in place of glutamic acid. The patient comes to the clinic regularly for blood transfusions. What is the most likely laboratory finding that can be observed in this patient?

A. Bone marrow hyperplasia
B. Elevated lactate dehydrogenase (Correct Answer)
C. Hemosiderin
D. Hemoglobinuria
E. Increased serum haptoglobin

Explanation: ***Elevated lactate dehydrogenase*** - The description of a single-point mutation leading to valine in place of glutamic acid in the beta-globin chain is characteristic of **sickle cell anemia**. In sickle cell anemia, chronic hemolytic anemia causes continuous red blood cell destruction. - **Lactate dehydrogenase (LDH)** is an intracellular enzyme released when red blood cells are destroyed. In chronic hemolysis, **elevated LDH** is a consistent laboratory finding reflecting ongoing cell lysis. - This is a routine blood test (true laboratory finding) and is characteristically elevated in all hemolytic anemias, including sickle cell disease. *Bone marrow hyperplasia* - The bone marrow does undergo **hyperplasia** in response to chronic hemolysis as it increases red blood cell production to compensate for accelerated destruction. - However, bone marrow hyperplasia is a **histopathological finding** requiring bone marrow biopsy or aspiration, not a routine laboratory test. The question specifically asks for a "laboratory finding." *Hemosiderin* - **Hemosiderin** is an iron-storage complex that accumulates in tissues due to iron overload, particularly common in patients receiving frequent blood transfusions. - While this patient will likely have hemosiderin accumulation (especially given the transfusion history), detecting it requires tissue examination or bone marrow evaluation with iron staining, not a routine laboratory test. - It reflects iron overload from transfusions rather than the primary hemolytic process. *Hemoglobinuria* - **Hemoglobinuria** (hemoglobin in the urine) occurs when free hemoglobin from intravascular hemolysis exceeds the binding capacity of haptoglobin. - While this can occur during acute hemolytic crises in sickle cell disease, it is **intermittent** rather than a consistent finding. - Elevated LDH is a more reliable and consistently present laboratory marker of chronic hemolysis. *Increased serum haptoglobin* - **Haptoglobin** binds to free hemoglobin released during hemolysis, and its levels are typically **decreased**, not increased, in hemolytic conditions like sickle cell anemia. - In chronic hemolysis, haptoglobin is consumed by binding free hemoglobin, leading to low or undetectable serum levels. - Increased haptoglobin would suggest an acute phase response to inflammation or infection, not hemolysis.

Question 5: A 31-year-old man comes to the emergency department for acute tearing chest pain that radiates to the back. Despite appropriate therapy, the patient dies. Autopsy shows an increase in mucoid extracellular matrix and loss of smooth muscle cell nuclei in the media of large arteries. Which of the following additional findings is most likely in this patient?

A. Nasal septum perforation
B. Ectopia lentis (lens dislocation) (Correct Answer)
C. Condylomata lata
D. Pes cavus with hammer toes
E. Pectus carinatum

Explanation: ***Ectopia lentis (lens dislocation)*** - The patient's presentation of acute **tearing chest pain radiating to the back**, with autopsy findings of **mucoid extracellular matrix increase** and **loss of smooth muscle cell nuclei in the media of large arteries** (cystic medial necrosis), is highly suggestive of **Marfan syndrome**. - **Ectopia lentis** (lens dislocation), particularly upward and temporal, is a classic ocular manifestation of Marfan syndrome, caused by a defect in **fibrillin-1**, a component of suspensory ligaments. *Nasal septum perforation* - This is typically associated with conditions like **Wegener's granulomatosis (granulomatosis with polyangiitis)**, repeated cocaine use, or chronic infections, which are not suggested by the clinical picture or autopsy findings. - It does not specifically relate to the arterial pathology described or a genetic connective tissue disorder. *Condylomata lata* - **Condylomata lata** are characteristic painless, flat-topped, moist lesions found in the anogenital region, indicating a manifestation of **secondary syphilis**. - There is no clinical or pathological evidence to suggest syphilis in this patient. *Pes cavus with hammer toes* - **Pes cavus** (high arch) and **hammer toes** can be associated with various neuromuscular disorders (e.g., Charcot-Marie-Tooth disease) or may be idiopathic. - While Marfan syndrome can have some skeletal abnormalities, these specific foot deformities are not a hallmark feature of the condition, and are less direct than ectopia lentis. *Pectus carinatum* - **Pectus carinatum** (pigeon chest) is a protrusion of the sternum, which can indeed be a skeletal manifestation of **Marfan syndrome**. - However, **ectopia lentis** is an even more distinctive and highly specific feature of Marfan syndrome, and the question asks for the "most likely additional finding" given the strong cardiovascular and histological evidence pointing to Marfan syndrome.

Question 6: Two hours after undergoing allogeneic kidney transplantation for polycystic kidney disease, a 14-year-old girl has lower abdominal pain. Examination shows tenderness to palpation in the area the donor kidney was placed. Ultrasound of the donor kidney shows diffuse tissue edema. Serum creatinine begins to increase and dialysis is initiated. Which of the following is the most likely cause of this patient's symptoms?

A. Preformed antibodies against class I HLA molecules (Correct Answer)
B. Immune complex deposition in donor tissue
C. T-lymphocyte activation by donor HLA peptides
D. Irreversible intimal fibrosis and obstruction of vessels
E. Proliferation of donor T lymphocytes

Explanation: ***Preformed antibodies against class I HLA molecules*** - This scenario describes **hyperacute rejection**, a rapid and severe immune response occurring minutes to hours post-transplant. - It is mediated by **preformed antibodies** (often anti-HLA antibodies) in the recipient's circulation that bind to donor antigens, leading to complement activation, endothelial damage, and graft thrombosis. *Immune complex deposition in donor tissue* - This mechanism is characteristic of **Type III hypersensitivity** reactions, which are not typically involved in hyperacute rejection. - Immune complex deposition is more common in conditions like **lupus nephritis** or **post-streptococcal glomerulonephritis**, not immediate graft failure. *T-lymphocyte activation by donor HLA peptides* - This describes the mechanism of **acute cellular rejection**, which is mediated by host T-lymphocytes recognizing donor HLA antigens. - Acute rejection typically occurs days to weeks or months after transplantation, not within hours. *Irreversible intimal fibrosis and obstruction of vessels* - This process is characteristic of **chronic rejection**, which develops months to years after transplantation. - Chronic rejection is a slow, progressive decline in graft function due to vascular damage, fibrosis, and ultimately graft failure. *Proliferation of donor T lymphocytes* - Proliferation of donor T lymphocytes is not a mechanism of transplant rejection but rather relevant to **graft-versus-host disease (GVHD)**. - GVHD occurs when immunocompetent T-cells in the donor tissue (e.g., bone marrow transplant) attack recipient tissues.

Question 7: A 41-year-old African American woman presents to her primary care physician with a 3-week history of lower extremity edema and shortness of breath. She says that she has also noticed that she gets fatigued more easily and has been gaining weight. Her past medical history is significant for sickle cell disease and HIV infection for which she is currently taking combination therapy. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia, and urinalysis demonstrates 4+ protein. Which of the following would most likely be seen on kidney biopsy in this patient?

A. Birefringence under polarized light
B. Segmental scarring (Correct Answer)
C. Subepithelial deposits
D. Expansion of the mesangium
E. Normal glomeruli

Explanation: ***Segmental scarring*** - The patient's history of **HIV infection**, symptoms of **nephrotic syndrome** (edema, weight gain, fatigue, hypoalbuminemia, 4+ proteinuria), and African American ethnicity are highly suggestive of **HIV-associated nephropathy (HIVAN)**. - HIVAN is a form of **collapsing focal segmental glomerulosclerosis (FSGS)**, a condition characterized by **segmental scarring** and collapse of the glomerular tuft. In HIVAN, this scarring is severe and progressive. *Birefringence under polarized light* - This finding is characteristic of **amyloidosis**, where protein deposits (amyloid) accumulate in tissues and exhibit apple-green birefringence under Congo red stain and polarized light. - While amyloidosis can cause nephrotic syndrome, it is not the most common kidney pathology in an HIV-positive patient with these specific features. *Subepithelial deposits* - **Subepithelial deposits** with a characteristic "spike and dome" appearance on electron microscopy are pathognomonic for **membranous glomerulonephritis**. - This type of glomerulonephritis is not typically associated with HIV infection, nor does it typically present with the rapidly progressive decline seen in HIVAN. *Expansion of the mesangium* - **Mesangial expansion** is a common feature in several glomerular diseases, including **diabetic nephropathy** and early-stage IgA nephropathy. - While it can be present in some forms of FSGS, it is not the primary or most characteristic finding for HIVAN, which is better described by collapsing glomeruli and segmental scarring. *Normal glomeruli* - Given the patient's profound **proteinuria (4+)**, hypoalbuminemia, and symptoms of **nephrotic syndrome**, it is highly unlikely that the glomeruli would appear normal on biopsy. - Normal glomeruli would not explain the significant kidney dysfunction and proteinuria observed in this patient.

Question 8: A 34-year-old woman with beta-thalassemia major is brought to the physician because of a 2-month history of fatigue, darkening of her skin, and pain in her ankle joints. She has also had increased thirst and frequent urination for 2 weeks. She receives approximately 5 blood transfusions every year; her last transfusion was 3 months ago. Physical examination shows hyperpigmented skin, scleral icterus, pale mucous membranes, and a liver span of 17 cm. Which of the following serum findings is most likely in this patient?

A. Decreased transferrin saturation
B. Elevated transferrin
C. Elevated hepcidin
D. Elevated ferritin (Correct Answer)
E. Decreased haptoglobin

Explanation: ***Elevated ferritin*** - The patient has **beta-thalassemia major**, which requires frequent **blood transfusions**, leading to chronic **iron overload**. - **Ferritin** is a storage protein for iron, and its levels are typically elevated in cases of **hemochromatosis** due to iron overload. *Decreased transferrin saturation* - **Transferrin saturation** is a measure of iron bound to transferrin. In iron overload conditions like **hemochromatosis**, **transferrin saturation is typically elevated**, not decreased. - A decreased percentage would indicate **iron deficiency**, which is not the case here given the history of transfusions and symptoms of iron overload. *Elevated transferrin* - **Transferrin** levels are usually **decreased** or normal in iron overload states as the body tries to reduce further iron absorption and transport. - Elevated transferrin is more characteristic of **iron deficiency anemia**, where the body increases iron transport capacity to obtain more iron. *Elevated hepcidin* - **Hepcidin** is a key regulator of iron metabolism, and it is usually **elevated** in response to inflammation and high iron stores to **reduce iron absorption** and release from stores. - However, in disorders such as **beta-thalassemia**, chronic anemia leads to **erythroid hyperplasia** and the production of factors that **suppress hepcidin production**, contributing to increased iron absorption and overload despite high body iron stores. *Decreased haptoglobin* - **Haptoglobin** binds **free hemoglobin** in the blood. It is **decreased** in conditions involving **hemolysis**, which is characteristic of thalassemia major. - While beta-thalassemia major indeed involves hemolysis causing anemia, the primary clinical picture of darkening skin, joint pain, thirst, frequent urination, and liver enlargement points strongly to **iron overload** and its systemic effects, making elevated ferritin a more direct and comprehensive indicator of the patient's immediate medical crisis.

Question 9: A 3-year-old boy is brought to the physician for evaluation of pallor and increasing lethargy for 3 days. Six days ago, he experienced abdominal pain, vomiting, and bloody diarrhea that have since resolved. The family returned from a road trip to Mexico 4-weeks ago. His temperature is 38.8°C (101.8°F), pulse is 128/min, respirations are 30/min, and blood pressure is 96/60 mm Hg. Examination shows pale conjunctivae and scleral icterus. The abdomen is soft, nontender, and nondistended. Bowel sounds are hyperactive. Laboratory studies show: Hemoglobin 7.8 g/dL Mean corpuscular volume 92 μm3 Leukocyte count 18,500/mm3 Platelet count 45,000/mm3 Prothrombin time 12 sec Partial thromboplastin time 34 sec Serum Urea nitrogen 32 mg/dL Creatinine 1.8 mg/dL Bilirubin Total 2.0 mg/dL Direct 0.1 mg/dL Lactate dehydrogenase 1685 U/L A peripheral blood smear shows schistocytes. Which of the following is the most likely mechanism of this patient's presentation?

A. IgA Immune complex-mediated vasculitis
B. Microthrombi formation (Correct Answer)
C. Deficiency of ADAMTS13
D. Bacteremia
E. Infection with an RNA picornavirus

Explanation: ***Microthrombi formation*** - This patient's presentation with **hemolytic anemia** (pallor, lethargy, low hemoglobin, elevated LDH, schistocytes), **thrombocytopenia** (low platelet count), and **acute kidney injury** (elevated BUN and creatinine) following a diarrheal illness, particularly after travel to Mexico (suggesting **Shiga toxin-producing E. coli**), is characteristic of **hemolytic uremic syndrome (HUS)**. - HUS is mediated by **Shiga toxin**, which damages endothelial cells, leading to the formation of **microthrombi** in small blood vessels, occluding them and causing fragmentation of red blood cells (schistocytes) and platelet consumption. *IgA Immune complex-mediated vasculitis* - This describes **Henoch-Schönlein purpura (HSP)**, which typically presents with palpable purpura, abdominal pain, arthralgia, and renal involvement (hematuria/proteinuria), but usually without the severe microangiopathic hemolytic anemia and thrombocytopenia seen here. - While HSP can follow an infection, the primary mechanism involves **IgA deposition** in small vessels, not Shiga toxin-induced microthrombi. *Deficiency of ADAMTS13* - A severe deficiency (<10%) of **ADAMTS13** (a von Willebrand factor-cleaving protease) is the hallmark of **thrombotic thrombocytopenic purpura (TTP)**. - While TTP shares features like microangiopathic hemolytic anemia and thrombocytopenia, it is typically distinguished from HUS by prominent **neurological symptoms** and fever, and less severe renal involvement. The recent diarrheal illness strongly points away from typical TTP. *Bacteremia* - While bacteremia can cause sepsis and lead to disseminated intravascular coagulation (DIC), this patient's clinical picture is more specific for HUS, characterized by the triad of hemolytic anemia, thrombocytopenia, and acute kidney injury following a diarrheal prodrome. - The elevated WBC count can be consistent with infection, but the specific pattern of organ damage and the presence of schistocytes point to a **toxin-mediated microangiopathy** rather than generalized bacteremia-induced DIC. *Infection with an RNA picornavirus* - Picornaviruses (e.g., enteroviruses, poliovirus, hepatitis A virus, rhinovirus) can cause various illnesses, including gastroenteritis, but they are not typically associated with the development of **hemolytic uremic syndrome** with its characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. - The diarrheal illness in HUS is most often caused by **Shiga toxin-producing E. coli**, a bacterium, not an RNA picornavirus.

Question 10: A 34-year-old woman comes to the physician because of recent fatigue and weakness that is exacerbated by cross-country skiing. Four weeks ago, she was diagnosed with pneumonia; sputum cultures on Eaton agar showed organisms that lacked a cell wall. Physical examination shows conjunctival pallor and cyanosis of the fingertips. Both lungs are clear to auscultation. Which of the following findings is most likely to confirm the diagnosis?

A. Erythrocytes with denatured hemoglobin inclusions
B. Neutrophils with hypersegmented nuclei
C. Erythrocytes coated with autoantibodies (Correct Answer)
D. Microcytic, hypochromic erythrocytes
E. Erythrocytes with basophilic granules

Explanation: ***Erythrocytes coated with autoantibodies*** - The patient's history of **pneumonia caused by *Mycoplasma pneumoniae*** (lacked a cell wall, grew on Eaton agar) is a classic trigger for **cold agglutinin hemolytic anemia**. - **Cold agglutinins** are autoantibodies (typically IgM) that bind to red blood cells at colder temperatures, causing **hemolysis** and symptoms like cyanosis of the fingertips and fatigue due to anemia. *Erythrocytes with denatured hemoglobin inclusions* - These inclusions, known as **Heinz bodies**, are characteristic of **G6PD deficiency** or other conditions causing **oxidative stress**. - While they cause hemolytic anemia, the context of *Mycoplasma pneumoniae* infection points away from this diagnosis. *Neutrophils with hypersegmented nuclei* - **Hypersegmented neutrophils** are a hallmark feature of **megaloblastic anemias**, such as those caused by **vitamin B12 deficiency** or **folate deficiency**. - These anemias present with fatigue and weakness, but the history of *Mycoplasma* pneumonia and cyanosis of the fingertips are not typical features. *Microcytic, hypochromic erythrocytes* - This morphology is characteristic of **iron deficiency anemia** or **thalassemia**. - While fatigue and weakness are symptoms, cyanosis of the fingertips and the recent *Mycoplasma* infection do not align with these diagnoses. *Erythrocytes with basophilic granules* - **Basophilic stippling** (basophilic granules) in red blood cells is typically seen in **lead poisoning** or **thalassemia**. - This finding also does not fit the clinical picture of *Mycoplasma pneumoniae*-induced cold agglutinin hemolytic anemia.

Question 11: A 30-year-old Caucasian male presents with hemoptysis and uremia. Blood tests show the presence of anti-basement membrane antibodies specific for collagen located in glomerular and pulmonary basement membranes. The patient undergoes plasmapheresis to help reduce the amount of anti-basement membrane antibodies. Which of the following diseases is of the same hypersensitivity category as this disease?

A. Myasthenia gravis (Correct Answer)
B. Poison ivy rash
C. Systemic lupus erythematosus
D. A PPD test
E. Seasonal allergies

Explanation: ***Myasthenia gravis*** - This condition is a **Type II hypersensitivity reaction** where antibodies target **acetylcholine receptors** at the neuromuscular junction, impairing nerve-to-muscle signaling. - The patient's presentation of hemoptysis and uremia with **anti-basement membrane antibodies** is characteristic of **Goodpasture syndrome**, which is also a **Type II hypersensitivity reaction**. *Poison ivy rash* - This is a classic example of a **Type IV hypersensitivity reaction** (delayed-type hypersensitivity), mediated by **T-cells** reacting to haptens from the plant. - Goodpasture syndrome, described in the stem, involves **antibody-mediated cytotoxicity** (Type II), not T-cell mediated delayed hypersensitivity. *Systemic lupus erythematosus* - This is primarily considered a **Type III hypersensitivity disorder**, involving the formation and deposition of **immune complexes** in various tissues. - While SLE can have Type II features (e.g., hemolytic anemia), its predominant mechanism is distinct from the **direct antibody-mediated destruction** seen in Goodpasture syndrome. *A PPD test* - A positive PPD (purified protein derivative) test for tuberculosis is a manifestation of **Type IV hypersensitivity**, or **delayed-type hypersensitivity**. - It involves the activation of **sensitized T-cells** upon re-exposure to the antigen, leading to an inflammatory response 24-72 hours later, rather than immediate antibody-mediated effects. *Seasonal allergies* - Also known as **allergic rhinitis**, this is a **Type I hypersensitivity reaction**, mediated by **IgE antibodies** binding to mast cells and basophils. - Upon re-exposure to pollen or other allergens, these cells release histamines and other inflammatory mediators, causing immediate symptoms like sneezing and rhinorrhea, which is distinct from Type II hypersensitivity.

Question 12: A 62-year-old man presents to the emergency department with a 2-day history of fatigue, exertional dyspnea, and the sensation of his heartbeat roaring in the ears. He informs you that he recently had an acute upper respiratory infection. He is a retired car salesman, and he informs you that he and his partner enjoy traveling to the tropics. His medical history is significant for gout, hypertension, hypercholesterolemia, diabetes mellitus type II, and multiple basal cell carcinomas on his face and neck. He currently smokes 1 pack of cigarettes per day, drinks a 6-pack of beer per day, and denies any illicit drug use. His vital signs include: temperature 36.7°C (98.0°F), blood pressure 126/74 mm Hg, heart rate 111/min, and respiratory rate 23/min. On physical examination, his pulses are bounding, his complexion is pale, and scleral icterus is apparent. The spleen is moderately enlarged. Oxygen saturation was initially 81% on room air, with a new oxygen requirement of 8 L by face mask. Laboratory analysis results show a hemoglobin level of 7.1 g/dL and elevated total bilirubin. Of the following options, which laboratory test can help to make the diagnosis?

A. Radioallergosorbent test (RAST)
B. Direct Coombs Test (Correct Answer)
C. Serum ferritin
D. Testing for hemosiderin in the urine sediment
E. Hemoglobin electrophoresis

Explanation: ***Direct Coombs Test*** - The patient's symptoms (fatigue, dyspnea, "roaring in the ears," bounding pulses, pallor, elevated heart rate, splenomegaly, low hemoglobin, and elevated bilirubin) are highly suggestive of **hemolytic anemia**. - A direct Coombs test (direct antiglobulin test) detects antibodies or complement components bound to the surface of red blood cells, which is the hallmark of **autoimmune hemolytic anemia**. *Radioallergosorbent test (RAST)* - The RAST is used to detect **IgE antibodies** to specific allergens in the blood. - It is a test for **allergies** and is not relevant to the diagnosis of hemolytic anemia. *Serum ferritin* - **Serum ferritin** is a measure of the body's iron stores and is used to diagnose **iron deficiency anemia**. - While the patient has anemia, the clinical picture points to a hemolytic process, not iron deficiency. *Testing for hemosiderin in the urine sediment* - **Hemosiderin in the urine** indicates chronic intravascular hemolysis when free hemoglobin is filtered by the kidneys and reabsorbed by renal tubules, leading to iron deposition. - While relevant to hemolysis, the direct Coombs test is a more specific and immediate diagnostic tool for **autoimmune hemolytic anemia** given the acute presentation. *Hemoglobin electrophoresis* - **Hemoglobin electrophoresis** is used to identify abnormal hemoglobin variants, such as those found in **sickle cell disease** or **thalassemia**. - While these conditions can cause hemolytic anemia, the acute onset following an upper respiratory infection and the overall clinical picture are more consistent with autoimmune destruction of red blood cells.

Question 13: A 63-year-old woman is brought to the physician by her husband for the evaluation of progressive memory loss for the past 5 months. During the last 2 weeks, she has also had problems getting dressed and finding her way back home from the grocery store. She has had several episodes of jerky, repetitive, twitching movements that resolved spontaneously. She used to work as a teacher but quit her job due to her memory loss. The patient has hypertension. There is no family history of serious illness. Her only medication is hydrochlorothiazide. Her temperature is 37°C (98.6°F), pulse is 65/min, and blood pressure is 125/80 mmHg. She is oriented only to person and place. She follows commands and speaks fluently, but sometimes cannot recall objects. She is unable to read and seems to have difficulty recognizing objects. Cranial nerves II-XII are intact. Examination shows full muscle strength. Deep tendon reflexes are 2+ bilaterally. Babinski sign is absent. Sensation to pinprick and light touch is normal. Which of the following is the most likely underlying cause of this patient's symptoms?

A. Severe cerebral ischemia
B. Substantia nigra degeneration
C. Mutant prion accumulation (Correct Answer)
D. Copper accumulation in the CNS
E. Decreased CSF absorption

Explanation: ***Mutant prion accumulation*** - The patient's rapidly progressive dementia, **myoclonus** (jerky, repetitive, twitching movements), and visual/spatial disorientation (problems getting dressed, finding way home) are highly characteristic of **Creutzfeldt-Jakob disease (CJD)**. - CJD is caused by the accumulation of abnormally folded prion proteins (PrPSc), leading to **spongiform encephalopathy** and rapid neurodegeneration. *Severe cerebral ischemia* - While it can cause cognitive impairment, severe cerebral ischemia (e.g., **vascular dementia**) typically presents with a more step-wise decline and focal neurological deficits, which are not explicitly described here. - **Myoclonus** is not a primary or typical feature of vascular dementia. *Substantia nigra degeneration* - Degeneration of the substantia nigra is characteristic of **Parkinson's disease**, leading to motor symptoms like **bradykinesia, rigidity, tremor, and postural instability**. - While Parkinson's can later involve dementia, it does not typically present with rapid cognitive decline and prominent myoclonus as the initial and dominant symptoms. *Copper accumulation in the CNS* - **Wilson's disease** involves copper accumulation, causing liver disease, psychiatric symptoms, and neurological issues like **dystonia, tremor, and dysarthria**. - It usually presents at a younger age and does not typically manifest with rapid dementia and myoclonus as the primary features. *Decreased CSF absorption* - **Normal pressure hydrocephalus (NPH)**, caused by decreased CSF absorption, classically presents with the triad of **gait disturbance, urinary incontinence, and dementia**. - The dementia in NPH is typically insidious, and prominent myoclonus is not a defining characteristic.

Question 14: A 21-year-old woman with a history of acute lymphoblastic leukemia comes to the physician because she has not had a menstrual period for 12 months. Menarche occurred at the age of 11 years, and menses occurred at regular 28-day intervals until they became irregular 1 year ago. Physical examination shows normal female genitalia and bimanual examination shows a normal-sized uterus. Laboratory studies show markedly elevated FSH levels consistent with premature ovarian failure. Fluorescence in situ hybridization studies show a 46,XY karyotype in the peripheral blood cells. Which of the following is the most likely explanation for the male karyotype found on chromosomal analysis?

A. Radiation therapy
B. Impaired SRY gene function
C. Müllerian duct agenesis
D. Allogeneic bone marrow transplant (Correct Answer)
E. 21-hydroxylase deficiency

Explanation: ***Allogeneic bone marrow transplant*** - The presence of a **46,XY karyotype** in the peripheral blood of a phenotypically female patient strongly suggests donor cells from a male individual. This phenomenon is known as **chimerism** and is a direct consequence of receiving a bone marrow transplant from a male donor. - Given the patient's history of **acute lymphoblastic leukemia**, an allogeneic bone marrow transplant (allo-BMT) is a common treatment, making this the most plausible explanation for the observed male karyotype in her blood. *Radiation therapy* - While radiation therapy is a treatment for leukemia and can cause **premature ovarian failure** (consistent with elevated FSH and amenorrhea), it does not alter the patient's intrinsic karyotype. - Radiation can cause **chromosomal damage** and mutations, but it would not introduce a 46,XY karyotype into the patient's somatic cells if she were genetically female. *Impaired SRY gene function* - Impaired **SRY gene** function in a genetically XY individual leads to **complete gonadal dysgenesis** or **Swyer syndrome**, resulting in a phenotypically female appearance but with streak gonads and lack of pubertal development. - This scenario would explain a 46,XY karyotype in a female body, but it would not account for menarche at age 11, regular menses, and subsequent premature ovarian failure, as individuals with impaired SRY function do not develop functional ovaries capable of menstruation. *Müllerian duct agenesis* - **Müllerian duct agenesis** (also known as Mayer-Rokitansky-Küster-Hauser syndrome) results in the congenital absence of a uterus and often parts of the vagina in a genetically 46,XX female. - This condition does not involve a 46,XY karyotype or premature ovarian failure; instead, patients have normal ovarian function and secondary sexual characteristics, but lack a uterus and thus do not menstruate. The patient **has** a normal-sized uterus. *21-hydroxylase deficiency* - **21-hydroxylase deficiency** is a form of congenital adrenal hyperplasia that can cause **virilization** in genetic females (46,XX) due to excessive androgen production. - It would not result in a 46,XY karyotype in peripheral blood, nor does it typically lead to premature ovarian failure. Instead, it often presents with ambiguous genitalia at birth or signs of androgen excess later in life.

Question 15: A 1-year-old boy presents to the physician with a fever and a persistent cough for the past 5 days. His parents noted that since birth, he has had a history of recurrent skin infections, ear infections, and episodes of pneumonia with organisms including Staphylococcus aureus, Pseudomonas, and Candida. Physical exam is notable for prominent facial scars in the periorbital and nasal regions, which his parents explain are a result of healed abscesses from previous skin infections. A sputum sample is obtained from the patient and the culture grows Aspergillus. Which of the following diagnostic test findings would confirm the patient’s underlying genetic disease?

A. Quantitative serum immunoglobulin test
B. Flow cytometry for CD18 protein
C. Complete blood count
D. Fluorescent in situ hybridization
E. Dihydrorhodamine test (Correct Answer)

Explanation: ***Dihydrorhodamine test*** - This patient's history of **recurrent bacterial and fungal infections** (Staphylococcus aureus, Pseudomonas, Candida, Aspergillus), especially with **catalase-positive organisms**, and the presence of severe skin abscesses, is highly suggestive of **chronic granulomatous disease (CGD)**. - The **dihydrorhodamine (DHR) test** measures the ability of phagocytes to produce a **respiratory burst** using **NADPH oxidase**, which is deficient in CGD. A decrease or absence of fluorescence in the DHR test confirms the diagnosis. *Quantitative serum immunoglobulin test* - This test measures the levels of different **immunoglobulin classes (IgA, IgG, IgM, IgE)** in the blood. - While helpful in diagnosing **humoral immunodeficiencies**, it would likely be normal or show non-specific abnormalities in CGD, which is a **phagocytic disorder**. *Flow cytometry for CD18 protein* - Flow cytometry for **CD18 protein** is used to diagnose **leukocyte adhesion deficiency (LAD)**, which is characterized by a defect in integrin components. - LAD presents with recurrent bacterial infections, but also commonly features **delayed umbilical cord separation** and **impaired wound healing**, which are not mentioned in this case. *Complete blood count* - A **complete blood count (CBC)** assesses the number and types of blood cells. - While a CBC might show **leukocytosis** (elevated white blood cell count) due to infection, it is a non-specific finding and would not confirm the underlying genetic disease. *Fluorescent in situ hybridization* - **Fluorescent in situ hybridization (FISH)** is a cytogenetic technique used to detect **chromosomal abnormalities** or specific gene deletions. - While CGD is a genetic disorder, FISH is not the primary diagnostic test for confirming the functional defect of **NADPH oxidase** in phagocytes.

Question 16: A 35-year-old woman comes to the physician for the evaluation of fatigue and dizziness for the past 2 months. During this period, she has also had mild upper abdominal pain that is not related to food intake. She has no personal or family history of serious illness. She immigrated to the United States from Italy 10 years ago. Menses occur at regular 28-day intervals with moderate flow. She does not smoke or drink alcohol. She takes no medications. Her vital signs are within normal limits. The spleen is palpated 2 cm below the left costal margin. There is no scleral icterus. Neurologic examination shows no abnormalities. Laboratory studies show: Hemoglobin 11.2 g/dL Mean corpuscular volume 62 μm3 Leukocyte count 7,000/mm3 Platelet count 260,000/mm3 A peripheral blood smear shows target cells. The patient is started on iron supplementation. Three weeks later, her laboratory studies are unchanged. Which of the following is the most likely underlying cause of this patient’s condition?

A. Defective ankyrin and spectrin production
B. Vitamin B12 deficiency
C. Mutation in the δ-ALA synthase gene
D. Ferrochelatase and ALA dehydratase inhibition
E. Mutation in the beta-globin gene (Correct Answer)

Explanation: ***Mutation in the beta-globin gene*** - The patient presents with **microcytic anemia** (MCV 62 µm$^3$) that is unresponsive to iron supplementation, a history of immigration from Italy, and splenomegaly. These findings are highly characteristic of **beta-thalassemia minor**, which results from mutations in the beta-globin gene leading to reduced or absent beta-globin chain synthesis. - The presence of **target cells** on the peripheral blood smear is also a classic finding in thalassemia, reflecting an excess of membrane relative to hemoglobin content within the red blood cells due to impaired hemoglobin synthesis. *Defective ankyrin and spectrin production* - This describes the underlying defect in **hereditary spherocytosis**, an inherited condition characterized by defective red blood cell membrane proteins. - While hereditary spherocytosis can cause anemia and splenomegaly, it typically presents with **spherocytes** (not target cells) on the peripheral smear and an elevated mean corpuscular hemoglobin concentration (MCHC). *Vitamin B12 deficiency* - Vitamin B12 deficiency (pernicious anemia) causes **macrocytic anemia** (high MCV), not the microcytic anemia seen in this patient. - It would also typically present with neurological symptoms and megaloblastic changes in the bone marrow, which are not described here. *Mutation in the $\delta$-ALA synthase gene* - A mutation in the $\delta$-ALA synthase gene (specifically the X-linked ALAS2 gene) is associated with **X-linked sideroblastic anemia**, which is a microcytic anemia. - However, sideroblastic anemias are typically characterized by **ringed sideroblasts** in the bone marrow and iron overload, and usually respond to pyridoxine (vitamin B6) rather than being unresponsive to iron supplementation in the way seen here, and splenomegaly is less common. *Ferrochelatase and ALA dehydratase inhibition* - This describes the mechanism of **lead poisoning**, where lead inhibits key enzymes in heme synthesis. - Lead poisoning typically causes **microcytic, hypochromic anemia** with **basophilic stippling** on peripheral blood smear, and often presents with neurological symptoms (e.g., foot drop) and abdominal pain (colic), though splenomegaly is not a classic feature, and the lack of iron responsiveness points away from this diagnosis when thalassemia is a strong contender.

Question 17: A 34-year-old Caucasian female presents with truncal obesity, a rounded "moon face", and a "buffalo hump". Serum analysis shows hyperglycemia. It is determined that a pituitary adenoma is the cause of these symptoms. Adrenal examination is expected to show?

A. Atrophy of the adrenal medulla
B. Atrophy of the adrenal gland
C. Atrophy of the adrenal cortex
D. Diffuse hyperplasia of the adrenal cortex (Correct Answer)
E. Adrenal adenoma

Explanation: ***Diffuse hyperplasia of the adrenal cortex*** - A **pituitary adenoma** causing **Cushing's disease** leads to excessive secretion of **ACTH**. - This chronic overstimulation promotes **diffuse hyperplasia** of the zona fasciculata and reticularis of the **adrenal cortex** to produce more cortisol. *Atrophy of the adrenal medulla* - The adrenal medulla is responsible for producing **catecholamines** (**epinephrine**, **norepinephrine**) and is not directly affected by ACTH or cortisol levels in this manner. - Its structure and function would remain largely unchanged in Cushing's disease stemming from a pituitary adenoma. *Atrophy of the adrenal gland* - **Atrophy of the adrenal glands** typically occurs with chronic exogenous corticosteroid use, which suppresses ACTH and leads to disuse atrophy. - In Cushing's disease, the adrenal glands are continually stimulated by elevated ACTH, leading to hypertrophy/hyperplasia, not atrophy. *Atrophy of the adrenal cortex* - **Adrenal cortical atrophy** occurs when ACTH stimulation is chronically suppressed, such as with prolonged exogenous glucocorticoid therapy. - In this case, autonomous excessive ACTH production from a pituitary adenoma would stimulate, not suppress, the adrenal cortex, leading to hyperplasia. *Adrenal adenoma* - An **adrenal adenoma** itself can cause **Cushing's syndrome** by autonomously producing cortisol, but it typically suppresses ACTH from the pituitary. - If the primary problem is a pituitary adenoma (Cushing's disease), the adrenal glands would be diffusely hyperplastic due to ACTH overstimulation, not present as a single adenoma.

Question 18: A 3-year-old girl presents with her mother for a well-child checkup. Recent laboratory data has demonstrated a persistent normocytic anemia. Her mother denies any previous history of blood clots in her past, but she says that her mother has also had to be treated for pulmonary embolism in the recent past, and her brother has had to deal with anemia his entire life. The patient's past medical history is noncontributory other than frequent middle ear infections. The vital signs upon arrival include: temperature, 36.7°C (98.0°F); blood pressure, 106/74 mm Hg; heart rate, 111/min and regular; and respiratory rate, 17/min. On physical examination, her pulses are bounding and fingernails are pale, but breath sounds remain clear. Oxygen saturation was initially 91% on room air and electrocardiogram (ECG) shows sinus tachycardia. The patient's primary care physician orders a peripheral blood smear to further evaluate this finding, and preliminary results show a hemolytic anemia. Based on the clinical presentation and laboratory findings, which of the following pathophysiologic mechanisms is most likely responsible for this patient's condition?

A. A recessive beta-globin mutation causing morphological changes to the RBC (Correct Answer)
B. An abnormality of the RBC membrane leading to morphological changes
C. Increased red blood cell sensitivity to complement activation, making patients prone to thrombotic events
D. An X-linked recessive disease in which red blood cells are increasingly sensitive to oxidative stress
E. Secondarily caused by EBV, mycoplasma, CLL, or rheumatoid disease

Explanation: ***A recessive beta-globin mutation causing morphological changes to the RBC*** - The presentation of **normocytic hemolytic anemia** in a young child with a family history of **anemia** in a brother and **thrombotic events** (pulmonary embolism in the mother) is highly suggestive of **sickle cell anemia**. - Sickle cell anemia is caused by a **recessive mutation in the beta-globin gene**, leading to **hemoglobin S (HbS)**, which polymerizes under deoxygenated conditions, causing **sickling of red blood cells** and subsequent hemolysis and vaso-occlusion. *An abnormality of the RBC membrane leading to morphological changes* - This description typically points to conditions like **hereditary spherocytosis** or **hereditary elliptocytosis**. - While these also cause hemolytic anemia and abnormal RBC morphology, they usually have different inheritance patterns and typically do not present with the thrombotic complications described in the family history here. *Increased red blood cell sensitivity to complement activation, making patients prone to thrombotic events* - This is characteristic of **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. - While PNH involves thrombotic events and hemolytic anemia, it is an acquired clonal disorder that usually presents later in life and is less likely to be the cause of lifelong anemia in a brother and present in a 3-year-old in this manner. *An X-linked recessive disease in which red blood cells are increasingly sensitive to oxidative stress* - This describes **Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency**. - G6PD deficiency causes hemolytic anemia, often triggered by **oxidative stressors** like certain foods, drugs, or infections, but typically does not present with the chronic baseline anemia and family history of thrombotic events seen here. *Secondarily caused by EBV, mycoplasma, CLL, or rheumatoid disease* - This refers to **autoimmune hemolytic anemia (AIHA)**, which can be triggered by infections (like EBV, Mycoplasma) or autoimmune conditions (like CLL, rheumatoid disease). - AIHA is typically an acquired condition, not a genetic one with a family history of lifelong anemia and thrombotic tendencies, and is less common as a chronic presenting condition in a 3-year-old without other underlying autoimmune signs.

Question 19: A pathologist receives a skin biopsy specimen from a patient who is suspected to have developed graft-versus-host disease (GVHD) following allogeneic stem-cell transplantation. The treating physician informs the pathologist that he is specifically concerned about the diagnosis as the patient developed skin lesions on the 90th-day post-transplantation and therefore, by definition, it should be considered a case of acute GVHD. However, the lesions clinically appear like those of chronic GVHD. The pathologist examines the slide under the microscope and confirms the diagnosis of chronic GVHD. Which of the following findings on skin biopsy is most likely to have helped the pathologist to confirm the diagnosis?

A. Complete separation of the dermis and epidermis
B. Focal vacuolization in the basal cell layer
C. Lymphocytic infiltration of the superficial dermis
D. Hypergranulosis (Correct Answer)
E. Diffuse vacuolization in the basal cell layer

Explanation: ***Hypergranulosis*** - The presence of **hypergranulosis** (thickening of the granular layer) is a characteristic histological feature often seen in **chronic graft-versus-host disease (GVHD)**, especially in the sclerodermoid variant. - This finding, along with other changes like epidermal atrophy and dermal fibrosis, helps differentiate chronic GVHD from acute forms. *Complete separation of the dermis and epidermis* - **Dermal-epidermal separation** (e.g., **subepidermal bullae**) is characteristic of severe acute GVHD (grade III-IV), indicating extensive tissue damage. - It is not a typical feature of chronic GVHD, and its presence would suggest a more acute process. *Focal vacuolization in the basal cell layer* - **Focal vacuolization** and **dyskeratosis** (apoptotic keratinocytes) in the basal layer are classic microscopic signs of **acute graft-versus-host disease (GVHD)**. - While some basal layer changes can occur in chronic GVHD, focal involvement specifically points towards an acute process rather than chronic features. *Lymphocytic infiltration of the superficial dermis* - **Lymphocytic infiltrate** in the superficial dermis is present in both acute and chronic GVHD, making it a **non-specific finding** for differentiating between the two. - More specific features are needed to confirm a diagnosis of chronic GVHD. *Diffuse vacuolization in the basal cell layer* - Diffuse **vacuolar degeneration** of the basal cell layer is also a hallmark of **acute graft-versus-host disease (GVHD)**, indicating early epidermal damage. - This feature points towards an acute process rather than the typical changes observed in chronic GVHD.

Question 20: A 57-year-old man with diabetes mellitus type 2 presents for a routine follow-up. His blood glucose levels have been inconsistently controlled with metformin and lifestyle modifications since his diagnosis 3 years ago. He is currently is on metformin and diet control with exercise. The vital signs are as follows a blood pressure of 122/82 mm Hg, a pulse of 83/min, a temperature of 36.3°C (97.4°F), and a respiratory rate of 10/min. At this current visit, the urinalysis results are as follows: pH 6.2 Color light yellow RBC none WBC none Protein 4+ Cast none Glucose absent Crystal none Ketone absent Nitrite absent 24-h urine protein excretion 3.7 g The urine albumin loss mapping shows: Urine albumin loss/24h current: 215 mg Urine albumin loss/24h 3 months ago: 28 mg The blood sugar analysis shows: Fasting blood sugar 153 mg/dL Post-prandial blood sugar 225 mg/dL HbA1c 7.4% Which of the following best describes the expected microscopic finding on renal biopsy?

A. Glomerular basement membrane thickening and mesangial expansion (Correct Answer)
B. Normal kidney biopsy; no pathological finding is evident at this time
C. Glomerular hypertrophy with slight glomerular basement membrane thickening
D. Kimmelstiel-Wilson nodules and tubulointerstitial fibrosis
E. Significant global glomerulosclerosis

Explanation: ***Glomerular basement membrane thickening and mesangial expansion*** - This patient presents with **nephrotic-range proteinuria (4+ protein, 3.7g/24-h urine protein excretion)** and poorly controlled diabetes, indicating **diabetic nephropathy**. - **Glomerular basement membrane (GBM) thickening** and **mesangial expansion** are the **earliest and most characteristic histological changes** of diabetic nephropathy, representing the diffuse form of diabetic glomerulosclerosis. - These changes precede more advanced findings like Kimmelstiel-Wilson nodules and occur before end-stage renal disease develops. *Normal kidney biopsy; no pathological finding is evident at this time* - The patient's **significant proteinuria (3.7 g/24h, nephrotic range)** and rapidly increasing **urine albumin loss (from 28 to 215 mg over 3 months)** indicate definite renal pathology, ruling out a normal biopsy. - Poorly controlled **diabetes** over three years, coupled with these abnormal findings, strongly suggests **diabetic nephropathy** with established structural changes. *Glomerular hypertrophy with slight glomerular basement membrane thickening* - While **glomerular hypertrophy** can be an early change in diabetic nephropathy, the extent of **proteinuria (4+ and 3.7g/24h, nephrotic range)** suggests more advanced damage than "slight" GBM thickening alone. - The biopsy would likely show **prominent GBM thickening and mesangial expansion**, not just slight changes, given the degree of proteinuria. *Kimmelstiel-Wilson nodules and tubulointerstitial fibrosis* - **Kimmelstiel-Wilson nodules** (nodular mesangial sclerosis) are pathognomonic for **diabetic nephropathy** but represent a more **advanced, nodular form** of glomerulosclerosis. - While these findings can occur in diabetic nephropathy, the **diffuse form with GBM thickening and mesangial expansion** is more common and typically precedes nodular changes. *Significant global glomerulosclerosis* - **Global glomerulosclerosis** implies widespread scarring of glomeruli, which is a feature of **end-stage renal disease**. - While the patient has significant diabetic nephropathy, **GBM thickening and mesangial expansion** are more precise descriptions of the characteristic findings at this stage of disease progression, before end-stage changes occur.

Question 21: A 68-year-old man presents with blisters on the flexor surfaces of his arms and legs. He notes that the lesions appeared 2 days ago and have not improved. He says that he has had similar blisters in the past but has not sought medical attention until now. The man has no significant past medical history. He is afebrile and his vital signs are within normal limits. On physical examination, there are tense bullae present on the flexor surfaces of his arms and legs. Biopsy of a lesion and histopathologic examination reveal a subepidermal blister with a polymorphous but predominantly eosinophilic infiltrate. Which of the following is the best next diagnostic step in this patient?

A. Swab and culture of the blister
B. Indirect immunofluorescence study
C. Bacteriological examination of fluid drained from the blister
D. Potassium hydroxide preparation (KOH prep) of the blister
E. Direct immunofluorescence study (Correct Answer)

Explanation: ***Direct immunofluorescence study*** - A **direct immunofluorescence (DIF) study** on a perilesional skin biopsy is the **gold standard** for diagnosing bullous pemphigoid. - It demonstrates the presence of **IgG and C3 deposits at the dermoepidermal junction** (basement membrane zone), characteristic of bullous pemphigoid. - DIF provides **direct visualization of antibody deposition** within the skin lesions, confirming the autoimmune nature of the disease. *Indirect immunofluorescence study* - Indirect immunofluorescence (IIF) detects circulating autoantibodies in the patient's serum, which can be positive in bullous pemphigoid but is **less sensitive than DIF** for initial diagnosis. - While IIF can support the diagnosis, it does not provide direct evidence of antibody deposition at the basement membrane zone. *Swab and culture of the blister* - Swab and culture are used to identify **bacterial infections**, which might present as secondary complications of bullous lesions but are not the primary diagnostic step for immune-mediated blistering disorders. - The clinical presentation and biopsy results (subepidermal blister, eosinophilic infiltrate) point away from a primary bacterial cause. *Potassium hydroxide preparation (KOH prep) of the blister* - A KOH preparation is used to identify **fungal elements** in skin scrapings or nail samples. - It is not indicated for the diagnosis of bullous skin conditions like bullous pemphigoid, which is an autoimmune disease. *Bacteriological examination of fluid drained from the blister* - Similar to swab and culture, bacteriological examination of blister fluid is primarily for detecting **secondary bacterial infection**. - It will not provide information on the autoimmune etiology of the blisters, which is suggested by the biopsy findings.

Question 22: A 67-year-old man presents to his physician for a follow-up examination. During his last visit 1 month ago, splenomegaly was detected. He has had night sweats for the past several months and has lost 5 kg (11 lb) unintentionally during this period. He has no history of severe illness and takes no medications. The vital signs are within normal limits. The examination shows no abnormalities other than splenomegaly. The laboratory studies show the following: Hemoglobin 9 g/dL Mean corpuscular volume 95 μm3 Leukocyte count 12,000/mm3 Platelet count 260,000/mm3 Ultrasound shows a spleen size of 15 cm and mild hepatomegaly. A peripheral blood smear shows teardrop-shaped and nucleated red blood cells (RBCs) and immature myeloid cells. The marrow is very difficult to aspirate but reveals hyperplasia of all 3 lineages. The tartrate-resistant acid phosphatase (TRAP) test is negative. Clonal marrow plasma cells are not seen. JAK-2 is positive. The cytogenetic analysis is negative for translocation between chromosomes 9 and 22. Which of the following is the most likely diagnosis?

A. Primary myelofibrosis (Correct Answer)
B. Polycythemia vera
C. Chronic myeloid leukemia
D. Multiple myeloma
E. Hodgkin’s lymphoma

Explanation: ***Primary myelofibrosis*** - The patient presents with **splenomegaly**, **constitutional symptoms** (night sweats, weight loss), **anemia**, **teardrop cells** and **nucleated red blood cells** on peripheral smear, **dry bone marrow tap**, and a **positive JAK-2 mutation**, all highly characteristic of primary myelofibrosis. - The negative Philadelphia chromosome (BCR-ABL translocation) excludes CML, and the significant bone marrow fibrosis (implied by dry tap and presence of extramedullary hematopoiesis indicators like teardrop cells) points away from PV alone. *Polycythemia vera* - While polycythemia vera (PV) is associated with a **JAK-2 mutation** and splenomegaly, its hallmark is **erythrocytosis** (high hemoglobin/hematocrit), which is not present; instead, the patient has anemia. - **Teardrop cells** and significant marrow fibrosis are less prominent in untreated PV and more suggestive of secondary myelofibrosis, but the constellation of findings strongly favors primary myelofibrosis. *Chronic myeloid leukemia* - Chronic myeloid leukemia (CML) is characterized by a high leukocyte count, splenomegaly, and immature myeloid cells, but the definitive diagnostic feature is the presence of the **Philadelphia chromosome (BCR-ABL1 translocation)**, which is explicitly stated as negative in this case. - While CML can cause splenomegaly and constitutional symptoms, the absence of the specific cytogenetic marker rules it out. *Multiple myeloma* - Multiple myeloma is a plasma cell malignancy characterized by **bone lesions**, **renal failure**, **hypercalcemia**, and **anemia**, but it does not typically cause splenomegaly or teardrop cells, and the marrow findings would show clonal plasma cells, which are noted as absent. - The **TRAP test** is irrelevant for multiple myeloma; it is used to diagnose hairy cell leukemia. *Hodgkin’s lymphoma* - Hodgkin’s lymphoma is a lymphatic malignancy that can present with **lymphadenopathy**, splenomegaly, and B symptoms (night sweats, weight loss, fever), but the peripheral blood smear findings (teardrop cells, nucleated RBCs, immature myeloid cells) and **JAK-2 mutation** are not characteristic of Hodgkin’s lymphoma. - Diagnosis typically relies on identifying **Reed-Sternberg cells** in lymph node biopsies, not peripheral blood or bone marrow findings like those described.

Question 23: A 45-year-old African American man presents with nausea and severe abdominal pain. He denies vomiting. He says that, 2 days ago, his divorce was finalized, so he went to a bar and had multiple shots of tequila and vodka. This morning, upon waking, he noticed his urine was red, which lasted throughout the day. The patient denies any history of similar symptoms. Past medical history is significant for low blood counts diagnosed on routine laboratory work 6 months ago, which was not followed up due to the stress of the divorce. A review of systems is significant for erectile dysfunction and chronic fatigue. His temperature is 37.2°C (99.0°F), the heart rate is 90/min, the blood pressure is 136/88 mm Hg, and the respiratory rate is 20/min. Physical examination shows scleral icterus. Mucous membranes are pale. Cardiac auscultation reveals a systolic flow murmur loudest along the left sternal border. There is moderate right upper quadrant abdominal tenderness with no rebound or guarding. The remainder of the exam is unremarkable. Laboratory findings are significant for the following: Hematocrit 27% Mean corpuscular volume 81 µm3 Leukocytes 6,000/mm3 Platelets 130,000/µL Haptoglobin 30 mg/dL (50–150 mg/dL) Reticulocyte count 3% Total bilirubin 7.1 mg/dL LDH 766 U/L AST 150 U/L ALT 195 U/L HbA1 96% HbA2 2% HbF 2% CD55 50% of expected The peripheral smear is unremarkable. Which of the following would be the most likely cause of mortality given this patient’s likely diagnosis?

A. Hemorrhage
B. High-output cardiac failure
C. Cerebral vein thrombosis
D. Infection
E. Budd-Chiari syndrome (Correct Answer)

Explanation: ***Budd-Chiari syndrome*** - The patient's symptoms, including **abdominal pain**, **fatigue**, **erectile dysfunction**, and **dark urine** after alcohol consumption, along with lab findings like **low haptoglobin**, **elevated LDH and bilirubin**, and **reduced CD55 expression**, are highly suggestive of **paroxysmal nocturnal hemoglobinuria (PNH)**. **Budd-Chiari syndrome**, caused by **hepatic vein thrombosis**, is a life-threatening complication and a common cause of mortality in PNH due to the prothrombotic state. - **PNH** is characterized by complement-mediated hemolysis due to deficient GPI-anchored proteins (CD55, CD59). The diagnosis is confirmed by **flow cytometry showing decreased CD55 and CD59** on red blood cells, which is indicated by the 50% CD55 of expected finding. *Hemorrhage* - While **thrombocytopenia** is present (platelets 130,000/µL), severe hemorrhage is not typically the leading cause of mortality in PNH. - The clinical picture points more towards thrombotic complications rather than bleeding. *High-output cardiac failure* - Chronic anemia can lead to **high-output cardiac failure** over time, but it is less common as an acute cause of mortality compared to thrombotic events in PNH patients. - The patient's current vital signs and symptoms do not strongly suggest immediate cardiac failure. *Cerebral vein thrombosis* - **Cerebral vein thrombosis** is indeed a serious thrombotic complication of PNH, but **Budd-Chiari syndrome** (hepatic vein thrombosis) is more frequently cited as a major and often fatal cause of mortality in PNH. - Although possible, the abdominal symptoms point more directly to hepatic involvement. *Infection* - PNH patients are not typically considered severely immunocompromised. While chronic disease can increase susceptibility, infection is not the primary cause of mortality associated with the pathophysiological mechanisms of PNH. - The clinical presentation does not strongly suggest an active, life-threatening infection as the most likely cause of mortality.

Question 24: A 55-year-old African American male presents to his primary care physician with complaints of persistent back pain and fatigue over 12 months. Physical examination reveals a blood pressure of 190/150 mm Hg, and laboratory tests reveal hyperlipidemia and a serum creatinine level of 3.0 mg/dL. 4.5 g of protein are excreted in the urine over 24 hours. Renal biopsy shows eosinophilic, acellular material in the glomerular tuft and capillary walls that display apple green-colored birefringence in polarized light upon Congo red tissue staining. The patient most likely suffers from which of the following:

A. Membranous nephropathy
B. Malignant hypertension
C. Focal segmental glomerular sclerosis
D. Amyloidosis (Correct Answer)
E. Multiple myeloma

Explanation: ***Amyloidosis*** - The renal biopsy findings of **eosinophilic, acellular material** in the glomerular tuft and capillary walls with **apple green birefringence on Congo red stain under polarized light** are **pathognomonic for amyloidosis**. - The clinical presentation of **nephrotic-range proteinuria** (4.5g/24h), **renal failure** (creatinine 3.0 mg/dL), and these characteristic biopsy findings establish the diagnosis of **renal amyloidosis**. - This patient likely has **AL (light chain) amyloidosis**, which is most commonly associated with plasma cell dyscrasias. The back pain may suggest an underlying multiple myeloma, but the diagnosed condition based on the biopsy is amyloidosis. - Amyloid deposits consist of misfolded proteins that form β-pleated sheets, which bind Congo red dye and produce the characteristic apple green birefringence. *Multiple myeloma* - While multiple myeloma is a common **cause** of AL amyloidosis and could be the underlying condition here (suggested by back pain), the question asks what the patient **suffers from** based on the biopsy findings. - The biopsy shows **amyloidosis**, not the plasma cell proliferation or light chain casts typical of multiple myeloma itself. - Further workup (serum/urine protein electrophoresis, bone marrow biopsy) would be needed to confirm multiple myeloma as the underlying cause. *Membranous nephropathy* - While it can cause significant proteinuria and nephrotic syndrome, membranous nephropathy shows **thickening of the glomerular basement membrane** with **subepithelial immune deposits**. - Characteristic findings include **spike and dome pattern** on silver stain or granular IgG/C3 deposits on immunofluorescence, not amyloid deposits. *Malignant hypertension* - Although the patient has severe hypertension (190/150 mm Hg), malignant hypertension causes **fibrinoid necrosis** of arterioles and **acute tubular injury**, not amyloid deposition. - The specific biopsy findings of Congo red-positive material with apple green birefringence are incompatible with hypertensive nephropathy alone. *Focal segmental glomerular sclerosis* - **FSGS** shows **segmental scarring** of glomeruli with foot process effacement on electron microscopy, leading to proteinuria. - The biopsy findings of eosinophilic, acellular amyloid material with characteristic birefringence are completely different from FSGS pathology.

Question 25: A 30-year-old woman was brought in by ambulance after being struck by a truck while crossing the street. She has lost a large volume of blood, and a transfusion of packed RBCs is indicated. The patient’s blood type is confirmed to be AB+. She is to be given two units of packed red blood cells (RBCs). Which of the following type(s) of packed RBCs would be safe to transfuse into this patient?

A. A+, B+
B. A+, A-, B+, B-, AB+, AB-, O+, O- (Correct Answer)
C. A-, B-, O-
D. AB+, O+
E. A+, B+, AB+, O+

Explanation: ***A+, A-, B+, B-, AB+, AB-, O+, O-*** - An individual with **AB+ blood type** is considered the **universal recipient** as they have both A and B antigens, and the Rh factor (D antigen) on their red blood cells. - This means they can receive packed RBCs from **any ABO and Rh blood type** without eliciting an immune reaction, as they do not produce antibodies against A, B, or Rh antigens. *A+, B+* - This option is partially correct as **AB+ individuals can receive A+ and B+ blood**, but it is not exhaustive, as they can receive many other types. - Selecting only these two types would **unnecessarily limit donor options** in an emergency when a broader range of compatible blood types is available. *A-, B-, O-* - While **AB+ individuals can receive A-, B-, and O- blood**, this option omits many other compatible types. - These are **universal donor red blood cell types (O-)** or types compatible based on ABO/Rh antigens, but the list is incomplete for an AB+ recipient. *AB+, O+* - **AB+ blood can certainly receive AB+ and O+ blood**, but this option overlooks the fact that they can receive many other blood types for transfusion. - **O+ is a common donor type**, and AB+ is the patient's own type, but these are not the only safe options. *A+, B+, AB+, O+* - This list is also **incomplete** because an AB+ individual can receive all Rh-negative blood types (A-, B-, AB-, O-) as well. - While safe, excluding Rh-negative types unnecessarily restricts the safe donor pool for an **AB+ universal recipient**.

Question 26: A 35-year-old man comes to the physician because of progressive swelling of his legs over the past 2 months. During this period, the patient has had an unintentional 5-kg (11-lb) weight gain. He also reports frequent numbness of the tips of his fingers and cramping in his back and leg muscles. He has a history of HIV infection treated with combined antiretroviral therapy. The patient immigrated to the US from Nigeria 3 years ago. His temperature is 37°C (98.6°F), pulse is 80/min, and blood pressure 150/90 mm Hg. Physical examination shows 3+ periorbital and lower extremity edema bilaterally. Sensation to pinprick and light touch is decreased around the mouth and along the fingers. Laboratory studies show: Serum Albumin 2.5 g/dL Total cholesterol 270 mg/dL HIV antibody positive Urine Blood negative Protein +4 RBC 1-2/hpf RBC casts negative A kidney biopsy is most likely to show which of the following findings under light microscopy?

A. Segmental sclerosis (Correct Answer)
B. Thickened glomerular capillary loops
C. Crescent formation, monocytes, and macrophages
D. No changes
E. Mesangial proliferation

Explanation: ***Segmental sclerosis*** - The patient's presentation with **nephrotic syndrome** (edema, proteinuria, hypoalbuminemia, hyperlipidemia) in the setting of **HIV infection** points toward **HIV-associated nephropathy (HIVAN)**. - **HIVAN** is a form of **focal segmental glomerulosclerosis (FSGS)**, specifically the collapsing variant, which is characterized by **segmental sclerosis** and collapse of the glomerular tuft on light microscopy. *Thickened glomerular capillary loops* - **Thickened glomerular capillary loops** are characteristic of **membranous nephropathy** or **diabetic nephropathy**. - While both can cause nephrotic syndrome, they are not typically seen with HIVAN and the patient's other symptoms do not suggest these conditions. *Crescent formation, monocytes, and macrophages* - **Crescent formation** is a hallmark of **rapidly progressive glomerulonephritis (RPGN)**, an aggressive inflammatory kidney disease. - RPGN typically presents with nephritic syndrome (hematuria, red blood cell casts) and rapid decline in kidney function, which is not the primary presentation here. *No changes* - The patient has clear clinical and laboratory evidence of significant kidney disease, including **nephrotic syndrome** and **proteinuria**, making it highly unlikely that there would be no changes on kidney biopsy. - A normal kidney biopsy would contradict the strong clinical picture of renal pathology. *Mesangial proliferation* - **Mesangial proliferation** is characteristic of several glomerular diseases, including **IgA nephropathy** and early **lupus nephritis**. - While some forms of FSGS might show mild mesangial changes, prominent mesangial proliferation is not the primary diagnostic feature of HIVAN.

Question 27: A 71-year-old male with worsening memory, behavior changes, and disorientation over the span of several years was admitted to the hospital for signs of severe pneumonia. He passes away after failed antibiotic therapy. Which of the following findings would most likely be identified on autopsy?

A. A spongiform cortex with large intracellular vacuoles
B. Pick bodies
C. Extracellular amyloid forming parenchymal plaques (Correct Answer)
D. Lewy bodies
E. Degeneration of the caudate nucleus

Explanation: ***Extracellular amyloid forming parenchymal plaques*** - The patient's symptoms of progressive memory loss, behavioral changes, and disorientation over several years are characteristic of **Alzheimer's disease**. - **Amyloid plaques** (extracellular deposits of amyloid-beta protein) and **neurofibrillary tangles** (intracellular aggregates of hyperphosphorylated tau protein) are the hallmark pathological findings in Alzheimer's disease on autopsy. *A spongiform cortex with large intracellular vacuoles* - This description is characteristic of **Creutzfeldt-Jakob disease**, a prion disease, which typically progresses much more rapidly (months) than the several years described in the patient. - While it causes dementia, the pace and specific neuropathological features are distinct from those presented. *Pick bodies* - **Pick bodies** (intracellular inclusions of tau protein) are characteristic of **Pick's disease**, a type of frontotemporal dementia. - While Pick's disease can cause behavioral and memory changes, the pattern of cognitive decline and the specific type of widespread neuronal loss differ from classical Alzheimer's. *Lewy bodies* - **Lewy bodies** (intracellular aggregates of alpha-synuclein protein) are the neuropathological hallmark of **Lewy body dementia** and Parkinson's disease. - Lewy body dementia often presents with prominent fluctuations in cognitive function, recurrent visual hallucinations, and parkinsonism, which are not explicitly mentioned in the patient's presentation. *Degeneration of the caudate nucleus* - **Degeneration of the caudate nucleus** is the primary pathological feature of **Huntington's disease**. - Huntington's disease is an inherited disorder characterized by chorea, psychiatric symptoms, and cognitive decline, typically with an earlier onset than described in this 71-year-old patient.

Question 28: A 46-year-old man is admitted to the hospital with a 3-day history of productive cough with purulent sputum and fever with chills. On the second day of admission, he develops bloody vomiting, altered mental status, and multiple red spots all over the body. He is oriented only to self. His temperature is 39.3°C (102.7°F), pulse is 110/min, respirations are 26/min, and blood pressure is 86/50 mm Hg. Physical examination shows ecchymoses on both lower extremities. Crackles are heard at the right lung base. Laboratory studies show a platelet count of 45,000/mm3, with a prothrombin time of 44 sec and partial thromboplastin time of 62 sec. D-dimer concentrations are elevated. Which of the following is the most likely cause of this patient's ecchymoses?

A. Disseminated intravascular coagulation (Correct Answer)
B. Thrombotic thrombocytopenic purpura
C. Immune thrombocytopenic purpura
D. Severe hepatic dysfunction
E. Hemolytic uremic syndrome

Explanation: ***Disseminated intravascular coagulation*** - The patient presents with **sepsis** (fever, productive cough, purulent sputum, altered mental status, **hypotension**, crackles in lung base) leading to widespread activation of the coagulation cascade. - The combination of **thrombocytopenia**, prolonged **PT** and **aPTT**, and elevated **D-dimer** is highly characteristic of **disseminated intravascular coagulation (DIC)**, which consumes clotting factors and platelets, causing bleeding manifestations like ecchymoses and bloody vomiting. *Thrombotic thrombocytopenic purpura* - This condition is characterized by a "pentad" of symptoms: **fever**, **neurological symptoms**, **renal dysfunction**, **thrombocytopenia**, and **microangiopathic hemolytic anemia**. - While thrombocytopenia and neurological symptoms are present, the absence of renal dysfunction and significant hemolytic anemia, coupled with markedly deranged coagulation times, makes DIC a more probable diagnosis. *Immune thrombocytopenic purpura* - **Immune thrombocytopenic purpura (ITP)** involves isolated **thrombocytopenia** due to autoimmune destruction of platelets. - In ITP, coagulation times (**PT, aPTT**) are typically normal, distinguishing it from the patient's presentation with prolonged PT and aPTT. *Severe hepatic dysfunction* - **Severe hepatic dysfunction** can lead to coagulopathy due to impaired synthesis of clotting factors, resulting in prolonged PT and aPTT, and sometimes thrombocytopenia. - However, it would not typically cause the acute, rapid onset of widespread systemic inflammation and organ dysfunction seen in this patient, nor the elevated D-dimer which indicates active fibrinolysis. *Hemolytic uremic syndrome* - **Hemolytic uremic syndrome (HUS)** is characterized by the triad of **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **acute kidney injury**. - While thrombocytopenia is present, the patient's primary presentation with severe respiratory infection, shock, and markedly deranged coagulation studies (prolonged PT/aPTT, elevated D-dimer) suggests DIC rather than HUS.

Question 29: A 66-year-old man is brought to the clinic with a history of recurrent falls. He has been slow in his movements and walks clumsily. He denies fever, vision problems, limb weakness, numbness, abnormal sensation in his limbs, trauma, or inability to pass urine. The past medical history is unremarkable, and he only takes calcium and vitamin D supplements. The vital signs include: blood pressure 128/72 mm Hg, heart rate 85/min, respiratory rate 16/min, and temperature 36.9°C (98.4°F). He is awake, alert, and oriented to time, place, and person. His eye movements are normal. There is a tremor in his hands bilaterally, more in the left-hand which decreases with voluntary movements. The muscle tone in all 4 limbs is increased with normal deep tendon reflexes. He walks with a stooped posture and takes small steps with decreased arm swinging movements. During walking, he has difficulty in taking the first few steps and also in changing directions. The speech is slow and monotonous. His mini-mental state examination (MMSE) score is 26/30. What is the most likely pathophysiology of the patient’s condition?

A. Generalized brain atrophy
B. Dilated ventricles with increased CSF volume
C. Demyelination of the white matter
D. Loss of dopaminergic neurons in the substantia nigra (Correct Answer)
E. Cerebellar atrophy

Explanation: ***Loss of dopaminergic neurons in the substantia nigra*** - The patient's symptoms, including **bradykinesia** (slow movements, difficulty initiating walking, small steps), **rigidity** (increased muscle tone), **resting tremor** (more prominent at rest, decreased with voluntary movement), **postural instability** (recurrent falls, stooped posture), **monotonous speech**, and **decreased arm swing**, are classic features of **Parkinson's disease**. - **Parkinson's disease** is primarily caused by the progressive degeneration and loss of **dopaminergic neurons** in the **substantia nigra pars compacta** within the midbrain, leading to a deficiency of dopamine in the basal ganglia. *Generalized brain atrophy* - While generalized brain atrophy can occur in many neurodegenerative conditions, it is a **non-specific finding** and does not specifically explain the characteristic motor symptoms seen in this patient. - Conditions with generalized atrophy, such as **Alzheimer's disease**, typically present with more prominent cognitive decline earlier in the disease course, which is not the primary complaint here (MMSE 26/30). *Dilated ventricles with increased CSF volume* - This description is characteristic of **normal pressure hydrocephalus (NPH)**, which presents with a triad of **gait disturbance**, **urinary incontinence**, and **dementia**. - While gait disturbance is present, the patient denies urinary incontinence and does not have significant dementia (MMSE 26/30), making NPH less likely than Parkinson's. *Demyelination of the white matter* - **Demyelination**, as seen in conditions like **multiple sclerosis**, typically presents with a range of neurological deficits that are often multifocal and can include **sensory disturbances**, **visual problems**, and **limb weakness**, none of which are reported by this patient. - The specific combination of tremor, rigidity, bradykinesia, and gait changes is not characteristic of primary demyelinating diseases. *Cerebellar atrophy* - **Cerebellar atrophy** would primarily manifest as **ataxia**, characterized by intention tremor (worsens with voluntary movement), dysmetria, dysdiadochokinesia, and nystagmus, as well as problems with balance and coordination. - The patient's tremor **decreases with voluntary movements** and his motor deficits are more indicative of **basal ganglia dysfunction** rather than cerebellar dysfunction.

Question 30: A 76-year-old man presents with progressive fatigue, shortness of breath, and brownish discoloration of the urine for the past 5 weeks. Past medical history is significant for aortic valve replacement surgery 2 years ago. His vital signs include: temperature 36.7°C (98.0°F), blood pressure 130/85 mm Hg, pulse 87/min. Physical examination reveals generalized pallor. Skin appears jaundiced. Laboratory findings are significant for the following: Hemoglobin 9.7 g/dL Reticulocyte count 8% Indirect bilirubin 4 mg/dL Lactate dehydrogenase 250 U/L Direct antiglobulin test Negative Which of the following would most likely be found on a peripheral blood smear in this patient?

A. Spherocytes
B. Schistocytes (Correct Answer)
C. Elliptocytes
D. Target cells
E. Ringed sideroblasts

Explanation: ***Schistocytes*** - The patient's history of **aortic valve replacement** and laboratory findings (anemia, elevated reticulocytes, indirect bilirubin, LDH, and negative direct antiglobulin test) are highly suggestive of **mechanical hemolytic anemia**. - **Schistocytes** (fragmented red blood cells) are pathognomonic for microangiopathic hemolytic anemias, including those caused by artificial heart valves which shear red blood cells as they pass through. *Spherocytes* - **Spherocytes** are typically seen in immune hemolytic anemias or hereditary spherocytosis, conditions ruled out by the negative direct antiglobulin test and the context of valve replacement. - They result from loss of red cell membrane without a corresponding decrease in cell volume, leading to a denser, more spherical appearance. *Elliptocytes* - **Elliptocytes** (ovalocytes) are characteristic of hereditary elliptocytosis and occasionally observed in myelodysplastic syndromes or iron deficiency. - They are not associated with mechanical hemolytic anemia or the patient's clinical presentation. *Target cells* - **Target cells** are associated with liver disease, thalassemia, and iron deficiency anemia, where there is an increased surface area-to-volume ratio of red blood cells. - They are not a feature of hemolytic anemia caused by mechanical shearing. *Ringed sideroblasts* - **Ringed sideroblasts** are red blood cell precursors with abnormal iron accumulation in the mitochondria, found in the bone marrow in conditions like myelodysplastic syndromes and sideroblastic anemias. - They are not a feature observed on a peripheral blood smear and are irrelevant to the patient's hemolytic anemia.

Question 31: A 15-year-old African-American male with a BMI of 22 is brought to his physician by his mother to address concerns about a change in his dietary habits. The patient's mother notes that he is constantly hungry and thirsty, despite his eating and drinking water in excess. She also reports an increase in his use of the bathroom. The physician begins explaining that her son's symptoms are likely due to which of the following?

A. Pancreatic islet hyperplasia and hypertrophy
B. The patient's weight
C. Insulitis (Correct Answer)
D. Amyloid deposition in pancreatic islets
E. Insensitivity to insulin

Explanation: ***Insulitis*** - This patient's symptoms of **polyphagia**, **polydipsia**, and **polyuria** are classic for **Type 1 Diabetes Mellitus (T1DM)**. - **Insulitis** is the characteristic autoimmune inflammation of the pancreatic islets that destroys insulin-producing beta cells in T1DM. *Pancreatic islet hyperplasia and hypertrophy* - This is typically seen in conditions of **chronic insulin resistance**, such as early **Type 2 Diabetes Mellitus**, as the body attempts to compensate for increased insulin demand. - It does not explain the acute onset of classic diabetic symptoms in a lean adolescent. *The patient's weight* - With a **BMI of 22**, the patient is within a healthy weight range and is not considered overweight or obese. - While obesity is a major risk factor for **Type 2 Diabetes**, it is not typical for **Type 1 Diabetes**. *Amyloid deposition in pancreatic islets* - **Amyloid deposition**, specifically from **islet amyloid polypeptide (IAPP)**, is a pathological hallmark of **Type 2 Diabetes Mellitus**, not Type 1. - This process contributes to beta-cell dysfunction and death in Type 2 Diabetes, but is secondary to the disease process, not the primary autoimmune destruction seen in Type 1. *Insensitivity to insulin* - **Insulin insensitivity** or **insulin resistance** is the defining feature of **Type 2 Diabetes Mellitus**. - This patient's presentation of sudden symptoms in a lean adolescent strongly points to an absolute **deficiency of insulin**, not resistance.

Question 32: A 28-year-old man seeks evaluation at a medical office for facial swelling and blood in his urine during the last 3 days. He claims that he has had weakness, malaise, and low-grade fevers for the past 3 months. On physical examination, the blood pressure is 160/96 mm Hg and he has periorbital edema bilaterally. The lab testing is significant for leukocytosis, elevated blood urea nitrogen, and elevated serum creatinine. Urinalysis shows gross hematuria, proteinuria, and red blood cell casts. You suspect that this patient has Goodpasture’s disease and decide to order additional tests to confirm the diagnosis. Antibodies to which of the following would most likely be present in this patient if your suspicion is correct?

A. Collagen type IV (Correct Answer)
B. Collagen type III
C. Collagen type V
D. Collagen type I
E. Collagen type II

Explanation: ***Collagen type IV*** - **Goodpasture's disease** is characterized by the presence of **autoantibodies** directed against the **non-collagenous 1 (NC1) domain** of the alpha-3 chain of type IV collagen. - This **type IV collagen** is a major component of the **glomerular and alveolar basement membranes**, explaining the renal and pulmonary manifestations. *Collagen type III* - **Collagen type III** is found in **reticular fibers** and is abundant in distensible tissues like the skin, lungs, and blood vessels. - Antibodies against **collagen type III** are not implicated in the pathogenesis of Goodpasture's disease. *Collagen type V* - **Collagen type V** is a minor fibrillar collagen that plays a role in regulating the assembly of type I collagen fibrils and is found in connective tissues. - Antibodies against **collagen type V** are not associated with Goodpasture's disease. *Collagen type I* - **Collagen type I** is the most abundant collagen in the human body, found in bone, skin, tendons, and ligaments. - Antibodies against **collagen type I** are not involved in the autoimmune response seen in Goodpasture's disease. *Collagen type II* - **Collagen type II** is the primary collagen found in **cartilage** and is essential for its structural integrity. - Antibodies primarily targeting **collagen type II** are associated with **rheumatoid arthritis** or other forms of autoimmune arthritis, not Goodpasture's disease.

Question 33: A 44-year-old female presents to her primary care physician complaining of fatigue. She reports a four-month history of increasing fatigue accompanied by occasional constipation. She also reports a 15-pound weight gain over the same time period. She is otherwise healthy and takes no medications. She has never been pregnant. On physical examination, her skin is dry and cracked. Patellar reflexes are 1+ bilaterally. Laboratory analysis reveals an elevated serum TSH and decreased serum and free T4. Her blood is positive for the presence of specific antibodies. A biopsy of this patient’s thyroid gland would most likely reveal which of the following?

A. Lymphocytic infiltrate with germinal center formation (Correct Answer)
B. Spindle cells with stromal amyloid deposition
C. Hyperplasia and hypertrophy of follicular cells
D. Large pleomorphic cells with vascular invasion and necrosis
E. Randomly oriented papillae with pleomorphic cells and dense fibrosis

Explanation: ***Lymphocytic infiltrate with germinal center formation*** - The patient presents with **hypothyroidism** (fatigue, constipation, weight gain, dry skin, decreased reflexes, elevated TSH, decreased free T4) and **positive antibodies**, which strongly suggests **Hashimoto's thyroiditis**. - Biopsy of a thyroid gland affected by Hashimoto's thyroiditis typically shows a **dense lymphocytic infiltrate**, often with well-formed **germinal centers**, and destruction of thyroid follicles. *Spindle cells with stromal amyloid deposition* - This finding is characteristic of **medullary thyroid carcinoma**, a neuroendocrine tumor arising from parafollicular C cells. - Medullary thyroid carcinoma does not present with the clinical or laboratory findings of hypothyroidism described in this patient. *Hyperplasia and hypertrophy of follicular cells* - This microscopic appearance is characteristic of **Graves' disease**, which causes **hyperthyroidism** due to diffuse follicular hyperplasia, not hypothyroidism. - The patient's symptoms and lab results (elevated TSH, decreased T4) are inconsistent with Graves' disease. *Large pleomorphic cells with vascular invasion and necrosis* - This describes features of **anaplastic thyroid carcinoma**, an extremely aggressive and undifferentiated malignancy. - Anaplastic thyroid carcinoma typically presents as a rapidly enlarging neck mass, not primarily with symptoms of hypothyroidism and positive antibodies. *Randomly oriented papillae with pleomorphic cells and dense fibrosis* - This description is most consistent with **papillary thyroid carcinoma**, which is characterized by specific nuclear features (Orphan Annie eye nuclei, nuclear grooves, intranuclear inclusions) and often a papillary architecture. - Patients with papillary thyroid carcinoma are typically euthyroid, and the presentation here is clearly one of hypothyroidism.

Question 34: A 53-year-old woman seeks medical care for superficial erosions and blisters over the skin of her head and trunk. She also has significant involvement of her buccal mucosa, which has made eating difficult. A year earlier, she developed tender sores on the oral mucosa and soft palate of her mouth, which was initially treated as herpes simplex stomatitis. Her condition worsened despite treatment, resulting in the development of eroded areas over her trunk and extremities, with a 10 kg weight loss. Upon further questioning, she denies itching, but she notes that the top layer of her skin could be easily removed when firm horizontal pressure was applied. What is the most likely diagnosis for this patient’s condition?

A. Dermatitis herpetiformis
B. Toxic epidermal necrolysis
C. Pemphigus vulgaris (Correct Answer)
D. Bullous pemphigoid
E. Behcet’s disease

Explanation: ***Pemphigus vulgaris*** - This condition is characterized by **superficial erosions and blisters**, significant **mucosal involvement** (especially oral), and a **positive Nikolsky sign** (skin easily removed with pressure), all classic features of pemphigus vulgaris. - The initial presentation often includes painful **oral lesions** that precede cutaneous involvement and can lead to **weight loss** due to difficult eating. *Dermatitis herpetiformis* - Typically presents with intensely **pruritic (itchy) urticarial papules and vesicles**, primarily on extensor surfaces, which is contrary to the patient's denial of itching. - Strongly associated with **celiac disease** and presents with distinct IgA deposits on direct immunofluorescence, unlike the IgG deposits seen in pemphigus vulgaris. *Toxic epidermal necrolysis* - Characterized by widespread **epidermal detachment**, often triggered by drugs, with fever and severe systemic symptoms, which are not detailed here. - The onset is usually acute and rapid, leading to extensive "sheet-like" skin loss, rather than the more gradual progression described. *Bullous pemphigoid* - Presents with **tense bullae** on an erythematous or urticarial base, and while oral involvement can occur, it is less common and less severe than in pemphigus vulgaris. - The **Nikolsky sign is typically negative** in bullous pemphigoid, and the blisters are subepidermal, remaining intact longer. *Behcet’s disease* - Characterized by **recurrent oral and genital aphthous ulcers**, along with ocular and skin lesions, but typically does not present with widespread blistering and positive Nikolsky sign. - It is a multisystem inflammatory disorder, and the skin lesions are usually **erythema nodosum-like** or papulopustular, not extensive superficial erosions and blisters.

Question 35: A 4-month-old boy with a history of multiple infections presents with muscle stiffness. On physical exam, he is found to have carpopedal spasm as well as a heart murmur. Based on your clinical suspicion you decide to obtain a chest X-ray which shows a diminished shadow in the mediastinum. A mutation in which of the following chromosomes is the most likely cause of this patient's presentation?

A. Chromosome 22 (Correct Answer)
B. Chromosome 17
C. Chromosome 5
D. Chromosome 7
E. Chromosome X

Explanation: ***Chromosome 22*** - This patient's presentation with **multiple infections**, **muscle stiffness** (indicating hypocalcemia), **carpopedal spasm**, a **heart murmur**, and a **diminished thymic shadow** on chest X-ray are classic signs of **DiGeorge syndrome**. - **DiGeorge syndrome** is caused by a microdeletion on **chromosome 22q11**, leading to abnormal development of the third and fourth pharyngeal pouches. *Chromosome 17* - Deletions or duplications on chromosome 17 are associated with conditions such as **Charcot-Marie-Tooth disease type 1A** or **Smith-Magenis syndrome**, which do not typically present with this constellation of symptoms. - While these disorders involve developmental issues, they do not specifically cause thymic aplasia or congenital heart defects characteristic of DiGeorge syndrome. *Chromosome 5* - Deletions on chromosome 5 can lead to **Cri-du-chat syndrome**, characterized by a cat-like cry, intellectual disability, and microcephaly. - This syndrome does not involve the characteristic immune deficiency or hypocalcemia seen in DiGeorge syndrome. *Chromosome 7* - Disorders associated with chromosome 7 include **Williams syndrome** (deletion on 7q11.23) and some forms of cystic fibrosis (due to mutations in the CFTR gene on 7q31.2). - **Williams syndrome** presents with distinct facial features, cardiovascular problems (supravalvular aortic stenosis), and intellectual disability, but not thymic aplasia or hypocalcemia. *Chromosome X* - Chromosome X abnormalities are linked to conditions like **Turner syndrome** (XO) or **Klinefelter syndrome** (XXY), which primarily affect sex development and reproduction. - While X-linked disorders can cause various health issues, they do not typically manifest with the specific combination of thymic hypoplasia, hypocalcemia, and congenital heart defects indicative of DiGeorge syndrome.

Question 36: A 7-year-old girl is brought to the emergency department because she has had abdominal pain and vomiting for the past day. The pain is intermittent, diffuse in nature, and worse after meals. She does not have loose or bloody stools. She has had a nonpruritic rash on her legs and swelling of her ankles for 6 days. She was treated with oral amoxicillin for a sore throat 2 weeks ago. Her immunizations are up-to-date. Vital signs are within normal limits. Examination of the lower extremities shows non-blanching, raised erythematous papules. The left ankle joint is swollen and warm, and its range of motion is limited by pain. Abdominal examination shows tenderness to palpation in the left lower quadrant without guarding or rebound. Bowel sounds are normal. Test of the stool for occult blood is positive. Laboratory studies show: Hemoglobin 10.1 g/dL Leukocyte count 11,800/mm3 Platelet count 431,000/mm3 Erythrocyte sedimentation rate 45 mm/h Serum Glucose 72 mg/dL Creatinine 0.9 mg/dL Which of the following is the most likely diagnosis?

A. Immune thrombocytopenic purpura
B. Juvenile idiopathic arthritis
C. Drug-induced hypersensitivity syndrome
D. Familial mediterranean fever
E. Leukocytoclastic vasculitis (Correct Answer)

Explanation: ***Leukocytoclastic vasculitis*** - This patient's presentation with **palpable purpura** on the legs, **abdominal pain** with gastrointestinal bleeding (**positive occult blood**), and **arthritis** (swollen, warm ankle) after a recent infection (sore throat treated with amoxicillin) is highly characteristic of **Henoch-Schönlein purpura** (HSP), which is a form of leukocytoclastic vasculitis caused by IgA deposition. - The elevated **ESR** and **leukocyte count** support an inflammatory process consistent with vasculitis. *Immune thrombocytopenic purpura* - This condition is characterized by **thrombocytopenia** (low platelet count), leading to petechiae, purpura, and bleeding. The patient's platelet count is elevated, ruling out ITP. - While purpura is present, the **palpable nature** and association with abdominal pain and arthritis point away from ITP. *Juvenile idiopathic arthritis* - JIA primarily presents with **chronic joint inflammation** (arthritis lasting >6 weeks). While arthritis is present here, the acute onset and multisystem involvement (rash, abdominal pain) are not typical. - JIA does not typically involve a **palpable purpuric rash** or **gastrointestinal bleeding**. *Drug-induced hypersensitivity syndrome* - DIHS usually presents with a **widespread morbilliform rash**, fever, lymphadenopathy, and internal organ involvement (e.g., hepatitis, nephritis) typically 2-8 weeks after drug exposure. The rash here is palpable purpura, and the systemic symptoms more closely align with vasculitis. - While there was prior antibiotic use, the specific constellation of symptoms, particularly **palpable purpura** and **abdominal colicky pain** with GI bleeding, is not classic for DIHS. *Familial mediterranean fever* - FMF is an *autoinflammatory disorder* characterized by recurrent, self-limiting episodes of fever, serositis (abdominal pain due to peritonitis, pleuritis), and arthritis. The rash in FMF is typically erysipelas-like, not palpable purpura. - The persistence of a rash for 6 days and positive occult blood, along with the specific type of rash, make FMF less likely.

Question 37: A 28-year-old woman at 36 weeks gestation presents with severe headache, epigastric pain, and visual disturbances. Her blood pressure is 160/110 mmHg. Laboratory studies show a hematocrit of 32%, leukocyte count of 9,400/mm³, and platelet count of 96,000/mm³. Serum studies reveal an aspartate aminotransferase of 94 U/L and an alanine aminotransferase of 92 U/L. Which of the following is the most likely cause of this patient's condition?

A. Overactivation of the coagulation pathway (Correct Answer)
B. Thrombotic obstruction of hepatic veins
C. Sequestration of platelets in the spleen
D. Embolism of amniotic fluid into maternal circulation
E. Viral reactivation and replication

Explanation: ***Overactivation of the coagulation pathway*** - This patient's symptoms (severe headache, epigastric pain, visual disturbances), hypertension (160/110 mmHg), **thrombocytopenia** (platelet count 96,000/mm³), and elevated liver enzymes (AST 94 U/L, ALT 92 U/L) are classic signs of **HELLP syndrome** (Hemolysis, Elevated Liver enzymes, Low Platelet count), a severe form of preeclampsia. - HELLP syndrome is characterized by widespread **endothelial dysfunction**, leading to microvascular damage, platelet activation, and consumption, which are consequences of overactive coagulation and fibrin deposition. *Thrombotic obstruction of hepatic veins* - This condition, known as **Budd-Chiari syndrome**, typically presents with **ascites**, hepatomegaly, and abdominal pain, which are not primary features in this patient. - While it can cause elevated liver enzymes, it doesn't usually explain the widespread microangiopathic changes or severe hypertension seen in HELLP syndrome. *Sequestration of platelets in the spleen* - **Hypersplenism** can lead to thrombocytopenia due to increased platelet destruction or sequestration in an enlarged spleen. - However, this condition does not explain the patient's severe hypertension, elevated liver enzymes, or visual disturbances. *Embolism of amniotic fluid into maternal circulation* - **Amniotic fluid embolism** is a rare and catastrophic event presenting with sudden **cardiovascular collapse**, **respiratory distress**, and coagulopathy, often immediately postpartum or during labor. - This patient's presentation with chronic symptoms like hypertension, epigastric pain, and visual disturbances is not consistent with an acute embolic event. *Viral reactivation and replication* - Viral infections, such as those causing **hepatitis**, can lead to elevated liver enzymes and sometimes thrombocytopenia. - However, they typically do not cause the severe hypertension, visual disturbances, and epigastric pain characteristic of severe preeclampsia or HELLP syndrome.

Question 38: A 16-month-old girl presents for a routine examination. The patient’s mother says that the child is craving ice and often gasps for breath while walking or playing. Family history is unremarkable. The patient is afebrile, and vital signs are within normal limits. Her weight is at the 20th percentile and height is at the 35th percentile for age and sex. Conjunctival pallor is noted on physical examination. Laboratory findings are significant for the following: Hemoglobin 9.2 g/dL Mean corpuscular volume 72 μm3 Mean corpuscular hemoglobin 21 pg/cell Serum ferritin 9 ng/mL Red cell distribution width 16% (ref: 11.5–14.5%) Which of the following additional laboratory findings would most likely be found in this patient?

A. ↑ reticulocyte count
B. ↑ total iron binding capacity (TIBC) (Correct Answer)
C. Bone marrow biopsy showing ringed sideroblasts
D. ↑ hemoglobin A2
E. ↑ transferrin saturation

Explanation: ***↑ total iron binding capacity (TIBC)*** - This patient's **microcytic, hypochromic anemia** (low MCV, low MCH) with **low ferritin** and **high RDW** is highly suggestive of **iron deficiency anemia**. In iron deficiency, the body attempts to increase iron absorption and transport, leading to an **elevated TIBC**. - A **low serum ferritin** (9 ng/mL) is the most definitive indicator of **iron depletion**, and the patient's symptoms like **pica** (craving ice) and **dyspnea on exertion** are classic for significant anemia. *↑ reticulocyte count* - An elevated reticulocyte count indicates a **robust bone marrow response** to anemia, typically seen in conditions like hemolytic anemia or acute blood loss. - In **iron deficiency anemia**, the bone marrow's ability to produce new red blood cells is impaired due to insufficient iron, so the reticulocyte count is usually normal or only slightly elevated, and not significantly increased. *Bone marrow biopsy showing ringed sideroblasts* - **Ringed sideroblasts** are characteristic of **sideroblastic anemia**, which is a disorder of heme synthesis that leads to iron accumulation in mitochondria. - This patient's symptoms and laboratory findings (low ferritin, high TIBC) are inconsistent with sideroblastic anemia, which typically presents with **iron overload**, not iron deficiency. *↑ hemoglobin A2* - An elevated **hemoglobin A2 (HbA2)** is a hallmark of **beta-thalassemia trait** (minor). - While beta-thalassemia can cause microcytic anemia, the patient's **low ferritin** and clinical presentation of iron deficiency (pica, dyspnea) point away from thalassemia, where ferritin levels are usually normal or elevated. *↑ transferrin saturation* - **Transferrin saturation** is calculated as (serum iron / TIBC) x 100%. In **iron deficiency anemia**, serum iron is low and TIBC is high, resulting in a **decreased transferrin saturation**. - An elevated transferrin saturation would suggest **iron overload** conditions like hemochromatosis or certain types of sideroblastic anemia, which contradicts the current patient's clinical picture.

Question 39: A 23-year-old man is brought to the emergency department by ambulance. The patient was found unconscious in his bedroom after a suicide attempt. The patient had cut his wrists using a kitchen knife. The patient is unresponsive and pale. His temperature is 96°F (35.6°C), blood pressure is 70/35 mmHg, pulse is 190/min, respirations are 19/min, and oxygen saturation is 92% on room air. Pressure is applied to his bilateral wrist lacerations. His Glasgow Coma Scale (GCS) is 7. A full trauma assessment is performed and reveals no other injuries. IV fluids are started as well as a rapid transfusion sequence. Norepinephrine is administered. Repeat vitals demonstrate that his blood pressure is 100/65 mmHg and pulse is 100/min. The patient is responsive and seems mildly confused. Resuscitation is continued and the patient's GCS improves to 15. Thirty minutes later, the patient's GCS is 11. His temperature is 103°F (39.4°C), blood pressure is 90/60 mmHg, pulse is 122/min, respirations are 22/min, and oxygen saturation is 99% on room air. The patient complains of flank pain. Laboratory values are ordered and demonstrate the following: Hemoglobin: 9 g/dL Hematocrit: 27% Leukocyte count: 10,500 cells/mm^3 with normal differential Haptoglobin: 11 mg/dL Platelet count: 198,000/mm^3 Serum: Na+: 139 mEq/L Cl-: 101 mEq/L K+: 4.4 mEq/L HCO3-: 23 mEq/L BUN: 27 mg/dL Glucose: 99 mg/dL Creatinine: 1.5 mg/dL Ca2+: 10.0 mg/dL Bilirubin: 3.2 mg/dL AST: 22 U/L ALT: 15 U/L Which of the following describes the most likely diagnosis?

A. Recipient antibody reaction against foreign leukocytes
B. Non-cardiogenic acute lung injury
C. Decreased IgA levels
D. Major blood group incompatibility (Correct Answer)
E. Minor blood group incompatibility

Explanation: ***Major blood group incompatibility*** - The patient's symptoms (fever, hypotension, expanding shock, flank pain) and laboratory findings (increased bilirubin, acute kidney injury indicated by elevated BUN and creatinine, decreasing hemoglobin despite transfusion) approximately 30 minutes after rapid transfusion of blood products are highly suggestive of an **acute hemolytic transfusion reaction (AHTR)**. AHTR is most commonly caused by **ABO incompatibility**, which leads to rapid intravascular hemolysis. - The rapid onset of symptoms after transfusion, coupled with signs of severe hemolysis like high bilirubin and decreasing haptoglobin (though haptoglobin levels here are less clear, the overall picture points to hemolysis), and signs of systemic inflammation (fever, declining GCS after initial improvement), are classic for a major blood group incompatibility. *Recipient antibody reaction against foreign leukocytes* - This description is characteristic of a **febrile non-hemolytic transfusion reaction (FNHTR)**. While fever is present, the severe **hypotension**, **flank pain**, and evidence of **hemolysis** (elevated bilirubin, acute kidney injury) are not typical features of FNHTR. - FNHTRs are generally milder and resolve with supportive care, unlike the life-threatening condition seen in this patient, which involves substantial organ dysfunction. *Non-cardiogenic acute lung injury* - This describes **transfusion-related acute lung injury (TRALI)**. While TRALI can cause hypoxemia and fever, the primary symptoms are acute respiratory distress and pulmonary infiltrates. - This patient's prominent symptoms are related to **hemolysis** and **systemic shock** (flank pain, elevated bilirubin, acute kidney injury), without significant mention of respiratory distress or lung involvement as the primary issue. *Decreased IgA levels* - **IgA deficiency** can lead to allergic reactions, including **anaphylaxis**, during transfusion if the recipient has anti-IgA antibodies and receives IgA-containing blood products. - While anaphylaxis can cause hypotension, it typically presents with urticaria, angioedema, bronchospasm, and abdominal pain. The **flank pain** and **biochemical evidence of hemolysis** (elevated bilirubin, acute kidney injury) are not features of IgA-related transfusion reactions. *Minor blood group incompatibility* - Reactions to minor blood group incompatibilities (e.g., Rh, Kell, Duffy, Kidd) generally cause **extravascular hemolysis**, which is often delayed (days to weeks post-transfusion) and typically less severe than ABO incompatibility. - The **immediate and severe intravascular hemolysis**, profound shock, and **acute organ damage** seen in this patient are more characteristic of major ABO incompatibility rather than minor blood group reactions.

Question 40: A 66-year-old woman comes to the physician because of a 1-week history of pruritic blister formation. Physical examination shows multiple 1–3 cm bullae on the palms, soles, lower legs, and inguinal folds. Gentle rubbing of the skin does not result in sloughing of the epidermis. Immunofluorescence studies of a perilesional skin biopsy specimen are most likely to show deposition of antibodies in which of the following areas?

A. In dermal papillae
B. Between epidermal keratinocytes
C. No staining
D. In dermal vessel walls
E. At the dermoepidermal junction (Correct Answer)

Explanation: ***At the dermoepidermal junction*** - This presentation of **tense bullae** on flexural surfaces in an elderly patient, with a negative **Nikolsky's sign** (no epidermal sloughing with rubbing), is classic for **bullous pemphigoid**. - **Direct immunofluorescence** in bullous pemphigoid typically reveals linear deposits of **IgG** and/or **C3** at the **dermoepidermal junction (basement membrane zone)**. *In dermal papillae* - Deposition in dermal papillae is characteristic of **dermatitis herpetiformis**, which typically presents with intensely pruritic papules and vesicles, often on extensor surfaces. - The morphology and distribution of lesions in this patient (large bullae on palms, soles, inguinal folds) are not consistent with dermatitis herpetiformis. *Between epidermal keratinocytes* - Deposition of autoantibodies (IgG) between epidermal keratinocytes is a hallmark of **pemphigus vulgaris**, resulting in suprabasal blistering and a positive **Nikolsky's sign**. - This patient exhibits **tense bullae** and a **negative Nikolsky's sign**, which rules out pemphigus vulgaris. *No staining* - The presence of pruritic blister formation in an elderly patient strongly suggests an autoimmune bullous disease, for which direct immunofluorescence is a key diagnostic tool. - A lack of staining would indicate a non-immunological cause of blistering or a different type of dermatological condition, which is unlikely given the clinical picture. *In dermal vessel walls* - Immune complex deposition in dermal vessel walls is characteristic of diseases like **leukocytoclastic vasculitis**, which presents with palpable purpura rather than tense bullae. - The clinical presentation of pruritic bullae in this patient is inconsistent with a vasculitis.

Question 41: A 52-year-old woman presents to the clinic complaining of dry mouth for the past 2 months. The patient states that she drinks a lot of water but that her mouth is always dry. She says that she recently went to the dentist and had 3 cavities, which is more than she has ever had in her adult life. She has a history of type 2 diabetes and rheumatoid arthritis. Her vital signs are within normal limits. Her physical exam is unremarkable except that her sclera are dry and erythematous and she has a deformity in the joints of her hands, bilaterally. What is the etiology of this patient’s symptoms?

A. Autoimmune destruction of exocrine glands (Correct Answer)
B. Obstruction of salivary ducts
C. Uncontrolled blood glucose levels
D. Poor hygiene due to inability to care for self
E. Deposition of collagen in the salivary glands

Explanation: ***Autoimmune destruction of exocrine glands*** - The patient's symptoms of **dry mouth (xerostomia)**, dry eyes (suggested by dry and erythematous sclera), and increased dental caries point towards **Sjögren's syndrome**, an autoimmune disease characterized by lymphocytic infiltration and destruction of **exocrine glands**, particularly salivary and lacrimal glands. - Her history of **rheumatoid arthritis** further supports this, as Sjögren's syndrome frequently **co-occurs with other autoimmune disorders**, especially rheumatoid arthritis and systemic lupus erythematosus. *Obstruction of salivary ducts* - Salivary duct obstruction, often due to **sialolithiasis (salivary stones)**, typically presents with sudden onset of pain and swelling exacerbated by eating, which is not described. - This condition primarily affects one or a few ducts, and it does not usually cause the **systemic dryness** affecting both the eyes and mouth seen in this patient. *Uncontrolled blood glucose levels* - **Uncontrolled diabetes** can cause **polyuria and polydipsia**, leading to dehydration and dry mouth; however, it is less likely to cause the specific combination of **dry eyes** and **increased dental caries** as the primary etiology of the dry mouth. - The patient's primary complaint is persistent dry mouth despite drinking a lot of water, which is more suggestive of a **glandular dysfunction** rather than simply dehydration from high glucose. *Poor hygiene due to inability to care for self* - While poor oral hygiene can lead to increased dental caries, it does not explain the **dry mouth** or the **dry and erythematous sclera**. - There is no information in the vignette to suggest that the patient has an inability to care for herself. *Deposition of collagen in the salivary glands* - **Collagen deposition** in salivary glands can occur in diseases like **systemic sclerosis (scleroderma)**, leading to xerostomia due to glandular fibrosis. - However, scleroderma would typically present with other prominent features like **skin thickening, Raynaud's phenomenon**, or **internal organ involvement**, which are not mentioned in this patient.

Question 42: A 69-year-old man presents to the urgent care clinic with a history of hypertension and a variety of systemic complaints including fatigue, occasional fever, abdominal pain, and diffuse palpable, pruritic eruptions over his lower extremities. He is currently unemployed. His medical history is significant for gout, hypertension, hypercholesterolemia, diabetes mellitus type II, HIV, and hepatitis C. He currently smokes 2 packs of cigarettes per day, drinks a 6-pack of beer per day, and endorses a history of injection drug use in the past with heroin but currently denies any drug use. His vital signs include: temperature 40.0°C (104.0°F), blood pressure 126/74 mm Hg, heart rate 111/min, and respiratory rate 23/min. On physical examination, the patient has motor weakness on dorsiflexion. Laboratory analysis shows an elevated erythrocyte sedimentation rate, elevated C-reactive protein, and proteinuria, increasing your suspicion of polyarteritis nodosa. Of the following options, which is the reaction mechanism that underlies polyarteritis nodosa?

A. Type IV–cell-mediated (delayed) hypersensitivity reaction
B. Type II–cytotoxic hypersensitivity reaction
C. Type I–anaphylactic hypersensitivity reaction
D. Type III–immune complex-mediated hypersensitivity reaction (Correct Answer)
E. Type I and IV–mixed anaphylactic and cell-mediated hypersensitivity reactions

Explanation: ***Type III–immune complex-mediated hypersensitivity reaction*** - Polyarteritis nodosa (PAN) is characterized by **necrotizing vasculitis** of medium-sized muscular arteries, a hallmark of **Type III hypersensitivity** involving antigen-antibody immune complexes. - In many cases, **Hepatitis B virus (HBV)** infection is a known trigger, leading to the formation of HBV antigen-antibody complexes that deposit in vessel walls, as seen in this patient's history of hepatitis C which can act similarly. *Type IV–cell-mediated (delayed) hypersensitivity reaction* - This type of reaction involves **T-lymphocytes** and **macrophages**, causing tissue damage that is delayed, such as in contact dermatitis or transplant rejection. - While inflammation is present in PAN, the primary mechanism of vascular damage is not mediated directly by T-cells but by immune complex deposition. *Type II–cytotoxic hypersensitivity reaction* - This reaction involves **antibodies binding to antigens on cell surfaces** or extracellular matrices, leading to cell destruction, as seen in hemolytic anemia or Graves' disease. - PAN is a vasculitis where circulating immune complexes deposit in vessels, rather than antibodies directly targeting vessel wall cells. *Type I–anaphylactic hypersensitivity reaction* - This is an **immediate hypersensitivity reaction** mediated by **IgE antibodies** binding to mast cells and basophils, leading to histamine release, as seen in allergies or anaphylaxis. - The chronic inflammatory nature and systemic symptoms of PAN are not characteristic of an acute, IgE-mediated response. *Type I and IV–mixed anaphylactic and cell-mediated hypersensitivity reactions* - There is currently **no established evidence** to support a combined Type I and Type IV hypersensitivity mechanism as the underlying cause of polyarteritis nodosa. - While various immune responses occur in vasculitis, the predominant mechanism directly responsible for the necrotizing inflammation in PAN aligns specifically with **immune complex deposition**.

Question 43: A 32-year-old Caucasian female required a kidney transplant 3 years ago. She presents with elevated creatinine levels (2.6 mg/dl) and an elevated blood pressure (160/90 mmHg). A biopsy is taken of the transplanted kidney. Following histological findings, a diagnosis of chronic graft rejection is made. Which of the following is NOT a likely finding?

A. Tubular atrophy
B. Glomerular destruction
C. Interstitial fibrosis
D. Glomerular crescents (Correct Answer)
E. Graft arteriosclerosis

Explanation: ***Glomerular crescents*** - **Glomerular crescents** are characteristic of rapidly progressive glomerulonephritis, an acute inflammatory process, and not typically associated with chronic allograft nephropathy. - While crescentic glomerulonephritis can lead to chronic kidney damage, the presence of **active crescents** suggests a more acute, severe immunological injury, rather than the established fibrotic changes of chronic rejection. *Tubular atrophy* - **Tubular atrophy** is a common feature in chronic allograft nephropathy, reflecting ongoing injury and loss of functional renal tubules. - It results from ischemia, inflammation, and fibrotic changes that compromise the tubules' integrity and function over time. *Glomerular destruction* - In chronic rejection, **glomeruli can undergo destruction** due to chronic inflammation, scarring, and ischemic changes, leading to glomerulosclerosis and loss of filtration capacity. - This is a progressive process where glomeruli become non-functional and eventually are replaced by fibrous tissue. *Interstitial fibrosis* - **Interstitial fibrosis** is a hallmark of chronic allograft nephropathy, representing the accumulation of fibrous tissue in the renal interstitium. - It significantly contributes to the decline in kidney function by impairing oxygen and nutrient delivery to tubules and compressing them. *Graft arteriosclerosis* - **Graft arteriosclerosis**, also known as transplant vasculopathy, is a key pathological feature of chronic rejection, characterized by concentric intimal thickening of arteries. - This vascular damage leads to chronic ischemia and contributes to the progressive loss of graft function observed in chronic rejection.

Question 44: A 55-year-old woman presents with pain in both hands and wrists for several years. It is associated with morning stiffness that lasts for almost an hour. She has a blood pressure of 124/76 mm Hg, heart rate of 71/min, and respiratory rate of 14/min. Physical examination reveals tenderness and swelling in both hands and wrists. Laboratory investigations reveal the presence of anti-cyclic citrullinated peptide. Which of the following immune-mediated processes is responsible for this patient’s condition?

A. Self-tolerance
B. Type IV hypersensitivity
C. IgE-mediated immune responses only
D. Both type II and III hypersensitivities
E. Type III hypersensitivity (Correct Answer)

Explanation: ***Type III hypersensitivity*** - Rheumatoid arthritis (RA), suggested by **symmetric joint pain**, **morning stiffness >1 hour**, and **positive anti-CCP antibodies**, is primarily mediated by **Type III hypersensitivity** (immune complex-mediated). - **Immune complexes** (rheumatoid factor-IgG complexes, anti-CCP complexes) deposit in the **synovium**, activate **complement**, and recruit inflammatory cells causing **chronic synovitis** and joint destruction. - Note: Type IV hypersensitivity (T cell-mediated) also contributes significantly to RA pathogenesis, though this option is not provided. *Self-tolerance* - **Self-tolerance** is the immune system's ability to recognize and not attack self-antigens. - RA represents a **breakdown of self-tolerance** (an autoimmune disease), not a mechanism of tissue damage itself. *Type IV hypersensitivity* - **Type IV hypersensitivity** (delayed-type, T cell-mediated) does play an important role in RA pathogenesis, with CD4+ T cells driving chronic inflammation. - However, the **primary mechanism** involves immune complex deposition (Type III), making Type III the more complete answer when Type IV is not combined with it. *IgE-mediated immune responses only* - **IgE-mediated responses** (Type I hypersensitivity) cause **allergic reactions** like anaphylaxis, asthma, and hay fever. - This involves IgE binding to mast cells/basophils with histamine release, which is **not characteristic of RA**. *Both type II and III hypersensitivities* - While **Type III hypersensitivity** is central to RA, **Type II hypersensitivity** (antibody-mediated cytotoxicity against cell surface antigens) is **not a primary mechanism** in RA. - Type II occurs in diseases like Goodpasture syndrome, Graves' disease, and myasthenia gravis, where antibodies directly target cell surface receptors or tissue antigens. - In RA, autoantibodies (RF, anti-CCP) primarily form **immune complexes** (Type III), not direct cell targeting (Type II).

Question 45: A 26-year-old African-American woman presents to the clinic for a routine check-up. Review of systems reveals that she often feels nervous and has recently developed a slight tremor. Of note, she has lost 15 pounds in the past 3 months, despite an increased appetite. The patient’s temperature is 99°F (37.2°C), blood pressure is 130/78 mmHg, pulse is 85/min, and respirations are 14/min with an oxygen saturation of 98% on room air. On physical exam, her skin is warm and she has mild exophthalmos. Which of the following is the direct mechanism causing the patient's ophthalmologic findings?

A. Decreased levels of T4/T3
B. Anti-myelin antibodies
C. Lymphocytic infiltration (Correct Answer)
D. Anti-thyroglobulin antibodies
E. Anti-thyroid peroxidase antibodies

Explanation: ***Lymphocytic infiltration*** - **Exophthalmos** in Graves' disease is caused by an **autoimmune inflammatory process** involving the **extraocular muscles** and **orbital connective tissue**. - This inflammation leads to **lymphocytic infiltration**, **fibrosis**, and the accumulation of **hyaluronic acid** and **glycosaminoglycans**, causing orbital tissue expansion and protrusion of the eyeballs. *Decreased levels of T4/T3* - **Decreased T4/T3 levels** are characteristic of **hypothyroidism**, not hyperthyroidism, as seen in this patient. - Hypothyroidism does not directly cause exophthalmos; rather, it can lead to **periorbital edema** due to generalized fluid retention. *Anti-myelin antibodies* - **Anti-myelin antibodies** are associated with **demyelinating diseases** like **multiple sclerosis**, affecting the central nervous system. - They are not involved in the pathogenesis of exophthalmos or thyroid-related ophthalmopathy. *Anti-thyroglobulin antibodies* - **Anti-thyroglobulin antibodies** are often seen in **Hashimoto's thyroiditis**, a cause of hypothyroidism, but can also be present in Graves' disease. - While they are markers of thyroid autoimmunity, they do not directly cause the **ophthalmologic changes** of Graves' disease. *Anti-thyroid peroxidase antibodies* - **Anti-thyroid peroxidase antibodies (TPOAbs)** are also primarily associated with **Hashimoto's thyroiditis** and, less commonly, Graves' disease. - Like anti-thyroglobulin antibodies, they indicate thyroid autoimmunity but are not the direct cause of the **orbital inflammation** and exophthalmos.

Question 46: Six days after undergoing open reduction and internal fixation of a left-sided femur fracture that he sustained in a motor vehicle collision, a 67-year-old man has sudden-onset severe pain and paresthesia in his right arm. The operation and the immediate postoperative course were uneventful. Prior to hospitalization, he did not take any medications. He has smoked 1 pack of cigarettes daily for 25 years. His temperature is 37.3°C (99.2°F), pulse is 105/min and regular, respirations are 22/min, and blood pressure is 156/94 mm Hg. Physical examination of the right arm shows decreased brachial and radial pulses, and a capillary refill time of 6 seconds. The skin over the right arm is pale and cold to the touch. His left leg is casted. Preoperative laboratory studies were within the reference range. Current laboratory studies show: Hemoglobin 13.8 g/dL Leukocyte count 8,300/mm3 Platelet count 60,000/mm3 Serum Partial thromboplastin time, activated 55 sec Prothrombin time 14 seconds D-Dimer positive Arterial Doppler ultrasonography shows occlusion of the right brachial artery. Which of the following is the most likely explanation for this patient's current symptoms?

A. Patent foramen ovale
B. Atrial fibrillation
C. Adverse effect of medication
D. Peripheral arterial disease
E. Disseminated intravascular coagulation (Correct Answer)

Explanation: ***Disseminated intravascular coagulation*** - The patient's **sudden-onset severe pain**, **paresthesia**, **decreased pulses**, **pallor**, and **coldness** in the right arm, along with **occlusion of the brachial artery**, are highly suggestive of **acute limb ischemia** due to **arterial thrombosis**. The laboratory findings of **thrombocytopenia (platelet count 60,000/mm3)**, **prolonged aPTT (55 sec)**, and **positive D-dimer** in a patient with a recent major trauma and surgery are classic signs of **disseminated intravascular coagulation (DIC)**. DIC involves widespread microvascular thrombosis and consumption of clotting factors and platelets, leading to both clotting and bleeding manifestations. - DIC is a severe condition that can follow **major trauma** (like a femur fracture from a motor vehicle collision) and **surgery**, especially when complicated by **sepsis** or prolonged immobility, which increases the inflammatory response and activates coagulation. The clinical picture points to a consumptive coagulopathy leading to thrombotic occlusion. *Patent foramen ovale* - While a **patent foramen ovale (PFO)** can allow for **paradoxical embolism** (e.g., a venous clot crossing to the arterial circulation), it typically doesn't present with the specific laboratory abnormalities of **thrombocytopenia**, **prolonged aPTT**, and **elevated D-dimer** that point to a systemic coagulopathy. - A PFO itself doesn't cause the hypercoagulable state or consume platelets and clotting factors, though it can provide a pathway for an embolus if a clot forms elsewhere. *Atrial fibrillation* - **Atrial fibrillation** is a common cause of **arterial emboli**, particularly to the brain and peripheral arteries due to thrombus formation in the left atrium. However, the patient's pulse is described as **105/min and regular**, which argues against atrial fibrillation as the primary cause. - Furthermore, atrial fibrillation would not explain the **thrombocytopenia** or **prolonged aPTT** seen in this patient, which are key indicators of DIC. *Adverse effect of medication* - While adverse drug reactions can cause a wide array of symptoms, there is no information about new medications started prior to the sudden onset of symptoms that would directly explain acute arterial occlusion, thrombocytopenia, and prolonged aPTT. - Heparin-induced thrombocytopenia and thrombosis (HITT) could cause similar symptoms, but it typically occurs 5-10 days after heparin exposure, and the patient's history doesn't mention recent heparin initiation as the cause, nor does it typically present with such a significant prolongation of aPTT in combination with severe thrombocytopenia and D-dimer elevation from global coagulopathy like DIC. *Peripheral arterial disease* - **Peripheral arterial disease (PAD)** is a chronic condition causing **atherosclerotic narrowing** of the arteries, and while it could lead to acute on chronic limb ischemia, it typically develops over time and is not characterized by the sudden onset of symptoms in a limb that was previously healthy or symptoms in conjunction with **acute onset thrombocytopenia**, **prolonged aPTT**, and **elevated D-dimer**. - Although the patient's smoking history increases his risk for PAD, the acute timing, severity, and associated laboratory findings are more indicative of an acute thrombotic process from a systemic coagulopathy rather than chronic PAD.

Question 47: A 41-year-old man comes to the physician for generalized fatigue and weakness of his left hand for 4 weeks. During this period he also had multiple episodes of cramping abdominal pain and nausea. He works at a battery manufacturing plant. His temperature is 37°C (98.6°F), pulse is 75/min, and blood pressure is 124/74 mm Hg. Examination shows pale conjunctivae and gingival hyperpigmentation. There is weakness when extending the left wrist against resistance. The brachioradialis reflex is 1+ on the left and 2+ on the right. The radial pulse is palpable bilaterally. The remainder of the examination shows no abnormalities. Further evaluation of this patient is most likely to show which of the following?

A. Septal thickening on chest x-ray
B. White bands across the nails
C. Beta‑2 microglobulin in urine
D. Increased total iron binding capacity
E. Basophilic stippling of erythrocytes (Correct Answer)

Explanation: ***Basophilic stippling of erythrocytes*** - This patient's symptoms (fatigue, weakness, abdominal pain, nausea, **wrist drop**, gingival hyperpigmentation) combined with his occupation (battery manufacturing) are highly suggestive of **lead poisoning**. - **Basophilic stippling** is a classic finding in **lead poisoning**, caused by the inhibition of erythrocyte pyrimidine 5'-nucleotidase, leading to aggregated ribosomes within red blood cells. *Septal thickening on chest x-ray* - **Septal thickening** on chest x-ray is often associated with pulmonary conditions like **pulmonary fibrosis** or **pneumoconiosis** (e.g., asbestosis), which are not indicated by the presenting symptoms. - While occupational exposures can lead to lung disease, the neurological and gastrointestinal symptoms, along with **gingival hyperpigmentation** and **wrist drop**, are not typical for a primary pulmonary pathology. *White bands across the nails* - **White bands across the nails** (Mee's lines) are typically associated with **arsenic poisoning**, thallium poisoning, or systemic illnesses like heart failure or Hodgkin's disease. - Although heavy metal poisoning is suspected, the constellation of symptoms points specifically to lead rather than arsenic. *Beta-2 microglobulin in urine* - Elevated **beta-2 microglobulin in urine** is a marker of **tubular proteinuria** and **renal tubular damage**, often seen in conditions like exposure to cadmium, mercury, or some medications. - While chronic lead exposure can affect renal function, **tubular proteinuria** is not the most immediate or characteristic finding associated with the acute symptoms presented, nor is it as specific as other findings for lead poisoning. *Increased total iron binding capacity* - **Increased total iron binding capacity (TIBC)** is typically seen in **iron deficiency anemia**, where the body's iron stores are low, and more transferrin is available to bind iron. - Lead poisoning causes anemia (often **sideroblastic anemia**), but it is generally characterized by **normal or decreased TIBC** due to impaired heme synthesis and often elevated iron stores rather than iron deficiency.

Question 48: A 31-year-old woman presents with pruritic vesicles on the right side of her torso. She notes that the lesions appeared 2 days ago and have not improved. One day prior to their appearance, she says that she experienced a burning sensation in the affected area. The patient is afebrile and vital signs are within normal limits. Upon physical examination, there are painful vesicles noted that are localized to the right T10 skin dermatome. Which of the following complications is associated with this patient’s likely diagnosis?

A. Cerebellar ataxia
B. Pneumonia
C. Fever
D. Postherpetic neuralgia (Correct Answer)
E. Bacterial superinfection of the affected skin

Explanation: ***Postherpetic neuralgia*** - The patient's symptoms of **pruritic vesicles** on one side of the torso, preceded by a **burning sensation**, localized to a **dermatome**, are highly suggestive of **herpes zoster** (shingles). - **Postherpetic neuralgia** is the most common and often debilitating complication of herpes zoster, characterized by persistent pain in the affected dermatome after the rash has resolved. *Cerebellar ataxia* - **Cerebellar ataxia** is not a typical complication of herpes zoster, although generalized varicella-zoster virus (VZV) infection (chickenpox) can rarely be associated with acute cerebellar ataxia, particularly in children. - This patient presents with localized herpes zoster, not generalized VZV infection. *Pneumonia* - **Pneumonia** can be a complication of primary varicella (chickenpox) in adults, but it is rare with herpes zoster, which represents reactivation of the latent virus. - The clinical presentation does not suggest respiratory involvement. *Fever* - While mild fever can sometimes accompany herpes zoster, it is generally not considered a "complication" but rather a possible systemic symptom during the acute phase. - The patient in this case is explicitly stated to be **afebrile**. *Bacterial superinfection of the affected skin* - **Bacterial superinfection** of zoster lesions can occur due to scratching or poor hygiene, but it is not the *most likely* or hallmark complication associated with herpes zoster. - There is no information in the vignette to suggest signs of bacterial superinfection, such as active pus, significant erythema beyond the vesicles, or increasing pain despite antiviral treatment (which would typically be administered).

Question 49: A previously healthy 38-year-old woman is brought to the emergency department by her husband because of left-sided weakness. As she was getting dressed this morning, she was suddenly unable to button up her shirt. When she showed her husband, he noticed that she seemed confused. She has a 3-year history of diabetes mellitus, for which she takes metformin. She had a knee operation 2 days ago. Her temperature is 38.9°C (102°F), pulse is 98/min, respirations are 17/min, and blood pressure is 138/85 mm Hg. She is confused and oriented only to person. Neurologic examination shows diminished muscle strength on the left side. There are scattered petechiae over the chest, arms, and legs. Laboratory studies show: Hemoglobin 7.5 g/dL Leukocyte count 10,500/mm3 Platelet count 40,000/mm3 Prothrombin time 15 seconds Partial thromboplastin time 36 seconds Serum Bilirubin Total 3.5 mg/dL Direct 0.3 mg/dL Urea nitrogen 35 mg/dL Creatinine 2.5 mg/dL Lactate dehydrogenase 1074 U/L A peripheral smear shows numerous schistocytes. Further evaluation is most likely going to show which of the following findings?

A. Decreased ADAMTS13 activity in serum (Correct Answer)
B. Enterohemorrhagic Escherichia coli on stool culture
C. Elevated fibrin degradation products in serum
D. Decreased megakaryocytes on bone marrow biopsy
E. Positive direct Coombs test

Explanation: **Decreased ADAMTS13 activity in serum** - The patient's presentation with **neurological symptoms (confusion, left-sided weakness)**, **renal dysfunction (elevated BUN and creatinine)**, **thrombocytopenia (platelet count 40,000/mm³)**, **microangiopathic hemolytic anemia (schistocytes on smear, high LDH, low hemoglobin, elevated bilirubin)**, and **fever** constitutes the classic pentad of **Thrombotic Thrombocytopenic Purpura (TTP)**. - TTP is characterized by a severe deficiency (<10%) in **ADAMTS13 activity**, a metalloprotease responsible for cleaving large multimers of von Willebrand factor, leading to widespread platelet adhesion and microthrombi formation. *Enterohemorrhagic Escherichia coli on stool culture* - This is characteristic of **hemolytic-uremic syndrome (HUS)**, which typically presents with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, often following a diarrheal illness. - However, the prominent neurological symptoms and absence of preceding diarrhea in this case make HUS less likely than TTP, though both fall under the umbrella of thrombotic microangiopathies. *Elevated fibrin degradation products in serum* - Elevated **fibrin degradation products (FDPs)** and **D-dimers** are hallmarks of **Disseminated Intravascular Coagulation (DIC)**, which involves systemic activation of coagulation leading to widespread microthrombi and consumption of clotting factors and platelets. - While thrombocytopenia and schistocytes can be seen in DIC, the constellation of prominent neurological findings and severe ADAMTS13 deficiency points more specifically to TTP, and the normal PT/PTT values make DIC less probable as they are typically prolonged in DIC due to consumption of clotting factors. *Decreased megakaryocytes on bone marrow biopsy* - A decrease in megakaryocytes would indicate a problem with platelet production in the bone marrow, as seen in **aplastic anemia** or other bone marrow failures. - In TTP, thrombocytopenia is due to increased peripheral consumption of platelets in thrombi, not decreased production; thus, megakaryocytes in the bone marrow would typically be normal or increased in response to the low platelet count. *Positive direct Coombs test* - A positive **direct Coombs test** indicates the presence of antibodies or complement on the surface of red blood cells, which is characteristic of **autoimmune hemolytic anemia**. - While hemolytic anemia is present, the associated thrombocytopenia, neurological symptoms, and renal dysfunction, along with schistocytes, are not typical features of autoimmune hemolytic anemia in isolation.

Question 50: A 36-year-old man presents to his primary care physician with increasing fatigue. He says that the fatigue started after he returned from vacation in South America 4 weeks ago and thinks that it may be related to an infection he got while abroad. He does not know the name of the infection but says that he went to a local clinic for treatment and was given an antibiotic. Since then, he has noticed that he is no longer able to perform his job as a contractor who renovates old homes because he feels short of breath after just a few minutes of work. Furthermore, he says that he has been experiencing prolonged nosebleeds that never occurred prior to this episode. He denies any neurologic symptoms. His past medical history is significant for alcoholic hepatitis secondary to alcohol abuse 3 years prior. Physical exam reveals conjunctival pallor as well as petechiae. Which of the following findings is associated with the most likely cause of this patient's symptoms?

A. Hypersegmented neutrophils
B. Hypocellular bone marrow with fatty infiltration (Correct Answer)
C. Schistocytes on peripheral blood smear
D. Low circulating levels of erythropoietin
E. Dense lines in the metaphysis of long bones

Explanation: ***Hypocellular bone marrow with fatty infiltration*** - The patient's history of **fatigue**, **shortness of breath**, **prolonged nosebleeds**, **conjunctival pallor**, and **petechiae** suggests **pancytopenia**, a hallmark of **aplastic anemia**. - Aplastic anemia is characterized by a **hypocellular bone marrow** with significant **fatty infiltration**, replacing hematopoietic tissue. - The history of antibiotic treatment abroad (possibly chloramphenicol) combined with the patient's symptoms points to **drug-induced aplastic anemia**. *Hypersegmented neutrophils* - **Hypersegmented neutrophils** are characteristic of **megaloblastic anemias**, such as those caused by **vitamin B12 deficiency** or **folate deficiency**. - This patient's symptoms are more indicative of bone marrow failure rather than a maturation defect in myeloid cells. *Schistocytes on peripheral blood smear* - **Schistocytes** are fragmented red blood cells seen in **microangiopathic hemolytic anemias** (e.g., TTP, HUS, DIC) or mechanical hemolysis. - While hemolysis can cause anemia, it does not explain the concurrent **thrombocytopenia** (leading to nosebleeds and petechiae) seen in this patient. *Low circulating levels of erythropoietin* - **Low erythropoietin** levels are typically seen in **anemia of chronic kidney disease**, where the kidneys fail to produce adequate erythropoietin to stimulate red blood cell production. - This patient's presentation with significant bleeding issues and pancytopenia points away from kidney-related anemia. *Dense lines in the metaphysis of long bones* - **Dense lines in the metaphysis of long bones** are characteristic of **lead poisoning**, which can cause **anemia** and **fatigue**. - However, lead poisoning does not typically cause the prominent bleeding symptoms (nosebleeds, petechiae) or pancytopenia seen in this patient. - While the patient's occupation renovating old homes suggests potential lead exposure, the clinical picture is more consistent with aplastic anemia.

Question 51: A 25-year-old woman, gravida 2, para 1, is brought to the emergency department at 39 weeks' gestation in active labor. Her first child was delivered at 40 weeks' gestation by elective cesarean section due to limited range of motion in her hip. The patient has sickle cell disease. She has had multiple episodes of acute chest syndrome and has required several transfusions in the past. An uncomplicated repeat cesarean section is performed, and a 2.7-kg (6-lb) infant is delivered with approx. 550 mL blood loss. Perioperatively, she received one dose of intravenous cefazolin. Following the surgery, the patient continues to bleed, and she receives a transfusion of 1 unit of packed red blood cells. One hour later, the patient begins to have flank pain and appears to be in acute distress. Her temperature is 38.5°C (101.3°F), pulse is 111/min, respirations are 22/min, and blood pressure is 99/50 mm Hg. Pulse oximetry on room air shows an oxygen saturation of 97%. Foley catheter shows dark brown urine. Further evaluation of this patient is most likely to show which of the following?

A. Serum antibodies against Class I HLA antigens
B. Positive blood cultures
C. Bilateral pulmonary infiltrates on chest x-ray
D. Positive direct Coombs test (Correct Answer)
E. Low levels of serum IgA immunoglobulins

Explanation: ***Positive direct Coombs test*** - The patient's symptoms (flank pain, fever, tachycardia, hypotension, dark urine) following a blood transfusion strongly indicate an **acute hemolytic transfusion reaction (AHTR)**. - A **positive direct Coombs test** confirms AHTR by detecting antibodies coating the transfused red blood cells, indicating immune-mediated hemolysis. *Serum antibodies against Class I HLA antigens* - While **HLA antibodies** can form after multiple transfusions, they are primarily associated with **febrile non-hemolytic transfusion reactions** or **transfusion-related acute lung injury (TRALI)**. - They do not typically cause the rapid and severe hemolytic signs (flank pain, dark urine, hypotension) seen in this patient. *Positive blood cultures* - **Bacterial contamination** of blood products can cause fever and hypotension, but it is less likely to cause immediate **flank pain** and **dark urine** indicative of hemolysis. - Sepsis takes longer to manifest the full spectrum of symptoms like organ dysfunction. *Bilateral pulmonary infiltrates on chest x-ray* - **Bilateral pulmonary infiltrates** are characteristic of **TRALI**, which involves acute respiratory distress and hypoxemia. - Although TRALI can occur post-transfusion, it does not typically present with flank pain or dark urine, which are signs of red blood cell destruction. *Low levels of serum IgA immunoglobulins* - **Selective IgA deficiency** can lead to severe anaphylactic reactions to transfused blood products containing IgA, especially in patients with anti-IgA antibodies. - While severe, these reactions usually present with **bronchospasm**, **urticaria**, and potential anaphylaxis, rather than the primary hemolytic signs observed here.

Question 52: A 16-year-old male presents to the emergency department with a hematoma after falling during gym class. He claims that he has a history of prolonged nosebleeds and bruising/bleeding after minor injuries. Physical exam is unrevealing other than the hematoma. Labs are obtained showing an increased bleeding time and an abnormal ristocetin cofactor assay. Coagulation assays reveal an increased partial thromboplastin time (PTT) but a normal prothrombin time (PT). The patient is given desmopressin and is asked to avoid aspirin. Which of the following findings is most likely directly involved in the etiology of this patient's presentation?

A. Decreased levels or dysfunction of von Willebrand factor (Correct Answer)
B. Decreased levels of factor IX
C. Decreased platelet count
D. Decreased plasma fibrinogen
E. Decreased activity of ADAMTS13

Explanation: ***Decreased levels or dysfunction of von Willebrand factor*** - The patient's presentation with mucosal bleeding (nosebleeds), easy bruising, prolonged **bleeding time**, increased **PTT**, and abnormal **ristocetin cofactor assay** is characteristic of **von Willebrand disease (vWD)**. - The **direct etiology** is a deficiency or dysfunction of **von Willebrand factor (vWF)**, which serves two critical functions: mediating platelet adhesion to damaged endothelium and stabilizing factor VIII in circulation. - The abnormal **ristocetin cofactor assay** specifically tests vWF function and is diagnostic for vWD. - Treatment with **desmopressin (DDAVP)** stimulates release of stored vWF, confirming the diagnosis. *Decreased levels of factor VIII* - While factor VIII levels are indeed **secondarily decreased** in vWD due to loss of vWF's stabilizing effect, this is a **consequence** rather than the direct etiologic defect. - Factor VIII deficiency alone (hemophilia A) would cause prolonged PTT and bleeding, but would not cause prolonged bleeding time or abnormal ristocetin cofactor assay, as these specifically reflect platelet function and vWF activity. *Decreased levels of factor IX* - This causes **hemophilia B**, characterized by prolonged **PTT** and bleeding into joints and muscles. - However, hemophilia B would not cause prolonged **bleeding time** or abnormal **ristocetin cofactor assay**, which indicate platelet dysfunction specific to vWD. *Decreased platelet count* - Thrombocytopenia causes prolonged **bleeding time** and mucocutaneous bleeding, but typically does not affect **PTT**. - The abnormal **ristocetin cofactor assay** indicates a qualitative platelet function defect (inability to aggregate with ristocetin due to absent vWF), not simply low platelet numbers. *Decreased activity of ADAMTS13* - This enzyme cleaves ultra-large vWF multimers; its deficiency causes **Thrombotic Thrombocytopenic Purpura (TTP)**. - TTP presents with thrombotic microangiopathy, hemolytic anemia, thrombocytopenia, renal failure, and neurological symptoms - not the bleeding diathesis seen here. - This patient's presentation indicates **insufficient** vWF function, not excessive vWF activity.

Question 53: A 66-year-old man is admitted to the medical floor after being diagnosed with community-acquired pneumonia. He has been in good health except for the use of steroids for the past 6 months for ulcerative colitis. The patient is started on the empiric therapy with ceftriaxone for the management of pneumonia. After 10 days of treatment in the hospital, he becomes tachypneic with a decreased level of consciousness. He develops generalized pustular eruptions all over his trunk. The temperature is 40.8°C (105.4°F), and the white blood cell count is 19,000/mm3. The gram stain of an aspirate shows many budding yeasts and neutrophils. A culture of the skin specimen is positive for Candida albicans. The nitroblue tetrazolium test is normal. What is the most likely condition related to his signs and symptoms?

A. X-linked agammaglobulinemia
B. Leukocyte adhesion deficiency-1
C. Myeloperoxidase deficiency (Correct Answer)
D. Chronic granulomatous disease
E. Chediak-Higashi syndrome

Explanation: ***Myeloperoxidase deficiency*** - This deficiency impairs the ability of **neutrophils** to produce hypochlorous acid (via the myeloperoxidase-H₂O₂-halide system), a potent antimicrobial agent, leading to increased susceptibility to fungal infections, especially *Candida* species. - The patient's presentation with **systemic candidiasis** (budding yeasts on gram stain, positive culture), high fever, and pustular eruptions in the setting of immunosuppression (steroid use) is consistent with this diagnosis. - The **normal nitroblue tetrazolium (NBT) test** is the key finding that rules out chronic granulomatous disease and points toward myeloperoxidase deficiency, as MPO deficiency has normal NADPH oxidase function (which NBT tests) but impaired downstream killing via hypochlorous acid. - While MPO deficiency is often asymptomatic, severe infections can occur, particularly in patients with additional risk factors such as prolonged steroid use. *X-linked agammaglobulinemia* - This condition is characterized by a defect in **B cell development** (BTK gene mutation), leading to absent or very low immunoglobulins and recurrent bacterial infections (particularly encapsulated organisms), not primarily fungal infections. - Patients typically present with recurrent sinopulmonary infections in infancy and early childhood, which doesn't fit this clinical picture of a 66-year-old with disseminated candidiasis. *Leukocyte adhesion deficiency-1* - This disorder involves a defect in **integrin expression** (CD18 deficiency), impairing leukocyte adhesion, migration, and chemotaxis, causing recurrent bacterial infections, impaired wound healing, and delayed umbilical cord separation. - Presents in early childhood, not adulthood, and is not primarily associated with systemic candidiasis. *Chronic granulomatous disease* - This condition results from a defect in **NADPH oxidase**, impairing the neutrophil's respiratory burst and ability to produce reactive oxygen species, leading to recurrent infections with catalase-positive organisms (e.g., *Staphylococcus aureus*, *Aspergillus*, *Serratia*, *Burkholderia*). - The **nitroblue tetrazolium (NBT) test would be abnormal** (fails to reduce NBT dye, remains colorless) in CGD, but it was stated as **normal** in this patient, effectively ruling out this diagnosis. *Chediak-Higashi syndrome* - This is a rare, autosomal recessive disorder caused by **LYST gene mutation**, characterized by defective lysosomal trafficking, leading to giant cytoplasmic granules in leukocytes. - Clinical features include **immunodeficiency**, partial oculocutaneous albinism, progressive neurological dysfunction, and bleeding tendency. - While associated with recurrent pyogenic infections, the characteristic albinism and neurological features are absent in this case.

Question 54: A 24-year-old healthy male presents to the emergency room complaining of severe abdominal pain. He reports that he was playing rugby for his college team when he was tackled on his left side by a member of the opposing team. He is currently experiencing severe left upper abdominal pain and left shoulder pain. A review of his medical record reveals that he was seen by his primary care physician two weeks ago for mononucleosis. His temperature is 99°F (37.2°C), blood pressure is 90/50 mmHg, pulse is 130/min, and respirations are 26/min. He becomes increasingly lethargic over the course of the examination. He demonstrates exquisite tenderness to palpation over the left 8th, 9th, and 10th ribs as well as rebound tenderness in the abdomen. He is eventually stabilized and undergoes definitive operative management. After this patient recovers, which of the following is most likely to be found on a peripheral blood smear in this patient?

A. Basophilic stippling
B. Erythrocytes lacking central pallor
C. Erythrocyte fragments
D. Basophilic nuclear remnants (Correct Answer)
E. Inclusions of denatured hemoglobin

Explanation: ***Basophilic nuclear remnants*** - The patient's history of **mononucleosis**, severe left upper abdominal pain, left shoulder pain (Kehr's sign), and signs of hypovolemic shock (hypotension, tachycardia) following trauma strongly suggest a **splenic rupture**. - After a **splenectomy** (implied by "definitive operative management" for a ruptured spleen), the spleen's function of removing abnormal red blood cells and inclusions is lost, leading to the persistence of **Howell-Jolly bodies** (basophilic nuclear remnants) on a peripheral blood smear. *Basophilic stippling* - This indicates the presence of **ribosomal precipitates** in red blood cells, commonly associated with conditions like **lead poisoning** or **thalassemia**. - It is not a typical finding after splenectomy or as a direct consequence of splenic rupture. *Erythrocytes lacking central pallor* - This describes **spherocytes**, which are red blood cells that have lost their biconcave shape and are often seen in conditions like **hereditary spherocytosis** or **autoimmune hemolytic anemia**. - While the spleen typically removes spherocytes, their presence without central pallor isn't the most specific finding post-splenectomy in a previously healthy individual. *Erythrocyte fragments* - These are also known as **schistocytes** and indicate **microangiopathic hemolytic anemia (MAHA)**, commonly seen in conditions like DIC, TTP, HUS, or mechanical heart valve hemolysis. - While trauma can potentially lead to some fragmentation, it is not the most characteristic finding following a splenic rupture and subsequent splenectomy. *Inclusions of denatured hemoglobin* - This describes **Heinz bodies**, which are formed when hemoglobin is denatured and precipitates within red blood cells, typical of **G6PD deficiency** or unstable hemoglobin variants. - Although the spleen normally removes cells containing Heinz bodies, they are not the primary or most common finding after splenectomy in a patient without a pre-existing hemoglobinopathy.

Question 55: A 25-year-old man comes to the physician for the evaluation of recurrent episodes of nosebleeds over the past 6 months. The nosebleeds occur spontaneously and stop after 10 minutes after pinching the nose at the nostrils. He has no history of serious illness except for prolonged bleeding following wisdom teeth extraction 2 years ago. He does not smoke or drink alcohol. He takes no medications. Vital signs are within normal limits. Examination of the nose shows no abnormalities. There are several bruises on the lower extremities. The remainder of the examination shows no abnormalities. Laboratory studies show: Hemoglobin 15 g/dL Leukocyte count 6,000/mm3 Platelet count 220,000/mm3 Bleeding time 9 minutes Prothrombin time 13 sec Partial thromboplastin time 55 sec Which of the following is the most likely diagnosis?

A. Von Willebrand disease (Correct Answer)
B. Bernard-Soulier Syndrome
C. Hemophilia A
D. Factor X deficiency
E. Wiskott-Aldrich syndrome

Explanation: ***Von Willebrand disease*** - This patient presents with a history consistent with a **primary hemostasis disorder** (recurrent nosebleeds, prolonged bleeding after tooth extraction, easy bruising) and laboratory findings of a **prolonged bleeding time** and a **prolonged PTT**. - Von Willebrand disease is the most common inherited bleeding disorder, characterized by a deficiency or dysfunction of **von Willebrand factor (vWF)**, which is crucial for platelet adhesion and also stabilizes factor VIII. *Bernard-Soulier Syndrome* - This syndrome is characterized by a defect in the **GP-Ib/IX/V receptor complex** on platelets, leading to impaired platelet adhesion and **thrombocytopenia**. - While it presents with mucocutaneous bleeding and prolonged bleeding time, the platelet count in this patient is normal, making Bernard-Soulier Syndrome less likely. *Hemophilia A* - Hemophilia A is an **X-linked recessive disorder** caused by a deficiency of **Factor VIII**, leading to a prolonged PTT but typically a **normal bleeding time** and platelet count. - While the PTT is prolonged in this case, the significant history of mucocutaneous bleeding and prolonged bleeding time points away from hemophilia A. *Factor X deficiency* - Factor X is involved in both the intrinsic and extrinsic coagulation pathways, so its deficiency would lead to **prolonged PT and PTT**. - In this case, only the PTT is prolonged, and the PT is normal, making Factor X deficiency an unlikely diagnosis. *Wiskott-Aldrich syndrome* - This is an **X-linked recessive immunodeficiency disorder** characterized by **thrombocytopenia** (small platelets), eczema, and recurrent infections. - While bleeding is a feature due to thrombocytopenia, the platelet count in this patient is normal, ruling out Wiskott-Aldrich syndrome.

Question 56: A mother brings her 6-year-old daughter in to the pediatrician’s clinic for a wellness visit. The mother has a history of von Willebrand’s disease (vWD) and is concerned that her daughter may be affected as well. The mother tells you that she has noticed that her daughter bruises very easily, and her bruises typically are visible for a longer period of time than those of her brother. She denies any personal history of blood clots in her past, but she says that her mother has had to be treated for pulmonary embolism in the recent past. Her birth history is significant for preeclampsia, preterm birth at 32 weeks, a NICU stay of two and a half weeks, and retinopathy of prematurity. She currently eats a diet full of green vegetables, fruits, and french fries. Her vital signs include: temperature, 36.7°C (98.0°F); blood pressure, 106/54 mm Hg; heart rate, 111/min; and respiratory, rate 23/min. On physical examination, her pulses are bounding, complexion is pale, scattered bruises throughout all extremities that are specifically scattered around the knees and elbows. After ordering a coagulation panel, which of the following would one expect to see in the lab panel of a patient with vWD?

A. Elevated platelet count
B. Prolonged PT
C. Normal bleeding time
D. Decreased factor IX
E. Prolonged PTT (Correct Answer)

Explanation: ***Prolonged PTT*** - **Von Willebrand factor (vWF)** stabilizes **Factor VIII**, and in vWD, reduced vWF levels lead to lower Factor VIII activity, which is reflected as a **prolonged PTT**. - The coagulation cascade components associated with PTT (intrinsic and common pathways) are affected due to the impaired function or deficiency of vWF. *Elevated platelet count* - **Platelet count** is typically **normal** in vWD, as the disorder primarily affects platelet function and adhesion, not platelet production. - Thrombocytosis is not characteristic of vWD and would suggest other primary hematologic conditions. *Prolonged PT* - The **prothrombin time (PT)** measures the extrinsic and common pathways of coagulation, which are typically **unaffected** in vWD. - PT prolongation would suggest deficiencies in factors VII, X, V, or prothrombin. *Normal bleeding time* - **Bleeding time** is typically **prolonged** in vWD because vWF is crucial for platelet adhesion to the subendothelium and platelet plug formation. - A normal bleeding time would argue against a platelet function disorder like vWD. *Decreased factor IX* - **Factor IX** deficiency is associated with **Hemophilia B**, a separate X-linked coagulopathy, and is not directly affected in vWD. - While vWD involves coagulation factor deficiencies, the primary factor stabilized by vWF is Factor VIII, not Factor IX.

Question 57: A 9-year-old boy is brought to the physician by his mother because of a 3-day history of fever and bleeding after brushing his teeth. His mother also reports that her son has asked to be picked up early from soccer practice the past few days because of fatigue. He appears pale and ill. His temperature is 38.3°C (101.1°F), pulse is 115/min, and blood pressure is 100/60 mm Hg. The lungs are clear to auscultation. Examination shows a soft, nontender abdomen with no organomegaly. There are several spots of subcutaneous bleeding on the abdomen and shins. Laboratory studies show a hemoglobin concentration of 7 g/dL, a leukocyte count of 2,000/mm3, a platelet count of 40,000/mm3, and a reticulocyte count of 0.2%. Serum electrolyte concentrations are within normal limits. A bone marrow biopsy is most likely to show which of the following findings?

A. Infiltration of the marrow with collagen and fibrous tissue
B. Normocellular bone marrow
C. Hypercellular, dysplastic bone marrow with ringed sideroblasts
D. Sheets of abnormal plasma cells
E. Hypocellular fat-filled marrow with RBCs of normal morphology (Correct Answer)

Explanation: ***Hypocellular fat-filled marrow with RBCs of normal morphology*** - The patient presents with **pancytopenia** (anemia, leukopenia, thrombocytopenia) and a very low **reticulocyte count**, indicating severe bone marrow failure. - A **hypocellular, fat-filled marrow** with normal RBC morphology is characteristic of **aplastic anemia**, which fits the clinical picture of fatigue, bleeding, and pallor due to suppressed hematopoiesis. *Infiltration of the marrow with collagen and fibrous tissue* - This finding is typical of **myelofibrosis**, which usually presents with **splenomegaly** due to extramedullary hematopoiesis and often **leukoerythroblastosis** in the peripheral blood. - The patient's abdomen is soft with **no organomegaly**, and the blood counts do not suggest myelofibrosis. *Normocellular bone marrow* - A **normocellular marrow** would not explain the severe pancytopenia seen in this patient; it suggests adequate cell production, which is clearly lacking here. - While other conditions can cause pancytopenia due to peripheral destruction, the **low reticulocyte count** points to a production problem in the bone marrow. *Hypercellular, dysplastic bone marrow with ringed sideroblasts* - This describes features of **myelodysplastic syndrome (MDS)**, which can cause pancytopenia and often presents with **dysplastic changes** in blood cells. - While MDS can occur in children, the sudden onset and severe pancytopenia, coupled with the absence of specific dysplastic features mentioned, make aplastic anemia more likely. *Sheets of abnormal plasma cells* - **Sheets of abnormal plasma cells** are seen in **multiple myeloma**, a malignancy typically affecting older adults and associated with **bone pain**, hypercalcemia, renal failure, and **monoclonal gammopathy**. - This diagnosis is highly unlikely in a 9-year-old boy with these symptoms.

Question 58: A 12-year-old boy is found on a routine auditory screening to have mild high frequency hearing impairment. On exam, he has no ear pain, no focal neurological deficits, and no cardiac murmurs. He has not had any recent illness. Laboratory studies show: Serum: Creatinine: 0.7 mg/dl Protein: 3.8 g/dl Antistreptolysin O titer: 60 Todd units (12-166 normal range) Urinalysis: Microscopic heme Protein: 4+ RBCs: 6/hpf A kidney biopsy is taken. Which of the following findings is most characteristic of this patient’s disease?

A. Thickened “tram-track” appearance of basement membrane on electron microscopy
B. “Spike and dome” appearance on electron microscopy
C. Crescent-moon shapes on light microscopy
D. Large eosinophilic nodular lesions on light microscopy
E. “Basket-weave” pattern of basement membrane on electron microscopy (Correct Answer)

Explanation: ***“Basket-weave” pattern of basement membrane on electron microscopy*** - The combination of **Sensorineural hearing loss**, **microscopic hematuria**, and **proteinuria** in a young boy is highly suggestive of **Alport syndrome**. - **Alport syndrome** is characterized by mutations in genes encoding **Type IV collagen**, leading to characteristic ultrastructural changes in the glomerular basement membrane, including splitting and thinning, which gives it a **"basket-weave" appearance** on electron microscopy. *Thickened “tram-track” appearance of basement membrane on electron microscopy* - This finding is characteristic of **dense deposit disease** (also known as C3 glomerulopathy), where dense deposits within the glomerular basement membrane lead to a unique pattern. - While dense deposit disease can cause hematuria and proteinuria, it is not typically associated with the high-frequency hearing loss seen in this patient. *“Spike and dome” appearance on electron microscopy* - This is a classic finding in **membranous nephropathy**, due to subepithelial immune deposits and new basement membrane material forming around them. - Membranous nephropathy typically presents with **nephrotic syndrome** in adults and is not associated with hearing impairment. *Crescent-moon shapes on light microscopy* - **Crescent formation** is characteristic of rapidly progressive glomerulonephritis (RPGN), indicating severe glomerular injury and often associated with systemic vasculitis or anti-GBM disease. - While RPGN can cause hematuria and proteinuria, the clinical presentation with hearing loss is not typical, and the underlying pathology is different. *Large eosinophilic nodular lesions on light microscopy* - This describes the **Kimmelstiel-Wilson lesions** seen in **diabetic nephropathy**, which are pathognomonic for this condition. - Diabetic nephropathy is a complication of long-standing diabetes and is not consistent with the patient's age or clinical presentation.

Question 59: A 55-year-old female presents with pain in both hands and wrists for the past several years. It is associated with morning stiffness that lasts for almost an hour. Physical examination reveals tenderness and swelling in both hands and wrists, most severe over the proximal interphalangeal joints. Laboratory investigation reveals the presence of anti-cyclic citrullinated peptide (anti-CCP). Which of the following immune-mediated injuries is responsible for this patient’s condition?

A. Both type II and III hypersensitivities
B. Type IV hypersensitivity (Correct Answer)
C. Type III hypersensitivity
D. Self-tolerance
E. IgE-mediated immune responses only

Explanation: ***Type IV hypersensitivity*** - **Rheumatoid arthritis** is primarily a **Type IV (delayed-type, cell-mediated) hypersensitivity** reaction involving **T-cells, macrophages, and cytokine-mediated inflammation**. - The synovial membrane is infiltrated by **CD4+ T-cells (Th1 and Th17)** that recognize self-antigens (citrullinated peptides), leading to activation of macrophages and release of inflammatory cytokines **(TNF-α, IL-1, IL-6, IL-17)**. - This **chronic T-cell driven inflammation** results in synovial hyperplasia, pannus formation, and progressive joint destruction—the hallmark pathology of RA. - **Anti-CCP antibodies** are highly specific diagnostic markers indicating immune targeting of citrullinated proteins, but the actual joint damage mechanism is **cell-mediated immunity** (Type IV). *Both type II and III hypersensitivities* - While **immune complexes** (Type III) involving rheumatoid factor can be present in RA, and there may be minor antibody-mediated effects (Type II), these are **secondary phenomena**. - The **primary pathogenic mechanism** driving synovial inflammation and joint destruction is **Type IV hypersensitivity** with T-cell and macrophage activation. - This option is incorrect because it does not identify the predominant mechanism. *IgE-mediated immune responses only* - **IgE-mediated immune responses** characterize **Type I hypersensitivity**, seen in allergic conditions such as asthma, allergic rhinitis, and anaphylaxis. - Rheumatoid arthritis involves **chronic autoimmune inflammation** with T-cell activation and cytokine release, not acute IgE-mediated mast cell degranulation. - The clinical presentation does not align with Type I hypersensitivity. *Type III hypersensitivity* - **Type III hypersensitivity** involves **immune complex deposition** causing tissue damage, as seen in serum sickness, post-streptococcal glomerulonephritis, and systemic lupus erythematosus. - While **rheumatoid factor immune complexes** can form in RA (particularly in seropositive patients), immune complex deposition is a **secondary feature**, not the primary driver of joint destruction. - The **dominant pathophysiology** of RA is **T-cell mediated chronic inflammation** (Type IV), making this option incorrect. *Self-tolerance* - **Self-tolerance** refers to the immune system's normal ability to **not react** against the body's own tissues. - RA results from a **breakdown of self-tolerance**, leading to autoimmunity—this is the **underlying defect**, not the **mechanism of tissue injury**. - The question asks for the **immune-mediated injury mechanism**, which is Type IV hypersensitivity, not the state of tolerance itself.

Question 60: A 7-year-old boy is brought to the emergency department by his parents with a 2-day history of severe fatigue. His parents say that he has no past medical history, but caught an illness that was going around his school 1 week ago. While ill, he had several days of abdominal pain and bloody diarrhea. His family history is significant for several family members who required blood transfusions, and he lives in an old house. Physical exam reveals conjunctival pallor and mild jaundice. Which of the following would most likely be seen on peripheral blood smear in this patient?

A. Schistocytes (Correct Answer)
B. Degmacytes
C. Spherocytes
D. Codocytes
E. Echinocytes

Explanation: ***Schistocytes*** - This patient's presentation with recent **bloody diarrhea**, **fatigue**, **conjunctival pallor**, and **mild jaundice** is highly suggestive of **hemolytic uremic syndrome (HUS)**, often triggered by Shiga toxin-producing E. coli (STEC) infection. - **Schistocytes**, or fragmented red blood cells, are a hallmark of **microangiopathic hemolytic anemia (MAHA)**, which is central to HUS pathogenesis due to damage to red blood cells as they pass through obstructed microvessels. *Degmacytes* - **Degmacytes**, also known as **bite cells**, are seen in conditions involving **oxidative stress** leading to Heinz body formation, such as **G6PD deficiency** or unstable hemoglobin variants. - While hemolysis is present in this patient, the clinical context of prior diarrheal illness and the specific findings point away from primary oxidative damage. *Spherocytes* - **Spherocytes** are typically associated with **hereditary spherocytosis** or **autoimmune hemolytic anemia (AIHA)**. - These conditions cause red blood cells to lose their biconcave shape and become spherical, leading to premature destruction, but they do not typically follow a diarrheal illness in this manner. *Codocytes* - **Codocytes**, or **target cells**, are characteristic of **thalassemias**, **liver disease**, and **iron deficiency anemia**. - They indicate an increase in surface area to volume ratio of the red blood cell and are not typically seen with the acute hemolytic picture presented here. *Echinocytes* - **Echinocytes**, or **burr cells**, are often associated with **uremia**, **pyruvate kinase deficiency**, and sometimes occur as an artifact of blood smear preparation. - While HUS can lead to kidney injury, echinocytes are not the primary and most characteristic finding in the acute hemolytic phase of HUS.

Question 61: A healthy 29-year-old woman comes to the doctor because of recurrent episodes of bleeding from the nose and gums during the past week. These episodes occur spontaneously and resolve with compression. She also had 1 episode of blood in the urine 2 days ago. Examination shows punctate, nonblanching, reddish macules over the neck, chest, and lower extremities. Her leukocyte count is 8,600/mm3, hemoglobin concentration is 12.9 g/dL, and platelet count is 26,500/mm3. A peripheral blood smear shows a reduced number of platelets with normal morphology. Evaluation of a bone marrow biopsy in this patient is most likely to show which of the following findings?

A. Ringed sideroblasts
B. Plasma cell hyperplasia
C. Megakaryocyte hyperplasia (Correct Answer)
D. Erythroid hyperplasia
E. Absence of hematopoietic cells

Explanation: ***Megakaryocyte hyperplasia*** - The patient's symptoms (bleeding from nose, gums, hematuria), signs (petechiae/purpura, **nonblanching reddish macules**), and lab findings (isolated **severe thrombocytopenia** with normal white cell and hemoglobin counts) are highly suggestive of **immune thrombocytopenia (ITP)**. - In ITP, peripheral platelets are destroyed, leading to compensatory **megakaryocyte hyperplasia** in the bone marrow and possibly large, immature platelets on peripheral smear. *Ringed sideroblasts* - **Ringed sideroblasts** are characteristic of **myelodysplastic syndromes** or certain **sideroblastic anemias**, which primarily affect red blood cell production and are not indicated by the patient's presentation of isolated thrombocytopenia. - While marrow abnormalities can occur, profound isolated thrombocytopenia as the primary symptom is not typical for sideroblastic disorders. *Plasma cell hyperplasia* - **Plasma cell hyperplasia** occurs in conditions like **multiple myeloma** or other plasma cell dyscrasias, characterized by monoclonal expansion of plasma cells often leading to bone pain, hypercalcemia, and renal issues, which are not present here. - These conditions do not typically present with isolated severe thrombocytopenia as the primary manifestation. *Erythroid hyperplasia* - **Erythroid hyperplasia** is observed in conditions of increased red blood cell demand or production, such as **hemolytic anemias** or **polycythemia**, which is inconsistent with the patient's normal hemoglobin and absence of anemia. - This finding would not explain the isolated and severe thrombocytopenia. *Absence of hematopoietic cells* - The **absence of hematopoietic cells** (i.e., **aplastic anemia**) would be associated with **pancytopenia** (low red blood cells, white blood cells, and platelets), which is not seen in this patient, who has isolated thrombocytopenia. - The patient's presentation points to increased peripheral destruction rather than bone marrow failure.

Question 62: A 68-year-old woman is being evaluated for fatigue during a follow-up visit after implantation of a prosthetic aortic valve a month ago. She reports she has been feeling more tired than usual but associates it with her recent surgery. A complete blood count (CBC) reveals a hemoglobin of 9.5 g/dL and a reticulocyte percentage of 2.8%. Additionally, the serum haptoglobin is decreased while the platelet count is within the normal range. The patient is suspected to have a type of hemolytic anemia secondary to her prosthetic heart valve. Which of the following will most likely be seen in this patient's blood smear?

A. Degmacytes
B. Basophilic stippling
C. Acanthocytes
D. Dacrocytes
E. Schistocytes (Correct Answer)

Explanation: ***Schistocytes*** - The presence of a **prosthetic aortic valve** and signs of **hemolytic anemia** (fatigue, decreased hemoglobin, elevated reticulocyte percentage, and decreased haptoglobin) strongly suggest **mechanical hemolysis**. - **Schistocytes** (fragmented red blood cells) are the hallmark of **microangiopathic hemolytic anemia** and are formed when red blood cells are mechanically damaged while passing through prosthetic heart valves or damaged capillaries. *Degmacytes* - **Degmacytes**, or "bite cells," are seen in conditions involving **oxidative stress**, such as **G6PD deficiency**, where hemoglobin precipitates as **Heinz bodies** and is subsequently removed by splenic macrophages. - While they are a sign of hemolysis, the clinical context of a prosthetic valve points more directly to mechanical fragmentation rather than oxidative damage. *Basophilic stippling* - **Basophilic stippling** refers to the presence of diffuse punctate basophilic granules within red blood cells, representing aggregated ribosomes. - This finding is characteristic of **lead poisoning** and certain **thalassemias**, neither of which is indicated in this patient's presentation. *Acanthocytes* - **Acanthocytes**, or "spur cells," are red blood cells with irregularly spaced, thorny projections. - They are typically associated with severe liver disease (**cirrhosis**), **abetalipoproteinemia**, or **splenectomy**, and are not commonly seen in mechanical hemolysis. *Dacrocytes* - **Dacrocytes**, or "teardrop cells," are red blood cells with a single elongated or pointed end. - They are classically associated with **myelofibrosis** and other infiltrative bone marrow disorders, which are not suggested by the patient's symptoms or laboratory findings.

Question 63: A 4-year-old boy is brought to the emergency department with 2 days of fever and painful lumps in his legs bilaterally. In addition, he says that his arms and legs are extremely itchy. Since birth he has had recurrent skin and soft tissue infections. Physical exam reveals a pruritic erythematous scaling rash along both upper and lower extremities bilaterally. Palpation of the painful lesions reveal indurated tissue without any production of pus. Which of the following protein functions is most likely disrupted in this patient?

A. Transcription factor activity (Correct Answer)
B. Reactive oxygen species production
C. Actin polymerization
D. B-cell survival during selection
E. Phagolysosome formation and development

Explanation: ***Transcription factor activity*** - This patient's presentation with **recurrent skin and soft tissue infections since birth**, **eczematous rash**, and **cold abscesses** (indurated tissue without pus) is characteristic of **Hyper-IgE syndrome (Job's syndrome)**. - Hyper-IgE syndrome is most commonly caused by autosomal dominant mutations in **STAT3 (Signal Transducer and Activator of Transcription 3)**, which is a critical **transcription factor**. - STAT3 regulates the expression of genes involved in **Th17 cell differentiation**, immune cell signaling, and inflammatory responses, leading to impaired neutrophil chemotaxis and the characteristic clinical features. *B-cell survival during selection* - This function is primarily associated with immune deficiencies affecting **B-cell development** and antibody production, such as **X-linked agammaglobulinemia** or **common variable immunodeficiency**. - While these can lead to recurrent infections, they do not present with the characteristic eczematous rash or cold abscesses seen in Hyper-IgE syndrome. *Actin polymerization* - Defects in **actin polymerization** are characteristic of **Wiskott-Aldrich syndrome (WAS)**, caused by mutations in the WAS protein, which regulates actin cytoskeleton reorganization. - WAS presents with thrombocytopenia, eczema, and recurrent infections, but the triad differs from the presentation here, and cold abscesses are not a typical feature. *Phagolysosome formation and development* - Deficiencies in **phagolysosome formation** are characteristic of **Chediak-Higashi syndrome (CHS)**, which presents with oculocutaneous albinism, peripheral neuropathy, and recurrent pyogenic infections. - The clinical picture here does not align with the features of CHS. *Reactive oxygen species production* - Impaired **reactive oxygen species (ROS) production** is the hallmark of **Chronic Granulomatous Disease (CGD)**, leading to recurrent catalase-positive bacterial and fungal infections with granuloma formation. - While CGD involves recurrent infections, it does not typically present with eczematous rash or the characteristic cold abscesses of Hyper-IgE syndrome.

Question 64: A previously healthy 59-year-old man comes to the physician with a 6-month history of worsening headaches, difficulty chewing, and progressive hearing loss. Examination shows a mildly tender, 1-cm, hard swelling over the left maxilla. The remainder of the examination shows no abnormalities. Serum studies show a calcium concentration of 8.5 mg/dL, alkaline phosphatase activity of 112 U/L, and parathyroid hormone concentration of 310 pg/mL. Audiometry shows bilateral mixed conductive and sensorineural hearing loss. Which of the following processes is the most likely cause of this patient's condition?

A. Defective synthesis of dynein
B. Decreased activity of carbonic anhydrase II
C. Decreased expression of menin protein
D. Increased activity of nuclear factor-κB (Correct Answer)
E. Defective synthesis of type I collagen

Explanation: ***Increased activity of nuclear factor-κB*** - The patient's symptoms (worsening headaches, difficulty chewing, hearing loss, localized bony swelling) and laboratory findings (elevated alkaline phosphatase, normal calcium, elevated PTH) are highly suggestive of **Paget's disease of bone** (osteitis deformans). - **Paget's disease** is characterized by focal areas of increased bone turnover, involving both excessive bone resorption by osteoclasts and disorganized bone formation by osteoblasts, often linked to increased **NF-κB activity** in osteoclasts. *Defective synthesis of dynein* - **Dynein defects** are associated with conditions like primary ciliary dyskinesia, which presents with chronic sinopulmonary infections and situs inversus. - This condition does not explain the patient's bone remodeling issues or localized bony swelling. *Decreased activity of carbonic anhydrase II* - **Carbonic anhydrase II deficiency** causes osteopetrosis (marble bone disease), a condition characterized by abnormally dense bones due to impaired osteoclast function. - This would typically lead to symptoms like bone fractures, cranial nerve compression, and pancytopenia, which are distinct from the presented case. *Decreased expression of menin protein* - **Menin protein deficiency**, due to mutations in the *MEN1* gene, is associated with Multiple Endocrine Neoplasia type 1 (MEN1), involving tumors of the parathyroid, pituitary, and pancreas. - While the patient has elevated PTH, the primary features of bone remodeling and localized swelling point away from MEN1 as the primary diagnosis. *Defective synthesis of type I collagen* - **Defective type I collagen synthesis** is characteristic of osteogenesis imperfecta, leading to brittle bones, frequent fractures, and blue sclera. - This is a generalized skeletal disorder with a genetic basis, typically presenting earlier in life, and does not align with the patient's localized bone overgrowth and increased osteoclast activity.

Question 65: An 11-month-old male is brought to the emergency room by his mother. The mother reports that the child is in severe pain and has not moved his right leg since earlier this morning when he was crawling on the floor. The child did not fall or sustain any obvious injury. The child’s past medical history is notable for anemia and recurrent infections since birth. His temperature is 99.1°F (37.3°C), blood pressure is 100/65 mmHg, pulse is 120/min, and respirations are 22/min. Physical examination reveals mild macrocephaly and hepatosplenomegaly. Palpation of the right femur seems to exacerbate the child’s pain. A radiograph demonstrates a transverse mid-shaft femur fracture. Which of the following is the most likely cause of this patient’s condition?

A. Endochondral ossification deficiency
B. Vitamin deficiency
C. Surreptitious child abuse
D. Collagen production deficiency
E. Acidification deficiency (Correct Answer)

Explanation: ***Acidification deficiency*** - This symptom describes **osteopetrosis**, a genetic disorder characterized by **defective osteoclast function**. Osteoclasts require an acidic environment (via carbonic anhydrase II and H+-ATPase) to resorb bone. This leads to impaired bone reabsorption, resulting in abnormally dense, yet brittle, bones prone to fracture. - The history of **anemia** and **recurrent infections** since birth, along with **mild macrocephaly** and **hepatosplenomegaly**, are classic features of osteopetrosis, as the bone marrow space is reduced by excess bone, impairing hematopoiesis. *Endochondral ossification deficiency* - This condition is characteristic of **achondroplasia**, where there is a failure of cartilage to convert to bone, leading to dwarfism. - While it affects bone development, it does not typically present with the described combination of **bone fragility** leading to fractures, **anemia**, **recurrent infections**, and **hepatosplenomegaly**. *Vitamin deficiency* - A common vitamin deficiency leading to bone issues is **Vitamin D deficiency** (rickets in children), which causes soft bones and deformities. - However, it would not explain the **anemia**, **recurrent infections**, **macrocephaly**, and **hepatosplenomegaly** seen in this patient. *Surreptitious child abuse* - While an unexplained transverse fracture, especially in a non-ambulatory child, always raises suspicion for abuse, the presence of **anemia**, **recurrent infections**, **macrocephaly**, and **hepatosplenomegaly** points to an underlying systemic disease. - Child abuse alone would not account for the systemic clinical findings, making it less likely given the comprehensive clinical picture. *Collagen production deficiency* - A deficiency in collagen production, such as in **osteogenesis imperfecta**, leads to extremely fragile bones and recurrent fractures. - However, osteogenesis imperfecta typically presents with **blue sclerae**, **hearing loss**, and **dental abnormalities**, which are not mentioned in this case, and it does not explain the **anemia**, **recurrent infections**, or **hepatosplenomegaly**.

Question 66: A 20-year-old man comes to the clinic complaining of fever and a sore throat for 5 days. He receives oral penicillin from his primary doctor. After a day of antibiotic treatment, he developed gross hematuria. As a child, he recalls having multiple episodes of hematuria. The vital signs are within normal limits. On physical examination, pharyngeal edema and cervical lymphadenopathy are present. His laboratory examination reveals the following: WBC 11,000/mm3 Neutrophils 76% Lymphocytes 23% Eosinophils 1% Platelets 150,000/mm3 Hemoglobin 14 g/dL Hct 41.2% BUN 16 mg/dL Creatinine 0.9 mg/dL ASO titer 100 Urinalysis shows hematuria but no proteinuria. Immunofluorescence shows granular IgA immune complex deposits in the mesangium. Hepatitis B, hepatitis C, and HIV serology are negative. ASO titers and C3 levels are within normal limits. What is the most likely diagnosis?

A. Berger’s disease (Correct Answer)
B. Penicillin-induced hypersensitivity reaction
C. Celiac disease
D. Hemolytic uremic syndrome
E. Post-streptococcal glomerulonephritis

Explanation: ***Berger's disease*** - The co-occurrence of **gross hematuria with an upper respiratory tract infection** (sore throat), the history of **recurrent hematuria**, and the urinalysis showing **hematuria without proteinuria** strongly suggest Berger's disease. - The definitive diagnostic finding is the **granular IgA immune complex deposits in the mesangium** on immunofluorescence of renal biopsy, which is pathognomonic for IgA nephropathy (Berger's disease). - The timing is classic for IgA nephropathy: hematuria occurring **concurrently or within 1-2 days** of the upper respiratory infection (synpharyngitic hematuria). *Penicillin-induced hypersensitivity reaction* - This condition typically presents with a **rash, fever, and eosinophilia**, not primarily with gross hematuria. While some drug-induced kidney injuries can occur, the specific IgA deposits and recurrent history point away from this. - The patient's lab results do not show **eosinophilia** (1%), which would be expected in a hypersensitivity reaction. *Celiac disease* - Celiac disease is an **autoimmune disorder of the small intestine** triggered by gluten; it primarily causes gastrointestinal symptoms like diarrhea, weight loss, and malabsorption. - While IgA nephropathy can be associated with celiac disease, celiac disease itself would not cause the presented acute onset of **gross hematuria** or the specific renal biopsy findings. *Hemolytic uremic syndrome* - HUS is characterized by the triad of **microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury**. - This patient does not have **anemia** (Hb 14 g/dL), **thrombocytopenia** (platelets 150,000/mm3), or an elevated **BUN/Creatinine** indicative of acute kidney injury. *Post-streptococcal glomerulonephritis* - PSGN typically occurs **1-3 weeks after a streptococcal infection**, presenting with hematuria, proteinuria, edema, and hypertension. In this case, the hematuria occurred **within days of the URI onset**, which is the typical timing for IgA nephropathy, not PSGN. - Key lab findings for PSGN include **low C3 levels** and significantly elevated **ASO titers**, neither of which (ASO titer 100, C3 within normal limits) were present in this patient.

Question 67: A 31-year-old man presents to his primary care physician with shortness of breath. He states that he had a “cold” 2 weeks ago and since then has had a persistent cough and worsening shortness of breath. He denies fever, chills, chest pain, sore throat, or rhinorrhea. His medical history is significant for seasonal allergies. He uses fluticasone nasal spray. He had his tonsils removed when he was 8 years of age. His mother and maternal grandfather have cirrhosis, and his father has depression and hypertension. The patient endorses that he smokes tobacco socially on the weekends and uses marijuana daily. He drinks 1-2 beers after work with his co-workers most evenings. A chest radiograph shows hyperinflation of the lungs and hyperlucency. Routine labs are drawn, as shown below. Serum: Na+: 139 mEq/L Cl-: 105 mEq/L K+: 4.0 mEq/L HCO3-: 26 mEq/L Urea nitrogen: 15 mg/dL Glucose: 100 mg/dL Creatinine: 0.8 mg/dL Alkaline phosphatase: 98 U/L Aspartate aminotransferase (AST, GOT): 46 U/L Alanine aminotransferase (ALT, GPT): 49 U/L Pulmonary function tests are pending. Which of the following is most likely to confirm the patient’s diagnosis?

A. Enzyme-linked immunosorbent assay (Correct Answer)
B. Bronchoalveolar lavage
C. Abdominal ultrasound
D. Viral hepatitis serologies
E. Pulmonary function tests

Explanation: ***Enzyme-linked immunosorbent assay (ELISA)*** - This patient's presentation with **early-onset emphysema at age 31**, **hyperinflation and hyperlucency** on chest X-ray, and **strong family history of cirrhosis** (mother and maternal grandfather) strongly suggests **alpha-1 antitrypsin deficiency**. - **ELISA is used to measure serum alpha-1 antitrypsin levels**, which is the key confirmatory test for this diagnosis. Low levels (<50-80 mg/dL) confirm the deficiency. - Alpha-1 antitrypsin deficiency causes **panacinar emphysema** (especially in lower lobes) and can also cause **liver cirrhosis**, explaining the family history and mildly elevated transaminases. - Once low levels are detected, **phenotyping or genotyping** can further characterize the specific mutation (most commonly PiZZ). *Pulmonary function tests* - PFTs would demonstrate **obstructive lung disease** with reduced FEV1/FVC ratio and confirm the presence of airflow limitation. - However, PFTs are **non-specific** and would not distinguish alpha-1 antitrypsin deficiency from other causes of COPD/emphysema (smoking-related, chronic bronchitis, etc.). - While diagnostically useful for characterizing severity, PFTs do not confirm the underlying etiology. *Bronchoalveolar lavage* - **Bronchoalveolar lavage (BAL)** is useful for diagnosing **infections**, **interstitial lung diseases**, **malignancies**, or **alveolar hemorrhage**. - It is not indicated for confirming emphysema or alpha-1 antitrypsin deficiency, as these are diagnosed through clinical presentation, imaging, and serologic testing. *Abdominal ultrasound* - An **abdominal ultrasound** could evaluate for **liver disease** (cirrhosis, hepatomegaly) associated with alpha-1 antitrypsin deficiency. - While it might reveal liver involvement, it does not confirm the pulmonary diagnosis or the underlying enzymatic deficiency itself. - It would be considered as part of a comprehensive evaluation but is not the confirmatory test. *Viral hepatitis serologies* - These would test for **hepatitis A, B, C** infection, which are common causes of cirrhosis and elevated transaminases. - However, the patient's respiratory symptoms, imaging findings of emphysema, young age, and family history point toward alpha-1 antitrypsin deficiency rather than viral hepatitis. - While worth checking given the liver enzyme elevation, this would not confirm the primary diagnosis.

Question 68: A previously healthy, 16-year-old boy is brought to the emergency department with persistent bleeding from his gums after an elective removal of an impacted tooth. Multiple gauze packs were applied with minimal effect. He has a history of easy bruising. His family history is unremarkable except for a maternal uncle who had a history of easy bruising and joint swelling. Laboratory studies show: Hematocrit 36% Platelet count 170,000/mm3 Prothrombin time 13 sec Partial thromboplastin time 65 sec Bleeding time 5 min Peripheral blood smear shows normal-sized platelets. Which of the following is the most likely diagnosis?

A. Hemophilia (Correct Answer)
B. Bernard-Soulier syndrome
C. Von Willebrand disease
D. Disseminated intravascular coagulation
E. Glanzmann thrombasthenia

Explanation: ***Hemophilia*** - The **prolonged partial thromboplastin time (PTT)** in the presence of a normal prothrombin time (PT) and platelet count strongly indicates an intrinsic pathway coagulation defect. - The patient's history of **easy bruising**, persistent bleeding after dental extraction, and a **maternal uncle with a history of easy bruising and joint swelling** (suggesting hemarthroses) is classic for hemophilia, which is an **X-linked recessive** disorder. *Bernard-Soulier syndrome* - This condition involves a defect in the **GP Ib-IX-V receptor complex**, leading to impaired platelet adhesion. - It would present with **thrombocytopenia (low platelet count)** and **abnormally large platelets** on a peripheral blood smear, neither of which are seen here. *Von Willebrand disease* - While it can cause easy bruising and prolonged bleeding, it typically results in a **prolonged bleeding time** due to defective platelet adhesion and sometimes a prolonged PTT (if factor VIII levels are significantly low). - The patient's **normal bleeding time** and the clear family history of hemarthrosis-like symptoms in a maternal uncle make hemophilia more likely. *Disseminated intravascular coagulation* - This condition is characterized by widespread activation of clotting, leading to consumption of clotting factors and platelets. - It would typically show **prolonged PT and PTT**, **thrombocytopenia**, and signs of microangiopathic hemolytic anemia, which are not present in this scenario. *Glanzmann thrombasthenia* - This is a rare **autosomal recessive** disorder characterized by a defect in the **GP IIb/IIIa receptor**, leading to impaired platelet aggregation. - It presents with a **normal platelet count** but a **severely prolonged bleeding time**, which is not observed in this patient.

Question 69: A 6-year-old boy is brought to the pediatrician by his mother after he reported having red urine. He has never experienced this before and did not eat anything unusual before the episode. His past medical history is notable for sensorineural deafness requiring hearing aids. He is otherwise healthy and enjoys being in the 1st grade. His birth history was unremarkable. His temperature is 98.8°F (37.1°C), blood pressure is 145/85 mmHg, pulse is 86/min, and respirations are 18/min. On examination, he is a well-appearing boy in no acute distress. Cardiac, respiratory, and abdominal exams are normal. A urinalysis is notable for microscopic hematuria and mild proteinuria. This patient’s condition is most commonly caused by which of the following inheritance patterns?

A. X-linked dominant
B. Autosomal recessive
C. Autosomal dominant
D. X-linked recessive (Correct Answer)
E. Mitochondrial inheritance

Explanation: ***X-linked recessive*** - This is the **most common inheritance pattern** for **Alport syndrome**, accounting for approximately **80-85% of all cases**. - This inheritance pattern is characteristic of **Alport syndrome**, which classically presents with **hematuria**, **sensorineural hearing loss**, and ocular abnormalities. - The patient's presentation with **red urine (hematuria)** and a history of **sensorineural deafness** strongly points to **Alport syndrome**, which is primarily caused by **X-linked recessive** inheritance due to mutations in the *COL4A5* gene encoding the alpha-5 chain of type IV collagen. - Males with the mutation are typically more severely affected, while female carriers may have variable manifestations. *X-linked dominant* - While Alport syndrome can manifest in females with an X-linked dominant-like pattern (due to mosaicism or severely affected carrier females), the **classic and most common inheritance** for severe forms in males is **X-linked recessive**. - Conditions like **Fragile X syndrome** or **Vitamin D-resistant rickets** are examples of X-linked dominant conditions, but they do not typically present with the specific triad observed here. *Autosomal recessive* - An autosomal recessive form of **Alport syndrome** exists, but it accounts for only approximately **10-15% of cases** compared to the X-linked recessive form. - While other conditions with **renal and auditory involvement** can be autosomal recessive (e.g., specific forms of branchio-oto-renal syndrome), the **combination of hematuria and sensorineural deafness with significant renal progression risk** in a male points most strongly to the X-linked form. *Autosomal dominant* - Alport syndrome also has an **autosomal dominant** form, which is typically due to mutations in *COL4A3* or *COL4A4* genes, but it accounts for only approximately **5% of cases** and is **less common** than the X-linked recessive form. - The autosomal dominant form often presents with a **later onset** and a **more variable phenotype** with milder disease progression. - While some forms of **polycystic kidney disease** are autosomal dominant and can cause hematuria, they typically involve cyst formation, which is not suggested by the clinical picture here. *Mitochondrial inheritance* - This inheritance pattern is associated with disorders affecting **energy production**, commonly involving multiple organ systems, including muscle, brain, and eye. - While some mitochondrial disorders can affect the kidneys or cause hearing impairment, the **specific combination of hematuria and sensorineural deafness** as the primary presentation in this context is not characteristic of mitochondrial inheritance.

Question 70: A 7-year-old girl presents with fatigue, jaundice, pruritus, and frequent pale stools. She developed these symptoms gradually over the past 3 months. Her past medical history is significant for multiple episodes of bronchitis and pneumonia. When asked about current respiratory symptoms, she says that she sometimes feels short of breath and has a dry, non-productive cough. Her mother was diagnosed with chronic obstructive pulmonary disease at age of 27. The girl's blood pressure is 110/80 mm Hg, the heart rate is 107/min, the respiratory rate is 18/min, and the temperature is 36.9°C (98.4°F). On physical examination, the patient is jaundiced with several petechiae over the inner surface of her upper and lower extremities. On auscultation, lung sounds are diminished and occasional wheezes are heard over the lower pulmonary lobes bilaterally. Heart auscultation reveals muffled heart sounds and no murmurs. On palpation, there is tenderness in the right upper quadrant of the abdomen and hepatomegaly. Her chest X-ray shows bilateral lower lobe emphysema. Which microscopic pathological changes are most characteristic of the patient’s condition?

A. Widespread positive staining with Prussian blue
B. Extensive Congo-red positive deposits in the liver
C. Feathery degeneration of the hepatocytes
D. Extensive perisinusoidal fibrosis and hepatic venule dilation
E. Periodic acid-Schiff (PAS)-positive, diastase-resistant cytoplasmic granules in the hepatocytes (Correct Answer)

Explanation: ***Periodic acid-Schiff (PAS)-positive, diastase-resistant cytoplasmic granules in the hepatocytes*** - The patient's symptoms (pediatric **emphysema**, **jaundice**, **pruritus**, **hepatomegaly**, **bronchitis**, family history of early-onset COPD) are highly suggestive of **alpha-1 antitrypsin deficiency (A1AT)**. - **A1AT deficiency** is characterized by the accumulation of misfolded alpha-1 antitrypsin protein within hepatocytes, which appears as **PAS-positive, diastase-resistant inclusions** on biopsy. *Widespread positive staining with Prussian blue* - **Prussian blue staining** is used to detect **iron deposits**, typically seen in conditions like **hemochromatosis**. - This patient's presentation, including lung disease and early-onset liver disease, is not characteristic of iron overload. *Extensive Congo-red positive cytoplasmic drops in the hepatocytes* - **Congo-red staining** detects **amyloid deposits**, which are associated with conditions like **amyloidosis**. - While amyloidosis can cause hepatomegaly, it typically doesn't present with pediatric emphysema or the specific liver/lung findings described. *Feathery degeneration of the hepatocytes* - **Feathery degeneration** is a characteristic microscopic finding in **cholestasis** and **bile duct obstruction**, often associated with **bile plugs** and portal inflammation. - While the patient has cholestasis (jaundice, pruritus, pale stools), feathery degeneration is a histological consequence rather than the underlying primary pathological change seen in A1AT deficiency. *Extensive perisinusoidal fibrosis and hepatic venule dilation* - **Perisinusoidal fibrosis** and **hepatic venule dilation** can be seen in various forms of liver injury, including **alcoholic liver disease** or **veno-occlusive disease**. - These findings are not specific to the underlying genetic defect in A1AT deficiency and do not explain the concomitant pulmonary involvement.

Question 71: A 21-year-old man comes to the emergency department because of a 2-week history of progressive shortness of breath and intermittent cough with blood-tinged sputum. During this time, he has also noticed blood in his urine. He has no history of serious illness and does not take any medications. His temperature is 37°C (98.6°F), pulse is 92/min, respirations are 28/min, and blood pressure is 152/90 mm Hg. Cardiopulmonary examination shows crackles at both lung bases. Urinalysis is positive for blood and results of a direct enzyme-linked immunoassay are positive for anti-GBM antibodies. The pathogenesis of this patient's disease is most similar to which of the following?

A. Henoch-Schönlein purpura
B. Autoimmune hemolytic anemia (Correct Answer)
C. Polyarteritis nodosa
D. Poststreptococcal glomerulonephritis
E. Graft versus host disease

Explanation: **Correct: Autoimmune hemolytic anemia** - This patient presents with **Goodpasture syndrome**, an autoimmune disease characterized by **anti-glomerular basement membrane (GBM) antibodies** attacking both the kidneys (glomerulonephritis) and lungs (pulmonary hemorrhage). - Autoimmune hemolytic anemia also involves **autoantibodies** (usually IgG or IgM) directly targeting and destroying host cells (red blood cells), representing a **type II hypersensitivity reaction** mediated by antibodies. - Both conditions share the same pathogenic mechanism: direct autoantibody-mediated tissue/cell destruction. *Incorrect: Henoch-Schönlein purpura* - This is an **IgA-mediated vasculitis** primarily affecting small vessels, presenting with palpable purpura, abdominal pain, arthralgias, and IgA nephropathy. - Its pathogenesis is distinctly different, involving **type III hypersensitivity** with IgA immune complex deposition rather than direct autoantibody attack on basement membranes. *Incorrect: Polyarteritis nodosa* - This is a **necrotizing vasculitis** of medium-sized arteries, which does not typically involve the glomerular capillaries directly or result in pulmonary hemorrhage. - It is often associated with hepatitis B and presents with diverse systemic symptoms due to inflammation and necrosis of arterial walls, rather than autoantibodies against basement membranes. *Incorrect: Poststreptococcal glomerulonephritis* - This condition is an **immune complex-mediated (type III hypersensitivity) glomerulonephritis** that follows a streptococcal infection, characterized by granular deposits of C3 and IgG in the glomeruli. - While it can cause hematuria and kidney damage, it does not involve anti-GBM antibodies or pulmonary hemorrhage, and its immune mechanism is distinct from type II hypersensitivity. *Incorrect: Graft versus host disease* - This is a complication of **allogeneic hematopoietic stem cell transplantation**, where donor T-cells attack host tissues. - It is a **T-cell-mediated (type IV hypersensitivity) reaction**, entirely different from the autoantibody-mediated pathogenesis seen in Goodpasture syndrome.

Question 72: A 56-year-old man presents with feelings of anxiety and fatigue for the past 4 months. He says that he has also had some weight loss, as well as occasional double vision and a gritty sensation in his eyes for the last 2 months, which is worse at the end of the day. He has also noticed some painless swelling in his fingers and lower legs during the same time period. The patient denies any recent history of fevers, chills, night sweats, nausea, or vomiting. Current medications include aspirin, simvastatin, and omeprazole. Which of the following mechanisms is most likely responsible for this patient’s condition?

A. Autoantibody stimulation of a receptor (Correct Answer)
B. Autoantibodies resulting in tissue destruction
C. Excessive exogenous hormone use
D. Mutation in a receptor resulting in focal hyperfunctioning
E. Infiltration of tissue by neoplastic cells

Explanation: **Autoantibody stimulation of a receptor** - The patient's symptoms of anxiety, fatigue, weight loss, double vision, gritty eyes, and painless swelling (consistent with pretibial myxedema) are classic for **hyperthyroidism**, specifically **Graves' disease**. - In Graves' disease, stimulating **autoantibodies** (thyroid-stimulating immunoglobulins, TSI) bind to and activate the **TSH receptor** on thyroid follicular cells, leading to excessive thyroid hormone production. *Autoantibodies resulting in tissue destruction* - This mechanism is characteristic of **Hashimoto's thyroiditis**, where autoantibodies and cytotoxic T lymphocytes destroy thyroid tissue, leading to **hypothyroidism**. - The patient's symptoms of weight loss, anxiety, and double vision (exophthalmos) are not consistent with hypothyroidism. *Excessive exogenous hormone use* - While excessive **exogenous thyroid hormone use** can cause hyperthyroidism, there is no indication in the patient's history of such use. - Furthermore, the presence of **ophthalmopathy** and **pretibial myxedema** strongly suggests an autoimmune etiology like Graves' disease rather than drug-induced hyperthyroidism. *Mutation in a receptor resulting in focal hyperfunctioning* - This mechanism refers to conditions like **toxic thyroid adenoma** or **multinodular goiter** with autonomously functioning nodules, where somatic mutations in the TSH receptor lead to focal hyperactivity. - While these can cause hyperthyroidism, they typically do not present with the diffuse ophthalmopathy and pretibial myxedema seen in Graves' disease with stimulating autoantibodies. *Infiltration of tissue by neoplastic cells* - **Neoplastic infiltration** of the thyroid gland (e.g., thyroid cancer) can sometimes lead to hyperthyroidism (though rare) or cause goiter. - However, the specific constellation of symptoms including exophthalmos and pretibial myxedema is not typical for thyroid malignancy and is highly indicative of Graves' disease.

Question 73: A 46-year-old Caucasian female presents with cold intolerance, weight gain, and constipation. She has also noticed that her nails have become thinner recently but denies any fever or neck pain. Which of the following is NOT an expected histological finding in the thyroid?

A. Hurthle cells
B. Lymphocytic infiltration
C. Multinucleate giant cells (Correct Answer)
D. Several germinal centers
E. Fibrosis

Explanation: ***Multinucleate giant cells*** - The patient's symptoms (cold intolerance, weight gain, constipation, thin nails) are highly suggestive of **hypothyroidism**, most commonly caused by **Hashimoto's thyroiditis**. - **Multinucleate giant cells** are typically associated with **subacute granulomatous (de Quervain's) thyroiditis**, which presents with painful thyroid enlargement and a biphasic course (transient hyperthyroidism followed by hypothyroidism). *Hurthle cells* - These are **eosinophilic, granular follicular cells** that represent metaplastic changes within the thyroid. - They are a common histological finding in **Hashimoto's thyroiditis**, often seen alongside chronic inflammation. *Lymphocytic infiltration* - This is a hallmark feature of **Hashimoto's thyroiditis**, characterized by extensive infiltration of the thyroid parenchyma by **lymphocytes**, plasma cells, and macrophages. - The immune response targets thyroid peroxidases and thyroglobulin, leading to gradual destruction of thyroid follicles. *Several germinal centers* - The presence of **germinal centers** within the thyroid is a characteristic histopathological feature of **Hashimoto's thyroiditis**. - These centers indicate active B-cell proliferation and are part of the autoimmune process in the gland. *Fibrosis* - Over time, chronic inflammation in **Hashimoto's thyroiditis** often leads to **fibrosis** within the thyroid gland. - Extensive fibrosis can result in a firm, enlarged thyroid and contribute to impaired thyroid function.

Question 74: A 51-year-old man presents to the clinic with a history of hematuria and hemoptysis following pneumonia several weeks ago. He works as a hotel bellhop. His medical history is significant for gout, hypertension, hypercholesterolemia, diabetes mellitus type II, and mild intellectual disability. He currently smokes 2 packs of cigarettes per day and denies any alcohol use or any illicit drug use. His vital signs include: temperature 36.7°C (98.0°F), blood pressure 126/74 mm Hg, heart rate 87/min, and respiratory rate 23/min. Physical examination shows minimal bibasilar rales, but otherwise clear lungs on auscultation, grade 2/6 holosystolic murmur, and benign abdominal findings. Pulmonary function tests demonstrate a restrictive pattern and a current chest radiograph shows bibasilar alveolar infiltrates. Clinical pathology analysis reveals antiglomerular basement membrane antibody, and his renal biopsy shows a linear immunofluorescence pattern. Of the following options, which type of hypersensitivity reaction underlies this patient’s diagnosis?

A. Type I and IV–mixed anaphylactic and cell-mediated hypersensitivity reaction
B. Type IV–cell-mediated (delayed) hypersensitivity reaction
C. Type I–anaphylactic hypersensitivity reaction
D. Type III–immune complex-mediated hypersensitivity reaction
E. Type II–cytotoxic hypersensitivity reaction (Correct Answer)

Explanation: ***Type II–cytotoxic hypersensitivity reaction*** - The presence of **antiglomerular basement membrane (anti-GBM) antibodies** targeting kidney and lung tissues (causing hematuria and hemoptysis) is characteristic of **Goodpasture syndrome**, which is a classic example of a **Type II hypersensitivity reaction**. - In Type II reactions, antibodies (IgG or IgM) bind to antigens on the surface of cells or within tissues, leading to **complement activation** and cell destruction (cytotoxicity) or dysfunction. *Type I and IV–mixed anaphylactic and cell-mediated hypersensitivity reaction* - This option describes a mixed reaction that doesn't fit the clinical picture of **anti-GBM disease**. Type I involves IgE-mediated mast cell degranulation, and Type IV involves T-cell-mediated delayed responses. - While infections often precede Goodpasture syndrome, the direct pathology from **anti-GBM antibodies** is distinct from typical mixed allergic or delayed-type reactions. *Type IV–cell-mediated (delayed) hypersensitivity reaction* - Type IV reactions are characterized by **T-cell-mediated inflammation** and do not involve antibodies binding to tissue antigens; examples include tuberculosis skin tests or contact dermatitis. - The presence of specific **anti-GBM antibodies** and a **linear immunofluorescence pattern** on renal biopsy clearly indicate an antibody-mediated process, ruling out a purely cell-mediated reaction. *Type I–anaphylactic hypersensitivity reaction* - Type I reactions involve **IgE antibodies** binding to mast cells and basophils, leading to histamine release and immediate allergic responses like anaphylaxis, asthma, or hives. - The symptoms of hematuria and hemoptysis due to **glomerular basement membrane damage** are inconsistent with an immediate IgE-mediated allergic reaction. *Type III–immune complex-mediated hypersensitivity reaction* - Type III reactions involve the formation of **soluble immune complexes** (antigen-antibody complexes) that deposit in tissues, leading to inflammation (e.g., lupus nephritis, serum sickness). - While antibodies are involved, the defining feature of Goodpasture syndrome is antibodies directly targeting and binding to fixed antigens on the **glomerular and alveolar basement membranes**, not circulating immune complex deposition, which would typically show a **granular immunofluorescence pattern**.

Question 75: A 6-year-old boy presents to his pediatrician accompanied by his mother for evaluation of a rash. The rash appeared a little over a week ago, and since that time the boy has felt tired. He is less interested in playing outside, preferring to remain indoors because his knees and stomach hurt. His past medical history is significant for an upper respiratory infection that resolved uneventfully without treatment 2 weeks ago. Temperature is 99.5°F (37.5°C), blood pressure is 115/70 mmHg, pulse is 90/min, and respirations are 18/min. Physical exam shows scattered maroon macules and papules on the lower extremities. The abdomen is diffusely tender to palpation. There is no cervical lymphadenopathy or conjunctival injection. Which of the following will most likely be found in this patient?

A. Coronary artery aneurysms
B. Leukocytoclastic vasculitis (Correct Answer)
C. Thrombocytopenia
D. Mitral regurgitation
E. Occult malignancy

Explanation: ***Leukocytoclastic vasculitis*** - This patient presents with symptoms highly suggestive of **Henoch-Schönlein Purpura (HSP)**, including a preceding URI, fatigue, low-grade fever, **abdominal pain**, and a **palpable purpura** primarily on the lower extremities. - HSP is characterized by IgA-mediated **small-vessel vasculitis**, which histologically presents as leukocytoclastic vasculitis with IgA deposition on immunofluorescence. *Coronary artery aneurysms* - **Coronary artery aneurysms** are a classic complication of **Kawasaki disease**, not Henoch-Schönlein Purpura. - Kawasaki disease presents with different clinical features, including prolonged fever, conjunctival injection, oral changes, and cervical lymphadenopathy. *Thrombocytopenia* - **Thrombocytopenia** is characterized by a low platelet count and often presents with petechiae, purpura, and bleeding, but the rash in HSP is due to inflammation and extravasation of red blood cells, not low platelets. - Platelet counts in HSP are typically **normal** or can be slightly elevated as an acute phase reactant. *Mitral regurgitation* - **Mitral regurgitation** is a common manifestation of **rheumatic fever**, particularly after recurrent episodes, caused by valvular damage. - Rheumatic fever is also preceded by infection (Group A Strep) but involves different symptoms like migratory polyarthritis, carditis, chorea, erythema marginatum, and subcutaneous nodules, which are not described here. *Occult malignancy* - While an **occult malignancy** can cause paraneoplastic syndromes or constitutional symptoms, the specific constellation of symptoms, including the migratory rash, abdominal pain, and preceding URI, points much more strongly to **HSP** in a 6-year-old. - The presentation is more consistent with an acute, inflammatory process rather than a chronic, insidious malignant one.

Question 76: You are seeing an otherwise healthy 66-year-old male in clinic who is complaining of localized back pain and a new rash. On physical exam, his vital signs are within normal limits. You note a vesicular rash restricted to the upper left side of his back. In order to confirm your suspected diagnosis, you perform a diagnostic test. What would you expect to find on the diagnostic test that was performed?

A. Gram negative bacilli
B. Branching pseudohyphae
C. Pear shaped motile cells
D. Multinucleated giant cells (Correct Answer)
E. Gram positive cocci

Explanation: ***Multinucleated giant cells*** - The patient's presentation of a **unilateral, vesicular rash** in an older adult, along with localized back pain, is highly suggestive of **herpes zoster (shingles)**. - A Tzanck smear, a common diagnostic test for vesicular lesions, would reveal **multinucleated giant cells** and **intranuclear inclusions**, characteristic cytopathic effects of herpesviruses like VZV. *Gram negative bacilli* - This finding would suggest a **bacterial infection**, typically not associated with vesicular rashes like shingles. - Gram-negative bacilli are often implicated in conditions such as **urinary tract infections** or **sepsis**, not dermatological viral infections. *Branching pseudohyphae* - This microscopic feature is characteristic of **fungal infections**, specifically **Candida species**, which present as a candidiasis rash, not a dermatomal vesicular rash. - Fungal rashes are typically erythematous and can be pruritic but do not usually form discrete vesicles in a dermatomal distribution. *Pear shaped motile cells* - This describes **Trichomonas vaginalis**, a parasite causing sexually transmitted infections, primarily **vaginitis** or **urethritis**. - This finding would be completely unrelated to a vesicular skin rash or the suspected diagnosis of shingles. *Gram positive cocci* - This finding is indicative of a **bacterial infection**, such as those caused by **Staphylococcus aureus** or **Streptococcus pyogenes**. - While these bacteria can cause skin infections (e.g., impetigo, cellulitis), they do not produce the classic unilateral vesicular rash of shingles and would not involve multinucleated giant cells on microscopy.

Question 77: A 36-year-old woman presents to the outpatient department with a recent onset of generalized weakness and weight gain. On physical examination, there is diffuse nontender enlargement of the thyroid gland. Fine-needle aspiration and cytology show lymphocytic infiltration with germinal centers and epithelial Hürthle cells. Which of the following autoantibodies is most likely to be found in this patient?

A. Anti-TSH receptor antibody
B. Antihistone antibody
C. Antimitochondrial antibody
D. Anti-parietal cell antibody
E. Anti-thyroid peroxidase (anti-TPO) antibody (Correct Answer)

Explanation: ***Anti-thyroid peroxidase (anti-TPO) antibody*** - The clinical presentation of **generalized weakness, weight gain**, and **diffuse nontender thyroid enlargement** points towards **hypothyroidism**, likely due to **Hashimoto's thyroiditis**. - **Fine-needle aspiration** findings of **lymphocytic infiltration with germinal centers** and **Hürthle cells** are classic for Hashimoto's, which is an autoimmune condition primarily mediated by **anti-TPO antibodies**. *Anti-TSH receptor antibody* - These antibodies are characteristic of **Graves' disease**, an autoimmune disorder causing **hyperthyroidism**, which presents with weight loss and symptoms of increased metabolism, the opposite of this patient's presentation. - They can be either stimulating (most common) or blocking, but their presence is strongly associated with **hyperthyroidism** and not the hypothyroid state suggested here. *Antihistone antibody* - This antibody is highly sensitive for **drug-induced lupus erythematosus** but can also be seen in systemic lupus erythematosus (SLE). - It is not directly related to thyroid pathologies. *Antimitochondrial antibody* - This antibody is a hallmark of **primary biliary cholangitis (PBC)**, an autoimmune liver disease, and has no direct association with thyroid conditions. - PBC typically presents with fatigue, pruritus, and elevated liver enzymes. *Anti-parietal cell antibody* - These antibodies are associated with **pernicious anemia**, an autoimmune condition leading to **vitamin B12 deficiency** due to malabsorption. - While pernicious anemia can cause weakness, it does not explain the thyroid enlargement or the specific cytological findings in the thyroid.

Question 78: A 45-year-old man presents to the office with complaints of facial puffiness and mild swelling in his lower back. He denies chest pain, blood in the urine, or fever. He was recently diagnosed with colon cancer. The vital signs include a blood pressure of 122/78 mm Hg, a pulse of 76/min, a temperature of 36.9°C (98.4°F), and a respiratory rate of 10/min. On physical examination, there is mild facial puffiness that is pitting in nature and presacral edema. His other systemic findings are within normal limits. Urinalysis shows: pH 6.2 Color light yellow RBC none WBC 3–4/HPF Protein 4+ Cast oval fat bodies Glucose absent Crystal none Ketone absent Nitrite absent 24 hours urine protein excretion 4.8 g A renal biopsy is ordered and diffuse capillary and basement membrane thickening is noted. Which of the following findings is expected to be present if an electron microscopy of the biopsy sample is performed?

A. Subepithelial humps
B. Effacement of foot process
C. Basket-weave appearance of GBM
D. Massive amyloid deposition and spicular aggregates
E. Spike and dome appearance (Correct Answer)

Explanation: ***Spike and dome appearance*** - The patient's presentation with **facial puffiness**, **presacral edema**, **4+ proteinuria**, **oval fat bodies**, and **4.8 g/24hr protein excretion** with **diffuse capillary and basement membrane thickening** on renal biopsy, in the setting of **colon cancer**, is highly suggestive of **membranous nephropathy**. - **Membranous nephropathy** is characterized on electron microscopy by **subepithelial immune complex deposits**, which often manifest as a **"spike and dome" appearance** due to new basement membrane material laid down between the immune deposits. *Subepithelial humps* - **Subepithelial humps** are characteristic of **post-streptococcal glomerulonephritis** and other forms of **acute post-infectious glomerulonephritis**. - This patient's presentation with **nephrotic syndrome** features and chronic disease does not align with acute glomerulonephritis. *Effacement of foot process* - **Effacement of foot processes** (podocyte effacement) is a finding seen in almost all causes of **heavy proteinuria** and **nephrotic syndrome**, including **minimal change disease**, **focal segmental glomerulosclerosis**, and **membranous nephropathy**. - While it would be present in this case, it is a non-specific finding of proteinuria itself, not a defining characteristic of **membranous nephropathy** itself, which is what "spike and dome" is. *Basket-weave appearance of GBM* - The **"basket-weave" appearance** refers to the irregular thickening and lamellation of the **glomerular basement membrane (GBM)**, typically seen in **Alport syndrome**. - This is a genetic disorder of type IV collagen and does not fit the clinical picture of an adult with recent colon cancer and acquired nephrotic syndrome. *Massive amyloid deposition and spicular aggregates* - **Massive amyloid deposition** with **spicular aggregates** is characteristic of **amyloidosis**. - While amyloidosis can cause nephrotic syndrome and be associated with chronic diseases, the light microscopy finding of **diffuse capillary and basement membrane thickening** without specific mention of congophilic deposits or apple-green birefringence makes membranous nephropathy a more direct fit with the "spike and dome" EM finding.

Question 79: A 29-year-old man comes to the emergency department because of progressively worsening fatigue and shortness of breath for the past 2 weeks. His only medication is insulin. Examination shows elevated jugular venous distention and coarse crackles in both lungs. Despite appropriate life-saving measures, he dies. Gross examination of the heart at autopsy shows concentrically thickened myocardium and microscopic examination shows large cardiomyocytes with intracellular iron granules. Examination of the spinal cord shows atrophy of the lateral corticospinal tracts, spinocerebellar tracts, and dorsal columns. Which of the following is the most likely underlying cause of this patient's condition?

A. CTG trinucleotide repeat expansion on chromosome 19
B. SOD1 gene mutation on chromosome 21
C. SMN1 gene mutation on chromosome 5
D. GAA trinucleotide repeat expansion on chromosome 9 (Correct Answer)
E. Dystrophin gene mutation on the X chromosome

Explanation: ***GAA trinucleotide repeat expansion on chromosome 9*** - The patient's presentation with **hypertrophic cardiomyopathy** (concentrically thickened myocardium, large cardiomyocytes) and **neurological degeneration** affecting the **lateral corticospinal tracts, spinocerebellar tracts, and dorsal columns** is characteristic of **Friedreich ataxia**. - **Friedreich ataxia** is caused by a **GAA trinucleotide repeat expansion** in the **FXN gene on chromosome 9**, leading to reduced frataxin protein and mitochondrial dysfunction. *CTG trinucleotide repeat expansion on chromosome 19* - This mutation is associated with **myotonic dystrophy type 1**, which presents with **myotonia**, muscle weakness, and often cardiac conduction abnormalities or dilated cardiomyopathy, but typically not hypertrophic cardiomyopathy or the specific spinal cord degeneration described. - While cardiac involvement can occur, the neurological pattern of **spinal cord tract degeneration** and **hypertrophic cardiomyopathy** is not typical for myotonic dystrophy type 1. *SOD1 gene mutation on chromosome 21* - Mutations in the **SOD1 gene** are a common cause of **familial amyotrophic lateral sclerosis (ALS)**, characterized by progressive degeneration of upper and lower motor neurons. - ALS primarily presents with muscle weakness, atrophy, and fasciculations, but does not typically involve **hypertrophic cardiomyopathy** or the specific pattern of **sensory tract degeneration** seen in this patient. *SMN1 gene mutation on chromosome 5* - This mutation causes **spinal muscular atrophy (SMA)**, a genetic disorder characterized by the loss of motor neurons in the spinal cord, leading to progressive muscle weakness and atrophy. - SMA does not typically involve **hypertrophic cardiomyopathy** or the specific combination of motor and sensory tract degeneration described in the patient. *Dystrophin gene mutation on the X chromosome* - Mutations in the **dystrophin gene** cause **Duchenne and Becker muscular dystrophies**, which are characterized by progressive muscle weakness and **dilated cardiomyopathy**, not hypertrophic cardiomyopathy. - While these disorders affect muscles, the specific pattern of **spinal cord tract atrophy** described is not a feature of dystrophinopathies.

Question 80: A 45-year-old man is brought to the hospital by his daughter with complaints of wide-based gait. His daughter reveals that he was sitting silently in the examination chair with a blank face. In addition, he was frequently talking to the empty chairs and told that his friends are sitting there. He has been forgetting many small things recently. On physical examination, fine movements are seen at resting condition that disappears when he is asked to drink water. A stepwise slowness in movement is also seen in his upper limb. Which of the following is most likely to be observed in the histological specimen of this patient?

A. Spongiform changes in cortex
B. Neuritic plaques in cortex
C. Lewy bodies in affected neurons (Correct Answer)
D. Tau protein aggregates in cortex
E. Neurofibrillary tangles in hippocampus

Explanation: ***Lewy bodies in affected neurons*** - The patient's symptoms of **wide-based gait**, **cognitive decline** (forgetting things, talking to empty chairs), **psychotic features** (visual hallucinations), and **motor symptoms** (resting tremor, bradykinesia) are highly suggestive of **Lewy body dementia** (LBD). - **Lewy bodies**, which are abnormal aggregates of **alpha-synuclein protein**, are the characteristic histological finding in neurons of individuals with LBD, found in both **cortical areas** (defining feature of LBD) and **substantia nigra**. - The presence of early prominent visual hallucinations with parkinsonism and cognitive fluctuations is pathognomonic for Lewy body dementia. *Spongiform changes in cortex* - This finding is characteristic of **prion diseases**, such as **Creutzfeldt-Jakob disease** (CJD), which typically present with rapidly progressive dementia and myoclonus. - While CJD involves cognitive decline, the presence of resting tremor, visual hallucinations, and a more gradual progression with parkinsonian features makes spongiform changes unlikely. *Neuritic plaques in cortex* - **Neuritic plaques**, composed of **amyloid-beta protein**, are a hallmark of **Alzheimer's disease**. - Although Alzheimer's disease causes cognitive decline, the prominent early motor symptoms (resting tremor, wide-based gait, bradykinesia) and early visual hallucinations are not typical features of Alzheimer's disease. *Tau protein aggregates in cortex* - **Tau protein aggregates** (neurofibrillary tangles) are another key histological feature of **Alzheimer's disease** and certain **tauopathies** like **frontotemporal dementia** and **progressive supranuclear palsy**. - While associated with dementia, they do not explain the unique combination of early parkinsonian motor features and prominent visual hallucinations seen in this patient. *Neurofibrillary tangles in hippocampus* - **Neurofibrillary tangles** composed of hyperphosphorylated **tau protein** in the hippocampus are characteristic of **Alzheimer's disease** and correlate with memory impairment. - However, Alzheimer's disease does not typically present with early parkinsonism, resting tremor, or prominent visual hallucinations as seen in this patient with Lewy body dementia.

Question 81: A 65-year-old man comes to the physician because of a 6-month history of progressive fatigue and abdominal pain. Physical examination shows pale mucous membranes and splenomegaly. Hemoglobin concentration is 9.1 g/dL and leukocyte count is 3,400/mm3. Peripheral blood smear shows nucleated red blood cells and teardrop poikilocytosis. A Janus kinase 2 gene mutation is present. Which of the following is the most likely underlying mechanism of this patient's condition?

A. Elevated levels of circulating hepcidin
B. Lymphocytic infiltration of reticuloendothelial system
C. Viral replication in lymphoid cells
D. Fibrosis in the bone marrow (Correct Answer)
E. Translocation between chromosome 9 and 22

Explanation: ***Fibrosis in the bone marrow*** - The constellation of **fatigue**, **anemia** (Hb 9.1 g/dL), **splenomegaly**, **teardrop poikilocytosis**, and a **JAK2 mutation** is highly suggestive of **primary myelofibrosis**. - **Bone marrow fibrosis** is the hallmark of primary myelofibrosis, leading to ineffective hematopoiesis and extramedullary hematopoiesis (causing splenomegaly). *Elevated levels of circulating hepcidin* - **Elevated hepcidin** is characteristic of **anemia of chronic disease** or **iron-refractory iron deficiency anemia**, where iron is trapped in macrophages despite adequate stores. - While anemia is present, the other features (splenomegaly, teardrop cells, JAK2 mutation) are not consistent with anemia of chronic disease as the primary mechanism. *Lymphocytic infiltration of reticuloendothelial system* - **Lymphocytic infiltration** is typical of **lymphoproliferative disorders** like leukemias or lymphomas, which would present with different CBC findings, not primarily myelofibrosis features. - This mechanism would lead to different peripheral smear findings (e.g., lymphocytosis) rather than nucleated red cells and teardrop cells. *Viral replication in lymphoid cells* - **Viral replication in lymphoid cells** can cause various hematologic abnormalities (e.g., infectious mononucleosis, some lymphomas), but it is not the underlying mechanism for the specific features of primary myelofibrosis. - This would not explain the **JAK2 mutation** or the characteristic **bone marrow fibrosis** and **extramedullary hematopoiesis**. *Translocation between chromosome 9 and 22* - A **translocation between chromosome 9 and 22** (the **Philadelphia chromosome**) is characteristic of **chronic myeloid leukemia (CML)**. - While CML can cause splenomegaly and myeloid abnormalities, it typically presents with marked leukocytosis and does not feature the prominent teardrop cells or the primary myelofibrosis features seen here; CML is characterized by the **BCR-ABL1 fusion gene**, not primarily a JAK2 mutation.

Question 82: A 12-year-old boy presents to the emergency department with a recent history of easy bleeding. He experienced multiple episodes of epistaxis and bleeding gums over the past two days. He also had flu-like symptoms a week ago which resolved over the past few days. His past medical history is notable for well-controlled asthma. His temperature is 98.9°F (37°C). Physical examination is notable for a petechial rash. No splenomegaly is noted. A coagulation panel reveals an elevation in bleeding time with normal PT and PTT. The blood component that is most likely deficient in this patient contains granules of which of the following?

A. Myeloperoxidase
B. Heparin
C. Tryptase
D. Major basic protein
E. von Willebrand factor (Correct Answer)

Explanation: ***von Willebrand factor*** - This patient's presentation with **easy bleeding** (epistaxis, bleeding gums), **petechial rash**, and a history of a recent **viral infection** followed by normal PT/PTT but **elevated bleeding time** is highly suggestive of **Immune Thrombocytopenic Purpura (ITP)**. - In ITP, antibodies attack **platelets**, leading to their destruction and a deficiency. Platelet alpha-granules contain **von Willebrand factor**, platelet factor 4, and fibrinogen, which are crucial for hemostasis. *Myeloperoxidase* - **Myeloperoxidase** is found in the **azurophilic granules** of neutrophils and monocytes, not platelets, and is involved in microbial killing. - A deficiency in myeloperoxidase would primarily impair immune function rather than cause a bleeding disorder with elevated bleeding time. *Heparin* - **Heparin** is an anticoagulant found primarily in the granules of **mast cells** and basophils, which are involved in allergic reactions and inflammation. - Heparin is not a component of platelet granules, and its deficiency would lead to increased clotting, not bleeding. *Tryptase* - **Tryptase** is an enzyme found in the granules of **mast cells**, released during allergic reactions and anaphylaxis. - It is not associated with platelet function or the type of bleeding disorder described here. *Major basic protein* - **Major basic protein (MBP)** is a cytotoxic protein found in the granules of **eosinophils**, primarily involved in defense against parasitic infections. - Its presence or absence is unrelated to platelet function or this patient's bleeding symptoms.

Question 83: An 18-year-old African-American woman comes to the physician for the evaluation of worsening fatigue that started 1 year ago. Physical examination shows mild jaundice and splenomegaly. Laboratory studies show: Hemoglobin 10.4 g/dL Mean corpuscular hemoglobin concentration 43% Hb/cell Platelet count 220,000/mm3 Reticulocyte count 7% A peripheral blood smear shows target cells and erythrocytes with hemoglobin crystals. Which of the following is the most likely underlying cause of this patient's findings?

A. Acquired mutation of membrane-bound glycosylphosphatidylinositol anchor
B. Decreased conversion of oxidized glutathione into its reduced form
C. Replacement of glutamate by valine in beta-globin chain
D. Replacement of glutamate by lysine in beta-globin chain (Correct Answer)
E. Reduced production of beta-globin due to a mutation in the HbB gene

Explanation: ***Replacement of glutamate by lysine in beta-globin chain*** - The combination of **mild jaundice**, **splenomegaly**, **anemia**, **elevated reticulocyte count**, and the presence of **target cells** and **hemoglobin C crystals** on peripheral smear is characteristic of **Hemoglobin C disease**. - **Hemoglobin C** results from the **replacement of glutamate by lysine at position 6 of the beta-globin chain**, leading to abnormal hemoglobin and erythrocyte morphology. *Acquired mutation of membrane-bound glycosylphosphatidylinositol anchor* - This describes **Paroxysmal Nocturnal Hemoglobinuria (PNH)**, which is characterized by **hemolytic anemia**, **thrombosis**, and **bone marrow failure**. - While it causes hemolytic anemia, the peripheral smear findings of **target cells** and **hemoglobin crystals** are not typical for PNH as seen in this patient. *Decreased conversion of oxidized glutathione into its reduced form* - This mechanism is characteristic of **Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency**, a cause of **hemolytic anemia**. - G6PD deficiency typically presents with episodic hemolysis triggered by **oxidative stress**, and the characteristic peripheral smear findings are **Heinz bodies** and **bite cells**, not hemoglobin crystals. *Replacement of glutamate by valine in beta-globin chain* - This mutation describes **Sickle Cell Anemia**, which also causes hemolytic anemia and splenomegaly. - While it leads to **sickle cells** on peripheral smear, **hemoglobin C crystals** and **target cells** are not the primary features; sickle cells and Howell-Jolly bodies would be expected. *Reduced production of beta-globin due to a mutation in the HbB gene* - This describes **Beta-thalassemia**, a group of disorders characterized by **reduced or absent beta-globin chain synthesis**. - Beta-thalassemia typically presents with **microcytic hypochromic anemia** and **target cells**, but the presence of **hemoglobin C crystals** is not a feature.

Question 84: A 34-year-old female presents to her primary care physician with complaints of fevers, nausea/vomiting, and severe left flank pain that has developed over the past several hours. She denies any prior episodes similar to her current presentation. Physical examination is significant for a body temperature of 39.1 C and costovertebral angle tenderness. A urinalysis and urine microscopy are ordered. Which of the following findings on kidney histology would be expected in this patient?

A. Enlarged, hypercellular glomeruli with 'wire-looping' of capillaries
B. Neutrophils filling the lumens of the renal tubules (Correct Answer)
C. Scarring of the glomeruli
D. Interstitial fibrosis and lymphocytic infiltrate
E. Thickening of the capillaries and glomerular basement membrane

Explanation: ***Neutrophils filling the lumens of the renal tubules*** - This patient's symptoms (fevers, nausea/vomiting, severe left flank pain, fever, and costovertebral angle tenderness) are highly suggestive of **acute pyelonephritis**, an infection of the kidney parenchyma. - Histologically, acute pyelonephritis is characterized by an acute inflammatory infiltrate, primarily **neutrophils**, within the **renal tubules** and interstitial tissue, often forming **abscesses**. *Enlarged, hypercellular glomeruli with 'wire-looping' of capillaries* - This description is characteristic of **diffuse proliferative glomerulonephritis**, often associated with conditions like **systemic lupus erythematosus (SLE)**. - The clinical presentation of sudden-onset severe flank pain and fever is not typical for glomerulonephritis, which usually presents with hematuria, proteinuria, and edema. *Scarring of the glomeruli* - **Glomerulosclerosis** (scarring of the glomeruli) is a feature of chronic kidney disease and various chronic glomerular disorders, not acute pyelonephritis. - Patients with glomerular scarring typically present with signs of chronic kidney injury, such as persistent proteinuria and declining renal function, rather than acute infectious symptoms. *Interstitial fibrosis and lymphocytic infiltrate* - This is a hallmark of **chronic interstitial nephritis**, which can be caused by long-term drug use, autoimmune diseases, or chronic obstructive uropathy. - While lymphocytes indicate inflammation, the presence of fibrosis suggests a chronic process, differing from the acute bacterial infection seen in pyelonephritis. *Thickening of the capillaries and glomerular basement membrane* - This finding is suggestive of various glomerular diseases, such as **membranous nephropathy** or **diabetic nephropathy**, where the glomerular basement membrane is significantly altered. - Such conditions typically manifest with proteinuria and nephrotic or nephritic syndromes, not the acute infectious symptoms described.

Question 85: A 12-year-old girl is presented to the office by her mother with complaints of cola-colored urine and mild facial puffiness that began 5 days ago. According to her mother, she had a sore throat 3 weeks ago. Her immunization records are up to date. The mother denies fever and any change in bowel habits. The vital signs include blood pressure 138/78 mm Hg, pulse 88/min, temperature 36.8°C (98.2°F), and respiratory rate 11/min. On physical examination, there is pitting edema of the upper and lower extremities bilaterally. An oropharyngeal examination is normal. Urinalysis shows the following results: pH 6.2 Color dark brown Red blood cell (RBC) count 18–20/HPF White blood cell (WBC) count 3–4/HPF Protein 1+ Cast RBC casts Glucose absent Crystal none Ketone absent Nitrite absent 24 h urine protein excretion 0.6 g HPF: high-power field Which of the following would best describe the light microscopy findings in this case?

A. Segmental sclerosis and hyalinosis
B. Wire looping of capillaries
C. Mesangial proliferation
D. Hypercellular and enlarged glomeruli (Correct Answer)
E. Crescentic proliferation consisting of glomerular parietal cells, macrophage, and fibrin

Explanation: ***Hypercellular and enlarged glomeruli*** - The patient's presentation with **cola-colored urine**, facial puffiness, edema, hypertension, and a recent history of sore throat points to **post-streptococcal glomerulonephritis (PSGN)**. - Light microscopy in PSGN typically reveals **diffuse hypercellularity** due to proliferation of mesangial and endothelial cells, and infiltration by inflammatory cells, leading to enlarged glomeruli. *Segmental sclerosis and hyalinosis* - This finding is characteristic of **focal segmental glomerulosclerosis (FSGS)**, which typically presents with **nephrotic syndrome** (heavy proteinuria, hypoalbuminemia, severe edema). - While there is proteinuria in this case, it is not in the nephrotic range, and other clinical features do not support FSGS. *Wire looping of capillaries* - **Wire looping** is a classic feature of **diffuse proliferative glomerulonephritis (DPGN)**, often seen in **lupus nephritis (Class III or IV)**. - The patient’s clinical picture, particularly the antecedent sore throat and acute presentation, is not consistent with lupus nephritis. *Mesangial proliferation* - While mesangial proliferation occurs in PSGN, it is usually accompanied by **endocapillary proliferation** and inflammatory cell infiltration, making the glomeruli appear diffusely hypercellular and enlarged. - Isolated mesangial proliferation is more characteristic of **IgA nephropathy**, which typically presents with recurrent episodes of gross hematuria, sometimes concurrent with or shortly after an upper respiratory infection. *Crescentic proliferation consisting of glomerular parietal cells, macrophage, and fibrin* - **Crescents** are pathognomonic of **rapidly progressive glomerulonephritis (RPGN)**, which involves severe and rapid loss of renal function. - While PSGN can occasionally progress to RPGN, the typical presentation of PSGN usually does not involve prominent crescent formation unless severe.

Question 86: A 7-year-old girl is brought to the physician with complaints of erythema and rashes over the bridge of her nose and on her forehead for the past 6 months. She also has vesiculobullous and erythematous scaly crusted lesions on the scalp and around the perioral areas. Her parents report a history of worsening symptoms during exposure to sunlight, along with a history of joint pain and oral ulcers. Her temperature is 38.6°C (101.4°F), pulse is 88/min, and respirations are 20/min. On physical examination, pallor and cervical lymphadenopathy are present. On cutaneous examination, diffuse hair loss and hyperpigmented scaly lesions are present. Her laboratory studies show: Hemoglobin 7.9 mg/dL Total leukocyte count 6,300/mm3 Platelet count 167,000/mm3 Erythrocyte sedimentation rate 30 mm/h ANA titer 1:520 (positive) Which of the following most likely explains the mechanism of this condition?

A. Type II hypersensitivity
B. Type IV hypersensitivity
C. Type V hypersensitivity
D. Type I hypersensitivity
E. Type III hypersensitivity (Correct Answer)

Explanation: ***Type III hypersensitivity*** - This condition describes **Systemic Lupus Erythematosus (SLE)**, characterized by the formation of **immune complexes** that deposit in various tissues and trigger inflammation. - The positive **ANA titer**, along with clinical features like **malar rash**, photosensitivity, arthritis, oral ulcers, and hematologic abnormalities (anemia, lymphadenopathy), are all consistent with SLE, which is a classic example of **Type III hypersensitivity**. *Type II hypersensitivity* - Involves **antibodies directly attacking antigens on cell surfaces**, leading to cell lysis or dysfunction. - While SLE can have Type II features (e.g., hemolytic anemia), the broad systemic inflammation and diverse organ involvement are primarily driven by immune complex deposition. *Type IV hypersensitivity* - This is a **delayed-type hypersensitivity** reaction mediated by **T cells** and macrophages, not antibodies. - Examples include contact dermatitis and tuberculin skin tests, which do not align with the multi-organ, immune complex-mediated pathology seen here. *Type V hypersensitivity* - A rare subtype of Type II hypersensitivity where antibodies **stimulate or inhibit cell function** by binding to cell surface receptors (e.g., Grave's disease, Myasthenia Gravis). - It does not explain the widespread immune complex deposition and systemic inflammation characteristic of SLE. *Type I hypersensitivity* - Involves **IgE antibodies** binding to mast cells, leading to immediate release of histamine and other mediators upon antigen exposure. - This type causes allergic reactions like hay fever or anaphylaxis and does not explain the chronic autoimmune manifestations of SLE.

Question 87: Physical exam of a 15-year-old female reveals impetigo around her mouth. A sample of the pus is taken and cultured. Growth reveals gram-positive cocci in chains that are bacitracin sensitive. Which of the following symptoms would be concerning for a serious sequela of this skin infection?

A. Myocarditis
B. Joint swelling
C. Fever
D. Chorea
E. Hematuria (Correct Answer)

Explanation: ***Hematuria*** - The description of **impetigo** around the mouth caused by **gram-positive cocci in chains** that are **bacitracin-sensitive** points to *Streptococcus pyogenes* (Group A Streptococcus). - A serious sequela of streptococcal skin infections (impetigo) is **post-streptococcal glomerulonephritis (PSGN)**, which presents with **hematuria**, proteinuria, edema, and hypertension. *Myocarditis* - **Myocarditis** can be a complication of **acute rheumatic fever (ARF)**, which is a sequela of **streptococcal pharyngitis**, not typically streptococcal skin infections (impetigo). - While both rheumatic fever and PSGN are caused by *Streptococcus pyogenes*, the specific **M-types** associated with skin infections differ from those causing pharyngitis and ARF. *Joint swelling* - **Arthritis** (joint swelling) is a major criterion for **acute rheumatic fever**, which follows **streptococcal pharyngitis**, not impetigo. - Although PSGN can cause arthralgia, significant arthritis is not a primary or alarming symptom of PSGN. *Fever* - **Fever** is a general symptom that can accompany any infection, including impetigo itself or many other conditions. - While fever can be present in PSGN, it is not a specific or unique indicator of this particular serious sequela. *Chorea* - **Sydenham's chorea** is a neurological manifestation of **acute rheumatic fever**, which develops after **streptococcal pharyngitis**, not impetigo. - It presents as involuntary, purposeless movements and is not associated with PSGN following impetigo.

Question 88: A 19-year-old male from rural West Virginia presents to his family medicine doctor to discuss why he is having trouble getting his wife pregnant. On exam, he is 6 feet 2 inches with a frail frame and broad hips for a male his size. He is noted to have mild gynecomastia, no facial hair, and small, underdeveloped testes. He claims that although he has a lower libido than most of his friends, he does have unprotected sex with his wife. His past medical history is notable for developmental delay and difficulties in school. What is the most likely chromosomal abnormality in this patient?

A. Trisomy 13
B. 45: XO
C. Trisomy 21
D. 47: XYY
E. 47: XXY (Correct Answer)

Explanation: ***47: XXY*** - The patient's presentation with **infertility**, small testes, **gynecomastia**, eunuchoid body habitus (tall, frail frame, broad hips), lack of facial hair, and **developmental delay** are classic features of **Klinefelter syndrome (47, XXY)**. - This chromosomal abnormality leads to primary **hypogonadism** due to the presence of an extra X chromosome in males. *Trisomy 13* - Trisomy 13, or **Patau syndrome**, is characterized by severe developmental anomalies, including **cleft lip and palate**, polydactyly, and severe neurological defects. - Infants with Trisomy 13 rarely survive beyond the first year and do not present with the described signs of hypogonadism or gynecomastia in adolescence. *45: XO* - **45, XO** or **Turner syndrome** affects females and is characterized by **short stature**, primary amenorrhea, webbed neck, and **gonadal dysgenesis (streak gonads)**. - This karyotype is incompatible with a male phenotype and the symptoms described. *Trisomy 21* - Trisomy 21, or **Down syndrome**, is associated with distinct facial features, intellectual disability, and congenital heart defects. - While individuals with Down syndrome may have fertility issues, they do not typically present with the specific combination of **gynecomastia**, eunuchoid habitus, and **small testes** seen in this patient. *47: XYY* - **47, XYY syndrome** is associated with increased height and potentially some learning difficulties, but typically does not cause the significant **hypogonadism**, **gynecomastia**, or **small testes** seen in this patient. - Men with 47, XYY usually have normal sexual development and fertility, though some may experience learning disabilities or behavioral problems.

Question 89: A 42-year-old woman comes to the physician because of a 2-month history of progressive muscular weakness. She has had difficulty climbing stairs, getting up from chairs, and brushing her hair. Her vital signs are within normal limits. Muscle strength is 2/5 with flexion of the hips and 3/5 with abduction of the shoulders. She is unable to stand up from her chair without the use of her arms for support. Laboratory studies show elevations in leukocyte count, erythrocyte sedimentation rate, and creatine kinase concentration. Histological evaluation of a biopsy specimen of the deltoid muscle is most likely to show which of the following?

A. Muscle fiber necrosis with rare inflammatory cells
B. Perimysial inflammation with perivascular CD4+ T lymphocytic infiltration
C. Sarcoplasmic rimmed vacuoles with CD8+ lymphocytic infiltration
D. Sarcolemmal MHC-I overexpression with CD8+ lymphocytic infiltration (Correct Answer)
E. Relative atrophy of type II muscle fibers with hypertrophy of type I muscle fibers

Explanation: ***Sarcolemmal MHC-I overexpression with CD8+ lymphocytic infiltration*** - This finding is characteristic of **polymyositis**, an inflammatory myopathy presenting with **progressive, proximal muscle weakness**, elevated **creatine kinase**, and inflammation. - The **MHC-I overexpression** on the sarcolemma makes muscle fibers susceptible to destruction by activated cytotoxic **CD8+ T cells**, leading to necrosis and weakness. *Muscle fiber necrosis with rare inflammatory cells* - While muscle fiber necrosis is present in inflammatory myopathies, the description of **rare inflammatory cells** is inconsistent with the significant inflammation seen in polymyositis. - This pattern might suggest other myopathies, such as toxic myopathies or muscular dystrophies, rather than a primary inflammatory process. *Perimysial inflammation with perivascular CD4+ T lymphocytic infiltration* - This histological pattern is highly suggestive of **dermatomyositis**, not polymyositis. - In dermatomyositis, inflammation primarily involves the **perivascular spaces** and **perimysium**, and **CD4+ T cells** are the predominant infiltrating lymphocytes. *Sarcoplasmic rimmed vacuoles with CD8+ lymphocytic infiltration* - This finding is characteristic of **inclusion body myositis (IBM)**, which typically presents in older individuals (>50 years) with **asymmetric distal and proximal weakness**. - The presence of **rimmed vacuoles** containing protein aggregates is a hallmark of IBM, differentiating it from polymyositis. *Relative atrophy of type II muscle fibers with hypertrophy of type I muscle fibers* - This pattern of muscle fiber atrophy and hypertrophy is more characteristic of **disuse atrophy**, **steroid-induced myopathy**, or other **neurogenic conditions**, not inflammatory myopathies like polymyositis. - Polymyositis involves inflammatory cell infiltration and necrosis, affecting various fiber types.

Question 90: A 20-year-old man presents with a painless neck mass that has gradually increased in size. The mass is anteromedial to the right sternocleidomastoid muscle and has been present for 3 years. The mass increased in size and became more tender following an upper respiratory infection. An ultrasound of the neck identifies a single, round cystic mass with uniform, low echogenicity, and no internal septations. A contrast-enhanced CT scan of the neck shows a homogeneous mass with low attenuation centrally and with smooth rim enhancement. Which of the following is the most likely diagnosis?

A. First branchial cleft cyst
B. Sternomastoid tumor
C. Second branchial cleft cyst (Correct Answer)
D. Ectopic thyroid tissue
E. Cervical lymphadenopathy

Explanation: **Second branchial cleft cyst** - The **location** (anteromedial to the sternocleidomastoid muscle), **painless** nature, and history of **gradual enlargement** becoming tender after an URI are classic presentations. - **Imaging findings** (single, round cystic mass with uniform low echogenicity on ultrasound; homogeneous mass with low attenuation centrally and smooth rim enhancement on CT) are highly characteristic of an infected branchial cleft cyst. *First branchial cleft cyst* - Typically presents with a mass located near the **external auditory canal** or **angle of the mandible**, often causing otorrhea or recurrent infections. - The presented mass is in a different anatomical location, **anteromedial** to the sternocleidomastoid. *Sternomastoid tumor* - This condition usually presents as a **fibrotic mass** within the sternocleidomastoid muscle in **neonates or infants**, associated with **congenital muscular torticollis**. - The patient's age (20 years old) and the **cystic nature** of the mass make this diagnosis unlikely. *Ectopic thyroid tissue* - While possible in the neck, ectopic thyroid tissue would typically present as a **solid mass** and would show **iodine uptake** on nuclear imaging, not a cystic appearance on ultrasound and CT. - It is more commonly located in the **midline** of the neck (e.g., lingual thyroid) rather than anteromedial to the sternocleidomastoid. *Cervical lymphadenopathy* - Enlarged lymph nodes typically present with **multiple, often tender, solid masses** or a single mass with typical lymph node morphology (e.g., hilar fat, oval shape), especially after an infection. - The **cystic nature** described by imaging, with uniform low echogenicity and rim enhancement, is not typical for uncomplicated lymphadenopathy.

Question 91: Following a recent myocardial infarction, a 60-year-old woman has been started on multiple medications at the time of discharge from the hospital. After 10 days of discharge, she presents to the emergency department with a history of fever, headache, and dark colored urine for 2 days. Her husband mentions that she has not passed urine for the last 24 hours. Her physical examination shows significant pallor, and multiple petechiae are present all over her limbs. Her vital signs include: temperature 38.9°C (102.0°F), pulse rate 94/min, blood pressure 124/82 mm Hg, and respiratory rate 16/min. Her sensorium is altered with the absence of spontaneous speech and spontaneous movements. She responds inappropriately to verbal stimuli. Her laboratory results show the presence of anemia and thrombocytopenia. Examination of peripheral blood smear shows the presence of schistocytes. Serum creatinine is 2 mg/dL. Serum levels of fibrinogen, fibrin monomers, fibrin degradation products and D-dimers are normal. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal. Which is the most likely treatment for this patient’s condition?

A. Renal dialysis
B. Platelet transfusion
C. Rehydration
D. Plasma exchange (Correct Answer)
E. Intravenous immunoglobulin

Explanation: ***Plasma exchange*** - The patient's presentation with **fever, altered mental status, renal failure, microangiopathic hemolytic anemia (schistocytes, anemia), and thrombocytopenia** is characteristic of **Thrombotic Thrombocytopenic Purpura (TTP)**. - **Plasma exchange (plasmapheresis)** is the mainstay of TTP treatment, as it removes inhibiting antibodies against **ADAMTS13** and replaces functional ADAMTS13. *Renal dialysis* - While the patient has **acute kidney injury (creatinine 2 mg/dL)** and **anuria**, dialysis is a supportive measure for renal failure, not a definitive treatment for the underlying TTP. - Addressing the primary cause (TTP) with plasma exchange will be crucial in potentially reversing the renal damage. *Platelet transfusion* - Platelet transfusions are generally **contraindicated in TTP** because they can worsen thrombosis by providing more substrate for platelet aggregation in the presence of severe ADAMTS13 deficiency. - They should only be considered if there is life-threatening hemorrhage and the benefits outweigh the risks. *Rehydration* - While the patient is anuric, rehydration alone will not address the **microangiopathic hemolytic anemia, thrombocytopenia, fever, or neurological symptoms** caused by TTP. - Overzealous rehydration could also exacerbate fluid overload in a patient with acute kidney injury. *Intravenous immunoglobulin* - **Intravenous immunoglobulin (IVIg)** is not a primary treatment for TTP. While it might be used in some autoimmune conditions, its role in TTP is limited and not supported as a first-line therapy. - The immediate and critical need for TTP is the removal of autoantibodies and replacement of ADAMTS13, which IVIg does not directly achieve.

Question 92: A 39-year-old man presents to the emergency department with the complaint of ‘cola-colored’ urine that he noticed this morning. Additionally, he complains of malaise and reports that he has not been able to be productive at work since last week. Lab results revealed a hemoglobin of 6.7 g/dL, leukocyte total count of 1,000 cells/mm3, and a reticulocyte count of 6%. Coomb test is negative and flow cytometry shows CD55/CD59-negative red blood cells. Concerned about the results of his complete blood count, his physician explains the diagnosis to the patient. Which of the following sets of events best describes the mechanism underlying the development of neutropenia?

A. ↑ release of neutrophils in the bone marrow, ↑ destruction of neutrophils, and ↑ activation of neutrophil adhesion molecules
B. ↓ activation of neutrophil adhesion molecules and ↓ production of neutrophils in the bone marrow
C. ↑ activation of neutrophil adhesion molecules, ↓ destruction of neutrophils, and ↓ production of neutrophils in the bone marrow
D. ↑ activation of neutrophil adhesion molecules, ↓ release of neutrophils in the bone marrow, and ↑ destruction of neutrophils
E. ↓ production of neutrophils in the bone marrow, ↑ destruction of neutrophils, and ↑ activation of neutrophil adhesion molecules (Correct Answer)

Explanation: ***↓ production of neutrophils in the bone marrow, ↑ destruction of neutrophils, and ↑ activation of neutrophil adhesion molecules*** - **Paroxysmal nocturnal hemoglobinuria (PNH)**, indicated by the **CD55/CD59-negative red blood cells** and **cola-colored urine (hemoglobinuria)**, is characterized by a defect in **hematopoietic stem cells** in the **bone marrow**, leading to the **decreased production of all myeloid cell lines**, including neutrophils. - The deficiency of **glycosylphosphatidylinositol-anchored proteins (GPI-APs)**, specifically **CD55** and **CD59**, on the surface of neutrophils in PNH makes them susceptible to **complement-mediated destruction**, and their increased activation of adhesion molecules can paradoxically lead to their sequestration or increased clearance. *↑ release of neutrophils in the bone marrow, ↑ destruction of neutrophils, and ↑ activation of neutrophil adhesion molecules* - **Neutropenia** (low leukocyte count) is due to a **decreased production** and/or **increased destruction**, not increased release, of neutrophils from the bone marrow. - While increased destruction and activation of adhesion molecules can contribute to neutropenia, the initial step in PNH is impaired production. *↓ activation of neutrophil adhesion molecules and ↓ production of neutrophils in the bone marrow* - While **decreased production of neutrophils** in the bone marrow correctly describes a component of neutropenia in PNH, **decreased activation of neutrophil adhesion molecules** is not a feature; instead, there is often paradoxically increased activation leading to sequestration. - Reduced adhesion molecule activation would typically lead to impaired margination and increased circulating neutrophils (leukocytosis) in the setting of inflammation, not neutropenia. *↑ activation of neutrophil adhesion molecules, ↓ destruction of neutrophils, and ↓ production of neutrophils in the bone marrow* - In PNH, the neutrophils are actually highly susceptible to **complement-mediated destruction** due to the lack of complement-inhibiting proteins like CD55 and CD59, hence there is **increased destruction**, not decreased. - While **decreased production** and **increased activation of adhesion molecules** may contribute, the statement incorrectly suggests decreased destruction. *↑ activation of neutrophil adhesion molecules, ↓ release of neutrophils in the bone marrow, and ↑ destruction of neutrophils* - Although there is **increased destruction** and **increased activation of neutrophil adhesion molecules**, the primary issue is **decreased production** of neutrophils from the bone marrow, not specifically decreased release of adequately produced cells. - The underlying **hematopoietic stem cell defect** results in a failure to generate sufficient neutrophils in the first place.

Question 93: A 35-year-old man presents with large tense blisters on the flexor surfaces of the upper extremities and trunk. The histologic findings show subepidermal blisters with an eosinophil-rich infiltrate. What is the most likely underlying pathology?

A. Linear band of IgA in the basement membrane
B. Autoantibodies to desmoglein 3
C. Autoantibodies to desmoglein 1
D. Linear band of immunoglobulin G (IgG) in the epidermal basement membrane (Correct Answer)
E. Granular deposits of immunoglobulin A (IgA) in the dermal papilla

Explanation: ***Linear band of immunoglobulin G (IgG) in the epidermal basement membrane*** - This finding, specifically targeting **hemidesmosomes** in the **dermal-epidermal junction**, is characteristic of **bullous pemphigoid**. - The clinical presentation of **large, tense blisters** on flexor surfaces and the histological finding of **subepidermal blisters** with an **eosinophil-rich infiltrate** are classic for bullous pemphigoid. *Linear band of IgA in the basement membrane* - This describes **linear IgA bullous dermatosis**, which typically presents with an **annular or rosette-like pattern of blisters** and is less common than bullous pemphigoid. - While it also involves subepidermal blistering, the immune reactant is IgA, not IgG, and the morphology of the lesions is often distinct. *Autoantibodies to desmoglein 3* - **Autoantibodies to desmoglein 3** are characteristic of **pemphigus vulgaris**, which typically presents with **flaccid blisters** and **mucosal involvement**. - Histologically, pemphigus vulgaris shows **intraepidermal blistering** (acantholysis), not subepidermal. *Autoantibodies to desmoglein 1* - **Autoantibodies to desmoglein 1** are primarily associated with **pemphigus foliaceus** (superficial form) or sometimes **pemphigus vulgaris**, particularly when combined with desmoglein 3 antibodies. - Pemphigus foliaceus presents with **superficial erosions and crusts**, not large tense blisters, and it is also an intraepidermal blistering disease. *Granular deposits of immunoglobulin A (IgA) in the dermal papilla* - This finding is pathognomonic for **dermatitis herpetiformis**, an intensely pruritic condition characterized by **grouped vesicles and urticarial plaques**, often on extensor surfaces. - The blisters in dermatitis herpetiformis are typically small, not large and tense, and the immune mechanism involves IgA interacting with transglutaminase.

Question 94: A 29-year-old woman comes to the office with the complaints of severe bleeding after a dental extraction which required local hemostatic therapy. She has a long-term excessive menstrual bleeding and iron-deficiency anemia that required treatment with iron supplement since the age of 17. In addition, she states that her mother also has a history of frequent nosebleeds. The vital signs include: pulse rate 107/min, respiratory rate 17/min, temperature 37.2°C (99.0°F), and blood pressure 90/60 mm Hg. Her physical exam shows generalized pallor. The complete blood count results are as follows: Hemoglobin 10.7 g/dL Hematocrit 41% Leukocyte count 8,000/mm3 Neutrophils 54% Bands 3% Eosinophils 1% Basophils 0% Lymphocytes 32% Monocytes 2% Mean corpuscular hemoglobin 25.4 pg/cell Mean corpuscular hemoglobin concentration 31% Hb/cell Mean corpuscular volume 76 μm3 Platelet count 380,000/mm³ The coagulation test results are as follows: Partial thromboplastin time (activated) 48.0 s Prothrombin time 14.0 s International normalized ratio 0.9 What is the most likely diagnosis?

A. Von Willebrand disease (Correct Answer)
B. Systemic lupus erythematosus
C. Sideroblastic anemia
D. Congenital thrombocytopenia
E. Hemophilia A

Explanation: ***Von Willebrand disease*** - This condition presents with a history of **excessive bleeding** from mucous membranes, menorrhagia, and prolonged bleeding after dental extraction, all indicative of a **primary hemostasis defect**. - The elevated **aPTT (48.0s)** along with normal PT and platelet count, coupled with a family history of frequent nosebleeds, strongly suggests von Willebrand disease, which affects both platelet adhesion and factor VIII activity. *Systemic lupus erythematosus* - This is an **autoimmune disorder** that can cause various manifestations, but **bleeding disorders** are typically due to **immune thrombocytopenia** or acquired coagulopathies, neither of which is directly supported by the normal platelet count or specific coagulation profile (normal PT/INR). - While it can cause anemia, the **microcytic anemia** presented is better explained by iron deficiency secondary to chronic blood loss. *Sideroblastic anemia* - This is a type of **microcytic hypochromic anemia** characterized by a defect in **heme synthesis**, leading to iron accumulation in mitochondria. - It does not typically present with bleeding disorders or an elevated aPTT, making it an unlikely cause of the patient's primary bleeding complaints. *Congenital thrombocytopenia* - This condition involves a chronically **low platelet count**, which would lead to bleeding symptoms similar to this patient's. - However, the patient's **platelet count is normal at 380,000/mm³**, ruling out a primary platelet deficiency. *Hemophilia A* - Hemophilia A is an **X-linked recessive disorder** primarily affecting males, characterized by a deficiency of **Factor VIII**, leading to prolonged aPTT. - While it explains the elevated aPTT, the patient is female, and the predominant mucous membrane bleeding (menorrhagia, dental extraction bleeding) is more typical of **platelet function defects or von Willebrand disease** than the deep tissue or joint bleeds seen in hemophilia.

Question 95: A 24-year-old woman presents with blisters and erosions on her upper face, chest, and back. The blisters have erythema, scales, and crust formation. Examination shows oromucosal involvement. Histopathologic evaluation reveals a tombstone arrangement at the base of the blister. What is the most likely cause for the patient's condition?

A. Pemphigus foliaceus
B. Pemphigus vulgaris (Correct Answer)
C. Linear immunoglobulin A (IgA) disease (LAD)
D. Dermatitis herpetiformis
E. Bullous pemphigoid

Explanation: ***Pemphigus vulgaris*** - The presence of widespread **blisters and erosions**, particularly with **oromucosal involvement**, is highly characteristic of pemphigus vulgaris. The **tombstone arrangement** on histopathology, indicative of **acantholysis** above the basal layer, further supports this diagnosis. - Unlike **pemphigus foliaceus**, pemphigus vulgaris typically involves **mucous membranes** and presents with deeper, flaccid blisters that rupture easily, leading to erosions. *Pemphigus foliaceus* - This condition primarily affects the **superficial epidermis**, resulting in **superficial blisters, erosions, and scaling**, often on the face and trunk. - A key differentiating feature is the **absence of mucosal involvement** in pemphigus foliaceus, which is present in this patient. *Linear immunoglobulin A (IgA) disease (LAD)* - LAD presents with tense bullae often in an **annular or rosette pattern**, and can involve mucous membranes, but the histopathology shows a **subepidermal blister** with a linear IgA deposit along the basement membrane zone. - The "tombstone arrangement" with intraepidermal acantholysis is not a feature of LAD, which points away from this diagnosis. *Dermatitis herpetiformis* - This condition typically presents with intensely **pruritic vesicles and papules**, primarily on extensor surfaces (e.g., elbows, knees, buttocks), and is strongly associated with **celiac disease**. - Histopathology reveals **subepidermal vesicles with neutrophils** at the dermal papillae, and **granular IgA deposits** in the dermal papillae, which is different from the described intraepidermal blistering. *Bullous pemphigoid* - Bullous pemphigoid is characterized by **tense bullae** on an erythematous or urticarial base, typically affecting the **flexural surfaces** and trunk in elderly patients. - Histopathologically, it shows **subepidermal blistering** with a linear deposition of IgG and C3 along the basement membrane zone, which differs from the intraepidermal acantholysis seen in this patient.

Question 96: A 32-year-old man comes to the physician because of a 3-week history of cough, weight loss, and night sweats. He migrated from Sri Lanka 6 months ago. He appears emaciated. His temperature is 38.1°C (100.5°F). Physical examination shows enlargement of the right supraclavicular lymph node. Chest and abdominal examination show no abnormalities. An interferon-gamma assay is positive. A biopsy specimen of the cervical lymph node is most likely to show the causal organism in which of the following locations?

A. Mantle zone
B. Medullary sinus
C. Germinal center
D. Subcapsular sinus
E. Paracortex (Correct Answer)

Explanation: ***Paracortex*** - The patient's symptoms (cough, weight loss, night sweats, fever), recent migration from an endemic area (Sri Lanka), **supraclavicular lymphadenopathy**, and positive **interferon-gamma release assay (IGRA)** strongly suggest **tuberculosis**. - In tuberculous lymphadenitis, **caseating granulomas** containing *Mycobacterium tuberculosis* organisms characteristically form in the **paracortex** (T-cell zone). - The **paracortex** is where **cell-mediated immunity** occurs, with T cells interacting with infected macrophages and dendritic cells to form the **epithelioid granulomas** with **Langhans giant cells** that are pathognomonic for TB. - The organisms are found within these **granulomas**, which predominantly occur in the paracortical (interfollicular) region. *Mantle zone* - The **mantle zone** primarily contains **naïve B cells** surrounding germinal centers. - This is a B-cell area not typically involved in granuloma formation or mycobacterial infection. *Germinal center* - **Germinal centers** are sites of B cell proliferation, somatic hypermutation, and antibody class switching. - TB is a disease of **cell-mediated immunity** (T cells and macrophages), not humoral immunity, so granulomas do not form in germinal centers. *Medullary sinus* - The **medullary sinuses** are channels in the medulla of the lymph node through which lymph flows toward the efferent lymphatic vessels. - While macrophages line these sinuses and may contain some organisms in acute infections, the characteristic **caseating granulomas** of chronic tuberculous lymphadenitis form in the **paracortex**, not in the sinuses. *Subcapsular sinus* - The **subcapsular sinus** is the initial entry point for afferent lymph into the lymph node. - While this is where pathogens first enter, chronic granulomatous infections like TB develop their characteristic pathology deeper in the node, specifically in the **paracortex** where T-cell-mediated granuloma formation occurs.

Question 97: A 43-year-old man presents to the emergency department following a work-related accident in which both arms were amputated. The patient lost a substantial amount of blood prior to arrival, and his bleeding is difficult to control due to arterial damage and wound contamination with debris. His complete blood count (CBC) is significant for a hemoglobin (Hgb) level of 5.3 g/dL. The trauma surgery resident initiates the massive transfusion protocol and orders whole blood, O negative, which she explains is the universal donor. The patient receives 6 units of O negative blood prior to admission. He subsequently develops fever, chills, hematuria, and pulmonary edema. Several hours later, the patient goes into hemodynamic shock requiring the emergent administration of vasopressors. Of the following options, which hypersensitivity reaction occurred?

A. Type 1 hypersensitivity reaction
B. Combined type 1 and type 4 hypersensitivity reaction
C. Type 3 hypersensitivity reaction
D. Type 2 hypersensitivity reaction (Correct Answer)
E. Type 4 hypersensitivity reaction

Explanation: ***Type 2 hypersensitivity reaction*** - This scenario describes an **acute hemolytic transfusion reaction (AHTR)**, a classic example of a **Type II hypersensitivity reaction**. The recipient's antibodies (IgM) recognize and bind to antigens on the transfused red blood cells, leading to their destruction (hemolysis) via complement activation and cellular mechanisms. - Symptoms like **fever, chills, hematuria (due to hemoglobinuria)**, and subsequent **shock** are characteristic of AHTR, even with O negative blood if other minor blood group antigens (e.g., Kell, Duffy) are incompatible or if the patient developed antibodies against these from previous transfusions or pregnancies. *Type 1 hypersensitivity reaction* - This type involves **IgE-mediated mast cell degranulation** and is associated with allergic reactions such as anaphylaxis, asthma, and hives. - While anaphylaxis can cause shock, the systemic symptoms of **hemolysis and hematuria** are not characteristic of a Type 1 reaction. *Combined type 1 and type 4 hypersensitivity reaction* - This combination is uncommon in an acute transfusion setting and does not align with the presented symptoms. - Type 1 is immediate allergic, and Type 4 is delayed cell-mediated, neither fully explaining the hemolytic features observed. *Type 3 hypersensitivity reaction* - This reaction involves the formation of **immune complexes** (antigen-antibody complexes) that deposit in tissues, leading to inflammation and damage (e.g., serum sickness, lupus nephritis). - While immune complexes can cause systemic symptoms, the prominent hemolytic features and immediate presentation of a transfusion reaction are more indicative of Type 2. *Type 4 hypersensitivity reaction* - This is a **delayed type hypersensitivity** reaction mediated by **T cells**, taking 24-72 hours or longer to develop (e.g., contact dermatitis, tuberculin skin test). - The acute onset of symptoms following transfusion makes a Type 4 reaction highly unlikely.

Question 98: A 37-year-old man presents to an urgent care clinic with complaints of speech problems and yellowing of his eyes for a week. He admits to using illicit intravenous drugs. His vital signs include: blood pressure 110/60 mm Hg, pulse rate 78/min, and respiratory rate 22/min. On examination, the patient appears jaundiced, and his speech is slurred. His liver enzymes and viral markers are as follows: Aspartate aminotransferase 6,700 IU/L Alanine aminotransferase 5,000 IU/L HBsAg Negative Anti-HBs Negative Anti-HCV Ab Positive HCV RNA Positive If this patient develops chronic hepatitis C infection, he is at risk of developing a secondary dermatological condition. A biopsy of this skin condition would most likely show which of the following findings?

A. Intraepithelial cleavage with acantholysis
B. Noncaseating granulomas
C. Microabscesses with fibrin and neutrophils
D. Crypt abscesses containing neutrophils
E. Lymphocytic infiltrate at the dermal-epidermal junction (Correct Answer)

Explanation: ***Lymphocytic infiltrate at the dermal-epidermal junction*** - Chronic hepatitis C infection is strongly associated with **lichen planus**, a dermatological condition characterized histologically by a **lymphocytic infiltrate along the dermal-epidermal junction**, often described as a "sawtooth" pattern. - The history of IV drug use, jaundiced eyes, elevated liver enzymes, and positive HCV RNA confirm a diagnosis of **acute hepatitis C**, which can progress to chronic infection and lead to extrahepatic manifestations like lichen planus. *Intraepithelial cleavage with acantholysis* - This finding is characteristic of **pemphigus vulgaris**, an autoimmune blistering disorder where antibodies target desmoglein 3, leading to loss of cohesion between keratinocytes. - Pemphigus vulgaris is not typically associated with chronic hepatitis C infection. *Noncaseating granulomas* - **Noncaseating granulomas** are the hallmark histological feature of **sarcoidosis** and Crohn's disease. - While sarcoidosis can have cutaneous manifestations, it is not directly linked to chronic hepatitis C in the way lichen planus is. *Microabscesses with fibrin and neutrophils* - This description aligns with findings in conditions such as **dermatitis herpetiformis** (neutrophilic infiltrates in dermal papillae) or acute neutrophilic dermatoses, but it is not the characteristic feature of skin conditions directly associated with chronic hepatitis C. - Skin conditions like vasculitis can also show neutrophilic infiltrates, but the primary association with HCV and the provided options points away from this. *Crypt abscesses containing neutrophils* - **Crypt abscesses** are histological features typically found in the intestinal lining in conditions like **ulcerative colitis**, an inflammatory bowel disease. - This finding is not relevant to dermatological conditions associated with chronic hepatitis C.

Question 99: A 36-year-old man comes to the physician for a 4-week history of swollen legs. He has difficulty putting on socks because of the swelling. Two years ago, he was diagnosed with sleep apnea. He takes no medications. He emigrated from Guatemala with his family when he was a child. He is 171 cm (5 ft 6 in) tall and weighs 115 kg (253 lb); BMI is 39 kg/m2. His pulse is 91/min and blood pressure is 135/82 mm Hg. Examination shows periorbital and bilateral lower extremity edema. Serum Albumin 3.1 g/dL Total cholesterol 312 mg/dL Urine Blood negative Protein +4 RBC 1-2/hpf RBC cast negative Fatty casts numerous A renal biopsy is obtained. Which of the following is most likely to be seen under light microscopy of the patient's renal biopsy specimen?

A. Diffuse thickening of glomerular capillaries
B. Amyloid deposition in the mesangium
C. Eosinophilic nodules within the glomeruli
D. Fibrin crescents within the glomerular space
E. Segmental sclerosis of the glomeruli (Correct Answer)

Explanation: ***Segmental sclerosis of the glomeruli*** - The patient presents with **nephrotic syndrome** (edema, proteinuria, hypoalbuminemia, hypercholesterolemia) and **obesity** (BMI 39 kg/m2), which are strong risk factors for **focal segmental glomerulosclerosis (FSGS)**. - **FSGS** is characterized by **segmental sclerosis** within some glomeruli, often affecting juxtamedullary glomeruli initially. *Diffuse thickening of glomerular capillaries* - **Diffuse thickening of glomerular capillaries** (due to subepithelial immune complex deposition causing SPIKES on silver stain) is characteristic of **membranous nephropathy**, which typically presents with nephrotic syndrome but is not directly linked to obesity in the way FSGS is. - While membranous nephropathy could cause nephrotic syndrome, the association with **morbid obesity** makes FSGS a stronger consideration. *Amyloid deposition in the mesangium* - **Amyloid deposition** typically presents with nephrotic syndrome and is associated with chronic inflammatory conditions or plasma cell dyscrasias, not primarily with obesity or the specific presentation described. - On light microscopy, amyloid appears as **acellular, eosinophilic congophilic deposits** in the mesangium and capillary walls, showing apple-green birefringence under polarized light, which is not suggested by the clinical picture. *Eosinophilic nodules within the glomeruli* - **Eosinophilic nodules within the glomeruli** (Kimmelstiel-Wilson lesions) are characteristic of **diabetic nephropathy**, which commonly causes nephrotic syndrome. - While the patient is obese, there is no information about diabetes or hyperglycemia to suggest diabetic nephropathy as the primary cause. *Fibrin crescents within the glomerular space* - **Fibrin crescents within the glomerular space** are indicative of **rapidly progressive glomerulonephritis (RPGN)**, which typically presents as nephritic syndrome (hematuria, hypertension, azotemia) rather than pure nephrotic syndrome. - The patient's urine microscopic findings show only 1-2 RBC/hpf and no RBC casts, making RPGN unlikely.

Question 100: A 15-year-old African American boy presents to a pediatrician with complaints of yellow discoloration of the sclerae for the last 3 days. His mother informs the pediatrician that the boy developed prolonged jaundice during the neonatal period. On physical examination, vital signs are stable and general examination shows mild icterus and pallor. Examination of the abdomen suggests mild splenomegaly. Laboratory results are as follows: Hemoglobin 9.9 g/dL Total leukocyte count 7,500/mm3 Platelet count 320,000/mm3 Reticulocyte count 5% Mean corpuscular hemoglobin 27.7 pg/cell Mean corpuscular hemoglobin concentration 32% g/dL Mean corpuscular volume 84 μm3 Serum total bilirubin 4.2 mg/dL Serum direct bilirubin 0.3 mg/dL Coombs test Negative Peripheral smear shows polychromasia, blister cells, and Heinz bodies. An abdominal ultrasonogram shows the presence of gallstones. Which of the following tests is most likely to be useful in diagnosing this patient?

A. Hepatoiminodiacetic acid scanning
B. Serum thyroxine, triiodothyronine, and thyroid-stimulating hormone
C. Methemoglobin reduction test
D. Serum lipoprotein-X level
E. G6PD enzyme assay (Correct Answer)

Explanation: ***Correct: G6PD enzyme assay*** - The clinical presentation (jaundice, pallor, splenomegaly, gallstones, neonatal jaundice history) along with laboratory findings (anemia, elevated reticulocyte count, indirect hyperbilirubinemia, negative Coombs test, **polychromasia**, **blister cells**, and **Heinz bodies** on peripheral smear) strongly suggests **glucose-6-phosphate dehydrogenase (G6PD) deficiency**. - **Heinz bodies** (denatured hemoglobin precipitates) and **blister cells** (bite cells from splenic removal of Heinz bodies) are **pathognomonic** for oxidative hemolysis due to G6PD deficiency. - The **G6PD enzyme assay** is the **gold standard diagnostic test** that directly measures G6PD enzyme activity in red blood cells, confirming the diagnosis. - Note: Testing should ideally be done after the acute hemolytic episode resolves, as reticulocytes (which have higher G6PD levels) may give falsely normal results during active hemolysis. *Incorrect: Methemoglobin reduction test* - This test assesses the ability of red blood cells to reduce methemoglobin and is used to diagnose **methemoglobinemia** or defects in the methemoglobin reductase system. - While G6PD deficiency can theoretically affect methemoglobin reduction (both require NADPH), this is **not** the standard or recommended diagnostic test for G6PD deficiency. *Incorrect: Hepatoiminodiacetic acid scanning* - This scan (HIDA scan) evaluates **gallbladder function** and patency of the **biliary tree**, primarily for diagnosing acute cholecystitis or biliary obstruction. - While the patient has gallstones (a complication of chronic hemolysis due to bilirubin pigment stones), the primary diagnostic need is to identify the underlying cause of hemolytic anemia. *Incorrect: Serum thyroxine, triiodothyronine, and thyroid-stimulating hormone* - These tests assess **thyroid function** and diagnose thyroid disorders. - The patient's symptoms and laboratory results (hemolytic anemia with characteristic peripheral smear findings) clearly point to a hematologic disorder, not a thyroid condition. *Incorrect: Serum lipoprotein-X level* - **Lipoprotein-X** is an abnormal lipoprotein elevated in **cholestatic** conditions and is associated with **target cells** on peripheral smear. - This patient has **indirect (unconjugated) hyperbilirubinemia** (total 4.2 mg/dL, direct 0.3 mg/dL), indicating hemolysis rather than cholestasis, and the peripheral smear shows blister cells and Heinz bodies, not target cells.

Question 101: A 38-year-old woman presents to a physician’s office for progressive weakness and pallor during the last few weeks. She also complains of shortness of breath during her yoga class. She denies fevers, cough, rhinorrhea, or changes in appetite or bowel and bladder habits. She is generally healthy except for an occasional migraine, which is relieved by acetaminophen. For the last month, she has been having more frequent migraine attacks and was started on prophylactic aspirin. The vital signs include: pulse 102/min, respirations 18/min, and blood pressure 130/84 mm Hg. Her blood pressure on previous visits has been 110/76 mm Hg, 120/78 mm Hg, and 114/80 mm Hg. The physical examination is otherwise unremarkable. Stool for occult blood is positive. In addition to a low hemoglobin concentration, which other laboratory finding is expected in this patient?

A. Prolonged prothrombin time (PT)
B. Decreased platelet count
C. Prolonged activated partial thromboplastin time (aPTT)
D. Elevated D-dimer
E. Prolonged bleeding time (Correct Answer)

Explanation: ***Prolonged bleeding time*** - The patient's symptoms (weakness, pallor, shortness of breath, positive stool occult blood) suggest **gastrointestinal bleeding** leading to **iron deficiency anemia**. - **Aspirin** use can impair platelet function by irreversibly inhibiting **cyclooxygenase-1 (COX-1)**, leading to a prolonged bleeding time. *Prolonged prothrombin time (PT)* - **PT** measures the extrinsic and common pathways of coagulation and is prolonged in deficiencies of factors VII, X, V, II, or fibrinogen, or with **warfarin use**. - There is no clinical information suggesting a vitamin K deficiency or liver disease that would prolong PT. *Decreased platelet count* - The patient's presentation does not suggest **thrombocytopenia**, which would be indicated by spontaneous bleeding, petechiae, or purpura. - While aspirin affects platelet function, it does not typically decrease the **platelet count**. *Prolonged activated partial thromboplastin time (aPTT)* - **aPTT** measures the intrinsic and common pathways of coagulation and is prolonged in deficiencies of factors XII, XI, IX, VIII, X, V, II, fibrinogen, or with **heparin use**. - There are no indications of these conditions or **heparin** administration in the patient's history. *Elevated D-dimer* - An **elevated D-dimer** indicates recent or ongoing fibrinolysis, often seen in conditions like deep vein thrombosis, pulmonary embolism, or **disseminated intravascular coagulation (DIC)**. - The patient's symptoms are characteristic of chronic blood loss and anemia, not a thrombotic or hypercoagulable state.

Question 102: A 72-year-old nursing home resident is complaining of pruritis. She is noted to have multiple, tense blisters on her trunk as well as the flexor surfaces of her extremities. The blisters have an erythematous base. You are unable to extend the blisters when you apply lateral traction. You suspect an autoimmune bullous dermatosis. Which of the following is the cause of the likely condition?

A. Antibodies to epidermal transglutaminase
B. Epidermal necrolysis
C. Antibodies to hemidesmosomes (Correct Answer)
D. Antibodies to desmoglein
E. Antibodies to desmosomes

Explanation: **Antibodies to hemidesmosomes** - The patient's presentation with **tense blisters** that do not extend with lateral traction (negative Nikolsky sign) is classic for **bullous pemphigoid**. - **Bullous pemphigoid** is an autoimmune disease caused by antibodies targeting components of the **hemidesmosomes** (specifically BP180 and BP230) at the dermal-epidermal junction. *Antibodies to epidermal transglutaminase* - Antibodies against **epidermal transglutaminase** are characteristic of **dermatitis herpetiformis**, which presents with intensely pruritic, grouped vesicles and papules, often on extensor surfaces. - This condition is also associated with **celiac disease**, and its classic lesions are small and vesicular, not the large, tense bullae described. *Epidermal necrolysis* - **Epidermal necrolysis**, including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), is characterized by widespread epidermal detachment and necrosis, often triggered by medications. - It presents with diffuse painful erythema and sheet-like skin loss, which is distinctly different from the described tense blisters of bullous pemphigoid. *Antibodies to desmoglein* - Antibodies to **desmoglein 1 and/or 3** (components of desmosomes) are the hallmark of **pemphigus vulgaris** and **pemphigus foliaceus**. - These conditions cause **flaccid blisters** that are easily ruptured and often exhibit a positive Nikolsky sign, contrary to the tense blisters in this case. *Antibodies to desmosomes* - Antibodies to **desmosomes** (specifically desmogleins) lead to **pemphigus**, which is characterized by intraepidermal blistering and a positive Nikolsky sign. - The described **tense blisters** and negative Nikolsky sign rule out pemphigus, where the defect is in keratinocyte adhesion within the epidermis.

Question 103: A 53-year-old woman presents to the emergency room with severe chest pain radiating to the back. She was diagnosed with acute aortic dissection. A few hours into the resuscitation, she was having oliguria. Laboratory findings show a serum creatinine level of 5.3 mg/dL. Which of the following casts are most likely to be seen on urinalysis?

A. RBC casts
B. Fatty casts
C. Muddy brown casts (Correct Answer)
D. Waxy casts
E. Hyaline casts

Explanation: ***Muddy brown casts*** - **Acute tubular necrosis (ATN)**, likely caused by **renal hypoperfusion** in the context of an aortic dissection, is characterized by the presence of **muddy brown granular casts** in urinalysis. The significantly elevated **creatinine (5.3 mg/dL)** and **oliguria** support a diagnosis of acute kidney injury with ATN. - These casts are pathognomonic for ATN and are formed from shed **epithelial cells** and debris accumulating in the renal tubules. *RBC casts* - **Red blood cell (RBC) casts** are indicative of **glomerulonephritis** or other causes of **glomerular injury**, which are not directly suggested by the presentation of aortic dissection and subsequent oliguria. - While hematuria can occur in various renal conditions, the presence of **RBC casts** points to bleeding originating from the glomerulus, which is a different pathology than ATN. *Fatty casts* - **Fatty casts** are typically associated with **nephrotic syndrome**, a condition characterized by significant proteinuria, hypoalbuminemia, and edema. - There is no clinical information to suggest nephrotic syndrome in this patient, whose acute renal failure is likely due to hypoperfusion. *Waxy casts* - **Waxy casts** are generally indicative of **chronic kidney disease** and highly advanced, severe tubular damage, representing a later stage of kidney injury. - While the patient has acute kidney injury, the timeline and acute nature of the insult make muddy brown casts more likely than waxy casts. *Hyaline casts* - **Hyaline casts** are composed primarily of Tamm-Horsfall mucoprotein, a normal protein secreted by renal tubule cells. - These casts can be seen in normal urine, especially after exercise or dehydration, and are not specific for any particular kidney pathology or acute kidney injury.

Question 104: A 9-year-old boy is brought to the emergency department by his parents with a 2-day history of weakness and joint pain. He was adopted 3 weeks ago from an international adoption agency and this is his first week in the United States. He says that he has been healthy and that he had an episode of sore throat shortly before his adoption. Physical exam reveals an ill-appearing boy with a fever, widespread flat red rash, and multiple subcutaneous nodules. The type of hypersensitivity seen in this patient's disease is also characteristic of which of the following diseases?

A. Contact dermatitis
B. Serum sickness
C. Asthma
D. Goodpasture syndrome (Correct Answer)
E. Osteogenesis imperfecta

Explanation: ***Goodpasture syndrome*** - The patient's presentation with a recent **sore throat**, **fever**, **widespread rash**, **joint pain**, and **subcutaneous nodules** is highly suggestive of **rheumatic fever**. - **Rheumatic fever** is a **Type II hypersensitivity reaction** where antibodies against streptococcal antigens cross-react with host tissues, a mechanism also seen in **Goodpasture syndrome** where antibodies target basement membranes in the kidneys and lungs. *Contact dermatitis* - This is a **Type IV hypersensitivity reaction**, mediated by T-cells upon re-exposure to an allergen. - It presents as a localized, eczematous rash and is not characterized by systemic symptoms like fever, joint pain, or subcutaneous nodules. *Serum sickness* - This is a **Type III hypersensitivity reaction** involving immune complex deposition, often occurring 7-14 days after exposure to certain drugs or foreign proteins. - While it can manifest with fever, rash, and joint pain, the formation of **subcutaneous nodules** and the typical progression following a **strep throat** episode are more indicative of rheumatic fever. *Asthma* - Asthma is primarily a **Type I hypersensitivity reaction**, characterized by IgE-mediated mast cell degranulation and bronchoconstriction. - It presents with respiratory symptoms like wheezing and shortness of breath, not directly related to joint pain, rash, or subcutaneous nodules seen here. *Osteogenesis imperfecta* - This is a **genetic disorder** affecting collagen production, leading to brittle bones and other connective tissue abnormalities. - It is not a hypersensitivity reaction and does not present with acute symptoms like fever, rash, or joint pain; rather, it is a congenital condition.

Question 105: A 73-year-old man presents to his primary care doctor with his son who reports that his father has been acting strangely. He has started staring into space throughout the day and has a limited attention span. He has been found talking to people who are not present and has gotten lost while driving twice. He has occasional urinary incontinence. His past medical history is notable for a stroke 5 years ago with residual right arm weakness, diabetes, hypertension, and hyperlipidemia. He takes aspirin, glyburide, metformin, lisinopril, hydrochlorothiazide, and atorvastatin. On examination, he is oriented to person and place but thinks the year is 1989. He is inattentive throughout the exam. He takes short steps while walking. His movements are grossly slowed. A brain biopsy in this patient would most likely reveal which of the following?

A. Large intracellular vacuoles within a spongiform cortex
B. Intracellular round aggregates of hyperphosphorylated microtubule-associated protein
C. Marked diffuse cortical atherosclerosis
D. Eosinophilic intracytoplasmic inclusions (Correct Answer)
E. Extracellular amyloid plaques

Explanation: **Eosinophilic intracytoplasmic inclusions** * The constellation of **fluctuating cognitive impairment**, **visual hallucinations** (talking to people not present), and **parkinsonian features** (slowed movements, short steps) are highly characteristic of **dementia with Lewy bodies (DLB)**. * Brain biopsies in DLB reveal **Lewy bodies**, which are **eosinophilic intracytoplasmic aggregates of alpha-synuclein**. *Large intracellular vacuoles within a spongiform cortex* * This description is characteristic of **spongiform encephalopathy**, such as **Creutzfeldt-Jakob disease**. * CJD presents with rapidly progressive dementia, myoclonus, and ataxia, which are not the primary features in this patient. *Intracellular round aggregates of hyperphosphorylated microtubule-associated protein* * This describes **neurofibrillary tangles**, primarily composed of **hyperphosphorylated tau protein**, which are a hallmark of **Alzheimer's disease**. * While Alzheimer's involves memory loss and cognitive decline, the prominent visual hallucinations and parkinsonism are more suggestive of DLB. *Marked diffuse cortical atherosclerosis* * While the patient has a history of stroke and vascular risk factors, **diffuse cortical atherosclerosis** is a pathological finding associated with **vascular dementia**. * Vascular dementia typically presents with a stepwise decline in cognitive function and focal neurological deficits, but the prominent hallucinations and parkinsonism point away from a primary diagnosis of vascular dementia alone. *Extracellular amyloid plaques* * These are **beta-amyloid plaques**, another key pathological feature of **Alzheimer's disease**. * While patients with DLB can sometimes have co-existing Alzheimer's pathology, the primary and most defining characteristic of DLB are the Lewy bodies.

Question 106: A 4-year-old girl is brought to the physician because of increasing swelling around her eyes and over both her feet for the past 4 days. During this period, she has had frothy light yellow urine. Her vital signs are within normal limits. Physical examination shows periorbital edema and 2+ pitting edema of the lower legs and ankles. A urinalysis of this patient is most likely to show which of the following findings?

A. Fatty casts (Correct Answer)
B. Epithelial casts
C. WBC casts
D. Waxy casts
E. Muddy brown casts

Explanation: ***Fatty casts*** - The presence of **periorbital edema**, **pitting edema** of the lower legs and ankles, and **frothy urine** in a child is highly suggestive of **nephrotic syndrome**. - **Fatty casts** are formed when lipid-laden renal tubular epithelial cells (oval fat bodies) aggregate and are expelled into the urine, and are characteristically associated with **nephrotic syndrome** due to massive proteinuria and lipiduria. - Among the cast types listed, fatty casts are the most specific finding for nephrotic syndrome. *Epithelial casts* - **Epithelial cell casts** indicate **acute tubular necrosis (ATN)** or other conditions involving damage to the renal tubular epithelium. - While ATN can cause edema, the clinical presentation here (frothy urine, periorbital edema, absence of oliguria or acute kidney injury) is more classic for nephrotic syndrome. *WBC casts* - **White blood cell (WBC) casts** are indicative of **renal parenchymal inflammation** or **infection**, such as pyelonephritis or interstitial nephritis. - The patient's symptoms do not suggest infection, and there is no mention of fever, dysuria, or flank pain. *Waxy casts* - **Waxy casts** typically indicate **chronic kidney disease** and advanced renal failure, representing severe urinary stasis and dilated, damaged tubules. - The acute onset of symptoms (4 days) in a 4-year-old child makes chronic kidney disease less likely as the primary diagnosis. *Muddy brown casts* - **Muddy brown casts** are pathognomonic for **acute tubular necrosis (ATN)**, often seen in cases of ischemia or nephrotoxic injury. - While ATN is a severe renal injury, the patient's presentation with frothy urine and prominent edema without signs of acute kidney injury points more specifically to nephrotic syndrome.

Question 107: A 31-year-old woman presents to her primary care provider to discuss the results from a previous urine analysis. She has no new complaints and feels well. Past medical history is significant for systemic lupus erythematosus. She was diagnosed 5 years ago and takes hydroxychloroquine every day and prednisone when her condition flares. Her previous urine analysis shows elevated protein levels (4+) and blood (3+). The urine sediment contained red blood cells (6 RBCs/high-power field). The treating physician would like to perform a renal biopsy to rule out lupus nephritis. What type of hypersensitivity is suggestive of lupus nephritis?

A. Type IV, mediated by IgG and IgM antibodies
B. Type IV, mediated by CD4+ T cells
C. Type III, mediated by IgG antibodies (Correct Answer)
D. Type I, mediated by IgE antibodies
E. Type II, mediated by IgG and IgM antibodies

Explanation: ***Type III, mediated by IgG antibodies*** - Lupus nephritis is a classic example of a **Type III hypersensitivity reaction**, characterized by the formation of **immune complexes** (combinations of antibodies and antigens) in the circulation. - These circulating **autoantibody-antigen complexes** deposit in the glomeruli of the kidneys, activating complement and initiating an inflammatory response that damages renal tissue. *Type IV, mediated by IgG and IgM antibodies* - **Type IV hypersensitivity** is a **delayed-type reaction** mediated by T cells, not antibodies. - IgG and IgM antibodies are involved in Type II and Type III hypersensitivity, not Type IV. *Type IV, mediated by CD4+ T cells* - While **Type IV hypersensitivity** is indeed mediated by **CD4+ T cells** (and CD8+ T cells), lupus nephritis is primarily an **immune complex-mediated (Type III)** disease. - T cells do play a role in the pathogenesis of SLE, but the direct kidney damage in lupus nephritis is driven by antibody-antigen complex deposition. *Type I, mediated by IgE antibodies* - **Type I hypersensitivity** is an **immediate allergic reaction** mediated by **IgE antibodies** binding to mast cells and basophils, leading to histamine release. - This type of reaction is responsible for conditions like asthma, allergies, and anaphylaxis, and is not involved in lupus nephritis. *Type II, mediated by IgG and IgM antibodies* - **Type II hypersensitivity** involves **antibodies directly targeting antigens on cell surfaces or extracellular matrix components**, leading to cell lysis or dysfunction. - While IgG and IgM are involved, the defining feature is direct binding to fixed tissue antigens rather than deposition of circulating immune complexes as seen in lupus nephritis.

Question 108: A 65-year-old patient presents with rapidly progressive dementia, myoclonus, and ataxia over 3 months. Laboratory studies, including serum vitamin B12 (cyanocobalamin), thyroxine (T4), and thyroid-stimulating hormone concentrations, are within normal limits. A lumbar puncture is performed. Cerebrospinal fluid (CSF) analysis is most likely to show which of the following?

A. Increased 14-3-3 protein concentration (Correct Answer)
B. Antiganglioside GM1 antibodies
C. Anti-glutamic acid decarboxylase antibodies
D. Increased α-synuclein protein concentration
E. Oligoclonal bands

Explanation: ***Increased 14-3-3 protein concentration*** - The constellation of **rapidly progressive dementia**, **myoclonus**, and **ataxia** over 3 months with normal routine labs is highly suggestive of **Creutzfeldt-Jakob disease (CJD)**. - An **elevated 14-3-3 protein concentration** in the CSF is a **classic diagnostic marker** for CJD, reflecting rapid neuronal destruction and included in the **WHO diagnostic criteria**. - This is the most characteristic CSF finding in CJD, with high sensitivity and specificity. *Oligoclonal bands* - **Oligoclonal bands** are indicative of intrathecal antibody production and are characteristic of **inflammatory or demyelinating conditions** such as **multiple sclerosis** and **CNS infections**. - They are **NOT typically found in prion diseases** like CJD, which involve protein misfolding rather than immune-mediated inflammation. *Increased α-synuclein protein concentration* - **Alpha-synuclein accumulation** is characteristic of **synucleinopathies** such as Parkinson's disease, Lewy body dementia, and multiple system atrophy. - While these can involve dementia and motor symptoms, they typically have a **slower progression** and different symptom profile than the rapid course seen in CJD. *Antiganglioside GM1 antibodies* - **Anti-ganglioside GM1 antibodies** are primarily associated with autoimmune **motor neuropathies**, particularly **multifocal motor neuropathy** and some forms of Guillain-Barré syndrome. - They are not typically associated with rapidly progressive dementia or CJD. *Anti-glutamic acid decarboxylase antibodies* - **Anti-glutamic acid decarboxylase (GAD) antibodies** are primarily associated with **stiff-person syndrome** and certain types of **autoimmune encephalitis**. - While these conditions can present with neurological symptoms, the clinical picture of rapidly progressive dementia with myoclonus and ataxia is not typical for GAD antibody-mediated disorders.

Question 109: A 17-year-old boy is brought to the physician because of a sore throat, nonproductive cough, and bloody urine for 3 days. He has had 2 similar episodes involving a sore throat and bloody urine over the past year. His sister has systemic lupus erythematosus. His temperature is 38.1°C (100.6°F). Serum studies show a urea nitrogen concentration of 8 mg/dL and a creatinine concentration of 1.4 mg/dL. Urinalysis shows acanthocytes and red blood cell casts. Renal ultrasonography shows no abnormalities. A renal biopsy is most likely to show which of the following findings?

A. Capillary wire looping
B. IgA mesangial deposition (Correct Answer)
C. Splitting of the glomerular basement membrane
D. Effacement of the foot processes
E. Granular deposits of IgG, IgM, and C3 complement

Explanation: ***IgA mesangial deposition*** - The patient's history of recurrent gross **hematuria** following pharyngitis, presence of **acanthocytes** and **RBC casts** in urine, and mild renal impairment with normal renal ultrasound strongly suggest **IgA nephropathy (Berger's disease)**. - **IgA nephropathy** is characterized by the deposition of **IgA immune complexes** in the **glomerular mesangium**, which is the hallmark finding on renal biopsy. *Capillary wire looping* - This finding is characteristic of **diffuse proliferative glomerulonephritis**, often associated with **lupus nephritis class IV**, a severe manifestation of **systemic lupus erythematosus (SLE)**. - While the patient's sister has SLE, his clinical presentation of recurrent hematuria linked to pharyngitis makes IgA nephropathy more likely than lupus nephritis in this individual. *Splitting of the glomerular basement membrane* - This is a classic finding in **Alport syndrome**, an inherited disorder characterized by progressive kidney disease, hearing loss, and ocular abnormalities. - While Alport syndrome can cause recurrent hematuria, the history of episodes following pharyngitis and the family history of SLE (rather than Alport) make it less probable. *Effacement of the foot processes* - **Effacement of foot processes (podocytes)** is a characteristic feature of **minimal change disease** and **focal segmental glomerulosclerosis (FSGS)**, which typically present with **nephrotic syndrome** (heavy proteinuria, edema) rather than isolated recurrent gross hematuria. - This patient's symptoms are more indicative of a nephritic rather than nephrotic process. *Granular deposits of IgG, IgM, and C3 complement* - Widespread granular deposits of IgG, IgM, and C3 are typical of **post-streptococcal glomerulonephritis (PSGN)**, which usually presents 1-3 weeks after a **streptococcal infection**. - While PSGN can cause hematuria, the recurrent nature of his symptoms over a year and rapid onset after pharyngitis are less typical for PSGN, which is usually a single, self-limited episode.

Question 110: A 29-year-old GP10 woman at 24 weeks estimated gestational age presents for follow-up. Six weeks ago, a complete blood count showed a microcytic hypochromic anemia for which she was prescribed iron sulfate tablets. A repeat complete blood count today shows no improvement in her hemoglobin level. Past medical history is significant for her being Rh-positive with an Rh-negative partner. She emigrated to the United States with her husband 7 years ago and did not have regular medical care in her country. An abdominal ultrasound shows findings consistent with hydrops fetalis. Which of the following is the most likely etiology of the condition of her fetus?

A. Deletion of 4 alpha-globin genes (Correct Answer)
B. Impaired synthesis of beta-globin chains
C. Pyruvate kinase deficiency
D. Parvovirus infection
E. Rh incompatibility

Explanation: ***Deletion of 4 alpha-globin genes*** - This condition (Hemoglobin Barts hydrops fetalis, alpha-thalassemia major) leads to a complete absence of **alpha-globin chains**, resulting in the formation of **Hb Barts** (tetramers of gamma-globin). - Hb Barts has an extremely high affinity for oxygen, preventing its release to tissues, leading to severe fetal hypoxia, profound anemia, and ultimately **hydrops fetalis**. The patient's microcytic hypochromic anemia unresponsive to iron, combined with her ethnicity (immigrated from a high-prevalence area), suggests an underlying thalassemia. *Impaired synthesis of beta-globin chains* - This describes **beta-thalassemia**, which typically causes anemia but usually does not manifest as **hydrops fetalis** in utero because beta-globin chains only become dominant after birth. - While beta-thalassemia can cause severe anemia, the characteristic in-utero presentation of hydrops fetalis points away from this diagnosis. *Pyruvate kinase deficiency* - This is an **autosomal recessive** disorder affecting glycolysis in red blood cells, leading to **hemolytic anemia**. - While it can cause anemia, it is a rare cause of **hydrops fetalis**, which is more commonly associated with severe hemoglobinopathies or infections. *Parvovirus infection* - **Parvovirus B19** can cause severe anemia in the fetus by directly infecting and destroying erythroid progenitor cells, which can lead to **hydrops fetalis**. - However, the mother's persistent **microcytic hypochromic anemia** unresponsive to iron suggests a chronic underlying genetic hematologic disorder rather than an acute viral infection. *Rh incompatibility* - This occurs when an **Rh-negative mother** is exposed to **Rh-positive fetal blood**, leading to alloimmunization and hemolytic disease of the fetus and newborn. - The patient is stated to be **Rh-positive**, making Rh incompatibility with an Rh-negative partner impossible as she would not produce antibodies against Rh-positive blood cells.

Question 111: A 25-year-old female with no significant past medical history presents to her primary care physician with several weeks of increased fatigue and decreased exercise tolerance. On physical exam, her skin and conjunctiva appear pale. The physician suspects some form of anemia and orders a complete blood panel, which is remarkable for hemoglobin 11.7 g/dl, MCV 79 fL, MCHC 38% (normal 31.1-34%), and reticulocyte index 3.6%. Peripheral blood smear shows red blood cells with a lack of central pallor. This patient would most likely develop which of the following conditions?

A. Stroke
B. Gallstones (Correct Answer)
C. Retinopathy
D. Avascular necrosis of the femoral head
E. Aplastic anemia with parvovirus B19 infection

Explanation: ***Gallstones*** - The patient's presentation with **anemia**, **low MCV**, **high MCHC**, and **reticulocyte index > 2%** suggests a **hemolytic anemia**, likely **hereditary spherocytosis** given the lack of central pallor (spherocytes). - Chronic hemolysis leads to **unconjugated hyperbilirubinemia**, which predisposes to the formation of **pigment (bilirubin) gallstones**. - Gallstones occur in approximately **50-85%** of adults with hereditary spherocytosis, making this the **most common chronic complication**. *Stroke* - While some hemolytic anemias can be associated with increased stroke risk (e.g., **sickle cell anemia**), this specific presentation with **spherocytes** and **high MCHC** does not directly confer a high risk of stroke. - Stroke is not a primary or highly frequent complication of **hereditary spherocytosis**. *Retinopathy* - **Retinopathy** is a common complication in **sickle cell disease**, due to vascular occlusions from sickled cells. - It is not a characteristic complication of **hereditary spherocytosis**, which is suggested by the patient's blood work. *Avascular necrosis of the femoral head* - **Avascular necrosis** is most commonly associated with **sickle cell disease** due to vaso-occlusive crises where sickled red blood cells block blood flow to the bone. - This condition is not a typical complication of **hereditary spherocytosis**, as spherocytes are fragile but do not cause vaso-occlusion. *Aplastic anemia with parvovirus B19 infection* - While **parvovirus B19** can cause **aplastic crisis** in patients with hereditary spherocytosis by transiently suppressing erythropoiesis, this is an **acute, intermittent complication** rather than a chronic one. - The patient's current **elevated reticulocyte index** indicates active hemolysis without suppressed erythropoiesis, so aplastic crisis is not occurring now. - Compared to gallstones (which develop in 50-85% of patients), aplastic crises are **less frequent** and episodic, making gallstones the "most likely" complication overall.

Question 112: An otherwise healthy 42-year-old man undergoes routine investigations prior to blood donation. His complete blood count is shown: Hemoglobin 9.3 g/dL Mean corpuscular volume (MCV) 71 μm3 Mean corpuscular hemoglobin (MCH) 21 pg/cell White blood cell count 8,200/mm3 Platelet count 317,000/mm3 Iron studies are shown: Serum iron 210 μg/dL Serum ferritin 310 ng/mL Total iron binding capacity (TIBC) 290 μg/dL Transferrin saturation 78% He occasionally drinks alcohol and denies smoking or use of illicit drugs. There is a family history of anemia including his brother and maternal uncle. Examination shows conjunctival pallor, but is otherwise unremarkable. Which of the following is the most likely diagnosis?

A. Hemochromatosis
B. Anemia of chronic disease
C. Acute myeloid leukemia
D. Sideroblastic anemia (Correct Answer)
E. Myelodysplastic syndrome

Explanation: ***Sideroblastic anemia*** - The patient presents with **microcytic anemia** (Hb 9.3 g/dL, MCV 71, MCH 21) and evidence of **iron overload** (serum iron 210, ferritin 310, transferrin saturation 78%). These findings, along with a **family history of anemia affecting males** (brother and maternal uncle), are classic for **hereditary sideroblastic anemia**, typically X-linked. - **Sideroblastic anemia** is characterized by the bone marrow producing ring sideroblasts (erythroblasts with iron-laden mitochondria), leading to ineffective erythropoiesis and iron accumulation. - The hereditary form presents in younger patients with isolated anemia and strong family history, distinguishing it from acquired forms. *Hemochromatosis* - While **hemochromatosis** also presents with iron overload (high serum iron, ferritin, and transferrin saturation), it typically does **not cause microcytic anemia** or any significant anemia. - The primary defect in hemochromatosis is increased iron absorption leading to tissue iron deposition (liver, heart, pancreas), without the erythropoietic dysfunction seen in sideroblastic anemia. *Anemia of chronic disease* - **Anemia of chronic disease (ACD)** typically presents with normal or slightly reduced MCV and MCH, and is characterized by **low serum iron** and **low TIBC**, with normal or elevated ferritin. - In this case, the patient has **elevated serum iron** and **high transferrin saturation (78%)**, making ACD unlikely. *Acute myeloid leukemia* - **Acute myeloid leukemia (AML)** involves the proliferation of immature myeloid cells and usually presents with pancytopenia or symptoms related to bone marrow failure (e.g., fatigue, bleeding, infections). - The blood counts here show **isolated anemia with normal WBC and platelet counts**, and the iron studies are not typical for AML. *Myelodysplastic syndrome* - **Myelodysplastic syndromes (MDS)** are clonal disorders of hematopoietic stem cells, often presenting with cytopenias and dysplastic features in the bone marrow. - While **acquired sideroblastic anemia** is a subtype of MDS (refractory anemia with ring sideroblasts), it typically occurs in **older adults (>60 years)** without a family history. - This patient's **young age (42 years)** and **strong family history** (brother and maternal uncle) point to **hereditary sideroblastic anemia** rather than MDS-associated acquired sideroblastic anemia.

Question 113: A 32-year-old woman is brought to your office by her husband. The husband says that she had been acting strange lately. She has been forgetful, and she sometimes becomes angered for no reason, which is highly unusual for her. She has also been having random, uncontrollable movements, which are also new. On examination, she appears withdrawn and flat. On further questioning, she reveals that her father died at age 45 from a movement disorder. Which of the following is the pathological hallmark of the patient's condition?

A. Lipohyalinosis
B. Loss of neurons in the caudate nucleus and putamen (Correct Answer)
C. Substantia nigra pars compacta
D. Alpha-synuclein intracellular inclusions
E. Beta-amyloid plaques

Explanation: ***Loss of neurons in the caudate nucleus and putamen*** - The patient's symptoms (forgetfulness, anger, uncontrolled movements) and family history of an early-onset movement disorder (father died at age 45) are highly suggestive of **Huntington's disease**. - **Huntington's disease** is characterized pathologically by **selective atrophy and loss of GABAergic neurons** in the **caudate nucleus and putamen** within the basal ganglia. *Lipohyalinosis* - **Lipohyalinosis** refers to the **thickening of the vessel walls** of small penetrating arteries, often seen in the brain, and is associated with **lacunar infarcts** due to hypertension and diabetes. - While it can lead to neurological symptoms, it does not explain the specific combination of psychiatric, cognitive, and choreiform movements with an autosomal dominant family history. *Substantia nigra pars compacta* - Degeneration of the **substantia nigra pars compacta** and the resultant **loss of dopaminergic neurons** is the hallmark of **Parkinson's disease**. - Parkinson's disease typically presents with tremor, rigidity, bradykinesia, and postural instability, which are different from the patient's choreiform movements. *Alpha-synuclein intracellular inclusions* - **Alpha-synuclein intracellular inclusions**, known as **Lewy bodies**, are the characteristic pathological finding in **Parkinson's disease** and **Lewy body dementia**. - These are not associated with Huntington's disease, and the clinical presentation of the patient is not typical of either Parkinson's or Lewy body dementia. *Beta-amyloid plaques* - **Beta-amyloid plaques** are extracellular protein deposits, along with **neurofibrillary tangles** (tau protein), that are the pathological hallmarks of **Alzheimer's disease**. - While Alzheimer's involves cognitive decline, it does not typically present with the prominent choreiform movements and specific genetic inheritance pattern seen in this patient.

Question 114: A 60-year-old African American woman presents to her family physician with shortness of breath on exertion. She also describes shortness of breath when she lies down to go to bed at night, as well as recent swelling in her ankles. Past medical history is significant for long-standing hypertension, for which she takes amlodipine and lisinopril. Her temperature is 36.8°C (98.2°F), the heart rate is 90/min, the respiratory rate is 15/min, and the blood pressure is 135/80 mm Hg. The physical exam is significant for JVD, lower extremity pitting edema, laterally displaced PMI, left ventricular heave, bilateral pulmonary crackles, and an S4 heart sound. Chest X-ray demonstrates pulmonary vascular congestion, Kerley B lines, and cardiomegaly. Echocardiogram demonstrates a preserved ejection fraction. Kidney biopsy would likely demonstrate which of the following?

A. Thinning of the intima and media
B. Onion-skinning
C. Nodular sclerosis
D. Intimal thickening and medial hypertrophy (Correct Answer)
E. Fibrinoid necrosis

Explanation: ***Intimal thickening and medial hypertrophy*** * The patient's presentation of **heart failure with preserved ejection fraction (HFpEF)**, long-standing **hypertension**, and findings like left ventricular heave and S4 heart sound strongly suggest **hypertensive cardiomyopathy**, which in turn causes **hypertensive nephrosclerosis**. * **Hypertensive nephrosclerosis** is characterized by **intimal thickening** and **medial hypertrophy** of renal arterioles, leading to **ischemia** and atrophy of glomeruli and tubules. *Thinning of the intima and media* * This is not a characteristic pathological change seen in hypertensive nephrosclerosis. * In hypertension, the vessel walls typically undergo thickening due to **hypertrophy** and **hyperplasia** of smooth muscle cells and increased extracellular matrix, not thinning. *Onion-skinning* * **"Onion-skinning"** is a hallmark feature of **malignant hypertension**, characterized by concentric laminar thickening of the arteriolar walls. * The patient's blood pressure (135/80 mmHg) is not consistent with malignant hypertension, which would typically involve much higher blood pressure readings. *Nodular sclerosis* * **Nodular sclerosis** (also known as **Kimmelstiel-Wilson lesions**) is characteristic of **diabetic nephropathy**, not primarily hypertensive nephrosclerosis. * While diabetes and hypertension often co-exist, the prompt in this case points more directly to long-standing hypertension as the primary cause of renal damage. *Fibrinoid necrosis* * **Fibrinoid necrosis** of arterioles is also associated with **malignant hypertension** and some forms of vasculitis. * This patient's blood pressure is controlled (135/80 mmHg) and does not indicate the severe, rapid increase in blood pressure seen in malignant hypertension.

Question 115: A 65-year-old African-American woman comes to the physician because of severe lower back pain. She has had dull lower back pain for several months, which suddenly become sharp in nature after lifting a heavy bucket of water 2 days ago. The pain is midline and does not radiate. She has had frequent vaginal dryness and hot flashes since menopause at the age of 55 years, for which she is on hormone replacement therapy. She has hypertension, hypercholesterolemia, and hypothyroidism. Her other medications include hydrochlorothiazide, simvastatin, and levothyroxine. She attends a 30-minute power walking class twice a week. She has smoked a pack of cigarettes daily for 40 years. She does not drink alcohol. She does not appear in distress. She is 165 cm (5 ft 5 in) tall and weighs 75 kg (165 lb); her BMI is 27.6 kg/m2. Vital signs are within normal limits. Examination shows midline lumbar tenderness. Muscle strength is full and deep tendon reflexes are 2+. Straight-leg raising is negative but painful. MRI of the spine shows an acute compression fracture of the L3 vertebral body and an old compression fracture of the L4 vertebra. Which of the following parts of this patient's history is the strongest predisposing factor for her condition?

A. Exercise activity
B. Hormone replacement therapy
C. Smoking history (Correct Answer)
D. Age at menopause
E. Ancestry

Explanation: ***Smoking history*** - **Smoking** is a significant predisposing factor for osteoporosis and vertebral compression fractures due to its negative impact on bone density. It decreases **osteoblast activity** and **estrogen levels**, and increases **cortisol**, all of which contribute to bone loss. - This patient's extensive 40-year smoking history (a pack a day for 40 years) makes it the strongest modifiable risk factor for her vertebral compression fractures in this scenario. *Exercise activity* - **Weight-bearing exercises**, such as power walking, generally help maintain bone density and are protective against osteoporosis. - While an acute injury occurred during heavy lifting, her regular exercise history is unlikely to be a predisposing factor for the underlying fragility fractures. *Hormone replacement therapy* - **Hormone replacement therapy (HRT)** is typically protective against **postmenopausal osteoporosis** by replacing estrogen, which helps maintain bone density. - Therefore, her use of HRT would generally mitigate, rather than predispose to, her condition. *Age at menopause* - An earlier age of menopause (before 45) is a risk factor for osteoporosis due to a longer period of **estrogen deficiency**. This patient experienced menopause at 55, which is an average age and not an early menopause. - While menopause itself increases osteoporosis risk, her age at menopause is not an unusually early onset that would be a particularly strong predisposing factor here. *Ancestry* - **African-American women** generally have higher bone mineral density and a lower risk of osteoporosis compared to Caucasian or Asian women, making ancestry less of a risk factor in this case. - Although risk still exists, it is not considered the strongest predisposing factor for osteoporosis and fractures in this demographic when compared to other presented risks.

Question 116: A 51-year-old woman with hyperlipidemia comes to the physician because of weakness for one month. At the end of the day, she feels too fatigued to cook dinner or carry a laundry basket up the stairs. She also complains of double vision after she reads for long periods of time. All of her symptoms improve with rest. Her only medication is pravastatin. Physical examination shows drooping of the upper eyelids. Strength is initially 5/5 in the upper and lower extremities but decreases to 4/5 after a few minutes of sustained resistance. Sensation to light touch is intact and deep tendon reflexes are normal. Which of the following best describes the pathogenesis of this patient's condition?

A. Type II hypersensitivity reaction (Correct Answer)
B. Anterior horn cell destruction
C. Impaired acetylcholine release
D. Peripheral nerve demyelination
E. Adverse drug effect

Explanation: ***Type II hypersensitivity reaction*** - This patient's symptoms of **fatigue** and **muscle weakness** that worsen with activity and improve with rest (**fatigable weakness**), along with **ptosis** (drooping eyelids) and **diplopia** (double vision), are classic for **myasthenia gravis**. - Myasthenia gravis is an **autoimmune disease** characterized by autoantibodies that target and destroy **acetylcholine receptors** at the neuromuscular junction, leading to impaired signal transmission. This is a classic example of a **Type II hypersensitivity reaction**, where antibodies directly mediate cellular destruction or dysfunction. *Anterior horn cell destruction* - **Anterior horn cell destruction**, as seen in **amyotrophic lateral sclerosis (ALS)**, typically presents with both upper and lower motor neuron signs, such as **spasticity**, **hyperreflexia**, **fasciculations**, and **muscle atrophy**. - In ALS, there is progressive weakness but typically **without fatigability** and oculomotor symptoms (ptosis, diplopia) are less common or occur late in the disease. *Impaired acetylcholine release* - **Impaired acetylcholine release** is characteristic of **Lambert-Eaton myasthenic syndrome (LEMS)**, which is often associated with small cell lung cancer. - Unlike myasthenia gravis, LEMS typically shows **improvement in muscle strength with sustained activity** (due to increased presynaptic acetylcholine release), rather than worsening. *Peripheral nerve demyelination* - **Peripheral nerve demyelination** is the hallmark of conditions like **Guillain-Barré syndrome (GBS)** or **chronic inflammatory demyelinating polyneuropathy (CIDP)**. - These conditions usually present with **sensory deficits**, **areflexia**, and **ascending paralysis/weakness**, which are absent in this patient. *Adverse drug effect* - While **statins** can cause **myopathy** (muscle pain and weakness), this typically involves diffuse muscle aches and elevated **creatine kinase** levels, and does not typically present with the classic fatigable weakness, ptosis, and diplopia seen here. - The specific pattern of fatigable weakness improving with rest and affecting specific muscle groups (e.g., ocular muscles) points away from a simple statin-induced myopathy.

Question 117: A 46-year-old man comes to the physician because of a 4-month history of progressively worsening fatigue and loss of appetite. Five years ago, he received a kidney transplant from a living family member. Current medications include sirolimus and mycophenolate. His blood pressure is 150/95 mm Hg. Laboratory studies show normocytic, normochromic anemia and a serum creatinine concentration of 3.1 mg/dL; his vital signs and laboratory studies were normal 6 months ago. Which of the following is the most likely underlying mechanism of this patient’s increase in creatinine concentration?

A. Drug-induced tubular vacuolization
B. CD8+ T cell-mediated parenchymal cell damage
C. CD4+ T cell-mediated intimal smooth muscle proliferation (Correct Answer)
D. Donor T cell-mediated epithelial cell damage
E. Donor endothelial cell damage by preformed host antibodies

Explanation: ***CD4+ T cell-mediated intimal smooth muscle proliferation*** - The patient's history of a kidney transplant 5 years ago, worsening fatigue, loss of appetite, elevated blood pressure (150/95 mm Hg), and a significant increase in serum creatinine from normal to 3.1 mg/dL, along with normocytic, normochromic anemia, strongly suggests **chronic rejection** of the renal allograft. - **Chronic rejection** in kidney transplantation is primarily mediated by **CD4+ T cells** which induce injury to vessel walls, leading to **intimal smooth muscle proliferation** and progressive obliteration of the vascular lumen, causing chronic ischemia and graft dysfunction. *Drug-induced tubular vacuolization* - **Drug-induced tubular vacuolization** can occur with medications like sirolimus, but it typically presents with **acute kidney injury** and specific biopsy findings, not the progressive, chronic decline seen here. - While sirolimus can cause nephrotoxicity, the clinical picture of hypertension, anemia, and a gradual increase in creatinine over months, years after transplant, is more indicative of chronic rejection rather than a primary direct tubular injury. *CD8+ T cell-mediated parenchymal cell damage* - **CD8+ T cell-mediated parenchymal cell damage** is characteristic of **acute cellular rejection** and typically presents with a more rapid onset of graft dysfunction and specific histological features like tubulitis and interstitial inflammation. - This patient's symptoms have developed progressively over 4 months, which is more consistent with chronic rather than acute processes. *Donor T cell-mediated epithelial cell damage* - **Donor T cell-mediated epithelial cell damage** is associated with **graft-versus-host disease (GVHD)**, which primarily occurs after **hematopoietic stem cell transplantation**, not solid organ transplants like a kidney. - GVHD manifests in organs like the skin, liver, and GI tract, not typically as isolated chronic allograft nephropathy. *Donor endothelial cell damage by preformed host antibodies* - **Donor endothelial cell damage by preformed host antibodies** is the mechanism of **hyperacute rejection**, which occurs within minutes to hours post-transplant due to pre-existing host antibodies (e.g., ABO incompatible, preformed anti-HLA antibodies) and leads to immediate graft failure. - The patient had a successful transplant 5 years ago and developed symptoms gradually, ruling out hyperacute rejection.

Question 118: A 53-year-old woman presents to her physician for evaluation of sudden onset respiratory distress for the past few hours. The past medical history includes a myocardial infarction 2 years ago. The vital signs include a blood pressure 70/40 mm Hg, pulse 92/min, respiratory rate 28/min, and SpO2 92% on room air. The physical examination reveals bilateral basal crepitations on auscultation. The echocardiogram reveals an ejection fraction of 34%. She is admitted to the medical floor and started on furosemide. The urine output in 24 hours is 400 mL. The blood urea nitrogen is 45 mg/dL and the serum creatinine is 1.85 mg/dL. The fractional excretion of sodium is 2.4%. Urinalysis revealed muddy brown granular casts. Which of the following is the most likely cause of the abnormal urinalysis?

A. Acute interstitial nephritis
B. Acute tubular necrosis (Correct Answer)
C. Acute pyelonephritis
D. Chronic kidney disease
E. Acute glomerulonephritis

Explanation: ***Acute tubular necrosis*** - The presence of **muddy brown granular casts** on urinalysis is pathognomonic for **acute tubular necrosis (ATN)**, indicating damage to the renal tubules. - The patient's history of **cardiogenic shock** (low BP 70/40 mm Hg, respiratory distress, low SpO2, low ejection fraction of 34%) led to **renal hypoperfusion** and ischemic tubular injury. - The **fractional excretion of sodium (FENa) of 2.4%** (>2%) is characteristic of **intrinsic renal injury** (ATN), as damaged tubules cannot effectively reabsorb sodium. - **Oliguria** (400 mL/24 hours), elevated **BUN (45 mg/dL)** and **creatinine (1.85 mg/dL)** further support acute kidney injury from ATN. *Acute interstitial nephritis* - This condition is typically associated with **drug hypersensitivity** (e.g., NSAIDs, antibiotics, PPIs) or **infections** and is characterized by inflammatory infiltrate in the renal interstitium. - Urinalysis typically shows **white blood cell casts** and **eosinophiluria**, not muddy brown granular casts. *Acute pyelonephritis* - This is an **infection of the kidney** parenchyma, usually caused by bacterial ascension from the urinary tract. - Symptoms often include **fever, flank pain, dysuria**, and urinalysis reveals **leukocyturia** (white blood cells) and **bacterial casts**, not muddy brown granular casts. *Chronic kidney disease* - While the patient has elevated creatinine and BUN, **chronic kidney disease (CKD)** develops over months to years and is characterized by persistent kidney damage or decreased function. - Urinalysis in CKD often shows **broad waxy casts** and typically does not present with such **acute, sudden onset** of severe renal dysfunction with muddy brown granular casts. *Acute glomerulonephritis* - This condition involves inflammation of the glomeruli and typically presents with **hematuria, proteinuria, and red blood cell casts** (dysmorphic RBCs). - The patient's clinical picture, including the absence of significant hematuria and the presence of **muddy brown granular casts**, does not fit acute glomerulonephritis.

Question 119: An autopsy of a patient's heart who recently died in a motor vehicle accident shows multiple nodules near the line of closure on the ventricular side of the mitral valve leaflet. Microscopic examination shows that these nodules are composed of immune complexes, mononuclear cells, and thrombi interwoven with fibrin strands. These nodules are most likely to be found in which of the following patients?

A. A 41-year-old female with a facial rash and nonerosive arthritis (Correct Answer)
B. A 6-year-old female with subcutaneous nodules and erythema marginatum
C. A 62-year-old male with Cardiobacterium hominis bacteremia
D. A 54-year-old male who recently underwent dental surgery
E. A 71-year-old male with acute-onset high fever and nail bed hemorrhages

Explanation: ***A 41-year-old female with a facial rash and nonerosive arthritis*** - The description of nodules composed of **immune complexes, mononuclear cells, and thrombi interwoven with fibrin strands** on the **ventricular side of the mitral valve leaflets** is classic for **Libman-Sacks endocarditis**. - **Libman-Sacks endocarditis** is strongly associated with **systemic lupus erythematosus (SLE)**, which commonly presents with a **malar rash** and **nonerosive arthritis** in young to middle-aged women. *A 6-year-old female with subcutaneous nodules and erythema marginatum* - This presentation is characteristic of **acute rheumatic fever**, which causes **Aschoff bodies** (fibrinoid necrosis surrounded by inflammatory cells) in the heart. - While it affects heart valves, the characteristic lesions are **fibrinous vegetations along the lines of closure** (Rheumatic Heart Disease) rather than immune complex-rich nodules on the ventricular surface described, and it is most commonly associated with **streptococcal infection**, not immune complexes as the primary driver. *A 62-year-old male with Cardiobacterium hominis bacteremia* - **Cardiobacterium hominis** is a HACEK group organism that can cause **subacute infective endocarditis**. - Infective endocarditis involves vegetations composed of **microorganisms, fibrin, inflammatory cells, and red blood cells**, which typically occur on the **atrial side of the mitral valve** or the **ventricular side of the aortic valve**, and the primary component is bacteria, not immune complexes. *A 54-year-old male who recently underwent dental surgery* - Recent dental surgery is a common risk factor for **infective endocarditis**, often caused by **viridans group streptococci**. - The lesions in infective endocarditis are primarily composed of **bacterial colonies and fibrin**, and they typically develop on the **atrial side of the mitral valve** (high-pressure side) and are destructive, differing from the immune complex-rich, non-destructive nodules of Libman-Sacks endocarditis. *A 71-year-old male with acute-onset high fever and nail bed hemorrhages* - **Acute-onset high fever** and **nail bed hemorrhages (splinter hemorrhages)** are signs of **acute infective endocarditis**, often caused by virulent organisms like *Staphylococcus aureus*. - Although vegetation can occur on the heart valves, the composition is primarily bacterial colonies and inflammatory cells, and the primary location is usually the **aortic or mitral valve**, typically in areas of turbulent flow or previous damage, differing microscopically from Libman-Sacks endocarditis.

Question 120: A 32-year-old man presents with a history of diarrhea several days after eating a hot dog at a neighborhood barbeque. He notes that the diarrhea is visibly bloody, but he has not experienced a fever. He adds that several other people from his neighborhood had similar complaints, many of which required hospitalization after eating food at the same barbeque. His temperature is 37°C (98.6°F ), respiratory rate is 16/min, pulse is 77/min, and blood pressure is 100/88 mm Hg. A physical examination is performed and is within normal limits. Blood is drawn for laboratory testing. The results are as follows: Hb%: 12 gm/dL Total count (WBC): 13,100/mm3 Differential count: Neutrophils: 80% Lymphocytes: 15% Monocytes: 5% ESR: 10 mm/hr Glucose, Serum: 90 mg/dL BUN: 21 mg/dL Creatinine, Serum: 1.96 mg/dL Sodium, Serum: 138 mmol/L Potassium, Serum: 5.2 mmol/L Chloride, Serum: 103 mmol/L Bilirubin, Total: 2.5 mg/dL Alkaline Phosphatase, Serum: 66 IU/L Aspartate aminotransferase (AST): 32 IU/L Alanine aminotransferase (ALT): 34 IU/L Urinalysis is normal except for RBC casts. What is the most concerning possible complication?

A. Disseminated intravascular coagulation
B. Guillain-Barré syndrome
C. Hemolytic uremic syndrome (Correct Answer)
D. Plummer-Vinson syndrome
E. Rotatory nystagmus

Explanation: ***Hemolytic uremic syndrome*** - The patient presents with **bloody diarrhea** following suspected food poisoning (likely *E. coli O157:H7* from undercooked hot dog), elevated creatinine (1.96 mg/dL) and BUN indicating **acute kidney injury**, elevated total bilirubin (2.5 mg/dL) suggesting **hemolysis**, and **RBC casts in the urine**, which are pathognomonic for glomerular disease. - HUS is characterized by a triad of **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **acute kidney injury**. While platelet count is not provided in this case, the combination of bloody diarrhea following food exposure, evidence of hemolysis (elevated bilirubin with normal liver enzymes), acute renal failure, and RBC casts strongly suggests HUS. - HUS is the most serious complication of **Shiga toxin-producing E. coli** infection and can lead to permanent renal damage or death if untreated. *Disseminated intravascular coagulation* - While DIC involves widespread clotting and bleeding, it typically presents with more severe systemic symptoms like **petechiae**, **purpura**, fever, and significant derangements in coagulation tests (e.g., prolonged PT/aPTT, decreased fibrinogen, elevated D-dimer), which are not described here. - The localized presentation with primarily renal involvement and absence of systemic coagulopathy makes HUS more likely than DIC. *Guillain-Barré syndrome* - GBS is an **autoimmune disorder** affecting the peripheral nervous system, characterized by **ascending paralysis** and areflexia, usually following an infection (often *Campylobacter jejuni*). - There are no neurological symptoms such as weakness, paresthesias, or paralysis mentioned in this patient's presentation, and the prominent renal findings point away from GBS. *Plummer-Vinson syndrome* - Plummer-Vinson syndrome is a rare condition characterized by **iron deficiency anemia**, **dysphagia** due to esophageal webs, and glossitis. - This patient presents with acute GI infection and acute kidney injury, not chronic iron deficiency anemia features or dysphagia. This option is not relevant to the clinical scenario. *Rotatory nystagmus* - **Rotatory nystagmus** is an involuntary eye movement pattern, usually indicating a vestibular or central nervous system disorder. - This is a physical examination finding, not a complication or syndrome. There is no mention of visual disturbances or neurological deficits in this patient's presentation.

Question 121: A 56-year-old African American woman comes to the physician because of frequent urination. For the past year, she has had to urinate multiple times every hour. She has been thirstier and hungrier than usual. She has not had any pain with urination. She has no time to exercise because she works as an accountant. Her diet mostly consists of pizza and cheeseburgers. Her vital signs are within normal limits. Physical examination shows no abnormalities. Today, her blood glucose level is 200 mg/dL and her hemoglobin A1c is 7.4%. Urinalysis shows microalbuminuria. Which of the following is the most likely cause of this patient's proteinuria?

A. Calcific sclerosis of glomerular arterioles
B. Loss of glomerular electrical charge
C. Renal papillary necrosis
D. Increased glomerular filtration
E. Diffuse nodular glomerulosclerosis (Correct Answer)

Explanation: ***Diffuse nodular glomerulosclerosis*** - The patient presents with symptoms of **polyuria**, **polydipsia**, and **polyphagia**, along with elevated **blood glucose** (200 mg/dL) and **HbA1c** (7.4%), confirming a diagnosis of **diabetes mellitus**. - **Diffuse nodular glomerulosclerosis**, also known as **Kimmelstiel-Wilson disease**, is a characteristic renal lesion seen in **diabetic nephropathy**, leading to proteinuria, including microalbuminuria. *Calcific sclerosis of glomerular arterioles* - While **vascular calcification** can occur in the context of chronic kidney disease, particularly in diabetic patients, **calcific sclerosis of glomerular arterioles** itself is not the primary mechanism leading to **proteinuria**. - More common and direct causes of proteinuria in diabetes are related to **glomerular damage**, such as the nodular or diffuse type of glomerulosclerosis. *Loss of glomerular electrical charge* - The **glomerular basement membrane (GBM)** possesses negatively charged proteoglycans (e.g., **heparan sulfate**), which repel negatively charged proteins like albumin, contributing to the filtration barrier. - While damage to the GBM in conditions like minimal change disease can cause a loss of this negative charge leading to massive proteinuria, it is not the primary or most characteristic mechanism of **microalbuminuria** in **early diabetic nephropathy**. *Renal papillary necrosis* - **Renal papillary necrosis** is characterized by ischemic coagulative necrosis of the renal papillae, most commonly associated with **analgesic abuse**, **sickle cell disease**, and severe **diabetes mellitus**. - While it can cause hematuria, flank pain, and even kidney failure, it is not the direct or primary cause of **proteinuria** in the context of early diabetic nephropathy. *Increased glomerular filtration* - **Increased glomerular filtration**, also known as **hyperfiltration**, is an early pathological change in diabetes mellitus, where GFR is elevated. - While hyperfiltration can contribute to **glomerular damage** over time and is a risk factor for nephropathy progression, it is not the direct cause of **microalbuminuria** itself; rather, it is the underlying **glomerular structural changes** that result from sustained hyperfiltration and metabolic derangements that lead to leakage of proteins.

Question 122: A 67-year-old man comes to the emergency department for the evaluation of two episodes of red urine since this morning. He has no pain with urination. He reports lower back pain and fever. Six months ago, he was diagnosed with osteoarthritis of the right knee that he manages with 1–2 tablets of ibuprofen per day. He has smoked one pack of cigarettes daily for the past 45 years. He does not drink alcohol. His temperature is 38.5°C (101.3°F), pulse is 95/min, and blood pressure is 130/80 mm Hg. Physical examination shows faint, diffuse maculopapular rash, and bilateral flank pain. The remainder of the examination shows no abnormalities. Urinalysis shows: Blood +3 Protein +1 RBC 10–12/hpf RBC cast negative Eosinophils numerous Which of the following is the most likely diagnosis?

A. Acute glomerulonephritis
B. Renal cell carcinoma
C. Acute tubular necrosis
D. Acute tubulointerstitial nephritis (Correct Answer)
E. Crystal-induced acute kidney injury

Explanation: ***Acute tubulointerstitial nephritis*** - The patient's history of daily **ibuprofen use**, along with **fever**, **rash**, **flank pain**, and **eosinophilia** in the urine, is highly suggestive of **acute tubulointerstitial nephritis (ATIN)**, often drug-induced. - The urinalysis showing **hematuria** (+3 blood, 10-12 RBCs/hpf), **proteinuria** (+1 protein), and significantly **numerous eosinophils** further supports this diagnosis, as ATIN is characterized by inflammation of the renal tubules and interstitium. *Acute glomerulonephritis* - While acute glomerulonephritis can present with hematuria and proteinuria, it typically involves the presence of **RBC casts**, which are noted as negative in this patient's urinalysis. - The significant eosinophilia and response to ibuprofen are not characteristic features of acute glomerulonephritis. *Renal cell carcinoma* - Renal cell carcinoma can cause painless hematuria and flank pain, but it is less likely to present with acute symptoms such as **fever**, **rash**, and **eosinophilia**. - This condition does not typically cause the diffuse maculopapular rash or the specific urinalysis findings of numerous eosinophils. *Acute tubular necrosis* - Acute tubular necrosis (ATN) is often associated with ischemia or nephrotoxic agents and typically presents with muddy brown casts in the urine, not red blood cell casts or numerous eosinophils. - While ATN can cause acute kidney injury, the rash, fever, and eosinophils point away from this diagnosis. *Crystal-induced acute kidney injury* - Crystal-induced AKI might occur with certain drugs or metabolic conditions and would typically show evidence of crystals in the urine (e.g., uric acid, oxalate), which are not mentioned here. - The presence of fever, rash, and marked eosinophilia is not typical for crystal-induced injury.

Question 123: A 12-year-old boy who recently immigrated from Namibia is being evaluated for exertional shortness of breath and joint pain for the past month. His mother reports that he used to play soccer but now is unable to finish a game before he runs out of air or begins to complain of knee pain. He was a good student but his grades have recently been declining over the past few months. The mother recalls that he had a sore throat and didn't go to school for 3 days a few months ago. He had chickenpox at the age of 5 and suffers from recurrent rhinitis. He is currently taking over-the-counter multivitamins. His blood pressure is 110/90 mm Hg, pulse rate is 55/min, and respiratory rate is 12/min. On physical examination, subcutaneous nodules are noted on his elbows bilaterally. On cardiac auscultation, a holosystolic murmur is heard over the mitral area that is localized. Lab work shows: Hemoglobin 12.9 g/dL Hematocrit 37.7% Leukocyte count 5,500/mm3 Neutrophils 65% Lymphocytes 30% Monocytes 5% Mean corpuscular volume 82.2 fL Platelet count 139,000/mm3 Erythrocyte sedimentation rate 35 mm/h C-reactive protein 14 mg/dL Antistreptolysin O (ASO) 400 IU (normal range: < 200 IU) Which is the mechanism behind the cause of this boy's symptoms?

A. Type III hypersensitivity reaction
B. Type I hypersensitivity reaction
C. Congenital immunodeficiency
D. Type II hypersensitivity reaction (Correct Answer)
E. Type IV hypersensitivity reaction

Explanation: ***Type II hypersensitivity reaction*** - This scenario describes **acute rheumatic fever (ARF)**, characterized by a preceding **streptococcal pharyngitis** followed by a Type II hypersensitivity reaction via **molecular mimicry**. The **anti-streptolysin O (ASO) titer of 400 IU** is elevated (normal < 200 IU), indicating a recent streptococcal infection. - In ARF, antibodies produced against **Streptococcus pyogenes M protein** cross-react with host tissues (molecular mimicry), leading to direct antibody-mediated damage to the **heart (rheumatic carditis)**, joints, skin, and CNS. The patient's exertional shortness of breath and holosystolic murmur point to **mitral regurgitation**, a hallmark of rheumatic heart disease. - Classic ARF presents with **Jones criteria**: carditis, polyarthritis, subcutaneous nodules, erythema marginatum, and Sydenham chorea. *Type III hypersensitivity reaction* - This involves the formation of **immune complexes** that deposit in tissues, leading to inflammation (e.g., serum sickness, **post-streptococcal glomerulonephritis**, lupus nephritis). While immune complexes may play a minor role in ARF, the primary mechanism is **direct antibody cross-reactivity** (Type II), not immune complex deposition. - **Key distinction**: Post-streptococcal glomerulonephritis (which occurs 1-2 weeks after strep infection with hematuria and edema) is Type III, while ARF (which occurs 2-4 weeks after with carditis and arthritis) is Type II. - The clinical features here—subcutaneous nodules, carditis, polyarthritis—are classic for ARF, not a Type III hypersensitivity reaction. *Type I hypersensitivity reaction* - This is an **immediate hypersensitivity** mediated by **IgE antibodies** and mast cell degranulation, causing reactions like asthma, anaphylaxis, or allergic rhinitis. - The presented symptoms of polyarthritis and carditis developing weeks after a streptococcal infection do not align with an IgE-mediated allergic response. *Congenital immunodeficiency* - This refers to genetic defects in the immune system, leading to increased susceptibility to infections or autoimmune conditions. - While immunodeficiencies can increase infection risk, they don't explain the specific constellation of symptoms—carditis, migratory polyarthritis, and subcutaneous nodules—following a streptococcal infection that points to acute rheumatic fever, an autoimmune sequela. *Type IV hypersensitivity reaction* - This is a **delayed-type hypersensitivity** reaction mediated by **T-cells** (e.g., contact dermatitis, tuberculin skin test, granuloma formation). - The pathophysiology of ARF involves antibody-mediated mechanisms (humoral immunity), not primarily T-cell-mediated delayed reactions.

Question 124: A 46-year-old man diagnosed with pancreatic adenocarcinoma is admitted with fever, malaise, and dyspnea. He says that symptoms onset 2 days ago and have progressively worsened. Past medical history is significant for multiple abdominal surgeries including stenting of the pancreatic duct. Current inpatient medications are rosuvastatin 20 mg orally daily, aspirin 81 mg orally daily, esomeprazole 20 mg orally daily, oxycontin 10 mg orally twice daily, lorazepam 2 mg orally 3 times daily PRN, and ondansetron 10 mg IV. On admission, his vital signs include blood pressure 105/75 mm Hg, respirations 22/min, pulse 90/min, and temperature 37.0°C (98.6°F). On his second day after admission, the patient acutely becomes obtunded. Repeat vital signs show blood pressure 85/55 mm Hg, respirations 32/min, pulse 115/min. Physical examination reveals multiple ecchymoses on the trunk and extremities and active bleeding from all IV and venipuncture sites. There is also significant erythema and swelling of the posterior aspect of the left leg. Laboratory findings are significant for thrombocytopenia, prolonged PT and PTT, and an elevated D-dimer. Blood cultures are pending. Which of the following is most likely responsible for this patient’s current condition?

A. Factor VIII inhibitor
B. von Willebrand disease
C. Vitamin K deficiency
D. Disseminated intravascular coagulation (Correct Answer)
E. Antiphospholipid syndrome

Explanation: ***Disseminated intravascular coagulation*** - The patient's presentation with **acute obtundation**, **hypotension**, **tachycardia**, multiple **ecchymoses**, bleeding from venipuncture sites, and swelling of the left leg, along with laboratory findings of **thrombocytopenia**, **prolonged PT and PTT**, and **elevated D-dimer**, are all classic signs of **disseminated intravascular coagulation (DIC)**. - DIC is a life-threatening condition often triggered by underlying conditions such as **sepsis** (indicated by fever, malaise, dyspnea, and potential infection associated with pancreatic duct stenting) or **malignancy** (pancreatic adenocarcinoma), leading to widespread uncontrolled activation of coagulation followed by consumption of clotting factors and platelets. *Factor VIII inhibitor* - While a **Factor VIII inhibitor** can cause bleeding and prolonged PTT, it would not typically cause **thrombocytopenia** or markedly elevated D-dimer. - It's a rare acquired condition, usually presenting as isolated bleeding, not the systemic collapse seen here. *von Willebrand disease* - **Von Willebrand disease** is a genetic bleeding disorder characterized by mucocutaneous bleeding and prolonged PTT if severe, but it does **not typically cause thrombocytopenia**, normal PT, or greatly elevated D-dimer. - The acute, severe, systemic nature of the patient's symptoms is not consistent with VWD. *Vitamin K deficiency* - **Vitamin K deficiency** can prolong PT and PTT, leading to bleeding, but it does **not cause thrombocytopenia** or elevated D-dimer. - This condition is often seen in malabsorption or liver disease, and while the patient has pancreatic cancer, the specific lab abnormalities point away from isolated vitamin K deficiency. *Antiphospholipid syndrome* - **Antiphospholipid syndrome** typically causes **thrombotic events** (clots) rather than bleeding, although it can be associated with some thrombocytopenia. - The patient's predominant symptoms of widespread bleeding and consumption coagulopathy are not consistent with this syndrome.

Question 125: A pathologist receives a patient sample for analysis. Cells in the sample are first labeled with fluorescent antibodies and then passed across a laser beam in a single file of particles. The light scatter and fluorescent intensity of the particles are plotted on a graph; this information is used to characterize the sample. This laboratory method would be most useful to establish the diagnosis of a patient with which of the following?

A. Ventricular septal defect and facial dysmorphism with low T-lymphocyte count
B. Painless generalized lymphadenopathy with monomorphic cells and interspersed benign histiocytes on histology
C. Pancytopenia and deep vein thrombosis with intermittent hemoglobinuria (Correct Answer)
D. Multiple opportunistic infections with decreased CD4 counts
E. Vesicular lesions with dermatomal distribution and dendritic corneal ulcers

Explanation: ***Pancytopenia and deep vein thrombosis with intermittent hemoglobinuria*** - The described laboratory method is **flow cytometry**, which is the **gold standard for diagnosing paroxysmal nocturnal hemoglobinuria (PNH)** by detecting the absence of **CD55** and **CD59** on red blood cells due to impaired GPI anchor synthesis. - PNH classically presents with **pancytopenia**, **hemolytic anemia** (leading to hemoglobinuria), and a high risk of **thrombosis** (e.g., deep vein thrombosis). *Ventricular septal defect and facial dysmorphism with low T-lymphocyte count* - This clinical picture suggests **DiGeorge syndrome**, which involves a developmental defect of the **third and fourth pharyngeal pouches**, leading to thymic hypoplasia and **T-cell deficiency**. - While flow cytometry is used to quantify T-lymphocyte subsets (e.g., CD3, CD4, CD8), the primary method for diagnosing DiGeorge syndrome is **fluorescent in situ hybridization (FISH)** for a **22q11 deletion**, making it less ideal for flow cytometry diagnosis. *Painless generalized lymphadenopathy with monomorphic cells and interspersed benign histiocytes on histology* - This description with "**monomorphic cells**" is more consistent with certain **non-Hodgkin lymphomas** (e.g., Burkitt lymphoma) rather than Hodgkin lymphoma, which typically shows a **polymorphic** cellular infiltrate. - While flow cytometry can be useful in characterizing lymphomas by identifying cell surface markers, the diagnosis is primarily established by **lymph node biopsy and histopathology** with **immunohistochemistry**, making flow cytometry a supplementary rather than primary diagnostic tool. *Multiple opportunistic infections with decreased CD4 counts* - This presentation is highly suggestive of **HIV infection leading to AIDS**. The "decreased CD4 counts" are a key diagnostic and prognostic marker. - While flow cytometry is used to **monitor CD4 cell counts** in HIV patients, the initial diagnosis of HIV is established via **antibody/antigen combination tests** and confirmed by **Western blot** or **PCR for viral load**, not by flow cytometry. *Vesicular lesions with dermatomal distribution and dendritic corneal ulcers* - This clinical presentation points to **herpes zoster ophthalmicus** (shingles affecting the eye due to **varicella-zoster virus** reactivation). - Diagnosis is primarily **clinical** based on the characteristic rash and eye findings, although **PCR** of vesicular fluid can confirm VZV infection. Flow cytometry has no role in this diagnosis.

Question 126: A 15-year-old boy is brought to the physician because his urine has been pink since that morning. During the past 2 days, he has had a sore throat and difficulty swallowing. He also reports having a low-grade fever. He has no pain with urination or changes in urinary frequency. He has had 2 similar episodes involving a sore throat and pink urine over the past 2 years. His older sister has systemic lupus erythematosus. His temperature is 38.3°C (101°F), pulse is 76/min, and blood pressure is 120/80 mm Hg. Oral examination shows an erythematous pharynx and enlarged tonsils. The remainder of the examination shows no abnormalities. Laboratory studies show: Leukocyte count 20,000/mm3 Serum Urea nitrogen 8 mg/dL Creatinine 1.4 mg/dL Urine Blood 3+ Protein 1+ RBC 15–17/hpf with dysmorphic features RBC casts numerous Ultrasound of both kidneys shows no abnormalities. A renal biopsy is most likely to show which of the following findings?

A. Splitting of the glomerular basement membrane
B. Capillary wire looping
C. IgA mesangial deposition (Correct Answer)
D. Crescents of fibrin and plasma proteins
E. Granular deposits of IgG, IgM, and C3 complement

Explanation: ***IgA mesangial deposition*** - The patient's presentation with **recurrent episodes of gross hematuria (pink urine) occurring simultaneously with pharyngitis** is highly suggestive of **IgA nephropathy (Berger's disease)**. - **IgA mesangial deposition** is the hallmark finding on renal biopsy for IgA nephropathy, which is an immune complex-mediated glomerulonephritis. - The **synpharyngitic** timing (hematuria concurrent with infection, not delayed) and **recurrent nature** are classic for IgA nephropathy. *Splitting of the glomerular basement membrane* - This finding is characteristic of **Alport syndrome**, a hereditary nephropathy associated with nerve deafness and ocular abnormalities, which are not present in this patient. - While Alport can cause recurrent hematuria, the history of recurrent gross hematuria following pharyngitis points away from Alport syndrome. *Capillary wire looping* - **Capillary wire looping** refers to thickening of the glomerular capillary walls due to subendothelial immune deposits and is a classic feature of **diffuse proliferative glomerulonephritis**, often seen in **lupus nephritis**. - Although the sister has lupus, the patient's symptoms and rapid resolution of previous episodes are less typical for acute lupus nephritis. *Crescents of fibrin and plasma proteins* - **Crescent formation** in Bowman's capsule is characteristic of **rapidly progressive glomerulonephritis (RPGN)**, indicating severe glomerular injury. - While RPGN can present with hematuria, the patient has a history of recurrent, self-limiting episodes, which is not typical for the rapidly progressive and often severe course of crescentic glomerulonephritis. *Granular deposits of IgG, IgM, and C3 complement* - This pattern of immune deposits is typical of **post-streptococcal glomerulonephritis (PSGN)**, which also presents with hematuria following infection. - However, PSGN typically has a **latent period of 1-3 weeks** between infection and renal symptoms, and **low C3 complement levels**, which are not seen in this patient; the quick onset and recurring episodes are more consistent with IgA nephropathy.

Question 127: A 17-year-old is brought to his primary care provider by his mother. They are concerned that his acne is getting worse and may leave scars. They have tried several over the counter products without success. He is otherwise healthy and without complaint. The boy was born at 39 weeks gestation via spontaneous vaginal delivery. He is up to date on all vaccines with some delay in reaching developmental milestones, especially in language development. He is having trouble with school and has a history of detentions for misbehavior and acting out. On examination, he stands 6 ft 3 inches tall, considerably taller than either parent or other family members with inflamed pustular acne on his face, shoulders, and chest. He is otherwise healthy. Which of the following karyotypes is most likely associated with this patient’s clinical features?

A. 46 XY
B. 47 XYY (Correct Answer)
C. 45 X0
D. 47, XY, +21
E. 47 XXY

Explanation: ***47 XYY*** - The patient's **tall stature**, **developmental delays** (especially language), and **behavioral problems** are features that can be associated with **47, XYY syndrome**. - Males with XYY syndrome are typically **taller than average** and may have **mild learning difficulties**, particularly with language and speech development. - **Behavioral issues** such as impulsivity and attention problems have been reported, though the historical association with aggressive behavior has been largely debunked. - While severe acne is mentioned in some older literature, it is not a well-established or consistent feature of XYY syndrome. *46 XY* - This is a **normal male karyotype** and would not explain the patient's constellation of symptoms, including exceptionally tall stature (significantly above family baseline) combined with developmental delays and behavioral issues. - While a typical 46 XY individual can have acne or be tall, the combination and severity described are atypical for a normal karyotype. *45 X0* - This karyotype describes **Turner syndrome**, which affects females and is characterized by **short stature**, **ovarian dysfunction**, and specific physical features, none of which are present in this male patient. - It's also incorrect because the patient is phenotypically male. *47, XY, +21* - This karyotype represents **Down syndrome**, characterized by specific **facial features**, **intellectual disability**, and various health problems, but not the exceptionally tall stature seen in this patient. - The developmental delays in Down syndrome are also typically more generalized and severe than just language and behavioral issues. *47 XXY* - This karyotype describes **Klinefelter syndrome**, a condition found in males characterized by **tall stature**, **hypogonadism**, and often **gynecomastia**. - While it can manifest with tall stature and some learning difficulties, **hypogonadism** would be expected on examination, which is not described in this patient. - The clinical picture of isolated tall stature with developmental and behavioral issues without signs of hypogonadism is more consistent with XYY syndrome.

Question 128: A 6-month-old male presents to the emergency department with his parents after his three-year-old brother hit him on the arm with a toy truck. His parents are concerned that the minor trauma caused an unusual amount of bruising. The patient has otherwise been developing well and meeting all his milestones. His parents report that he sleeps throughout the night and has just started to experiment with solid food. The patient’s older brother is in good health, but the patient’s mother reports that some members of her family have an unknown blood disorder. On physical exam, the patient is agitated and difficult to soothe. He has 2-3 inches of ecchymoses and swelling on the lateral aspect of the left forearm. The patient has a neurological exam within normal limits and pale skin with blue irises. An ophthalmologic evaluation is deferred. Which of the following is the best initial step?

A. Genetic testing
B. Complete blood count and coagulation panel (Correct Answer)
C. Ensure the child's safety and alert the police
D. Peripheral blood smear
E. Hemoglobin electrophoresis

Explanation: ***Complete blood count and coagulation panel*** - The unusual amount of **bruising** after minor trauma, along with a family history of an unknown blood disorder, strongly suggests a potential **bleeding disorder**. A **CBC** and a **coagulation panel** (PT, aPTT, fibrinogen) are essential initial steps to evaluate for abnormalities in platelets, clotting factors, or other hematologic conditions. - These tests can help narrow down the differential diagnosis between **platelet dysfunction**, **coagulopathies** (like hemophilia or von Willebrand disease), or other less common bleeding disorders, guiding further specific investigations. - **Important consideration:** The presence of **blue sclera** (described as "blue irises") raises concern for **osteogenesis imperfecta (OI)**, a connective tissue disorder causing bone fragility. However, initial hematologic screening is still appropriate given the family history of blood disorder and presentation of excessive bruising. If coagulation studies are normal, imaging and further workup for OI would be indicated. *Genetic testing* - While a genetic component is plausible given the patient's family history and clinical presentation (blue sclera may suggest osteogenesis imperfecta), **genetic testing** is typically performed *after* initial laboratory workup has identified a specific type of bleeding or inherited disorder. - Starting with genetic testing without basic hematologic parameters is not the most efficient or cost-effective initial diagnostic approach. *Ensure the child's safety and alert the police* - While child abuse should always be considered in cases of unexplained or excessive bruising, the presence of a **family history of a blood disorder** and the **blue sclera** (suggesting possible osteogenesis imperfecta) make **medical causes** more immediate concerns for initial investigation. - Pursuing a medical workup first often clarifies whether abuse is the primary explanation, although child protective services should be notified if suspicion remains high after medical evaluation. *Peripheral blood smear* - A **peripheral blood smear** provides information on red blood cell morphology, platelet size and number, and white blood cell differential. While useful in assessing for some hematologic conditions, it is often performed *after* a CBC has indicated abnormalities or in conjunction with specialized testing. - It would not be the *best initial step* as it doesn't directly assess clotting factor function, which is critical in evaluating significant bruising severity. *Hemoglobin electrophoresis* - **Hemoglobin electrophoresis** is used to diagnose **hemoglobinopathies** like sickle cell anemia or thalassemia. - The patient's symptoms (easy bruising) are not characteristic of hemoglobinopathies, and while he has pale skin, this test would not be the initial step to investigate a bleeding disorder.

Question 129: A 69-year-old white man comes to the physician because of a 15-day history of fatigue and lower leg swelling. Over the past 8 months, he has had a 3.8-kg (8.3-lb) weight loss. He has smoked one pack of cigarettes daily for 48 years. Vital signs are within normal limits. He appears thin. Examination shows 2+ pretibial edema bilaterally. An x-ray of the chest shows a right upper lobe density. Laboratory studies show: Hemoglobin 11.3 g/dL Leukocyte count 8600/mm3 Platelet count 140,000/mm3 Serum Urea nitrogen 25 mg/dL Glucose 79 mg/dL Creatinine 1.7 mg/dL Albumin 1.6 mg/dL Total cholesterol 479 mg/dL Urine Blood negative Glucose negative Protein 4+ WBC 0–1/hpf Fatty casts numerous Light microscopic examination of a kidney biopsy reveals thickening of glomerular capillary loops and the basal membrane. Which of the following is the most likely diagnosis?

A. Rapidly progressive glomerulonephritis
B. Granulomatosis with polyangiitis
C. Membranous nephropathy (Correct Answer)
D. Focal segmental glomerulosclerosis
E. Membranoproliferative glomerulonephritis

Explanation: ***Membranous nephropathy*** - The patient's presentation with **nephrotic syndrome** (edema, severe proteinuria 4+, hypoalbuminemia, hyperlipidemia, and fatigue) in an older adult, along with a **right upper lobe density** concerning for malignancy, strongly suggests secondary membranous nephropathy. - The renal biopsy finding of **thickening of glomerular capillary loops and the basal membrane** is a hallmark of membranous nephropathy. *Rapidly progressive glomerulonephritis* - Characterized by a **rapid decline in renal function** over days to weeks, often with oliguria and symptoms of severe systemic illness. - While proteinuria can be present, the classic biopsy finding is **crescent formation**, which is not described here. *Granulomatosis with polyangiitis* - This is a systemic vasculitis often involving the **upper and lower respiratory tracts** and kidneys, commonly presenting with **hemoptysis, sinusitis, and glomerulonephritis**. - While a lung density is present, the absence of **hemoptysis** and the specific biopsy findings of membranous nephropathy make it less likely. *Focal segmental glomerulosclerosis* - This typically causes nephrotic syndrome but is characterized by **segmental sclerosis of glomeruli** on biopsy. - While it can be idiopathic or secondary, the specific biopsy description and association with a potential malignancy point away from FSGS. *Membranoproliferative glomerulonephritis* - This condition presents with features of both **nephrotic and nephritic syndromes** and is characterized by a "tram-track" appearance on biopsy due to mesangial cell proliferation and basement membrane splitting. - This specific microscopic finding is not mentioned in the patient's biopsy report.

Question 130: A 6-year-old boy presents to your office with hematuria. Two weeks ago the patient had symptoms of a sore throat and fever. Although physical exam is unremarkable, laboratory results show a decreased serum C3 level and an elevated anti-DNAse B titer. Which of the following would you most expect to see on renal biopsy?

A. Immune complex deposits with a "spike and dome" appearance on electron microscopy
B. Large, hypercellular glomeruli on light microscopy (Correct Answer)
C. Wirelooping and hyaline thrombi on light microscopy
D. Polyclonal IgA deposition on immunofluorescence
E. Antibodies to GBM resulting in a linear immunofluorescence pattern

Explanation: ***Large, hypercellular glomeruli on light microscopy*** - The clinical presentation, including recent **sore throat**, **hematuria**, decreased **C3**, and elevated **anti-DNAse B titer**, is highly suggestive of **post-streptococcal glomerulonephritis (PSGN)**. - On light microscopy, PSGN characteristically shows **diffuse proliferative glomerulonephritis** with **enlarged, hypercellular glomeruli** due to inflammatory cell infiltration and proliferation of intrinsic glomerular cells. *Immune complex deposits with a "spike and dome" appearance on electron microscopy* - This "spike and dome" appearance refers to **subepithelial deposits** with new basement membrane formation, which is characteristic of **membranous nephropathy**, not PSGN. - Membranous nephropathy typically presents with **nephrotic syndrome** in adults, which is different from the child's presentation here. *Wirelooping and hyaline thrombi on light microscopy* - These features, particularly **"wire-loop" lesions** and **hyaline thrombi**, suggest severe **lupus nephritis**, a manifestation of **systemic lupus erythematosus**. - Lupus nephritis often presents with a range of kidney pathologies and systemic symptoms not seen in this patient. *Polyclonal IgA deposition on immunofluorescence* - **IgA deposition** in the mesangium is the hallmark of **IgA nephropathy (Berger's disease)**, which typically presents with recurrent hematuria, often after an upper respiratory infection. - While there is hematuria and a recent infection, the decreased C3 and elevated anti-DNAse B titer point away from IgA nephropathy. *Antibodies to GBM resulting in a linear immunofluorescence pattern* - A **linear pattern** of IgG deposits along the glomerular basement membrane (GBM) is characteristic of **Goodpasture syndrome (anti-GBM disease)**. - This condition involves antibodies specifically targeting the GBM and often presents with rapidly progressive glomerulonephritis and pulmonary hemorrhage, which are not described here.

Question 131: A 50-year-old man presents to a clinic with oliguria. Four weeks ago, he had a kidney transplant. Postoperative follow-up was normal. He is currently on cyclosporine and admits that sometimes he forgets to take his medication. On physical examination, the vital signs include: temperature 37.1°C (98.8°F), blood pressure 165/110 mm Hg, heart rate 80/min, and respiratory rate 16/min. There is mild tenderness on renal palpation. His serum creatinine level is 4 mg/dL, well above his baseline level after the transplant. Which of the following best describes the histological finding if a biopsy is taken from the transplanted kidney?

A. Lymphocytic infiltration of graft vessels and endothelial damage (Correct Answer)
B. Thrombosis and occlusion of vessels
C. Atherosclerosis on angiography
D. Necrosis with granulation tissue
E. Thickening of blood vessels, fibrosis of graft vessels, and parenchymal atrophy

Explanation: ***Lymphocytic infiltration of graft vessels and endothelial damage*** - The patient's presentation with **oliguria**, elevated **creatinine**, and **hypertension** following a recent kidney transplant, especially with a history of non-adherence to **cyclosporine** (an immunosuppressant), strongly indicates **acute rejection**. - Histologically, acute rejection is characterized by **lymphocytic infiltration** of the graft vessels (often referred to as **vasculitis** or **endotheliitis**) and associated **endothelial damage**. *Thrombosis and occlusion of vessels* - This finding is more characteristic of **hyperacute rejection**, which typically occurs within minutes to hours of transplantation, not weeks later. - Hyperacute rejection is mediated by **pre-formed antibodies** and leads to severe, rapid graft failure due to widespread intravascular thrombosis. *Atherosclerosis on angiography* - While post-transplant patients can develop accelerated atherosclerosis (a form of **chronic rejection**), it is typically a long-term complication developing months to years after transplantation. - The acute presentation with rapid creatinine elevation is not typical for primary atherosclerosis. *Necrosis with granulation tissue* - **Necrosis** with **granulation tissue** is a general healing response to significant tissue injury or inflammation. - While some cellular necrosis can occur in severe rejection, it's not the defining feature, and granulation tissue indicates a more prolonged, subacute process rather than the primary histological hallmark of acute rejection. *Thickening of blood vessels, fibrosis of graft vessels, and parenchymal atrophy* - These are classic features of **chronic rejection**, which manifests months to years after transplantation as a gradual decline in graft function. - **Chronic rejection** involves progressive damage leading to vasculopathy, interstitial fibrosis, and tubular atrophy, rather than the acute inflammatory cellular infiltrate seen here.

Question 132: A 22-year-old woman presents to her primary care physician complaining of a red, itchy rash on her elbows and shoulders for 2 months. She has no history of medical problems, and review of systems is positive only for occasional loose stools. She is appropriately prescribed dapsone, which relieves the rash within hours. What is the diagnosis?

A. Porphyria cutanea tarda
B. Candida intertrigo
C. Leprosy
D. Dermatitis herpetiformis (Correct Answer)
E. Systemic lupus erythematosus

Explanation: ***Dermatitis herpetiformis*** - The combination of a **red, itchy rash** on the **elbows and shoulders**, occasional **loose stools**, and a rapid response to **dapsone** is highly characteristic of dermatitis herpetiformis. - This condition is strongly associated with **celiac disease** (explaining the loose stools) and is characterized by IgA deposits in the dermal papillae, which are targeted by dapsone. *Porphyria cutanea tarda* - This condition presents with **photosensitive blistering lesions**, often on sun-exposed areas, and is associated with **liver disease** and iron overload, which are not described here. - While skin fragility and hypertrichosis can occur, the itching and dapsone response are not typical features. *Candida intertrigo* - This is a **fungal infection** typically found in **skin folds** (e.g., groin, axilla, inframammary folds) and presents with a beefy red rash with satellite lesions. - It would not typically affect the elbows and shoulders in this manner, nor would it respond rapidly to dapsone. *Leprosy* - Leprosy presents with **hypopigmented or erythematous skin lesions** with **sensory loss** and nerve involvement. - The symptoms described (itchy rash, specific location, quick dapsone response for itch) are not consistent with leprosy. *Systemic lupus erythematosus* - SLE can present with various skin manifestations, including a **malar rash** or discoid lesions, but a highly itchy rash on the elbows and shoulders rapidly responding to dapsone is not typical. - SLE is a **multi-system autoimmune disease** with other characteristic symptoms (e.g., arthralgia, fatigue, serositis) and laboratory findings that are not mentioned.

Question 133: A 10-year-old male presents with his mother with multiple complaints. A few weeks ago, he had a sore throat for several days that improved without specific therapy. Additionally, over the past several days he has experienced pain in his ankles and wrists and, more recently, his left knee. His mother also noted several bumps on both of his elbows, and he has also had some pain in his center of his chest. He thinks the pain is better when he leans forward. On physical examination, he is noted to be mildly febrile, and a pericardial friction rub is auscultated. Which of the following histopathologic findings is most likely associated with this patient's condition?

A. Interstitial myocardial granulomas containing plump macrophages with nuclei incorporating central wavy ribbons of chromatin (Correct Answer)
B. Sterile vegetations on both the ventricular and atrial aspects of the mitral valve, a proliferative glomerulonephritis, and serum anti-dsDNA and anti-Sm positivity
C. Needle-shaped, negatively birefringent crystal deposits surrounded by palisading histiocytes in the synovial fluid of an affected joint
D. Plasmodium falciparum ring forms in red blood cells on peripheral blood smear
E. Atypical lymphocytes noted on peripheral blood smear with an initial positive heterophil antibody test

Explanation: ***Interstitial myocardial granulomas containing plump macrophages with nuclei incorporating central wavy ribbons of chromatin*** - The clinical presentation, including a recent **sore throat**, **migratory polyarthritis**, **subcutaneous nodules** (bumps on elbows), **pericardial pain** relieved by leaning forward, and **pericardial friction rub**, is highly suggestive of **acute rheumatic fever (ARF)**. - **Aschoff bodies**, which are **interstitial myocardial granulomas** containing **Anitschkow cells** (plump macrophages with centrally wavy chromatin, often described as "caterpillar cells"), are the **pathognomonic histopathologic finding** for ARF. *Sterile vegetations on both the ventricular and atrial aspects of the mitral valve, a proliferative glomerulonephritis, and serum anti-dsDNA and anti-Sm positivity* - This description points to **Libman-Sacks endocarditis** in the context of **systemic lupus erythematosus (SLE)**, characterized by **sterile vegetations** on both sides of the valve and associated with **lupus nephritis** and specific **autoantibodies (anti-dsDNA, anti-Sm)**. - While ARF can cause endocarditis, the vegetations are typically on the atrial side and not usually associated with the described glomerulonephritis or autoantibody profile. *Needle-shaped, negatively birefringent crystal deposits surrounded by palisading histiocytes in the synovial fluid of an affected joint* - This describes the characteristic findings in **gout**, where **monosodium urate crystals** accumulate in joints, causing inflammatory arthritis. - The patient's symptoms of migratory polyarthritis and pericarditis are not typical for gout, and gout is rare in children. *Plasmodium falciparum ring forms in red blood cells on peripheral blood smear* - This is the diagnostic finding for **malaria**, specifically infection with *Plasmodium falciparum*. - The patient's symptoms, while including fever, do not suggest malaria, and signs such as arthritis and pericarditis are not primary features of malaria. *Atypical lymphocytes noted on peripheral blood smear with an initial positive heterophil antibody test* - This describes the classic laboratory findings for **infectious mononucleosis**, typically caused by the **Epstein-Barr virus (EBV)**. - While a sore throat can precede mononucleosis, the severe migratory arthritis, subcutaneous nodules, and pericarditis are not characteristic features of this condition.

Question 134: A 6-year-old child presents for evaluation of a medical condition associated with recurrent infections. After reviewing all of the medical history, gene therapy is offered to treat a deficiency in adenosine deaminase (ADA). ADA deficiency is the most common autosomal recessive mutation in which of the following diseases?

A. Wiskott-Aldrich Syndrome
B. Bruton's Agammaglobulinemia
C. Severe Combined Immunodeficiency (Correct Answer)
D. DiGeorge Syndrome
E. Hyper-IgM Syndrome

Explanation: ***Severe Combined Immunodeficiency*** - **Adenosine deaminase (ADA) deficiency** leads to the accumulation of toxic metabolites that impair lymphocyte development and function, primarily affecting **T and B cells**, which is a common cause of SCID. - Patients with SCID present with **recurrent, severe infections** due to profound immunodeficiency, making them candidates for treatments like gene therapy. *Wiskott-Aldrich Syndrome* - This is an **X-linked recessive disorder** characterized by eczema, thrombocytopenia, and immunodeficiency, but it is caused by a mutation in the **WASP gene**, not ADA deficiency. - While it involves immunodeficiency and recurrent infections, the underlying genetic defect and specific clinical triad are distinct from ADA deficiency. *Bruton's Agammaglobulinemia* - This is an **X-linked recessive disorder** caused by a defect in the **BTK gene**, leading to a lack of mature B cells and hence very low levels of immunoglobulins. - While it results in recurrent bacterial infections due to absent antibodies, its genetic cause and primary immunological defect (B cell specific) differ from ADA deficiency. *DiGeorge Syndrome* - This is a developmental disorder caused by a **microdeletion on chromosome 22q11.2**, leading to abnormal development of the third and fourth pharyngeal pouches. - It results in **T-cell deficiency** due to thymic aplasia/hypoplasia, hypocalcemia due to parathyroid hypoplasia, and congenital heart defects, but not ADA deficiency. *Hyper-IgM Syndrome* - This syndrome is characterized by normal or elevated IgM levels and deficiencies in other immunoglobulins (IgG, IgA, IgE), largely due to defects in **CD40-CD40L interaction** or other genes involved in isotype switching. - Patients suffer from recurrent infections and opportunistic infections but the genetic basis and specific immunological defect are distinct from ADA deficiency.

Question 135: A 49-year-old woman with a history of intravenous drug use comes to the physician because of a 6-month history of fatigue, joint pain, and episodic, painful discoloration in her fingers when exposed to cold weather. She takes no medications. She has smoked one pack of cigarettes daily for the past 22 years. She appears tired. Physical examination shows palpable, nonblanching purpura over the hands and feet. Neurological examination shows weakness and decreased sensation in all extremities. Serum studies show: Alanine aminotransferase 78 U/L Aspartate aminotransferase 90 U/L Urea nitrogen 18 mg/dL Creatinine 1.5 mg/dL Which of the following processes is the most likely explanation for this patient's current condition?

A. Fibroblast proliferation
B. Immune complex formation (Correct Answer)
C. Spirochete infection
D. Tobacco hypersensitivity
E. Plasma cell malignancy

Explanation: **Immune complex formation** * The patient's history of **intravenous drug use** and a constellation of symptoms including **fatigue**, **joint pain**, **Raynaud phenomena**, and **palpable purpura** are highly suggestive of **mixed cryoglobulinemia**. * **Mixed cryoglobulinemia** is characterized by the presence of **immune complexes** (immunoglobulins that precipitate in the cold) that can deposit in small and medium-sized vessels, leading to **vasculitis** and organ damage, often triggered by chronic infections like **Hepatitis C** (common in IV drug users). *Fibroblast proliferation* * While **fibroblast proliferation** is involved in fibrosis and scaring, it does not explain the widespread systemic symptoms such as **purpura**, **neuropathy**, and **renal involvement** seen here. * Conditions driven primarily by fibroblast proliferation, such as **scleroderma**, present with skin thickening and organ fibrosis but typically lack prominent vasculitic features like palpable purpura. *Spirochete infection* * **Spirochete infections** (e.g., syphilis, Lyme disease) can cause fatigue and joint pain, but they do not typically present with **palpable purpura**, **Raynaud phenomenon**, or the specific pattern of organ involvement (liver and kidney dysfunction) seen in this patient. * While syphilis can cause central nervous system issues, the **peripheral neuropathy** described here along with cutaneous vasculitis does not align with a typical spirochetal presentation. *Tobacco hypersensitivity* * **Tobacco hypersensitivity** is not a recognized medical condition explaining this array of symptoms. * Smoking is a risk factor for various vascular diseases (e.g., Buerger's disease), but it does not cause **immune-complex mediated vasculitis** with palpable purpura and neuropathy. *Plasma cell malignancy* * **Plasma cell malignancies** like **multiple myeloma** can cause fatigue, kidney problems, and neuropathy due to monoclonal immunoglobulin deposition or amyloidosis. * However, **palpable purpura** and **Raynaud phenomena** are very uncommon primary manifestations of plasma cell malignancies, making immune complex vasculitis a more fitting diagnosis for this patient's presentation.

Question 136: A 52-year-old woman presents with erosions in her mouth that are persistent and painful. She says that symptoms appeared gradually 1 week ago and have progressively worsened. She also notes that, several days ago, flaccid blisters appeared on her skin, which almost immediately transformed to erosions as well. Which of the following is the most likely diagnosis?

A. Molluscum contagiosum
B. Psoriasis
C. Pemphigus vulgaris (Correct Answer)
D. Bullous pemphigoid
E. Staphylococcal infection (scalded skin syndrome)

Explanation: **Pemphigus vulgaris** - The presence of **persistent and painful oral erosions** followed by **flaccid blisters** that quickly break into erosions on the skin is highly characteristic of pemphigus vulgaris. This is due to **acantholysis** (loss of cell-to-cell adhesion) within the epidermis. - The oral lesions typically precede skin lesions and are often the first symptom, as seen in this patient, and are very painful. *Molluscum contagiosum* - Causes **dome-shaped, umbilicated papules** and does not present with widespread flaccid blisters or painful erosions. - It is a viral infection common in children and immunocompromised individuals. *Psoriasis* - Characterized by **erythematous plaques with silvery scales**, typically found on extensor surfaces. - It does not involve flaccid blisters or widespread mucosal erosions. *Bullous pemphigoid* - Presents with **tense bullae** on an erythematous or urticarial base, which are less likely to rupture quickly compared to the flaccid blisters of pemphigus vulgaris. Oral lesions are less common (affecting 10-30%) and generally less severe than in pemphigus vulgaris. - It involves autoantibodies against **hemidesmosomes**, leading to subepidermal blistering. *Staphylococcal infection (scalded skin syndrome)* - Primarily affects infants and young children, causing widespread **erythema and superficial blistering**, resembling a burn, leading to epidermal sloughing. - It can cause diffuse nonscarring exfoliation and not well-demarcated oral erosions or flaccid blisters leading to erosions in this age group as is seen in this patient.

Question 137: A 24-year-old man comes to the emergency department because of progressive shortness of breath and intermittent cough with blood-tinged sputum for the past 10 days. During this time, he had three episodes of blood in his urine. Six years ago, he was diagnosed with latent tuberculosis after a positive routine tuberculin skin test, and he was treated accordingly. His maternal aunt has systemic lupus erythematosus. The patient does not take any medications. His temperature is 37°C (98.6°F), pulse is 92/min, respirations are 28/min, and blood pressure is 152/90 mm Hg. Diffuse crackles are heard at both lung bases. Laboratory studies show: Serum Urea nitrogen 32 mg/dL Creatinine 3.5 mg/dL Urine Protein 2+ Blood 3+ RBC casts numerous WBC casts negative A chest x-ray shows patchy, pulmonary infiltrates bilaterally. A renal biopsy in this patient shows linear deposits of IgG along the glomerular basement membrane. Which of the following is the most likely diagnosis?

A. Goodpasture syndrome (Correct Answer)
B. Lupus nephritis
C. Granulomatosis with polyangiitis
D. Reactivated tuberculosis
E. Microscopic polyangiitis

Explanation: **Goodpasture syndrome** - The patient presents with **pulmonary hemorrhage** (shortness of breath, blood-tinged sputum, diffuse crackles, patchy infiltrates) and **rapidly progressive glomerulonephritis** (elevated creatinine, proteinuria, hematuria, RBC casts), which is characteristic of **Goodpasture syndrome**. - The renal biopsy finding of **linear deposits of IgG along the glomerular basement membrane** is pathognomonic for Goodpasture syndrome, indicating the presence of anti-GBM antibodies. *Lupus nephritis* - While **systemic lupus erythematosus** can cause glomerulonephritis, the biopsy would show **granular immune complex deposits** (Class III, IV, or V lupus nephritis), not linear IgG deposits. - Pulmonary involvement in lupus can occur but does not typically present as diffuse alveolar hemorrhage with linear IgG deposits. *Granulomatosis with polyangiitis* - This condition is characterized by **granulomatous inflammation** and **necrotizing vasculitis** affecting the respiratory tract and kidneys, often with c-ANCA positivity. - However, the renal biopsy in granulomatosis with polyangiitis would typically show **pauci-immune glomerulonephritis** (i.e., minimal or no immune deposits), which contradicts the linear IgG deposits found. *Reactivated tuberculosis* - Although the patient has a history of latent tuberculosis, his current symptoms of **severe kidney failure** and **diffuse alveolar hemorrhage** are not typical presentations of reactivated pulmonary tuberculosis. - Reactivated TB would be more likely to cause cavitation, chronic cough, and constitutional symptoms, not rapidly progressive glomerulonephritis with linear IgG deposition. *Microscopic polyangiitis* - Like granulomatosis with polyangiitis, microscopic polyangiitis is a **pauci-immune vasculitis** affecting small vessels and can cause lung and kidney involvement, often associated with p-ANCA. - The key differentiating factor is the absence of immune complex or linear IgG deposition on renal biopsy in microscopic polyangiitis, which is inconsistent with the patient's findings.

Question 138: A 1-year-old infant is brought to the emergency department by his parents because of fever and rapid breathing for the past 2 days. He had a mild seizure on the way to the emergency department and developed altered sensorium. His mother states that the patient has had recurrent respiratory infections since birth. He was delivered vaginally at term and without complications. He is up to date on his vaccines and has met all developmental milestones. His temperature is 37.0°C (98.6°F), pulse rate is 200/min, and respirations are 50/min. He is lethargic, irritable, and crying excessively. Physical examination is notable for a small head, an elongated face, broad nose, low set ears, and cleft palate. Cardiopulmonary exam is remarkable for a parasternal thrill, grade IV pansystolic murmur, and crackles over both lung bases. Laboratory studies show hypocalcemia and lymphopenia. Blood cultures are drawn and broad-spectrum antibiotics are started, and the child is admitted to the pediatric intensive care unit. The intensivist suspects a genetic abnormality and a fluorescence in situ hybridization (FISH) analysis is ordered which shows 22q11.2 deletion. Despite maximal therapy, the infant succumbs to his illness. The parents of the child request an autopsy. Which of the following findings is the most likely to be present on autopsy?

A. Aplastic thymus (Correct Answer)
B. Hypercellular bone marrow
C. Accessory spleen
D. Hypertrophy of Hassall's corpuscles
E. Absent follicles in the lymph nodes

Explanation: ***Aplastic thymus*** - This infant's presentation with 22q11.2 deletion, recurrent respiratory infections, hypocalcemia, and congenital heart disease (parasternal thrill, pansystolic murmur) is classic for **DiGeorge syndrome**. - **DiGeorge syndrome** is characterized by thymic aplasia or hypoplasia, leading to **T-cell immunodeficiency**, and parathyroid hypoplasia, resulting in **hypocalcemia**. *Hypercellular bone marrow* - **Hypercellular bone marrow** indicates increased hematopoietic activity and is not a characteristic finding in DiGeorge syndrome. - In immunodeficiency states like DiGeorge, the bone marrow itself is often normal or may show lymphoid depletion. *Accessory spleen* - **Accessory spleen** is a common congenital anomaly and is not specifically associated with DiGeorge syndrome or its immunodeficiency. - While it can occur in individuals with DiGeorge syndrome, it is not a direct pathological consequence of the 22q11.2 deletion. *Hypertrophy of Hassall's corpuscles* - **Hassall's corpuscles** are found in the medulla of the thymus, and their hypertrophy would indicate an active or hyperplastic thymus, which is contrary to the **thymic aplasia/hypoplasia** seen in DiGeorge syndrome. - In DiGeorge syndrome, the thymus is either absent or severely underdeveloped. *Absent follicles in the lymph nodes* - **Absent follicles in the lymph nodes** would indicate a B-cell deficiency, as follicles are primarily composed of B lymphocytes. - DiGeorge syndrome primarily affects **T-cell development** due to thymic abnormalities, not B-cell development or lymph node follicular formation directly.

Question 139: A 48-year-old man comes to the emergency department because of a 2-hour history of severe left-sided colicky flank pain that radiates towards his groin. He has vomited twice. Last year, he was treated with ibuprofen for swelling and pain of his left toe. He drinks 4-5 beers most days of the week. Examination shows left costovertebral angle tenderness. An upright x-ray of the abdomen shows no abnormalities. A CT scan of the abdomen and pelvis shows an 9-mm stone in the proximal ureter on the left. Which of the following is most likely to be seen on urinalysis?

A. Rhomboid-shaped crystals
B. Coffin-lid-like crystals
C. Red blood cell casts
D. Wedge-shaped crystals (Correct Answer)
E. Hexagon-shaped crystals

Explanation: ***Wedge-shaped crystals*** - The patient's history of **left toe swelling and pain** (suggestive of **gout**) and **alcohol consumption** strongly indicate **hyperuricemia** and predisposition to **uric acid stone** formation. - **Uric acid stones are radiolucent**, which explains why the **X-ray showed no abnormalities** despite a 9-mm stone being visible on CT scan—this is a classic presentation. - **Uric acid crystals** appear as **wedge-shaped, rhomboid, or pleomorphic** yellow-brown crystals in **acidic urine** (pH <5.5). - This is the most likely finding on urinalysis given the clinical context. *Rhomboid-shaped crystals* - **Rhomboid-shaped crystals** are also characteristic of **uric acid**, making this another acceptable description of the same crystal type. - Both "wedge-shaped" and "rhomboid" refer to **uric acid crystals**; however, "wedge-shaped" is the more commonly used descriptor in clinical practice. - If this were an option and wedge-shaped were not available, it would also be correct, but wedge-shaped is the better answer when both are present. *Coffin-lid-like crystals* - **Coffin-lid crystals** are characteristic of **struvite stones** (magnesium ammonium phosphate), which form in **alkaline urine** (pH >7) and are associated with **urease-producing bacteria** (e.g., Proteus, Klebsiella). - Struvite stones are **radiopaque** and would be visible on X-ray, which contradicts this presentation. - The patient has no signs of urinary tract infection. *Red blood cell casts* - **RBC casts** indicate **glomerular bleeding** and are seen in conditions like **glomerulonephritis**, not obstructive uropathy from stones. - While **hematuria** (RBCs in urine) is common with nephrolithiasis, **RBC casts** are not typical and would suggest primary renal parenchymal disease. *Hexagon-shaped crystals* - **Hexagonal crystals** are pathognomonic for **cystine stones**, which occur in **cystinuria**, a rare autosomal recessive disorder of amino acid transport. - Cystine stones are **weakly radiopaque** and would show faint opacity on X-ray. - This condition typically presents in childhood or young adulthood, not at age 48, and has no association with gout.

Question 140: A 7-year-old girl is brought to the physician by her mother because of a 5-day history of fever, fatigue, and red spots on her body. Her temperature is 38.3°C (101.1°F), pulse is 115/min, and blood pressure is 100/60 mm Hg. Physical examination shows pallor and petechiae over the trunk and lower extremities. Laboratory studies show a hemoglobin concentration of 7 g/dL, a leukocyte count of 2,000/mm3, a platelet count of 40,000/mm3, and a reticulocyte count of 0.2%. Peripheral blood smear shows normochromic, normocytic cells. A bone marrow aspirate shows hypocellularity. Which of the following is the most likely cause of this patient's findings?

A. Idiopathic thrombocytopenic purpura
B. Aplastic anemia (Correct Answer)
C. Acute lymphoblastic leukemia
D. Multiple myeloma
E. Primary myelofibrosis

Explanation: ***Aplastic anemia*** - This diagnosis is strongly supported by the **pancytopenia** (anemia, leukopenia, thrombocytopenia), **fatigue**, and **petechiae**, coupled with a **hypocellular bone marrow** aspirate. - The **low reticulocyte count** further indicates reduced erythropoiesis, a hallmark of bone marrow failure. *Idiopathic thrombocytopenic purpura* - This condition primarily causes isolated **thrombocytopenia**, while the patient also exhibits severe anemia and leukopenia. - Bone marrow in ITP is typically normal or shows increased megakaryocytes, not hypocellularity. *Acute lymphoblastic leukemia* - While ALL can present with pancytopenia, fatigue, and petechiae, the bone marrow in ALL would show **hypercellularity** with an abundance of **blasts**, not hypocellularity. - The absence of blasts on the peripheral smear and hypocellular marrow makes ALL unlikely. *Multiple myeloma* - This is a malignancy of **plasma cells** predominantly affecting older adults and is characterized by bone pain, hypercalcemia, renal failure, and monoclonal gammopathy. - The patient's age and clinical presentation, especially the hypocellular bone marrow, are inconsistent with multiple myeloma. *Primary myelofibrosis* - Myelofibrosis typically presents with **extramedullary hematopoiesis**, splenomegaly, and a "dry tap" on bone marrow aspirate, which would show fibrosis. - The patient's bone marrow is described as hypocellular, and no splenomegaly is mentioned, making myelofibrosis less likely.

Question 141: A 25-year-old woman comes to the physician because of a 2-week history of episodic bleeding from the nose and gums and one episode of blood in her urine. She was treated with chloramphenicol 1 month ago for Rickettsia rickettsii infection. Her pulse is 130/min, respirations are 22/min, and blood pressure is 105/70 mm Hg. Examination shows mucosal pallor, scattered petechiae, and ecchymoses on the extremities. Laboratory studies show: Hemoglobin 6.3 g/dL Hematocrit 26% Leukocyte count 900/mm3 (30% neutrophils) Platelet count 50,000/mm3 The physician recommends a blood transfusion and informs her of the risks and benefits. Which of the following red blood cell preparations will most significantly reduce the risk of transfusion-related cytomegalovirus infection?

A. Warming
B. Irradiation
C. Centrifugation
D. Washing
E. Leukoreduction (Correct Answer)

Explanation: ***Leukoreduction*** - **Cytomegalovirus (CMV)** is primarily transmitted via **leukocytes** in blood products, as it is a latent infection within these cells. - **Leukoreduction** removes most white blood cells, thereby significantly reducing the risk of CMV transmission, especially in immunocompromised patients or those at high risk. *Warming* - **Warming blood** to body temperature before transfusion helps prevent hypothermia in the recipient and reduces the risk of cardiac arrhythmias. - It does not, however, have any significant effect on reducing the transmission of infectious agents like CMV. *Irradiation* - **Irradiation** of blood products inactivates donor T lymphocytes, preventing **transfusion-associated graft-versus-host disease (TA-GVHD)**, predominantly in immunocompromised recipients. - It does not effectively remove or inactivate viruses like CMV that reside within cells. *Centrifugation* - **Centrifugation** is used to separate blood components based on their different densities (e.g., plasma, platelets, red blood cells). - While it separates components, it does not specifically remove or inactivate CMV-infected white blood cells from the remaining red blood cell product in a manner that significantly reduces infection risk. *Washing* - **Washing red blood cells** with saline removes plasma proteins, antibodies, and some white blood cells, which can prevent allergic reactions to plasma proteins or hyperkalemia. - While it may remove some leukocytes, it is generally less effective than leukoreduction for preventing CMV transmission and is primarily indicated for other specific transfusion reactions.

Question 142: A 73-year-old man comes to the physician because of progressive fatigue and shortness of breath on exertion for 3 weeks. He has swelling of his legs. He has not had nausea or vomiting. His symptoms began shortly after he returned from a trip to Cambodia. He occasionally takes ibuprofen for chronic back pain. He has a history of arterial hypertension and osteoarthritis of both knees. He had an episode of pneumonia 4 months ago. His current medications include lisinopril and hydrochlorothiazide. He has no history of drinking or smoking. His temperature is 37°C (98.6°F), pulse is 101/min, and blood pressure is 135/76 mm Hg. Examination shows pitting edema of the upper and lower extremities. Laboratory studies show: Hemoglobin 14.1 g/dL Leukocyte count 6,800/mm3 Platelet count 216,000/mm3 Serum Urea nitrogen 26 mg/dL Creatinine 2.9 mg/dL Albumin 1.6 g/dL Urine Blood negative Protein 4+ Glucose negative Renal biopsy with Congo red stain shows apple-green birefringence under polarized light. Further evaluation of this patient is most likely to show which of the following findings?

A. Positive interferon-γ release assay
B. Dilated bronchi on chest CT
C. Elevated anti-citrullinated peptide antibodies
D. Positive HLA-B27 test
E. Rouleaux formation on peripheral smear (Correct Answer)

Explanation: ***Rouleaux formation on peripheral smear*** - The renal biopsy showing **apple-green birefringence** with Congo red stain is pathognomonic for **amyloidosis**. - The clinical presentation of **nephrotic syndrome** (massive proteinuria, hypoalbuminemia, edema) with renal amyloidosis in an elderly patient is most commonly due to **AL (light chain) amyloidosis** caused by plasma cell dyscrasia. - AL amyloidosis is associated with **monoclonal gammopathy** which causes increased serum protein viscosity, leading to **rouleaux formation** (stacking of RBCs like coins) on peripheral blood smear. - Further workup would typically show serum/urine protein electrophoresis with monoclonal protein and possibly bone marrow plasmacytosis. *Positive interferon-γ release assay* - This test diagnoses **latent or active tuberculosis**. - While TB can cause **AA (secondary) amyloidosis** through chronic inflammation, and the patient traveled to an endemic area, the renal-limited presentation without active systemic infection makes AL amyloidosis more likely. - AA amyloidosis typically presents with chronic inflammatory conditions lasting months to years. *Dilated bronchi on chest CT* - **Bronchiectasis** causes chronic inflammation and can lead to **AA amyloidosis**. - However, a single episode of pneumonia 4 months ago is insufficient to cause the chronic inflammation needed for AA amyloidosis. - This finding would not directly relate to the amyloid deposition causing current symptoms. *Elevated anti-citrullinated peptide antibodies* - These antibodies are highly specific for **rheumatoid arthritis**, which can cause AA amyloidosis. - However, the patient has **osteoarthritis** (degenerative joint disease), not inflammatory arthritis. - There are no clinical features suggesting RA (no joint inflammation, no morning stiffness). *Positive HLA-B27 test* - **HLA-B27** is associated with **seronegative spondyloarthropathies** which can rarely cause AA amyloidosis. - The patient's back pain is attributed to chronic mechanical issues, not inflammatory spondyloarthropathy. - This finding is unrelated to the renal amyloidosis presentation.

Question 143: A 23-year-old African American man presents to the emergency department with severe pain. The patient, who is a construction worker, was at work when he suddenly experienced severe pain in his arms, legs, chest, and back. He has experienced this before and was treated 2 months ago for a similar concern. His temperature is 100°F (37.8°C), blood pressure is 127/68 mmHg, pulse is 120/min, respirations are 17/min, and oxygen saturation is 98% on room air. Physical exam is notable for tenderness to palpation of the patient's legs, chest, abdomen, and arms. Laboratory values are obtained and shown below. Hemoglobin: 10 g/dL Hematocrit: 30% Leukocyte count: 8,500/mm³ with normal differential Platelet count: 199,000/mm³ Reticulocyte count: 8% Serum: Na+: 139 mEq/L Cl-: 100 mEq/L K+: 4.9 mEq/L HCO3-: 25 mEq/L BUN: 23 mg/dL LDH: 327 U/L Glucose: 99 mg/dL Creatinine: 1.1 mg/dL Ca2+: 10.2 mg/dL AST: 12 U/L ALT: 10 U/L Which of the following is the most likely diagnosis?

A. Infection of the bone
B. Microvascular occlusion (Correct Answer)
C. Autoimmune hemolysis
D. Infarction of a major organ
E. Avascular necrosis

Explanation: ***Microvascular occlusion*** - The patient's presentation with **severe, diffuse pain** (arms, legs, chest, back) and a history of similar episodes, especially in an **African American male**, strongly suggests a **vaso-occlusive crisis** due to **sickle cell disease**. - **Elevated reticulocyte count** (8%) and **mild anemia** (Hb 10 g/dL) with normal WBC and platelet counts are consistent with **chronic hemolysis** and the body's attempt to compensate, typical for sickle cell disease. *Infection of the bone* - While patients with **sickle cell disease** are prone to **osteomyelitis**, a bone infection generally presents with more localized pain and higher fever, not diffuse body pain. - The presented vital signs and lab values, particularly the **normal leukocyte count**, do not strongly support an acute, widespread infectious process like osteomyelitis. *Autoimmune hemolysis* - **Autoimmune hemolysis** typically causes anemia, reticulocytosis, and elevated LDH, but it does not cause the characteristic **severe, diffuse body pain** seen in this patient. - The patient's symptoms are more indicative of a vaso-occlusive event rather than immune-mediated destruction of red blood cells. *Infarction of a major organ* - While **sickle cell disease** can lead to organ infarction, the broad, diffuse pain described typically represents a **vaso-occlusive crisis** affecting multiple tissues rather than a single major organ. - Lab results and symptoms do not point to a specific organ infarction, such as myocardial (normal AST/ALT) or renal (normal creatinine with mild BUN elevation which is usually present in dehydrated active people) infarction. *Avascular necrosis* - **Avascular necrosis** (AVN) is a complication of sickle cell disease, causing chronic joint pain, most commonly in the hips or shoulders. - The patient's symptoms describe **acute, severe, diffuse pain** affecting multiple body parts, which is more characteristic of a vaso-occlusive crisis than the localized, chronic pain of avascular necrosis.

Question 144: A 33-year-old G2P2 woman presents with a history of fatigue and difficulty breathing upon exertion. She was not able to tolerate antenatal vitamin supplements due to nausea and constipation. Her vital signs include: temperature 37.0°C (98.6°F), blood pressure 112/64 mm Hg, and pulse 98/min. Physical examination reveals conjunctival pallor and spoon nails. Laboratory findings are significant for the following: Hemoglobin 9.1 g/dL Hematocrit 27.3% Mean corpuscular volume (MCV) 73 μm3 Mean corpuscular hemoglobin (MCH) 21 pg/cell Red cell distribution width (RDW) 17.5% (ref: 11.5–14.5%) Serum ferritin 9 ng/mL Which of the following would most likely be seen on a peripheral blood smear in this patient?

A. Teardrop cells
B. Degmacytes
C. Basophilic stippling
D. Echinocytes
E. Anisopoikilocytosis (Correct Answer)

Explanation: ***Anisopoikilocytosis*** - The patient's blood work (low **hemoglobin**, **hematocrit**, **MCV**, **MCH**, and **serum ferritin**) indicates **microcytic hypochromic anemia** due to **iron deficiency**. The elevated **RDW** suggests significant variation in red blood cell size (anisocytosis) and shape (poikilocytosis), making **anisopoikilocytosis** on the smear most likely. - **Iron deficiency anemia** is characterized by the presence of red blood cells that vary widely in size and shape on a peripheral smear. In severe cases, a wide variety of abnormal shapes are observed (poikilocytosis), along with variations in size (anisocytosis). *Teardrop cells* - **Teardrop cells** (dacryocytes) are typically seen in conditions like **myelofibrosis**, **thalassemia**, or other types of **myelophthisic anemia**, which are not suggested by this patient’s presentation. - While they can be seen in severe iron deficiency, the primary and most defining feature would be the overall variation in size and shape encapsulated by anisopoikilocytosis. *Degmacytes* - **Degmacytes**, also known as **bite cells**, are formed when phagocytes remove denatured hemoglobin (Heinz bodies) from red blood cells, which is characteristic of **G6PD deficiency** or other **oxidative hemolytic anemias**. - This is not consistent with the patient's presentation of iron deficiency, which is a production problem rather than a premature destruction problem. *Basophilic stippling* - **Basophilic stippling** refers to the presence of small, dark blue granules in red blood cells that represent aggregated ribosomes and is typically associated with conditions such as **lead poisoning**, **thalassemia**, or **sideroblastic anemia**. - These conditions are not indicated by the patient's symptoms or lab findings. *Echinocytes* - **Echinocytes**, or **burr cells**, are red blood cells with evenly spaced, spiny projections and are commonly seen in **uremia**, **pyruvate kinase deficiency**, or as an artifact of slide preparation. - They are not a characteristic finding in iron deficiency anemia.

Question 145: A 35-year-old G4P1 woman presents for follow-up after her 3rd miscarriage. All 3 miscarriages occurred during the 2nd trimester. Past medical history is significant for systemic lupus erythematosus (SLE) and a deep vein thrombosis (DVT) in her right lower leg 3 years ago. Her current medication is hydroxychloroquine. The patient denies any tobacco, alcohol, and illicit substance use. Her vitals include: temperature 36.8℃ (98.2℉), blood pressure 114/76 mm Hg, pulse 84/min, respiration rate 12/min. Physical examination reveals a lacy, violaceous discoloration on her lower legs. Which of the following autoantibodies would this patient most likely test positive for?

A. Anti-smooth muscle
B. Anti-Ro
C. Anti-Scl-70
D. Anti-centromere
E. Anti-phospholipid (Correct Answer)

Explanation: ***Anti-phospholipid*** - This patient presents with a history of **recurrent second-trimester miscarriages** and a **deep vein thrombosis (DVT)**, classic features of **antiphospholipid syndrome (APS)**. - The **lacy, violaceous discoloration (livedo reticularis)** on her lower legs is also a common cutaneous manifestation of APS, further supporting this diagnosis. *Anti-smooth muscle* - **Anti-smooth muscle antibodies (ASMAs)** are primarily associated with **autoimmune hepatitis**. - While autoimmune conditions can coexist, the patient's presentation does not include features indicative of hepatitis. *Anti-Ro* - **Anti-Ro (SSA) antibodies** are associated with **Sjögren's syndrome** and a subset of **systemic lupus erythematosus (SLE)**, particularly with **subacute cutaneous lupus erythematosus** and **neonatal lupus**. - Although the patient has SLE, the key thrombotic and obstetric complications point more strongly to APS than to conditions primarily associated with anti-Ro antibodies. *Anti-Scl-70* - **Anti-Scl-70 antibodies** (also known as **anti-topoisomerase I**) are highly specific for **systemic sclerosis (scleroderma)**, particularly the **diffuse cutaneous form**. - The patient's symptoms are not consistent with systemic sclerosis. *Anti-centromere* - **Anti-centromere antibodies** are characteristic of **CREST syndrome**, a limited form of systemic sclerosis. - The patient's clinical picture does not align with the typical features of CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias).

Question 146: Two weeks after undergoing allogeneic stem cell transplant for multiple myeloma, a 55-year-old man develops a severely pruritic rash, abdominal cramps, and profuse diarrhea. He appears lethargic. Physical examination shows yellow sclerae. There is a generalized maculopapular rash on his face, trunk, and lower extremities, and desquamation of both soles. His serum alanine aminotransferase is 115 U/L, serum aspartate aminotransferase is 97 U/L, and serum total bilirubin is 2.7 mg/dL. Which of the following is the most likely underlying cause of this patient's condition?

A. Preformed cytotoxic anti-HLA antibodies
B. Proliferating transplanted B cells
C. Activated recipient T cells
D. Donor T cells in the graft (Correct Answer)
E. Newly formed anti-HLA antibodies

Explanation: ***Donor T cells in the graft*** - The symptoms (rash, GI symptoms, liver dysfunction) after an allogeneic stem cell transplant are classic signs of **acute graft-versus-host disease (GVHD)**. This condition occurs when **immunocompetent T cells from the donor graft** recognize the recipient's tissues as foreign and mount an immune attack. - The rapid onset within two weeks post-transplant, elevated liver enzymes, jaundice (**yellow sclerae**, **elevated bilirubin**), severe pruritic rash, and GI symptoms (**abdominal cramps**, **profuse diarrhea**) are all characteristic manifestations of acute GVHD. *Preformed cytotoxic anti-HLA antibodies* - Preformed antibodies would typically cause **hyperacute rejection**, which occurs within minutes to hours of transplantation and involves widespread thrombosis and necrosis of the graft, not the systemic symptoms seen here. - This reaction is mediated by the recipient's antibodies attacking donor antigens, leading to immediate graft failure. *Proliferating transplanted B cells* - Transplanted B cells can contribute to chronic GVHD through antibody production, but they are not the primary mediators of **acute GVHD**; acute GVHD is predominantly a T cell-mediated process. - Proliferation of donor B cells is more commonly associated with post-transplant lymphoproliferative disorders (PTLD) or chronic GVHD, not the acute presentation described. *Activated recipient T cells* - In an allogeneic transplant, the recipient's immune system is usually heavily suppressed beforehand to prevent host-versus-graft rejection. - If recipient T cells were active, they would primarily cause **rejection of the donor stem cells** (graft rejection), not the systemic symptoms of GVHD, which is a reaction of the donor cells against the host. *Newly formed anti-HLA antibodies* - Newly formed antibodies the recipient develops against the donor's HLA antigens would cause graft rejection, a process often delayed but not presenting as the widespread organ damage of acute GVHD. - These antibodies are part of the host's attempt to reject the foreign graft, not the donor cells attacking the host.

Question 147: A 61-year-old woman comes to the physician for evaluation of numbness and a burning sensation in her feet for the past 5 months. She has type 2 diabetes mellitus and hypercholesterolemia. Her blood pressure is 119/82 mm Hg. Neurologic examination shows decreased sensation to pinprick, light touch, and vibration over the soles of both feet. There is a nontender ulcer on the plantar surface of her left foot. Pedal pulses are strong bilaterally. Her hemoglobin A1c concentration is 8.6%. Which of the following processes is most likely involved in the pathogenesis of this patient's current symptoms?

A. Demyelination of posterior columns and lateral corticospinal tracts
B. Increased protein deposition in endoneural vessel walls (Correct Answer)
C. Accumulation of lipids and foam cells in arteries
D. Elevated hydrostatic pressure in arteriolar lumen
E. Osmotic damage to oligodendrocyte nerve sheaths

Explanation: ***Increased protein deposition in endoneural vessel walls*** - The patient exhibits symptoms consistent with **diabetic neuropathy**, including numbness, burning sensation, decreased sensation to pinprick, light touch, and vibration, along with a plantar ulcer and poorly controlled diabetes (HbA1c 8.6%). - **Chronic hyperglycemia** in diabetes leads to the accumulation of advanced glycation end products (AGEs) and activation of the polyol pathway, which cause **thickening and hyalinization of endoneural vessel walls**, impairing blood flow to peripheral nerves. *Demyelination of posterior columns and lateral corticospinal tracts* - **Posterior column demyelination** occurs in conditions like **vitamin B12 deficiency** (subacute combined degeneration) and results in loss of vibratory and proprioceptive sensation. - **Lateral corticospinal tract demyelination** is associated with **motor deficits** (e.g., spasticity, weakness), which are not the primary symptoms described in this patient. *Accumulation of lipids and foam cells in arteries* - This process describes **atherosclerosis**, which can lead to peripheral artery disease (PAD) and contribute to foot ulcers due to **ischemia**. - However, the patient has **strong pedal pulses**, making significant atherosclerosis of the macrovessels less likely to be the primary cause of her neuropathic symptoms. *Elevated hydrostatic pressure in arteriolar lumen* - **Elevated hydrostatic pressure** in arterioles (hypertension) contributes to various microvascular complications, but it is not the direct or most prominent mechanism for the **nerve damage** seen in diabetic neuropathy. - The patient's blood pressure is relatively normotensive, making this cause less likely to be the predominant factor. *Osmotic damage to oligodendrocyte nerve sheaths* - **Oligodendrocytes** are responsible for myelin formation in the **central nervous system**, not the peripheral nervous system. - While osmotic damage can occur in conditions like **rapid correction of hyponatremia** (osmotic demyelination syndrome), it primarily affects the CNS and is not typically associated with chronic diabetic peripheral neuropathy.

Question 148: A 59-year-old woman comes to the physician because of upper extremity weakness and fatigue for the past 4 months. She has had difficulty combing her hair and lifting objects. She has also had difficulty rising from her bed in the mornings for 2 months. Over the past month, she started using over-the-counter mouth rinses for dry mouth. She has smoked 1 pack of cigarettes daily for 40 years. Examination shows decreased deep tendon reflexes. Repetitive muscle tapping shows increased reflex activity. There are no fasciculations or muscle atrophy. A low-dose CT scan of the chest shows a 3-cm mass with heterogeneous calcifications in the center of the right lung. Which of the following is the most likely underlying mechanism responsible for this patient’s current symptoms?

A. Metastasis
B. Infection
C. Invasion
D. Autoimmunity (Correct Answer)
E. Inflammation

Explanation: ***Autoimmunity*** - The patient's symptoms of **proximal muscle weakness**, fatigue, difficulty rising from bed, and a lung mass with **heterogeneous calcifications** (suggesting lung cancer in a heavy smoker) are highly indicative of **Lambert-Eaton myasthenic syndrome (LEMS)**, a **paraneoplastic autoimmune disorder** strongly associated with **small cell lung cancer** (60% of cases). - LEMS is caused by **autoantibodies against presynaptic P/Q-type voltage-gated calcium channels** at the neuromuscular junction, leading to **impaired acetylcholine release** and muscle weakness. The **dry mouth** (autonomic dysfunction), **decreased reflexes that improve with repetitive muscle tapping** (post-tetanic potentiation), and absence of fasciculations or atrophy are characteristic features that distinguish LEMS from other neuromuscular disorders. *Metastasis* - While lung cancer can metastasize to various sites, including bone and brain, muscle weakness of this type and presentation is **unlikely to be directly caused by muscle metastases** in the absence of significant muscle atrophy or focal lesions. - Furthermore, the specific neurological findings like **increased reflex activity with repetitive muscle tapping** (post-tetanic potentiation) and dry mouth point away from direct metastatic involvement as the primary mechanism for the muscle weakness. *Infection* - An infection would typically present with a more **acute onset** of symptoms, fever, or other signs of systemic inflammation, which are not described here. - While some infections can cause muscle weakness (e.g., botulism, tetanus), the chronic nature, association with a lung mass, and specific neurological examination findings make infection a less likely primary cause. *Invasion* - Direct invasion of the tumor into nerves or muscles would typically cause more **focal or asymmetric weakness**, pain, or sensory deficits. - The **generalized, proximal weakness** and the unique electrophysiological findings (repetitive muscle tapping improves reflexes) are not characteristic of direct tumor invasion. *Inflammation* - While some inflammatory myopathies (e.g., polymyositis or dermatomyositis) cause proximal muscle weakness, they typically present with **elevated muscle enzymes** and may have different clinical features (e.g., rash in dermatomyositis). - The combination of a lung mass, dry mouth, and the specific neurological findings of LEMS points to a **paraneoplastic autoimmune process** rather than a primary inflammatory myopathy.

Question 149: A 38-year-old woman comes to the physician because of a 1-month history of fatigue and pruritus. Examination of the abdomen shows an enlarged, nontender liver. Serum studies show an alkaline phosphatase level of 140 U/L, aspartate aminotransferase activity of 18 U/L, and alanine aminotransferase activity of 19 U/L. Serum antimitochondrial antibody titers are elevated. A biopsy specimen of this patient's liver is most likely to show which of the following findings?

A. Intracytoplasmic eosinophilic inclusions in hepatocytes and cellular swelling
B. Ballooning degeneration and apoptosis of hepatocytes
C. Macrovesicular fatty infiltration and necrosis of hepatocytes
D. Fibrous, concentric obliteration of small and large bile ducts
E. Lymphocytic infiltration of portal areas and periductal granulomas (Correct Answer)

Explanation: ***Lymphocytic infiltration of portal areas and periductal granulomas*** - Elevated **antimitochondrial antibodies (AMAs)**, fatigue, pruritus, and cholestatic liver enzyme elevation (high alkaline phosphatase) are classic features of **primary biliary cholangitis (PBC)**. - Liver biopsy in PBC typically reveals **nonsuppurative destructive cholangitis**, characterized by lymphocytic infiltration, inflammation, and granuloma formation around small and medium-sized bile ducts. *Intracytoplasmic eosinophilic inclusions in hepatocytes and cellular swelling* - This description is characteristic of **alcoholic hepatitis**, where **Mallory bodies (eosinophilic inclusions)** are found in hepatocytes. - The patient's presentation with high alkaline phosphatase and AMAs does not suggest alcoholic liver disease. *Ballooning degeneration and apoptosis of hepatocytes* - These findings are more typical of **viral hepatitis** or **drug-induced liver injury**, indicating hepatocellular damage. - While some hepatocyte injury can occur in PBC, the primary pathological process is bile duct destruction, and AMA positivity points away from these causes. *Macrovesicular fatty infiltration and necrosis of hepatocytes* - **Macrovesicular steatosis** is prominent in **non-alcoholic fatty liver disease (NAFLD)** or **alcoholic fatty liver disease**. - While necrosis can occur, the combination of AMA positivity and cholestatic enzymes makes these findings less likely to be the primary diagnosis. *Fibrous, concentric obliteration of small and large bile ducts* - This "onion skin" fibrosis is the hallmark of **primary sclerosing cholangitis (PSC)**. - PSC is typically associated with **inflammatory bowel disease** and **p-ANCA** positivity, not AMAs, and affects larger bile ducts more often.

Question 150: A 42-year-old male presents to his primary care physician with complaints of fatigue and occasionally darkened urine over the past 3 months. Upon further questioning, the patient reveals that he has regularly had dark, 'cola-colored' urine when he has urinated at night or early in the morning. However, when he urinates during the day, it appears a much lighter yellow color. Laboratory work-up is initiated and is significant for a hemoglobin of 10.1 g/dL, elevated LDH, platelet count of 101,000/uL, and leukopenia. Urinalysis, taken from an early morning void, reveals brown, tea-colored urine with hemoglobinuria and elevated levels of hemosiderin. Which of the following is responsible for this patient's presentation?

A. Deficiency of CD-55 and CD-59 cell membrane proteins (Correct Answer)
B. Autosomal recessive deficiency of platelet Glycoprotein IIb/IIIa receptor
C. Deficiency of C1 esterase-inhibitor
D. Autosomal dominant deficiency of spectrin protein in the RBC membrane
E. Presence of a temperature-dependent IgM autoantibody

Explanation: ***Deficiency of CD-55 and CD-59 cell membrane proteins*** - The patient's symptoms of **dark, 'cola-colored' urine** particularly in the morning, along with **fatigue**, anemia (Hb 10.1 g/dL), elevated **LDH**, **thrombocytopenia** (platelet count 101,000/uL), and leukopenia are classic findings of **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. - PNH is caused by an acquired mutation in the **PIGA gene**, leading to a deficiency of **glycosylphosphatidylinositol (GPI)-anchored proteins** on the surface of hematopoietic cells, most notably **CD55** (decay-accelerating factor) and **CD59** (membrane inhibitor of reactive lysis), which protect red blood cells from complement-mediated lysis. *Autosomal recessive deficiency of platelet Glycoprotein IIb/IIIa receptor* - This describes **Glanzmann's thrombasthenia**, a rare bleeding disorder characterized by severe bleeding and impaired platelet aggregation. - It would present primarily with **mucocutaneous bleeding** (e.g., epistaxis, menorrhagia, purpura) and prolonged bleeding time after injury, not hemolytic anemia and hemoglobinuria. *Presence of a temperature-dependent IgG autoantibody* - This describes **cold agglutinin disease**, where **IgM antibodies** (not typically IgG) bind to red blood cells at colder temperatures, causing agglutination and hemolysis. - The hemolysis is usually triggered by cold exposure and presents as acrocyanosis or Raynaud phenomenon, with hemoglobinuria being less prominent or nocturnal-specific. *Deficiency of C1 esterase-inhibitor* - This condition is responsible for **hereditary angioedema**, which is characterized by recurrent episodes of **localized swelling** of the skin, respiratory tract, or gastrointestinal tract, often without urticaria. - It does not cause hemolytic anemia, hemoglobinuria, or cytopenias. *Autosomal dominant deficiency of spectrin protein in the RBC membrane* - This is the underlying cause of **hereditary spherocytosis**, characterized by fragile, spherical red blood cells that are prematurely destroyed in the spleen. - While it causes hemolytic anemia and sometimes jaundice, it typically does not present with paroxysmal nocturnal hemoglobinuria or the associated cytopenias seen in this patient, and the urine discoloration is not usually limited to morning voids.

Question 151: A 39-year-old man presents to the emergency room for epistaxis. He reports having frequent nosebleeds over the past 48 hours. He also reports a constant pounding headache over the same timeframe. He is accompanied by his wife who reports that he has seemed "off" lately, frequently forgetting recent events and names of his friends. His past medical history is notable for hypertension and rheumatoid arthritis. He takes lisinopril and methotrexate. He has a 10 pack-year smoking history and drinks 2-3 beers per day. His temperature is 101.1°F (38.4°C), blood pressure is 145/90 mmHg, pulse is 110/min, and respirations are 18/min. On exam, he appears pale, diaphoretic, and has mild scleral icterus. His spleen is palpable but non-tender. Laboratory analysis is shown below: Hemoglobin: 8.9 g/dL Hematocrit: 26% Leukocyte count: 4,900/mm^3 with normal differential Platelet count: 25,000/mm^3 Prothrombin time: 14 seconds Partial thromboplastin time (activated): 27 seconds International normalized ratio: 1.1 Bleeding time: 9 minutes This patient has a condition that is caused by a defect in which of the following processes?

A. Nucleotide excision repair
B. Porphobilinogen metabolism
C. Platelet binding to von Willebrand factor
D. Platelet binding to fibrinogen
E. Metalloproteinase-mediated protein degradation (Correct Answer)

Explanation: ***Metalloproteinase-mediated protein degradation*** - This patient's symptoms (epistaxis, headache, neurological changes, fever, anemia, thrombocytopenia, and palpable spleen) are highly suggestive of **Thrombotic Thrombocytopenic Purpura (TTP)**. - TTP is caused by a severe deficiency of **ADAMTS13**, a metalloproteinase responsible for cleaving ultra-large **von Willebrand factor (vWF)** multimers. *Nucleotide excision repair* - Defects in **nucleotide excision repair** are associated with conditions like **xeroderma pigmentosum**, which presents with extreme photosensitivity and a high risk of skin cancers. *Porphobilinogen metabolism* - Disorders of **porphobilinogen metabolism** are seen in **acute intermittent porphyria**, characterized by acute neurovisceral attacks, but not typically accompanied by severe thrombocytopenia and microangiopathic hemolytic anemia leading to epistaxis. *Platelet binding to von Willebrand factor* - A defect in **platelet binding to von Willebrand factor** (e.g., in **Bernard-Soulier syndrome** due to GP Ib/IX/V deficiency) would cause bleeding, but typically features giant platelets and less severe neurological symptoms or fever as seen in TTP. *Platelet binding to fibrinogen* - A defect in **platelet binding to fibrinogen** (e.g., in **Glanzmann thrombasthenia** due to GP IIb/IIIa deficiency) leads to impaired aggregation and bleeding. - This condition presents with mucocutaneous bleeding and does not typically involve the microangiopathic hemolytic anemia, organ damage, or neurological symptoms characteristic of TTP.

Question 152: A 33-year-old woman is brought to the emergency department after she was involved in a high-speed motor vehicle collision. She reports severe pelvic pain. Her pulse is 124/min and blood pressure is 80/56 mm Hg. Physical examination shows instability of the pelvic ring. As part of the initial emergency treatment, she receives packed red blood cell transfusions. Suddenly, the patient starts bleeding from peripheral venous catheter insertion sites. Laboratory studies show decreased platelets, prolonged prothrombin time and partial thromboplastin time, and elevated D-dimer. A peripheral blood smear of this patient is most likely to show which of the following findings?

A. Grouped erythrocytes with a stacked-coin appearance
B. Erythrocytes with a bullseye appearance
C. Crescent-shaped, fragmented erythrocytes (Correct Answer)
D. Erythrocytes with cytoplasmic hemoglobin inclusions
E. Erythrocytes with irregular, thorny projections

Explanation: ***Crescent-shaped, fragmented erythrocytes*** - The clinical picture of **hypotension**, **tachycardia**, **pelvic instability**, and widespread bleeding, along with laboratory findings of **decreased platelets**, **prolonged PT/PTT**, and **elevated D-dimer**, is highly suggestive of **Disseminated Intravascular Coagulation (DIC)**. - **Fragmented erythrocytes** (schistocytes) are a hallmark of **DIC** on peripheral blood smear, as red blood cells are mechanically sheared while passing through areas of microvascular thrombosis. *Grouped erythrocytes with a stacked-coin appearance* - This describes **rouleaux formation**, commonly seen in conditions with **elevated plasma proteins**, such as multiple myeloma or severe inflammation. - While inflammation can be part of trauma, the specific constellation of lab findings points more strongly to DIC, where rouleaux is not a primary diagnostic feature. *Erythrocytes with a bullseye appearance* - This describes **target cells**, which are characteristic of **thalassemia**, **liver disease**, or **postsplenectomy states**. - These conditions are not indicated by the patient's acute presentation or laboratory results. *Erythrocytes with cytoplasmic hemoglobin inclusions* - These are **Heinz bodies**, which are denatured hemoglobin precipitates seen in conditions like **G6PD deficiency** or **unstable hemoglobin variants**. - This patient's symptoms are acute and related to trauma and hemorrhage, not a chronic hemolytic disorder. *Erythrocytes with irregular, thorny projections* - This describes **acanthocytes** (spur cells), typically associated with **severe liver disease** or **abetalipoproteinemia**. - These findings are not consistent with an acute presentation of trauma-induced coagulopathy.

Question 153: A 52-year-old man is diagnosed with chronic renal failure. He is on hemodialysis. The physicians have advised him that he needs a renal transplant. The human leukocyte antigen (HLA) genotype is A7/A5, B2/B9, and C8/C3. For each locus, the maternal allele is listed 1st and the paternal allele is listed 2nd. There are several potential donors available for the renal graft. Which of the following donors would be the closest match?

A. Donor E: A7/A8, B9/B27, C3/C4
B. Donor D: A4/A7, B1/B8, C8/C3
C. Donor B: A5/A12, B22/9, C4/C3
D. Donor C: A7/A4, B2/B4, C8/C3
E. Donor A: A7/A5, B8/B2, C3/C8 (Correct Answer)

Explanation: ***Donor A: A7/A5, B8/B2, C3/C8*** - **A locus:** Perfect match (A7 and A5 both shared) - 2/2 alleles - **B locus:** Partial match (B2 shared, B8 not) - 1/2 alleles - **C locus:** Perfect match (C8 and C3 both shared) - 2/2 alleles - **Total: 5 out of 6 alleles match** - This is the **best possible match** among all donors, minimizing risk of graft rejection through maximum HLA compatibility. *Donor C: A7/A4, B2/B4, C8/C3* - A locus: Partial match (A7 shared) - 1/2 alleles - B locus: Partial match (B2 shared) - 1/2 alleles - C locus: Perfect match (C8 and C3 both shared) - 2/2 alleles - Total: 4 out of 6 alleles match - Second best option *Donor B: A5/A12, B22/9, C4/C3* - A locus: Partial match (A5 shared) - 1/2 alleles - B locus: Partial match (B9 shared) - 1/2 alleles - C locus: Partial match (C3 shared) - 1/2 alleles - Total: 3 out of 6 alleles match *Donor D: A4/A7, B1/B8, C8/C3* - A locus: Partial match (A7 shared) - 1/2 alleles - B locus: No match (neither B1 nor B8 shared) - 0/2 alleles - C locus: Perfect match (C8 and C3 both shared) - 2/2 alleles - Total: 3 out of 6 alleles match *Donor E: A7/A8, B9/B27, C3/C4* - A locus: Partial match (A7 shared) - 1/2 alleles - B locus: Partial match (B9 shared) - 1/2 alleles - C locus: Partial match (C3 shared) - 1/2 alleles - Total: 3 out of 6 alleles match

Question 154: A 40-year-old male with a history of chronic alcoholism recently received a liver transplant. Two weeks following the transplant, the patient presents with a skin rash and frequent episodes of bloody diarrhea. A colonoscopy is performed and biopsy reveals apoptosis of colonic epithelial cells. What is most likely mediating these symptoms?

A. Donor T-cells (Correct Answer)
B. Recipient T-cells
C. Recipient B-cells
D. Recipient antibodies
E. Donor B-cells

Explanation: ***Donor T-cells*** - This clinical presentation of **skin rash**, **bloody diarrhea**, and **colonic epithelial apoptosis** following an allogeneic transplant (like a liver transplant) is classic for **Graft-versus-Host Disease (GVHD)**. - In GVHD, **immunocompetent T-cells from the donor** recognize the recipient's tissues as foreign and mount an immune attack, causing damage to organs like the skin, gastrointestinal tract, and liver. *Recipient T-cells* - **Recipient T-cells** are typically immunosuppressed following an organ transplant to prevent organ rejection. - Furthermore, if activated, recipient T-cells would target the donor organ (the liver in this case), leading to **rejection**, rather than the systemic symptoms observed (skin rash, bloody diarrhea) which suggest an attack by donor cells on recipient tissues. *Recipient B-cells* - While recipient B-cells can be involved in **antibody-mediated rejection** of the transplanted organ, they are not the primary mediators of **cellular GVHD**. - **Antibody-mediated rejection** would typically involve antibodies targeting the donor liver, leading to liver dysfunction, not the widespread GVHD symptoms described. *Recipient antibodies* - **Recipient antibodies** are primarily involved in **antibody-mediated rejection** of the transplanted organ, which would manifest as dysfunction of the transplanted liver. - They do not mediate the symptoms of **Graft-versus-Host Disease (GVHD)**, which is a cell-mediated immune response. *Donor B-cells* - **Donor B-cells** are generally not the primary mediators of GVHD. - While donor immune cells are crucial for GVHD, the major players are **donor T-cells**, which directly recognize and attack host tissues.

Question 155: A 16-year-old presents to the primary care physician because he has noticed an increase in the size of his breast tissue over the past 3 years. He states that he is significantly taller than his entire class at school although he feels increasingly weak and uncoordinated. He performs at the bottom of his grade level academically. On physical exam the patient has marked gynecomastia with small firm testes. The physician decides to perform a karyotype on the patient. What is the most likely outcome of this test?

A. 47, XYY
B. 45, XO
C. 47, XXY (Correct Answer)
D. 47, XXX
E. 46, XY

Explanation: ***47, XXY*** The constellation of **gynecomastia, tall stature, learning difficulties, and small testes** is classic for **Klinefelter syndrome**, which is characterized by a **47, XXY** karyotype. The presence of an extra X chromosome leads to **hypogonadism** and **endocrine imbalances**, explaining the physical and developmental findings. *47, XYY* - Individuals with **47, XYY syndrome** are typically tall but do not usually present with breast enlargement or other features of hypogonadism. - They may have an increased risk of learning difficulties and behavioral problems. *45, XO* - This karyotype, also known as **Turner syndrome**, is characterized by the absence of an X chromosome and typically affects **females**. - Common features include **short stature, webbed neck, and ovarian dysfunction**, which are inconsistent with the patient's presentation. *47, XXX* - This karyotype, known as **Triple X syndrome**, affects **females** and is characterized by the presence of an extra X chromosome. - While some individuals may experience learning difficulties or developmental delays, it does not cause gynecomastia or small testes in males. *46, XY* - This is the **normal male karyotype** and would not explain the patient's symptoms of gynecomastia, small testes, tall stature, or learning difficulties. - These symptoms suggest an underlying chromosomal abnormality.

Question 156: A 35-year-old African American man presents with fever, abdominal pain, and severe weakness since yesterday. On physical examination, the patient is jaundiced and shows a generalized pallor. Past medical history is significant for recently receiving anti-malaria prophylaxis before visiting Nigeria. Laboratory tests show decreased glucose-6-phosphate dehydrogenase (G6PD) levels. Peripheral smear shows the presence of bite cells and Heinz bodies. Which of the following is the most likely diagnosis in this patient?

A. Autoimmune hemolytic anemia
B. Sickle cell disease
C. Glucose-6-phosphate-dehydrogenase (G6PD) deficiency (Correct Answer)
D. Microangiopathic hemolytic anemia
E. Paroxysmal nocturnal hemoglobinuria (PNH)

Explanation: ***Glucose-6-phosphate-dehydrogenase (G6PD) deficiency*** - The patient's presentation with **fever, abdominal pain, jaundice, and pallor** following **anti-malarial prophylaxis** (known triggers for G6PD deficiency) is highly suggestive of an acute hemolytic crisis. - The laboratory findings of **decreased G6PD levels, bite cells, and Heinz bodies** on peripheral smear are pathognomonic for G6PD deficiency causing hemolytic anemia. *Autoimmune hemolytic anemia* - This condition is typically characterized by a **positive Coombs test**, which is not mentioned here and would not explain the presence of bite cells or Heinz bodies. - It results from the body's immune system attacking its own red blood cells, rather than oxidative stress from drug exposure. *Sickle cell disease* - Patients with sickle cell disease have **abnormally shaped red blood cells** (sickle cells) and experience vaso-occlusive crises, often presenting with severe pain, but the key findings of bite cells and Heinz bodies are not characteristic. - While it can manifest with anemia and jaundice, the specific trigger and peripheral smear findings point away from sickle cell disease. *Microangiopathic hemolytic anemia* - This involves red blood cell fragmentation due to passage through fibrin strands in small vessels, leading to **schistocytes** on peripheral smear, not bite cells or Heinz bodies. - Conditions like **DIC, TTP, or HUS** are common causes, none of which are suggested by the clinical picture or lab findings. *Paroxysmal nocturnal hemoglobinuria (PNH)* - PNH is characterized by **dark urine in the morning (hemoglobinuria)**, thrombosis, and bone marrow failure, and it is a clonal hematopoietic stem cell disorder. - The diagnosis is confirmed by flow cytometry showing absence of **CD55 and CD59** on red blood cells, and the peripheral smear findings are not consistent with PNH.

Question 157: A 4-year-old boy is brought to the physician because of yellowish discoloration of his eyes and skin for 5 days. He has had generalized fatigue and mild shortness of breath over the past 2 months. Two weeks ago, he was treated for a urinary tract infection with antibiotics. His father has a history of undergoing a splenectomy in his childhood. Examination shows pale conjunctivae and jaundice. The abdomen is soft and nontender; the spleen is palpated 4 to 5 cm below the left costal margin. Laboratory studies show: Hemoglobin 9.9 g/dL Mean corpuscular volume 88 μm3 Mean corpuscular hemoglobin 31.7 pg/cell Mean corpuscular hemoglobin concentration 37.0% Hb/cell Leukocyte count 6600/mm3 Platelet count 233,000/mm3 Red cell distribution width 24.3% (N = 13–15) Serum Bilirubin Total 12.3 mg/dL Direct 1.8 mg/dL Lactate dehydrogenase 401 U/L Which of the following is the most likely cause of these findings?

A. Decreased synthesis of alpha chains of hemoglobin
B. Thrombotic microangiopathy
C. Decreased CD55 and CD59 in RBC
D. Defective spectrin in the RBC membrane (Correct Answer)
E. Deficient glucose-6 phosphate dehydrogenase

Explanation: ***Defective spectrin in the RBC membrane*** - This presentation is highly suggestive of **hereditary spherocytosis**, an autosomal dominant disorder characterized by **defects in red blood cell membrane proteins** like spectrin, ankyrin, or band 3. - The patient exhibits classic signs of **hemolytic anemia** (jaundice, fatigue, splenomegaly, elevated unconjugated bilirubin, high LDH, high RDW), a family history of splenectomy, and a high MCHC, all consistent with hereditary spherocytosis. *Decreased synthesis of alpha chains of hemoglobin* - This describes **alpha-thalassemia**, which is caused by reduced or absent alpha-globin chain production, leading to **microcytic, hypochromic anemia**. - While it can cause hemolysis, the **normal MCV** (88 μm3) and **high MCHC** observed in this patient make alpha-thalassemia less likely. *Thrombotic microangiopathy* - This is a group of disorders characterized by **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **organ damage** due to microvascular thrombi. - While it causes hemolytic anemia (high LDH, jaundice), the patient's **normal platelet count** and lack of severe multi-organ involvement make this diagnosis unlikely. *Decreased CD55 and CD59 in RBC* - This is the hallmark of **paroxysmal nocturnal hemoglobinuria (PNH)**, an acquired clonal stem cell disorder resulting in unregulated complement activation on red blood cells. - PNH causes hemolytic anemia and often presents with **hemoglobinuria**, **thrombosis**, and bone marrow failure, which are not described in this case, and usually has a normal MCHC. *Deficient glucose-6 phosphate dehydrogenase* - **G6PD deficiency** is an X-linked disorder causing episodic hemolytic anemia, typically triggered by **oxidative stress** from certain foods (fava beans), drugs (sulfa drugs, antimalarials), or infections. - While the patient was treated with antibiotics, his symptoms are prolonged, and the absence of specific triggers or evidence of **Heinz bodies** (oxidized hemoglobin seen in G6PD deficiency) makes this less likely.

Question 158: A 42-year-old man presents to his primary care provider complaining of foamy urine for the last 2 weeks. He has also begun to notice swelling in his hands and feet, and he says that his shoes have not been fitting normally. On exam, the patient has a temperature of 98.8°F (37.1°C), blood pressure is 132/84 mmHg, pulse is 64/min, and respirations are 12/min. The patient has 2+ pitting edema bilaterally up to his shins. A 24-hour urine study is found to contain 9.0 g of protein. The patient is referred to a specialist and undergoes a renal biopsy. On light microscopy, the glomeruli demonstrate basement membrane thickening. On electron microscopy, subepithelial deposits are seen. Which of the following is a characteristic of this patient’s disease?

A. X-linked condition
B. Antibodies to alveolar basement membrane
C. Loss of podocyte foot processes
D. Antibodies to phospholipase A2 receptor (Correct Answer)
E. IgA immune complex deposition

Explanation: ***Antibodies to phospholipase A2 receptor*** - The patient's presentation with **foamy urine**, **edema**, and **9.0 g of protein** in a 24-hour urine study indicates **nephrotic syndrome**. Renal biopsy findings of **glomerular basement membrane thickening** on light microscopy and **subepithelial deposits** on electron microscopy are characteristic of **membranous nephropathy**. - Approximately 70-80% of primary membranous nephropathy cases are associated with **autoantibodies to the M-type phospholipase A2 receptor (PLA2R)**, a protein expressed on podocytes. *X-linked condition* - This description is characteristic of **Alport syndrome**, a genetic disorder leading to progressive kidney disease, hearing loss, and eye abnormalities. - Alport syndrome presents with **hematuria** rather than significant proteinuria, and biopsy would show **laminar splitting of the glomerular basement membrane**. *Antibodies to alveolar basement membrane* - This describes **Goodpasture syndrome**, which is characterized by the presence of anti-glomerular basement membrane (anti-GBM) antibodies that target both the kidney and the lung. - Patients typically present with rapidly progressive glomerulonephritis and pulmonary hemorrhage, and biopsy would show **linear IgG deposition** along the glomerular basement membrane on immunofluorescence. *Loss of podocyte foot processes* - This is a characteristic finding in **minimal change disease** and **focal segmental glomerulosclerosis (FSGS)**, two other causes of nephrotic syndrome. - Minimal change disease typically shows normal glomeruli on light microscopy, while FSGS shows segmental sclerosis. Neither shows subepithelial deposits. *IgA immune complex deposition* - This is the hallmark of **IgA nephropathy (Berger's disease)** or **Henoch-Schönlein purpura** in children. - Patients typically present with **hematuria**, often macroscopic, following an upper respiratory or gastrointestinal infection. Biopsy would show IgA deposits in the mesangium, not subepithelial deposits.

Question 159: A 72-year-old woman is brought to the emergency department because of severe pain in her left hip after a fall this morning. She has smoked one pack of cigarettes daily for 45 years. Her only medication is a vitamin D supplement. Physical examination shows that her left leg is externally rotated and appears shorter than her right leg. An x-ray of the pelvis shows a fracture of the neck of the left femur. Which of the following changes in bone architecture is the most likely underlying cause of this patient's symptoms?

A. Subperiosteal bone resorption and cystic degeneration
B. Deposition of lamellar bone interspersed with woven bone
C. Formation of multiple sclerotic lesions in bony cortex
D. Loss of cortical bone mass and thinning of trabeculae (Correct Answer)
E. Overgrowth of cortical bone and reduced marrow space

Explanation: ***Loss of cortical bone mass and thinning of trabeculae*** - The patient's age (72 years), female sex, and smoking history are significant risk factors for **osteoporosis**, which leads to **reduced bone mineral density**. - **Osteoporotic bones** are characterized by **thinning of cortical bone** and **loss of trabecular bone**, making them brittle and highly susceptible to **fragility fractures**, such as a femoral neck fracture after a fall. *Subperiosteal bone resorption and cystic degeneration* - This pattern of bone change is characteristic of **hyperparathyroidism**, specifically **osteitis fibrosa cystica**. - While hyperparathyroidism can cause bone fragility, the clinical presentation (isolated fall-related fracture, no other symptoms of hyperparathyroidism) does not specifically point to this condition. *Deposition of lamellar bone interspersed with woven bone* - This describes bone changes seen in conditions with **disordered bone remodeling**, such as **Paget's disease of bone**. - Paget's disease commonly presents with focal areas of enlarged, deformed, and weak bones, which would typically be reported on X-ray as thickened cortices rather than fragility fracture in this context. *Formation of multiple sclerotic lesions in bony cortex* - **Sclerotic lesions** indicate areas of increased bone density, which can be seen in conditions like **osteoblastic metastases** or **osteopetrosis**. - These conditions typically increase bone mass or density, making bones harder but often more brittle, but usually not associated with the primary pathology in this scenario. *Overgrowth of cortical bone and reduced marrow space* - This describes changes seen in various **sclerotic bone disorders**, including **osteopetrosis** (marble bone disease) or severe forms of **sclerotic dysplasias**. - These conditions are rare and result in abnormally dense but fragile bones, but they are not the most likely underlying cause for a hip fracture in an elderly woman with typical risk factors for osteoporosis.

Question 160: A 23-year-old Sicilian male presents to his primary care physician complaining of lethargy, joint pain, and urinary frequency. Vitals signs include T 98.7 F, HR 96 bpm, BP 135/71 mm/Hg, RR 18 breaths/minute, O2 99%. Laboratory findings include: random glucose 326 mg/dL, Hemoglobin 7.1, and elevated reticulocyte count and transferrin saturation. The patient is not surprised that his "blood level is low" and suggests that he might need another transfusion. An echocardiogram demonstrates restrictive cardiomyopathy. The disorder with which this patient presents can be characterized by which of the following?

A. Mutations resulting in copper accumulation
B. Presence of the fetal hemoglobin
C. Absence of the hemoglobin alpha-chain
D. Mutation resulting in increased iron absorption
E. Absence of the hemoglobin beta-chain (Correct Answer)

Explanation: ***Absence of the hemoglobin beta-chain*** - The patient's symptoms (lethargy, joint pain, elevated glucose, restrictive cardiomyopathy, high transferrin saturation, and need for transfusions) in a **Sicilian male** are highly suggestive of **beta-thalassemia major**, which involves a reduced or absent production of hemoglobin beta-chains. - This leads to ineffective erythropoiesis, **chronic anemia**, and subsequent **iron overload** due to frequent transfusions and increased intestinal iron absorption. *Mutation resulting in increased iron absorption* - This describes **hereditary hemochromatosis**, which can present with increased iron absorption, joint pain, and diabetes, but typically does not involve the severe, transfusion-dependent anemia and high reticulocyte count seen in this patient. - While iron overload is present in this patient, it's primarily secondary to the underlying anemia and transfusions, not a primary mutation in iron absorption regulation. *Absence of the hemoglobin alpha-chain* - This describes **alpha-thalassemia**. The most severe form, **hydrops fetalis**, is incompatible with life, and milder forms present differently, often without the severe, transfusion-dependent anemia and systemic iron overload from transfusions seen here. - Beta-thalassemia is more common in Mediterranean populations and aligns better with the clinical picture of profound anemia, extramedullary hematopoiesis, and resultant iron overload. *Presence of the fetal hemoglobin* - While patients with thalassemia may have **increased fetal hemoglobin (HbF)** as a compensatory mechanism, its *presence* is not the primary characteristic of the disease itself, but rather a response to the deficient or absent adult hemoglobin chain production. - The fundamental genetic defect lies in the reduced or absent synthesis of adult hemoglobin chains (alpha or beta). *Mutations resulting in copper accumulation* - This describes **Wilson's disease**, which involves copper accumulation and can affect the liver, brain, and other organs, but does not present with severe anemia requiring transfusions or the specific type of iron overload-related cardiomyopathy and diabetes seen here. - The laboratory findings of high reticulocytes, low hemoglobin, and high transferrin saturation specifically point to a primary hematological disorder with secondary iron loading rather than a copper metabolism disorder.

Question 161: A 48-year-old Caucasian male suffering from ischemic heart disease is placed on a heart transplant list. Months later, he receives a heart from a matched donor. During an endomyocardial biopsy performed 3 weeks later, there is damage consistent with acute graft rejection. What is most likely evident on the endomyocardial biopsy?

A. Granuloma
B. Atherosclerosis
C. Lymphocytic infiltrate (Correct Answer)
D. Tissue necrosis
E. Fibrosis

Explanation: ***Lymphocytic infiltrate*** - Acute graft rejection, especially within weeks of transplantation, is characterized by a **cellular immune response** dominated by **T lymphocytes** invading the allograft. - These lymphocytes target donor major histocompatibility complex (MHC) molecules, leading to myocyte damage and dysfunction, which would be visible as a lymphocytic infiltrate on biopsy. *Granuloma* - Granulomas are aggregates of **macrophages**, often seen in chronic inflammatory conditions like tuberculosis, sarcoidosis, or fungal infections. - They are not typical findings in the context of acute allograft rejection. *Atherosclerosis* - Atherosclerosis is a disease of large and medium-sized arteries characterized by **plaque formation**, primarily involving lipid deposition and inflammation, which narrows the arterial lumen. - While it can affect transplanted organs (e.g., transplant vasculopathy, a form of chronic rejection), it is not the primary mechanism or histological finding in **acute cellular rejection** occurring three weeks post-transplant. *Tissue necrosis* - While acute rejection can *lead* to tissue necrosis due to severe inflammation and ischemia, necrosis alone is a broad term and not the most specific or defining histological feature of acute cellular rejection. - The preceding and primary histopathological hallmark of acute cellular rejection is the **inflammatory cell infiltrate**, particularly lymphocytes attacking the graft. *Fibrosis* - Fibrosis, or the deposition of excess connective tissue, is a characteristic feature of **chronic rejection** or chronic injury processes. - It indicates long-standing damage and repair, which is unlikely to be the predominant finding in a biopsy three weeks after transplantation indicative of acute rejection.

Question 162: An 11-year-old boy presents to the emergency department with sudden pain. The patient's parents state the child suddenly felt pain in his hands an hour ago. He has not eaten anything new lately. He did play football earlier this morning and admits to being tackled forcefully multiple times. The child is doing well in school and is proud that he has a new girlfriend. The child has a past medical history of obesity and is not currently on any medications. His temperature is 100°F (37.8°C), blood pressure is 120/68 mmHg, pulse is 100/min, respirations are 11/min, and oxygen saturation is 98% on room air. Cardiopulmonary exam is within normal limits. On physical exam of the patient's extremities, there was painful and symmetrical swelling of his hands and feet but no rashes were present. The patient is started on analgesics. Which of the following is the most likely cause of this patient's presentation?

A. Viral infection
B. Osteomyelitis
C. Sexually transmitted infection
D. Benign edema secondary to trauma
E. Altered red blood cell morphology (Correct Answer)

Explanation: ***Altered red blood cell morphology*** - The sudden onset of **painful, symmetrical swelling of hands and feet** (dactylitis) in an 11-year-old African American boy, especially in the context of physical stress (football), is highly suggestive of a **vaso-occlusive crisis** in **sickle cell disease**. - **Sickle cell disease** involves genetically altered hemoglobin leading to **sickling of red blood cells**, which obstructs small blood vessels and causes pain and inflammation in extremities. *Viral infection* - While viral infections can cause musculoskeletal pain, they typically do not present with such **acute, symmetrical, and painful swelling** confined primarily to the hands and feet. - The absence of other common viral symptoms like widespread rash, upper respiratory symptoms, or severe fatigue makes this less likely. *Osteomyelitis* - **Osteomyelitis** usually presents with localized, severe bone pain and often has a focal area of tenderness or swelling, rather than **symmetrical swelling of hands and feet**. - It is typically associated with **fever** and elevated inflammatory markers, but the widespread nature of the pain makes a single focus of infection less probable. *Sexually transmitted infection* - An 11-year-old boy, despite having a girlfriend, is **unlikely to have an STI** as the cause of sudden, painful hand and foot swelling. - While some STIs can cause reactive arthritis, the presentation here is not typical of such conditions (e.g., usually affecting larger joints). *Benign edema secondary to trauma* - While trauma could cause swelling, the **symmetrical and sudden onset of pain and swelling in both hands and feet** makes isolated benign edema from trauma less likely. - Furthermore, trauma-induced edema is generally localized to the site of injury and not typically diffuse across multiple extremities simultaneously without significant, widespread injury.

Question 163: A 35-year-old woman comes to the physician because of a 3-month history of progressive fatigue, shortness of breath, and pain in her knees and ankles. Her temperature is 37.6°C (99.7°F). Physical examination shows mild hepatomegaly and tender, red nodules on her shins. There are purple, indurated lesions on her nose, nasolabial fold, and cheeks. A biopsy of the liver shows scattered aggregations of multinucleated giant cells with cytoplasmic inclusions and eosinophilic, needle-shaped structures arranged in a star-like pattern. Which of the following is the most likely cause of this patient's symptoms?

A. Hypereosinophilic syndrome
B. Hemochromatosis
C. Sarcoidosis (Correct Answer)
D. Serum sickness
E. Systemic lupus erythematosus

Explanation: ***Sarcoidosis*** - The constellation of **fatigue**, **dyspnea**, **polyarthritis**, **hepatomegaly**, **erythema nodosum** (tender, red nodules on shins), and facial lesions consistent with **lupus pernio** (purple, indurated lesions on nose, nasolabial fold, and cheeks) strongly points to multisystem involvement characteristic of sarcoidosis. - The liver biopsy findings of **scattered aggregations of multinucleated giant cells with cytoplasmic inclusions** and **eosinophilic, needle-shaped structures arranged in a star-like pattern** describes **non-caseating granulomas** with **asteroid bodies** and **Schaumann bodies**, which are pathognomonic for sarcoidosis. *Hypereosinophilic syndrome* - This syndrome is characterized by **persistent eosinophilia** (>1.5 x 10^9/L for >6 months) and organ damage due to eosinophil infiltration, but the biopsy findings and specific skin lesions presented are not typical. - While it can affect multiple organs, including the skin and heart, it would not typically present with the described granulomatous features or lupus pernio. *Hemochromatosis* - Hemochromatosis is an **iron overload disorder** leading to iron deposition in various organs, causing fatigue, arthralgia, and hepatomegaly, but the skin lesions described and the specific biopsy findings of granulomas are not characteristic. - The classic skin presentation in hemochromatosis is generally a **bronze pigmentation**, not the nodular lesions or lupus pernio described. *Serum sickness* - Serum sickness is a **Type III hypersensitivity reaction** typically manifesting with fever, rash (often urticarial), arthralgia, and lymphadenopathy, usually arising 7-14 days after exposure to certain agents (e.g., antitoxins, medications). - It does not cause the specific granulomatous liver changes or chronic skin lesions like erythema nodosum or lupus pernio seen in this patient. *Systemic lupus erythematosus* - SLE is a **multisystem autoimmune disease** that can present with fatigue, arthralgia, and skin manifestations, but the classical skin lesions are often malar rash or discoid lupus, and the liver biopsy findings of non-caseating granulomas are not typical. - While lupus can affect the liver, it usually manifests as autoimmune hepatitis or fatty liver, not the specific granulomatous pathology seen here.

Question 164: A 61-year-old woman comes to the physician because of a constant, dull headache and generalized body pains for the past 8 months. She has also had difficulty hearing from her left side, which started a month after the onset of the headaches. Five months ago, she had surgery to correct a fracture of the right femur that occurred without a fall or any significant trauma. Five years ago, she underwent a total thyroidectomy for localized thyroid carcinoma. She takes levothyroxine and calcium supplements, which she started after menopause. Physical examination reveals a prominent forehead and irregular, tender skull surface. Bony tenderness is present over bilateral hip and knee joints, with decreased range of motion of the right hip joint and increased anterior curvature of both tibias. Laboratory studies show a highly elevated level of alkaline phosphatase, with vitamin D, calcium and PTH levels within normal limits. A plain x-ray of the head is most likely to show which of the following findings?

A. Mixed lytic and sclerotic lesions (Correct Answer)
B. Periosteal trabeculations with radiolucent marrow hyperplasia
C. Generalized dense, sclerotic bone
D. Multiple, well-defined, punched out lytic lesions
E. Lytic lesions with no sclerotic margin

Explanation: ***Mixed lytic and sclerotic lesions*** - The patient's symptoms (headache, hearing loss, pathological fracture, bony pain, prominent forehead, enlarged skull, increased tibial curvature, and elevated alkaline phosphatase with normal calcium and PTH) are classic for **Paget's disease of bone**. - **Paget's disease** is characterized by disorganized bone remodeling, which radiographically appears as a mixture of osteolytic (bone destruction) and osteosclerotic (bone formation) lesions, often described as a "cotton wool" appearance in the skull. *Periosteal trabeculations with radiolucent marrow hyperplasia* - This finding is more characteristic of conditions like **myelofibrosis**, where there is marrow replacement and extramedullary hematopoiesis, leading to bony changes. - While Paget's can affect bone structure, it primarily involves remodeling within the bone itself rather than periosteal trabeculations and marrow hyperplasia as a primary radiological feature. *Generalized dense, sclerotic bone* - **Osteopetrosis** (Albers-Schönberg disease) is characterized by excessively dense, brittle bones due to defective osteoclast function, leading to generalized sclerosis. - The clinical presentation with mixed lytic and sclerotic phases, hearing loss, and characteristic bone deformities points away from uniform bone sclerosis. *Multiple, well-defined, punched out lytic lesions* - This finding is most suggestive of **multiple myeloma**, a plasma cell malignancy that causes discrete areas of bone destruction without much osteoblastic (bone-forming) activity. - The patient's symptoms, particularly the prominent forehead, increased tibial curvature, and highly elevated alkaline phosphatase, are not typical of multiple myeloma. *Lytic lesions with no sclerotic margin* - This pattern can be seen in aggressive **metastatic bone disease** (e.g., from renal cell carcinoma or thyroid carcinoma, although the patient had a thyroidectomy 5 years ago for localized cancer, making widespread metastases less likely to present this way). - While Paget's does have lytic phases, the entire clinical picture and the eventual mixed lytic-sclerotic appearance differentiate it from purely lytic, unsclerofed lesions of aggressive metastatic disease.

Question 165: A 48-year-old man is being evaluated for an acquired defect of the myeloid stem cell line with a mutation in the PIG-A gene. His diagnosis was first suspected due to anemia and recurrent pink-tinged urine. Which of the markers will be negative in the flow cytometry test for his condition?

A. CD18
B. CD3
C. CD19
D. CD40L
E. CD55 (Correct Answer)

Explanation: ***CD55*** - This patient presents with symptoms and genetic findings (PIG-A mutation) consistent with **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. PNH is characterized by a defect in the synthesis of **GPI anchors**, which attach certain proteins, like CD55 (DAF) and CD59 (MIRL), to the cell surface. - In PNH, cells lacking GPI anchors, specifically **erythrocytes, granulocytes, and monocytes**, will show reduced or absent expression of CD55 and CD59 on flow cytometry, making CD55 a key diagnostic marker that will be **negative**. *CD18* - **CD18** is part of the **integrin family** and is expressed on **leukocytes**, playing a crucial role in cell adhesion and migration. It is not directly affected by the PIG-A gene mutation or the GPI anchor deficiency seen in PNH. - Its expression would typically be normal in PNH patients. *CD3* - **CD3** is a surface marker specific to **T lymphocytes**, involved in T-cell receptor signaling. PNH primarily affects myeloid stem cells and their descendants, leading to GPI anchor deficiency on cells like erythrocytes, granulocytes, and monocytes. - T-lymphocytes are generally not affected by the PIG-A mutation, so CD3 expression would be normal. *CD19* - **CD19** is a marker expressed on **B lymphocytes** and is involved in B-cell development and activation. The PIG-A mutation and subsequent GPI anchor deficiency primarily impact myeloid cells and, to a lesser extent, erythroid cells. - B-lymphocytes are not typically affected by the GPI-anchor deficiency; therefore, CD19 expression would be normal. *CD40L* - **CD40L (CD154)** is a protein expressed on activated **T lymphocytes** and plays a critical role in T-cell-dependent B-cell activation and antibody production. Like CD3, it relates to T-cell function and is not directly linked to the PIG-A mutation or GPI anchor deficiency in PNH. - Its expression would not be negative in this condition.

Question 166: A 13-year-old girl is brought to the pediatrician due to a 4-month history of heavy vaginal bleeding during menstrual periods. She endorses episodes of bleeding gums after brushing her teeth and experienced prolonged bleeding after tonsillectomy 6 years ago. Her mother states that she bled significantly during childbirth and that the girl’s older brother has similar symptoms including easy bruising. Vitals were stable and physical exam was not revealing. Laboratory studies show: Platelet count: 72,000/mm^3 Bleeding time: 14 min Prothrombin time: 12 secs (INR = 1) Partial thromboplastin time: 40 secs Blood smear demonstrates increased megakaryocytes and enlarged platelets. Platelets do not aggregate to ristocetin. Which of the following is the most likely diagnosis?

A. Glanzmann thrombasthenia
B. Idiopathic thrombocytopenic purpura (ITP)
C. Bernard-Soulier syndrome (Correct Answer)
D. Aspirin or NSAID use
E. von Willebrand disease (vWD)

Explanation: ***Bernard-Soulier syndrome*** - The patient presents with **thrombocytopenia** (platelet count 72,000/mm^3), **prolonged bleeding time** (14 min), and **enlarged platelets** and **megakaryocytes** on blood smear. - The key diagnostic feature is the **failure of platelets to aggregate to ristocetin**, indicating a defect in the GPIb-IX-V receptor complex which mediates platelet adhesion to von Willebrand factor. This clinical picture in a patient with a family history of bleeding is classic for Bernard-Soulier syndrome. *Glanzmann thrombasthenia* - This condition is characterized by a defect in the **GPIIb/IIIa receptor**, which is crucial for platelet aggregation; however, patients with Glanzmann thrombasthenia typically have a **normal platelet count** and **normal platelet morphology**. - Platelets in Glanzmann thrombasthenia would fail to aggregate to ADP, collagen, and epinephrine, but aggregation to **ristocetin** would generally be normal (unless very high concentrations are used), making it less likely given the specific finding of failed ristocetin aggregation and thrombocytopenia. *Idiopathic thrombocytopenic purpura (ITP)* - ITP causes isolated **thrombocytopenia** (low platelet count) and **increased megakaryocytes** in the bone marrow, but platelets are typically of **normal size** or may be **larger than normal** but not giant platelets. - While ITP would cause a prolonged bleeding time, it would not typically show **enlarged platelets** on blood smear, nor would the platelets specifically fail to aggregate to ristocetin due to a receptor defect. *Aspirin or NSAID use* - Aspirin and NSAIDs inhibit **cyclooxygenase**, leading to impaired platelet aggregation and a **prolonged bleeding time**, but they do not cause **thrombocytopenia** or changes in **platelet morphology** like enlarged platelets or increased megakaryocytes. - Platelet aggregation to ristocetin would be normal in the context of aspirin or NSAID use, as the GP Ib-IX-V and GP IIb/IIIa complexes are unaffected. *von Willebrand disease (vWD)* - vWD involves a deficiency or defect in **von Willebrand factor**, leading to impaired platelet adhesion and sometimes reduced factor VIII levels, which causes a **prolonged bleeding time**; however, platelet count and morphology are typically **normal**. - While vWD can show decreased ristocetin-induced platelet aggregation, it does **not present with thrombocytopenia** or **enlarged platelets/megakaryocytes** as seen in this patient.

Question 167: A 43-year-old man comes to the physician for a 1-week history of swelling around his eyes and decreased urination. His pulse is 87/min, and blood pressure is 152/95 mm Hg. Physical examination shows 1+ periorbital and pretibial edema. Serum studies show a urea nitrogen concentration of 21 mg/dL and a creatinine concentration of 1.4 mg/dL. Urinalysis shows 3+ blood and 1+ protein. Further evaluation of this patient is most likely to show which of the following?

A. Urinary rhomboid crystals
B. Renal interstitial inflammation
C. Hypoalbuminemia
D. Detached renal tubular epithelial cells
E. Red blood cell casts (Correct Answer)

Explanation: ***Red blood cell casts*** - The patient's presentation with **periorbital and pretibial edema**, **hypertension**, elevated **creatinine**, **hematuria** (3+ blood), and mild **proteinuria** (1+ protein) is highly suggestive of **acute glomerulonephritis**. - **Red blood cell casts** are pathognomonic for **glomerulonephritis**, indicating that red blood cells are leaking from the glomeruli and congealing in the renal tubules. *Urinary rhomboid crystals* - **Urinary rhomboid crystals** are typically associated with conditions like **uric acid nephrolithiasis** or gout, which are not suggested by the patient's symptoms or lab findings. - Their presence would indicate a risk for **kidney stones**, not evidence of glomerular inflammation. *Renal interstitial inflammation* - **Renal interstitial inflammation** is characteristic of **acute interstitial nephritis**, which often presents with fever, rash, eosinophilia, and flank pain, usually due to drug reactions or infections. - While kidney injury can occur, the primary findings of **hematuria** and **proteinuria** in this context strongly point away from an interstitial process as the initial diagnosis. *Hypoalbuminemia* - **Hypoalbuminemia** is a hallmark of **nephrotic syndrome**, characterized by severe proteinuria (>3.5 g/day), significant edema, and hyperlipidemia. - This patient has only 1+ proteinuria, which is not severe enough to cause significant hypoalbuminemia or the full nephrotic picture. *Detached renal tubular epithelial cells* - **Detached renal tubular epithelial cells** and **tubular cell casts** are characteristic findings in **acute tubular necrosis (ATN)**, usually resulting from ischemia or nephrotoxins. - While ATN can cause acute kidney injury, the prominent **hematuria** and **hypertension** in this case are more indicative of a glomerular process than tubular damage.

Question 168: A 43-year-old woman comes to the physician because of a 6-week history of hoarseness and difficulty swallowing. She also has a history of lower back pain treated with ibuprofen. She is 162 cm (5 ft 4 in) tall and weighs 77 kg (169 lb); BMI is 29 kg/m2. Her pulse is 64/min and blood pressure is 130/86 mm Hg. Physical examination shows dry skin, swelling of the lower extremities, and a hard nontender anterior neck swelling that does not move with swallowing. Femoral and pedal pulses are decreased bilaterally. A biopsy of the neck swelling is most likely to show which of the following findings?

A. Atypical nuclei and concentric lamellar calcifications
B. Giant cells and noncaseating granulomas
C. Lymphocytic infiltrate and germinal center formation
D. Collagen deposition and decreased number of follicles (Correct Answer)
E. Spindle cells and areas of focal necrosis

Explanation: ***Collagen deposition and decreased number of follicles*** - The patient's symptoms of **hoarseness**, **difficulty swallowing**, **dry skin**, **lower extremity swelling**, and **decreased pulses** suggest **hypothyroidism**. - The presence of a **hard, nontender anterior neck swelling that does not move with swallowing** points towards a **fibrotic thyroiditis**, specifically **Riedel's thyroiditis**, which is characterized by extensive **collagen deposition** and a reduction in normal thyroid follicles. *Atypical nuclei and concentric lamellar calcifications* - This describes **psammoma bodies** and atypical nuclei, which are characteristic of **papillary thyroid carcinoma**. - While thyroid cancer can cause hoarseness and dysphagia, the diffuse, hard, nontender neck swelling, and systemic symptoms of hypothyroidism are less typical for papillary carcinoma. *Giant cells and noncaseating granulomas* - This histological finding is characteristic of **De Quervain's (subacute) thyroiditis**, which typically presents with a **painful** thyroid gland and often precedes a transient hypothyroid phase. - The patient's thyroid swelling is explicitly described as **nontender**, ruling out De Quervain's. *Lymphocytic infiltrate and germinal center formation* - This describes **Hashimoto's thyroiditis**, which is an autoimmune cause of hypothyroidism and diffuse goiter, but the goiter is usually **rubbery** and not typically described as **hard** and fixed like in this case. - While it causes hypothyroidism, the fibrotic nature of the mass and lack of mobility suggest a more chronic, sclerosing process. *Spindle cells and areas of focal necrosis* - This is a description more consistent with an **anaplastic thyroid carcinoma**, a highly aggressive malignancy. - While anaplastic carcinoma can cause rapid neck swelling, hoarseness, and dysphagia, the other systemic signs of hypothyroidism are less directly indicative of anaplastic carcinoma itself.

Question 169: A 33-year-old Caucasian female presents to her primary care provider for skin problems and difficulty breathing. She has not sought medical care in over 10 years due to anxiety around physicians. However, she has experienced gradual onset of diffuse pruritus, skin induration, and limited finger mobility over the past 5 years that has negatively impacted her work as an accountant. More recently, she has developed exertional shortness of breath and is concerned that it may impact her ability to care for her 3-year-old son. She reports no prior medical conditions and takes fish oil. She smokes 1 pack of cigarettes per day and drinks socially. Her temperature is 98.6°F (37°C), blood pressure is 145/85 mmHg, pulse is 85/min, and respirations are 22/min. On exam, she appears anxious with minimally increased work of breathing. Dry rales are heard at her lung bases bilaterally. Her fingers appear shiny and do not have wrinkles on the skin folds. A normal S1 and S2 are heard on cardiac auscultation. This patient’s lung disease is caused by increased secretion of which of the following substances within the lungs?

A. Interleukin 1
B. Tumor necrosis factor alpha
C. Interleukin 2
D. Transforming growth factor beta (Correct Answer)
E. Interferon gamma

Explanation: ***Transforming growth factor beta*** - The patient's symptoms of **diffuse pruritus, skin induration, limited finger mobility**, exertional shortness of breath, and **shiny fingers without wrinkles** are highly suggestive of **systemic sclerosis (scleroderma)**. - The lung disease in scleroderma, often **interstitial lung disease (ILD)**, is characterized by **fibrosis driven by excessive collagen deposition**, a process significantly mediated by **transforming growth factor beta (TGF-β)**. *Interleukin 1* - **Interleukin-1 (IL-1)** is a pro-inflammatory cytokine primarily involved in acute inflammation and fever, not directly implicated as the primary driver of fibrosis in scleroderma-associated lung disease. - While IL-1 can contribute to inflammation in various autoimmune diseases, it does not directly stimulate the **fibrotic pathways** in the same manner as TGF-β. *Tumor necrosis factor alpha* - **Tumor necrosis factor-alpha (TNF-α)** is a prominent pro-inflammatory cytokine involved in many autoimmune and inflammatory conditions, including rheumatoid arthritis. - Although it plays a role in the inflammatory process, TNF-α is not considered the primary mediator responsible for the **fibrotic changes** seen in systemic sclerosis. *Interleukin 2* - **Interleukin-2 (IL-2)** is crucial for the proliferation and differentiation of T cells, particularly regulatory T cells, and is primarily involved in immune regulation and response to infection. - Its direct role in the **pathogenesis of fibrosis** in the context of scleroderma-associated lung disease is not as central as that of TGF-β. *Interferon gamma* - **Interferon-gamma (IFN-γ)** is a cytokine predominantly associated with anti-viral responses and the activation of macrophages and natural killer cells in cell-mediated immunity. - While it has immunomodulatory effects, IFN-γ is generally considered to have **anti-fibrotic properties** in some contexts, rather than promoting fibrosis in scleroderma.

Question 170: A 38-year-old woman was brought to the emergency department after she experienced dizziness and shortness of breath while walking with her friend. She recently immigrated to the United States and is unable to report her previous medical history. Physical exam reveals pallor underneath her eyelids. Labs are obtained with the following results: Hemoglobin: 8.4 g/dL Platelet count: 62,000/mm^3 Mean corpuscular volume: 89 µm^3 Reticulocyte count: 0.1% Lactate dehydrogenase: 175 U/L Which of the following is associated with the most likely cause of this patient's symptoms?

A. Living in an old house
B. Recent infection with a toxin producing gram-negative rod
C. Vegan diet
D. Chronic alcohol abuse
E. Administration of a 50S ribosomal inhibitor (Correct Answer)

Explanation: ***Administration of a 50S ribosomal inhibitor*** - The patient's symptoms (dizziness, shortness of breath, pallor) and lab results (anemia, thrombocytopenia, normal MCV, very low reticulocyte count) are highly suggestive of **aplastic anemia**. - Aplastic anemia is often caused by exposure to toxins or medications; **chloramphenicol**, a 50S ribosomal inhibitor, is a classic cause of dose-independent, idiosyncratic aplastic anemia. *Living in an old house* - Living in an old house is associated with **lead poisoning**, which typically causes a **microcytic anemia** with **basophilic stippling**, not normocytic anemia with thrombocytopenia and low reticulocytes. - Lead poisoning does not typically cause severe thrombocytopenia as seen in this patient. *Recent infection with a toxin producing gram-negative rod* - This scenario would suggest **hemolytic uremic syndrome (HUS)**, which presents with microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. - The patient's **normal LDH** and **low reticulocyte count** argue against hemolysis as the primary cause of anemia. *Vegan diet* - A vegan diet can lead to **vitamin B12 deficiency**, which causes **macrocytic anemia**, often with pancytopenia. - This patient has a **normal MCV (89 µm^3)**, ruling out macrocytic anemia. *Chronic alcohol abuse* - Chronic alcohol abuse can cause **folate deficiency** leading to **macrocytic anemia** and **thrombocytopenia**. - The patient's **normal MCV** makes macrocytic anemia due to folate deficiency unlikely.

Question 171: A 32-year-old woman presents with a 3-month history of intermittent blurred vision and problems walking. The patient states that she often feels “pins and needles” in her legs that cause her problems when she’s walking. The patient is afebrile, and her vital signs are within normal limits. An autoimmune disorder is suspected. Which of the following findings would most likely be present in this patient?

A. Damaged myelin sheath and myelin-producing cells (Correct Answer)
B. Absence of interneurons
C. Destruction of blood-brain barrier
D. Degeneration of anterior horn cells
E. Decreased cerebrospinal fluid due to destruction of cells

Explanation: ***Damaged myelin sheath and myelin-producing cells*** - The patient's symptoms of intermittent **blurred vision** (optic neuritis), **problems walking** (ataxia, spasticity), and **paresthesias** ("pins and needles") are classical presentations of Multiple Sclerosis (MS). - MS is characterized by multifocal areas of inflammation and **demyelination** in the central nervous system, where the **myelin sheath** surrounding axons is damaged, and the **oligodendrocytes** (myelin-producing cells) are attacked. - This demyelination disrupts saltatory conduction, leading to the varied and intermittent neurological symptoms. *Absence of interneurons* - The absence of **interneurons** is typically associated with conditions like **spinal muscular atrophy** or certain **neuropathies**, which present with different clinical features (e.g., muscle weakness, atrophy) than those described. - While interneurons are crucial for neuronal communication, their absence doesn't explain the *intermittent* and multifocal symptoms seen in this case. *Destruction of blood-brain barrier* - While **blood-brain barrier (BBB) breakdown** does occur in MS, it is a *consequence* of the inflammatory process rather than the primary *pathological finding* that directly explains the neurological symptoms. - BBB destruction allows inflammatory cells to enter the CNS, contributing to demyelination, but the core issue remains the myelin damage itself. *Degeneration of anterior horn cells* - **Anterior horn cell degeneration** is the hallmark of **amyotrophic lateral sclerosis (ALS)** and **spinal muscular atrophy**, presenting with progressive muscle weakness, atrophy, and fasciculations. - These conditions lack the sensory symptoms (paresthesias) and visual disturbances seen in this patient, and typically show a progressive rather than intermittent course. *Decreased cerebrospinal fluid due to destruction of cells* - **Decreased CSF volume** is not a characteristic feature of MS; in fact, CSF analysis often shows increased protein and **oligoclonal bands**. - The destruction of cells in MS primarily affects myelin and oligodendrocytes, not cells responsible for CSF production or volume regulation.

Question 172: A 7-year-old boy is brought to the emergency department by his parents. He is complaining of left-sided knee pain which has progressively increased in severity over the past 2 days. It started when he was playing football with his brothers but he does not recall falling or getting any injury. Past medical history is significant for prolonged bleeding and easy bruising. His maternal uncle has similar problems. Physical exam reveals swollen and painful left knee. His laboratory investigations reveal: Hemoglobin 11.8 g/dL WBC count 7,000/mL Platelets 250,000/mL INR 0.9 aPTT 62 sec, fully corrected with a mixing study Which of the following disorders have the same mode of inheritance as this patient’s disease?

A. Hereditary spherocytosis
B. Alkaptonuria
C. Duchenne muscular dystrophy (Correct Answer)
D. Sickle cell disease
E. Huntington's disease

Explanation: ***Duchenne muscular dystrophy*** - The patient's presentation with **hemarthrosis** (knee pain and swelling without trauma), **prolonged bleeding**, and **easy bruising**, along with a **prolonged aPTT** that corrects with a mixing study, is highly suggestive of **hemophilia A or B**. Both conditions are **X-linked recessive disorders**, affecting males predominantly. - **Duchenne muscular dystrophy** is also an **X-linked recessive disorder**, making its mode of inheritance identical to the suspected diagnosis of hemophilia in this patient. *Hereditary spherocytosis* - This condition is inherited in an **autosomal dominant** pattern, which is different from the mode of inheritance for hemophilia. - It is characterized by **hemolytic anemia** due to a defect in red blood cell membrane proteins. *Alkaptonuria* - Alkaptonuria is an **autosomal recessive** disorder, caused by a deficiency of homogentisate 1,2-dioxygenase. - It leads to the accumulation of **homogentisic acid**, causing **dark urine** when exposed to air, **ochronosis**, and **arthropathy**, distinct from the patient's bleeding disorder. *Sickle cell disease* - **Sickle cell disease** is an **autosomal recessive** disorder, characterized by abnormal hemoglobin leading to chronic hemolytic anemia and vaso-occlusive crises. - While it can cause joint pain due to avascular necrosis or infarction, its inheritance pattern is different from the patient's condition. *Huntington's disease* - **Huntington's disease** is an **autosomal dominant** neurodegenerative disorder that manifests with progressive motor, cognitive, and psychiatric symptoms, typically in middle age. - Its inheritance pattern and clinical presentation are distinct from the patient's bleeding disorder.

Question 173: A 15-year-old boy comes to the physician for the evaluation of progressive difficulty climbing stairs for the last 2 years. During this period, he has also had problems running and standing up from a seated position. He is at the 50th percentile for height and weight. Examination shows enlarged calf muscles bilaterally and a waddling gait. Which of the following is the most likely cause of this patient's condition?

A. Large deletions (Correct Answer)
B. Frameshift mutation
C. Splice site mutation
D. Missense mutation
E. Nonsense mutation

Explanation: ***Large deletions*** - The presented symptoms (progressive difficulty climbing stairs, running, standing, enlarged calf muscles, waddling gait) are classic for **Duchenne muscular dystrophy (DMD)**. - **Large deletions** (involving one or more exons) are the **most common cause of DMD**, accounting for approximately **60-70%** of cases. - These deletions typically cause a **frameshift** that leads to a premature stop codon, resulting in absent or severely truncated **dystrophin protein**. - The **dystrophin gene** is one of the largest human genes, making it particularly susceptible to deletion mutations. *Frameshift mutation* - A **frameshift mutation** (insertion or deletion of nucleotides not in multiples of three) leads to an altered reading frame, resulting in a **premature stop codon** downstream. - While frameshifts do cause **DMD**, they are typically the **consequence** of deletions or small insertions/duplications, not a primary mutation category. - The question asks for the underlying genetic cause, which is most commonly a large deletion. *Splice site mutation* - **Splice site mutations** affect the splicing of introns and exons, potentially leading to exon skipping or inclusion of intronic sequences. - These account for a small percentage of **DMD** cases but are much less common than large deletions. - While they can disrupt the reading frame, they represent a minority of causative mutations. *Missense mutation* - A **missense mutation** results in a single amino acid change, producing an altered but full-length protein. - This type of mutation is more characteristic of **Becker muscular dystrophy (BMD)**, a milder form with later onset and slower progression. - The severe, early-onset phenotype described here is typical of **DMD**, which requires near-complete absence of functional dystrophin. *Nonsense mutation* - A **nonsense mutation** introduces a premature stop codon, leading to a truncated protein. - While nonsense mutations do cause **DMD**, they account for only about **10-15%** of cases as part of the broader category of point mutations. - Large deletions remain significantly more common as the causative mutation type.

Question 174: A 62-year-old female with a history of uncontrolled hypertension undergoes kidney transplantation. One month following surgery she has elevated serum blood urea nitrogen and creatinine and the patient complains of fever and arthralgia. Her medications include tacrolimus and prednisone. If the patient were experiencing acute, cell-mediated rejection, which of the following would you most expect to see upon biopsy of the transplanted kidney?

A. Granular immunofluorescence around the glomerular basement membrane
B. Lymphocytic infiltrate of the tubules and interstitium (Correct Answer)
C. Crescent formation in Bowman’s space
D. Drug precipitation in the renal tubules
E. Sloughing of proximal tubular epithelial cells

Explanation: ***Lymphocytic infiltrate of the tubules and interstitium*** - **Acute cell-mediated rejection** is primarily characterized by the infiltration of **T lymphocytes** and macrophages into the allograft, leading to inflammation and damage. - This cellular infiltrate is typically observed in the **interstitium and tubules** of the transplanted kidney. *Granular immunofluorescence around the glomerular basement membrane* - This finding is characteristic of **immune complex-mediated glomerulonephritis**, such as post-streptococcal glomerulonephritis, and signifies deposition of immune complexes. - It is not typical of acute cell-mediated rejection, which is driven by T-cells rather than circulating immune complexes. *Crescent formation in Bowman’s space* - **Crescents** in Bowman's space are indicative of rapidly progressive glomerulonephritis (RPGN), a severe form of glomerular inflammation usually associated with conditions like Goodpasture syndrome or ANCA-associated vasculitis. - While crescentic glomerulonephritis can cause acute kidney injury, it is not the primary histological hallmark of acute cell-mediated transplant rejection. *Drug precipitation in the renal tubules* - **Drug precipitation** can occur with certain medications, leading to acute kidney injury (e.g., sulfonamides, methotrexate), but it is a chemical injury, not an immune-mediated rejection process. - The patient's symptoms of fever and arthralgia, along with elevated creatinine, point towards an inflammatory immune response rather than drug toxicity alone. *Sloughing of proximal tubular epithelial cells* - **Sloughing of proximal tubular epithelial cells** is a hallmark of **acute tubular necrosis (ATN)**, often caused by ischemia or nephrotoxic agents. - While ATN can also lead to elevated creatinine, the presence of fever and arthralgia, plus the context of transplantation, makes acute cell-mediated rejection a more likely diagnosis.

Question 175: A 25-year-old male visits his primary care physician with complaints of hemoptysis and dysuria. Serum blood urea nitrogen and creatinine are elevated, blood pressure is 160/100 mm Hg, and urinalysis shows hematuria and RBC casts. A 24-hour urine excretion yields 1 gm/day protein. A kidney biopsy is obtained, and immunofluorescence shows linear IgG staining in the glomeruli. Which of the following antibodies is likely pathogenic for this patient’s disease?

A. Anti-phospholipid antibody
B. Anti-neutrophil cytoplasmic antibody (C-ANCA)
C. Anti-neutrophil perinuclear antibody (P-ANCA)
D. Anti-glomerular basement membrane antibody (Anti-GBM) (Correct Answer)
E. Anti-DNA antibody

Explanation: ***Anti-glomerular basement membrane antibody (Anti-GBM)*** - The combination of **hemoptysis** (indicating pulmonary hemorrhage), **dysuria** (indicating renal involvement), rapidly progressive renal failure (elevated BUN/creatinine, hematuria, RBC casts, hypertension, proteinuria), and **linear IgG staining** on kidney biopsy is highly characteristic of **Goodpasture's syndrome**, which is caused by anti-GBM antibodies. - These antibodies target collagen type IV in the **glomerular and alveolar basement membranes**, leading to a dual presentation of glomerulonephritis and pulmonary hemorrhage. *Anti-phospholipid antibody* - These antibodies are associated with a **hypercoagulable state**, leading to recurrent venous or arterial thromboses, and recurrent pregnancy loss. - They do not typically cause **hemoptysis** or **glomerulonephritis** with linear IgG staining. *Anti-neutrophil cytoplasmic antibody (C-ANCA)* - **C-ANCA** is associated with **Wegener's granulomatosis** (granulomatosis with polyangiitis), a small vessel vasculitis that can cause pulmonary-renal syndrome but would show **pauci-immune glomerulonephritis** (no or minimal immune deposits) on biopsy, not linear IgG staining. - The staining pattern on immunofluorescence is key to differentiating this from Goodpasture's. *Anti-neutrophil perinuclear antibody (P-ANCA)* - **P-ANCA** is associated with microscopic polyangiitis and Churg-Strauss syndrome, which are also causes of **pauci-immune vasculitis** affecting the lungs and kidneys. - Similar to C-ANCA, these conditions do not present with **linear IgG staining** on immunofluorescence. *Anti-DNA antibody* - **Anti-DNA antibodies**, particularly anti-dsDNA, are characteristic of **systemic lupus erythematosus (SLE)**, which can cause glomerulonephritis (lupus nephritis). - Lupus nephritis typically presents with **granular immune complex deposits** on immunofluorescence, not linear IgG staining.

Question 176: A 45-year-old homeless man is brought to the emergency department after he was found unconscious at the park. The patient's past medical history is unknown; however, he was admitted to the emergency department 2 times over the past year for severe pain treated with hydromorphone and IV fluids. His temperature is 100°F (37.8°C), blood pressure is 97/48 mmHg, pulse is 140/min, respirations are 18/min, and oxygen saturation is 99% on room air. The patient smells of alcohol and is covered in emesis. Basic laboratory values are ordered as seen below. Hemoglobin: 6 g/dL Hematocrit: 20% Leukocyte count: 6,500/mm^3 with normal differential Platelet count: 197,000/mm^3 Reticulocyte count: 0.4% Which of the following is associated with the most likely diagnosis?

A. Iron deficiency
B. Parvovirus B19 infection (Correct Answer)
C. Folate deficiency
D. Vitamin B12 deficiency
E. Benign genetic carrier condition

Explanation: ***Parvovirus B19 infection*** - This patient presents with **severe anemia (Hb 6 g/dL)** and **profound reticulocytopenia (0.4%)** - the combination of severe anemia with a markedly suppressed reticulocyte count indicates **bone marrow suppression** affecting red cell production. - **Parvovirus B19** specifically targets **erythroid progenitor cells** in the bone marrow, causing **transient aplastic crisis** characterized by acute cessation of red blood cell production (hence the reticulocytopenia). - While aplastic crisis classically occurs in patients with **underlying chronic hemolytic anemias** (e.g., sickle cell disease), the patient's history of **recurrent severe pain episodes** requiring opioid analgesia suggests a possible undiagnosed hemolytic disorder. In such patients, Parvovirus B19 infection can cause life-threatening anemia because the bone marrow cannot compensate for ongoing hemolysis. - The **homeless status** increases risk of viral infections, and the acute presentation with fever supports an infectious etiology. - **Key diagnostic clue**: Severe anemia + reticulocytopenia (not reticulocytosis) = bone marrow suppression, most consistent with Parvovirus B19 aplastic crisis. *Iron deficiency* - **Iron deficiency anemia** typically presents with **microcytic, hypochromic** red cells and develops gradually over time. - Importantly, iron deficiency would trigger a **compensatory reticulocytosis** (elevated reticulocyte count) as the bone marrow attempts to respond to anemia - the opposite of what is seen here with reticulocytopenia. - Does not explain the **acute presentation** with profound bone marrow suppression. *Folate deficiency* - **Folate deficiency** causes **macrocytic anemia** (elevated MCV) and is common in chronic alcoholics due to poor nutrition. - While folate deficiency can impair red cell production, it typically shows an **inadequate reticulocyte response** (low but not profoundly suppressed) rather than the severe reticulocytopenia (0.4%) seen here. - The **megaloblastic changes** from folate deficiency develop gradually, not acutely as in this presentation. *Vitamin B12 deficiency* - **Vitamin B12 deficiency** also causes **macrocytic anemia** with elevated MCV and may present with neurological symptoms (subacute combined degeneration). - Like folate deficiency, B12 deficiency shows **ineffective erythropoiesis** but not the profound acute reticulocytopenia characteristic of bone marrow suppression. - The time course is typically chronic, not acute as presented. *Benign genetic carrier condition* - A **benign genetic carrier condition** (e.g., thalassemia trait) causes **mild, chronic microcytic anemia** that is typically asymptomatic and stable. - Carrier states do not cause **severe acute anemia** or **reticulocytopenia** - in fact, thalassemia trait often shows normal or elevated red cell counts with low MCV. - Does not explain the acute clinical decompensation, fever, or profound bone marrow suppression.

Question 177: A 14-year-old girl is brought to the emergency department because of a 3-day history of worsening confusion, high-grade fever, and a productive cough. She has had recurrent respiratory infections and bulky, foul-smelling, oily stools since infancy. She is at the 14th percentile for height and 8th percentile for weight. Despite appropriate care, the patient dies 2 days after admission. Autopsy of the lungs shows bronchial mucus plugging and bronchiectasis. Which of the following is the most likely underlying cause of this patient's condition?

A. Mutation of DNAI1 gene on chromosome 9
B. Deficiency in alpha-1 antitrypsin
C. Deficiency in apolipoprotein B-48
D. Deficiency in adenosine deaminase
E. Deletion of phenylalanine codon on chromosome 7 (Correct Answer)

Explanation: ***Deletion of phenylalanine codon on chromosome 7*** - The patient's presentation of **recurrent respiratory infections**, **bronchial mucus plugging**, **bronchiectasis**, and **malabsorption** (foul-smelling, oily stools, failure to thrive) is classic for **cystic fibrosis**. - **Cystic fibrosis** is most commonly caused by a **deletion of three base pairs** coding for phenylalanine at position 508 (**ΔF508**) on the **CFTR gene** located on **chromosome 7**. *Mutation of DNAI1 gene on chromosome 9* - A mutation in the **DNAI1 gene** on chromosome 9 is associated with **primary ciliary dyskinesia (PCD)**. - While PCD can cause recurrent respiratory infections and bronchiectasis due to impaired mucociliary clearance, it typically **does not involve the pancreatic insufficiency** and malabsorption suggested by the oily stools and failure to thrive in this patient. *Deficiency in alpha-1 antitrypsin* - **Alpha-1 antitrypsin deficiency** primarily leads to early-onset **emphysema** and liver disease, not typically the severe pancreatic insufficiency and recurrent bacterial infections seen in cystic fibrosis. - While it can cause lung damage, the absence of symptoms related to **pancreatic dysfunction** makes this less likely. *Deficiency in apolipoprotein B-48* - A deficiency in **apolipoprotein B-48** is associated with **abetalipoproteinemia**, a disorder characterized by the inability to synthesize chylomicrons, leading to severe malabsorption of dietary fats and fat-soluble vitamins. - While it causes malabsorption and greasy stools, it **does not typically present with recurrent respiratory infections, mucus plugging, and bronchiectasis**, which are prominent features in this case. *Deficiency in adenosine deaminase* - A deficiency in **adenosine deaminase (ADA)** leads to **severe combined immunodeficiency (SCID)**, characterized by profound lymphopenia and recurrent infections (bacterial, viral, fungal). - While SCID causes recurrent infections and failure to thrive, it typically **does not present with the specific pulmonary pathology of mucus plugging and bronchiectasis**, nor the **pancreatic exocrine insufficiency** suggested by the oily stools.

Question 178: A 64-year-old man presents to his primary care provider after noticing the development of a blistering rash. The patient states that his symptoms began 1 week ago after he noticed a blister develop on the inside of his mouth that eventually ruptured. Over the past several days, he has noticed several more blisters on his torso. The patient denies a fever or any other symptoms. He has a history of high blood pressure, for which he takes hydrochlorothiazide. He is otherwise healthy and denies any recent changes to his medication. Today, the patient’s temperature is 99.0°F (37.2°C), blood pressure is 124/84 mmHg, pulse is 66/min, and respirations are 12/min. On exam, the patient’s mouth is notable for a previously ruptured blister on his left buccal mucosa. On his left flank and anterior abdomen are scattered 10-15-cm bullae that appear flaccid and filled with serous fluid. The lesions are erythematous but there is no surrounding erythema. On manual rubbing of the skin near the lesions, new blisters form within minutes. Which of the following is involved in the pathogenesis of this disease?

A. IgA antibodies depositing in the dermal papillae
B. Autoantibodies against hemidesmosomes
C. Exotoxin destroying keratinocyte attachments
D. Viral infection of skin
E. IgG against transmembrane proteins between cells (Correct Answer)

Explanation: ***IgG against transmembrane proteins between cells*** - This clinical presentation, including flaccid bullae, Nikolsky sign (new blisters with manual rubbing), and oral involvement, is characteristic of **pemphigus vulgaris**. - Pemphigus vulgaris is caused by **IgG autoantibodies** targeting **desmoglein 1** and **desmoglein 3**, which are transmembrane proteins forming desmosomes that connect keratinocytes. *IgA antibodies depositing in the dermal papillae* - This describes the pathogenesis of **dermatitis herpetiformis**, which presents with intensely pruritic papulovesicular lesions, typically on extensor surfaces. - The lesions in dermatitis herpetiformis are small, grouped vesicles, not the large, flaccid bullae seen in this patient. *Autoantibodies against hemidesmosomes* - This mechanism is characteristic of **bullous pemphigoid**, which typically presents with tense bullae that do not rupture easily and are often associated with pruritus. - Unlike pemphigus vulgaris, bullous pemphigoid usually spares the oral mucosa, and the Nikolsky sign is typically absent. *Exotoxin destroying keratinocyte attachments* - This mechanism is seen in conditions like **staphylococcal scalded skin syndrome (SSSS)**, caused by exfoliating toxins that cleave **desmoglein 1**. - SSSS typically presents with diffuse erythema and superficial epidermal peeling, often in children, and the patient's history does not suggest an acute infection. *Viral infection of skin* - Viral infections leading to blistering rashes, such as **herpes simplex** or **varicella-zoster virus**, typically cause painful, grouped vesicles on an erythematous base. - The extensive, flaccid bullae and lack of fever or prodromal symptoms are inconsistent with a primary viral blistering eruption.

Question 179: A 63-year-old female enrolls in a research study evaluating the use of iron studies to screen for disease in a population of post-menopausal women. Per study protocol, past medical history and other identifying information is unknown. The patient's iron studies return as follows: Serum iron: 200 µg/dL (normal 50–170 µg/dL) TIBC: 220 µg/dL (normal 250–370 µg/dL) Transferrin saturation: 91% (normal 15–50%) Serum ferritin: 180 µg/L (normal 15-150 µg/L) Which of the following is the most likely cause of these findings?

A. Iron deficiency
B. Lead poisoning
C. Excess iron absorption (Correct Answer)
D. Pregnancy
E. Chronic inflammation

Explanation: ***Excess iron absorption*** - The combination of **elevated serum iron**, **high transferrin saturation**, and **normal to elevated ferritin** is characteristic of **iron overload** due to excess absorption. - Reduced **TIBC** (Total Iron-Binding Capacity) further supports iron overload, as fewer binding sites are available for iron due to saturation. *Iron deficiency* - **Iron deficiency** would show **low serum iron**, **low ferritin**, **high TIBC**, and **low transferrin saturation**. - This clinical picture is the opposite of the given lab values, indicating a surplus, not a deficit, of iron. *Lead poisoning* - While **lead poisoning** can affect red blood cell production and lead to **anemia**, it typically causes microcytic, hypochromic anemia and does not directly result in the described pattern of **iron overload**. - Iron studies in lead poisoning may show normal or mildly elevated ferritin, but not the high serum iron and transferrin saturation seen here. *Pregnancy* - **Pregnancy** is a state of **increased iron demand**, and iron studies typically show **dilutional anemia**, **low serum iron**, and **increased TIBC** as the body tries to absorb more iron. - This patient is **post-menopausal** and, therefore, pregnancy is not a relevant condition for these findings. *Chronic inflammation* - **Chronic inflammation** (anemia of chronic disease) would typically present with **low serum iron**, **low TIBC**, but **normal or elevated ferritin** (as ferritin is an acute phase reactant). - The **high transferrin saturation** seen in this patient is not consistent with anemia of chronic disease.

Question 180: A 42-year-old man presents to his primary care physician complaining of subjective fever, cough, and night sweats. He states that over the past 2 months he has “not felt like myself.” He has lost 12 lbs over this time period. Two weeks ago, he started experiencing night sweats and cough. This morning he decided to take his temperature and reports it was “high.” He has a history of HIV and admits to inconsistently taking his anti-retrovirals. A chest radiograph reveals a cavitary lesion in the left upper lobe. An interferon-gamma release assay is positive, and the patient is started on appropriate antimicrobial therapy. A month later he is seen in clinic for follow-up. Lab work is obtained, as shown below: Leukocyte count: 11,000/mm^3 with normal differential Hemoglobin: 9.2 g/dL Platelet count: 400,000/mm^3 Mean corpuscular volume (MCV): 75 µm^3 Based on these results, a peripheral smear is sent and shows Pappenheimer bodies. Which of the following is the most accurate test for the patient’s diagnosis?

A. Hemoglobin electrophoresis
B. Methylmalonic acid level
C. Genetic testing
D. Iron studies
E. Prussian blue staining (Correct Answer)

Explanation: ***Prussian blue staining*** - The patient presents with **microcytic anemia** (MCV 75 µm³, Hb 9.2 g/dL) and **Pappenheimer bodies** on peripheral smear, which are **iron-containing granules** suggestive of **sideroblastic anemia**. - In the context of **anti-tuberculosis therapy** (especially **isoniazid**), drug-induced sideroblastic anemia is highly likely, as isoniazid interferes with **pyridoxine (vitamin B6)** metabolism, which is essential for heme synthesis. - **Prussian blue staining of bone marrow** is the **gold standard and most accurate test** for diagnosing sideroblastic anemia, as it definitively demonstrates **ring sideroblasts** (erythroblasts with iron-loaded mitochondria forming a perinuclear ring). - This is the **definitive diagnostic test** that directly visualizes the pathologic finding. *Iron studies* - While **iron studies** (elevated serum iron, ferritin, and transferrin saturation with low/normal TIBC) are **suggestive** of sideroblastic anemia, they are **not diagnostic**. - Iron studies help support the diagnosis and differentiate from iron deficiency anemia, but they cannot definitively confirm sideroblastic anemia. - The question asks for the **most accurate test**, which requires definitive pathologic confirmation, not just supportive laboratory findings. *Hemoglobin electrophoresis* - This test is used to diagnose **hemoglobinopathies** such as **thalassemia** or **sickle cell disease**. - While thalassemia can cause microcytic anemia, the presence of **Pappenheimer bodies** and the clinical context of **TB treatment** make drug-induced sideroblastic anemia the primary diagnosis. *Methylmalonic acid level* - **Methylmalonic acid** levels are elevated in **vitamin B12 deficiency**, which causes **macrocytic anemia** (high MCV). - The patient has **microcytic anemia** (MCV 75 µm³), making B12 deficiency inconsistent with the presentation. *Genetic testing* - **Genetic testing** identifies **hereditary sideroblastic anemia**, a rare congenital disorder. - This patient's sideroblastic anemia is **acquired** (drug-induced by isoniazid), making genetic testing unnecessary. - Even if genetic testing were relevant, **Prussian blue staining** would still be needed first to confirm the diagnosis of sideroblastic anemia.

Question 181: A previously healthy 4-year-old boy is brought to the emergency department because of a 1-day history of pain and swelling of his left knee joint. He has not had any trauma to the knee. His family history is unremarkable except for a bleeding disorder in his maternal uncle. His temperature is 36.9°C (98.4°F). The left knee is erythematous, swollen, and tender; range of motion is limited. No other joints are affected. An x-ray of the knee shows an effusion but no structural abnormalities of the joint. Arthrocentesis is conducted. The synovial fluid is bloody. Further evaluation of this patient is most likely to show which of the following findings?

A. Prolonged prothrombin time
B. Synovial fluid leukocytosis
C. Elevated antinuclear antibody levels
D. Prolonged partial thromboplastin time (Correct Answer)
E. Decreased platelet count

Explanation: ***Prolonged partial thromboplastin time*** - The clinical presentation of a young boy with **spontaneous hemarthrosis** (bloody synovial fluid in the knee) and a family history of a **bleeding disorder in a maternal uncle** is highly suggestive of **hemophilia A or B**. - Both hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) present with a **prolonged PTT** due to impaired intrinsic coagulation pathway, while PT and platelet count typically remain normal. *Prolonged prothrombin time* - A prolonged **prothrombin time (PT)** primarily indicates a deficiency in the **extrinsic coagulation pathway**, involving factor VII, or severe deficiencies in common pathway factors (II, V, X, fibrinogen). - This is not characteristic of hemophilia A or B, which are deficiencies in the **intrinsic pathway**. *Synovial fluid leukocytosis* - **Synovial fluid leukocytosis** (increased white blood cells) is typically seen in **inflammatory or infectious arthritis**, such as septic arthritis or juvenile idiopathic arthritis. - While the knee is swollen and tender, the **bloody synovial fluid without trauma** points away from infection and towards a bleeding disorder. *Elevated antinuclear antibody levels* - **Elevated antinuclear antibody (ANA) levels** are a hallmark of **systemic autoimmune diseases** like systemic lupus erythematosus (SLE) or certain forms of juvenile idiopathic arthritis. - These conditions do not typically present with spontaneous gross hemarthrosis as the primary symptom, nor would they explain the family history of a bleeding disorder. *Decreased platelet count* - A **decreased platelet count (thrombocytopenia)** would lead to a bleeding disorder characterized by mucocutaneous bleeding (e.g., petechiae, purpura, epistaxis) rather than deep joint bleeds. - Platelet dysfunction or thrombocytopenia would cause a **prolonged bleeding time**, not typically a prolonged PTT, and the overall clinical picture does not align with a primary platelet disorder.

Question 182: A 45-year-old man comes to the physician for a 2-day history of headache and breathlessness on exertion. During the same period, he has vomited twice and not passed urine. He also reports pain and stiffness in his fingers that has worsened progressively over the past 2 years. He has no history of serious illness and takes no medications. He does not smoke or drink alcohol. He is in moderate distress. His temperature is 37.2°C (98.9°F), pulse is 88/min, blood pressure is 170/100 mm Hg, and respirations are 24/min. Pulse oximetry on room air shows an oxygen saturation of 91%. Examination reveals pallor, 2+ pretibial edema, and jugular venous distention. The skin on the arms, chest, and upper back is coarse and thickened. Diffuse cutaneous hyperpigmentation and hypopigmented patches with perifollicular hypopigmentation are noted. Contractures are present in the proximal interphalangeal joints of both hands. Diffuse crackles are heard on auscultation of the chest. There is dullness to percussion and decreased breath sounds over both lung bases. S1 and S2 are normal. An S3 gallop is heard at the apex. The remainder of the examination shows no abnormalities. His hemoglobin concentration is 8.1 g/dL, and his serum creatinine is 5.3 mg/dL. Further evaluation of this patient is most likely to show which of the following?

A. Decreased serum complement levels
B. Decreased serum haptoglobin levels (Correct Answer)
C. Increased anti-CCP antibody titers
D. Increased anticentromere antibody titers
E. Increased total iron binding capacity

Explanation: ***Decreased serum haptoglobin levels*** - This patient presents with symptoms and signs highly suggestive of **scleroderma renal crisis** (hypertension, acute kidney injury, headache, breathlessness, oliguria) in the context of long-standing systemic sclerosis (skin thickening, joint contractures, pulmonary findings). **Microangiopathic hemolytic anemia (MAHA)**, characterized by red blood cell fragmentation and consumption of haptoglobin, is a common complication of scleroderma renal crisis. - **Decreased haptoglobin** levels occur as it binds free hemoglobin released from destroyed red blood cells, indicating active hemolysis. The **anemia (Hb 8.1 g/dL)** in this patient, along with the renal crisis and other systemic sclerosis features, makes MAHA a strong consideration. *Decreased serum complement levels* - Decreased complement levels (C3, C4) are typically associated with **immune complex-mediated diseases** like **systemic lupus erythematosus (SLE)** or **cryoglobulinemia**. - While systemic sclerosis can overlap with other autoimmune conditions, profoundly low complement levels as a primary feature of scleroderma renal crisis or MAHA are not typical. *Increased anti-CCP antibody titers* - **Anti-cyclic citrullinated peptide (anti-CCP) antibodies** are highly specific for **rheumatoid arthritis**. - The patient's presentation with prominent skin thickening, renal crisis, and lung involvement is not characteristic of rheumatoid arthritis. *Increased anticentromere antibody titers* - **Anticentromere antibodies** are specific for the **limited cutaneous form of systemic sclerosis (CREST syndrome)**. - While the patient has systemic sclerosis, the severe multi-organ involvement (renal crisis, extensive skin thickening, pulmonary fibrosis) is more consistent with **diffuse cutaneous systemic sclerosis**, which is typically associated with **anti-Scl-70 (anti-topoisomerase I) antibodies**, not anticentromere. *Increased total iron binding capacity* - **Increased total iron binding capacity (TIBC)** is characteristic of **iron deficiency anemia**, where the body attempts to absorb more iron due to low stores. - While the patient has anemia, the context of acute kidney injury and likely MAHA points towards different underlying mechanisms of anemia, such as chronic disease, hemolysis, or uremic suppression of erythropoiesis, rather than primary iron deficiency causing an increased TIBC.

Question 183: At a routine exam, a 68-year-old woman is discovered to have a serum calcium level of 11.5 mg/dL. Follow-up laboratory tests show a high parathyroid hormone with low phosphorus and mildly elevated alkaline phosphatase. 24-hour urine calcium level is elevated. Review of symptoms includes complaints of fatigue, constipation, and diffuse bone pain for which she takes vitamin D. Past medical history is significant for type 2 diabetes mellitus for 25 years and essential hypertension for 15 years. The patient has a history of kidney stones. Family history is irrelevant. Which of the following radiologic findings is consistent with the patient's condition?

A. Subperiosteal bone resorption on hand X-ray (Correct Answer)
B. Osteopenia, osteolytic lesions and pathological fractures
C. Fibronodular opacities in upper lobes of the lung with or without cavitation
D. Lytic changes in early stage and sclerotic picture in later stage
E. Hilar and/or paratracheal adenopathy with bilateral upper lobe lung infiltrates

Explanation: ***Subperiosteal bone resorption on hand X-ray*** - The patient's symptoms and lab findings (hypercalcemia, high PTH, low phosphorus, elevated alkaline phosphatase, elevated 24-hour urine calcium) are classic for **primary hyperparathyroidism**. - **Subperiosteal bone resorption**, particularly in the phalanges of the hands, is a highly characteristic radiologic sign of significant **hyperparathyroidism (osteitis fibrosa cystica)**, indicating excessive bone turnover due to PTH. *Osteopenia, osteolytic lesions and pathological fractures* - While osteopenia and pathological fractures can occur in hyperparathyroidism due to chronic bone loss, **multiple osteolytic lesions** are more characteristic of other conditions like **multiple myeloma** or metastatic cancer, which are not suggested by the lab findings. - Hyperparathyroidism typically causes **generalized osteopenia/osteoporosis** rather than isolated, distinct osteolytic lesions throughout the skeleton. *Fibronodular opacities in upper lobes of the lung with or without cavitation* - These findings are more typical of **chronic granulomatous diseases** like **tuberculosis**, particularly in the upper lobes. - This is a pulmonary finding and not directly related to the **skeletal manifestations of hyperparathyroidism**. *Lytic changes in early stage and sclerotic picture in later stage* - This pattern of bone changes (lytic to sclerotic) is characteristic of **Paget's disease of bone**, which is associated with different biochemical markers and often localized bone pain/deformity, not diffuse bone pain and the specific calcium/PTH/phosphorus profile seen here. - Paget's disease typically has a significantly **elevated alkaline phosphatase** but normal calcium and PTH levels. *Hilar and/or paratracheal adenopathy with bilateral upper lobe lung infiltrates* - These are classic radiographic findings for **sarcoidosis**, a systemic inflammatory disease that can cause hypercalcemia through **extra-renal 1-alpha hydroxylation of vitamin D**, but typically with suppressed PTH levels, not elevated PTH. - The adenopathy and infiltrates are not direct skeletal manifestations of the primary hyperparathyroidism described.

Question 184: A 42-year-old woman comes to the physician with acute, severe pain in the middle of her lower back. She also complains of constipation and trouble sleeping recently. Menses occur regularly at 28-day intervals. Examination shows localized tenderness to palpation over the lumbar spine. Serum calcium is 14 mg/dL and serum phosphorus is 1.5 mg/dL. An x-ray of the lumbar spine shows a compression fracture of the L4 vertebral body and osteopenia. Which of the following is the most likely underlying cause of this patient's decreased bone mineral density?

A. Increase in parathyroid hormone secretion (Correct Answer)
B. Decrease in RANKL expression
C. Decrease in osteoblast activity
D. Increase in calcitonin secretion
E. Decrease in estrogen production

Explanation: ***Increase in parathyroid hormone secretion*** - This patient presents with the classic triad of **primary hyperparathyroidism**: hypercalcemia (14 mg/dL), hypophosphatemia (1.5 mg/dL), and bone disease (compression fracture with osteopenia). - **PTH excess** causes increased bone resorption by stimulating osteoclast activity, leading to decreased bone mineral density and pathologic fractures. - PTH increases renal phosphate excretion (causing hypophosphatemia) and increases calcium reabsorption and bone resorption (causing hypercalcemia). - The **constipation is a manifestation of hypercalcemia** ("stones, bones, abdominal groans, and psychiatric overtones"). - Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients and frequently presents with osteopenia/osteoporosis. *Decrease in estrogen production* - While estrogen deficiency causes osteoporosis in postmenopausal women, this patient has **regular menses at 28-day intervals**, indicating she is not menopausal. - Estrogen deficiency causes **normocalcemic osteoporosis**, not the hypercalcemia (14 mg/dL) and hypophosphatemia (1.5 mg/dL) seen in this patient. - The laboratory abnormalities clearly point to a different etiology. *Decrease in RANKL expression* - RANKL (receptor activator of nuclear factor-κB ligand) stimulates osteoclast differentiation and activity. - A **decrease** in RANKL would **reduce** osteoclast activity and **increase** bone mineral density, which is opposite to this patient's presentation. - PTH actually works partly by increasing RANKL expression, further supporting hyperparathyroidism as the diagnosis. *Decrease in osteoblast activity* - While decreased osteoblast activity can contribute to low bone density, this is typically seen in conditions like multiple myeloma or aging. - This mechanism does not explain the **hypercalcemia and hypophosphatemia** seen in this patient. - The primary pathology here is **increased osteoclast activity** driven by excess PTH. *Increase in calcitonin secretion* - Calcitonin **lowers** serum calcium by inhibiting osteoclast activity. - An increase in calcitonin would cause **hypocalcemia**, not the hypercalcemia (14 mg/dL) observed in this patient. - This is physiologically opposite to the patient's presentation.

Question 185: A 70-year-old woman is on hospital day 2 in the medical intensive care unit. She was admitted from the emergency department for a 2-day history of shortness of breath and fever. In the emergency department, her temperature is 39.4°C (103.0°F), the pulse is 120/min, the blood pressure is 94/54 mm Hg, the respiratory rate is 36/min, and oxygen saturation was 82% while on 4L of oxygen via a non-rebreather mask. Chest X-ray shows a right lower lobe consolidation. She was intubated, sedated, and started on broad-spectrum antibiotics for sepsis of pulmonary origin and intravenous norepinephrine for blood pressure support. Since then, her clinical condition has been stable, though her vasopressor and oxygen requirements have not improved. Today, her physician is called to the bedside because her nurse noted some slow bleeding from her intravenous line sites and around her urinary catheter. Which of the following most likely represents the results of coagulation studies for this patient?

A. D-dimer: negative, fibrinogen level: low, platelet count: low
B. D-dimer: elevated, fibrinogen level: normal, platelet count: normal
C. D-dimer: elevated, fibrinogen level: low, platelet count: low (Correct Answer)
D. D-dimer: negative, fibrinogen level: elevated, platelet count: elevated
E. D-dimer: negative, fibrinogen level: normal, platelet count: normal

Explanation: ***D-dimer: elevated, fibrinogen level: low, platelet count: low*** - The patient's presentation with **sepsis** requiring intubation and vasopressors, along with diffuse **bleeding from IV sites and urinary catheter**, strongly suggests **disseminated intravascular coagulation (DIC)**. - In DIC, widespread activation of the coagulation cascade leads to consumption of **platelets** and **clotting factors (including fibrinogen)**, resulting in thrombocytopenia and hypofibrinogenemia. The breakdown of clots produces **elevated D-dimer** levels. *D-dimer: negative, fibrinogen level: low, platelet count: low* - A **negative D-dimer** would contradict the diagnosis of DIC, as D-dimer is a product of fibrin degradation and is almost always elevated in DIC due to extensive clot formation and subsequent fibrinolysis. - While low fibrinogen and platelet count are characteristic of DIC, the negative D-dimer makes this option unlikely in the context of active bleeding from multiple sites. *D-dimer: elevated, fibrinogen level: normal, platelet count: normal* - While an **elevated D-dimer** is consistent with fibrinolysis occurring in DIC, normal **fibrinogen** and **platelet counts** would argue against the consumptive coagulopathy that defines DIC. - The presence of diffuse bleeding in a patient with sepsis usually indicates significant depletion of clotting factors and platelets. *D-dimer: negative, fibrinogen level: elevated, platelet count: elevated* - This profile suggests an **inflammatory state** or a hypercoagulable state without significant fibrinolysis or consumption of clotting factors. - A **negative D-dimer** and **elevated fibrinogen/platelets** contradict the signs and symptoms of DIC with active bleeding. *D-dimer: negative, fibrinogen level: normal, platelet count: normal* - This result would be inconsistent with **DIC** and the patient's clinical picture of widespread bleeding. - In DIC, there is active coagulation and fibrinolysis, leading to consumption of platelets and fibrinogen and production of D-dimers.

Question 186: A 19-year-old man and recent immigrant from Brazil present to the clinic. He has no known past medical, past surgical, or family history. The patient admits to having several regular sexual partners. Today, he complains of a skin rash on his back. He is unclear when it started but became aware when one of his partners pointed it out. A review of systems is otherwise negative. Physical examination reveals numerous hypopigmented skin lesions over his upper back. When questioned, he states that they do not get darker after spending time in the sun. On examination, there is a 5 cm (1.9 in) patch of hypopigmented skin in the center of his back with a fine-scale overlying it. What is the most likely diagnosis?

A. Tinea versicolor (Correct Answer)
B. Secondary syphilis
C. Pityriasis rosea
D. Mycosis fungoides
E. Vitiligo

Explanation: ***Tinea versicolor*** - The presence of **hypopigmented patches** with **fine scale** that fail to tan in sun-exposed areas is characteristic of tinea versicolor, a superficial fungal infection. - This condition is common in warm, humid climates, making it relevant for someone from Brazil. *Secondary syphilis* - The rash of secondary syphilis is typically **erythematous** or **copper-colored** and often involves the palms and soles, which is not described. - While syphilis can cause various skin manifestations, **hypopigmentation with fine scale** that doesn't tan is not a classic presentation. *Pityriasis rosea* - Pityriasis rosea usually begins with a **herald patch** followed by smaller, oval, erythematous, and scaly lesions distributed in a **Christmas tree pattern**, which is not consistent with the described findings. - The lesions are typically pink or red, not hypopigmented. *Mycosis fungoides* - Mycosis fungoides is a type of **cutaneous T-cell lymphoma** that presents with various skin lesions, including patches, plaques, and tumors, often over long periods. - It is a chronic and progressive condition, and while hypopigmentation can occur, the discrete, scaled patches specifically not tanning are less typical for an initial presentation. *Vitiligo* - Vitiligo is characterized by **complete depigmentation** (amelanotic) of the skin, resulting in sharply demarcated, milky-white patches. - Unlike tinea versicolor, vitiligo lesions are completely devoid of pigment and do not have a fine scale.

Question 187: A 16-year-old boy is brought to the pediatrician by his mother because she is concerned about the “spots” on his abdomen and back. The patient’s mother reports that there are several “light spots” on the patient’s trunk that have been slowly increasing in number. The lesions are not painful nor pruritic. The patient’s mother is worried because her nephew had vitiligo. The patient reports that he feels “fine,” but reports occasional headaches and increasing difficulty with seeing the board at school. In addition to the patient’s cousin having vitiligo, the patient’s paternal grandfather and uncle have bilateral deafness, and his mother has systemic lupus erythematous. On physical examination, there are multiple, discrete, 2-3 cm hypopigmented macules on the chest, abdomen, back, and posterior shoulders. Which of the following head and neck computed tomography findings is the patient most likely to develop?

A. Subependymal hamartomas
B. Optic nerve glioma
C. Bilateral vestibular schwannomas (Correct Answer)
D. Cerebral atrophy
E. Thyroid nodule

Explanation: ***Bilateral vestibular schwannomas*** - The family history of **bilateral deafness** in the paternal grandfather and uncle is highly suggestive of **Neurofibromatosis type 2 (NF2)**, which is inherited in an autosomal dominant pattern. - **NF2** is characterized by the development of **bilateral vestibular schwannomas** (acoustic neuromas), which typically present with progressive hearing loss, tinnitus, and balance problems in the second or third decade of life. - The patient's headaches and vision difficulties may represent early CNS manifestations of NF2 (meningiomas, cataracts, or other tumors). - Unlike NF1, **skin findings in NF2 are minimal** - café-au-lait spots are rare and usually fewer than 6. The hypopigmented macules described here are atypical for NF2 but the strong family history makes this the most likely diagnosis. *Subependymal hamartomas* - These are characteristic findings in **Tuberous Sclerosis Complex (TSC)**, which presents with hypopigmented **ash-leaf spots**, seizures, developmental delay, and facial angiofibromas. - TSC does not typically present with a family history of bilateral deafness, which is the key distinguishing feature pointing toward NF2 in this case. *Optic nerve glioma* - **Optic nerve gliomas** are associated with **Neurofibromatosis type 1 (NF1)**, which presents with multiple café-au-lait spots (≥6, and these are **hyperpigmented**, not hypopigmented), axillary/inguinal freckling, Lisch nodules, and neurofibromas. - NF1 does not typically cause bilateral deafness, making this diagnosis less likely given the family history. *Cerebral atrophy* - **Cerebral atrophy** is a nonspecific finding seen in various neurodegenerative disorders, aging, or conditions causing chronic brain injury. - It is not a characteristic or primary finding in any of the neurocutaneous syndromes suggested by this clinical presentation. *Thyroid nodule* - **Thyroid nodules** are common in the general population but are not specifically associated with the constellation of symptoms presented here. - There is no direct link between NF2 and an increased risk of thyroid nodules.

Question 188: A 72-year-old African American man presents with progressive fatigue, difficulty breathing on exertion, and lower extremity swelling for 3 months. The patient was seen at the emergency department 2 times before. The first time was because of back pain, and the second was because of fever and cough. He took medications at the emergency room, but he refused to do further tests recommended to him. He does not smoke or drink alcohol. His family history is irrelevant. His vital signs include a blood pressure of 110/80 mm Hg, temperature of 37.2°C (98.9°F), and regular radial pulse of 90/min. On physical examination, the patient looks pale, and his tongue is enlarged. Jugular veins become distended on inspiration. Pitting ankle edema is present on both sides. Bilateral basal crackles are audible on the chest auscultation. Hepatomegaly is present on abdominal palpation. Chest X-ray shows osteolytic lesions of the ribs. ECG shows low voltage waves and echocardiogram shows a speckled appearance of the myocardium with diastolic dysfunction and normal appearance of the pericardium. Which of the following best describes the mechanism of this patient’s illness?

A. Thickening of the parietal pericardium with dystrophic calcification
B. Calcification of the aortic valve orifice with obstruction of the left ventricular outflow tract
C. Concentric hypertrophy of the myocytes with thickening of the interventricular septum
D. Diastolic cardiac dysfunction with reciprocal variation in ventricular filling with respiration
E. Deposition of an extracellular fibrillar protein that stains positive for Congo red in the myocardium (Correct Answer)

Explanation: - ***Deposition of an extracellular fibrillar protein that stains positive for Congo red in the myocardium*** - The patient's presentation with **progressive fatigue, dyspnea, edema, enlarged tongue, jugular venous distention with inspiration** (Kussmaul's sign), **basal crackles, hepatomegaly, osteolytic lesions, low voltage on ECG, and a speckled appearance of the myocardium on echocardiogram with diastolic dysfunction** is highly suggestive of **amyloidosis**. - **Amyloidosis** involves the deposition of misfolded, insoluble **fibrillar proteins** in various tissues, including the heart, leading to restrictive cardiomyopathy. These amyloid deposits typically stain **positive with Congo red** and demonstrate **apple-green birefringence** under polarized light. - *Thickening of the parietal pericardium with dystrophic calcification* - This description is characteristic of **constrictive pericarditis**, which can cause symptoms similar to restrictive cardiomyopathy (e.g., Kussmaul's sign, edema). - However, the echocardiogram in this patient shows a **speckled appearance of the myocardium** and a **normal pericardium**, ruling out constrictive pericarditis. - *Calcification of the aortic valve orifice with obstruction of the left ventricular outflow tract* - This describes **aortic stenosis**, which would lead to signs of left ventricular outflow obstruction, such as a systolic murmur and possibly left ventricular hypertrophy. - While it can cause dyspnea and fatigue, it does not typically explain the **speckled myocardium**, **enlarged tongue**, or **osteolytic lesions** seen in this patient. - *Concentric hypertrophy of the myocytes with thickening of the interventricular septum* - This is characteristic of **hypertensive heart disease** or **hypertrophic cardiomyopathy**. - While these conditions can cause diastolic dysfunction, they typically do not present with **osteolytic lesions**, **enlarged tongue**, or the **speckled appearance of the myocardium** on echocardiography that is seen in amyloidosis. - *Diastolic cardiac dysfunction with reciprocal variation in ventricular filling with respiration* - While **diastolic cardiac dysfunction** is present, this option is too general and describes a physiological consequence rather than the underlying mechanism for the constellation of symptoms. - **Reciprocal variation in ventricular filling with respiration** can be seen in both restrictive cardiomyopathy and constrictive pericarditis but does not explain the specific findings of **osteolytic lesions** or **enlarged tongue**, which point towards a systemic infiltrative disease like amyloidosis.

Question 189: A 56-year-old African-American man comes to the physician for intermittent episodes of dark urine and mild flank pain. The patient has had 3 episodes of frank reddish discoloration of his urine within 1 month. He has chronic headaches and back pain for which he has been taking aspirin and ibuprofen daily for 1 year. The patient has sickle cell trait. He has smoked a pack of cigarettes daily for 10 years. He appears well. His temperature is 37.4°C (99.3°F). His pulse is 66/min, and his blood pressure is 150/90 mm Hg. Physical exam shows mild, bilateral flank tenderness. Laboratory analysis shows a serum creatinine concentration of 2.4 mg/dL. Urine studies are shown below. Urine Blood 3+ Protein 2+ RBC > 10/hpf WBC 3/hpf Which of the following is the most likely underlying cause of this patient's hematuria?

A. Direct nephrotoxic injury
B. Purulent renal inflammation
C. Renal reperfusion injury
D. Chronic hemoglobin filtration
E. Renal papillary ischemia (Correct Answer)

Explanation: ***Renal papillary ischemia*** - The patient's **sickle cell trait** predisposes him to episodes of renal papillary ischemia, which can lead to **papillary necrosis** and subsequent gross hematuria and flank pain. - The use of **NSAIDs (aspirin and ibuprofen)** chronically can also contribute to renal papillary necrosis, exacerbating the risk in a patient with sickle cell trait. *Direct nephrotoxic injury* - While chronic NSAID use can cause **nephrotoxic injury**, it typically manifests as interstitial nephritis or acute kidney injury, not primarily recurrent gross hematuria. - The level of proteinuria (2+) and absence of specific casts associated with direct toxic tubular injury make this less likely as the primary cause of hematuria. *Purulent renal inflammation* - This would typically present with symptoms of **urinary tract infection** (e.g., dysuria, fever), significant pyuria (WBCs > 10/hpf), and potentially bacterial casts, which are not seen here. - The urinalysis shows only 3 WBCs/hpf, making a purulent infection unlikely. *Renal reperfusion injury* - This type of injury occurs after a period of **ischemia followed by restoration of blood flow**, often in the context of surgery, trauma, or organ transplantation. - There is no history in the patient suggestive of an event that would lead to renal reperfusion injury. *Chronic hemoglobin filtration* - While sickle cell trait involves abnormal hemoglobin, **chronic hemoglobin filtration** itself does not typically cause the discreet episodes of gross hematuria and flank pain described. - Hemoglobinuria without red blood cells in the urine is characteristic of chronic intravascular hemolysis, which is not indicated by the RBCs > 10/hpf.

Question 190: A 67-year-old male presents with left hip pain. Examination reveals mild effusions in both knees, with crepitus in both patellofemoral joints. He states his hearing has worsened recently and that he feels like his hats don't fit anymore. Bone scan reveals diffuse uptake in the calvarium, right proximal femur, and left ilium. Which of the following laboratory abnormalities would be expected in this patient?

A. Increased serum calcium
B. Increased serum alkaline phosphatase (Correct Answer)
C. Decreased serum alkaline phosphatase
D. Increased serum parathyroid hormone
E. Decreased serum parathyroid hormone

Explanation: ***Increased serum alkaline phosphatase*** - The clinical picture (hip pain, worsened hearing, hats not fitting, diffuse bone uptake on scan) is highly suggestive of **Paget's disease of bone**. - In Paget's disease, there is increased bone turnover with excessive osteoclastic activity followed by compensatory, disorganized osteoblastic activity, leading to a marked elevation in **serum alkaline phosphatase (ALP)**, a marker of osteoblastic activity. *Increased serum calcium* - While bone breakdown occurs in Paget's disease, hypercalcemia is uncommon; it usually only occurs in immobilized patients. - The bone remodeling is typically balanced, with increased formation countering increased resorption. *Decreased serum alkaline phosphatase* - Paget's disease is characterized by significantly *increased* bone turnover and osteoblastic activity, leading to **elevated** rather than decreased serum alkaline phosphatase. - A decreased ALP level would suggest conditions like hypophosphatasia, not Paget's disease. *Increased serum parathyroid hormone* - **Primary hyperparathyroidism** would lead to increased PTH, causing hypercalcemia and bone resorption, but the widespread, disorganized bone changes and localized uptake on a bone scan are more consistent with Paget's disease. - Increased PTH is not a direct consequence or feature of uncomplicated Paget's disease. *Decreased serum parathyroid hormone* - This would typically be seen in states of hypercalcemia not driven by PTH, or in conditions like primary hypoparathyroidism. - There is no direct mechanism in Paget's disease that would cause decreased PTH levels.

Question 191: A 23-year-old woman presents to the emergency department with a 3-day history of fever and headache. She says that the symptoms started suddenly after she woke up 3 days ago, though she has been feeling increasingly fatigued over the last 5 months. On presentation, her temperature is 102°F (38.9°C), blood pressure is 117/74 mmHg, pulse is 106/min, and respirations are 14/min. Physical exam reveals diffuse petechiae and conjunctival pallor and selected laboratory results are shown as follows: Bleeding time: 11 minutes Platelet count: 68,000/mm^3 Lactate dehydrogenase: 105 U/L Which of the following would also most likely be true for this patient?

A. Increased serum von Willebrand factor multimers (Correct Answer)
B. Large platelets on peripheral blood smear
C. Immune production of anti-platelet antibodies
D. Decreased platelet aggregation on platelet function studies
E. Increased prothrombin time and partial thromboplastin time

Explanation: ***Increased serum von Willebrand factor multimers*** - This patient's presentation with **fever**, **thrombocytopenia** (platelet count 68,000/mm^3), **fatigue**, and **petechiae** suggests **Thrombotic Thrombocytopenic Purpura (TTP)**. - TTP is characterized by a deficiency of **ADAMTS13**, which normally cleaves large **von Willebrand factor (vWF) multimers**. Without ADAMTS13 activity, these large multimers accumulate, leading to widespread platelet adhesion and microthrombi formation. *Large platelets on peripheral blood smear* - The presence of **large platelets** (macrocytosis) on a peripheral blood smear is typically associated with conditions where platelet production is increased or dysplastic, such as in **Immune Thrombocytopenic Purpura (ITP)** or myelodysplastic syndromes. - In TTP, platelets are consumed rapidly in the microvasculature, and the morphology of remaining platelets isn't typically characterized by uniformly large size, although some megakaryocyte fragments might be seen. *Immune production of anti-platelet antibodies* - **Immune Thrombocytopenic Purpura (ITP)** is characterized by the production of autoantibodies against platelets, leading to their destruction. - While ITP can cause thrombocytopenia and petechiae, the presence of **fever** and the systemic nature of symptoms (fatigue, potential renal/neurological involvement not explicitly ruled out) in this case point more strongly towards TTP. *Decreased platelet aggregation on peripheral blood smear* - Platelet aggregation tests evaluate platelet function. While there is a functional defect leading to microthrombi in TTP, the problem is related to inappropriate activation by large vWF multimers, not an inherent inability of platelets to aggregate in response to standard stimuli in vitro. - **Decreased platelet aggregation** is more characteristic of intrinsic platelet disorders or the effect of antiplatelet medications. *Increased prothrombin time and partial thromboplastin time* - **Activated partial thromboplastin time (aPTT)** and **prothrombin time (PT)** measure the integrity of the coagulation cascade. - In TTP, the primary defect is in platelet adhesion and aggregation due to vWF abnormalities, not in the coagulation cascade. Therefore, these coagulation times are typically **normal** in TTP, distinguishing it from conditions like **Disseminated Intravascular Coagulation (DIC)**.

Question 192: A previously healthy 6-year-old girl is brought to the physician by her parents because of slowed growth and fatigue. Over the past year, she went from average height for her age group to the shortest in her class. She has also been having more problems concentrating in class and is less interested in playing. She has not had any change in appetite or diet. She is at the 10th percentile for height and the 90th percentile for weight. Vital signs are within normal limits. There is a nontender mass palpated on the anterior cervical examination. Serum laboratory studies show thyroid-stimulating hormone level of 6.7 μU/mL. Further evaluation is most likely to show which of the following findings?

A. Positive serum thyroid stimulating hormone receptor antibody
B. Psammoma bodies on fine needle aspiration
C. Lymphocytic infiltration on fine needle aspiration (Correct Answer)
D. Increased uptake on I-131 scan in a discrete 1-cm nodule
E. Low urine iodine levels

Explanation: ***Lymphocytic infiltration on fine needle aspiration*** - The patient presents with symptoms of **hypothyroidism** (slowed growth, fatigue, poor concentration, weight gain) and an elevated **TSH** level (6.7 μU/mL). This clinical picture, along with a firm, nontender goiter, is highly suggestive of **Hashimoto's thyroiditis**. - **Lymphocytic infiltration** of the thyroid gland is the characteristic histological finding in Hashimoto's thyroiditis, typically confirmed by **fine-needle aspiration (FNA)**. *Positive serum thyroid stimulating hormone receptor antibody* - **TSH receptor antibodies** are characteristic of **Graves' disease**, which causes hyperthyroidism, not the hypothyroidism seen in this patient. - While antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) are found in Hashimoto's thyroiditis, TSH receptor antibodies are not. *Psammoma bodies on fine needle aspiration* - **Psammoma bodies** are concentric calcifications seen on histology, primarily associated with **papillary thyroid carcinoma**. - This patient's presentation (fatigue, slowed growth, elevated TSH) is not indicative of thyroid malignancy. *Increased uptake on I-131 scan in a discrete 1-cm nodule* - **Increased radioactive iodine uptake** in a discrete nodule suggests **hot nodule** or **toxic adenoma**, conditions associated with hyperthyroidism. - This finding is inconsistent with the patient's symptoms and elevated TSH, which indicate hypothyroidism. *Low urine iodine levels* - **Low urine iodine levels** indicate **iodine deficiency**, which can lead to hypothyroidism and goiter. - While possible, the presence of a distinct goiter and likely autoimmune etiology in a developed country makes primary **Hashimoto's thyroiditis** a more direct diagnosis for lymphocytic infiltration during further evaluation.

Question 193: A 19-year-old woman presents to the primary care clinic to establish care. She has no acute complaints or concerns. Upon further questioning, she shares that she gets frequent nosebleeds and often bleeds from her gums a little after brushing her teeth. She also typically has relatively heavy menstrual periods, soaking eight tampons per day. She has not had any serious bleeding events, and she has never had a blood transfusion. Physical exam is unremarkable. A complete blood count shows mild anemia with a normal platelet count. Which of the following is the next best step in the management of this patient?

A. Perform platelet aggregation tests (Correct Answer)
B. Start desmopressin
C. Start intravenous immunoglobulin
D. Start corticosteroids
E. Perform bone marrow biopsy

Explanation: ***Perform platelet aggregation tests*** - The patient's history of **frequent nosebleeds, gum bleeding after tooth brushing**, and **heavy menstrual bleeding (menorrhagia) with a normal platelet count** is highly suggestive of **von Willebrand disease** or a **platelet function disorder**. - **Platelet aggregation tests** and **von Willebrand factor (vWF) studies** are necessary to differentiate between various platelet function defects and von Willebrand disease, and to guide appropriate treatment. - The combination of mucocutaneous bleeding with normal platelet count indicates a **qualitative platelet defect or vWF deficiency** rather than a quantitative platelet problem. *Start desmopressin* - **Desmopressin** is used to treat certain bleeding disorders, including types of von Willebrand disease and mild hemophilia A, by promoting the release of vWF and factor VIII. - However, initiating this treatment **without a definitive diagnosis** is premature; further diagnostic testing is required to identify the underlying cause of her bleeding and determine if desmopressin would be effective. *Start intravenous immunoglobulin* - **Intravenous immunoglobulin (IVIG)** is typically used for conditions like **immune thrombocytopenia (ITP)**, where there is an autoimmune destruction of platelets, leading to a low platelet count. - This patient has a **normal platelet count**, ruling out ITP as the direct cause of her bleeding symptoms, making IVIG an inappropriate first-line treatment. *Start corticosteroids* - **Corticosteroids** are anti-inflammatory and immunosuppressive agents often used in the management of autoimmune conditions affecting blood counts, such as **ITP**. - Given the patient's **normal platelet count** and the absence of clear autoimmune markers or thrombocytopenia, corticosteroids are not indicated and would likely delay proper diagnosis. *Perform bone marrow biopsy* - A **bone marrow biopsy** is indicated in cases of unexplained cytopenias (low blood cell counts) or suspected hematologic malignancies to assess bone marrow function and cellularity. - This patient has **normal platelet counts** and no signs of malignancy, and her bleeding symptoms point towards a primary hemostasis defect (platelet function or vWF), making a bone marrow biopsy an unnecessary and invasive procedure at this stage.

Question 194: A 61-year-old construction worker comes to the physician because of a 3-month history of progressively worsening cough and shortness of breath. He has had a 7.5-kg (16.5-lb) weight loss during this period. He smokes occasionally and does not drink alcohol. Physical examination shows clubbing of the fingers. End-inspiratory crackles are heard in both lower lung fields. X-ray of the chest shows bilateral reticulonodular densities with interstitial fibrosis. Histologic examination of a lung biopsy specimen shows noncaseating granulomas in the interstitium. Which of the following is the most likely underlying mechanism of this patient's condition?

A. Aspergillus-induced eosinophil release
B. IgE-mediated histamine release
C. Elastase-mediated parenchymal destruction
D. IgG-mediated immune complex deposition
E. Silica-induced macrophage activation (Correct Answer)

Explanation: ***Silica-induced macrophage activation*** - The patient's presentation with **progressive cough and shortness of breath**, **weight loss**, **clubbing**, **interstitial crackles**, and **bilateral reticulonodular densities with interstitial fibrosis** in a **construction worker** suggests **silicosis**. - **Silicosis** is characterized by the inhalation of silica particles, which are then phagocytosed by **macrophages**, leading to their activation, release of inflammatory mediators, and subsequent **granuloma formation** and **fibrosis**. - Construction workers have occupational exposure to **crystalline silica dust** from cutting, grinding, or drilling concrete, stone, or masonry materials. *Aspergillus-induced eosinophil release* - This mechanism is characteristic of **allergic bronchopulmonary aspergillosis (ABPA)**, which typically presents with asthma-like symptoms, recurrent pulmonary infiltrates, and eosinophilia. - The patient's biopsy showing **noncaseating granulomas without eosinophils** makes ABPA unlikely. *IgE-mediated histamine release* - This describes a **Type I hypersensitivity reaction** often seen in **allergic asthma** or anaphylaxis, where IgE antibodies bind to mast cells and basophils, releasing histamine upon allergen exposure. - This mechanism does not explain the **interstitial fibrosis** and **noncaseating granulomas** observed in the patient's lung biopsy. *Elastase-mediated parenchymal destruction* - This mechanism is central to the pathogenesis of **emphysema**, where an imbalance between proteases (like elastase) and antiproteases leads to the destruction of alveolar walls. - While smoking is a risk factor for emphysema, the imaging findings of **reticulonodular densities** and **interstitial fibrosis**, along with **noncaseating granulomas**, point away from isolated emphysema. *IgG-mediated immune complex deposition* - This mechanism (Type III hypersensitivity) is seen in conditions like **hypersensitivity pneumonitis** or some forms of vasculitis. - **Hypersensitivity pneumonitis** can occur in farmers exposed to organic antigens (e.g., moldy hay causing "Farmer's Lung") and can present with interstitial lung disease and granulomas. - However, this patient's occupational exposure as a construction worker and the classic histologic finding of **noncaseating granulomas in the interstitium** with the clinical presentation point more strongly to **silicosis** from silica dust exposure rather than hypersensitivity pneumonitis.

Question 195: A 32-year-old woman presents to the office with complaints of frothy urine and swelling in her body that started 6 days ago. She says that she first noticed the swelling in her face that gradually involved other parts of her body. On further questioning, she gives a history of rheumatoid arthritis for 2 years. She is taking Penicillamine and Methotrexate for the past 6 months. Vitals include: blood pressure 122/89 mm Hg, pulse rate 55/min, temperature 36.7°C (98.0°F), and a respiratory rate 14/min. On examination, there is generalized pitting edema along with some subcutaneous nodules on the dorsal aspect of the forearm. Urinalysis pH 6.6 Color light yellow RBC none WBC 1–2/HPF Protein 4+ Cast fat globules Glucose absent Crystal none Ketone absent Nitrite absent 24 hours urine protein excretion 4.8 g Basic metabolic panel Sodium 141 mEq/L Potassium 5.1 mEq/L Chloride 101 mEq/L Bicarbonate 22 mEq/L Albumin 3.2 mg/dL Urea nitrogen 17 mg/dL Creatinine 1.3 mg/dL Uric Acid 6.8 mg/ dL Calcium 8.9 mg/ dL Glucose 111 mg/dL A renal biopsy is ordered which shows diffuse capillary and glomerular basement membrane thickening. Which of the following is the most likely cause for her impaired renal function?

A. Membranous nephropathy (Correct Answer)
B. Diabetic glomerulonephropathy
C. Minimal change disease
D. Renal amyloidosis
E. Lipoid nephrosis

Explanation: **Membranous nephropathy** - The patient's presentation with **nephrotic syndrome** (frothy urine, generalized edema, significant proteinuria > 3.5g/24h, hypoalbuminemia) and **renal biopsy findings of diffuse capillary and glomerular basement membrane thickening** are characteristic of membranous nephropathy. - **Penicillamine**, which the patient is taking for rheumatoid arthritis, is a known cause of **secondary membranous nephropathy**. *Diabetic glomerulonephropathy* - While diabetes can cause nephrotic syndrome and renal impairment, there is **no history or evidence of diabetes** in this patient (fasting glucose 111 mg/dL is borderline but not diagnostic). - Diabetic nephropathy typically shows **nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) and mesangial expansion** on biopsy, not the diffuse GBM thickening described here. - The patient's age and clinical presentation do not suggest longstanding diabetes. *Minimal change disease* - This condition typically presents with **abrupt onset of nephrotic syndrome**, primarily in children, and is characterized by a **normal renal biopsy on light microscopy** (hence "minimal change") with effacement of foot processes on electron microscopy. - The patient's **diffuse capillary and glomerular basement membrane thickening** on biopsy contradicts minimal change disease. *Renal amyloidosis* - While amyloidosis can cause nephrotic syndrome and generalized edema, the **renal biopsy findings for amyloidosis would typically show Congo red-positive amyloid deposits**, which are not described here. - Although rheumatoid arthritis can be a risk factor for secondary amyloidosis (AA amyloidosis), the description of diffuse capillary and glomerular basement membrane thickening is more specific to membranous nephropathy. *Lipoid nephrosis* - **Lipoid nephrosis** is an older term for **minimal change disease**. - As explained above, minimal change disease is inconsistent with the **diffuse capillary and glomerular basement membrane thickening** observed on renal biopsy.

Question 196: An 80-year-old woman died due to the respiratory complications of lung cancer. She had been a heavy smoker, and battled COPD and adenocarcinoma of the lungs for the last 20 years. The autopsy also revealed a pathological finding in the mitral valve. Which of the following was most likely seen?

A. Ruptured papillary muscle
B. Destructive vegetations
C. Discoloration of leaflets
D. Stenosis of leaflets
E. Non-destructive vegetations (Correct Answer)

Explanation: ***Non-destructive vegetations*** - The patient's age (80 years old), history of **lung cancer**, and prolonged illness are all factors associated with **non-bacterial thrombotic endocarditis (NBTE)**. - NBTE, also known as **marantic endocarditis**, involves the formation of sterile, non-destructive vegetations on heart valves, commonly linked to **malignancy** and **hypercoagulable states**. *Ruptured papillary muscle* - This is typically a complication of an **acute myocardial infarction**, not specifically associated with cancer or COPD. - Would lead to **acute severe mitral regurgitation**, presenting with more acute cardiac symptoms. *Destructive vegetations* - **Destructive vegetations** are characteristic of **infective endocarditis**, which typically presents with fever, new murmurs, and signs of infection, none of which are mentioned. - There is no indication of bacterial infection or other conditions predisposing to infective endocarditis. *Discoloration of leaflets* - While other forms of valve disease or post-mortem changes might cause discoloration, it is not a specific pathological finding related to the patient's underlying conditions in the way that NBTE vegetations are. - Discoloration alone does not represent a primary disease process of the valve. *Stenosis of leaflets* - **Mitral stenosis** is more commonly caused by **rheumatic heart disease** or age-related calcification, which is not indicated by the patient's history. - While severe calcification can occur with age, the presence of **malignancy** and prolonged illness points more strongly to NBTE.

Question 197: A 30-year-old man presents to the emergency department with complaints of red, pinkish urine in the morning. He adds that he has been feeling some abdominal pain. The patient is not taking any medication, and his laboratory test results are as follows: Hb 11.0 g/dL RBC 3.7 x 1012/L WBC 4,000/mm3 PLT 100,000/mm3 Reticulocytes 17% of red cells Coombs test Negative Blood smear Polychromasia Which statement is true about this patient’s condition?

A. CD25 deficiency is expected to be seen
B. Rituximab therapy is effective
C. Patient is at great risk for bleeding
D. Urinary hemosiderin testing will be negative
E. Eculizumab can be used to treat this condition (Correct Answer)

Explanation: ***Eculizumab can be used to treat this condition*** - The patient's symptoms (red, pinkish urine in the morning, abdominal pain), laboratory findings (anemia, thrombocytopenia, reticulocytosis, negative Coombs test, polychromasia), and clinical presentation are highly suggestive of **Paroxysmal Nocturnal Hemoglobinuria (PNH)**. - **Eculizumab** is a monoclonal antibody that inhibits C5 complement protein, preventing the formation of the membrane attack complex and thus reducing hemolysis in PNH. *CD25 deficiency is expected to be seen* - **CD25** is a component of the IL-2 receptor, and its deficiency is not characteristic of PNH. - PNH is characterized by a deficiency of **GPI-anchored proteins** like CD55 and CD59 on the surface of red blood cells, which protect against complement-mediated lysis. *Rituximab therapy is effective* - **Rituximab** is an anti-CD20 monoclonal antibody used primarily for B-cell lymphomas and autoimmune conditions, not PNH. - Its mechanism of action is unrelated to the pathophysiology of PNH, which involves complement dysregulation. *Patient is at great risk for bleeding* - The patient has **thrombocytopenia** (PLT 100,000/mm3), which does put them at an increased risk of bleeding. - However, in PNH, patients are at a higher risk of **thrombosis** (blood clots), which can be life-threatening, in addition to hemolysis and bone marrow failure. *Urinary hemosiderin testing will be negative* - The patient experiences **hemoglobinuria** ("red, pinkish urine in the morning"), which is indicative of chronic intravascular hemolysis. - With ongoing hemolysis and hemoglobinuria, **urinary hemosiderin** (iron stored in renal tubular cells as a result of chronic hemoglobin reabsorption) would be expected to be positive, not negative.

Question 198: A 49-year-old female with a long history of poorly controlled diabetes mellitus visits her primary care physician with 2+ non-pitting edema in her legs. The patient has a serum creatinine of 2.9 mg/dL and a blood urea nitrogen of 61 mg/dL. A 24-hour urine collection reveals 8.5 grams of protein. A renal biopsy is obtained. Which of the following histologic findings is most likely to be seen upon tissue analysis:

A. Normal glomeruli
B. Crescentic proliferation in Bowman’s space
C. Nodular thickening of the glomerular basement membrane (Correct Answer)
D. Lymphocytic infiltration of glomerular tufts
E. Non-caseating interstitial granuloma

Explanation: ***Nodular thickening of the glomerular basement membrane*** - The patient's history of **poorly controlled diabetes**, **nephrotic range proteinuria** (8.5 grams/24 hours), elevated creatinine, and BUN are highly suggestive of **diabetic nephropathy**. - **Kimmelstiel-Wilson lesions**, characterized by **nodular thickening of the glomerular basement membrane** due to deposition of mesangial matrix, are pathognomonic for diabetic nephropathy. *Normal glomeruli* - The presence of **severe proteinuria** (8.5g/24h) and **renal insufficiency** (creatinine 2.9 mg/dL, BUN 61 mg/dL) indicates significant renal damage, making perfectly normal glomeruli highly unlikely. - These clinical findings directly contradict a diagnosis of normal glomerular function. *Crescentic proliferation in Bowman’s space* - **Crescentic proliferation**, which is characterized by the accumulation of cells (macrophages, epithelial cells) in Bowman's space, is typical of rapidly progressive glomerulonephritis (RPGN). - While RPGN can cause renal failure, it's not the primary or most characteristic finding in the context of long-standing, poorly controlled diabetes with nephrotic-range proteinuria. *Lymphocytic infiltration of glomerular tufts* - **Lymphocytic infiltration of glomerular tufts** is observed in certain forms of glomerulonephritis, such as lupus nephritis or some immune complex-mediated diseases. - This finding is not characteristic of diabetic nephropathy, which primarily involves structural changes to the glomerular basement membrane and mesangium. *Non-caseating interstitial granuloma* - **Non-caseating granulomas** in the kidney are a hallmark of **sarcoidosis**, an inflammatory disease that can affect various organs, including the kidneys. - While sarcoidosis can cause renal dysfunction, it does not typically present with the specific combination of long-standing diabetes and massive proteinuria described in this case, nor is it histologically characterized by nodular glomerular changes.

Question 199: A 26-year-old woman presents with episodes of intermittent fever, arthralgias, constant fatigue, weight loss, and plaque-like rash on sun-exposed areas, which have been gradually increasing over the last 6 months. On presentation, her vital signs include: blood pressure is 110/80 mm Hg, heart rate is 87/min, respiratory rate is 14/min, and temperature is 37.5°C (99.5°F). Physical examination reveals an erythematous scaling rash on the patient’s face distributed in a ‘butterfly-like’ fashion, erythematous keratinized patches on the sun-exposed areas, and mild lower leg edema. During the workup, the patient is found to be positive for anti-Sm (anti-Smith) antibodies. Which process is altered in this patient?

A. Protein folding
B. Base-excision repair
C. DNA transcription
D. Ineffective clearance of cellular debris (Correct Answer)
E. Mismatch repair

Explanation: ***Ineffective clearance of cellular debris*** - The patient's symptoms (fever, arthralgias, fatigue, weight loss, malar rash, photosensitive rash) along with a positive **anti-Sm antibody** are highly indicative of **Systemic Lupus Erythematosus (SLE)**. - SLE is characterized by a defect in the **clearance of apoptotic cellular debris**, often due to complement deficiencies (particularly C1q, C2, C4) or defects in phagocytic clearance mechanisms. - This ineffective clearance leads to prolonged exposure of intracellular nuclear antigens (including Smith antigen), which triggers autoantibody formation and immune complex deposition, causing the multisystem manifestations seen in SLE. *Protein folding* - **Protein folding disorders** involve the misfolding of proteins, which can lead to conditions like cystic fibrosis or Alzheimer's disease. - This process is not directly implicated in the pathogenesis of SLE or the symptoms presented. *Base-excision repair* - **Base-excision repair** is a DNA repair pathway that primarily fixes damaged bases in DNA. - While DNA damage can contribute to disease, defects in this specific repair mechanism are not a hallmark of SLE. *DNA transcription* - **DNA transcription** is the process by which genetic information from DNA is "transcribed" into RNA. - While various autoimmune diseases can affect gene expression, a primary defect in the basic process of transcription itself is not characteristic of SLE. *Mismatch repair* - **Mismatch repair** is a DNA repair system that corrects errors, such as mispaired bases, that occur during DNA replication. - Defects in mismatch repair are associated with conditions like Lynch syndrome, not the autoimmune manifestations seen in SLE.

Question 200: A 47-year-old woman presents for a routine wellness checkup. She complains of general fatigue and lethargy for the past 6 months. She does not have a significant past medical history and is currently not taking any medications. The patient reports that she drinks “socially” approx. 6 nights a week. She says she also enjoys a “nightcap,” which is 1–2 glasses of wine before bed every night. She denies any history of drug use or smoking. The patient is afebrile, and her vital signs are within normal limits. A physical examination reveals pallor of the mucous membranes. Her laboratory findings are significant for a mean corpuscular volume of 72 fL, leukocyte count of 5,300/mL, hemoglobin of 11.0 g/dL, and platelet count of 420,000/mL. Which of the following is the most likely cause of this patient’s thrombocytosis?

A. Iron deficiency anemia (Correct Answer)
B. Essential thrombocytosis
C. Aplastic anemia
D. Chronic alcohol abuse
E. Chronic myelogenous leukemia (CML)

Explanation: ***Iron deficiency anemia*** - The patient presents with **microcytic anemia** (MCV 72 fL, Hb 11.0 g/dL) and **pallor**, which are classic signs of iron deficiency. - **Iron deficiency** is a common cause of **secondary thrombocytosis**, as iron plays a role in platelet production and maturation. *Essential thrombocytosis* - This is a **myeloproliferative neoplasm** characterized by significantly elevated platelet counts, usually much higher than 420,000/mL (often > 600,000/mL). - While it causes thrombocytosis, it typically doesn't present with microcytic anemia unless there's a co-existing iron deficiency, which is the primary finding here. *Aplastic anemia* - **Aplastic anemia** would present with **pancytopenia** (low red blood cells, white blood cells, and platelets), which is not consistent with the patient's elevated platelet count and normal leukocyte count. - The patient's presentation of fatigue and pallor would likely be more severe due to significant anemia, and thrombocytosis would not be present. *Chronic alcohol abuse* - **Chronic alcohol abuse** typically causes **macrocytic anemia** (elevated MCV) due to folate deficiency or direct bone marrow toxicity, not microcytic anemia. - While it can sometimes lead to thrombocytopenia, it is not a direct cause of robust thrombocytosis, especially in the context of microcytic anemia. *Chronic myelogenous leukemia (CML)* - CML is a **myeloproliferative neoplasm** characterized by the **Philadelphia chromosome (BCR-ABL1 fusion gene)**, leading to a significant increase in **granulocytes** (leukocytosis) and often thrombocytosis. - Although thrombocytosis can occur, the primary hallmark is significant leukocytosis, which is not seen here (leukocyte count is normal), and the anemia would typically be normocytic or even macrocytic if folate deficient.

Question 201: A 25-year-old woman comes to the physician because of recurrent episodes of reddish discoloration of her urine. She also has a 3-month history of intermittent abdominal pain, yellowish discoloration of the skin and eyes, and fatigue. Physical examination shows pallor and scleral icterus. The spleen is not palpable. Her hemoglobin concentration is 7.8 g/dL, leukocyte count is 2,000/mm3, and platelet count is 80,000/mm3. Serum LDH and unconjugated bilirubin concentrations are elevated. Addition of a serum containing anti-human globulins to a blood sample shows no agglutination. A urine dipstick shows blood; urinalysis shows no RBCs. A CT scan of the abdomen shows a thrombus in a distal branch of the superior mesenteric vein. Which of the following is the most likely cause of this patient's condition?

A. Activation and consumption of platelets and coagulation factors
B. Absence of protective factors against destruction by complement (Correct Answer)
C. Replacement of a single amino acid in a β-globin chain
D. Formation of IgG antibodies against glycoprotein IIb/IIIa
E. Endothelial cell dysfunction from bacterial toxin production

Explanation: ***Absence of protective factors against destruction by complement*** - The patient's presentation is **classic for Paroxysmal Nocturnal Hemoglobinuria (PNH)**: hemoglobinuria (positive urine dipstick with no RBCs), intravascular hemolysis (elevated LDH/unconjugated bilirubin), pancytopenia, negative Coombs test, and venous thrombosis. - PNH is caused by an acquired **PIGA gene mutation** leading to deficiency of **GPI-anchored proteins CD55 and CD59** on hematopoietic cells. - Without these complement regulatory proteins, red blood cells undergo uncontrolled **complement-mediated hemolysis**, and platelet activation leads to thrombotic complications. *Activation and consumption of platelets and coagulation factors* - This describes **Disseminated Intravascular Coagulation (DIC)**, which presents with both bleeding and thrombosis, prolonged PT/aPTT, decreased fibrinogen, and elevated D-dimer. - While PNH can cause thrombosis, the primary pathophysiology is complement dysregulation, not consumption coagulopathy. The negative Coombs test, hemoglobinuria pattern, and pancytopenia point to PNH rather than DIC. *Replacement of a single amino acid in a β-globin chain* - This describes **sickle cell disease** (glutamic acid → valine substitution in β-globin), causing RBC sickling under hypoxic conditions. - Sickle cell typically presents with painful vaso-occlusive crises, acute chest syndrome, and splenic sequestration. The hemoglobinuria without RBCs, pancytopenia, and mesenteric vein thrombosis are characteristic of PNH, not sickle cell disease. *Formation of IgG antibodies against glycoprotein IIb/IIIa* - This describes **Immune Thrombocytopenic Purpura (ITP)**, characterized by isolated thrombocytopenia with mucocutaneous bleeding. - ITP does not cause hemolytic anemia, leukopenia, hemoglobinuria, or thrombosis—features central to this patient's presentation. *Endothelial cell dysfunction from bacterial toxin production* - This describes **Hemolytic Uremic Syndrome (HUS)**, typically caused by Shiga toxin-producing E. coli, presenting with the classic triad: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. - HUS features schistocytes on blood smear and renal failure, not pancytopenia or the typical venous thrombosis pattern seen in PNH.

Question 202: A 15-year-old girl presents with menorrhagia for the last 4 months. The patient’s mother says that she just started getting her period 4 months ago, which have been heavy and prolonged. The patient does recall getting a tooth extracted 3 years ago that was complicated by persistent bleeding afterward. She has no other significant past medical history and takes no current medications. Her vital signs include: blood pressure 118/76 mm Hg, respirations 17/min, pulse 64/min, temperature 36.7°C (98.0°F). Physical examination is unremarkable. Which of the following laboratory tests is most likely to be of the greatest diagnostic value in the workup of this patient?

A. Anti-cardiolipin antibodies
B. Prothrombin time (PT)
C. Factor IX assay
D. Ro/La autoantibodies
E. Partial thromboplastin time (PTT) (Correct Answer)

Explanation: ***Partial thromboplastin time (PTT)*** - The patient's history of **menorrhagia** and **post-extraction bleeding** suggests an underlying **bleeding disorder**, most likely **von Willebrand disease** (most common inherited bleeding disorder) or a **coagulation factor deficiency**. - Among the available options, **PTT is the best screening test** as it assesses the **intrinsic and common coagulation pathways** (Factors XII, XI, IX, VIII, X, V, II, I). - PTT can detect **hemophilia A and B** (Factor VIII or IX deficiency) and **severe von Willebrand disease** (Type 3 or severe Type 1, where Factor VIII is significantly reduced). - **Important limitation:** PTT may be **normal in mild to moderate von Willebrand disease** (Type 1), which is the most common type. If PTT is normal but clinical suspicion remains high, specific **von Willebrand factor testing** (vWF antigen, vWF activity, Factor VIII) should be performed. - PTT is preferred over more specific factor assays as an initial screening test to guide further workup. *Anti-cardiolipin antibodies* - These antibodies are associated with **antiphospholipid syndrome**, which causes **hypercoagulability and thrombosis**, not bleeding. - While antiphospholipid syndrome can cause a paradoxically prolonged PTT in vitro, it does not explain the bleeding symptoms in this patient. *Prothrombin time (PT)* - PT measures the **extrinsic and common coagulation pathways** (Factors VII, X, V, II, I). - **Menorrhagia with mucocutaneous bleeding** is more characteristic of **intrinsic pathway defects** (detected by PTT) or **platelet disorders**, not extrinsic pathway defects. - Isolated extrinsic pathway deficiencies (Factor VII) are rare and typically cause post-surgical bleeding rather than menorrhagia. *Factor IX assay* - A Factor IX assay specifically diagnoses **hemophilia B**. - However, hemophilia B is **X-linked recessive** and would be extremely rare in a female (requires homozygosity or X-inactivation). - **PTT should be performed first** as a screening test; if prolonged, specific factor assays (including Factor IX) can then be ordered to identify the exact deficiency. *Ro/La autoantibodies* - These autoantibodies are associated with **Sjögren's syndrome** and **systemic lupus erythematosus (SLE)**. - While SLE can cause bleeding due to **thrombocytopenia** or **acquired coagulation factor deficiencies**, Ro/La antibodies themselves are not directly linked to bleeding disorders and would not be the initial diagnostic test for this presentation.

Question 203: A 22-year-old man comes to the physician because of several episodes of painless bloody urine over the past 6 months. The episodes are not related to physical activity. He has had frequent nosebleeds since early childhood and an episode of heavy bleeding after a tooth extraction one year ago. He smokes one pack of cigarettes daily. He drinks 1 to 2 beers on social occasions. He appears pale. His vital signs are within normal limits. Physical examination shows several small hematomas in different stages of healing over his arms and legs. Examination of the extremities shows decreased passive range of motion with crepitus in both ankles. His abdomen is soft and nontender. Laboratory studies show: Hemoglobin 9.5 mg/dL Leukocyte count 5000/mm3 Platelet count 240,000/mm3 Bleeding time 5 minutes Prothrombin time 14 seconds Partial thromboplastin time 68 seconds Urine RBC 30–40/hpf RBC casts negative WBC none Protein negative An x-ray of the pelvis shows no abnormalities. Further evaluation of this patient is most likely to show which of the following findings?

A. Nephrolithiasis
B. Palpable spleen below the left costal margin
C. Intraarticular iron deposition (Correct Answer)
D. Hemosiderin-laden alveolar macrophages
E. Evasive behavior when asked about the hematomas

Explanation: ***Intraarticular iron deposition*** - The patient's history of **painless hematuria**, **recurrent epistaxis**, prolonged bleeding after tooth extraction, and multiple hematomas, combined with **prolonged PTT** and normal platelet count/bleeding time, strongly suggests **Hemophilia A or B**. - In such clotting disorders, **recurrent hemarthroses (joint bleeding)** lead to **hemosiderin deposition** and subsequent joint damage, explaining the decreased range of motion and crepitus in the ankles. *Nephrolithiasis* - While nephrolithiasis can cause **hematuria**, it typically presents with **flank pain** radiating to the groin, which is not mentioned here. - It does not explain the widespread bleeding tendencies (nosebleeds, post-extraction bleeding, hematomas) or the prolonged PTT. *Palpable spleen below the left costal margin* - **Splenomegaly** can be seen in various hematological disorders, but it is not a direct or common complication of hemophilia itself. - The patient's symptoms primarily point to a coagulation defect, not a condition directly causing splenomegaly. *Hemosiderin-laden alveolar macrophages* - These "heart failure cells" are typically seen in conditions like **pulmonary hypertension** or **congestive heart failure** leading to extravasation of red blood cells into the alveoli. - There is no clinical evidence (e.g., respiratory symptoms, cardiac findings) in the patient's presentation to suggest such pulmonary pathology. *Evasive behavior when asked about the hematomas* - This option refers to a psychological or social finding which is not directly related to the underlying medical pathology suggested by the constellation of severe bleeding symptoms and lab findings. - While possible in cases of abuse, it would not explain the other specific bleeding manifestations (epistaxis, post-extraction bleeding, hematuria) and the abnormal PTT.

Question 204: A 17-year-old boy is brought to the physician because of swelling of his face and legs for 5 days. He immigrated to the United States from Korea with his family 10 years ago. He has been healthy except for an episode of sore throat 2 weeks ago. His younger sister has type 1 diabetes mellitus. His temperature is 37°C (98.6°F), pulse is 90/min, and blood pressure is 145/87 mm Hg. Examination shows periorbital edema and 3+ pitting edema of the lower extremities. Laboratory studies show: Hemoglobin 13.9 g/dL Leukocyte count 8,100/mm3 Serum Glucose 78 mg/dL Albumin 2.4 g/dL Hepatitis B surface antigen positive Hepatitis B surface antibody negative Complement C4 decreased Urine Blood negative Protein 4+ Glucose negative Protein/creatinine ratio 8.1 (N ≤ 0.2) Further evaluation is most likely to show which of the following additional findings?

A. Increased IgA levels in serum
B. Normal-appearing glomeruli on renal biopsy
C. Subepithelial deposits on renal biopsy (Correct Answer)
D. Antineutrophil cytoplasmic antibody level in serum
E. Eosinophilic nodules on renal biopsy

Explanation: ***Subepithelial deposits on renal biopsy*** - The patient presents with **nephrotic syndrome** (edema, proteinuria, hypoalbuminemia), a history of **hepatitis B infection** (HBsAg positive), and decreased **complement C4** levels. These findings are highly suggestive of **membranous nephropathy**, which is characterized by **subepithelial immune complex deposits**. - **Membranous nephropathy** is a common cause of nephrotic syndrome in adults and can be secondary to infections like **hepatitis B**, systemic lupus erythematosus, or certain medications. *Increased IgA levels in serum* - **Increased IgA levels** are characteristic of **IgA nephropathy**, which typically presents with recurrent episodes of **hematuria**, often following an upper respiratory infection. - While there was a sore throat, the dominant presentation here is **nephrotic syndrome** with significant proteinuria and **hypocomplementemia**, which is not typical for IgA nephropathy. *Normal-appearing glomeruli on renal biopsy* - In cases of significant proteinuria and nephrotic syndrome, it is highly unlikely for the glomeruli to appear **normal** on biopsy. - Conditions causing nephrotic syndrome, such as **minimal change disease**, do show normal glomeruli on light microscopy, but this patient's presentation with **Hepatitis B** and **hypocomplementemia** points away from minimal change disease. *Antineutrophil cytoplasmic antibody level in serum* - **Antineutrophil cytoplasmic antibodies (ANCAs)** are associated with **vasculitic diseases** such as granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss). - These conditions typically present with **rapidly progressive glomerulonephritis** and systemic vasculitis, which is different from the predominant nephrotic syndrome seen in this patient. *Eosinophilic nodules on renal biopsy* - **Eosinophilic nodules**, also known as **Kimmelstiel-Wilson lesions**, are characteristic findings in **diabetic nephropathy**. - Although the patient's sister has type 1 diabetes, there is no indication that the patient himself has diabetes (normal serum glucose), making this finding unlikely.

Question 205: A 17-year-old boy is brought to the physician with complaints of an ataxic gait and hearing deficits for the past few days. His parents also reported a history of tonic gaze deviation on the right side and the spontaneous remission of a similar episode 6 months ago. His temperature is 37°C (98.6°F), pulse is 88/min, and respirations are 20/min. On physical examination, no abnormality is found, but evoked potential tests are abnormal. Magnetic resonance imaging of the head shows multiple lesions with high T2 signal intensity and one large white matter lesion showing contrast enhancement. His laboratory studies show: Hemoglobin 12.9 g/dL CSF leukocyte count 1000/μL CSF gamma globulin 15.4% (normal 7–14%) Erythrocyte sedimentation rate 16 mm/h Which of the following most likely explains the mechanism of this condition?

A. Type IV hypersensitivity (Correct Answer)
B. Type II hypersensitivity
C. Type V hypersensitivity
D. Type I hypersensitivity
E. Type III hypersensitivity

Explanation: ***Type IV hypersensitivity*** - The constellation of **ataxic gait**, **hearing deficits**, **tonic gaze deviation**, **remitting-relapsing episodes**, **abnormal evoked potentials**, and **MRI findings** (multiple lesions, contrast enhancement) is highly suggestive of **multiple sclerosis (MS)**. - MS is primarily mediated by **T-cells** reacting against **myelin antigens** in the central nervous system, classifying it as a **Type IV (delayed-type) hypersensitivity reaction**. *Type II hypersensitivity* - This type involves **antibodies binding to antigens on cell surfaces** or in the extracellular matrix, leading to cell destruction, functional changes, or inflammation. - Conditions like **Goodpasture syndrome** or **autoimmune hemolytic anemia** are examples, which do not fit the neurological presentation and demyelinating pathology described. *Type V hypersensitivity* - This is a variant of **Type II hypersensitivity** where antibodies bind to and **stimulate cell surface receptors**, rather than destroying them. - **Graves' disease**, where antibodies activate TSH receptors, is a classic example; it does not involve T-cell mediated demyelination. *Type I hypersensitivity* - This is an **immediate hypersensitivity reaction** mediated by **IgE antibodies** binding to mast cells and basophils, leading to mediator release upon allergen exposure. - It's associated with allergic reactions like **anaphylaxis** or **asthma** and doesn't explain the chronic demyelinating process seen in the patient. *Type III hypersensitivity* - This type involves the formation of **immune complexes** (antigen-antibody complexes) that deposit in tissues, leading to inflammation and tissue damage. - Diseases like **systemic lupus erythematosus** or **serum sickness** are examples, which typically present with systemic inflammation and vasculitis, not primary demyelination.

Question 206: An investigator studying immune-mediated pulmonary damage performs an autopsy on a bilateral lung transplant recipient who died of hypercapnic respiratory failure. The patient underwent lung transplantation for idiopathic pulmonary fibrosis. Microscopic examination of the lung shows diffuse eosinophilic scarring of the terminal and respiratory bronchioles and near-complete luminal obliteration by polypoidal plugs of granulation tissue. Examination of the skin shows no abnormalities. The findings in this patient are most consistent with which of the following conditions?

A. Acute graft rejection
B. Recurrence of primary disease
C. Transfusion-related acute lung injury
D. Chronic graft rejection (Correct Answer)
E. Acute graft-versus-host disease

Explanation: ***Chronic graft rejection*** - Chronic rejection in lung transplant recipients classically manifests as **bronchiolitis obliterans**, characterized by diffuse **eosinophilic scarring** and **luminal obliteration** of small airways by polypoidal granulation tissue. - This process leads to irreversible airflow obstruction and progressive respiratory failure, which aligns with the patient's death from **hypercapnic respiratory failure**. *Acute graft rejection* - Acute graft rejection typically presents with perivascular and interstitial mononuclear infiltrates, not necessarily diffuse eosinophilic scarring or luminal obliteration of bronchioles. - While it can cause respiratory decline, the described microscopic features are more characteristic of a chronic process. *Recurrence of primary disease* - **Idiopathic pulmonary fibrosis** is characterized by usual interstitial pneumonia (UIP) pattern with patchy interstitial fibrosis, honeycombing, and fibroblast foci, which is distinct from the described bronchiolar scarring and obliteration. - While IPF can recur, the histological findings described are not typical for recurrent IPF but rather for chronic rejection. *Transfusion-related acute lung injury* - **TRALI** is an acute lung injury reaction to blood products, usually occurring within 6 hours of transfusion, and is characterized by non-cardiogenic pulmonary edema. - The described pathology of chronic scarring and obliteration is not consistent with the acute inflammatory and edematous changes seen in TRALI. *Acute graft-versus-host disease* - **Acute GVHD** primarily affects the skin, liver, and gastrointestinal tract; lung involvement is rare and typically presents as a diffuse interstitial pneumonitis. - The absence of skin abnormalities and the specific bronchiolar pathology described do not fit the typical presentation of acute GVHD.

Question 207: A 45-year-old woman with β-thalassemia major comes to the physician with a 1-week history of fatigue. She receives approximately 8 blood transfusions per year; her last transfusion was 1 month ago. Examination shows conjunctival pallor. Her hemoglobin level is 6.5 mg/dL. Microscopic evaluation of a liver biopsy specimen in this patient would most likely show which of the following?

A. Cytoplasmic pink-staining granules that stain positive with PAS
B. Macrophages with yellow-brown, lipid-containing granules
C. Extracellular deposition of pink-staining proteins
D. Cytoplasmic brown-pigmented granules that stain positive for S-100
E. Macrophages with cytoplasmic golden-brown granules that stain positive with Prussian blue (Correct Answer)

Explanation: ***Macrophages with cytoplasmic golden-brown granules that stain positive with Prussian blue*** - The patient's history of **β-thalassemia major** and frequent **blood transfusions** (8 per year) strongly suggests **secondary hemochromatosis** (transfusional hemosiderosis). Iron overload results from the chronic transfusion of red blood cells, as the body has no physiological mechanism for actively excreting excess iron. - **Hemosiderin** is an iron-storage complex formed in macrophages (Kupffer cells in the liver) and hepatocytes. On histological examination, hemosiderin appears as **golden-brown cytoplasmic granules** on routine H&E staining and stains **blue with Prussian blue stain** (Perls' stain), which is the definitive test for iron. - Chronic iron overload can lead to liver fibrosis, cirrhosis, and hepatic dysfunction if untreated. *Cytoplasmic pink-staining granules that stain positive with PAS* - This description is characteristic of **glycogen storage diseases** or some lysosomal storage disorders, such as **Pompe disease** (lysosomal glycogen accumulation). - These conditions involve **carbohydrate accumulation**, not iron overload, and are not directly related to chronic blood transfusions. *Macrophages with yellow-brown, lipid-containing granules* - This description is indicative of **lipofuscin**, a "wear-and-tear" pigment that accumulates in aging or atrophying cells, particularly in the heart, liver, and brain. - While lipofuscin is a yellow-brown pigment, it is **lipid-derived** and does not stain for iron (Prussian blue negative), thus differing from hemosiderin associated with iron overload. *Extracellular deposition of pink-staining proteins* - This suggests **amyloidosis**, a condition characterized by the deposition of **abnormal protein fibrils** in extracellular spaces. Amyloid typically stains pink with **hematoxylin and eosin (H&E)** and shows apple-green birefringence under polarized light with **Congo red stain**. - Amyloidosis is not the primary consequence of iron overload from chronic transfusions. *Cytoplasmic brown-pigmented granules that stain positive for S-100* - **S-100 protein** is a marker for cells of neural crest origin, such as Schwann cells, melanocytes, and some dendritic cells (e.g., Langerhans cells). The presence of **brown-pigmented granules** could suggest conditions like **melanin accumulation** or certain **tumors involving melanocytes** (e.g., melanoma). - This finding is unrelated to the iron overload pathology seen in β-thalassemia patients receiving multiple transfusions.

Question 208: A 29-year-old woman presents to the office with the complaint of a tingling sensation over her face and distal parts of her lower limbs. Three weeks ago, she had an episode of bloody diarrhea and was successfully treated with erythromycin. She is a full-time radiology technician. Currently, she takes oral contraceptives and zopiclone (1 mg) at bedtime. Her blood pressure is 100/80 mm Hg, her heart rate is 91/min, her respiratory rate is 15/min, and her temperature is 36.7°C (98.0°F). Neurological examination reveals loss of all sensation over the face and in the distal part of her lower limbs. Strength in calf flexor and extensor muscles is diminished bilaterally (4/5 on all of the muscle groups). Deep tendon reflexes are 1+ in the knees and 1+ in the ankles. Plantar reflexes are flexor. What is the most probable mechanism of the pathological findings in this patient?

A. Failure of Schwann cells to produce myelin
B. Direct damage to myelin caused by diarrhea causing organism
C. Granulomatous alteration of the vessels supplying peripheral nerves
D. Antibody-mediated destruction of peripheral myelin by cytotoxic cells (Correct Answer)
E. Radiation-induced oxidative stress in the neurons of dorsal ganglia

Explanation: ***Antibody-mediated destruction of peripheral myelin by cytotoxic cells*** - The patient's symptoms (tingling, facial numbness, distal limb weakness, and reduced reflexes) after a **bloody diarrhea** episode strongly suggest **Guillain-Barré Syndrome (GBS)**, which is an **autoimmune demyelinating polyneuropathy**. - GBS often follows infections (like *Campylobacter jejuni*, which causes bloody diarrhea) where the immune system produces **antibodies** that cross-react with **peripheral myelin components** (molecular mimicry), leading to its destruction by cytotoxic cells. *Failure of Schwann cells to produce myelin* - This mechanism is characteristic of certain **hereditary demyelinating neuropathies** or conditions affecting Schwann cell function developmentally. - It does not explain the acute onset following an infection, which is typical for post-infectious autoimmune neuropathies like GBS. *Direct damage to myelin caused by diarrhea causing organism* - While infections can trigger neuropathies, **direct damage** to myelin by the pathogen itself is rare in GBS. - The primary mechanism in GBS is an **immune-mediated attack**, not direct microbial destruction of neural tissue. *Granulomatous alteration of the vessels supplying peripheral nerves* - **Granulomatous vasculitis** affecting peripheral nerve vessels is characteristic of conditions like **vasculitic neuropathy**. - This mechanism typically involves inflammation and damage to the blood vessels, leading to nerve ischemia, which differs from the immune-mediated demyelination seen in GBS. *Radiation-induced oxidative stress in the neurons of dorsal ganglia* - Radiation-induced nerve damage would be related to her occupation but typically manifests in areas exposed to **high-dose radiation** and is usually chronic. - It would not explain the acute, ascending pattern of sensory and motor deficits following a gastrointestinal infection.

Question 209: A 22-year-old man has had dyspnea and hemoptysis for the past week. He has no known sick contacts. There is no personal or family history of serious illness. He takes no medications. His temperature is 37°C (98.6°F), pulse is 82/min, respirations are 22/min, and blood pressure is 152/90 mm Hg. Examination shows inspiratory crackles at both lung bases. The remainder of the examination shows no abnormalities. His hemoglobin is 14.2 g/dL, leukocyte count is 10,300/mm3, and platelet count is 205,000/mm3. Urinalysis shows a proteinuria of 2+, 70 RBC/hpf, and 1–2 WBC/hpf. Chest x-ray shows pulmonary infiltrates. Further evaluation is most likely to show which of the following findings?

A. Increased serum IgA titers
B. Increased anti-GBM antibody titers (Correct Answer)
C. Increased c-ANCA titers
D. Increased anti-dsDNA antibody titers
E. Increased p-ANCA titers

Explanation: ***Increased anti-GBM antibody titers*** - The patient's presentation with **hemoptysis** (pulmonary involvement) and **renal symptoms** (proteinuria, hematuria) suggests a **pulmonary-renal syndrome**. - **Increased anti-GBM antibody titers** are characteristic of **Goodpasture syndrome**, which classically presents with rapidly progressive glomerulonephritis and pulmonary hemorrhage due to antibodies targeting the alpha-3 chain of type IV collagen in the glomerular and alveolar basement membranes. *Increased serum IgA titers* - While seen in **IgA nephropathy** (Berger's disease), this condition primarily causes **renal disease** and typically does not present with significant **pulmonary hemorrhage**. - IgA nephropathy is also more commonly associated with gross hematuria following an upper respiratory infection, which is not the primary feature here. *Increased c-ANCA titers* - Increased **c-ANCA (PR3-ANCA)** titers are associated with **Granulomatosis with Polyangiitis (GPA)**, which can also cause pulmonary-renal syndrome. - However, GPA more often involves **upper and lower airway inflammation** (e.g., sinusitis, otitis) and can present with **granulomatous inflammation**, which are not specified in this case. *Increased anti-dsDNA antibody titers* - **Anti-dsDNA antibodies** are a hallmark of **Systemic Lupus Erythematosus (SLE)**, which can cause glomerulonephritis (lupus nephritis) and pulmonary manifestations (e.g., pleurisy, pneumonitis). - However, SLE typically presents with a broader range of systemic symptoms like **arthralgias, skin rashes (malar rash)**, and serositis, which are absent in this acute presentation. *Increased p-ANCA titers* - **Increased p-ANCA (MPO-ANCA)** titers are associated with **Microscopic Polyangiitis (MPA)** and **Eosinophilic Granulomatosis with Polyangiitis (EGPA)**, both of which can cause pulmonary-renal syndrome. - While MPA is a possibility, Goodpasture syndrome is a more direct fit for the sudden onset of **hemoptysis** and **glomerulonephritis** specifically targeting basement membranes.

Question 210: A 36-year-old man presents with massive hematemesis. Past medical history is significant for a gastric ulcer. He has a pulse of 115/min, respiratory rate of 20/min, temperature of 36°C (96.8°F), and blood pressure of 90/59 mm Hg. The patient receives a transfusion of 2 units of packed red blood cells. Around 5–10 minutes after the transfusion, he starts having chills, pain in the lumbar region, and oliguria. His vital signs change to pulse of 118/min, respiratory rate of 19/min, temperature of 38°C (100.4°F), and blood pressure of 60/40 mm Hg. Which of the following is the most likely cause of this patient’s condition?

A. Febrile non-hemolytic transfusion reaction
B. Acute hemolytic transfusion reaction (Correct Answer)
C. Transfusion-associated sepsis
D. Transfusion-related acute lung injury
E. Anaphylactic transfusion reaction

Explanation: ***Acute hemolytic transfusion reaction*** - The rapid onset of **fever**, **chills**, **lumbar pain**, **oliguria**, and **hypotension** immediately after a blood transfusion is highly indicative of an acute hemolytic transfusion reaction (AHTR). - This reaction results from **intravascular hemolysis** due to recipient antibodies (usually ABO incompatibility) reacting with donor red blood cells. *Febrile non-hemolytic transfusion reaction* - This reaction typically presents with **fever and chills**, but it lacks the severe symptoms of **renal failure (oliguria)** and profound **hypotension** seen in this patient. - It is usually caused by cytokines released from donor leukocytes or recipient antibodies to white blood cell antigens. *Transfusion-associated sepsis* - While sepsis can present with fever and hypotension, it typically involves a **delay in onset** after transfusion as bacterial growth takes time, and the patient's initial symptoms are too immediate (5-10 minutes). - This condition is usually due to **bacterial contamination** in the transfused blood product. *Transfusion-related acute lung injury* - TRALI primarily manifests as **acute respiratory distress**, including hypoxemia and bilateral pulmonary infiltrates, which are not described in this patient's symptoms. - While fever and hypotension can occur, the prominent **lumbar pain** and **oliguria** point away from TRALI. *Anaphylactic transfusion reaction* - Anaphylaxis would also present with rapid onset but would typically include widespread **urticaria**, **angioedema**, **bronchospasm**, or severe respiratory distress, which are absent in this presentation. - It usually occurs in patients with **IgA deficiency** who develop anti-IgA antibodies.

Question 211: A 59-year-old patient presented to his family physician 8 years ago with initial complaints of increasing generalized stiffness with trouble initiating movement and worsening micrographia. He was started on levodopa after further evaluation led to a suspected diagnosis of Parkinson's disease; however, this therapy ultimately failed to improve the patient's symptoms. Additionally, over the ensuing 8 years since his initial presentation, the patient also developed symptoms including worsening balance, orthostatic hypotension, urinary incontinence, and impotence. The patient's overall condition deteriorated ever since this initial diagnosis with increasing disability from his motor symptoms, and he recently passed away at the age of 67, 8 years after his first presentation to his physician. The family requests an autopsy. Which of the following would be expected on autopsy evaluation of this patient's brain tissue?

A. Round intracellular tau protein aggregates
B. Periventricular white matter plaques
C. Beta-amyloid plaques
D. Glial cytoplasmic inclusions (Correct Answer)
E. Astrocytosis and caudate atrophy

Explanation: ***Glial cytoplasmic inclusions*** - The patient's presentation with **atypical Parkinsonian features** (poor response to levodopa, early autonomic dysfunction like orthostatic hypotension and urinary incontinence, and rapid progression) suggests **multiple system atrophy (MSA)**. - MSA is pathologically characterized by the presence of **alpha-synuclein-containing glial cytoplasmic inclusions (Papp-Lantos bodies)**, primarily in oligodendrocytes. *Round intracellular tau protein aggregates* - **Round intracellular tau protein aggregates** are characteristic of conditions like **argyrophilic grain disease** or **corticobasal degeneration**. - While they are tauopathies, they do not align with the broad clinical picture of autonomic dysfunction and parkinsonism seen in this patient. *Beta-amyloid plaques* - **Beta-amyloid plaques** are the hallmark pathological features of **Alzheimer's disease**. - Alzheimer's primarily presents with cognitive decline, which is not the predominant feature in this case, and the motor and autonomic symptoms are not typical. *Periventricular white matter plaques* - **Periventricular white matter plaques** are characteristic lesions found in **multiple sclerosis**. - Multiple sclerosis typically presents with relapsing-remitting neurological deficits, often sensory or motor, and does not align with the progressive parkinsonism and autonomic failure described. *Astrocytosis and caudate atrophy* - **Astrocytosis and caudate atrophy** are typical findings in **Huntington's disease**. - Huntington's disease is characterized by chorea, psychiatric symptoms, and cognitive decline, which are distinct from the patient's presentation of parkinsonism and autonomic dysfunction.

Question 212: A 10-year-old boy presents to your office with puffy eyes. The patient's mother states that his eyes seem abnormally puffy and thinks he may have an eye infection. Additionally, he had a sore throat a week ago which resolved with over the counter medications. The mother also thought that his urine was darker than usual and is concerned that blood may be present. His temperature is 99.5°F (37.5°C), blood pressure is 107/62 mmHg, pulse is 100/min, respirations are 17/min, and oxygen saturation is 98% on room air. Physical exam is notable for bilateral periorbital edema. Cranial nerves are grossly intact bilaterally. Which of the following is the most likely finding on renal biopsy for this patient?

A. Sub-epithelial electron dense deposits on electron microscopy (Correct Answer)
B. Linear Ig deposits along the basement membrane
C. Podocyte fusion on electron microscopy
D. Alternating thickening and thinning of basement membrane with splitting of the lamina densa
E. No abnormalities

Explanation: ***Sub-epithelial electron dense deposits on electron microscopy*** - The patient's presentation with periorbital edema, dark urine (suggesting hematuria), and a recent history of pharyngitis strongly points towards **post-streptococcal glomerulonephritis (PSGN)**. - Renal biopsy in PSGN characteristically shows **sub-epithelial humps** (electron-dense deposits) primarily composed of IgG and C3, which are best visualized on electron microscopy. *Linear Ig deposits along the basement membrane* - **Linear immunoglobulin G (IgG) deposits** along the glomerular basement membrane (GBM) are characteristic of **Goodpasture syndrome (anti-GBM disease)**. - This condition presents with rapidly progressive glomerulonephritis and often pulmonary hemorrhage, which is not suggested by this patient's symptoms. *Podocyte fusion on electron microscopy* - **Podocyte effacement** (fusion of foot processes) is the hallmark finding in **minimal change disease**. - Minimal change disease typically presents with **nephrotic syndrome** (heavy proteinuria, hypoalbuminemia, severe edema) without significant hematuria or a history of recent infection. *Alternating thickening and thinning of basement membrane with splitting of the lamina densa* - This description is characteristic of **Alport syndrome**, an inherited disorder affecting collagen IV. - Alport syndrome presents with progressive hematuria, sensorineural hearing loss, and ocular abnormalities, which are not mentioned in this acute presentation. *No abnormalities* - Given the patient's clear symptoms of **nephritic syndrome** (edema, hematuria following infection), it is highly unlikely that a renal biopsy would show no abnormalities. - A significant pathological process is indicated by the clinical picture.

Question 213: A 21-year-old man comes to the physician because of a 3-day history of yellowing of his eyes. He has also noticed a decrease in his exercise capacity and gets quickly exhausted after minor physical activity. Examination shows scleral icterus and pale mucous membranes. He has splenomegaly. His hemoglobin concentration is 7.9 g/dL, leukocyte is count 8500/mm3, and platelet count is 187,000/mm3. Direct antiglobulin and heterophile antibody tests are positive. Which of the following additional laboratory findings are most likely present in this patient?

A. Decreased reticulocyte count
B. Increased direct to total bilirubin ratio
C. Decreased mean corpuscular volume
D. Decreased haptoglobin levels (Correct Answer)
E. Increased bleeding time

Explanation: ***Decreased haptoglobin levels*** - This patient presents with **anemia**, **jaundice**, and **splenomegaly**, along with a **positive direct antiglobulin test** and **heterophile antibody test**. This clinical picture is highly suggestive of **autoimmune hemolytic anemia (AIHA)**, likely triggered by Epstein-Barr virus (IM). - In AIHA, red blood cells are prematurely destroyed extravascularly, leading to the release of **free hemoglobin**. **Haptoglobin** binds to free hemoglobin and is subsequently cleared by the reticuloendothelial system, resulting in **decreased haptoglobin levels**. *Decreased reticulocyte count* - In **hemolytic anemia**, the bone marrow typically responds by increasing **red blood cell production** to compensate for the accelerated destruction. - This compensatory response would manifest as an **increased reticulocyte count**, not a decreased one. *Increased direct to total bilirubin ratio* - The jaundice in this patient is due to **unconjugated hyperbilirubinemia**, a hallmark of **hemolytic anemia**, where increased breakdown of red blood cells leads to an overload of heme metabolism. - Therefore, the **indirect (unconjugated) bilirubin** would be predominantly elevated, making the **direct to total bilirubin ratio** actually decreased or normal. *Decreased mean corpuscular volume* - The mean corpuscular volume (MCV) reflects the average size of red blood cells. While some anemias are microcytic (decreased MCV), **hemolytic anemias** are often **normocytic** or even **macrocytic** due to the presence of larger **reticulocytes**. - There is no indication here for a **microcytic anemia** (e.g., iron deficiency, thalassemia). *Increased bleeding time* - **Bleeding time** assesses platelet function and the integrity of the vascular wall; it is not typically affected in **hemolytic anemia**. - While splenomegaly can sometimes lead to **thrombocytopenia** (platelet sequestration), the patient's platelet count is normal (**187,000/mm3**), and there is no other information suggesting a platelet dysfunction or intrinsic coagulation defect.

Question 214: A pathologist performed an autopsy on an 18-month-old infant boy who died of pneumonia. Clinical notes revealed the infant had repeated respiratory infections that started after he was weaned off of breast-milk. Laboratory investigation revealed hypogammaglobulinemia and an absence of B-cells. T-cell levels were normal. Histological evaluation of an axillary lymph node revealed an absence of germinal centers. Which of the following is the mode of inheritance of the disorder that afflicted this infant?

A. Autosomal dominant
B. Mitochondrial inheritance
C. Autosomal recessive
D. X-linked recessive (Correct Answer)
E. X-linked dominant

Explanation: ***X-linked recessive*** - This presentation, including **recurrent respiratory infections** after weaning, **hypogammaglobulinemia**, absence of B-cells, normal T-cells, and absent germinal centers, is classic for **X-linked agammaglobulinemia (XLA)**, also known as Bruton's agammaglobulinemia. - XLA is caused by a mutation in the **Bruton's tyrosine kinase (BTK)** gene on the X chromosome, leading to a block in B-cell maturation. *Autosomal dominant* - Autosomal dominant disorders typically affect males and females equally, and often a parent is also affected; this pattern is not consistent with the described **X-linked inheritance** characteristic of XLA. - While some immune deficiencies can be autosomal dominant, the specific constellation of symptoms strongly points away from this mode of inheritance for this particular disease. *Mitochondrial inheritance* - Mitochondrial disorders are transmitted maternally, affecting all offspring of an affected mother, which is not characteristic of the described **immunodeficiency's inheritance pattern**. - These disorders typically manifest with **neurological** or **muscular dysfunction**, which are not the primary symptoms here. *Autosomal recessive* - Autosomal recessive disorders affect individuals who inherit two copies of the mutated gene (one from each parent), and often there's a family history of affected siblings but not typically affected parents. - While some combined immunodeficiencies can be autosomal recessive, the specific B-cell maturation defect described here for XLA is **X-linked recessive**. *X-linked dominant* - X-linked dominant disorders affect both males and females, with an affected father passing the trait to all his daughters but none of his sons, and an affected mother having a 50% chance of passing it to each child regardless of sex. - This pattern of inheritance is **not consistent** with the manifestation and prevalence of XLA, which primarily affects males due to its recessive nature.

Question 215: A 12-year-old boy comes to the physician for the evaluation of intermittent blood-tinged urine for several months. Four months ago, he had an episode of fever and sore throat that resolved without treatment after 5 days. During the past 2 years, he has also had recurrent episodes of swelling of his face and feet. 5 years ago, he was diagnosed with mild bilateral sensorineural hearing loss. His brother died of a progressive kidney disease at the age of 23. The patient appears pale. His temperature is 37°C (98.6°F), pulse is 70/min, and blood pressure is 145/85 mm Hg. Slit lamp examination shows a conical protrusion of both lenses. Laboratory studies show a hemoglobin concentration of 11 g/dL, urea nitrogen concentration of 40 mg/dL, and creatinine concentration of 2.4 mg/dL. Urinalysis shows: Blood 2+ Protein 1+ RBC 5–7/hpf RBC casts rare Which of the following is the most likely underlying cause of this patient's symptoms?

A. IgA deposits
B. WT1 gene mutation
C. Defective type IV collagen (Correct Answer)
D. Autosomal-recessive kidney disease
E. Type II hypersensitivity reaction

Explanation: ***Defective type IV collagen*** - This patient presents with a classic triad of symptoms: **progressive kidney disease** (elevated creatinine, blood-tinged urine, family history), **sensorineural hearing loss**, and **ocular abnormalities** (lenticonus on slit lamp exam). These findings are highly suggestive of **Alport syndrome**, which is caused by a defect in **type IV collagen**. - The family history of a brother dying of progressive kidney disease at a young age further supports a genetic cause, and the intermittent blood-tinged urine after an upper respiratory infection can be a feature of Alport syndrome, often misinterpreted as IgA nephropathy early in its course. *IgA deposits* - **IgA nephropathy** can present with recurrent episodes of gross hematuria, often following an upper respiratory infection, similar to the initial presentation of this patient's blood-tinged urine. - However, IgA nephropathy typically does not involve **sensorineural hearing loss** or **ocular abnormalities** like lenticonus. *WT1 gene mutation* - A **WT1 gene mutation** is associated with **Denys-Drash syndrome** and **Frasier syndrome**, which involve nephropathy and, in some cases, gonadal abnormalities or ambiguous genitalia. - While these can cause kidney disease, they do not typically present with the characteristic ocular findings (lenticonus) or sensorineural hearing loss seen in this patient. *Autosomal-recessive kidney disease* - While Alport syndrome can have autosomal recessive inheritance (10-15% of cases), this option is too broad and does not specify the underlying **molecular defect** (type IV collagen). - The family history pattern here (affected brother, male proband) is more consistent with **X-linked Alport syndrome** (85% of cases), and this non-specific option does not pinpoint the actual pathogenic mechanism that links all the patient's symptoms. *Type II hypersensitivity reaction* - A **type II hypersensitivity reaction** involves antibody-mediated cellular destruction or dysfunction, such as in Goodpasture syndrome, where antibodies attack the glomerular basement membrane. - This mechanism does not explain the long-standing, progressive nature of kidney disease combined with sensorineural hearing loss and ocular defects. Instead, these are characteristic of an underlying structural protein defect.

Question 216: A 3-month-old is referred to a pediatric immunologist by his pediatrician for further workup of recurrent sinopulmonary infections which have not abated despite adequate treatment. During the workup flow cytometry demonstrates a decrease in normal CD40L cells. Based on these findings, the immunologist decides to pursue a further workup and obtains immunoglobulin levels. Which of the following immunoglobulin profiles is most likely to be observed in this patient?

A. Decreased IgE, IgM, IgA, IgG
B. Increased IgE; Decreased IgG, IgM
C. Increased IgM; Decreased IgG, IgA, IgE (Correct Answer)
D. Increased IgE
E. Increased IgE, IgA; Decreased IgM

Explanation: ***Increased IgM; Decreased IgG, IgA, IgE*** - The patient's presentation with recurrent sinopulmonary infections and a decrease in normal **CD40L cells** is highly suggestive of **X-linked hyper-IgM syndrome**. - This syndrome is characterized by a defect in the CD40L on T helper cells, which impairs the ability of B cells to undergo **class switch recombination**; thus, patients produce excessive amounts of **IgM** but are deficient in other antibody classes like **IgG**, **IgA**, and **IgE**. *Decreased IgE, IgM, IgA, IgG* - This profile is characteristic of **severe combined immunodeficiency (SCID)** or **agammaglobulinemia**, where there is a generalized defect in antibody production, which is not the primary issue in X-linked hyper-IgM syndrome. - While the patient has recurrent infections, the specific defect in CD40L points to a problem with class switching rather than overall immunoglobulin production. *Increased IgE; Decreased IgG, IgM* - This combination is not typically seen together in primary immunodeficiency disorders. Increased IgE with decreased IgG and IgM would suggest a highly specific and unusual defect in IgE regulation unrelated to the described CD40L deficiency. - **Hyper-IgE syndrome (Job syndrome)** presents with markedly elevated IgE but not typically decreased IgG and IgM; it is also associated with distinct clinical features like recurrent cold abscesses and eczema. *Increased IgE* - Isolated elevated IgE is often seen in conditions like **allergic reactions**, **parasitic infections**, or **Hyper-IgE syndrome**. - While IgE can be relevant in immunodeficiencies, a sole increase in IgE without other immunoglobulin changes is not the hallmark of X-linked hyper-IgM syndrome or a general deficiency in CD40L. *Increased IgE, IgA; Decreased IgM* - This profile is unlikely as X-linked hyper-IgM syndrome specifically leads to elevated IgM due to the inability to class switch. - A decrease in IgM with increased IgE and IgA would indicate a different underlying immunological defect, not the result of a CD40L deficiency.

Question 217: A 31-year-old man presents to the office with complaints of multiple episodes of blood in his urine as well as coughing of blood for the past 3 days. He also reports a decrease in urinary frequency, and denies pain with urination. No previous similar symptoms or significant past medical history is noted. There is no history of bleeding disorders in his family. His vitals include a blood pressure of 142/88 mm Hg, a pulse of 87/min, a temperature of 36.8°C (98.2°F), and a respiratory rate of 11/min. On physical examination, chest auscultation reveals normal vesicular breath sounds. Abdominal exam is normal. The laboratory results are as follows: Complete blood count Hemoglobin 12 g/dL RBC 4.9 x 106 cells/µL Hematocrit 48% Total leukocyte count 6,800 cells/µL Neutrophils 70% Lymphocyte 25% Monocytes 4% Eosinophil 1% Basophils 0% Platelets 200,000 cells/µL Urine examination pH 6.2 Color dark brown RBC 18–20/HPF WBC 3–4/HPF Protein 1+ Cast RBC casts Glucose absent Crystal none Ketone absent Nitrite absent 24 hours urine protein excretion 1.3 g A renal biopsy under light microscopy shows a crescent formation composed of fibrin and macrophages. Which of the following best describes the indirect immunofluorescence finding in this condition?

A. Linear immunofluorescence deposits of IgG and C3 along GBM (Correct Answer)
B. Granular sub-endothelial deposits
C. Granular lumpy bumpy appearance along GBM and mesangium
D. Negative immunofluorescence
E. Mesangial deposition of IgA often with C3

Explanation: ***Linear immunofluorescence deposits of IgG and C3 along GBM*** - This finding is characteristic of **Goodpasture's syndrome**, an **anti-glomerular basement membrane (anti-GBM) disease**, which classically presents with rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage (**hemoptysis**). - The patient's presentation of hematuria with RBC casts, hemoptysis, and crescentic glomerulonephritis on biopsy strongly suggests Goodpasture's syndrome, where autoantibodies target the **alpha-3 chain of type IV collagen in the GBM**, leading to a **linear deposition pattern** of IgG and C3 on immunofluorescence. *Granular sub-endothelial deposits* - This pattern is typically seen in conditions like **lupus nephritis** or **membranoproliferative glomerulonephritis (MPGN)** where immune complexes are trapped within the glomerular structures. - While these conditions can cause RPGN, they do not align with the patient's specific presentation of simultaneous pulmonary hemorrhage alongside renal disease (without other systemic lupus symptoms). *Granular lumpy bumpy appearance along GBM and mesangium* - A "lumpy bumpy" granular pattern is characteristic of **post-streptococcal glomerulonephritis** or other **immune complex-mediated glomerulonephritis**, often involving deposition of IgG and C3. - However, post-streptococcal glomerulonephritis typically follows an infection and presents acutely, not with the specific systemic involvement of both lungs and kidneys seen here. *Negative immunofluorescence* - A negative immunofluorescence pattern, in the context of crescentic glomerulonephritis, suggests **pauci-immune glomerulonephritis**. - This form is usually associated with **ANCA-associated vasculitides** (e.g., granulomatosis with polyangiitis, microscopic polyangiitis), where there are no significant immune deposits. The patient's case, with significant symptoms pointing to an autoimmune cause with immune deposits, does not fit this description. *Mesangial deposition of IgA often with C3* - This finding is the hallmark of **IgA nephropathy (Berger's disease)**, which is characterized by recurrent episodes of macroscopic hematuria, often following an upper respiratory or gastrointestinal infection. - While IgA nephropathy can cause hematuria, the presence of hemoptysis and crescentic glomerulonephritis with RPGN makes IgA nephropathy a less likely diagnosis, as it does not typically affect the lungs in this manner or present with such severe rapidly progressive disease.

Question 218: A 9-year-old boy is brought to the emergency room by his mother. She is concerned because her son’s face has been swollen over the past 2 days. Upon further questioning, the boy reports having darker urine without dysuria. The boy was seen by his pediatrician 10 days prior to presentation with a crusty yellow sore on his right upper lip that has since resolved. His medical history is notable for juvenile idiopathic arthritis. His temperature is 99°F (37.2°C), blood pressure is 140/90 mmHg, pulse is 95/min, and respirations are 18/min. On exam, he has mild periorbital edema. Serological findings are shown below: C2: Normal C3: Decreased C4: Normal CH50: Decreased Additional workup is pending. This patient most likely has a condition caused by which of the following?

A. Antigen-antibody complex deposition (Correct Answer)
B. Effector T cell sensitization and activation
C. IgE-mediated complement activation
D. IgM-mediated complement activation targeting antigens on the cellular surface
E. IgG-mediated complement activation targeting antigens on the cellular surface

Explanation: ***Antigen-antibody complex deposition*** - The patient presents with **periorbital edema**, **hypertension**, and **dark urine** (suggesting hematuria), following a recent skin infection (impetigo, characterized by a "crusty yellow sore"). This clinical picture is highly suggestive of **post-streptococcal glomerulonephritis (PSGN)**. - PSGN is a **Type III hypersensitivity reaction** where **antigen-antibody complexes** form in the circulation and then deposit in the glomeruli, activating the complement system and leading to inflammation and kidney damage. The **decreased C3 and CH50** with **normal C4** pattern indicates activation of the classical pathway by immune complexes, with additional disproportionate C3 consumption via the alternative pathway. This complement activation pattern is characteristic of PSGN. *Effector T cell sensitization and activation* - This mechanism describes **Type IV hypersensitivity reactions**, such as **contact dermatitis** or **tuberculosis skin tests**. - These reactions are typically **delayed** and involve organ-specific immune responses mediated by T cells, not circulating immune complexes affecting the glomeruli. *IgE-mediated complement activation* - This describes **Type I hypersensitivity reactions**, such as **anaphylaxis** or **allergic rhinitis**. - These reactions involve **IgE antibodies** binding to mast cells and basophils, leading to immediate degranulation and release of inflammatory mediators, and do not involve complement activation in this manner. *IgM-mediated complement activation targeting antigens on the cellular surface* - This describes **Type II hypersensitivity reactions** where **IgM antibodies** (and sometimes IgG) bind to antigens directly on cell surfaces, leading to cell lysis via complement activation. - Examples include **transfusion reactions** or **autoimmune hemolytic anemia**, where entire cells are targeted, not just deposited complexes in specific tissues like the kidney. *IgG-mediated complement activation targeting antigens on the cellular surface* - This also describes **Type II hypersensitivity reactions**, similar to the IgM mechanism, where **IgG antibodies** bind to antigens on cell surfaces. - While IgG is involved, the primary mechanism in PSGN is the *deposition of pre-formed immune complexes*, not direct binding to intrinsic glomerular cell surface antigens causing complement activation *in situ*.

Question 219: A young Caucasian couple in their late twenties present for an infertility evaluation after trying to conceive over 2 years. On physical exam, the female appears healthy and states that she has regular menstrual cycles. The male partner is noted to have long extremities with wide hips, low muscle mass, gynecomastia, sparse facial or chest hair, and small, firm testes. Laboratory tests of the male partner reveal elevated serum LH and FSH and low testosterone levels. If cytogenetic tests were performed, which of the following would be seen in this male?

A. Trisomy of chromosome 18
B. Trisomy of chromosome 13
C. Absence of a Barr body
D. Absence of a second sex chromosome
E. Presence of a Barr body (Correct Answer)

Explanation: ***Presence of a Barr body*** - The male's presentation of **long extremities**, **gynecomastia**, **small, firm testes**, and **elevated LH/FSH with low testosterone** is classic for **Klinefelter syndrome** (47, XXY). - Individuals with **47, XXY karyotype** have two X chromosomes, one of which undergoes **X-inactivation** to form a Barr body. *Trisomy of chromosome 18* - This describes **Edwards syndrome**, which is associated with distinct features such as **microcephaly**, **rocker-bottom feet**, and severe developmental delays, not seen here. - Individuals with Edwards syndrome typically have a very **poor prognosis** and often do not survive beyond infancy. *Trisomy of chromosome 13* - This describes **Patau syndrome**, characterized by **cleft lip/palate**, **polydactyly**, and severe neurological defects. - Like Edwards syndrome, Patau syndrome is associated with **high mortality** in early life. *Absence of a Barr body* - An absence of a Barr body would indicate a **46, XY karyotype** (normal male) or **45, X karyotype** (Turner syndrome), neither of which fits the clinical picture. - In Turner syndrome, females present with **short stature**, **gonadal dysgenesis**, and other distinct features. *Absence of a second sex chromosome* - This condition is known as **Turner syndrome** (45, X), which primarily affects females and is characterized by features such as **short stature**, **webbed neck**, and **ovarian dysgenesis**. - This is inconsistent with the male patient described, who exhibits signs of **testicular dysfunction** and an **extra X chromosome**.

Question 220: A 10-year-old boy is presented to the hospital for a kidney transplant. In the operating room, the surgeon connects an allograft kidney renal artery to the aorta, and after a few moments, the kidney becomes cyanotic, edematous, and dusky with mottling. Which of the following in the recipient’s serum is responsible for this rejection?

A. Macrophages
B. CD4+ T cells
C. IgA
D. CD8+ T cells
E. IgG (Correct Answer)

Explanation: ***IgG*** - The rapid onset of tissue necrosis and the immediate signs of rejection (cyanotic, edematous, dusky with mottling) upon vascular anastomosis are characteristic of **hyperacute rejection**. - **Hyperacute rejection** is mediated by pre-formed recipient antibodies, primarily **IgG**, targeting donor ABO or HLA antigens. These antibodies activate complement, leading to rapid thrombosis and graft destruction. *Macrophages* - While macrophages play a role in chronic allograft rejection and delayed type hypersensitivity, they are not the primary mediators of **hyperacute rejection**. - Their involvement typically presents with a more delayed and less immediate profound tissue damage than seen in this scenario. *CD4+ T cells* - **CD4+ T cells** are central to acute cellular rejection, which typically manifests days to weeks after transplantation. - They are not responsible for the immediate, pre-formed antibody-mediated response seen in **hyperacute rejection**. *IgA* - **IgA antibodies** are primarily involved in mucosal immunity and are generally not implicated in solid organ transplant rejection, especially hyperacute rejection. - While IgA can contribute to immune complex formation, it's not the main antibody type driving hyperacute allograft destruction. *CD8+ T cells* - **CD8+ T cells** (cytotoxic T lymphocytes) are key players in acute cellular rejection, mediating direct lysis of donor cells. - Their action is part of a cellular immune response that takes days to weeks to develop and is not responsible for the immediate, antibody-mediated hyperacute rejection.

Question 221: A 21-year-old male presents to your office with hematuria 3 days after the onset of a productive cough and fever. Following renal biopsy, immunofluorescence shows granular IgA deposits in the glomerular mesangium. Which of the following do you suspect in this patient?

A. Lipoid nephrosis
B. Berger’s disease (Correct Answer)
C. HIV infection
D. Systemic lupus erythematosus
E. Poststreptococcal glomerulonephritis

Explanation: ***Berger’s disease*** - The presentation of **hematuria occurring 3 days after a respiratory infection** (productive cough and fever) is characteristic of **IgA nephropathy** or Berger's disease, showing a synpharyngitic pattern. - **Immunofluorescence showing granular IgA deposits in the glomerular mesangium** is the histological hallmark of IgA nephropathy. *Lipoid nephrosis* - This condition is also known as **minimal change disease** and typically presents with **nephrotic syndrome** (heavy proteinuria, edema, hypoalbuminemia), not primarily hematuria. - Renal biopsy would reveal **effacement of foot processes** on electron microscopy with normal light microscopy and negative immunofluorescence, unlike the IgA deposits described. *HIV infection* - HIV can lead to **HIV-associated nephropathy (HIVAN)**, which typically presents as **focal segmental glomerulosclerosis** (FSGS) and can include proteinuria and progressive renal failure. - While hematuria can occur, the characteristic **IgA deposits in the mesangium** described are not typical for HIVAN. *Systemic lupus erythematosus* - **Lupus nephritis** is a common complication of SLE, and can present with hematuria, proteinuria, and various patterns of glomerulonephritis. - However, immunofluorescence in lupus nephritis usually shows **IgG, IgM, IgA, C3, and C1q deposits** (full-house staining), not isolated IgA deposits. *Poststreptococcal glomerulonephritis* - This condition typically presents with **hematuria 10-14 days after a streptococcal infection** (post-infectious glomerulonephritis), a longer latency period than seen in this patient. - Immunofluorescence would show unique **"lumpy-bumpy" granular deposits of C3 and IgG** along the glomerular basement membrane, often with characteristic subepithelial humps on electron microscopy, rather than mesangial IgA.

Question 222: A 42-year-old woman is brought to the emergency department because of two episodes of hemoptysis over the past 24 hours. The patient has a 6-month history of severe sinusitis and bloody nasal discharge. Her vital parameters are as follows: blood pressure, 155/75 mm Hg; pulse, 75/min; respiratory rate, 14/min; and temperature, 37.9°C (100.2°F). Examination reveals red conjunctiva, and an ulcer on the nasal septum. Pulmonary auscultation indicates diffuse rhonchi. Cardiac and abdominal examinations reveal no abnormalities. Laboratory studies show: Urine Blood 3+ Protein 2+ RBC 10-15/hpf with dysmorphic features RBC cast numerous Based on these findings, this patient is most likely to carry which of the following antibodies?

A. Antideoxyribonuclease antibody
B. Antiglomerular basement membrane antibody
C. Antiproteinase 3 antineutrophil cytoplasmic antibody (Correct Answer)
D. Anticyclic citrullinated peptide antibody
E. Antimyeloperoxidase antibody

Explanation: ***Antiproteinase 3 antineutrophil cytoplasmic antibody*** - This patient presents with symptoms highly suggestive of **Granulomatosis with Polyangiitis (GPA)**, including **hemoptysis**, **severe sinusitis**, **bloody nasal discharge**, **red conjunctiva**, **nasal septum ulcer**, and likely **glomerulonephritis** (blood and protein in urine with dysmorphic RBCs and RBC casts). - **Antiproteinase 3 (PR3-ANCA)** is the specific antibody associated with GPA, a systemic vasculitis affecting small and medium-sized vessels. *Antideoxyribonuclease antibody* - This antibody is associated with **post-streptococcal glomerulonephritis** and is a marker for recent streptococcal infection. - The clinical presentation of chronic sinusitis, hemoptysis, and nasal ulcer is not typical for post-streptococcal glomerulonephritis. *Antiglomerular basement membrane antibody* - This antibody is characteristic of **Goodpasture syndrome**, which involves **pulmonary hemorrhage** and **glomerulonephritis**. - However, it does not typically cause the prominent upper airway granulomatous disease (sinusitis, nasal ulcer) seen in this patient. *Anticyclic citrullinated peptide antibody* - This antibody is a hallmark of **rheumatoid arthritis**, a chronic inflammatory autoimmune disease primarily affecting the joints. - The patient's symptoms are inconsistent with rheumatoid arthritis, which does not cause glomerulonephritis or upper respiratory tract granulomas. *Antimyeloperoxidase antibody* - **Antimyeloperoxidase (MPO-ANCA)** is associated with other forms of ANCA-associated vasculitis, such as **Microscopic Polyangiitis** and **Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)**. - While MPO-ANCA can cause glomerulonephritis and lung involvement, it is less commonly associated with the prominent upper airway granulomatous features (sinusitis, nasal ulcer) seen in GPA, which is primarily PR3-ANCA positive.

Question 223: A 10-year-old boy comes to the physician because of a 4-month history of intermittent red urine. During the past 2 years, he has had recurrent episodes of swelling of his face and feet. Five years ago, he was diagnosed with mild bilateral sensorineural hearing loss. His uncle died of kidney disease in his twenties. His blood pressure is 145/85 mm Hg. Laboratory studies show a hemoglobin concentration of 12.5 g/dL, urea nitrogen concentration of 40 mg/dL, and creatinine concentration of 2.4 mg/dL. Urinalysis shows 5–7 RBC/hpf. Which of the following is the most likely underlying cause of this patient's symptoms?

A. Vascular IgA deposits
B. Autosomal-recessive gene defect in fibrocystin
C. Phospholipase A2 receptor antibody
D. Defective type IV collagen (Correct Answer)
E. Prior streptococcal infection

Explanation: ***Defective type IV collagen*** - This patient presents with a classic triad of **hematuria**, **sensorineural hearing loss**, and a **family history of kidney disease** (uncle died in twenties), which are hallmarks of **Alport syndrome**. Alport syndrome is caused by a genetic defect in **Type IV collagen**, essential for the structure of the glomerular basement membrane, cochlea, and lens. - The elevated blood pressure, BUN, and creatinine indicate progressive **renal failure**, which is a common and severe complication of Alport syndrome. *Vascular IgA deposits* - **IgA vasculitis** (Henoch-Schonlein Purpura) or **IgA nephropathy** can cause hematuria and edema, but they are not typically associated with **sensorineural hearing loss** or a strong **family history of progressive renal failure**. - While IgA nephropathy can recur, the specific combination of auditory defects and family history points away from primary IgA-mediated disease. *Autosomal-recessive gene defect in fibrocystin* - An autosomal-recessive gene defect in **fibrocystin** (PKHD1 gene) causes **Autosomal Recessive Polycystic Kidney Disease (ARPKD)**, which is characterized by **enlarged, cystic kidneys** and **hepatic fibrosis**. - ARPKD does not typically present with **sensorineural hearing loss**, and while it causes renal failure, the presence of hearing loss is a key differentiator. *Phospholipase A2 receptor antibody* - **Phospholipase A2 receptor (PLA2R) antibody** is primarily associated with **idiopathic membranous nephropathy**, which is a common cause of **nephrotic syndrome** in adults. - While it can lead to proteinuria and renal impairment, it is not associated with **sensorineural hearing loss** or the specific family history described. *Prior streptococcal infection* - A **prior streptococcal infection** can lead to **post-streptococcal glomerulonephritis (PSGN)**, which causes hematuria, edema, and hypertension, typically within 1-3 weeks after the infection. - PSGN is usually a self-limiting condition and rarely involves **sensorineural hearing loss** or a **chronic, progressive family history of kidney disease**.

Question 224: A 45-year-old male immigrant with rheumatoid arthritis comes to the physician because of severe pain and swelling in both his knees. He also reports an unintentional weight loss of around 10 kg over 3 months and episodic abdominal pain, varying in intensity and location. He has been having loose stools with no blood, 2–3 times a day for 1 month. He denies fever, night sweats, cough, or shortness of breath. Current medications include methotrexate, naproxen, and folic acid. His weight is 68 kg (150 lbs), temperature is 37.4°C (99.3°F), pulse is 90/min, and blood pressure is 130/80 mm Hg. Examination shows pale conjunctivae, cheilitis, and hyperpigmentation of the skin around his neck. Generalized lymphadenopathy is present. Examination of the knee joints shows bilateral warmth, erythema, swelling, tenderness, and limited range of motion. A grade 2/6 early diastolic murmur is heard over the right second intercostal space and an S3 is heard. Abdominal examination shows no abnormalities. Laboratory studies show: Hemoglobin 9.1 g/dL Leukocyte count 3800/mm3 Platelet count 140,000/mm3 Mean corpuscular volume 67 μm3 Erythrocyte sedimentation rate 62 mm/h Serum Glucose 100 mg/dL Creatinine 0.7 mg/dL TIBC 500 mcg/dL Ferritin 10 mcg/dL Rheumatoid factor negative Anti -CCP negative An esophagogastroduodenoscopy is ordered. A biopsy specimen of the duodenum is likely to show which of the following?

A. Poorly differentiated cells
B. Granuloma with caseating necrosis
C. Villous atrophy and crypt hyperplasia
D. PAS-positive macrophages (Correct Answer)
E. Noncaseating granulomas

Explanation: ***PAS-positive macrophages*** - This patient's symptoms (rheumatoid arthritis, severe joint pain, weight loss, abdominal pain, diarrhea, anemia, low platelets, lymphadenopathy, cardiac murmur, and skin hyperpigmentation) are highly suggestive of **Whipple's disease**, caused by the bacterium *Tropheryma whipplei*. - Biopsy of the duodenum in Whipple's disease classically reveals infiltration of the lamina propria with **foamy macrophages** that stain positive with **periodic acid-Schiff (PAS)** due to the presence of undigested bacterial cell wall glycolipids. *Poorly differentiated cells* - This finding suggests **malignancy**, such as adenocarcinoma. While malignancy can cause weight loss and anemia, the combination of migratory arthralgia, lymphadenopathy, and cardiac involvement points away from a primary gastrointestinal malignancy as the sole explanation. - There are no specific features in the presentation (e.g., severe localized abdominal pain, hematochezia, obstructive symptoms, specific imaging findings) to strongly suggest a poorly differentiated gastrointestinal carcinoma. *Granuloma with caseating necrosis* - **Caseating granulomas** are characteristic of **tuberculosis**. Although tuberculosis can cause weight loss, lymphadenopathy, and anemia, the chronic diarrhea, arthralgia, and specific cardiac findings described are less typical for tuberculosis. - The absence of fever, night sweats, or cough also makes tuberculosis less likely in this context, especially in the absence of pulmonary involvement. *Villous atrophy and crypt hyperplasia* - This pattern is characteristic of **celiac disease**. While celiac disease causes malabsorption, weight loss, and diarrhea, it typically presents with iron-deficiency anemia due to malabsorption. - The additional features of arthritis, lymphadenopathy, cardiac involvement (murmur, S3), and skin hyperpigmentation are not characteristic of celiac disease. *Noncaseating granulomas* - **Noncaseating granulomas** are a hallmark of **Crohn's disease**, another inflammatory bowel disease that can cause abdominal pain, diarrhea, and weight loss. - However, the widespread systemic involvement including polyarthralgia, lymphadenopathy, and cardiac manifestations (murmur, S3 indicating potential endocarditis or valvular involvement), is not typical for Crohn's disease, which primarily affects the gastrointestinal tract and can have extraintestinal manifestations but usually not to this extent when considering the combination of all symptoms.

Question 225: A 25-year-old man of Mediterranean descent makes an appointment with his physician because his skin and sclera have become yellow. He complains of fatigue and fever that started at the same time icterus appeared. On examination, he is tachycardic and tachypneic. The oxygen (O2) saturation is < 90%. He has increased unconjugated bilirubin, hemoglobinemia, and an increased number of reticulocytes in the peripheral blood. What is the most likely diagnosis?

A. Microcytic anemia caused by iron deficiency
B. Aplastic anemia
C. Autoimmune hemolytic anemia (AIHA)
D. Anemia caused by renal failure
E. Hemolytic anemia caused by glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) (Correct Answer)

Explanation: ***Hemolytic anemia caused by glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)*** - The patient's presentation with **jaundice**, **fatigue**, fever, **tachycardia**, **tachypnea**, and **low oxygen saturation** points to an acute hemolytic crisis. - The laboratory findings of **increased unconjugated bilirubin**, **hemoglobinemia** (evidence of red blood cell destruction), and **increased reticulocytes** (bone marrow's attempt to compensate for red blood cell loss) are classic for hemolytic anemia. A young man of **Mediterranean descent** makes G6PD deficiency a strong possibility, as it is common in this population and can be triggered by various factors leading to oxidative stress. *Microcytic anemia caused by iron deficiency* - **Iron deficiency anemia** typically presents with **microcytic hypochromic red blood cells**, and while it causes fatigue and pallor, it does not typically lead to acute jaundice and hemoglobinemia. - Reticulocyte count is usually normal or only mildly elevated, not significantly increased as seen in rapid red blood cell destruction. *Aplastic anemia* - **Aplastic anemia** is characterized by **pancytopenia** (decreased red blood cells, white blood cells, and platelets) due to bone marrow failure. - It does not present with signs of hemolytic crisis such as jaundice, hemoglobinemia, or increased reticulocytes. *Autoimmune hemolytic anemia (AIHA)* - While AIHA causes **hemolytic anemia** with similar lab findings (jaundice, increased unconjugated bilirubin, reticulocytosis), the context of a young man of **Mediterranean descent** makes G6PD deficiency a more likely primary consideration, especially without specific triggers for AIHA or a positive direct Coombs test result. - AIHA involves autoantibodies against red blood cells. *Anemia caused by renal failure* - Anemia due to **renal failure** is primarily caused by decreased production of **erythropoietin** leading to **normocytic, normochromic anemia**. - It does not involve acute hemolysis, jaundice, hemoglobinemia, or increased reticulocytes.

Question 226: A 27-year-old woman presents to the emergency department complaining of a left-sided headache and right-sided blurry vision. She states that 2 weeks ago she developed dark urine and abdominal pain. She thought it was a urinary tract infection so she took trimethoprim-sulfamethoxazole that she had left over. She planned on going to her primary care physician today but then she developed headache and blurry vision so she came to the emergency department. The patient states she is otherwise healthy. Her family history is significant for a brother with sickle cell trait. On physical examination, there is mild abdominal tenderness, and the liver edge is felt 4 cm below the right costal margin. Labs are drawn as below: Hemoglobin: 7.0 g/dL Platelets: 149,000/mm^3 Reticulocyte count: 5.4% Lactate dehydrogenase: 3128 U/L Total bilirubin: 2.1 mg/dL Indirect bilirubin: 1.4 mg/dL Aspartate aminotransferase: 78 U/L Alanine aminotransferase: 64 U/L A peripheral smear shows polychromasia. A Doppler ultrasound of the liver shows decreased flow in the right hepatic vein. Magnetic resonance imaging of the brain is pending. Which of the following tests, if performed, would most likely identify the patient’s diagnosis?

A. Flow cytometry (Correct Answer)
B. Glucose-6-phosphate-dehydrogenase levels
C. Anti-histone antibodies
D. Bone marrow biopsy
E. Hemoglobin electrophoresis

Explanation: ***Flow cytometry*** - The patient's symptoms (headache, blurry vision, dark urine, abdominal pain, hepatomegaly) along with laboratory findings of **hemolytic anemia** (low hemoglobin, elevated reticulocyte count, high LDH, elevated indirect bilirubin) and signs of **thrombosis** (decreased hepatic vein flow, neurological symptoms) are highly suggestive of **paroxysmal nocturnal hemoglobinuria (PNH)**. - **Flow cytometry** is the gold standard for diagnosing PNH by detecting the absence of **CD55** and **CD59** on red blood cells, granulocytes, and monocytes, indicating a deficiency in the **GPI anchor protein**. *Glucose-6-phosphate-dehydrogenase levels* - **G6PD deficiency** typically presents with hemolytic anemia triggered by **oxidant stressors** (like trimethoprim-sulfamethoxazole) but does not typically cause **thrombosis** or widespread organ involvement (e.g., hepatic vein thrombosis, neurological symptoms) as seen in this patient. - Measuring G6PD levels would be appropriate if G6PD deficiency was suspected, but the clinical picture points more strongly to PNH due to the thrombotic events. *Anti-histone antibodies* - **Anti-histone antibodies** are primarily associated with drug-induced **lupus erythematosus**, which can manifest with various systemic symptoms, but not typically with severe hemolytic anemia and thrombotic microangiopathy in this specific pattern. - While drug exposure is present (trimethoprim-sulfamethoxazole), the overall clinical and lab findings (especially the severe hemolytic picture and thrombosis) are not characteristic of drug-induced lupus in this context. *Bone marrow biopsy* - A **bone marrow biopsy** might show findings consistent with increased erythropoiesis due to hemolysis but is not a primary diagnostic test for PNH or its associated thrombotic complications. - While it could be part of an evaluation for underlying bone marrow disorders, it would not directly confirm a diagnosis of PNH, which requires specific surface marker detection. *Hemoglobin electrophoresis* - **Hemoglobin electrophoresis** is used to diagnose **hemoglobinopathies** such as **sickle cell disease** or **thalassemia**. The patient's brother has sickle cell trait, but the patient's symptoms, particularly the prominent hemolytic anemia and thrombotic events, are not typical of a hemoglobinopathy in this acute presentation. - While it could rule out a hemoglobinopathy, it wouldn't explain the full spectrum of symptoms, especially the thrombosis and the specific pattern of hemolysis (e.g., elevated LDH, indirect bilirubin).

Question 227: A 3080-g (6-lb 13-oz) male newborn is delivered at term to a 27-year-old woman, gravida 2, para 1. Pregnancy was uncomplicated. He appears pale. His temperature is 36.8°C (98.2°F), pulse is 167/min, and respirations are 56/min. Examination shows jaundice of the skin and conjunctivae. The liver is palpated 2–3 cm below the right costal margin, and the spleen is palpated 1–2 cm below the left costal margin. The lungs are clear to auscultation. No murmurs are heard. His hemoglobin concentration is 10.6 g/dL and mean corpuscular volume is 73 μm3. Hemoglobin DNA testing shows 3 missing alleles. Which of the following laboratory findings is most likely present in this patient?

A. Increased hemoglobin Barts concentration (Correct Answer)
B. Elevated HbA2
C. Low reticulocyte count
D. Low serum ferritin
E. Elevated HbF

Explanation: **Increased hemoglobin Barts concentration** - The clinical presentation with **pallor**, **jaundice**, hepatosplenomegaly, and **microcytic anemia** (Hb 10.6 g/dL, MCV 73 fL) in a newborn, along with **3 missing alpha globin alleles** (Genomic DNA testing shows 3 missing alleles for the alpha-globin gene indicating alpha-thalassemia intermedia), is highly suggestive of **HbH disease**, a form of alpha-thalassemia. - **Hemoglobin Barts** (γ4) is typically seen in fetuses and newborns with severe alpha-thalassemia, particularly **hydrops fetalis (4-gene deletion)**, but can also be present in HbH disease (3-gene deletion) due to the presence of excess gamma chains that cannot form HbF and instead form gamma tetramers (Hb Barts). *Elevated HbA2* - **Elevated HbA2** is characteristic of **beta-thalassemia minor**, not alpha-thalassemia, as increased quantities of delta chains (δ) compensate for reduced beta globin production. - In alpha-thalassemia, the primary issue is reduced alpha globin chains, and HbA2 levels are typically normal or even low. *Low reticulocyte count* - A low reticulocyte count would indicate **hypoproliferative anemia**, where the bone marrow is not producing enough red blood cells. - In hemolytic conditions like **alpha-thalassemia**, the bone marrow attempts to compensate for red blood cell destruction, leading to an **elevated reticulocyte count** due to increased erythropoiesis. *Low serum ferritin* - Low serum ferritin is a hallmark of **iron deficiency anemia**. - While alpha-thalassemia is a microcytic anemia, the underlying pathology is a **globin chain imbalance** rather than iron deficiency; iron stores are typically normal or even elevated due to ineffective erythropoiesis and repeated transfusions. *Elevated HbF* - **Elevated HbF** (fetal hemoglobin, α2γ2) can be seen in some conditions like **beta-thalassemia** (as a compensatory mechanism) or hereditary persistence of fetal hemoglobin. - In alpha-thalassemia, the problem is with alpha-globin chain synthesis, which is required for both HbA and HbF; thus, HbF levels are usually not significantly elevated and may even be lower than expected relative to healthy newborns if the alpha chain deficiency is severe.

Question 228: A 61-year-old man presents to the emergency department because he has developed blisters at multiple locations on his body. He says that the blisters appeared several days ago after a day of hiking in the mountains with his colleagues. When asked about potential triggering events, he says that he recently had an infection and was treated with antibiotics but he cannot recall the name of the drug that he took. In addition, he accidentally confused his medication with one of his wife's blood thinner pills several days before the blisters appeared. On examination, the blisters are flesh-colored, raised, and widespread on his skin but do not involve his mucosal surfaces. The blisters are tense to palpation and do not separate with rubbing. Pathology of the vesicles show that they continue under the level of the epidermis. Which of the following is the most likely cause of this patient's blistering?

A. Depletion of protein C and protein S levels
B. Antibodies to proteins connecting two sets of intermediate filaments
C. Necrosis of skin in reaction to a drug
D. Antibodies to proteins connecting intermediate filaments to type IV collagen (Correct Answer)
E. Infection with an enveloped dsDNA virus

Explanation: ***Antibodies to proteins connecting intermediate filaments to type IV collagen*** - The patient's presentation of **tense blisters** that do not separate with rubbing (negative Nikolsky sign), **widespread distribution** on skin surfaces without **mucosal involvement**, and **subepidermal blistering** on pathology is classic for **bullous pemphigoid**. - **Bullous pemphigoid** is caused by autoantibodies targeting hemidesmosomal proteins, specifically BP180 (type XVII collagen) and BP230, which connect **intermediate filaments to the basal lamina (containing type IV collagen)**. *Depletion of protein C and protein S levels* - This scenario describes **warfarin-induced skin necrosis**, which typically presents as painful, erythematous plaques that rapidly progress to **hemorrhagic bullae and necrosis**. - While the patient might have inadvertently taken a blood thinner, the clinical presentation of widespread **tense, non-hemorrhagic blisters** is inconsistent with warfarin-induced skin necrosis. *Antibodies to proteins connecting two sets of intermediate filaments* - This describes the pathophysiology of **pemphigus vulgaris**, where autoantibodies target **desmogleins** (desmosomal proteins that connect keratinocytes via intermediate filaments). - Pemphigus vulgaris typically presents with **flaccid blisters** that are easily ruptured, readily separate with rubbing (**positive Nikolsky sign**), and commonly involve **mucosal surfaces**, which contradicts this patient's findings. *Necrosis of skin in reaction to a drug* - While drug reactions can cause blistering conditions like **Stevens-Johnson Syndrome (SJS)** or **Toxic Epidermal Necrolysis (TEN)**, these conditions typically involve **widespread epidermal necrosis**, mucosal involvement, and often present with a **positive Nikolsky sign** and targetoid lesions for SJS. - The description of **tense blisters** and **subepidermal cleavage** without significant epidermal necrosis makes SJS/TEN less likely. *Infection with a enveloped dsDNA virus* - This likely refers to **herpes simplex virus (HSV)** or **varicella-zoster virus (VZV)** infections, which cause vesicular eruptions. - Viral blisters are typically **grouped vesicles on an erythematous base** (e.g., herpes zoster), often painful, and **rarely widespread tense bullae** as described in this patient.

Question 229: A 61-year-old man comes to the physician because of progressively worsening swelling of his ankles. He says he has felt exhausted lately. Over the past 3 months, he has gained 5 kg. He has smoked one pack of cigarettes daily for 30 years. His pulse is 75/min and his blood pressure is 140/90 mmHg. Examination shows 2+ pitting edema in the lower extremities. Neurologic exam shows diminished two-point discrimination in the fingers and toes. A urine sample is noted to be foamy. Laboratory studies show a hemoglobin A1c of 7.9% and creatinine of 1.9 mg/dL. A biopsy specimen of the kidney is most likely to show which of the following?

A. Nodular glomerulosclerosis (Correct Answer)
B. Wire looping of capillaries
C. Immune complex deposition
D. Split glomerular basement membrane
E. Interstitial inflammation

Explanation: ***Nodular glomerulosclerosis*** - The patient's history of **elevated HbA1c (7.9%)**, **pitting edema**, **foamy urine**, and **elevated creatinine (1.9 mg/dL)** strongly indicates **diabetic nephropathy**. Nodular glomerulosclerosis (**Kimmelstiel-Wilson lesions**) is a characteristic pathological finding in advanced diabetic nephropathy. - The **diminished two-point discrimination** also points to **peripheral neuropathy**, a common complication of diabetes, further supporting the diagnosis of diabetes-related end-organ damage. *Wire looping of capillaries* - **Wire looping** of capillaries, along with **subendothelial immune complex deposits**, is characteristic of **diffuse proliferative glomerulonephritis**, often associated with **lupus nephritis (Class III or IV)**. - While this patient has renal involvement, the clinical picture (diabetes, neuropathy) does not suggest a systemic autoimmune disease like lupus. *Immune complex deposition* - **Immune complex deposition** is a general feature of many forms of **glomerulonephritis**, including post-infectious glomerulonephritis or lupus nephritis. - However, the specific clinical context of uncontrolled diabetes makes **diabetic nephropathy** the most likely cause, which is primarily a metabolic rather than immune-mediated injury. *Split glomerular basement membrane* - A **split glomerular basement membrane** (often described as duplication or tram-track appearance) is characteristic of **membranoproliferative glomerulonephritis (MPGN)** types I and II. - This finding is not typically associated with diabetic nephropathy, which involves thickening of the basement membrane and mesangial expansion but not splitting. *Interstitial inflammation* - **Interstitial inflammation** is a prominent feature of **interstitial nephritis**, often caused by drug reactions (e.g., NSAIDs, antibiotics) or certain systemic diseases. - While renal damage in diabetes can lead to some interstitial fibrosis and inflammation, it is not the primary histological hallmark, and the prominent glomerular changes are more specific.

Question 230: A 54-year-old man comes to the physician because of a cough with blood-tinged sputum for 1 week. He also reports fever and a 5-kg (11 lb) weight loss during the past 2 months. Over the past year, he has had 4 episodes of sinusitis. Physical examination shows palpable nonblanching skin lesions over the hands and feet. Examination of the nasal cavity shows ulceration of the nasopharyngeal mucosa and a depressed nasal bridge. Oral examination shows a painful erythematous gingival enlargement that bleeds easily on contact. Which of the following is the most likely cause of the patient's symptoms?

A. Metalloprotease enzyme deficiency
B. Malignant myeloid cell proliferation
C. Arteriovenous malformation
D. Immune complex deposition
E. Neutrophil-mediated damage (Correct Answer)

Explanation: ***Neutrophil-mediated damage*** - The constellation of **sinusitis**, **pulmonary symptoms** (cough with blood-tinged sputum), **renal involvement** (indicated by systemic symptoms and often associated with microhematuria in this condition), and **skin lesions (palpable purpura)**, along with **nasal ulceration**, a **depressed nasal bridge**, and **gingival enlargement**, is highly characteristic of **Granulomatosis with Polyangiitis (GPA)**. - GPA is an **ANCA-associated vasculitis** characterized by **necrotizing granulomatous inflammation** and **vasculitis** of small to medium-sized vessels, primarily driven by **neutrophil activation** and subsequent tissue damage. *Metalloprotease enzyme deficiency* - This description commonly refers to conditions like **alpha-1 antitrypsin deficiency**, which primarily causes **emphysema** and liver disease, not the widespread vasculitic manifestations seen here. - It does not explain the diverse multi-organ involvement including skin, ENT, and likely renal symptoms. *Malignant myeloid cell proliferation* - This would suggest conditions like **leukemia** or **myelodysplastic syndromes**, which present with altered blood counts, fatigue, infections, and bleeding, but typically not this specific pattern of vasculitis and granulomatous inflammation. - While constitutional symptoms like weight loss can occur, the localized findings like depressed nasal bridge and gingival enlargement are not characteristic. *Arteriovenous malformation* - An **arteriovenous malformation (AVM)** is an abnormal connection between arteries and veins; depending on its location, it can cause bleeding (e.g., hemoptysis if pulmonary) or neurological symptoms if cerebral. - However, AVMs do not explain the systemic inflammatory symptoms, skin lesions, sinusitis, depressed nasal bridge, or gingival changes. *Immune complex deposition* - **Immune complex vasculitis** (e.g., IgA vasculitis, cryoglobulinemic vasculitis) often presents with palpable purpura and can affect kidneys and GI tract. - However, the prominent **granulomatous inflammation** causing **nasal ulceration** and **depressed nasal bridge**, and the specific type of **pulmonary-renal syndrome** seen in GPA, are more indicative of **ANCA-mediated neutrophil damage** rather than immune complex deposition.

Question 231: A 3-year-old boy is brought to the physician by his parents for a well-child examination. The boy was born at term via vaginal delivery and has been healthy except for impaired vision due to severe short-sightedness. He is at the 97th percentile for height and 25th percentile for weight. Oral examination shows a high-arched palate. He has abnormally long, slender fingers and toes, and his finger joints are hyperflexible. The patient is asked to place his thumbs in the palms of the same hand and then clench to form a fist. The thumbs are noted to protrude beyond the ulnar border of the hand. Slit lamp examination shows lens subluxation in the superotemporal direction bilaterally. Which of the following is the most likely underlying cause of this patient's condition?

A. Nondisjunction of sex chromosomes
B. Mutation in fibrillin-1 gene (Correct Answer)
C. Defective collagen cross-linking
D. Mutation in RET gene
E. Mutation of the FMR1 gene

Explanation: **Mutation in fibrillin-1 gene** - The patient's presentation with **tall stature**, **long slender fingers and toes (arachnodactyly)**, **hyperflexible joints**, **high-arched palate**, and **lens subluxation** (especially superotemporal) are classic features of **Marfan syndrome**. - **Marfan syndrome** is an autosomal dominant disorder caused by a mutation in the **FBN1 gene**, which codes for **fibrillin-1**, a glycoprotein essential for the formation of elastic fibers in connective tissue. *Nondisjunction of sex chromosomes* - **Nondisjunction of sex chromosomes** can lead to conditions like Klinefelter syndrome (XXY) or Turner syndrome (XO), which present with distinct symptom complexes, such as infertility, developmental delay, or specific dysmorphic features. - These conditions do not typically cause the combination of skeletal, ocular, and cardiovascular abnormalities seen in this patient, especially the tall stature, arachnodactyly, and lens subluxation. *Defective collagen cross-linking* - **Defective collagen cross-linking** is characteristic of **Ehlers-Danlos syndromes**, which primarily manifest as extremely hypermobile joints, skin hyperelasticity, and potential vascular fragility. - While there is some overlap with joint hyperflexibility, the overall clinical picture including tall stature, arachnodactyly, and lens subluxation is not typical for Ehlers-Danlos syndromes. *Mutation in RET gene* - A **mutation in the RET gene** is associated with conditions like **Multiple Endocrine Neoplasia type 2 (MEN2)** or **Hirschsprung disease**. - These disorders involve endocrine tumors or gastrointestinal motility issues, which are unrelated to the skeletal and ocular features observed in this patient. *Mutation of the FMR1 gene* - A **mutation of the FMR1 gene** causes **fragile X syndrome**, an X-linked dominant disorder characterized by intellectual disability, behavioral problems (e.g., autism spectrum features), and distinct physical features such as a long face, large ears, and macroorchidism in males. - The symptoms presented by the patient, particularly the connective tissue abnormalities and tall stature, are not consistent with fragile X syndrome.

Question 232: A 20-month-old boy is brought to the emergency department by his parents with fever and diarrhea that have persisted for the past 2 days. He has a history of repeated bouts of diarrhea, upper respiratory tract infections, and failure to thrive. His vital signs are as follows: blood pressure 80/40 mm Hg, pulse 130/min, temperature 39.0°C (102.2°F), and respiratory rate 30/min. Blood tests are suggestive of lymphopenia. The child is diagnosed with severe combined immune deficiency after additional testing. Which of the following is the most common association with this type of immunodeficiency?

A. Janus-associated kinase 3 (JAK3) deficiency
B. Adenosine deaminase deficiency
C. Bare lymphocyte syndrome
D. Reticular dysgenesis
E. X-linked severe combined immunodeficiency (Correct Answer)

Explanation: ***X-linked severe combined immunodeficiency*** - **X-linked immunodeficiency** is the most common form of SCID, accounting for about **50% of all cases**. - It results from mutations in the **IL2RG gene**, leading to defective cytokine signaling and impaired T-cell and natural killer cell development. *Janus-associated kinase 3 (JAK3) deficiency* - **JAK3 deficiency** results in a SCID phenotype that is clinically indistinguishable from **X-linked SCID**. - While it is a cause of SCID, it is **less common** than the X-linked form. *Adenosine deaminase deficiency* - **Adenosine deaminase (ADA) deficiency** is the second most common cause of SCID, accounting for about **15% of cases**. - It leads to the accumulation of toxic metabolites that impair lymphocyte development and function. *Bare lymphocyte syndrome* - **Bare lymphocyte syndrome (BLS)** is a rare group of genetic disorders affecting **MHC class I** or **MHC class II molecule** expression. - Type 2 BLS, affecting MHC class II, can present as SCID but is significantly less common than X-linked SCID. *Reticular dysgenesis* - **Reticular dysgenesis** is the most severe form of SCID, characterized by a complete absence of **lymphocytes and myeloid cells**, including neutrophils. - It is an extremely rare condition, often leading to death in infancy, and is much less common than X-linked SCID.

Question 233: A 49-year-old woman is brought to the emergency department by her daughter because of increasing arthralgia, headache, and somnolence for the past week. She has a history of systemic lupus erythematosus without vital organ involvement. She last received low-dose glucocorticoids 2 months ago. Her temperature is 38.6 °C (101.5 °F), pulse is 80/min, respirations are 21/min, and blood pressure is 129/80 mm Hg. She is confused and disoriented. Examination shows scleral icterus and ecchymoses over the trunk and legs. Neurological examination is otherwise within normal limits. Laboratory studies show: Hemoglobin 8.7 g/dL Leukocyte count 6,200/mm3 Platelet count 25,000/mm3 Prothrombin time 15 seconds Partial thromboplastin time 39 seconds Fibrin split products negative Serum Bilirubin Total 4.9 mg/dL Direct 0.5 mg/dL A blood smear shows numerous fragmented red blood cells. Urinalysis shows hematuria and proteinuria. Which of the following is the most likely diagnosis?

A. Glanzmann thrombasthenia
B. Disseminated intravascular coagulation
C. Immune thrombocytopenic purpura
D. Hemolytic uremic syndrome
E. Thrombotic thrombocytopenic purpura (Correct Answer)

Explanation: ***Thrombotic thrombocytopenic purpura*** - This patient presents with the classic pentad of **thrombotic thrombocytopenic purpura (TTP)**: **fever**, **neurological symptoms** (confusion, disorientation, somnolence), **renal impairment** (hematuria, proteinuria), **thrombocytopenia** (platelet count 25,000/mm3, ecchymoses), and **microangiopathic hemolytic anemia** (hemoglobin 8.7 g/dL, elevated total bilirubin with indirect predominance, fragmented red blood cells on blood smear, scleral icterus). - The history of **systemic lupus erythematosus (SLE)** is a risk factor for TTP, as SLE can induce autoantibodies against **ADAMTS13**, the enzyme responsible for cleaving von Willebrand factor. *Glanzmann thrombasthenia* - This is an **autosomal recessive disorder** characterized by a defect in **platelet aggregation** due to a deficiency or dysfunction of the **glycoprotein IIb/IIIa receptor**. - While it causes bleeding, it does not typically present with the multi-organ damage, microangiopathic hemolytic anemia, or neurological symptoms seen in this patient. *Disseminated intravascular coagulation* - **DIC** is characterized by widespread activation of the clotting cascade, leading to both **thrombosis** and **hemorrhage**, consumptive coagulopathy, and **microangiopathic hemolytic anemia**. - However, in DIC, you would expect to see **markedly prolonged PT and PTT**, **decreased fibrinogen**, and **positive fibrin split products/D-dimers**. This patient has only mildly prolonged PT (15 sec) and PTT (39 sec) with **negative fibrin split products**, indicating that coagulation factors are relatively preserved, which is typical of TTP rather than DIC. *Immune thrombocytopenic purpura* - **ITP** is an autoimmune condition resulting in isolated **thrombocytopenia** due to increased destruction of platelets and impaired platelet production. - While it explains the low platelet count and ecchymoses, it does **not explain the microangiopathic hemolytic anemia**, **renal involvement**, **fever**, or **neurological symptoms** seen in this case. *Hemolytic uremic syndrome* - **Hemolytic uremic syndrome (HUS)** shares features with TTP, including **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **acute kidney injury**. - However, HUS typically presents with more prominent **renal failure** and is often preceded by **diarrhea** (especially in children) due to Shiga toxin-producing E. coli, and **neurological symptoms are less common and less severe** than in TTP. The patient's prominent neurological symptoms make TTP more likely.

Question 234: An investigator studying disorders of hemostasis performs gene expression profiling in a family with a specific type of bleeding disorder. These patients were found to have abnormally large von Willebrand factor (vWF) multimers in their blood. Genetic analysis shows that the underlying cause is a mutation in the ADAMTS13 gene. This mutation results in a deficiency of the encoded metalloprotease, which is responsible for cleavage of vWF. Which of the following additional laboratory findings is most likely in these patients?

A. Prolonged partial thromboplastin time
B. Elevated haptoglobin
C. Urinary red blood cell casts
D. Elevated platelet count
E. Fragmented erythrocytes (Correct Answer)

Explanation: ***Fragmented erythrocytes*** - This condition is **Thrombotic Thrombocytopenic Purpura (TTP)**, characterized by a deficiency in **ADAMTS13**, leading to uncleaved vWF multimers. These large multimers spontaneously bind platelets, forming microthrombi that shear **red blood cells**, creating **schistocytes** (fragmented erythrocytes), a hallmark of microangiopathic hemolytic anemia. - The shearing of red blood cells by microthrombi in small vessels is the direct cause of **microangiopathic hemolytic anemia**, which is a key component of the TTP pentad. *Prolonged partial thromboplastin time* - **PTT** measures the intrinsic and common coagulation pathways and is typically normal in TTP because the coagulation cascade itself is not directly affected. - While there is platelet consumption, it does not typically prolong PTT unless severe factor deficiencies are also present, which is not the primary issue in TTP. *Elevated haptoglobin* - **Haptoglobin** binds free hemoglobin released during red blood cell destruction. In hemolytic conditions like TTP, haptoglobin levels would be **decreased** as it is consumed. - Therefore, an elevated haptoglobin level would indicate a lack of significant intravascular hemolysis, which contradicts the expected findings in TTP. *Urinary red blood cell casts* - **Red blood cell casts** indicate **glomerulonephritis** or severe renal injury, where red blood cells leak into the renal tubules and are molded into casts. - While TTP can cause renal dysfunction due to microthrombi in glomeruli, the primary finding is often **proteinuria** and elevated creatinine, not typically RBC casts, which are more specific to inflammatory glomerular diseases. *Elevated platelet count* - TTP is characterized by **thrombocytopenia** (low platelet count) due to the consumption of platelets in the formation of microthrombi. - An elevated platelet count would contradict the fundamental pathophysiology of TTP, where platelets are rapidly being consumed.

Question 235: A 32-year-old man presents with a 2-month history of increasing lethargy, frequent upper respiratory tract infections, and easy bruising. Past medical history is unremarkable. The patient reports a 14-pack-year smoking history and says he drinks alcohol socially. No significant family history. His vital signs include: temperature 36.8°C (98.2°F), blood pressure 132/91 mm Hg and pulse 95/min. Physical examination reveals conjunctival pallor and scattered ecchymoses on the lower extremities. Laboratory results are significant for the following: Hemoglobin 8.2 g/dL Leukocyte count 2,200/mm3 Platelet count 88,000/mm3 Reticulocyte count 0.5% A bone marrow biopsy is performed, which demonstrates hypocellularity with no abnormal cell population. Which of the following is the most likely diagnosis in this patient?

A. Infectious mononucleosis
B. Aplastic anemia (Correct Answer)
C. Drug-induced immune pancytopenia
D. Myelodysplastic syndrome
E. Acute lymphocytic leukemia

Explanation: ***Aplastic anemia*** - This condition is characterized by **pancytopenia** (anemia, leukopenia, and thrombocytopenia) along with a **hypocellular bone marrow** without abnormal cells. - The patient's symptoms of **lethargy**, frequent **infections**, and **easy bruising** are consistent with bone marrow failure affecting all hematopoietic cell lines. *Infectious mononucleosis* - Typically presents with **lymphadenopathy**, **splenomegaly**, and atypical lymphocytes on the peripheral smear, none of which are noted here. - While it can cause some cytopenias, it usually does not lead to severe **pancytopenia** and **hypocellular marrow** as seen in this patient. *Drug-induced immune pancytopenia* - This would require a history of **medication use** known to cause bone marrow suppression or immune-mediated destruction, which is not mentioned. - The mechanism usually involves drug-induced immune destruction or toxicity, but a primary diagnosis of aplastic anemia is more fitting given the bone marrow findings in the absence of a clear drug trigger. *Myelodysplastic syndrome* - Characterized by **dysplastic changes** in one or more myeloid cell lines and often an **increased cellularity** or specific cytogenetic abnormalities in the bone marrow. - Although it can cause pancytopenia, the **hypocellular bone marrow with no abnormal cells** makes it less likely than aplastic anemia. *Acute lymphocytic leukemia* - Presents with a significant increase in **lymphoblasts** in the bone marrow (typically >20%), which is not present in this patient's biopsy showing **hypocellularity with no abnormal cell population**. - While it can cause cytopenias due to marrow crowding, the key feature of a highly cellular marrow with blasts is absent.

Question 236: Four days after admission to the hospital for acute pancreatitis, a 41-year-old man develops hypotension and fever. His temperature is 39.1°C (102.3°F), pulse is 115/min, and blood pressure is 80/60 mm Hg. Physical examination shows warm extremities, asymmetric calf size, and blood oozing around his IV sites. There are numerous small, red, non-blanching macules and patches covering the extremities, as well as several large ecchymoses. His hemoglobin concentration is 9.0 g/dL. A peripheral blood smear shows schistocytes and decreased platelets. Which of the following sets of serum findings are most likely in this patient? $$$ Prothrombin time %%% Partial thromboplastin time %%% Fibrinogen %%% D-dimer $$$

A. ↑ ↑ ↓ ↑ (Correct Answer)
B. Normal ↑ normal normal
C. Normal normal normal ↑
D. ↑ ↑ ↓ normal
E. Normal normal normal normal

Explanation: ***↑ ↑ ↓ ↑*** - This patient's presentation with **hypotension**, **fever**, **bleeding (oozing IV sites, ecchymoses)**, **schistocytes**, and **thrombocytopenia** is highly suggestive of **Disseminated Intravascular Coagulation (DIC)**. **DIC** leads to consumption of clotting factors and platelets, resulting in prolonged **PT**, prolonged **aPTT**, decreased **fibrinogen**, and increased **D-dimer** as fibrin is broken down. - The elevated **D-dimer** specifically indicates increased **fibrinolysis** due to the widespread clot formation and subsequent degradation, which is characteristic of **DIC**. *Normal ↑ normal normal* - **Isolated prolonged aPTT** with normal **PT**, **fibrinogen**, and **D-dimer** is not consistent with the widespread coagulation activation and consumption seen in this patient's severe, multi-systemic illness involving both bleeding and thrombosis. - This pattern might suggest a deficiency in an **intrinsic pathway factor** or the presence of a **heparin effect**, neither of which explains the full clinical picture of **DIC**. *Normal normal normal ↑* - A normal **PT**, **aPTT**, and **fibrinogen** with an **isolated elevated D-dimer** could suggest a more localized **thrombotic event** with secondary fibrinolysis, such as **deep vein thrombosis (DVT)**, but without significant consumption of clotting factors or platelets. - This pattern does not account for the **bleeding manifestations**, **thrombocytopenia**, or the presence of **elevated PT** and **aPTT** that would be expected in **DIC**. *↑ ↑ ↓ normal* - While **prolonged PT** and **aPTT** and decreased **fibrinogen** are consistent with consumption of clotting factors in **DIC**, a normal **D-dimer** would contradict the extensive **fibrinolysis** that accompanies the widespread microvascular thrombosis in this condition. - An elevated **D-dimer** is a crucial diagnostic marker for **DIC**, reflecting the breakdown products of fibrin clots. *Normal normal normal normal* - Normal coagulation parameters with the profound clinical picture of **hypotension**, **fever**, **bleeding**, **schistocytes**, and **thrombocytopenia** would be highly contradictory. - This pattern effectively rules out any significant **coagulopathy**, which is clearly present given the patient's symptoms and blood smear findings.

Question 237: A 12-year-old boy is brought by his parents to the physician for a fever for the past 2 days. His temperature is 101.3°F (38.5°C). His medical history is significant for sickle cell disease and recurrent infections. A year ago, he underwent spleen scintigraphy with technetium-99m that revealed functional hyposplenism. Which of the following findings would be found in a peripheral blood smear from this patient?

A. Schistocytes
B. Acanthocytes
C. Howell-Jolly bodies (Correct Answer)
D. Basophilic stippling
E. Heinz bodies

Explanation: ***Howell-Jolly bodies*** - The patient has **functional hyposplenism** due to sickle cell disease, meaning the spleen is not effectively filtering the blood. - **Howell-Jolly bodies** are nuclear remnants of red blood cells that are normally removed by the spleen; their presence indicates **splenic dysfunction** or **asplenia**. *Schistocytes* - **Schistocytes** are fragmented red blood cells, indicating **microangiopathic hemolytic anemia** (e.g., DIC, TTP-HUS, mechanical heart valves). - While sickle cell disease can cause hemolysis, schistocytes are not the primary or expected finding directly related to hyposplenism. *Acanthocytes* - **Acanthocytes** (spur cells) are red blood cells with irregular, spiny projections, typically seen in severe liver disease or abetalipoproteinemia. - They are not a characteristic finding associated with hyposplenism or sickle cell disease in this context. *Basophilic stippling* - **Basophilic stippling** refers to ribosomal precipitates within red blood cells, commonly seen in **lead poisoning**, severe anemias, or myelodysplastic syndromes. - It does not directly indicate splenic dysfunction or hyposplenism. *Heinz bodies* - **Heinz bodies** are denatured hemoglobin precipitates within red blood cells, seen in conditions causing **oxidative stress** or **hemoglobinopathies** like G6PD deficiency. - Although sickle cell disease involves abnormal hemoglobin, Heinz bodies are not the classic finding of hyposplenism; rather, they suggest a different underlying pathology for red cell damage.

Question 238: A previously healthy 15-year-old girl is brought to the physician by her parents for lethargy, increased thirst, and urinary frequency for 10 days. She is 173 cm (5 ft 8 in) tall and weighs 54 kg (120 lb); BMI is 18 kg/m2. Physical examination shows no abnormalities. Her serum glucose concentration is 224 mg/dL. A urine dipstick is positive for ketone bodies. Which of the following is most likely involved in the pathogenesis of this patient's condition?

A. Pancreatic islet amyloid polypeptide deposition
B. T-cell infiltration of pancreatic islets (Correct Answer)
C. B-cell production of antimitochondrial antibodies
D. Complement-mediated destruction of insulin receptors
E. Expression of human leukocyte antigen subtype A3

Explanation: ***T-cell infiltration of pancreatic islets*** - The patient's symptoms (lethargy, increased thirst, urinary frequency, weight loss shown by BMI 18) combined with **hyperglycemia** (224 mg/dL) and **ketonuria** are classic for **Type 1 Diabetes Mellitus (T1DM)**. - T1DM is an autoimmune disease characterized by the **T-cell mediated destruction of pancreatic beta cells**, leading to absolute insulin deficiency. *Pancreatic islet amyloid polypeptide deposition* - **Amyloid polypeptide (amylin) deposition** is characteristic of **Type 2 Diabetes Mellitus (T2DM)**, particularly in later stages. - T2DM typically presents in older, obese individuals due to insulin resistance, which does not fit this patient's profile (thin, young, acute onset). *B-cell production of antimitochondrial antibodies* - **Antimitochondrial antibodies** are highly specific for **primary biliary cholangitis**, an autoimmune liver disease. - These antibodies are not associated with diabetes mellitus. *Complement-mediated destruction of insulin receptors* - Conditions involving **autoantibodies against insulin receptors** can cause extreme insulin resistance, presenting with hyperglycaemia. - However, this is a very rare form of diabetes and does not typically involve ketosis or the classic acute presentation seen in T1DM. *Expression of human leukocyte antigen subtype A3* - **HLA-A3** is associated with **hemochromatosis**, a genetic disorder of iron overload. - While certain HLA types (e.g., HLA-DR3, DR4) are associated with T1DM, HLA-A3 is not a primary risk factor for uncomplicated diabetes.

Question 239: A 30-year-old woman comes to the emergency department because of weakness and fatigue for 2 days. She has also noticed that her urine is darker than usual. For the past week, she has had a persistent non-productive cough and low-grade fever. She has seasonal allergies. She drinks one to two glasses of wine on social occasions and does not smoke. Her temperature is 37.9°C (100.2°F), pulse is 88/min, respirations are 18/min, and blood pressure is 110/76 mm Hg. She has conjunctival pallor and scleral icterus. Cardiopulmonary examination shows bibasilar crackles. The remainder of the physical examination shows no abnormalities. Laboratory studies show: Leukocyte count 8,000/mm3 Hemoglobin 7.1 g/dL Hematocrit 21% Platelet count 110,000/mm3 MCV 94 μm3 Serum Total bilirubin 4.3 mg/dL Direct 1.1 mg/dL Indirect 3.2 mg/dL AST 15 U/L ALT 17 U/L LDH 1,251 U/L Haptoglobin 5.8 mg/dL (N = 41–165) An x-ray of the chest shows bilateral patchy infiltrates. A peripheral blood smear shows spherocytes. Which of the following is most likely to confirm the diagnosis?

A. Flow cytometry
B. Hemoglobin electrophoresis
C. Direct Coombs test (Correct Answer)
D. ADAMTS13 activity and inhibitor profile
E. Osmotic fragility test

Explanation: ***Direct Coombs test*** - The patient presents with classic signs of **autoimmune hemolytic anemia (AIHA)**: anemia (Hb 7.1), indirect hyperbilirubinemia (indirect 3.2 mg/dL), elevated LDH (1251 U/L), low haptoglobin (5.8 mg/dL), and spherocytes on peripheral smear. - A **direct Coombs test** (direct antiglobulin test) detects antibodies or complement components bound to the surface of red blood cells, which is the definitive diagnostic test for AIHA. - The recent respiratory symptoms with bilateral infiltrates suggest **atypical pneumonia** (likely Mycoplasma or viral), which is a classic trigger for **cold agglutinin disease**, a type of AIHA. *Flow cytometry* - **Flow cytometry** is used to identify and quantify specific cell populations, often in hematologic malignancies or immune deficiencies. - It can be used to diagnose **paroxysmal nocturnal hemoglobinuria (PNH)** by detecting CD55 and CD59 deficiency, but the clinical picture and spherocytes point to AIHA rather than PNH. *Hemoglobin electrophoresis* - **Hemoglobin electrophoresis** is used to diagnose hemoglobinopathies like **sickle cell anemia** or **thalassemia**. - While these can cause hemolytic anemia, the presence of spherocytes and the acute presentation with signs of immune-mediated destruction (triggered by infection) points away from these inherited disorders as the primary cause. *ADAMTS13 activity and inhibitor profile* - This test is used to diagnose **Thrombotic Thrombocytopenic Purpura (TTP)**, which presents with microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurological symptoms, and fever. - While the patient has anemia and mild thrombocytopenia, the presence of **spherocytes** (not schistocytes) and indirect hyperbilirubinemia with low haptoglobin is more consistent with AIHA rather than TTP. *Osmotic fragility test* - The **osmotic fragility test** is used to diagnose hereditary spherocytosis, which also presents with spherocytes and hemolytic anemia. - However, hereditary spherocytosis is typically a chronic, inherited condition, and the acute presentation with a likely infectious trigger (non-productive cough and low-grade fever suggesting atypical pneumonia) makes **acquired autoimmune hemolysis** more probable.

Question 240: A 57-year-old female visits her primary care physician with 2+ pitting edema in her legs. She takes no medications and does not use alcohol, tobacco, or illicit drugs. 4.5 grams of protein are collected during 24-hour urine excretion. A kidney biopsy is obtained. Examination with light microscopy shows diffuse thickening of the glomerular basement membrane. Electron microscopy shows subepithelial spike and dome deposits. Which of the following is the most likely diagnosis:

A. Membranous nephropathy (Correct Answer)
B. Postinfectious glomerulonephritis
C. Minimal change disease
D. Focal segmental glomerulosclerosis
E. Rapidly progressive glomerulonephritis

Explanation: ***Membranous nephropathy*** - The classic renal biopsy findings of **diffuse thickening of the glomerular basement membrane** on light microscopy and **subepithelial spike and dome deposits** on electron microscopy are pathognomonic for membranous nephropathy. - The patient presents with **nephrotic syndrome** (4.5 grams of protein in 24-hour urine excretion and 2+ pitting edema), which is the primary presentation of membranous nephropathy. *Postinfectious glomerulonephritis* - This condition typically follows an infection (e.g., streptococcal) and presents with **nephritic syndrome** (hematuria, hypertension, mild proteinuria), not nephrotic levels of proteinuria. - Biopsy would show **subepithelial humps** on electron microscopy and mesangial/endocapillary proliferation on light microscopy, which differs from the findings described. *Minimal change disease* - While it causes nephrotic syndrome, light microscopy would show a **normal glomerulus**, not diffuse thickening of the glomerular basement membrane. - Electron microscopy would reveal **effacement of podocyte foot processes**, without immune deposits. *Focal segmental glomerulosclerosis* - This condition presents with nephrotic syndrome, but light microscopy would show **sclerosis of some glomeruli** (focal) and within parts of affected glomeruli (segmental). - Electron microscopy might show **effacement of foot processes** but typically without the prominent subepithelial immune deposits seen in membranous nephropathy. *Rapidly progressive glomerulonephritis* - This is a clinical syndrome characterized by a **rapid decline in glomerular function** and often presents with nephritic features and prominent **crescent formation** on light microscopy. - It does not typically show diffuse glomerular basement membrane thickening and subepithelial spike and dome deposits.

Question 241: A 40-year-old woman has complaints of dyspnea, cough, and arthritis in her ankle joints. A CT scan reveals multiple granulomas in both lungs, as well as bilateral hilar lymphadenopathy. On examination, cutaneous nodules over the trunk are found. Erythrocyte sedimentation rate, angiotensin-converting enzyme, and serum calcium levels are elevated. She is treated with steroids. What is the most likely diagnosis?

A. Sarcoidosis (Correct Answer)
B. Silicosis
C. Tuberculosis
D. Adenocarcinoma of the lung
E. Hodgkin's lymphoma

Explanation: ***Sarcoidosis*** - The combination of **dyspnea, cough, arthritis, pulmonary granulomas, bilateral hilar lymphadenopathy**, cutaneous nodules, and elevated **ACE, ESR, and serum calcium** is highly characteristic of sarcoidosis. - This multisystem inflammatory disease often presents with non-caseating granulomas affecting the lungs, lymph nodes, skin, and joints, and it typically responds well to corticosteroids. *Silicosis* - **Silicosis** is an occupational lung disease caused by inhaling **crystalline silica dust**, leading to pulmonary fibrosis, but it does not typically present with arthritis, elevated ACE, or widespread cutaneous nodules. - While it can cause **pulmonary nodules**, these are usually different from the granulomas seen in sarcoidosis, and it lacks the other systemic features. *Tuberculosis* - **Tuberculosis** can cause **pulmonary granulomas**, cough, and dyspnea, but it typically presents with caseating granulomas and is usually associated with **night sweats, weight loss, and fever**, which are not mentioned here. - While TB can rarely cause arthritis (Pott's disease of the spine), widespread **hilar lymphadenopathy**, elevated ACE, and cutaneous nodules are not typical features. *Adenocarcinoma of the lung* - **Adenocarcinoma of the lung** is a malignant condition that can cause cough, dyspnea, and lung nodules, but it typically does not present with **bilateral hilar lymphadenopathy**, arthritis, or the characteristic systemic elevations of ACE and calcium. - The patient's clinical picture is more suggestive of a systemic inflammatory process rather than a primary lung malignancy. *Hodgkin's lymphoma* - **Hodgkin's lymphoma** can cause **lymphadenopathy** (including hilar), cough, and dyspnea, but it is a **hematological malignancy** characterized by Reed-Sternberg cells. - It does not typically cause diffuse pulmonary granulomas, arthritis, elevated ACE, or hypercalcemia in the manner described.

Question 242: A physician is describing a case to his residents where a kidney transplant was rapidly rejected by the recipient minutes after graft perfusion. The physician most likely describes all of the following manifestations EXCEPT?

A. Graft cyanosis
B. Histological evidence of vascular damage
C. Graft mottling
D. Histological evidence of arteriosclerosis (Correct Answer)
E. Low urine output with evidence of blood

Explanation: ***Histological evidence of arteriosclerosis*** - **Arteriosclerosis** is a chronic process involving hardening and narrowing of arteries due to plaque buildup, developing over years, and is not an acute manifestation of hyperacute rejection. - Hyperacute rejection occurs minutes to hours after transplant due to pre-existing **antibodies** in the recipient targeting donor antigens, leading to immediate graft dysfunction due to **vascular damage**. *Graft cyanosis* - **Graft cyanosis** reflects poor blood flow and oxygenation to the transplanted organ, a direct consequence of the vascular occlusion and **ischemia** characteristic of hyperacute rejection. - The rapid immune response in hyperacute rejection leads to immediate **thrombosis** within the graft's vessels, impairing perfusion and causing cyanosis. *Histological evidence of vascular damage* - **Vascular damage**, including thrombosis and **endothelial injury**, is the hallmark of hyperacute rejection, caused by antibody-mediated complement activation and inflammation. - This damage is directly observed upon histological examination and is the underlying cause for the immediate graft failure. *Graft mottling* - **Graft mottling** describes a patchy, discolored appearance of the organ, indicating uneven and compromised blood flow within the graft. - It is a macroscopic sign of the severe microvascular obstruction and **ischemia** resulting from the rapid immunological attack. *Low urine output with evidence of blood* - **Low urine output** (oliguria or anuria) is a critical sign of acute kidney injury, which occurs rapidly when the transplanted kidney's perfusion is severely compromised. - The presence of **blood in the urine** (hematuria) would indicate severe vascular damage within the kidney, as cellular components and frank blood leak from damaged vessels.

Question 243: A 15-year-old Caucasian male is brought to his pediatrician by his parents, who note the development of a tremor in their child. Urine and serum analysis reveal elevated levels of copper. Which of the following clinical manifestations would the physician most expect to see in this patient?

A. Kaiser-Fleischer rings (Correct Answer)
B. Diabetes mellitus
C. Hepatocytes that stain with Prussian blue
D. Panacinar emphysema
E. Increased serum ceruloplasmin

Explanation: ***Kaiser-Fleischer rings*** - Elevated copper levels, tremor, and young age are classic signs of **Wilson's disease**, an autosomal recessive disorder leading to copper accumulation. - **Kaiser-Fleischer rings** are greenish-brown deposits of copper in the cornea, a hallmark ocular manifestation of Wilson's disease. *Diabetes mellitus* - While copper dysregulation can affect various organs, **diabetes mellitus** is not a typical clinical manifestation of Wilson's disease. - Pancreatic involvement leading to diabetes is more commonly associated with conditions like **hemochromatosis** (iron overload) or chronic pancreatitis. *Hepatocytes that stain with Prussian blue* - **Prussian blue stain** is used to detect **iron deposits**, not copper. - In Wilson's disease, copper accumulates in hepatocytes, which would not stain positive with Prussian blue. *Panacinar emphysema* - **Panacinar emphysema** is primarily associated with **alpha-1 antitrypsin deficiency**, a genetic disorder affecting elastic tissue in the lungs. - It has no direct association with copper metabolism or Wilson's disease. *Increased serum ceruloplasmin* - **Ceruloplasmin** is a copper-carrying protein, and in Wilson's disease, the **serum ceruloplasmin level is typically reduced**, not increased. - This reduction is due to impaired copper incorporation into ceruloplasmin by the dysfunctional ATP7B protein.

Question 244: A 19-year-old college student is brought to the emergency department by his roommates after being found unconscious on their dorm room floor. His temperature is 102.0°F (38.9°C) and blood pressure is 85/64 mmHg. On physical examination, he has multiple petechiae on the skin covering his abdomen and lower limbs. Lab tests reveal hyperkalemia and an arterial blood gas test that reads pH: 7.04, pCO2: 30.1 mmHg, pO2: 83.4 mmHg. What is the most likely diagnosis for this patient's condition?

A. Diabetic ketoacidosis
B. Addison disease
C. Dengue hemorrhagic fever
D. Waterhouse-Friderichsen syndrome (Correct Answer)
E. Typhoid fever

Explanation: ***Waterhouse-Friderichsen syndrome*** - The combination of **fever**, **hypotension**, **petechial rash**, and signs of metabolic acidosis (low pH, hyperkalemia) in a young, previously healthy individual is highly suggestive of **meningococcemia** complicated by Waterhouse-Friderichsen syndrome, which involves **bilateral adrenal hemorrhage** and acute adrenal insufficiency. - The **petechiae** (non-blanching purplish spots) are a hallmark of severe **Neisseria meningitidis** infection due to disseminated intravascular coagulation (DIC) and vasculitis. - **Hyperkalemia** and metabolic acidosis result from acute adrenal insufficiency (loss of aldosterone and cortisol). *Diabetic ketoacidosis* - While DKA can cause **metabolic acidosis** and altered mental status, it typically presents with **hyperglycemia**, polyuria, polydipsia, and Kussmaul respirations (deep, rapid breathing). - The characteristic **petechial rash** and severe hypotension with septic shock are not typical of DKA. - DKA does not cause hyperkalemia in the same context (though total body potassium is depleted, serum levels may initially be elevated). *Addison disease* - **Chronic primary adrenal insufficiency** can cause hypotension, hyperkalemia, and acidosis, but it develops gradually over weeks to months with features like **hyperpigmentation**, fatigue, and weight loss. - It does not present with acute fever and petechial rash characteristic of fulminant bacterial sepsis. *Dengue hemorrhagic fever* - Dengue can cause fever, thrombocytopenia, and hemorrhagic manifestations, but the typical rash is **maculopapular** (often described as "islands of white in a sea of red"). - Severe dengue presents with plasma leakage and shock, but **hyperkalemia** and severe metabolic acidosis with adrenal hemorrhage are not characteristic features. - The geographic context (college dormitory, likely in temperate region) makes meningococcemia more likely than dengue. *Typhoid fever* - Typhoid fever can cause fever and characteristic **"rose spots"** (blanching, salmon-colored macules), but these typically appear in the second week of illness on the trunk and are much more subtle than petechiae. - Typhoid presents with **step-ladder fever**, relative bradycardia, and abdominal symptoms (constipation/diarrhea), not acute septic shock with petechial rash. - The acute severity, rapid deterioration, and hemorrhagic adrenal involvement point to meningococcemia, not typhoid.

Question 245: A 28-year-old female suffering from a urinary tract infection is given trimethoprim-sulfamethoxazole (TMP-SMX) by her physician. Several days later, she begins to experience itchiness and joint pain. Laboratory and histologic analysis reveals vasculitis and antibody complexes deposited near the basement membrane of the glomerulus. What other serological finding is expected with this presentation?

A. Decreased levels of IgE
B. Increased serum levels of complement protein C3
C. Increased levels of IgE
D. Decreased neutrophil count
E. Lowered serum levels of complement protein C3 (Correct Answer)

Explanation: ***Lowered serum levels of complement protein C3*** - The presentation of itchiness, joint pain, vasculitis, and **immune complex deposition** in the glomerulus after TMP-SMX administration, points to a **Type III hypersensitivity reaction**. - In Type III hypersensitivity, **immune complexes** activate the complement system, leading to its consumption and thus **decreased serum levels of complement proteins** like C3. *Decreased levels of IgE* - This scenario describes a **Type III hypersensitivity**, which is mediated by immune complexes and complement, not typically IgE. - Decreased IgE levels are not characteristic of drug-induced vasculitis or immune complex glomerulonephritis. *Increased serum levels of complement protein C3* - **Complement activation** by immune complexes leads to its consumption, resulting in **decreased**, not increased, serum levels of complement proteins. - High C3 levels would suggest an active inflammatory process without significant complement consumption, which contradicts the described pathology. *Increased levels of IgE* - **Increased IgE** levels are characteristic of **Type I hypersensitivity** (allergic reactions), which typically present with immediate symptoms like anaphylaxis, urticaria, or asthma, not immune complex deposition. - While TMP-SMX can cause Type I reactions, the described vasculitis and glomerular immune complex deposition point away from this mechanism. *Decreased neutrophil count* - A decreased **neutrophil count (neutropenia)** can be a side effect of TMP-SMX, but it is not directly linked to the immune complex-mediated vasculitis and glomerulonephritis described. - While relevant to drug toxicity, it is not the expected serological finding related to the described immune pathology.

Question 246: An 8-year-old girl is brought to the emergency department because of a 2-day history of an intermittent, diffuse abdominal pain. She has also had a nonpruritic rash on her legs and swelling of her ankles for 1 week. Two weeks ago, she had a sore throat, which was treated with oral amoxicillin. Examination of the lower extremities shows non-blanching, raised erythematous papules. The ankle joints are swollen and warm, and their range of motion is limited by pain. Laboratory studies show a platelet count of 450,000/mm3. Test of the stool for occult blood is positive. Which of the following is the most likely diagnosis?

A. Familial Mediterranean fever
B. Henoch-Schönlein purpura (Correct Answer)
C. Acute rheumatic fever
D. Immune thrombocytopenic purpura
E. Juvenile idiopathic arthritis

Explanation: ***Henoch-Schönlein purpura*** - The constellation of **palpable purpura** on the lower extremities, **arthralgia** (swollen ankles), **abdominal pain**, and **gastrointestinal bleeding** (occult blood in stool) in a child, especially following a recent upper respiratory infection, is highly characteristic of Henoch-Schönlein purpura (now known as **IgA vasculitis**). - The normal to elevated platelet count (450,000/mm3) rules out conditions causing purpura due to thrombocytopenia and supports a primary vasculitic process. *Familial Mediterranean fever* - This is an **autosomal recessive** disorder characterized by recurrent episodes of fever, serositis (peritonitis, pleuritis, pericarditis), and arthritis, but typically **lacks the characteristic vasculitic rash** and gastrointestinal bleeding seen here. - While fever might be present, the specific rash and GI involvement make it less likely. *Acute rheumatic fever* - This condition can present with migratory **polyarthritis**, carditis, chorea, erythema marginatum, and subcutaneous nodules, usually following a **Streptococcal infection**. - However, it does not typically cause **palpable purpura** or significant **gastrointestinal bleeding**. *Immune thrombocytopenic purpura* - Characterized by **isolated thrombocytopenia** leading to petechiae, purpura, and bleeding, typically **without systemic symptoms** like joint swelling or significant abdominal pain unless severe bleeding is present. - The patient's **elevated platelet count** (450,000/mm3) directly contradicts this diagnosis. *Juvenile idiopathic arthritis* - This is a chronic inflammatory arthritis that commonly presents with joint pain and swelling. - However, it typically **does not cause palpable purpura** or **gastrointestinal bleeding**, which are prominent features in this case.

Question 247: A 13-year-old boy is brought to the physician because of swelling around his eyes for the past 2 days. His mother also notes that his urine became gradually darker during this time. Three weeks ago, he was treated for bacterial tonsillitis. His temperature is 37.6°C (99.7°F), pulse is 79/min, and blood pressure is 158/87 mm Hg. Examination shows periorbital swelling. Laboratory studies show: Serum Urea nitrogen 9 mg/dL Creatinine 1.7 mg/dL Urine Protein 2+ RBC 12/hpf RBC casts numerous A renal biopsy would most likely show which of the following findings?

A. Effacement of podocyte foot processes on electron microscopy
B. Granular deposits of IgG, IgM, and C3 on immunofluorescence (Correct Answer)
C. Splitting and alternating thickening and thinning of the glomerular basement membrane on light microscopy
D. Mesangial IgA deposits on immunofluorescence
E. "Spike-and-dome" appearance of subepithelial deposits on electron microscopy

Explanation: ***Granular deposits of IgG, IgM, and C3 on immunofluorescence*** - This finding is characteristic of **post-streptococcal glomerulonephritis (PSGN)**, supported by the history of recent tonsillitis, periorbital swelling, dark urine, hypertension, and features of nephritic syndrome (RBC casts, proteinuria). - The granular deposition pattern reflects the immune complex-mediated nature of PSGN, where **antigen-antibody complexes** deposit in the glomeruli. *Effacement of podocyte foot processes on electron microscopy* - This is the hallmark finding in **minimal change disease**, which typically presents with abrupt onset of nephrotic syndrome (severe proteinuria, hypoalbuminemia, edema) without hematuria or hypertension. - The patient's presentation with **dark urine** (hematuria), hypertension, and RBC casts is inconsistent with minimal change disease. *Splitting and alternating thickening and thinning of the glomerular basement membrane on light microscopy* - This describes the characteristic changes seen in **Alport syndrome**, an inherited disorder affecting collagen IV. - Alport syndrome presents with **hematuria**, progressive renal failure, and often includes hearing loss and ocular abnormalities, which are not mentioned in this acute presentation. *Mesangial IgA deposits on immunofluorescence* - This is the diagnostic feature of **IgA nephropathy (Berger's disease)**. - IgA nephropathy often presents with **recurrent macroscopic hematuria** occurring concurrent with or shortly after an upper respiratory infection, rather than 2-3 weeks later like PSGN. *"Spike-and-dome" appearance of subepithelial deposits on electron microscopy* - This appearance is characteristic of **membranous nephropathy**, which is a common cause of **nephrotic syndrome** in adults. - Membranous nephropathy typically presents with significant proteinuria and edema, and it is less common in children with acute nephritic symptoms like those described.

Question 248: A 68-year-old man comes to the physician because of a 2-day history of a rash across his trunk and extremities. For the past 3 months, he has had persistent pruritus in these areas. He started hiking in the woods with his grandson last week to try to lose weight. His grandson, who often spends the weekends with him, recently had impetigo. He has hypertension, hyperlipidemia, and osteoarthritis of his thumbs. Five months ago, he was treated for a gout attack of his left hallux. Current medications include captopril, hydrochlorothiazide, simvastatin, allopurinol, and ibuprofen. Vital signs are within normal limits. There are diffuse vesicles and tense blisters involving the chest, flexures of the arms, and shoulders. Rubbing the skin on his chest does not produce blisters. Oral examination shows no abnormalities. This patient's condition is most likely associated with which of the following findings?

A. Subepidermal separation with full thickness epidermal necrosis on skin biopsy
B. Spongiotic dermatitis on skin biopsy
C. Antibodies to tissue transglutaminase on serologic testing
D. Growth of Gram-positive bacteria on blood culture
E. Linear deposits of IgG and C3 along the basement membrane on direct immunofluorescence studies (Correct Answer)

Explanation: ***Linear deposits of IgG and C3 along the basement membrane on direct immunofluorescence studies*** - The patient's presentation of **tense blisters** on the trunk and extremities, along with **pruritus**, in an older individual, is highly suggestive of **bullous pemphigoid**. - **Direct immunofluorescence** showing **linear deposits of IgG and C3** along the **dermal-epidermal junction** (basement membrane zone) is the hallmark diagnostic finding for bullous pemphigoid. *Subepidermal separation with full thickness epidermal necrosis on skin biopsy* - This finding, particularly with **epidermal necrosis**, is characteristic of conditions like **toxic epidermal necrolysis (TEN)** or severe **drug reactions**, which typically present with widespread epidermal detachment and often systemic symptoms, unlike this patient's localized tense blisters. - While subepidermal separation occurs in bullous pemphigoid, **full-thickness epidermal necrosis** is not a typical feature and would indicate a different, more severe pathology. *Spongiotic dermatitis on skin biopsy* - **Spongiotic dermatitis** (eczema) is characterized by **intercellular edema** (spongiosis) in the epidermis and typically presents with erythematous, scaly, and pruritic patches or plaques, sometimes with vesicles, but usually not large, tense bullae. - This finding is more consistent with conditions like **allergic contact dermatitis** or **atopic dermatitis**, which differ significantly from the described blister morphology. *Antibodies to tissue transglutaminase on serologic testing* - **Antibodies to tissue transglutaminase (tTG)** are **serological markers for celiac disease**, an autoimmune condition affecting the small intestine. - While celiac disease can be associated with **dermatitis herpetiformis** (which presents with pruritic papules and vesicles, often on elbows and knees, and granular IgA deposits), it does not cause the large, tense bullae of bullous pemphigoid, and the serologic findings are distinct. *Growth of Gram-positive bacteria on blood culture* - A positive blood culture for **Gram-positive bacteria** would indicate **bacteremia** or **sepsis**, which is typically associated with systemic signs of infection (fever, chills, hemodynamic instability) and can sometimes manifest with secondary skin lesions. - The patient's current presentation is of a primary blistering skin condition with normal vital signs, making a primary bacterial infection the cause of the rash less likely.

Question 249: A 6-year-old male presents to the emergency department after falling from his scooter. The patient reports that he fell sideways off the scooter as he rounded a curve in the road, and he describes dull, aching pain along his left side where he hit the ground. The patient’s parents report that he has never had any serious injury but that he has always seemed to bruise easily, especially after he started playing youth soccer this fall. His parents deny that he has ever had nosebleeds or bleeding from the gums, and they have never seen blood in his stool or urine. His mother notes that her brother has had similar problems. On physical exam, the patient has extensive bruising of the lateral left thigh and tenderness to palpation. Laboratory tests are performed and reveal the following: Hemoglobin: 14 g/dL Hematocrit: 41% Mean corpuscular volume: 89 µm3 Reticulocyte count: 0.8% Leukocyte count: 4,700/mm3 Prothrombin time (PT): 13 seconds Partial thromboplastin time (PTT): 56 seconds Bleeding time (BT): 4 minutes Which of the following is the most likely underlying pathophysiology of this patient's presentation?

A. Factor VIII deficiency (Correct Answer)
B. Anti-platelet antibodies
C. Factor IX deficiency
D. Factor VIII antigen deficiency
E. GP1b deficiency

Explanation: ***Factor VIII deficiency*** - The patient's presentation with **easy bruising** and a **prolonged PTT** coupled with a normal PT, bleeding time, and platelet count strongly points to a **coagulation factor deficiency** in the intrinsic pathway. - The **X-linked recessive inheritance** pattern (mother's brother had similar problems) in a male child is classic for **Hemophilia A**, which is caused by a deficiency in Factor VIII. - Hemophilia A is the **most common hereditary coagulation disorder**, accounting for approximately 80% of hemophilia cases, making it the most likely diagnosis in the absence of specific factor assays. *Anti-platelet antibodies* - Anti-platelet antibodies typically cause **immune thrombocytopenia (ITP)**, leading to a **low platelet count** and a **prolonged bleeding time**. - This patient has a normal platelet count and bleeding time, making ITP unlikely. *Factor IX deficiency* - **Factor IX deficiency (Hemophilia B)** also presents with a prolonged PTT and has an X-linked recessive inheritance pattern similar to Hemophilia A. - Hemophilia A and B are **clinically indistinguishable** without specific factor assays. However, Hemophilia A is approximately **4 times more common** than Hemophilia B, making Factor VIII deficiency the more likely diagnosis based on epidemiology. *Factor VIII antigen deficiency* - A deficiency in **Factor VIII antigen** is typically associated with **von Willebrand disease (vWD)**, which often presents with mucocutaneous bleeding (nosebleeds, gum bleeding). - vWD would also typically feature a **prolonged bleeding time** due to impaired platelet adhesion, which is **not seen in this patient** (BT = 4 minutes, which is normal). *GP1b deficiency* - **GP1b deficiency** is characteristic of **Bernard-Soulier syndrome**, a qualitative platelet disorder. - This would result in **thrombocytopenia** (low platelet count) and a **prolonged bleeding time**, neither of which are present in this patient.

Question 250: A 58-year-old man comes to the physician because of a 3-month history of diffuse muscle pain, malaise, pain in both knees, recurrent episodes of abdominal and chest pain. He has also had a 5-kg (11-lb) weight loss over the past 4 months. Four years ago, he was diagnosed with chronic hepatitis B infection and was started on tenofovir. There are several ulcerations around the ankle and calves bilaterally. Perinuclear anti-neutrophil cytoplasmic antibodies are negative. Urinalysis shows proteinuria and hematuria. Muscle biopsy shows a transmural inflammation of the arterial wall with leukocytic infiltration and fibrinoid necrosis. Which of the following is the most likely diagnosis?

A. Granulomatosis with polyangiitis
B. Thromboangiitis obliterans
C. Polyarteritis nodosa (Correct Answer)
D. Giant cell arteritis
E. Microscopic polyangiitis

Explanation: ***Polyarteritis nodosa*** - The constellation of **diffuse muscle pain**, **constitutional symptoms** (malaise, weight loss), **arthralgia** (knee pain), **abdominal and chest pain**, **cutaneous ulcerations**, and **renal involvement** (proteinuria, hematuria) are classic features of **polyarteritis nodosa (PAN)**. The **transmural inflammation of the arterial wall with leukocytic infiltration and fibrinoid necrosis** on muscle biopsy confirms the diagnosis. - A significant association exists between **Hepatitis B infection** and **PAN**, making this diagnosis highly likely in a patient with chronic Hepatitis B. *Granulomatosis with polyangiitis* - Characterized by **granulomatous inflammation** of the respiratory tract, **glomerulonephritis**, and **small vessel vasculitis**. This patient's biopsy shows transmural inflammation of medium-sized arteries, not granulomas. - It classically presents with **positive c-ANCA** (cytoplasmic anti-neutrophil cytoplasmic antibodies), whereas this patient's p-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies) are negative, and c-ANCA was not mentioned. *Thromboangiitis obliterans* - Primarily affects **small and medium-sized arteries and veins** of the extremities, leading to **ischemia** and sometimes gangrene, especially in **smokers**. While ulcerations are present, the systemic involvement (abdominal pain, chest pain, renal disease) and the biopsy findings are not typical for this condition. - The pathology of thromboangiitis obliterans involves an **inflammatory thrombus** occluding the vessel, rather than the transmural inflammation and fibrinoid necrosis seen in PAN. *Giant cell arteritis* - Typically affects **large and medium-sized arteries**, predominantly in individuals over 50 (which fits the patient's age). However, it classically presents with **headache**, **jaw claudication**, and risk of **vision loss** due to temporal artery involvement. - Biopsy would show **skip lesions** with **granulomatous inflammation** and **multinucleated giant cells**, which are not described in the patient's muscle biopsy. *Microscopic polyangiitis* - A **small vessel vasculitis** characterized by **necrotizing glomerulonephritis** and **pulmonary capillaritis**. It is often associated with **p-ANCA** positivity. - The biopsy demonstrating **transmural inflammation of a medium-sized artery** is inconsistent with microscopic polyangiitis, which typically affects smaller vessels and rarely shows fibrinoid necrosis.

Question 251: An 8-year-old boy is brought by his mother to his pediatrician because his urine is tea-colored and his face has appeared puffy for the past 2 days. He suffered a fever and sore throat several weeks ago that was treated with ibuprofen. The boy was born at 39 weeks gestation via spontaneous vaginal delivery. He is up to date on all vaccines and is meeting all developmental milestones. Today, his heart rate is 100/min, the respiratory rate is 22/min, the blood pressure is 130/80 mm Hg, and the temperature is 36.8°C (98.2°F). On physical exam the boy has mild periorbital swelling. A urine dipstick reveals 1+ proteinuria and urinalysis reveals 10–15 red cells/high power field and dysmorphic red cells. The pediatrician is concerned with the child’s hypertension, facial edema, and abnormal urine analysis results. Which of the following best represents the mechanism of this patient’s condition?

A. Complement-independent reaction
B. Diffuse mesangial IgA deposition
C. Immune complex deposition (Correct Answer)
D. Podocyte injury
E. Complement-dependent antibody reaction

Explanation: ***Immune complex deposition*** - The patient's history of a recent **streptococcal infection** (sore throat), followed by **tea-colored urine**, **facial puffiness**, hypertension, and hematuria with dysmorphic red cells, is highly suggestive of **post-streptococcal glomerulonephritis (PSGN)**. - PSGN is characterized by the deposition of **immune complexes** (containing bacterial antigens, antibodies, and complement) in the glomerular basement membrane and mesangium, leading to inflammation and injury. *Complement-independent reaction* - This option is incorrect because PSGN is a **type III hypersensitivity reaction** heavily involving the **complement system**. - Activation of complement by immune complexes plays a crucial role in mediating glomerular injury in PSGN. *Diffuse mesangial IgA deposition* - This is characteristic of **IgA nephropathy** (Berger's disease), which typically presents with **recurrent gross hematuria** often coincident with or immediately following an upper respiratory infection. - While both can present with hematuria, the lag period and diffuse immune complex deposition pattern in PSGN differentiate it from IgA nephropathy. *Podocyte injury* - Podocyte injury is characteristic of **minimal change disease** or **focal segmental glomerulosclerosis**, which typically present with **nephrotic syndrome** (heavy proteinuria, hypoalbuminemia, severe edema). - This patient presents with features of **nephritic syndrome** (hematuria, mild proteinuria, hypertension, edema). *Complement-dependent antibody reaction* - While PSGN involves complement, the primary mechanism is **immune complex deposition**, not direct complement-dependent antibody-mediated cytotoxicity against glomerular components (which would be more akin to anti-GBM disease if antibodies directly target the basement membrane). - In PSGN, the immune complexes themselves activate complement, leading to inflammation.

Question 252: A 39-year-old man presents to his primary care physician with new onset lower extremity edema, fatigue, and hematuria. His symptoms began approximately 2 weeks prior to presentation and have progressively worsened. Medical history is significant for opioid-use disorder with heroin treated with methadone. He is in a monogamous relationship with a female partner of 4 years and does not use condoms. He denies cigarette smoking, alcohol use, and last used heroin approximately 1 month ago. His temperature is 99°F (37.2°C), blood pressure is 152/98 mmHg, pulse is 83/min, and respirations are 17/min. On physical exam, there is conjunctival pallor, scleral icterus, a 14 cm liver span, acrocyanosis, and lower extremity 2+ pitting edema. Urinalysis demonstrates proteinuria and dysmorphic red blood cells. Laboratory testing reveals a mildly decreased C3 and decreased C4 serum concentration. Which of the following will most likely be present on renal biopsy in this patient?

A. Normal appearing glomerulus
B. Apple-green birefringence on Congo red stain
C. Glomerular basement membrane thinning and splitting
D. Enlarged and hypercellular glomeruli
E. Diffuse mesangial cell proliferation with capillary wall thickening (Correct Answer)

Explanation: ***Diffuse mesangial cell proliferation with capillary wall thickening*** - This patient's **IV drug use history**, **hepatomegaly with scleral icterus**, combined with **nephritic-nephrotic syndrome** (edema, hematuria, proteinuria, hypertension) and **low C3 AND C4** strongly suggests **Hepatitis C-associated Membranoproliferative Glomerulonephritis (MPGN Type I)**. - The key diagnostic clue is **both C3 and C4 are decreased**, indicating **classical complement pathway activation** (unlike post-infectious GN which shows low C3 with normal C4). This pattern is characteristic of **cryoglobulinemia** associated with Hepatitis C infection. - **MPGN Type I** shows characteristic **mesangial cell proliferation** and **capillary wall thickening** (double contour/"tram-track" appearance on silver stain) due to **subendothelial immune complex deposition** and mesangial interposition. - IV drug users have high rates of **Hepatitis C infection**, which can cause type II cryoglobulinemia leading to MPGN with this exact complement pattern and histologic appearance. *Normal appearing glomerulus* - Completely inconsistent with this patient's significant **nephritic-nephrotic syndrome** (proteinuria, hematuria with dysmorphic RBCs, edema, hypertension). - Would not explain the **complement consumption** or progressive renal dysfunction. *Apple-green birefringence on Congo red stain* - This finding is pathognomonic for **amyloidosis**, which can cause nephrotic syndrome in IV drug users ("skin-popping" amyloidosis from subcutaneous injection). - However, amyloidosis typically presents with **nephrotic syndrome alone** (not nephritic features like hematuria with dysmorphic RBCs), does **not cause complement consumption**, and shows apple-green birefringence rather than proliferative changes. *Glomerular basement membrane thinning and splitting* - **GBM thinning** is seen in **thin basement membrane disease** (benign familial hematuria), while **GBM splitting** is seen in **Alport syndrome**. - These are **hereditary conditions** presenting earlier in life, typically without acute nephrotic syndrome, hypertension, or complement abnormalities. - The acute presentation with complement consumption argues against these diagnoses. *Enlarged and hypercellular glomeruli* - While this describes **endocapillary proliferative glomerulonephritis** (like post-streptococcal GN), it lacks the specific feature of **capillary wall thickening** that is crucial for MPGN. - Post-streptococcal GN would show **low C3 with normal C4** (alternative pathway), not the low C3 and C4 pattern seen here. - The chronic liver disease signs (hepatomegaly, icterus) point to Hepatitis C-associated disease rather than post-infectious GN.

Question 253: A 73-year-old man dies 4 months after being diagnosed with advanced adenocarcinoma of the colon. Examination of the heart at autopsy shows vegetations lining the mitral valve margins. The vegetations are loosely attached and can be easily scraped off. Microscopic examination shows the vegetations to be composed of interwoven fibrin strands with mononuclear cells. The mitral valve endothelium is intact. Which of the following is the most likely underlying cause of these autopsy findings?

A. Bacterial colonization
B. Metastatic infiltration
C. Procoagulant release (Correct Answer)
D. Antibody cross-reactivity
E. Dystrophic calcifications

Explanation: ***Procoagulant release*** - The patient has **adenocarcinoma of the colon**, a malignancy known to be associated with **nonbacterial thrombotic endocarditis (NBTE)**, also known as marantic endocarditis. - Tumors, particularly adenocarcinomas, can release **procoagulant factors** (e.g., mucin, thromboplastin) that activate the coagulation cascade, leading to the formation of **fibrin and platelet vegetations** on otherwise normal heart valves. *Bacterial colonization* - **Bacterial endocarditis** typically involves microbial colonization of the vegetations and often causes more destructive lesions, microabscesses, or ulceration of the valve leaflets. - The description of **interwoven fibrin strands with mononuclear cells** and an **intact endothelium** without bacterial organisms suggests a sterile process rather than infection. *Metastatic infiltration* - While the patient has cancer, **metastatic infiltration** of the heart valves by tumor cells is rare and usually presents as discreet tumor deposits, not as large, easily scraped-off vegetations composed primarily of fibrin and inflammatory cells. - There is no mention of tumor cells within the vegetations. *Antibody cross-reactivity* - **Rheumatic heart disease** involves sterile vegetations (verrucae) due to **antibody cross-reactivity** following Group A streptococcal infection, but these are typically small, firm, and occur on inflamed valve leaflets often years after the inciting event. - The patient's presentation with a recent cancer diagnosis and the nature of the vegetations do not fit the typical picture of rheumatic heart disease. *Dystrophic calcifications* - **Dystrophic calcification** is a hallmark of **aging or damaged heart valves** (e.g., calcific aortic stenosis) and involves the deposition of calcium in necrotic or degenerated tissue. - The described vegetations are composed of **fibrin and mononuclear cells**, not calcified material, and are easily scraped off, which is not characteristic of dystrophic calcification.

Question 254: A 36-year-old woman comes to the physician for evaluation of unintentional weight gain of 5.5 kg (12.2 lb) and irregular menstrual cycles over the past 2 months. She does not take any medications. Her blood pressure is 155/85 mm Hg. Physical examination shows central obesity, hyperpigmentation of the palmar creases, and violaceous scarring of the abdomen. Early morning serum cortisol levels are elevated and serum adrenocorticotropic hormone (ACTH) is within the reference range after a low-dose dexamethasone suppression test. A high-dose dexamethasone suppression test shows suppression of ACTH. Further evaluation is most likely to show which of the following findings?

A. Atrophy of the pituitary gland
B. Nodular hypertrophy of the zona reticularis
C. Unilateral carcinoma of the adrenal cortex
D. Benign adenoma of the adrenal medulla
E. Bilateral hyperplasia of the zona fasciculata (Correct Answer)

Explanation: ***Bilateral hyperplasia of the zona fasciculata*** - The clinical presentation (weight gain, irregular menses, hypertension, central obesity, hyperpigmentation, violaceous striae) is classic for **Cushing's syndrome**. - **Elevated early morning cortisol** with **ACTH within reference range** after low-dose dexamethasone (failure to suppress) confirms Cushing's syndrome. - **Suppression of ACTH with high-dose dexamethasone** indicates **pituitary Cushing's disease** (ACTH-dependent), where a pituitary adenoma secretes excess ACTH. - Chronic ACTH stimulation leads to **bilateral adrenal hyperplasia**, specifically of the zona fasciculata (which produces cortisol). *Atrophy of the pituitary gland* - Pituitary atrophy would cause **decreased ACTH production**, resulting in secondary adrenal insufficiency with low cortisol and low ACTH. - This contradicts the patient's presentation of hypercortisolism. *Nodular hypertrophy of the zona reticularis* - The **zona reticularis** primarily produces androgens (DHEA, androstenedione), not cortisol. - While it may be affected in Cushing's, the hypercortisolism and clinical features point to excess glucocorticoid production from the **zona fasciculata**, not isolated zona reticularis pathology. *Unilateral carcinoma of the adrenal cortex* - Adrenal carcinoma causes **ACTH-independent Cushing's syndrome** with **suppressed ACTH levels** (due to negative feedback from autonomous cortisol production). - Primary adrenal tumors (adenomas or carcinomas) do **not suppress with high-dose dexamethasone**, which rules out this diagnosis. *Benign adenoma of the adrenal medulla* - An adrenal medullary adenoma is a **pheochromocytoma**, which secretes catecholamines (epinephrine, norepinephrine). - This presents with **paroxysmal hypertension**, headaches, palpitations, and diaphoresis—distinct from the hypercortisolism features described here.

Question 255: A 3-year-old African-American boy presents with a rapid onset of severe abdominal pain. He has a palpably enlarged mass in the left upper quadrant of his abdomen. Complete blood count is notable for a hemoglobin of 7.2 g/dL. Serum haptoglobin level returns normal. Serum unconjugated bilirubin is elevated. The corrected reticulocyte count is elevated. Which of the following is the most likely explanation for the findings above?

A. Intravascular hemolysis
B. Renal infarction
C. Aplastic crisis
D. Extravascular hemolysis (Correct Answer)
E. Acute chest syndrome

Explanation: ***Extravascular hemolysis*** - The combination of **elevated unconjugated bilirubin** and a normal **haptoglobin** level points towards extravascular hemolysis. The spleen, which would be involved in extravascular hemolysis, is enlarged (palpable mass in the LUQ representing splenomegaly). - The patient's presentation with severe abdominal pain, anemia (Hb 7.2 g/dL), elevated reticulocyte count, and especially in an **African-American child**, suggests a **hemolytic crisis** in the context of **sickle cell disease**, where extravascular hemolysis is common, and an acutely enlarging spleen can signal **splenic sequestration crisis**. *Intravascular hemolysis* - In **intravascular hemolysis**, **haptoglobin** would be significantly decreased or undetectable, as it binds to free hemoglobin released into circulation. - While it presents with anemia and elevated unconjugated bilirubin, the normal haptoglobin level makes it less likely than extravascular hemolysis. *Renal infarction* - This typically presents with **flank pain** and may show hematuria or proteinuria, but it does not explain the **anemia**, **elevated reticulocyte count**, or **jaundice** (elevated unconjugated bilirubin). - A palpable mass in the left upper quadrant is more consistent with **splenomegaly** than a renal infarction. *Aplastic crisis* - An **aplastic crisis** would be characterized by a **low reticulocyte count**, indicating bone marrow failure and reduced red blood cell production. - The patient's **elevated reticulocyte count** directly contradicts an aplastic crisis. *Acute chest syndrome* - This condition is characterized by **fever**, **chest pain**, and **pulmonary infiltrates** on chest X-ray. - While common in **sickle cell disease**, it does not explain the prominent **abdominal mass** or the specific laboratory findings of **hemolysis** (elevated unconjugated bilirubin, normal haptoglobin, elevated reticulocytes).

Question 256: A 62-year-old woman is seen in the hospital for neutropenic fever. She was admitted 1 week ago for newly diagnosed acute myeloid leukemia. Due to her chemotherapy, she became pancytopenic. Last night, during a packed red blood cell transfusion, she became febrile to 102.6°F (39.3°C), her blood pressure was 92/55, pulse was 112/min, respirations were 16/min, and oxygen saturation was 94% on room air. The transfusion was stopped, intravenous fluids were started, and blood cultures were drawn. The patient also complained of chest pain and shortness of breath. A chest radiograph was obtained and was normal. This morning, she reports "dark urine" but denies dysuria or abnormal vaginal discharge. Her prophylactic antimicrobials started at the time of her chemotherapy include acyclovir, levofloxacin, and fluconazole. The patient's temperature this morning is 98.7°F (37.1°C), blood pressure is 110/72 mmHg, pulse is 88/min, and respirations are 17/min with an oxygen saturation of 95% on room air. On physical examination, she has 1+ pitting peripheral edema of bilateral lower extremities to the mid-shin. Her jugular venous pressure is 6 cm. Her labs show neutropenia, normocytic anemia, thrombocytopenia, elevated lactate dehydrogenase, elevated total bilirubin, and decreased haptoglobin. Coagulation studies show an increase in bleeding time with normal D-dimer levels. Which of the following is the most likely cause of the patient's symptoms?

A. ABO incompatibility (Correct Answer)
B. Disseminated intravascular coagulation
C. Transfusion related acute lung injury
D. Severe urosepsis
E. Transfusion associated circulatory overload

Explanation: **ABO incompatibility** - The patient's symptoms, including **fever**, **hypotension**, **chest pain**, **shortness of breath**, and subsequent **dark urine** with elevations in **lactate dehydrogenase** and **bilirubin** and decreased haptoglobin, are classic signs of an **acute hemolytic transfusion reaction** due to ABO incompatibility. - This type of reaction involves immediate destruction of transfused red blood cells, leading to **hemoglobinuria** ("dark urine") and systemic inflammation. *Disseminated intravascular coagulation* - Although DIC can cause **thrombocytopenia** and **hemolysis**, it typically presents with significantly **elevated D-dimer levels** and prolonged prothrombin time/activated partial thromboplastin time, which are not seen here. - The primary event in this case points to red blood cell destruction rather than a widespread procoagulant activation. *Transfusion related acute lung injury* - TRALI is characterized by **acute respiratory distress** and **hypoxemia** occurring during or within 6 hours of transfusion, often with bilateral pulmonary infiltrates on chest X-ray. - The patient's **normal chest radiograph** makes TRALI less likely. *Severe urosepsis* - While severe sepsis can cause **fever** and **hypotension**, the rapid onset of symptoms immediately following a transfusion, combined with **hemolytic markers** like dark urine and elevated LDH, points away from sepsis as the primary cause of these acute symptoms. - Her prophylactic antibiotics make urosepsis less likely, although not impossible. *Transfusion associated circulatory overload* - TACO is characterized by signs of **volume overload**, such as **dyspnea**, **hypertension**, **jugular venous distension**, and **pulmonary edema**. - While the patient has **peripheral edema** and slightly elevated JVP, her **hypotension** and the presence of significant **hemolytic markers** are not typical for TACO.

Question 257: A 70-year-old woman comes to the physician because of a 4-month history of fatigue, worsening swelling of her ankles, and a 5-kg (11-lb) weight gain. Neurologic examination shows diminished two-point discrimination in her fingers. Laboratory studies show a hemoglobin A1c concentration of 9.2% and a creatinine concentration of 1.3 mg/dL. Urine dipstick shows heavy proteinuria. A biopsy specimen of this patient's kidney is most likely to show which of the following?

A. Nodular glomerulosclerosis (Correct Answer)
B. Interstitial inflammation
C. Immune complex deposition
D. Split glomerular basement membrane
E. Wire looping of capillaries

Explanation: ***Nodular glomerulosclerosis*** - The patient's history of **fatigue**, **edema**, **weight gain**, **elevated HbA1c (9.2%)**, and **neuropathic symptoms** (diminished two-point discrimination) strongly point towards **long-standing diabetes mellitus with associated end-organ damage**. - **Nodular glomerulosclerosis**, specifically **Kimmelstiel-Wilson lesions**, is the **pathognomonic histological finding in diabetic nephropathy**, characterized by **mesangial expansion and nodule formation**. *Interstitial inflammation* - This finding is more characteristic of **acute interstitial nephritis**, often drug-induced, or **chronic pyelonephritis**, which doesn't align with the patient's presentation of **heavy proteinuria** and **diabetic complications**. - While some inflammation can occur in diabetic kidney disease, it's not the primary or most characteristic finding compared to glomerular changes. *Immune complex deposition* - This is typical of various **glomerulonephritides** such as **post-streptococcal glomerulonephritis** or **lupus nephritis**, where **immune complexes** lead to glomerular injury. - The clinical picture provided, particularly the **high HbA1c** and **neuropathy**, is not suggestive of an **immune complex-mediated glomerulonephritis**. *Split glomerular basement membrane* - **Splitting of the glomerular basement membrane (GBM)** is a characteristic feature of **Alport syndrome** or **membranoproliferative glomerulonephritis (MPGN)**. - The patient's history and laboratory findings do not suggest either of these conditions. *Wire looping of capillaries* - **Wire looping of glomerular capillaries** is a classic finding in **diffuse proliferative glomerulonephritis**, often associated with **lupus nephritis**. - This finding is not associated with **diabetic nephropathy**, which is the most likely diagnosis given the patient's presentation.

Question 258: A 21-year-old woman comes to the physician because of a 1-week history of shortness of breath and dry cough. Eight weeks ago, she received a lung transplant from an unrelated donor. Current medications include prednisone, cyclosporine, and azathioprine. Her temperature is 37.8°C (100.1°F). Physical examination is unremarkable other than a well-healed surgical scar. Pulmonary function tests show a decline in FEV1 and FVC compared to values from several weeks ago. Histological examination of a lung biopsy specimen shows perivascular and interstitial lymphocytic infiltrates with bronchiolar inflammation. This patient's condition is most likely caused by T cell sensitization against which of the following?

A. Donor MHC class II antigen (Correct Answer)
B. Recipient MHC class I antigen
C. Streptococcal C polysaccharide antigen
D. CMV glycoprotein B antigen
E. Donor ABO antigen

Explanation: ***Donor MHC class II antigen*** - The patient's symptoms (shortness of breath, dry cough, decline in FEV1/FVC) and a lung biopsy showing **perivascular and interstitial lymphocytic infiltrates with bronchiolar inflammation** 8 weeks after transplantation are consistent with **acute cellular rejection**. - **Acute cellular rejection** in a lung transplant is primarily mediated by **recipient T cells** recognizing **donor MHC class II antigens** presented by donor antigen-presenting cells (direct allorecognition) or recipient APCs (indirect allorecognition). *Recipient MHC class I antigen* - **Recipient MHC class I antigens** would be expressed on the recipient's own cells, which are not the target of rejection in this donor organ. - T cell sensitization against recipient MHC class I would indicate an **autoimmune process**, which is not typical for transplant rejection. *Streptococcal C polysaccharide antigen* - This antigen is associated with **Streptococcus pyogenes** infections and diseases like **rheumatic fever** or **post-streptococcal glomerulonephritis**. - It is unrelated to acute lung transplant rejection. *CMV glycoprotein B antigen* - **Cytomegalovirus (CMV) infection** is a common complication after transplant, but the biopsy findings of perivascular and interstitial lymphocytic infiltrates with bronchiolar inflammation are more typical of **cellular rejection**. - CMV infection often presents with viral cytopathic effects on histology and serological evidence (e.g., rising PCR viral load), which are not mentioned. *Donor ABO antigen* - Mismatching in **ABO antigens** would typically lead to **hyperacute rejection**, which occurs within minutes to hours after transplantation. - The presentation 8 weeks post-transplant rules out hyperacute rejection, and ABO incompatibility would have been identified and avoided during donor-recipient matching.

Question 259: A 68-year-old man with alcohol use disorder is brought to the physician by his sister for frequent falls and an unsteady gait over the past 2 months. He has not seen a physician in 10 years. He appears emaciated and inattentive. He is oriented to person only. Physical examination shows a wide-based gait with slow, short steps. Eye examination shows lateral gaze paralysis and horizontal nystagmus. One month later, he dies. Which of the following is the most likely finding on autopsy?

A. Degeneration of the frontotemporal lobe
B. Atrophy of the caudate and putamen
C. Depigmentation of the substantia nigra
D. Small vessel hemorrhage in mammillary bodies (Correct Answer)
E. Widespread atrophy of cerebral cortex

Explanation: ***Small vessel hemorrhage in mammillary bodies*** - This patient presents with symptoms consistent with **Wernicke encephalopathy** (ataxia, confusion, ophthalmoplegia due to **thiamine deficiency** in alcohol use disorder). - Autopsy findings in Wernicke encephalopathy commonly include **petechial hemorrhages** and necrosis, particularly in the **mammillary bodies** and periventricular gray matter around the third and fourth ventricles. *Degeneration of the frontotemporal lobe* - This is characteristic of **frontotemporal dementia**, which presents with behavioral changes, personality alterations, and language difficulties. - While dementia may be present in chronic alcohol use, the specific neurological signs like **nystagmus** and **gait ataxia** point away from primary frontotemporal degeneration. *Atrophy of the caudate and putamen* - This finding is characteristic of **Huntington disease**, a neurodegenerative genetic disorder. - Huntington disease typically presents with **chorea**, psychiatric symptoms, and dementia, which are not the primary features reported here. *Depigmentation of the substantia nigra* - This is the hallmark pathological finding in **Parkinson disease**, resulting from the loss of dopaminergic neurons. - Parkinson disease typically presents with **bradykinesia**, rigidity, tremor, and postural instability, rather than the acute confusion and ophthalmoplegia seen in this patient. *Widespread atrophy of cerebral cortex* - While chronic alcohol use can lead to **generalized cerebral atrophy**, this finding is non-specific and doesn't explain the acute and localized neurological signs (ataxia, ophthalmoplegia, confusion) that specifically indicate **Wernicke encephalopathy**. - More specific lesions in areas like the **mammillary bodies** better correlate with the distinct clinical presentation.

Question 260: A 57-year-old male with diabetes mellitus type II presents for a routine check-up. His blood glucose levels have been inconsistently controlled with medications and diet since his diagnosis 3 years ago. At this current visit, urinalysis demonstrates albumin levels of 250 mg/day. All prior urinalyses have shown albumin levels below 20 mg/day. At this point in the progression of the patient’s disease, which of the following is the most likely finding seen on kidney biopsy?

A. Glomerular hypertrophy with slight glomerular basement membrane thickening
B. Normal kidney biopsy, no pathological finding is evident at this time
C. Significant global glomerulosclerosis
D. Kimmelstiel-Wilson nodules and tubulointerstitial fibrosis
E. Glomerular basement membrane thickening and mesangial expansion (Correct Answer)

Explanation: ***Glomerular basement membrane thickening and mesangial expansion*** - This patient's **diabetes mellitus type II** and new-onset **microalbuminuria** (albumin levels 30-300 mg/day) are classic features of early to moderate **diabetic nephropathy**. - **Glomerular basement membrane (GBM) thickening** and **mesangial expansion** are the earliest and most common histological changes seen in diabetic nephropathy, preceding the formation of Kimmelstiel-Wilson nodules. *Glomerular hypertrophy with slight glomerular basement membrane thickening* - **Glomerular hypertrophy** is an early compensatory change in response to hyperfiltration, but **microalbuminuria** indicates more significant underlying structural damage beyond simple hypertrophy. - While slight **GBM thickening** can occur, the additional finding of **mesangial expansion** is more characteristic at this stage of albuminuria. *Normal kidney biopsy, no pathological finding is evident at this time* - The presence of **albuminuria (250 mg/day)** confirms there is a pathological process occurring in the kidneys, making a normal biopsy highly unlikely. - Albumin excretion is a direct indicator of **glomerular damage** or altered permeability. *Significant global glomerulosclerosis* - **Significant global glomerulosclerosis** represents a more advanced stage of kidney disease, typically associated with overt proteinuria or macroalbuminuria (>300 mg/day) and declining kidney function. - While it will develop later, it is unlikely to be the primary finding with only **microalbuminuria**. *Kimmelstiel-Wilson nodules and tubulointerstitial fibrosis* - **Kimmelstiel-Wilson nodules** are pathognomonic but typically occur in later stages of diabetic nephropathy, usually with significant **proteinuria** or established kidney failure. - **Tubulointerstitial fibrosis** is also a hallmark of more advanced chronic kidney disease, often accompanying significant glomerular damage, which is beyond this early stage of microalbuminuria.

Question 261: A 44-year-old man presents to his primary care physician for muscle pain and weakness. He says that his muscle pain mainly affects his legs. He also experiences difficulty with chewing gum and has poor finger dexterity. Medical history is significant for infertility and cataracts. On physical exam, the patient's face is long and narrow with a high arched palate and mild frontal balding. There is bilateral ptosis and temporalis muscle and sternocleidomastoid muscle wasting. Creatine kinase level is mildly elevated. Which of the following is most likely to be found on genetic testing?

A. Dystrophin gene non-frameshift mutation
B. Dystrophin gene nonsense mutation
C. DMPK gene CTG expansion (Correct Answer)
D. DYSF gene missense mutation
E. No genetic abnormality

Explanation: ***DMPK gene CTG expansion*** - This patient's presentation with **myotonia** (difficulty chewing, poor finger dexterity, muscle weakness), **facial weakness** (long, narrow face, frontal balding, ptosis, muscle wasting), **cataracts**, and **infertility** is highly characteristic of **myotonic dystrophy type 1** (DM1). - DM1 is caused by an abnormally expanded trinucleotide repeat (CTG) in the **dystrophia myotonica protein kinase (DMPK)** gene. *Dystrophin gene non-frameshift mutation* - Non-frameshift mutations in the **dystrophin gene** are associated with **Becker muscular dystrophy**, which typically presents with **proximal muscle weakness** and does not usually involve the diverse systemic features seen here (cataracts, infertility, myotonia). - While there is muscle pain and weakness, the unique constellation of symptoms points away from Becker muscular dystrophy. *Dystrophin gene nonsense mutation* - **Nonsense mutations** in the dystrophin gene lead to a complete absence of functional dystrophin, causing **Duchenne muscular dystrophy**, a severe, rapidly progressive muscle wasting disease. - Duchenne muscular dystrophy typically presents in early childhood with **significant proximal muscle weakness**, Gowers' sign, and does not commonly manifest with myotonia, cataracts, or infertility as the primary features. *DYSF gene missense mutation* - Missense mutations in the **DYSF gene** are associated with **Dysferlinopathy**, which presents as limb-girdle muscular dystrophy type 2B or Miyoshi myopathy (distal dominant weakness). - While it causes muscle weakness, it does not explain the prominent **myotonia**, **cataracts**, **facial dysmorphism**, or **infertility** observed in this patient. *No genetic abnormality* - Given the classic presentation of **myotonia**, distinctive **facial features**, **cataracts**, **infertility**, and muscle weakness, it is highly improbable that there is no underlying genetic abnormality. - This symptom complex is a well-recognized genetic disorder, making a genetic cause very likely.

Question 262: A 31-year-old woman presents to the emergency department with a 2-week history of dry cough and shortness of breath on exertion. She says that she has also been feeling joint pain that has been increasing over time and is worst in the mornings. Finally, she has noticed painful swellings that have been appearing on her body over the last month. Her past medical history is significant for childhood asthma that does not require any current medications. She drinks socially and has smoked 2 packs per day since she was 16 years old. Physical exam reveals erythematous nodular lesions on her trunk and upper extremities. Serum protein electrophoresis shows polyclonal gammopathy. Which of the following would most likely also be seen in this patient?

A. Noncaseating granulomas (Correct Answer)
B. Macrophages with black phagocytosed particles
C. Golden-brown fusiform rods
D. Antibodies to small nuclear ribonucleoproteins
E. Acid-fast rods

Explanation: ***Noncaseating granulomas*** - The patient's symptoms of **dry cough**, **shortness of breath**, **joint pain**, and **erythematous nodular lesions** (suggestive of **erythema nodosum**) are classic manifestations of **sarcoidosis**. - **Sarcoidosis** is pathologically characterized by the presence of **noncaseating granulomas** in affected organs, most commonly the lungs. - **Polyclonal gammopathy** is commonly seen in sarcoidosis due to chronic immune activation. *Macrophages with black phagocytosed particles* - This finding, often referred to as **"dust cells"** or **carbon-laden macrophages**, is characteristic of conditions like **anthracosis** or **coal worker's pneumoconiosis**. - While the patient is a smoker, the constellation of symptoms including **erythema nodosum**, **arthralgias**, and **polyclonal gammopathy** points toward sarcoidosis rather than isolated pneumoconiosis. *Golden-brown fusiform rods* - These are **asbestos bodies**, which are found in the lungs of patients with **asbestosis**, a form of pneumoconiosis caused by asbestos exposure. - The patient's presentation does not suggest asbestos exposure or asbestosis. *Antibodies to small nuclear ribonucleoproteins* - **Anti-Sm antibodies** and **anti-RNP antibodies** are highly specific for **Systemic Lupus Erythematosus (SLE)**, a systemic autoimmune disease. - While SLE can cause arthralgias and pulmonary symptoms, **erythema nodosum** is not a typical feature of SLE (which more commonly presents with malar rash, discoid lesions, or photosensitivity). The clinical picture is more consistent with sarcoidosis. *Acid-fast rods* - **Acid-fast rods** are characteristic of mycobacterial infections, such as **tuberculosis**. - While tuberculosis can cause pulmonary symptoms and granulomas, these are typically **caseating granulomas** (not noncaseating), and the overall clinical picture with **erythema nodosum** and **polyclonal gammopathy** is more consistent with sarcoidosis than tuberculosis.

Question 263: A 33-year-old woman comes to the physician for the evaluation of bleeding from her gums for 2 weeks. These episodes occur spontaneously and are self-limiting. She has also had purplish skin lesions over her legs for 2 months. Last week, she had one episode of hematuria and watery diarrhea, both of which resolved without treatment. She has mild asthma. Her brother has hemophilia. Her only medication is a fenoterol inhaler. She appears healthy. Her temperature is 37.1°C (99.3°F), pulse is 88/min, respirations are 14/min, and blood pressure is 122/74 mm Hg. Cardiopulmonary examination shows no abnormalities. The abdomen is soft and nontender; there is no organomegaly. Oropharyngeal examination shows gingival bleeding. There are petechiae over the neck and the right upper extremity and purpuric spots over both lower extremities. Laboratory studies show: Hemoglobin 13.3 mg/dL Mean corpuscular volume 94 μm3 Leukocyte count 8,800/mm3 Platelet count 18,000/mm3 Bleeding time 9 minutes Prothrombin time 14 seconds (INR=0.9) Partial thromboplastin time 35 seconds Serum Glucose 88 mg/dL Creatinine 0.9 mg/dL Which of the following is the most likely underlying mechanism of this patient's symptoms?

A. Consumptive coagulopathy
B. IgG antibodies against platelets (Correct Answer)
C. Shiga-like toxin
D. Decrease in ADAMTS13 activity
E. Deficient Von Willebrand factor

Explanation: ***IgG antibodies against platelets*** - The patient's symptoms, including **gingival bleeding**, **purpuric skin lesions**, **hematuria**, and a significantly **low platelet count (18,000/mm3)** with a prolonged **bleeding time (9 minutes)**, are highly indicative of **immune thrombocytopenia (ITP)**. - ITP is characterized by the production of **IgG autoantibodies against platelet surface glycoproteins**, leading to accelerated platelet destruction by the reticuloendothelial system, primarily in the spleen. *Consumptive coagulopathy* - **Disseminated intravascular coagulation (DIC)** is a consumptive coagulopathy that would present with low platelets, but also with prolonged **PT** and **aPTT**, and evidence of microangiopathic hemolytic anemia due to widespread thrombosis and subsequent consumption of clotting factors and platelets. - The patient's **normal PT and aPTT** rule out DIC. *Shiga-like toxin* - **Shiga-like toxin** is associated with **hemolytic uremic syndrome (HUS)**, which typically involves a triad of **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **acute kidney injury** following a diarrheal illness. - While the patient had watery diarrhea and hematuria, her kidney function is normal (creatinine 0.9 mg/dL), and there is no mention of schistocytes or features of hemolytic anemia, making HUS less likely. *Decrease in ADAMTS13 activity* - A decrease in **ADAMTS13 activity** causes **thrombotic thrombocytopenic purpura (TTP)**, which is characterized by a pentad of **fever, neurologic symptoms, renal dysfunction, microangiopathic hemolytic anemia**, and **thrombocytopenia**. - While thrombocytopenia is present, the absence of fever, neurologic symptoms, significant renal dysfunction, and hemolytic anemia makes TTP unlikely. *Deficient Von Willebrand factor* - **Deficient von Willebrand factor (vWF)** causes **Von Willebrand disease**, which presents with mucocutaneous bleeding and a **prolonged bleeding time**. - However, the **platelet count is typically normal** in von Willebrand disease, which contradicts this patient's severely low platelet count.

Question 264: A 48-year-old African American male presents to his primary care provider complaining of facial swelling. He reports a three-day history of worsening swelling primarily around his eyes. The patient’s medical history is notable for sickle cell disease and poorly controlled hypertension. The patient currently takes enalapril, hydrochlorothiazide, and amlodipine but has a history of medication non-adherence. He has a 15 pack-year smoking history. His temperature is 99.1°F (37.3°C), blood pressure is 155/100 mmHg, pulse is 90/min, and respirations are 20/min. Physical examination is notable for periorbital swelling and 1+ bilateral lower extremity edema. Multiple serum and urine labs are ordered. A kidney biopsy in this patient would most likely yield which of the following sets of findings on light and electron microscopy?

A. Wire looping capillaries and subendothelial immune complex deposition
B. Increased mesangial cellularity and mesangial immune complex deposition
C. Hypercellular glomeruli with neutrophils and subepithelial immune complex deposition
D. Segmental sclerosis and negative immunofluorescence and foot process effacement (Correct Answer)
E. Diffusely thickened capillaries and subepithelial immune complex deposition

Explanation: ***Segmental sclerosis and negative immunofluorescence and foot process effacement*** - The patient's presentation with **facial swelling (periorbital edema)**, **lower extremity edema**, and **poorly controlled hypertension** suggests a nephrotic syndrome. Given his **African American ethnicity** and history of poorly controlled hypertension, **focal segmental glomerulosclerosis (FSGS)** is a strong possibility. - **FSGS** typically presents with **segmental sclerosis** on light microscopy, **foot process effacement** on electron microscopy, and **negative immunofluorescence** for immune deposits. *Wire looping capillaries and subendothelial immune complex deposition* - This description is characteristic of **diffuse proliferative glomerulonephritis (DPGN)**, often associated with **lupus nephritis (Class III or IV)**. - While lupus can cause nephrotic syndrome, the patient's history doesn't mention systemic lupus erythematosus, and the specific findings don't align with this diagnosis. *Increased mesangial cellularity and mesangial immune complex deposition* - This is typical of **IgA nephropathy** or early stages of lupus nephritis (Class II). - IgA nephropathy is less common in African Americans as the primary cause of nephrotic syndrome and does not typically present with the same level of edema and hypertension without other systemic symptoms. *Hypercellular glomeruli with neutrophils and subepithelial immune complex deposition* - This description, especially the presence of neutrophils and **subepithelial immune complex deposition**, is characteristic of **post-streptococcal glomerulonephritis (PSGN)**. - PSGN typically follows a streptococcal infection and presents with hematuria and acute renal failure, which are not the primary complaints here. *Diffusely thickened capillaries and subepithelial immune complex deposition* - This is the hallmark of **membranous nephropathy**, another common cause of nephrotic syndrome. - While membranous nephropathy can cause nephrotic syndrome, it typically presents with dense **subepithelial immune deposits** and is less frequently seen with negative immunofluorescence unless it is secondary to another condition not mentioned.

Question 265: A 49-year-old obese woman presents with a chronic non-healing ulcer on the right medial malleolus. Past medical history is significant for type 2 diabetes mellitus, diagnosed 10 years ago, poorly managed with metformin. Review of systems is significant for a recurrent white vaginal discharge. The patient is afebrile, and her vital signs are within normal limits. Her BMI is 31 kg/m2. On physical examination, there is a 2 cm by 2 cm nontender, erythematous shallow ulcer present over the right medial malleolus. Sensation is decreased symmetrically in the lower extremities below the level of the midcalf. Which of the following histopathological findings would most likely be seen in the peripheral nerves in this patient?

A. Reduced axonal fiber diameter and fiber density (Correct Answer)
B. Accumulation of beta-pleated sheets of amyloid protein
C. Wallerian degeneration
D. Lymphocytic infiltration of the endoneurium
E. Acute perivascular inflammation

Explanation: ***Reduced axonal fiber diameter and fiber density*** - This is characteristic of **diabetic neuropathy**, where chronic hyperglycemia leads to damage and degeneration of nerve fibers, particularly **small myelinated and unmyelinated fibers**. - The patient's history of poorly controlled **type 2 diabetes** for 10 years and decreased sensation in the lower extremities strongly suggest this microvascular complication. *Accumulation of beta-pleated sheets of amyloid protein* - This finding is characteristic of **amyloid neuropathy**, a type of peripheral neuropathy caused by the deposition of **amyloid protein** in nerve tissue. - While amyloidosis can cause neuropathy, it is not the primary or most common cause in a patient with a long history of poorly controlled type 2 diabetes. *Wallerian degeneration* - **Wallerian degeneration** is an active process of degeneration that occurs in the distal stump of an axon after it has been transected or crushed. - While parts of diabetic neuropathy can involve axonal damage, Wallerian degeneration specifically refers to acute, complete axonal disruption, rather than the chronic, progressive process seen in diabetes. *Lymphocytic infiltration of the endoneurium* - **Lymphocytic infiltration** of the endoneurium is typically seen in **inflammatory neuropathies** such as **Guillain-Barré syndrome** or **chronic inflammatory demyelinating polyneuropathy (CIDP)**. - The patient's presentation with chronic, progressive sensory loss in the context of diabetes does not suggest an acute or chronic inflammatory polyneuropathy. *Acute perivascular inflammation* - **Acute perivascular inflammation** is a feature of **vasculitic neuropathies**, where inflammation of the blood vessels supplying nerves leads to nerve damage. - While diabetes can have microvascular complications, the primary mechanism of diabetic neuropathy is metabolic and ischemic damage to the nerves themselves, not acute inflammation of the surrounding vessels as the predominant histopathological feature.

Question 266: A 2-year-old boy is brought to the pediatrician for recurrent nosebleeds. The boy was adopted two months ago and the parents have no record of his medical or family history. They report that the child has had frequent prolonged nosebleeds several times per week. Despite them applying pressure on the distal aspect of the nares and keeping his head elevated, the bleeding generally continues for hours. On exam, the boy appears pale and lethargic. A blood sample is obtained but the child bleeds through multiple pieces of gauze. No agglutination is observed when ristocetin is added to the patient’s blood. The addition of normal plasma to the sample still does not lead to agglutination. This patient has a condition that is most consistent with which of the following modes of transmission?

A. X-linked dominant
B. Mitochondrial
C. Autosomal recessive (Correct Answer)
D. Autosomal dominant
E. X-linked recessive

Explanation: ***Autosomal recessive*** - This presentation is classic for **Bernard-Soulier syndrome**, a rare **autosomal recessive** bleeding disorder characterized by a deficiency or defect in the **glycoprotein (GP) Ib/IX/V receptor complex** on platelets. - The lack of ristocetin-induced platelet agglutination despite the addition of normal plasma indicates a **platelet function defect** rather than a deficiency of plasma factors like von Willebrand factor. *X-linked dominant* - X-linked dominant inheritance would typically show affected females and affected males, with male-to-male transmission not occurring, and all daughters of an affected father being affected. - While bleeding disorders can be X-linked, the specific pattern of ristocetin non-agglutination points away from common X-linked dominant bleeding disorders, which are rare. *Mitochondrial* - Mitochondrial inheritance involves genes in the mitochondria and is passed down from the mother to all her children. - Bleeding disorders are not typically associated with mitochondrial inheritance patterns. *Autosomal dominant* - Autosomal dominant disorders typically affect individuals in every generation, with a 50% chance of passing the condition to offspring. - While **von Willebrand disease** is a common autosomal dominant bleeding disorder, the **ristocetin agglutination test result with normal plasma** effectively rules it out by pointing to a platelet receptor defect directly. *X-linked recessive* - **X-linked recessive** disorders like **hemophilia A** or **B** primarily affect males, with carrier females usually asymptomatic. - These conditions are characterized by deficiencies in specific clotting factors, which would manifest differently in clotting assays and would not typically present with the specific ristocetin aggregation abnormality seen here.

Question 267: A 25-year-old man is brought to the emergency department by ambulance after a motor vehicle accident. His car was rear-ended by a drunk driver while he was stopped at a traffic light. At the scene, he was noted to have multiple small lacerations over his upper extremities from broken glass. He has otherwise been healthy, does not smoke, and drinks 5 beers per night. He notes that he recently started trying out a vegan diet and moved to an apartment located in a historic neighborhood that was built in the 1870s. Physical exam reveals several small lacerations on his arms bilaterally but is otherwise unremarkable. A complete blood workup is sent and some of the notable findings are shown below: Hemoglobin: 12.1 g/dL (normal: 13.5-17.5 g/dL) Platelet count: 261,000/mm^3 (normal: 150,000-400,000/mm^3) Mean corpuscular volume: 74 µm^3 (normal: 80-100 µm^3) Further testing using serum hemoglobin electrophoresis reveals: Hemoglobin A1 92% (normal 95-98%) Hemoglobin A2: 6% (normal: 1.5-3.1%) Which of the following cell morphologies would most likely be seen on blood smear in this patient?

A. Spherocytes
B. Schistocytes
C. Codocytes (Correct Answer)
D. Megaloblasts
E. All cells appear normal

Explanation: ***Codocytes*** - Elevated Hb A2 (6%), low MCV (74), and mild anemia are classic findings of **beta-thalassemia minor (beta-thalassemia trait)**, which is associated with the presence of **codocytes (target cells)** on blood smear. - **Codocytes** result from an imbalance in the globin chains causing excess membrane relative to hemoglobin content, which then folds in on itself, giving the cell a "target-like" appearance. - The elevated **HbA2 >3.5%** is diagnostic of beta-thalassemia trait, as the beta chain deficiency leads to compensatory increase in delta chain production (HbA2 = α2δ2). *Spherocytes* - **Spherocytes** are small, round red blood cells lacking central pallor, characteristic of **hereditary spherocytosis** or **autoimmune hemolytic anemia**. - These conditions typically present with hemolytic anemia (elevated bilirubin, reticulocytosis, positive Coombs test), which are not present in this patient. - The elevated HbA2 confirms beta-thalassemia trait, not a hemolytic process. *Schistocytes* - **Schistocytes** are fragmented red blood cells that indicate **microangiopathic hemolytic anemia** (TTP, HUS, DIC) or mechanical red cell destruction. - There are no signs of hemolysis, thrombocytopenia, or organ dysfunction in this patient. *Megaloblasts* - **Megaloblasts** are large, immature red blood cell precursors seen in bone marrow in **megaloblastic anemia**, often due to **vitamin B12** or **folate deficiency**. - This patient presents with **microcytic anemia** (MCV 74), not macrocytic anemia, ruling out megaloblastic causes. *All cells appear normal* - The patient has **low hemoglobin** and **low MCV**, indicating microcytic anemia, which rules out a normal blood smear appearance. - The elevated HbA2 confirms beta-thalassemia trait with expected target cells on blood smear.

Question 268: A 55-year-old male presents to his primary care physician complaining of right hip pain for the past eight months. He also reports progressive loss of hearing over the same time period. Radiographic imaging reveals multiple areas of expanded bony cortices and coarsened trabeculae in his right hip and skull. Laboratory analysis reveals an isolated elevation in alkaline phosphatase with normal levels of serum calcium and phosphate. Which of the following histologic findings is most likely to be seen if one of the lesions were biopsied?

A. Mature lamellar bone with collagen fibers arranged in lamellae
B. Immature woven bone with collagen fibers arranged irregularly (Correct Answer)
C. Chondroblasts and chondrocytes forming a cartilaginous matrix
D. Sheets of monotonous round blue cells
E. Large pleomorphic cells with numerous atypical mitotic figures and “lacey” osteoid formation

Explanation: ***Immature woven bone with collagen fibers arranged irregularly*** - The clinical presentation (hip pain, hearing loss, elevated **alkaline phosphatase**, and radiographic findings of expanded cortices and coarsened trabeculae) is highly suggestive of **Paget's disease of bone** (osteitis deformans). - Biopsy of a Pagetic lesion classically shows a **mosaic pattern of woven and lamellar bone**, with prominent cement lines, reflecting the chaotic and rapid bone turnover. **Immature woven bone** is a hallmark. *Mature lamellar bone with collagen fibers arranged in lamellae* - This describes normal healthy adult bone and would not be seen in a condition characterized by **disordered bone remodeling** such as Paget's disease. - **Lamellar bone** is the characteristic type of bone found in healthy adults, where collagen fibers are organized in parallel layers. *Chondroblasts and chondrocytes forming a cartilaginous matrix* - This describes **cartilage**, which is not the primary tissue affected in Paget's disease within bone lesions. - This finding would be typical of cartilaginous tumors or normal epiphyseal plates, not a bone remodeling disorder. *Sheets of monotonous round blue cells* - This description is characteristic of certain **hematologic malignancies** or small round cell tumors, such as lymphomas, Ewing sarcoma, or neuroblastoma. - These findings are not associated with Paget's disease, which is a disorder of bone remodeling. *Large pleomorphic cells with numerous atypical mitotic figures and “lacey” osteoid formation* - This describes **osteosarcoma**, a primary malignant bone tumor, which can be a rare complication of long-standing Paget's disease but is not the primary histological finding of Paget's disease itself. - While the patient has Paget's, the question asks for the most likely finding of the lesion itself, not a potential malignant transformation.

Question 269: A 57-year-old man presents to his primary care physician with a 2-month history of right upper and lower extremity weakness. He noticed the weakness when he started falling far more frequently while running errands. Since then, he has had increasing difficulty with walking and lifting objects. His past medical history is significant only for well-controlled hypertension, but he says that some members of his family have had musculoskeletal problems. His right upper extremity shows forearm atrophy and depressed reflexes while his right lower extremity is hypertonic with a positive Babinski sign. Which of the following is most likely associated with the cause of this patient's symptoms?

A. HLA-DR2 haplotype
B. Mutation in SOD1 (Correct Answer)
C. Viral infection
D. HLA-B8 haplotype
E. Mutation in SMN1

Explanation: ***Mutation in SOD1*** - The patient exhibits features of both **upper motor neuron (UMN)** and **lower motor neuron (LMN)** lesions, specifically **forearm atrophy** and depressed reflexes (LMN) alongside **hypertonicity** and a **positive Babinski sign** (UMN). This combination is characteristic of **amyotrophic lateral sclerosis (ALS)**. - Mutations in the **superoxide dismutase 1 (SOD1)** gene are responsible for approximately 20% of familial ALS cases, aligning with the patient's report of "some members of his family have had musculoskeletal problems." *HLA-DR2 haplotype* - The **HLA-DR2 haplotype** is strongly associated with **multiple sclerosis (MS)**, an autoimmune demyelinating disease. - While MS can cause UMN symptoms, it typically does not present with the pronounced LMN signs like **atrophy** and **depressed reflexes** seen in this patient. *Viral infection* - **Viral infections** can trigger various neurological conditions, such as **Guillain-Barré syndrome** (GBS) which causes demyelination of peripheral nerves. - GBS primarily results in **ascending motor weakness** and **areflexia** (LMN signs), but it does not cause UMN signs like hypertonicity or a positive Babinski sign. *HLA-B8 haplotype* - The **HLA-B8 haplotype** is associated with several autoimmune diseases, including **myasthenia gravis** and **celiac disease**. - While myasthenia gravis causes **muscle weakness**, it is characterized by **fluctuating weakness** that worsens with activity and improves with rest, affecting specific muscle groups, unlike the progressive UMN and LMN involvement seen here. *Mutation in SMN1* - A **mutation in the SMN1 gene** is the primary cause of **spinal muscular atrophy (SMA)**, a genetic disorder. - SMA specifically leads to the death of **lower motor neurons** in the spinal cord, resulting in exclusively LMN signs such as **muscle weakness** and **atrophy**, without any UMN involvement (e.g., hypertonicity or Babinski sign).

Question 270: A 3-year-old girl is brought to her pediatrician because of a nosebleed that will not stop. Her parents say that she started having a nosebleed about 1 hour prior to presentation. Since then they have not been able to stop the bleeding. Her past medical history is remarkable for asthma, and she has a cousin who has been diagnosed with hemophilia. Physical exam reveals diffuse petechiae and purpura. A panel of bleeding tests are obtained with the following results: Bleeding time: 11 minutes Prothrombin time: 14 seconds Partial thromboplastin time: 32 seconds Platelet count: 195,000/mm^3 Peripheral blood smear shows normal cell morphology. Which of the following characteristics is most likely true about this patient?

A. Mutation in glycoprotein IIb/IIIa (Correct Answer)
B. Mutation in glycoprotein Ib
C. Production of anti platelet antibodies
D. Production of antibodies against ADAMTS13
E. Decreased levels of von Willebrand factor

Explanation: ***Mutation in glycoprotein IIb/IIIa*** - The patient's symptoms (nosebleed, petechiae, purpura) and laboratory findings (prolonged **bleeding time**, normal platelet count, normal PT/PTT) are characteristic of **Glanzmann's thrombasthenia**, which is caused by a qualitative defect in **glycoprotein IIb/IIIa**. - **Glycoprotein IIb/IIIa** is crucial for platelet aggregation, and a mutation in this protein prevents platelets from forming a stable clot. *Mutation in glycoprotein Ib* - A mutation in **glycoprotein Ib** leads to **Bernard-Soulier syndrome**, characterized by prolonged bleeding time, normal platelet count, and **abnormally large platelets** on peripheral smear, which are not seen here. - Glycoprotein Ib is involved in platelet adhesion to von Willebrand factor, not aggregation. *Production of anti platelet antibodies* - This describes **Immune Thrombocytopenic Purpura (ITP)**, which would typically present with a **low platelet count**, not a normal count as seen in this patient. - While ITP can cause petechiae and bleeding, the normal platelet count rules it out. *Production of antibodies against ADAMTS13* - This condition is **Thrombotic Thrombocytopenic Purpura (TTP)**, characterized by a **low platelet count**, microangiopathic hemolytic anemia, renal failure, neurological symptoms, and fever, none of which fully align with this patient's presentation. - TTP usually has significant **thrombocytopenia** and normal bleeding time, despite symptoms of bleeding. *Decreased levels of von Willebrand factor* - **Von Willebrand disease (vWD)** would typically show a **prolonged bleeding time** and, depending on the type, may also have a prolonged PTT (due to low factor VIII). - However, the diffuse petechiae and purpura with a normal platelet count and normal PT/PTT point more strongly towards a platelet function defect rather than a primary coagulation factor deficiency or vWD.

Question 271: An 8-year-old boy is brought to the physician by his parents because of fever for 3 days. During the period, he has had fatigue, severe burning with urination, and increased urination. The mother reports that his urine has red streaks and a “strange” odor. He has taken acetaminophen twice a day for the past two days with no improvement in his symptoms. He has had multiple ear infections in the past but has been healthy in the past year. His immunizations are up-to-date. He appears uncomfortable. His temperature is 39°C (102.2°F). Examination shows right-sided costovertebral angle tenderness. Laboratory studies show a leukocyte count of 16,000/cm3 and an erythrocyte sedimentation rate of 40 mm/hr. Urine dipstick shows leukocyte esterase and nitrites. Urinalysis shows: Blood 2+ Protein 2+ WBC 24/hpf RBC 50/hpf RBC casts none WBC casts numerous Granular casts none Urine cultures are sent to the laboratory. Damage to which of the following structures is the most likely cause of this patient's hematuria?

A. Renal tubules
B. Urethral epithelium
C. Mucosa of the bladder
D. Renal papilla
E. Renal interstitium (Correct Answer)

Explanation: ***Renal interstitium*** - This patient has **acute pyelonephritis**, indicated by fever, **costovertebral angle tenderness**, elevated inflammatory markers (WBC 16,000, ESR 40), positive leukocyte esterase and nitrites, and most importantly, **WBC casts** in the urine. - Acute pyelonephritis is characterized by **bacterial infection of the renal parenchyma**, primarily affecting the **renal interstitium** (the tissue between tubules containing blood vessels, inflammatory cells, and connective tissue). - The **hematuria** (RBC 50/hpf, Blood 2+) results from **inflammatory damage to interstitial capillaries** and disruption of the normal tissue architecture due to bacterial invasion and immune response. - **WBC casts** form when WBCs from the inflamed interstitium enter the tubular lumen and aggregate with Tamm-Horsfall protein, confirming upper urinary tract (kidney) infection rather than simple cystitis. *Renal papilla* - **Papillary necrosis** can cause severe hematuria but typically occurs in specific settings: diabetes mellitus, sickle cell disease, chronic analgesic abuse (NSAIDs), or severe obstruction—none of which are present in this otherwise healthy child. - While severe pyelonephritis can rarely lead to papillary necrosis, the clinical presentation here is consistent with **uncomplicated acute pyelonephritis** where interstitial inflammation is the primary pathology. *Renal tubules* - **Acute tubular necrosis (ATN)** presents with acute kidney injury, elevated creatinine, and **muddy brown granular casts**, which are not seen here. - While tubular cells may be affected secondarily in pyelonephritis, the primary site of damage is the **interstitium**, not the tubules themselves. *Urethral epithelium* - **Urethritis** causes dysuria and urethral discharge but does not produce **fever**, **CVA tenderness**, or **WBC casts**, which indicate kidney involvement. - Urethral inflammation would not explain the systemic inflammatory response or the casts originating from the kidney. *Mucosa of the bladder* - **Cystitis** (bladder infection) causes dysuria, frequency, and urgency, but typically lacks **high fever** and **CVA tenderness**, which are hallmarks of kidney infection. - While cystitis can cause hematuria, the presence of **WBC casts** definitively localizes the infection to the kidney (renal parenchyma/interstitium), not the bladder.

Question 272: An 8-year-old boy is brought to the pediatrician because his mother is concerned about recent behavioral changes. His mother states that she has started to notice that he is slurring his speech and seems to be falling more than normal. On exam, the pediatrician observes the boy has pes cavus, hammer toes, and kyphoscoliosis. Based on these findings, the pediatrician is concerned the child has a trinucleotide repeat disease. Which of the following trinucleotide repeats is this child most likely to possess?

A. CTG
B. GAA (Correct Answer)
C. CGG
D. CAG
E. GCC

Explanation: ***GAA*** - This trinucleotide repeat is associated with **Friedreich's ataxia**, an autosomal recessive neurodegenerative disorder. - The presented symptoms of **ataxia** (slurred speech, falling), **pes cavus**, **hammer toes**, and **kyphoscoliosis** are classic features of Friedreich's ataxia. *CTG* - This trinucleotide repeat is associated with **myotonic dystrophy type 1**, an autosomal dominant disorder. - While it causes muscle weakness, it is characterized by **myotonia** (delayed muscle relaxation), cataracts, and frontal baldness, which are not described here. *CGG* - This trinucleotide repeat is associated with **fragile X syndrome**, an X-linked dominant disorder. - Fragile X syndrome primarily causes intellectual disability, behavioral issues (e.g., autism spectrum disorder), and characteristic facial features, but not the specific neurological and orthopedic findings seen in this patient. *CAG* - This trinucleotide repeat is associated with several neurodegenerative diseases, including **Huntington's disease**, spinocerebellar ataxias, and **dentatorubral-pallidoluysian atrophy**. - Huntington's disease, for example, presents with chorea, cognitive decline, and psychiatric symptoms, differing from the patient's presentation. *GCC* - This trinucleotide repeat is associated with **fragile X-associated tremor/ataxia syndrome (FXTAS)**. - FXTAS typically affects older adult carriers of premutation alleles for fragile X, presenting with intention tremor and gait ataxia, not the early childhood onset and specific orthopedic deformities seen here.

Question 273: A 52-year-old man presents to the Emergency Department because of bilateral leg swelling and puffiness of both eyes in the morning. His symptoms started about 2 weeks ago. He denies smoking or alcohol use and his family history is noncontributory. Today, his vital signs include a temperature of 36.8°C (98.2°F), blood pressure of 162/87 mm Hg, and a pulse of 85/min. On physical examination, he is jaundiced and there is hepatosplenomegaly and 2+ lower extremity edema up to the mid-thigh. Laboratory results are shown: Anti-HCV reactive Serum albumin 3 g/dL Urine dipstick 3+ protein Urinalysis 10–15 red blood cells/high power field and red cell casts Which of the following is a feature of this patient’s condition?

A. Few immune complex deposits
B. Phospholipase A2 receptor antibodies
C. Subendothelial immune complex deposits (Correct Answer)
D. Renal vasoconstriction and altered autoregulation
E. Normal complement level

Explanation: ***Subendothelial immune complex deposits*** - The patient's presentation with **jaundice**, **hepatosplenomegaly**, **reactive anti-HCV**, and **nephritic-range proteinuria with red cell casts** and edema points to **hepatitis C-associated membranoproliferative glomerulonephritis (MPGN)**, also known as cryoglobulinemic glomerulonephritis. - MPGN is characterized by **immune complex deposition** within the glomerular capillary walls, specifically in the subendothelial space, often with C3 deposits and mesangial proliferation. *Few immune complex deposits* - This is incorrect as **MPGN type I** (the most common type, frequently associated with hepatitis C) is characterized by prominent **immune complex deposition**. - Conditions with few immune complex deposits often include **minimal change disease** or some forms of **focal segmental glomerulosclerosis (FSGS)**, which do not fit the entire clinical picture. *Phospholipase A2 receptor antibodies* - These antibodies are strongly associated with **idiopathic membranous nephropathy**, a different form of glomerulonephritis presenting primarily with **nephrotic syndrome**. - While membranous nephropathy can cause proteinuria, the presence of **red cell casts** and **hepatosplenomegaly** with **HCV infection** makes MPGN much more likely. *Renal vasoconstriction and altered autoregulation* - This describes the pathophysiology of **hepatorenal syndrome**, a complication of advanced liver disease characterized by functional renal failure without intrinsic kidney disease. - However, the presence of **proteinuria** and especially **red cell casts** in the urine indicates significant glomerular inflammation and **intrinsic kidney disease**, rather than functional renal impairment. *Normal complement level* - In **HCV-associated MPGN**, circulating **mixed cryoglobulins** lead to widespread immune complex formation and **complement activation** (primarily via the classical pathway), resulting in **decreased C4 and C3 complement levels**. - A normal complement level would be unusual for active cryoglobulinemic glomerulonephritis.

Question 274: A 22-year-old man comes to the physician because of a 2-week history of cough and decreased urination. The cough was initially nonproductive, but in the last few days he has coughed up small amounts of blood-tinged sputum with clots. He has not had any fevers, chills, or weight loss. He has smoked one pack of cigarettes daily for 5 years. Pulse is 115/min and blood pressure is 125/66 mm Hg. Physical examination shows dried blood around the lips. Serum studies show a creatinine of 2.9 mg/dL. Results of a serum antineutrophil cytoplasm antibody test are negative. A biopsy specimen of the kidney is most likely to show which of the following light microscopy findings?

A. Thinning of the basement membrane
B. Fibrin crescents in Bowman space (Correct Answer)
C. Expansion of the mesangial matrix
D. Enlarged and hypercellular glomeruli
E. Neutrophilic infiltration of the capillaries

Explanation: ***Fibrin crescents in Bowman space*** - The patient's presentation with **hemoptysis** (coughing up blood) and **acute kidney injury** (decreased urination, elevated creatinine 2.9 mg/dL) suggests a **pulmonary-renal syndrome**. The **negative ANCA** is a key distinguishing feature pointing towards **Goodpasture syndrome (anti-GBM disease)**. - Goodpasture syndrome is characterized by **rapidly progressive glomerulonephritis**, classically showing **crescent formation** (fibrin and proliferating parietal epithelial cells) in Bowman's space on light microscopy. The linear IgG deposition on basement membrane would be seen on immunofluorescence. *Thinning of the basement membrane* - This finding is characteristic of **Alport syndrome**, a hereditary nephritis presenting with hematuria, sensorineural hearing loss, and ocular abnormalities. - The patient's acute presentation with hemoptysis and rapidly progressive renal failure is inconsistent with Alport syndrome, which typically has a more chronic course. *Expansion of the mesangial matrix* - **Mesangial matrix expansion** is seen in **diabetic nephropathy** and **IgA nephropathy**. - While IgA nephropathy can cause hematuria and occasionally upper respiratory symptoms, it typically does not present with significant hemoptysis and the acute, severe renal failure seen here. *Enlarged and hypercellular glomeruli* - **Glomerular enlargement and hypercellularity** are features of **post-streptococcal glomerulonephritis** (diffuse proliferative glomerulonephritis). - The absence of preceding infection history and the prominent hemoptysis with negative ANCA make this less likely than Goodpasture syndrome. *Neutrophilic infiltration of the capillaries* - **Neutrophilic infiltration** (endocapillary proliferation) is characteristic of **acute post-infectious glomerulonephritis**. - The pulmonary-renal syndrome presentation without clear evidence of recent infection and negative ANCA makes this diagnosis unlikely.

Question 275: A 4-year-old girl is brought to the physician because of worsening jaundice that started 8 days ago. She has had similar episodes in the past. Her father underwent a splenectomy during adolescence. Physical examination shows mild splenomegaly. Laboratory studies show: Hemoglobin 10.1 g/dL WBC count 7200/mm3 Mean corpuscular volume 81 μm3 Mean corpuscular hemoglobin concentration 41% Hb/cell Platelet count 250,000/mm3 Red cell distribution width 16% (N=13%–15%) Reticulocytes 11% Erythrocyte sedimentation rate 10 mm/h Serum Na+ 139 mEq/L K+ 4.2 mEq/L Cl- 100 mEq/L Urea nitrogen 16 mg/dL A peripheral blood smear shows red blood cells that appear round, smaller, and without central pallor. Which of the following is the most sensitive test for confirming this patient's condition?

A. Coombs test
B. Osmotic fragility test
C. Serum ferritin level
D. Eosin-5-maleimide binding test (Correct Answer)
E. Hemoglobin electrophoresis

Explanation: ***Eosin-5-maleimide binding test*** - This test measures the binding of **eosin-5-maleimide (EMA)**, a fluorescent dye, to **band 3 protein** on the red blood cell membrane. - In **hereditary spherocytosis**, there is a deficiency or dysfunction of red cell membrane proteins (e.g., **spectrin, ankyrin, band 3**), leading to decreased EMA binding, making it the most sensitive and specific diagnostic test. *Coombs test* - The Coombs test (direct antiglobulin test) is used to detect **antibodies** on the surface of red blood cells, which is characteristic of **autoimmune hemolytic anemia**. - Hereditary spherocytosis is an **intrinsic red blood cell defect**, not an immune-mediated hemolysis, so the Coombs test would be negative. *Osmotic fragility test* - In this test, red blood cells are exposed to **hypotonic solutions**, and the degree of lysis is observed; spherocytes lyse more readily due to their decreased surface area-to-volume ratio. - While supportive, the **osmotic fragility test** can have false negatives in mild cases and may not be as sensitive or specific as the EMA binding test. *Serum ferritin level* - **Serum ferritin** measures the body's iron stores and is used to diagnose **iron deficiency** or **iron overload**. - It is not directly related to the diagnosis of hereditary spherocytosis, which is a red blood cell membrane disorder. *Hemoglobin electrophoresis* - **Hemoglobin electrophoresis** is used to identify abnormal hemoglobin variants, such as those found in **sickle cell disease** or **thalassemia**. - Hereditary spherocytosis is a membrane defect and does not involve abnormal hemoglobin structure.

Question 276: An otherwise healthy 47-year-old woman comes to the physician for the evaluation of a 4-month history of worsening fatigue and constipation. She has also noticed that her cheeks appear fuller and her voice has become hoarse. Her temperature is 36.3°C (97.3°F) and pulse is 59/min. Examination of the neck shows a painless, mildly enlarged thyroid gland. Her skin is dry and cool and her nails appear brittle. Serum studies show antibodies against thyroid peroxidase. A biopsy of the thyroid gland is most likely to show which of the following?

A. Tall follicular cells, scalloped colloid, and vascular congestion
B. Lymphocytic infiltration, Hürthle cells, and germinal centers (Correct Answer)
C. Large, irregular nuclei, nuclear grooves, and Psammoma bodies
D. Spindle cells, pleomorphic giant cells, and mitotic figures
E. Multinucleated giant cells, macrophages, and degenerated follicular cells

Explanation: ***Lymphocytic infiltration, Hürthle cells, and germinal centers*** - The patient's symptoms (fatigue, constipation, fuller cheeks, hoarse voice, dry and cool skin, brittle nails, bradycardia, mildly enlarged thyroid gland) are classic for **hypothyroidism**. The presence of **anti-thyroid peroxidase antibodies** confirms an autoimmune etiology, specifically **Hashimoto's thyroiditis**. - **Hashimoto's thyroiditis** is characterized pathologically by extensive **lymphocytic infiltration** of the thyroid parenchyma, the presence of **Hürthle cells** (metaplastic follicular cells with abundant eosinophilic cytoplasm), and the formation of **germinal centers** within the thyroid gland. *Tall follicular cells, scalloped colloid, and vascular congestion* - This description is characteristic of **Graves' disease**, an autoimmune cause of **hyperthyroidism**. - The patient's symptoms and signs (e.g., bradycardia, dry skin, constipation) are consistent with **hypothyroidism**, not hyperthyroidism. *Large, irregular nuclei, nuclear grooves, and Psammoma bodies* - These are classic histological features of **papillary thyroid carcinoma**, the most common type of thyroid cancer. - While thyroid nodules can occur in Hashimoto's, the overall clinical picture points strongly to a benign autoimmune inflammatory process, not malignancy. *Spindle cells, pleomorphic giant cells, and mitotic figures* - This describes **anaplastic thyroid carcinoma**, a highly aggressive and undifferentiated thyroid malignancy. - Anaplastic carcinoma typically presents as a rapidly enlarging, painful neck mass in older individuals, which is not consistent with this patient's chronic, milder presentation. *Multinucleated giant cells, macrophages, and degenerated follicular cells* - This histological pattern is characteristic of **subacute granulomatous thyroiditis (de Quervain's thyroiditis)**. - Subacute thyroiditis typically presents with painful thyroid enlargement and often follows a viral infection, which is not suggested by the patient's symptoms or antibody findings.

Question 277: A 19-year-old woman presents to her primary care physician because she has been feeling increasingly lethargic over the last 6 months. Specifically, she says that she feels tired easily and has been cold even though she is wearing lots of layers. Her medical history is significant for seasonal allergies but is otherwise unremarkable. When prompted, she also says that she has a hard time swallowing food though she has no difficulty drinking liquids. Physical exam reveals a midline mass in her neck. Which of the following structures would most likely be seen if this patient's mass was biopsied?

A. Lymphatic ducts
B. Neutrophilic invasion
C. Blood vessels
D. Follicles with colloid (Correct Answer)
E. Hollow epithelial duct

Explanation: ***Follicles with colloid*** - The patient's symptoms (lethargy, cold intolerance, difficulty swallowing solids, midline neck mass) are highly suggestive of **hypothyroidism** due to a **goiter**, which often arises from an enlarged thyroid gland. - The **thyroid gland** is composed of follicles filled with **colloid**, which is the storage form of thyroid hormones. A biopsy of an enlarged thyroid gland would therefore show these structures. *Lymphatic ducts* - **Lymphatic ducts** are part of the lymphatic system, which is involved in immune function and fluid balance, not typically found in a thyroid biopsy under these circumstances. - While neck masses can sometimes be enlarged lymph nodes, the symptoms point specifically to thyroid dysfunction rather than a lymphatic issue. *Neutrophilic invasion* - **Neutrophilic invasion** indicates an acute inflammatory or infectious process, which is not suggested by the chronic and systemic symptoms presented here. - This finding would be more typical of an abscess or acute thyroiditis, which usually presents with pain and fever. *Blood vessels* - While **blood vessels** are present in all tissues, including the thyroid, they are not the *most characteristic* or defining structure seen during a biopsy of a mass suspected to be an enlarged thyroid gland. - The question asks for the structure *most likely* to be seen, implying a unique and diagnostic histological feature. *Hollow epithelial duct* - **Hollow epithelial ducts** are characteristic of structures like salivary glands or cysts formed from developmental remnants (e.g., thyroglossal duct cyst), but less likely to be the primary finding in an enlarged thyroid gland causing systemic symptoms of hypothyroidism. - A thyroglossal duct cyst would typically present as a midline neck mass that moves with tongue protrusion, and while it could cause dysphagia, it typically doesn't cause symptoms of hypothyroidism.

Question 278: A 27-year-old man presents to the emergency room complaining of shortness of breath and productive cough for a few days. He says that his sputum is mostly yellow with tiny red specks. He denies fever, chills, recent weight loss, or joint pain. He has no history of recent travel or sick contacts. His medical history is unremarkable. He smokes a pack of cigarettes daily. He has had 3 sexual partners in the past year. His temperature is 37°C (98.6°F), blood pressure is 110/70 mm Hg, pulse is 98/min, and respirations are 20/min. On physical examination, the patient is in mild respiratory distress. Cardiopulmonary auscultation reveals diffuse bilateral rales. An HIV test is negative. His laboratory results are as follow: Complete blood count Hemoglobin 12 gm/dL Serum chemistry Sodium 143 mEq/L Potassium 4.1 mEq/L Chloride 98 mEq/L Bicarbonate 22 mEq/L Blood urea nitrogen 26 mg/dL Creatinine 2.3 mg/dL Glucose 86 mg/dL Urine dipstick Protein trace Blood positive Leukocytes negative Nitrates negative Which of the following is the most likely cause of his current condition?

A. Heart failure
B. Ruptured alveolar bleb
C. Basement membrane antibodies (Correct Answer)
D. Pneumocystis pneumonia
E. Pulmonary embolism

Explanation: ***Basement membrane antibodies*** - The patient's **shortness of breath**, productive cough with **yellow sputum and red specks**, and diffuse **bilateral rales** suggest a pulmonary etiology, while the **elevated BUN and creatinine** with **trace proteinuria** and **positive blood on urine dipstick** point to renal involvement. This combination of **pulmonary-renal syndrome** in a young patient is highly suggestive of **Goodpasture syndrome**, which is caused by antibodies against the glomerular and alveolar basement membranes. - The absence of fever, negative HIV test, and relatively acute presentation further support **Goodpasture syndrome** over infectious or other systemic vasculitic causes. His smoking history is a known risk factor for developing Goodpasture's syndrome. *Heart failure* - While **shortness of breath** and **bilateral rales** can be seen in heart failure, the patient's **normal blood pressure** and **unremarkable medical history** (no history of cardiac disease) make it less likely. - The presence of **renal failure (elevated BUN and creatinine)** and **hemoptysis (red specks in sputum)** are not typical primary manifestations of heart failure. *Ruptured alveolar bleb* - A ruptured alveolar bleb typically presents as a **spontaneous pneumothorax**, causing **sudden onset of pleuritic chest pain** and **shortness of breath** due to lung collapse. - This condition does not explain the **productive cough with hemoptysis**, **bilateral rales**, or the **acute kidney injury** observed in this patient. *Pneumocystis pneumonia* - While **Pneumocystis pneumonia** causes **shortness of breath** and cough, it is typically seen in **immunocompromised individuals**, especially those with **HIV/AIDS**. The patient's **HIV test is negative**. - Furthermore, **Pneumocystis pneumonia** does not typically cause **hemoptysis** (red specks in sputum) or **acute kidney injury**. *Pulmonary embolism* - A pulmonary embolism often presents with **sudden onset of dyspnea**, **pleuritic chest pain**, and sometimes **hemoptysis**. However, **bilateral rales** are not a typical finding. - A **pulmonary embolism** would not explain the **acute kidney injury** (elevated BUN and creatinine, positive urine blood) in the absence of other systemic conditions.

Question 279: A 29-year-old woman presents with skin lesions on her elbows and forearms. She notes that they first started appearing 2 months ago and have not improved. She describes the lesions as painless and rarely itchy. She denies any similar symptoms in the past, and has no other significant past medical history. Review of systems is significant for recent joint pain, conjunctivitis, and corneal dryness. The patient is afebrile and vital signs are within normal limits. Non-tender, raised, inflamed, white-silver maculopapular lesions are present. Which of the following are the most likely histopathologic findings in this patient's skin biopsy?

A. Intercellular edema with detachment at basal level
B. Acanthosis, hyperkeratosis with parakeratosis, and dermal papillary capillary proliferation (Correct Answer)
C. Cytoplasmic vacuolation
D. Nuclear atypia, cellular pleomorphism, and a disorganized structure of cells from basal to apical layers of the tissue
E. Subepidermal blister with detachment at dermal-epidermal junction

Explanation: ***Acanthosis, hyperkeratosis with parakeratosis, and dermal papillary capillary proliferation*** - The patient's presentation with **raised, inflamed, white-silver maculopapular lesions** on elbows and forearms, along with joint pain and conjunctivitis, is highly suggestive of **psoriasis**. - **Acanthosis** (epidermal hyperplasia), **hyperkeratosis with parakeratosis** (retained nuclei in the stratum corneum), and **dermal papillary capillary proliferation** (elongated dermal papillae with dilated blood vessels) are classic histopathological findings in psoriasis. *Intercellular edema with detachment at basal level* - This description is more consistent with conditions causing **spongiosis** (intercellular edema in the epidermis) or **dermatitis**, which typically present with different clinical features (e.g., vesicles, oozing). - Basal layer detachment can be seen in **bullous pemphigoid** or other blistering disorders, which are characterized by large tense blisters, unlike the described lesions. *Cytoplasmic vacuolation* - **Cytoplasmic vacuolation** is a non-specific finding that can be observed in various conditions, including **viral infections** (e.g., HPV), certain **drug reactions**, or **degenerative changes**. - It does not specifically describe the characteristic changes seen in psoriasis. *Subepidermal blister with detachment at dermal-epidermal junction* - A **subepidermal blister** (detachment of the epidermis from the dermis at the dermal-epidermal junction) is characteristic of conditions like **bullous pemphigoid**. - The patient's lesions are described as maculopapular, not blistering, making this diagnosis unlikely. *Nuclear atypia, cellular pleomorphism, and a disorganized structure of cells from basal to apical layers of the tissue* - These findings (**nuclear atypia**, **cellular pleomorphism**, **disorganized cell structure**) are hallmarks of **dysplasia** or **carcinoma in situ**. - The patient's symptoms are recent onset, widespread, and associated with joint pain, which are not typical of a malignant skin lesion.

Question 280: A 43-year-old male visits the emergency room around 4 weeks after getting bitten by a bat during a cave diving trip. After cleansing the wound with water, the patient reports that he felt well enough not to seek medical attention immediately following his trip. He does endorse feeling feverish in the past week but a new onset of photophobia and irritability led him to seek help today. What would the post-mortem pathology report show if the patient succumbs to this infection?

A. Howell-Jolly bodies
B. Heinz bodies
C. Psammoma bodies
D. Pick bodies
E. Negri bodies (Correct Answer)

Explanation: ***Negri bodies*** - This patient's symptoms (fever, photophobia, irritability) and history of a bat bite point to rabies. **Negri bodies** are eosinophilic inclusions found in the cytoplasm of hippocampal and Purkinje cells in cases of rabies. - They are **pathognomonic** for rabies infection and represent viral nucleocapsid proteins. *Howell-Jolly bodies* - These are **nuclear remnants** found in red blood cells that indicate impaired splenic function or asplenia. - They are not associated with viral infections like rabies and are observed in conditions like sickle cell disease or after splenectomy. *Heinz bodies* - **Heinz bodies** are inclusions within red blood cells composed of denatured hemoglobin. - They are typically seen in conditions involving **oxidative stress** to red blood cells, such as G6PD deficiency or alpha-thalassemia, not rabies. *Psammoma bodies* - These are **calcified, laminated, concentric spherules** found in some tumors (e.g., papillary thyroid carcinoma, meningioma, serous ovarian cystadenocarcinoma). - They are a marker of specific neoplastic conditions and have no relevance to viral infections. *Pick bodies* - **Pick bodies** are aggregates of tau protein found in neurons, characteristic of **Pick's disease**, a type of frontotemporal dementia. - They are neurodegenerative markers and are unrelated to infectious diseases.

Question 281: A 44-year-old man is brought to the emergency department by his daughter for a 1-week history of right leg weakness, unsteady gait, and multiple falls. During the past 6 months, he has become more forgetful and has sometimes lost his way along familiar routes. He has been having difficulties operating simple kitchen appliances such as the dishwasher and the coffee maker. He has recently become increasingly paranoid, agitated, and restless. He has HIV, hypertension, and type 2 diabetes mellitus. His last visit to a physician was more than 2 years ago, and he has been noncompliant with his medications. His temperature is 37.2 °C (99.0 °F), blood pressure is 152/68 mm Hg, pulse is 98/min, and respirations are 14/min. He is somnolent and slightly confused. He is oriented to person, but not place or time. There is mild lymphadenopathy in the cervical, axillary, and inguinal areas. Neurological examination shows right lower extremity weakness with normal tone and no other focal deficits. Laboratory studies show: Hemoglobin 9.2 g/dL Leukocyte count 3600/mm3 Platelet count 140,000/mm3 CD4+ count 56/μL HIV viral load > 100,000 copies/mL Serum Cryptococcal antigen negative Toxoplasma gondii IgG positive An MRI of the brain shows disseminated, nonenhancing white matter lesions with no mass effect. Which of the following is the most likely diagnosis?

A. Vascular dementia
B. Primary CNS lymphoma
C. Neurocysticercosis
D. Cerebral toxoplasmosis
E. Progressive multifocal leukoencephalopathy (Correct Answer)

Explanation: ***Progressive multifocal leukoencephalopathy*** - The patient's severe **immunosuppression** (CD4 count 56/μL) and **non-enhancing white matter lesions** disseminated throughout the brain are highly characteristic of **PML**, caused by the **JC virus**. - **Progressive neurological deficits** including cognitive decline, motor weakness, and personality changes are typical presentations of PML in advanced HIV. *Vascular dementia* - While the patient has **hypertension** and a history of falls, the MRI findings of **disseminated non-enhancing white matter lesions** are not classic for vascular dementia, which typically shows lacunar infarcts or larger areas of ischemic damage. - The rapid progression of symptoms and severe immunosuppression also point away from typical vascular dementia as the primary cause. *Primary CNS lymphoma* - **Primary CNS lymphoma** in HIV patients usually presents as **solitary or multiple mass lesions** that are typically **ring-enhancing** on MRI, which contradicts the described non-enhancing lesions. - While it can cause neurological deficits, the MRI findings are a strong differentiating factor. *Neurocysticercosis* - **Neurocysticercosis** is caused by the parasite *Taenia solium* and is more common in endemic areas; MRI typically shows **cysts, calcifications, or enhancing lesions**, often with associated edema. - The patient's non-enhancing white matter lesions and high HIV viral load make this diagnosis less likely, despite the global prevalence of the infection. *Cerebral toxoplasmosis* - **Cerebral toxoplasmosis** is common in HIV patients with low CD4 counts and positive *Toxoplasma gondii* IgG, but it typically presents with **multiple ring-enhancing lesions** on MRI, often with **mass effect**. - The absence of enhancement and mass effect on MRI makes toxoplasmosis less probable despite the positive IgG serology.

Question 282: A 7-year-old girl presents to a new pediatrician with fever, shortness of breath, and productive cough. She had similar symptoms a few weeks ago. The girl was born at 39 weeks gestation via spontaneous vaginal delivery. She is up to date on all vaccines and is meeting all developmental milestones. A further review of her history reveals seizures, upper respiratory infections, and cellulitis. On physical examination, the patient is pale with white-blonde hair and pale blue eyes. Which of the following would you expect to see on a peripheral blood smear for this patient?

A. Polymorphonuclear leukocytes containing giant inclusion bodies (Correct Answer)
B. Predominance of band leukocytes
C. Downey cells
D. Stippled eosinophils
E. Significant basophil predominance

Explanation: ***Polymorphonuclear leukocytes containing giant inclusion bodies*** - This constellation of symptoms: **recurrent infections** (respiratory infections, cellulitis), **neurological abnormalities** (seizures), and **partial albinism** (pale skin, white-blonde hair, pale blue eyes) is characteristic of **Chédiak-Higashi syndrome**. - **Chédiak-Higashi syndrome** is an autosomal recessive disorder characterized by defective lysosomal trafficking, leading to the formation of abnormally large **lysosomes** and **granules** in various cell types, including melanocytes, lymphocytes, and granulocytes. These giant granules are visible as **inclusion bodies** within polymorphonuclear leukocytes on a peripheral blood smear. *Predominance of band leukocytes* - A predominance of **band leukocytes** (immature neutrophils) indicates a **left shift**, which is commonly seen in acute bacterial infections and suggests the bone marrow is rapidly producing neutrophils. - While this patient has infections, a left shift is a general response to infection and not a specific finding for Chédiak-Higashi syndrome, which primarily involves abnormal inclusion bodies. *Downey cells* - **Downey cells** are atypical lymphocytes, specifically activated cytotoxic T cells, classically associated with **infectious mononucleosis** caused by the Epstein-Barr virus (EBV). - This patient's chronic and recurrent bacterial infections and characteristic albinism do not suggest infectious mononucleosis. *Stippled eosinophils* - **Stippled eosinophils** (basophilic stippling within eosinophils) are not a recognized abnormality or an indicator of any specific disease. - While eosinophilia can occur in certain conditions (e.g., parasitic infections, allergic reactions), the presence of "stippled" eosinophils is not a known hematologic feature. *Significant basophil predominance* - A significant basophil predominance, or **basophilia**, can be seen in conditions like **myeloproliferative neoplasms** (e.g., chronic myeloid leukemia) or certain allergic reactions. - This finding is not consistent with the clinical presentation of recurrent infections, neurological issues, and albinism seen in this patient.

Question 283: A 2-year-old girl with a history of SS-hemoglobin is brought to her pediatrician by her mother, who noted an abdominal mass. On exam, the girl's spleen is palpably enlarged, and her palms and conjunctiva are noted to be extremely pale. Serum haptoglobin levels are decreased. Which of the following is the most likely cause of this patient's symptoms?

A. Intravascular hemolysis
B. Extravascular hemolysis (Correct Answer)
C. Hemolytic uremic syndrome
D. Complement-mediated hemolysis
E. Decreased red blood cell production

Explanation: ***Extravascular hemolysis*** - This patient presents with **anemia** (pale conjunctiva and palms) and an **enlarged spleen**, which are classic signs of **extravascular hemolysis**. **Sickle cell disease** is a condition known to cause chronic hemolysis through this mechanism, where damaged red blood cells are removed by the reticuloendothelial system, primarily in the spleen. - In **extravascular hemolysis**, red blood cells are destroyed outside of the bloodstream by macrophages in the spleen, liver, and bone marrow. While this process releases less **free hemoglobin** into circulation than intravascular hemolysis, **chronic hemolysis in sickle cell disease still leads to decreased haptoglobin levels** due to ongoing red cell destruction and some degree of intravascular hemolysis. - The **splenomegaly** in this young patient is characteristic, as the spleen becomes engorged with sequestered and destroyed sickled red blood cells before it undergoes autoinfarction in later childhood. *Intravascular hemolysis* - **Intravascular hemolysis** involves the destruction of red blood cells within the circulation, leading to the release of **free hemoglobin**. - While sickle cell disease does have some intravascular component, the **primary mechanism is extravascular**, and the presence of **significant splenomegaly** with palpable abdominal mass points to splenic sequestration and extravascular destruction as the dominant process. *Hemolytic uremic syndrome* - **Hemolytic uremic syndrome (HUS)** is characterized by a triad of **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **acute kidney injury**. - While it involves hemolysis, the patient's presentation lacks **thrombocytopenia** and evidence of **renal failure**, making HUS less likely. Additionally, HUS is not typically associated with **sickle cell disease**. *Complement-mediated hemolysis* - **Complement-mediated hemolysis** is seen in conditions like **paroxysmal nocturnal hemoglobinuria (PNH)** or some autoimmune hemolytic anemias. - This typically results in **intravascular hemolysis** due to complement activation on red cell surfaces. The patient's known diagnosis of **sickle cell disease** makes this mechanism less likely as the primary cause. *Decreased red blood cell production* - Conditions with **decreased red blood cell production**, such as **aplastic anemia** or **pure red cell aplasia**, would present with anemia but not typically with an **enlarged spleen** or evidence of significant red blood cell destruction. - The patient's history of **SS-hemoglobin (sickle cell disease)** and **decreased haptoglobin** point towards a hemolytic process rather than bone marrow suppression as the primary cause of anemia.

Question 284: Several weeks following a kidney transplantation, a 50-year-old Caucasian female presents for evaluation of the transplanted organ. Biopsy shows inflammation involving the endothelial cells of the kidney vasculature and the presence of mononuclear cells in the interstitium. Which cells are most likely responsible for this presentation?

A. Recipient T-cells (Correct Answer)
B. Donor antibodies
C. Preformed recipient antibodies
D. Deposition of antibody immune complexes
E. Donor T-cells

Explanation: ***Recipient T-cells*** - The presence of **mononuclear cells in the interstitium** and inflammation of the **endothelial cells** several weeks post-transplantation is characteristic of **acute cellular rejection (ACR)**. - ACR is primarily mediated by the recipient's **cytotoxic T-cells** recognizing donor major histocompatibility complex (MHC) molecules on graft cells. *Donor antibodies* - Donor antibodies are not responsible for rejection; rather, recipient antibodies (either preformed or newly formed) are implicated. - The donor's immune system is suppressed or non-existent in the context of the transplanted organ itself after removal from the donor. *Preformed recipient antibodies* - While preformed recipient antibodies cause **hyperacute rejection**, which occurs minutes to hours after transplant, the presentation here is several weeks later. - Hyperacute rejection involves widespread thrombosis and necrosis due to rapid antibody-mediated complement activation within the graft vasculature. *Deposition of antibody immune complexes* - Immune complex deposition typically causes a different pattern of injury (e.g., glomerulonephritis) and is not the primary mechanism of acute cellular rejection. - This mechanism is more associated with certain autoimmune diseases or chronic transplant rejection, not the acute phase described. *Donor T-cells* - Donor T-cells would not be attacking the transplanted organ since it is *their own tissue*. - Donor T-cells can cause **graft-versus-host disease (GVHD)** in bone marrow transplantation, where immunocompetent donor T-cells attack recipient tissues, but this is not applicable to solid organ transplantation.

Question 285: A 67-year-old man comes to the emergency department for evaluation of progressively worsening edema and decreased urine output over the past few days. He has a history of chronic sinus infections and was hospitalized last year for a suspected pneumonia with hemoptysis. Physical exam shows bilateral pitting edema of the lower extremities. Serum studies show a creatinine of 3.4 mg/dL and blood urea nitrogen of 35 mg/dL. Urine dipstick shows 3+ blood. A kidney biopsy is performed and light microscopy shows crescent-shaped glomeruli. Immunofluorescent microscopy of the tissue sample is most likely to show which of the following findings?

A. Subendothelial deposits
B. Mesangial deposits
C. Intramembranous deposits
D. No deposits (Correct Answer)
E. Subepithelial deposits

Explanation: ***No deposits*** - The presence of **crescentic glomeruli** on light microscopy and a history of chronic sinus infections and hemoptysis strongly suggest **Granulomatosis with Polyangiitis (GPA)**, a form of **pauci-immune glomerulonephritis**. - In pauci-immune glomerulonephritis, immunofluorescence typically shows **scanty or no immune deposits** in the glomeruli. *Subendothelial deposits* - **Subendothelial deposits** are characteristic of conditions like **membranoproliferative glomerulonephritis** (types I and III) or **lupus nephritis**, which typically do not present with the described clinical picture of chronic upper respiratory issues and hemoptysis. - These deposits would be associated with significant immune complex deposition, which contradicts the "pauci-immune" nature suggested by the clinical presentation. *Mesangial deposits* - **Mesangial deposits** are a hallmark of **IgA nephropathy** or early stages of lupus nephritis, where IgA or other immune complexes accumulate in the mesangium. - While IgA nephropathy can cause hematuria, the crescentic glomerulonephritis and systemic features (sinusitis, hemoptysis) point away from isolated mesangial involvement as the primary pathology. *Intramembranous deposits* - **Intramembranous deposits** are typically seen in conditions like **dense deposit disease** (a complement-mediated glomerulonephritis) or some forms of cryoglobulinemic glomerulonephritis. - These conditions usually have distinct clinical presentations and specific patterns of complement activation or cryoglobulinemia, which are not indicated in this case. *Subepithelial deposits* - **Subepithelial deposits** (e.g., "humps") are characteristic of **post-streptococcal glomerulonephritis** and are rich in C3 and IgG. - While post-streptococcal glomerulonephritis can cause crescent formation, the patient's age, chronic sinus issues, and hemoptysis make GPA a more fitting diagnosis.

Question 286: A 9-year-old boy is brought to the physician by his parents because of right-sided shoulder pain for 1 day. He has not had chills or sweating. Over the past year, he was treated twice in the emergency department for painful swelling of his hands and feet. He emigrated with his family from Kenya 2 years ago. His temperature is 37.4°C (99.3°F), pulse is 96/min, and blood pressure is 123/82 mm Hg. Physical examination shows no tenderness, erythema, or joint swelling of the shoulder. Laboratory studies show: Hemoglobin 7 g/dL Mean corpuscular volume 88 μm Reticulocyte count 9% Leukocyte count 12,000/mm3 A peripheral blood smear is most likely to show which of the following abnormalities?

A. Ring-shaped inclusions in erythrocytes
B. Erythrocytes with no central pallor
C. Teardrop-shaped erythrocytes
D. Fragmentation of erythrocytes
E. Nuclear remnants in erythrocytes (Correct Answer)

Explanation: ***Nuclear remnants in erythrocytes*** - This patient's history of **recurrent painful swelling** of hands and feet, emigration from Kenya, and current shoulder pain, combined with **anemia** (hemoglobin 7 g/dL) and **elevated reticulocyte count (9%)**, strongly suggests **sickle cell disease**. - Complications such as **vaso-occlusive crises** can cause bone pain. **Nuclear remnants (Howell-Jolly bodies)** in erythrocytes are characteristic of **functional asplenia**, a common complication of sickle cell disease due to splenic infarction. *Ring-shaped inclusions in erythrocytes* - **Ring-shaped inclusions** are primarily associated with parasitic infections like **malaria** (ring forms of *Plasmodium* parasites within red blood cells). - While the patient is from Kenya, the clinical picture here is not typical for an acute malaria presentation (no fever/chills), and other findings point more strongly to sickle cell disease complications. *Erythrocytes with no central pallor* - **Erythrocytes with no central pallor** (spherocytes) are characteristic of **hereditary spherocytosis** or **autoimmune hemolytic anemia**. - While both can cause anemia and an elevated reticulocyte count, the history of recurrent painful swelling of hands and feet strongly points away from these disorders. *Teardrop-shaped erythrocytes* - **Teardrop-shaped erythrocytes (dacryocytes)** are typically seen in **myelofibrosis** and other myeloproliferative neoplasms, or severe marrow infiltration. - This finding is not consistent with the clinical presentation of sickle cell disease. *Fragmentation of erythrocytes* - **Fragmentation of erythrocytes (schistocytes)** indicates **microangiopathic hemolytic anemia (MAHA)**, seen in conditions like thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), or disseminated intravascular coagulation (DIC). - While sickle cell crises can involve microvascular occlusion, the primary red cell abnormality in sickle cell disease isn't schistocyte formation as a hallmark feature.

Question 287: An 8-year-old boy presents to the emergency department with puffy eyes. The patient’s parents noticed that his eyes were very puffy this morning thus prompting his presentation. They state their son has always been very healthy and other than a rash acquired from wrestling treated with a topical antibiotic has been very healthy. His temperature is 98.3°F (36.8°C), blood pressure is 125/85 mmHg, pulse is 89/min, respirations are 18/min, and oxygen saturation is 99% on room air. Physical exam is notable for periorbital edema but is otherwise unremarkable. Urinalysis is notable for red blood cells and an amber urine sample. Which of the following is the most likely etiology of this patient’s symptoms?

A. Deposition of circulating immune complexes (Correct Answer)
B. Increased glomerular permeability to protein only
C. IgE-mediated degranulation
D. IgA-mediated vasculitis
E. Autoimmune type IV collagen destruction

Explanation: ***Deposition of circulating immune complexes*** - The patient's symptoms, including **periorbital edema**, **hypertension**, and **hematuria** with a history of a **recent skin infection (wrestling rash)**, are classic for **post-streptococcal glomerulonephritis (PSGN)**. - PSGN is caused by the deposition of **immune complexes** (antibodies bound to streptococcal antigens) in the glomeruli, leading to inflammation and damage. *Increased glomerular permeability to protein only* - This describes **nephrotic syndrome**, which is primarily characterized by **massive proteinuria** and severe edema, but typically **lacks hematuria** and significant hypertension. - While there is edema, the presence of **red blood cells in the urine** points away from isolated protein permeability. *IgE-mediated degranulation* - This mechanism is characteristic of immediate type I hypersensitivity reactions, such as **allergic reactions** (e.g., anaphylaxis, urticaria). - While it can cause angioedema, it does not typically lead to the **hematuria** and **hypertension** seen in this patient. *IgA-mediated vasculitis* - This describes **Henoch-Schönlein Purpura (HSP)**, which presents with a classic triad of palpable purpura, abdominal pain, and arthralgia, along with renal involvement **(IgA nephropathy)**. - While HSP can cause hematuria, the absence of the characteristic **purpuric rash** and other systemic symptoms makes it less likely than PSGN in this context. *Autoimmune type IV collagen destruction* - This mechanism is associated with conditions like **Goodpasture syndrome**, where antibodies target the **alpha-3 chain of type IV collagen** in the glomerular and alveolar basement membranes. - Goodpasture syndrome typically presents with **rapidly progressive glomerulonephritis** and often **pulmonary hemorrhage**, which are not indicated in this case.

Question 288: An 11-year-old African American boy is brought to your office by his parents with a 1-day history of severe left hip pain. It is too painful for him to walk without support. He took ibuprofen, which brought no relief. He has had no chills or sweats. Similar painful episodes in the past required multiple hospitalizations. He returned from a trip to Kenya with his family 2 months ago. His vaccinations are up-to-date. His temperature is 38°C (100.4° F), pulse is 100/min, blood pressure is 120/80 mm Hg. Physical examination shows pale conjunctivae. The abdomen is soft with no organomegaly. Passive movement of the hip causes severe pain. There is tenderness on palpation, but no swelling, warmth, or erythema of the hip. His laboratory studies show a hematocrit of 25% and leukocyte count of 14 000/mm3. A peripheral blood smear would most likely show which of the following?

A. Howell-Jolly bodies (Correct Answer)
B. Decreased number of reticulocytes
C. Trophozoites
D. Decreased number of thrombocytes
E. Gram-negative bacilli

Explanation: ***Howell-Jolly bodies*** - The patient's history of recurrent pain, African American ethnicity, and profound anemia (hematocrit 25%) are highly suggestive of **sickle cell disease**. - Howell-Jolly bodies are **nuclear remnants** in red blood cells, typically removed by the spleen. Their presence indicates **functional asplenia**, which is common in sickle cell disease due to splenic auto-infarction. *Decreased number of reticulocytes* - This patient is experiencing a **painful vaso-occlusive crisis** and significant anemia, which usually stimulates increased erythropoiesis. - A decreased reticulocyte count would suggest **aplastic crisis** (e.g., due to parvovirus B19), which is a possible complication but less likely the primary finding in an active crisis with marked anemia. *Trophozoites* - Trophozoites on a peripheral blood smear are characteristic of **malaria**, which is a consideration given his recent travel to Kenya. - However, the history of **recurrent painful episodes** since childhood points more strongly to an underlying chronic condition like sickle cell disease, and malaria would typically present with cyclic fevers, chills, and sweats, which are absent here. *Decreased number of thrombocytes* - A decreased number of thrombocytes (thrombocytopenia) is not a typical finding in an uncomplicated sickle cell crisis. - While possible in severe illness or specific complications, the presenting symptoms do not specifically point to a primary platelet disorder. *Gram-negative bacilli* - The presence of Gram-negative bacilli on a peripheral blood smear would indicate **bacteremia** or **sepsis**. - While patients with sickle cell disease are at increased risk of infection, especially encapsulated bacteria due to functional asplenia, the primary diagnostic finding in the context of recurrent pain and anemia would be related to the underlying sickle cell pathology rather than an immediate infectious agent in this scenario.

Question 289: An 18-month-old boy is presented to the emergency department by his parents due to swelling in his right knee after playing in the park. His parents say there was no obvious injury. After questioning, the mother says that an uncle of hers had similar problems. The vital signs include heart rate 146/min, respiratory rate 26/min, temperature 37.1°C (98.8°F) and blood pressure 90/52 mm Hg. On physical examination, the swelling of the right knee is evident. The rest of the physical findings are unremarkable. The ultrasound is compatible with the hemarthrosis of the right knee. The complete blood count (CBC) results are as follows: Hemoglobin 12.2 g/dL Hematocrit 36% Leukocyte count 7,300/mm3 Neutrophils 45% Bands 3% Eosinophils 1% Basophils 0% Lymphocytes 44% Monocytes 2% Platelet count 200,000/mm³ The coagulation test results are as follows: Partial thromboplastin time (activated) 52.0 s Prothrombin time 14.0 s Reticulocyte count 1.2% Thrombin time < 2 seconds deviation from control What is the most likely diagnosis?

A. Bernard-Soulier disease
B. Hemophilia A (Correct Answer)
C. Von Willebrand disease
D. Marfan syndrome
E. Ehlers-Danlos syndrome

Explanation: ***Hemophilia A*** - The patient presents with **hemarthrosis** (joint bleeding) after minor trauma, which is characteristic of hemophilia. The **prolonged activated partial thromboplastin time (aPTT)** indicates an intrinsic pathway coagulation disorder. - The family history of a male uncle having "similar problems" suggests an **X-linked recessive inheritance pattern**, which is classic for hemophilia A due to factor VIII deficiency. *Bernard-Soulier disease* - This is a **platelet function disorder** characterized by **giant platelets** and **thrombocytopenia**, none of which are observed in the patient's CBC. - It would typically present with **mucocutaneous bleeding** (e.g., epistaxis, petechiae) rather than hemarthrosis alone, and coagulation times (aPTT, PT) would be normal. *Von Willebrand disease* - While it can manifest with bleeding, it usually causes **mucocutaneous bleeding** and **menorrhagia**, rather than spontaneous deep joint bleeds. - Type 1 von Willebrand disease typically has a **normal or slightly prolonged aPTT**, and the bleeding tends to be less severe than in hemophilia A. *Marfan syndrome* - This is a **connective tissue disorder** affecting the skeletal, ocular, and cardiovascular systems. - It does not primarily cause coagulation defects or hemarthrosis, and clinical features would include **tall stature**, **long limbs** (arachnodactyly), and **lens dislocation**. *Ehlers-Danlos syndrome* - This is another **connective tissue disorder** characterized by **skin hyperextensibility**, **joint hypermobility**, and tissue fragility. - While patients can have easy bruising and some bleeding tendencies due to fragile vessels, it does not typically cause severe hemarthrosis with a prolonged aPTT in the absence of trauma, and it's not a primary coagulation factor deficiency.

Question 290: A 52-year-old man comes to the physician because of malaise and dark urine for the past 5 days. He has also had recurrent episodes of sinus congestion, productive cough, and fever for 3 months. Additionally, he has noticed a rash on his arms and feet. He has seasonal allergic conjunctivitis treated with ketotifen eye drops. Vital signs are within normal limits. Examination shows several erythematous and necrotic papules on his arms and feet. He has inflamed nasopharyngeal mucosa and a perforated nasal septum. The nasal bridge is collapsed. Laboratory studies show: Hemoglobin 11.3 g/dL Leukocyte count 12000/mm3 Platelet count 270,000/mm3 ESR 55 mm/hr Serum Urea nitrogen 28 mg/dL Creatinine 2.9 mg/dL Anti-DNA antibodies negative Antineutrophil cytoplasmic antibodies positive Urine Protein 2+ Glucose negative RBC 35–37/hpf RBC casts numerous Which of the following biopsy findings is most likely to be observed in this patient?

A. Granulomatous vasculitis of small and medium-sized vessels (Correct Answer)
B. Immunoglobulin and complement deposits at the dermoepidermal junction
C. Nongranulomatous fibrinoid necrosis with infiltration of neutrophils
D. Tissue eosinophilia with granulomatous reactions
E. Transmural necrotizing arteritis and fibrinoid necrosis in muscles

Explanation: ***Granulomatous vasculitis of small and medium-sized vessels*** * This client's presentation with **recurrent sinusitis**, **perforated nasal septum** with a collapsed nasal bridge (indicating saddle nose deformity), lung involvement (productive cough), **skin rash** (erythematous and necrotic papules), and **rapidly progressive glomerulonephritis** (dark urine, elevated creatinine, RBC casts, proteinuria) is highly characteristic of **granulomatosis with polyangiitis (GPA)**. * **Positive ANCA** (specifically PR3-ANCA/c-ANCA) further supports the diagnosis of GPA, which is histopathologically defined by **granulomatous inflammation** and **vasculitis of small to medium-sized vessels**. *Immunoglobulin and complement deposits at the dermoepidermal junction* * This finding is characteristic of **Lupus Erythematosus**, particularly in the skin, where it is known as the **lupus band test**. * The patient's symptoms (e.g., severe renal involvement with RBC casts, saddle nose deformity, positive ANCA) and negative anti-DNA antibodies do not align with a diagnosis of lupus. *Nongranulomatous fibrinoid necrosis with infiltration of neutrophils* * This description is more typical of **microscopic polyangiitis (MPA)** or **ANCA-associated vasculitis without granuloma formation**. * While MPA is ANCA-positive and causes rapidly progressive glomerulonephritis and pulmonary infiltrates, it generally lacks the prominent **granulomatous inflammation** and upper airway destruction (perforated nasal septum, saddle nose deformity) seen in GPA. *Tissue eosinophilia with granulomatous reactions* * This finding is characteristic of **eosinophilic granulomatosis with polyangiitis (EGPA)**, formerly Churg-Strauss syndrome. * EGPA is strongly associated with **asthma** and **peripheral eosinophilia**, neither of which are prominent features in this patient's presentation. *Transmural necrotizing arteritis and fibrinoid necrosis in muscles* * These are hallmark features of **polyarteritis nodosa (PAN)**, which involves **medium-sized muscular arteries** but typically **spares the lungs** and **is not associated with ANCA**. * The patient's significant pulmonary involvement (productive cough) and positive ANCA make PAN an unlikely diagnosis.

Question 291: An 8-year-old boy is brought to the pediatric emergency department by his parents with a complaint of abdominal pain and diarrhea for the past week. He states that for the past two days, he has noticed blood in his stool. His parents note that they attended a neighbor’s barbecue last weekend, but otherwise have not eaten any new foods or changed their usual diet. The patient is admitted to the hospital unit for further work-up. The provider team finds that the patient’s blood is positive for Shiga-like toxin and notes the following lab values: creatinine of 4.2 mg/dL, platelet count of 50,000/mm^3, and hemoglobin of 6.0 g/dL. Which of the following additional lab findings would be consistent with the diagnosis?

A. Microthrombi within glomerular vessels on kidney biopsy (Correct Answer)
B. Blunting of villi on ileal biopsy
C. Crypt abscesses and ulcers on colonic biopsy
D. Foamy macrophages in intestinal lamina propria on duodenal biopsy
E. Sickling of red blood cells on peripheral blood smear

Explanation: ***Microthrombi within glomerular vessels on kidney biopsy*** - The clinical presentation (bloody diarrhea, elevated **creatinine**, low **platelets**, and low **hemoglobin**), a history of recent barbecue exposure, and presence of **Shiga-like toxin** are classic for **hemolytic uremic syndrome (HUS)**, typically caused by *E. coli* O157:H7. - **HUS** is characterized by a **microangiopathic hemolytic anemia**, **thrombocytopenia**, and **acute kidney injury**, which pathology often reveals **microthrombi** in the glomerular capillaries. *Blunting of villi on ileal biopsy* - **Villus blunting** is characteristic of **celiac disease** or other malabsorptive syndromes but is not directly associated with the acute presentation of bloody diarrhea, kidney injury, and thrombocytopenia seen in HUS. - **Celiac disease** typically presents with chronic diarrhea and malabsorption, not acute onset bloody diarrhea and hemolytic markers. *Crypt abscesses and ulcers on colonic biopsy* - These findings are typical of **inflammatory bowel disease (IBD)**, particularly **ulcerative colitis**, or severe infectious colitis like that caused by *Clostridium difficile*. - While there is bloody diarrhea, the presence of **Shiga-like toxin**, **thrombocytopenia**, and **acute kidney injury** points away from IBD as the primary diagnosis. *Foamy macrophages in intestinal lamina propria on duodenal biopsy* - The presence of **foamy macrophages** in the lamina propria is characteristic of **Whipple's disease**, a rare systemic bacterial infection. - This disease typically presents with chronic malabsorption, arthralgias, and neurological symptoms, which are distinct from the acute presentation of HUS. *Sickling of red blood cells on peripheral blood smear* - **Sickling of red blood cells** is diagnostic of **sickle cell anemia** or **sickle cell disease**, a genetic disorder. - While it can cause hemolytic anemia and kidney complications, the presence of **Shiga-like toxin** and the specific clinical picture strongly point to HUS, not sickle cell crisis.

Question 292: A 34-year-old man comes to the physician for evaluation of a rash on the elbows for several months. A biopsy of the affected area shows a thinned stratum granulosum as well as retained nuclei and spongiotic clusters of neutrophils in the stratum corneum. This patient's skin findings are most likely associated with which of the following conditions?

A. Hypersensitivity to gliadin
B. Hashimoto thyroiditis
C. Psoriasis (Correct Answer)
D. Insulin resistance
E. Infection with hepatitis C virus

Explanation: ***Psoriasis*** - The biopsy findings of a **thinned stratum granulosum**, **retained nuclei (parakeratosis)** and **spongiotic clusters of neutrophils in the stratum corneum (Munro microabscesses)** are characteristic histological features of psoriasis. - Psoriasis often presents as **erythematous plaques with silvery scales**, commonly on extensor surfaces like the elbows, consistent with the patient's presentation. *Hypersensitivity to gliadin* - This is associated with **dermatitis herpetiformis**, which presents with intensely pruritic vesicles and bullae, typically on extensor surfaces, but has a different histopathological picture. - Biopsy of dermatitis herpetiformis shows **subepidermal blistering** with **neutrophil and eosinophil infiltration**, and granular IgA deposition along the dermal papillae, not the findings described. *Hashimoto thyroiditis* - This is an **autoimmune disorder affecting the thyroid gland** and typically presents with symptoms of hypothyroidism, such as fatigue, weight gain, and cold intolerance. - While autoimmune conditions can sometimes coexist, Hashimoto thyroiditis does not directly cause the *specific skin rash and biopsy findings* described in this patient. *Insulin resistance* - This condition is often associated with **acanthosis nigricans**, which presents as velvety, hyperpigmented plaques, typically in skin folds. - The histological features of acanthosis nigricans show hyperkeratosis and papillomatosis, which are distinct from the findings of a thinned stratum granulosum and Munro microabscesses. *Infection with hepatitis C virus* - Hepatitis C infection can be associated with various dermatological manifestations, including **lichen planus**, **porphyria cutanea tarda**, and **leukocytoclastic vasculitis**. - None of these associated skin conditions exhibit the specific biopsy findings of a thinned stratum granulosum and Munro microabscesses seen in this case.

Question 293: A 55-year-old male presents to his primary care physician with right upper quadrant pain that has progressed over the last three months with unexplained weakness and joint pains that have been "out of the ordinary" over the last year. On history, you note the patient lives a sedentary lifestyle, rarely leaves the house, has controlled diabetes diagnosed 15 years ago, and has documented cardiomyopathy. On physical exam the man appears non-toxic, sclera are icteric, cornea appear normal, generalized pain is elicited on palpation of the right upper quadrant, and skin appears quite bronzed on his extremities. What is this patient most at risk for ten to fifteen years later due to his underlying condition?

A. Pulmonary fibrosis
B. Movement disorders
C. Colonic adenocarcinoma
D. Hepatocellular carcinoma (Correct Answer)
E. Prostatic adenocarcinoma

Explanation: ***Hepatocellular carcinoma*** - The patient's presentation with **bronzed skin**, **diabetes**, **cardiomyopathy**, and **right upper quadrant pain** strongly suggests **hemochromatosis** due to iron overload. - **Cirrhosis** is a common complication of iron overload in hemochromatosis, and **hepatocellular carcinoma** is a significant long-term risk for patients with cirrhosis. *Pulmonary fibrosis* - While chronic iron overload can affect various organs, **pulmonary fibrosis** is not a characteristic or common long-term complication of hemochromatosis. - This condition is more typically associated with environmental exposures, autoimmune diseases, or idiopathic causes. *Movement disorders* - **Movement disorders** like Parkinsonism can be seen in other neurodegenerative conditions involving metal accumulation (e.g., Wilson's disease with copper), but it is not a primary or significant long-term complication of hemochromatosis. - Neurological manifestations in hemochromatosis are rare and typically involve cognitive dysfunction rather than movement disorders. *Colonic adenocarcinoma* - While diabetes (a feature of hemochromatosis) is a mild risk factor for **colorectal cancer**, there is no direct strong link between **hemochromatosis** itself and a significantly increased risk of **colonic adenocarcinoma**. - The primary cancer risk in hemochromatosis is associated with the **liver**. *Prostatic adenocarcinoma* - There is no established direct link or significantly increased risk of **prostatic adenocarcinoma** specifically due to **hemochromatosis**. - General age-related risk factors would apply, but it's not a condition specifically exacerbated by iron overload.

Question 294: A 47-year-old woman comes to the physician for a 2-month history of fatigue, intermittent left-sided flank pain, and diffuse extremity pain. She was treated for a prolactinoma 5 years ago and has had recurrent antral and duodenal peptic ulcers despite medical therapy. Her only medication is omeprazole. Physical examination shows a moderately distended abdomen that is diffusely tender to palpation. There is mild left-sided costovertebral angle tenderness. Serum studies show a calcium of 12 mg/dL, phosphorus of 2 mg/dL, and parathyroid hormone level of 826 pg/mL. An ultrasound of the abdomen shows multiple kidney stones in the left ureteropelvic junction. This patient is most likely to have which of the following protein abnormalities?

A. Mutation of VHL tumor suppressor
B. Activation of RET proto-oncogene
C. Altered menin protein (Correct Answer)
D. Mutation in C-Kit protein
E. Altered merlin protein expression

Explanation: ***Altered menin protein*** - This patient presents with a **prolactinoma**, **recurrent peptic ulcers** (suggesting gastrinoma), and **hypercalcemia with elevated PTH** (indicating primary hyperparathyroidism). This triad of tumors (pituitary, parathyroid, and pancreatic/duodenal neuroendocrine tumors) is characteristic of **Multiple Endocrine Neoplasia type 1 (MEN1) syndrome**. - **MEN1 syndrome** is caused by germline mutations in the *MEN1* gene, which encodes the **menin tumor suppressor protein**. An altered or dysfunctional menin protein leads to uncontrolled cell growth in these endocrine glands. *Mutation of VHL tumor suppressor* - Mutations in the **VHL (Von Hippel-Lindau) tumor suppressor gene** are associated with **Von Hippel-Lindau disease**. - This syndrome is characterized by **hemangioblastomas** of the retina and CNS, **renal cell carcinoma**, **pheochromocytomas**, and pancreatic neuroendocrine tumors, which does not fit the patient's presentation. *Activation of RET proto-oncogene* - **Activating mutations in the RET proto-oncogene** are associated with **Multiple Endocrine Neoplasia type 2 (MEN2)** syndromes (MEN2A and MEN2B). - These syndromes primarily involve **medullary thyroid carcinoma**, pheochromocytomas, and either primary hyperparathyroidism (MEN2A) or mucosal neuromas/Marfanoid habitus (MEN2B), none of which are present in this case. *Mutation in C-Kit protein* - Mutations in the **C-Kit protein** (encoded by the *KIT* gene) are primarily associated with certain types of **gastrointestinal stromal tumors (GISTs)** and **mastocytosis**. - These conditions do not explain the pituitary adenoma, hyperparathyroidism, or the specific constellation of symptoms observed in the patient. *Altered merlin protein expression* - **Altered merlin protein expression** (encoded by the *NF2* gene) is characteristic of **Neurofibromatosis type 2 (NF2)**. - NF2 is primarily associated with **bilateral vestibular schwannomas**, other schwannomas, meningiomas, and ependymomas, without the endocrine tumors seen in this patient.

Question 295: A 51-year-old woman with Sjogren’s syndrome presents to her physician for suddenly developed palpitations. She feels more anxious than usual and has had difficulty sleeping well for the past 2 weeks. She has lost 2 kg (4.4 lb) since her last routine appointment 6 months ago. She also has had diarrhea and often feels like her heart is beating very quickly. On physical examination, her skin appears warm and moist. Her reflexes are hyperactive. Her thyroid is moderately enlarged and is non-tender. She has mild dry eyes and dry mouth. Her blood pressure is 136/88 mm Hg, pulse is 76/min, respirations are 17/min and temperature is 36.7°C (98.1°F). Which of the following pathologic findings is this patient likely to have?

A. Lymphoma
B. Chronic lymphocytic thyroiditis (Correct Answer)
C. Silent thyroiditis
D. Fibrous thyroiditis
E. Granulomatous thyroiditis

Explanation: ***Chronic lymphocytic thyroiditis*** - This patient with **Sjogren's syndrome** (an autoimmune disease) presenting with hyperthyroidism most likely has **Hashimoto's thyroiditis** (chronic lymphocytic thyroiditis) in its early hyperthyroid phase, known as **"Hashitoxicosis"**. - Patients with one autoimmune disease have an increased risk of developing other autoimmune conditions, and **Hashimoto's thyroiditis** frequently coexists with Sjogren's syndrome. - The pathologic finding is **lymphocytic infiltration with germinal center formation** in the thyroid, along with destruction of thyroid follicles. - Early in Hashimoto's disease, destruction of follicles releases stored thyroid hormone, causing **transient hyperthyroidism** before eventual progression to hypothyroidism. - The **enlarged, non-tender thyroid** is characteristic of Hashimoto's thyroiditis. *Lymphoma* - While Sjogren's syndrome does increase the risk of **B-cell lymphoma** (particularly MALT lymphoma in salivary glands), this patient's presentation is classic for **hyperthyroidism from thyroiditis**, not lymphoma. - Primary thyroid lymphoma typically presents as a **rapidly enlarging, firm thyroid mass** with **compressive symptoms** (dysphagia, dyspnea, hoarseness), which are absent here. *Silent thyroiditis* - Also called **painless thyroiditis** or **postpartum thyroiditis**, this involves transient thyroid inflammation with a hyperthyroid phase followed by hypothyroidism. - While it can occur, the patient's **established autoimmune disease (Sjogren's syndrome)** makes **chronic lymphocytic thyroiditis (Hashimoto's)** a more likely underlying pathology, as these conditions frequently coexist. - Silent thyroiditis is typically a **self-limited condition** without the chronic lymphocytic infiltration seen in Hashimoto's. *Fibrous thyroiditis* - **Riedel's thyroiditis** is a rare condition characterized by **dense fibrous tissue replacement** of the thyroid, often extending beyond the capsule to involve surrounding structures. - It presents as a **hard, fixed, "woody" thyroid mass** and typically causes **hypothyroidism** due to thyroid destruction, not hyperthyroidism. - The patient's **moderately enlarged, non-tender thyroid** does not fit this presentation. *Granulomatous thyroiditis* - **De Quervain's (subacute granulomatous) thyroiditis** typically follows a **viral upper respiratory infection** and presents with a **painful, tender thyroid gland** and systemic symptoms (fever, malaise). - The pathologic finding is **granulomatous inflammation** with giant cells. - The **absence of thyroid tenderness** and the presence of another autoimmune condition (Sjogren's) make chronic lymphocytic thyroiditis more likely than granulomatous thyroiditis.

Question 296: An investigator is studying the outcomes of a malaria outbreak in an endemic region of Africa. 500 men and 500 women with known malaria exposure are selected to participate in the study. Participants with G6PD deficiency are excluded from the study. The clinical records of the study subjects are reviewed and their peripheral blood smears are evaluated for the presence of Plasmodium trophozoites. Results show that 9% of the exposed population does not have clinical or laboratory evidence of malaria infection. Which of the following best explains the absence of infection seen in this subset of participants?

A. Translocation of c-myc gene
B. Glutamic acid substitution in the β-globin chain (Correct Answer)
C. Inherited mutation affecting ribosome synthesis
D. Inherited defect in erythrocyte membrane ankyrin protein
E. Defective X-linked ALA synthase gene

Explanation: ***Glutamic acid substitution in the β-globin chain*** - This describes **sickle cell trait (heterozygous HbS)**, which confers significant protection against severe malaria, explaining the absence of infection despite exposure. - Individuals with sickle cell trait have **abnormally shaped red blood cells** under low oxygen conditions, which are less hospitable for **Plasmodium falciparum** growth and are more rapidly cleared by the spleen. *Translocation of c-myc gene* - A **t(8;14) translocation of the c-myc gene** is characteristic of **Burkitt lymphoma**, a B-cell malignancy, and has no protective effect against malaria. - This genetic alteration leads to overexpression of **c-myc**, a proto-oncogene, contributing to uncontrolled cell growth. *Inherited mutation affecting ribosome synthesis* - Defects in **ribosome synthesis** can lead to various **ribosomopathies**, affecting cell proliferation and function, but they are not known to provide protection against malaria. - Such mutations often result in syndromes with **developmental abnormalities** or **bone marrow failure**. *Inherited defect in erythrocyte membrane ankyrin protein* - Defects in **ankyrin protein** are associated with **hereditary spherocytosis**, causing fragile, spherical red blood cells that are prematurely destroyed. - While hereditary spherocytosis can reduce malaria severity, its role in preventing initial infection is less pronounced, and the question refers to absence of infection. *Defective X-linked ALA synthase gene* - A defective **X-linked ALA synthase gene** (ALAS2) is associated with **X-linked sideroblastic anemia**, causing impaired heme synthesis. - This condition is characterized by **microcytic, hypochromic anemia** and iron overload in erythroid precursors, with no known protective effect against malaria.

Question 297: A four-year-old boy is brought to his pediatrician by his mother for recurrent nosebleeds. The mother reports that the boy has had five nosebleeds within the past 2 weeks, each lasting between 15 and 20 minutes. The patient was born at term and has been hospitalized twice for pneumonia treatment. There is no family history of serious illness. The patient is at the 8th percentile for height and the 30th percentile for weight. Vital signs are within normal limits. Examination shows a small, thin child with two flat, dark brown areas of hyperpigmentation across the upper back and a similar discoloration on the left buttock. There is bilateral esotropia. Laboratory studies show a hemoglobin concentration of 9.3 g/dL, mean corpuscular volume of 107 μm3, leukocyte count of 3,800/mm3, and platelet count of 46,000/mm3. Which of the following is the most likely underlying cause of this patient's condition?

A. Defect in DNA crosslink repair (Correct Answer)
B. Postviral autoimmune reaction
C. Parvovirus B19 infection
D. Recent history of NSAID use
E. Mutation in WAS protein

Explanation: **Defect in DNA crosslink repair** - This constellation of symptoms, including **pancytopenia** (low hemoglobin, leukocytes, and platelets), **macrocytosis** (high MCV), **short stature**, recurrent infections, and **cafe-au-lait spots**, is highly suggestive of **Fanconi anemia**. - **Fanconi anemia** is an autosomal recessive disorder caused by a defect in **DNA crosslink repair**, leading to increased chromosomal fragility and bone marrow failure. *Postviral autoimmune reaction* - While a postviral autoimmune reaction could cause pancytopenia, it typically does not present with the **congenital abnormalities** (short stature, cafe-au-lait spots, esotropia) seen in this patient. - There is no direct evidence of a recent viral illness preceding the onset of pancytopenia in this case. *Parvovirus B19 infection* - **Parvovirus B19** can cause transient aplastic crisis, particularly in individuals with pre-existing hematological conditions, leading to severe anemia. - However, it would not explain the **pancytopenia**, **macrocytosis**, and the characteristic **physical findings** like cafe-au-lait spots and short stature. *Recent history of NSAID use* - **NSAIDs** can cause various side effects, including gastrointestinal bleeding (exacerbating anemia) or rarely drug-induced aplastic anemia. - However, NSAID use does not account for the **pancytopenia**, **macrocytosis**, recurrent infections, and the specific **congenital anomalies** noted. *Mutation in WAS protein* - A **mutation in the WAS protein** is responsible for **Wiskott-Aldrich syndrome**, which presents with recurrent infections, thrombocytopenia (leading to epistaxis), and eczema. - This syndrome typically involves **micro-thrombocytopenia** (small platelets) and immunodeficiency, but it does not cause **macrocytosis**, pancytopenia beyond thrombocytopenia, or the skeletal/cutaneous abnormalities like cafe-au-lait spots.

Question 298: A 29-year-old woman presents with shortness of breath and chest pain for the past week. She says her chest pain is aggravated by deep breathing and she becomes short of breath while walking upstairs in her home. She also has been feeling feverish and fatigued for the past week, as well as pain in her wrists, hands, and left knee. Review of systems is significant for a 4.5 kg (10.0 lb) weight loss over the previous month. Past medical history consists of 2 spontaneous abortions, both of which occurred in the 1st trimester. On physical examination, there is a pink rash present over her face, which is aggravated by exposure to sunlight. There are decreased breath sounds on the right. A chest radiograph is performed which reveals evidence of a right pleural effusion. Serum ANA and anti-dsDNA autoantibodies are positive. Urinalysis is unremarkable. Errors with which of the following is most likely to lead to her disease?

A. Intrinsic pathway
B. Cytotoxic CD8+ T cells
C. Bcl-2 overexpression
D. Necrosis
E. Fas-FasL interaction (Correct Answer)

Explanation: ***Fas-FasL interaction*** - This patient presents with multiple symptoms suggestive of **systemic lupus erythematosus (SLE)**, including photosensitive rash, arthritis, serositis (pleural effusion), weight loss, recurrent spontaneous abortions, and positive ANA/anti-dsDNA. - Genetic defects in the **Fas** or **Fas ligand (FasL) apoptotic pathway** are strongly associated with increased risk of autoimmunity, particularly SLE, as they impair the deletion of autoreactive lymphocytes. *Intrinsic pathway* - The intrinsic apoptotic pathway is primarily activated by intracellular stress and mitochondria-dependent signals. - While essential for cell death, defects in the intrinsic pathway are not as specifically implicated in the pathogenesis of SLE as the Fas-FasL (extrinsic) pathway. *Cytotoxic CD8+ T cells* - **CD8+ T cells** are primarily involved in killing virally infected or cancerous cells and are crucial for cellular immunity. - While involved in some autoimmune processes, their dysfunction is not the primary or most common error leading to the development of SLE, which is largely mediated by autoantibodies. *Bcl-2 overexpression* - **Bcl-2** is an anti-apoptotic protein, and its overexpression inhibits apoptosis. - While Bcl-2 overexpression could theoretically prevent the deletion of autoreactive cells, specific defects in the direct Fas-FasL signaling pathway are more directly and commonly linked to the immune dysregulation seen in SLE. *Necrosis* - **Necrosis** is an uncontrolled form of cell death often associated with inflammation and tissue damage. - While certainly present in tissues affected by SLE due to inflammation, necrosis itself is a consequence of the disease process, not an upstream error in cell death regulation that leads to the autoimmunity of SLE.

Question 299: A 51-year-old African American man presents to his primary care physician’s office for an annual visit. He has no major concerns and says that he has been healthy for the last year. His past medical history is significant for diabetes as well as long standing hypertension that has developed gradually since his 30's; however, he has refused to take any medications. Physical exam shows no abnormal findings. Routine laboratory testing reveals the following: Serum creatinine concentration: 1.5 mg/dL Blood urea nitrogen: 31 mg/dL Based on these results, urine studies are conducted that reveal mild proteinuria of less than 1 g/day and no casts. Which of the following is most likely associated with the cause of this patient's elevated creatinine?

A. String of beads on angiography
B. Kimmelstiel-Wilson lesions (Correct Answer)
C. Apple-green birefringent lesions
D. Renal cortex necrosis
E. Flea-bitten kidney

Explanation: **Kimmelstiel-Wilson lesions** - The patient has a history of long-standing diabetes and hypertension, which are the primary risk factors for **diabetic nephropathy**. - **Kimmelstiel-Wilson lesions** are nodular glomerulosclerosis pathognomonic for **diabetic nephropathy**, characterized by hyaline nodules in the mesangium. - This is the most likely cause given the combination of diabetes, mild proteinuria (<1 g/day), and chronic renal insufficiency. *String of beads on angiography* - This finding is characteristic of **fibromuscular dysplasia**, a non-inflammatory vascular disease that can cause **renal artery stenosis**. - While renal artery stenosis can cause hypertension and renal impairment, the patient's long-standing diabetes and gradual progression make diabetic nephropathy a more probable cause. *Apple-green birefringent lesions* - This describes the characteristic staining of **amyloid deposits** with **Congo red stain** under polarized light. - While amyloidosis can cause renal failure with proteinuria, it is less common than diabetic nephropathy in a patient with long-standing diabetes and the typical presentation described. *Renal cortex necrosis* - This is a rare and severe form of **acute kidney injury** often associated with conditions like severe sepsis, obstetric complications, or disseminated intravascular coagulation. - The patient's history of gradual onset hypertension and diabetes, along with mild proteinuria and elevated creatinine, points to a chronic rather than acute process. *Flea-bitten kidney* - This describes the gross appearance of kidneys in **malignant hypertension**, showing petechial hemorrhages on the renal surface. - While the patient has long-standing hypertension, the presentation suggests chronic kidney disease from diabetic nephropathy rather than acute malignant hypertension, which would present with markedly elevated blood pressure and acute kidney injury.

Question 300: A 35-year-old man presents with acute onset of chest pain, trouble breathing, and abdominal pain. He says he had recently been training for a triathlon competition when, over the past week, he noticed that he was getting more tired than usual. He figured that it was due to his age since most of the people training with him were in their 20s. However, after completing a particularly difficult workout over this last weekend he noticed left-sided chest pain that did not radiate, and abdominal pain, worse on the right side. The pain persisted after he stopped exercising. This morning he noticed red urine. The patient reports similar past episodes of red urine after intense exercise or excessive alcohol intake for the past 5 years, but says it has never been accompanied by pain. Past medical history is significant for a urinary tract infection last week, treated with trimethoprim-sulfamethoxazole. Physical examination is significant for a systolic flow murmur loudest at the right upper sternal border and right upper quadrant tenderness without guarding or rebound. Laboratory findings are significant for the following: Hemoglobin 8.5 g/dL Platelets 133,000/µL Total bilirubin 6.8 mg/dL LDH 740 U/L Haptoglobin 25 mg/dL An abdominal MRI with contrast is performed which reveals hepatic vein thrombosis. Which of the following laboratory tests would most likely to confirm the diagnosis in this patient?

A. Peripheral blood smear
B. Sucrose hemolysis test
C. Hemoglobin electrophoresis
D. Flow cytometry (Correct Answer)
E. Genetic testing

Explanation: ***Flow cytometry*** - **Flow cytometry** is the gold standard for diagnosing **paroxysmal nocturnal hemoglobinuria (PNH)** by detecting the absence of **GPI-anchored proteins (CD55 and CD59)** on the surface of red blood cells, granulocytes, and monocytes. - The patient's symptoms (fatigue, exertional dyspnea, acute chest and abdominal pain, dark urine after exercise, hemolytic anemia with low haptoglobin and elevated LDH, and hepatic vein thrombosis) are classic for PNH in the setting of physical stress and prior infection. *Peripheral blood smear* - A peripheral blood smear might show features of **hemolytic anemia** (e.g., **polychromasia**, occasionally spherocytes or schistocytes if there is concurrent microangiopathy), but it is not specific for PNH. - PNH is characterized by a defect in red blood cell surface proteins, which is not directly visualizable on a standard blood smear. *Sucrose hemolysis test* - The **sucrose hemolysis test** (or Zucker-Heller test) is an older screening test for PNH that detects complement-mediated lysis of red blood cells in a low ionic strength solution. - It has been largely replaced by flow cytometry due to its lower sensitivity and specificity compared to modern methods. *Hemoglobin electrophoresis* - **Hemoglobin electrophoresis** is used to detect abnormal hemoglobin variants, such as those seen in **sickle cell disease** or **thalassemias**. - While these can cause hemolytic anemia, they do not present with the specific constellation of symptoms, including thrombotic episodes like hepatic vein thrombosis, characteristic of PNH. *Genetic testing* - Genetic testing for mutations in the **PIGA gene**, which is responsible for the GPI anchor defect in PNH, can be performed but is generally reserved for atypical cases or research. - It is not the primary diagnostic test and is typically performed after flow cytometry has established the diagnosis.

Question 301: A 29-year-old woman comes to the clinic for complaints of fatigue and palpitations for the past 3 days. She reports that even standing up and walking around takes “a lot of energy.” She was forced to call in sick today to her work as a kindergarten teacher. She denies any previous episodes but does endorse symmetric joint pain of her hands, wrists, knees, and ankles that was worse in the morning over the past week that self-resolved. She also reports a runny nose and congestion. Past medical history is unremarkable. Physical examination demonstrates splenomegaly, pallor, and generalized weakness; there is no lymphadenopathy. What is the most likely explanation for this patient’s symptoms?

A. Rheumatoid arthritis
B. Substitution of glutamic acid with valine at the beta chain
C. Anemia of chronic disease
D. Mutation of ankyrin
E. Infection with Epstein-Barr virus (Correct Answer)

Explanation: **Infection with Ebstein-Barr virus** - The patient's symptoms of **fatigue**, **palpitations**, **splenomegaly**, and recent **runny nose/congestion** are highly suggestive of **infectious mononucleosis**, which is caused by the Epstein-Barr virus (EBV). - The transient, symmetric polyarthralgia followed by resolution is consistent with a viral prodrome, and the pallor and generalized weakness point towards **anemia**, a common complication of infectious mononucleosis. *Rheumatoid arthritis* - While **symmetric joint pain** is characteristic of rheumatoid arthritis, the rapid onset, transient nature, and association with a viral-like prodrome and splenomegaly make this diagnosis less likely. - Rheumatoid arthritis typically causes chronic, progressive joint inflammation and destruction, not self-resolving symptoms followed by systemic signs like splenomegaly. *Substitution of glutamic acid with valine at the beta chain* - This describes the genetic mutation responsible for **sickle cell anemia**. The patient's symptoms are acute and associated with a viral illness, not chronic hemolytic anemia or sickle cell crisis. - There is no mention of a history of anemia or family history to suggest a genetic hemoglobinopathy. *Anemia of chronic disease* - Anemia of chronic disease typically presents with more insidious onset and is associated with chronic inflammatory conditions, infections, or malignancies. - While fatigue and pallor are present, the acute presentation, viral prodrome, and splenomegaly point towards a more acute infectious process rather than a chronic disease. *Mutation of ankyrin* - A mutation in ankyrin or spectrin is associated with **hereditary spherocytosis**, a genetic hemolytic anemia. - This condition usually presents with chronic or episodic hemolysis, jaundice, and often a family history of anemia, which are not described in this patient's acute presentation.

Question 302: A 52-year-old man comes to the physician because of right knee pain and swelling for 2 days. Four days ago, he tripped at home and landed on his knees. He reports an episode of diarrhea 3 weeks ago that resolved after 4 days without treatment. He has a history of hypertension and hypercholesterolemia, and was recently diagnosed with parathyroid disease. He drinks 1–2 ounces of whiskey daily and occasionally more on weekends. His brother has ankylosing spondylitis. Vital signs are within normal limits. Examination of the right leg shows an abrasion below the patella. There is swelling and tenderness of the right knee; range of motion is limited by pain. Arthrocentesis of the right knee joint yields 15 mL of cloudy fluid with a leukocyte count of 26,300/mm3 (91% segmented neutrophils). Microscopic examination of the synovial fluid under polarized light shows rhomboid-shaped, weakly positively birefringent crystals. Which of the following is the strongest predisposing factor for this patient's condition?

A. Alcohol consumption
B. Dyslipidemia
C. Local skin abrasion
D. Hyperparathyroidism (Correct Answer)
E. Recent gastrointestinal infection

Explanation: ***Hyperparathyroidism*** - The presence of **rhomboid-shaped, weakly positively birefringent crystals** in the synovial fluid indicates **calcium pyrophosphate dihydrate (CPPD) crystal deposition disease**, also known as pseudogout. - **Hyperparathyroidism** leads to **increased calcium concentration**, which is a significant predisposing factor for CPPD crystal formation and subsequent pseudogout attacks. *Alcohol consumption* - While excessive alcohol intake is a risk factor for **gout** (uric acid crystal deposition), it is **not a direct or strong predisposing factor for pseudogout**. - The crystals found in this patient are characteristic of pseudogout, not gout. *Dyslipidemia* - **Dyslipidemia** (high cholesterol) is a risk factor for cardiovascular disease but has **no direct causal link** to the formation of calcium pyrophosphate crystals or pseudogout. - It is a comorbidity often seen in older adult populations but is not a predisposing factor for this specific arthritic condition. *Local skin abrasion* - A **local skin abrasion** could potentially present a portal of entry for infection leading to **septic arthritis**, but the presence of specific crystals in the synovial fluid points away from a primary bacterial infection. - While trauma can sometimes trigger a pseudogout flare in individuals with CPPD, the abrasion itself is not the underlying predisposing factor for the crystal formation. *Recent gastrointestinal infection* - A recent gastrointestinal infection is a known trigger for **reactive arthritis**, which presents with sterile synovitis, but typically involves different clinical features and no crystals. - This patient's symptoms and synovial fluid analysis (CPPD crystals) are not consistent with reactive arthritis.

Question 303: A 63-year-old man is brought to the emergency department by the police after he was found in the streets lying unconscious on the ground. Both of his pupils are normal in size and reactive to light. There are no obvious signs of head trauma. The finger prick test shows a blood glucose level of 20 mg/dL. He has been brought to the emergency department due to acute alcohol intoxication several times. The vital signs include: blood pressure 100/70 mm Hg, heart rate 110/min, respiratory rate 22/min, and temperature 35℃ (95℉). On general examination, he is pale looking and disheveled with an odor of EtOH. On physical examination, the abdomen is soft and non-tender with no hepatosplenomegaly. After giving a bolus of intravenous dextrose, thiamine, and naloxone, he spontaneously opens his eyes. Blood and urine samples are drawn for toxicology screening. The blood alcohol level comes out to be 300 mg/dL. What will be the most likely laboratory findings in this patient?

A. Howell-Jolly bodies
B. Macrocytosis MCV > 100fL (Correct Answer)
C. Sickle cells
D. Hypersegmented neutrophils
E. Schistocytes

Explanation: ***Macrocytosis MCV > 100fL*** - **Chronic alcohol abuse** is the most common cause of macrocytosis in clinical practice, occurring through **multiple mechanisms**: direct bone marrow toxicity, interference with folate metabolism, and effects on lipid incorporation into RBC membranes. - **Macrocytosis is nearly universal** in chronic alcoholics and can occur **even without folate or B12 deficiency**, making it the most consistent laboratory finding. - The patient's history of recurrent acute alcohol intoxication, disheveled appearance, and blood alcohol level of 300 mg/dL strongly indicate chronic alcoholism. *Howell-Jolly bodies* - These are **nuclear remnants** in red blood cells that indicate **hyposplenism or asplenism**, meaning the spleen is not effectively removing these inclusions. - There is no clinical evidence of splenic dysfunction, hyposplenism, or prior splenectomy in this patient. *Sickle cells* - **Sickle cells** are characteristic of **sickle cell disease**, an inherited hemolytic disorder caused by a mutation in the beta-globin gene. - The clinical presentation is related to alcohol toxicity, not a hemolytic crisis or chronic hemolytic anemia. *Hypersegmented neutrophils* - **Hypersegmented neutrophils** (≥ 5 lobes) are a hallmark of **megaloblastic anemia** due to **vitamin B12 or folate deficiency**. - While chronic alcoholics can develop folate deficiency and may have hypersegmented neutrophils in **advanced cases**, this finding is **less consistent** than macrocytosis. - **Macrocytosis appears earlier** and is present in virtually all chronic alcoholics, whereas hypersegmented neutrophils require significant nutritional deficiency to develop. - The question asks for the **most likely** finding, making macrocytosis the better answer. *Schistocytes* - **Schistocytes** are **fragmented red blood cells** indicating **microangiopathic hemolytic anemia** (e.g., DIC, TTP, HUS) or mechanical hemolysis (e.g., prosthetic heart valves). - The patient's presentation does not suggest intravascular hemolysis, coagulopathy, or mechanical RBC destruction.

Question 304: A 4-year-old boy presents to the emergency department with a 1 hour history of severe knee pain after he bumped his knee against a door. He has no past medical history though his parents say that he seems to bruise fairly easily. His parents say that they are afraid he may have accidentally taken his grandfather's warfarin medication. On presentation, he is found to have an erythematous, warm, swollen knee. Based on this presentation, a panel of laboratory tests are ordered with the following results: Bleeding time: 3 minutes Prothrombin time (PT): 12 seconds Partial thromboplastin time (PTT): 56 seconds Mixing studies show correction of the PTT Which of the following is most likely the cause of this patient's symptoms?

A. Production of an autoantibody
B. Warfarin toxicity
C. Platelet defect
D. Deficiency in a coagulation factor (Correct Answer)
E. Deficiency of von Willebrand factor

Explanation: ***Deficiency in a coagulation factor*** - The prolonged **partial thromboplastin time (PTT)** with a normal **prothrombin time (PT)** indicates an issue in the **intrinsic coagulation pathway**, suggesting a deficiency in factors VIII, IX, XI, or XII. - **Mixing studies show correction of the PTT**, which confirms a **factor deficiency** rather than an inhibitor (autoantibody). In factor deficiency, adding normal plasma provides the missing factor, correcting the PTT. - The presentation of **severe knee pain** after minor trauma, along with easy bruising, strongly points towards **hemarthrosis**, a classic sign of **hemophilia A or B**, caused by deficiency in factor VIII or IX respectively. - The patient's young age (4 years) and clinical presentation are consistent with **congenital hemophilia**. *Production of an autoantibody* - An autoantibody, such as a **factor VIII inhibitor** or **lupus anticoagulant**, would also prolong the PTT, but mixing studies would show **no correction** or incomplete correction because the autoantibody in the patient's plasma inhibits the factors in the normal plasma. - Since mixing studies show **correction** in this case, an autoantibody is ruled out. *Warfarin toxicity* - **Warfarin** primarily inhibits **vitamin K-dependent factors (II, VII, IX, X)**, affecting the **extrinsic** and **common pathways**, which would prolong the **PT** first and more significantly than the PTT. - The patient's **normal PT** rules out warfarin toxicity. *Platelet defect* - A **platelet defect** (e.g., thrombocytopenia or platelet dysfunction) would typically lead to a prolonged **bleeding time**, but the patient's bleeding time is normal (3 minutes). - Platelet defects are also associated with **mucocutaneous bleeding** (e.g., petechiae, purpura, epistaxis), not typically deep joint bleeding or hemarthrosis. *Deficiency of von Willebrand factor* - A deficiency in **von Willebrand factor (vWF)** would typically cause a prolonged **bleeding time** due to impaired platelet adhesion, which is normal in this patient. - While severe vWF deficiency (Type 3) can also cause a prolonged PTT (as vWF carries and protects factor VIII from degradation), the primary laboratory finding would be an **elevated bleeding time**, which is not present here.

Question 305: A previously healthy 17-year-old boy is brought to the emergency department by his mother for further evaluation after elective removal of his wisdom teeth. During the procedure, the patient had persistent bleeding from the teeth's surrounding gums. Multiple gauze packs were applied with minimal effect. The patient has a history of easy bruising. The mother says her brother had similar problems when his wisdom teeth were removed, and that he also has a history of easy bruising and joint swelling. The patient takes no medications. His temperature is 37°C (98.6°F), pulse is 90/min, and blood pressure is 108/74 mm Hg. Laboratory studies show: Hematocrit 35% Leukocyte count 8,500/mm3 Platelet count 160,000/mm3 Prothrombin time 15 sec Partial thromboplastin time 60 sec Bleeding time 6 min Fibrin split products negative Serum Urea nitrogen 20 mg/dL Creatinine 1.0 mg/dL Bilirubin Total 1.0 mg/dL Direct 0.5 mg/dL Lactate dehydrogenase 90 U/L Peripheral blood smear shows normal-sized platelets. Which of the following is the most likely diagnosis?

A. Hemophilia
B. Bernard-Soulier syndrome
C. Glanzmann thrombasthenia
D. Von Willebrand disease (Correct Answer)
E. Immune thrombocytopenia

Explanation: ***Von Willebrand disease*** - This patient presents with a **history of easy bruising** and **persistent bleeding after a surgical procedure**, along with a **prolonged bleeding time** and **prolonged PTT**. The family history of similar bleeding issues and joint swelling (which can represent hemarthroses) in his maternal uncle is also highly suggestive of an inherited bleeding disorder. These findings, particularly the prolonged bleeding time with normal platelet count and the prolonged PTT (due to Factor VIII deficiency), are classic for **von Willebrand disease (vWD)**. - Von Willebrand disease is the **most common inherited bleeding disorder**, characterized by a deficiency or dysfunction of **von Willebrand factor (vWF)**. vWF plays a dual role in hemostasis: it mediates platelet adhesion to the subendothelium (reflected by prolonged bleeding time) and also chaperones and protects **Factor VIII** from degradation, leading to a mild to moderate deficiency of Factor VIII (reflected by prolonged PTT). *Hemophilia* - Hemophilia A (Factor VIII deficiency) or Hemophilia B (Factor IX deficiency) would present with a **prolonged PTT** but a **normal bleeding time** and **platelet count**. - While the patient has a prolonged PTT and family history of joint swelling (consistent with hemarthroses seen in hemophilia), his **prolonged bleeding time** is inconsistent with hemophilia alone. *Bernard-Soulier syndrome* - This syndrome is characterized by a defect in **platelet adhesion** due to a deficiency of **glycoprotein Ib (GP Ib)**, leading to **macrothrombocytopenia** (large platelets and reduced platelet count) and a **prolonged bleeding time**. - The patient has a **normal platelet count** and **normal-sized platelets** on peripheral smear, which makes Bernard-Soulier syndrome less likely. *Glanzmann thrombasthenia* - This is a disorder of **platelet aggregation** due to a deficiency in **glycoprotein IIb/IIIa (GP IIb/IIIa)**, resulting in a **prolonged bleeding time** despite a normal platelet count and morphology. - However, Glanzmann thrombasthenia typically presents with a **normal PTT**, whereas this patient has a **prolonged PTT**, making it less likely. *Immune thrombocytopenia* - **Immune thrombocytopenia (ITP)** is characterized by an **isolated low platelet count** (thrombocytopenia) and a **prolonged bleeding time**, with other coagulation parameters (PT, PTT) being normal. - The patient has a **normal platelet count** (160,000/mm3) and a **prolonged PTT**, which is inconsistent with ITP.

Question 306: A 34-year-old man presents with acute-onset fever and weakness followed by shifting neurologic deficits (aphasia, motor deficits), which have lasted for a few days. His relatives add that his quantity of urine has reduced significantly over the last few days. He has never had any similar symptoms. Laboratory findings are significant for the following: Hb 8.6 g/dL WBC 6.5 × 1000/mm3 Platelets 43 × 1000/mm3 Cr 3.1 mg/dL BUN 25 mg/dL Na+ 136 mg/dL K+ 4.2 mg/dL Cl- 101 mg/dL HCO3- 24 mg/dL Glu 101 mg/dL Examination of the peripheral smear shows the presence of schistocytes, helmet cells, and spherocytes. Which of the following is true regarding this patient's condition?

A. A platelet transfusion should be given.
B. Bleeding time will be normal.
C. The condition is caused by the deficiency of a sodium transporter.
D. Plasmapheresis is the treatment of choice. (Correct Answer)
E. Splenectomy should be performed as early as possible.

Explanation: ***Plasmapheresis is the treatment of choice.*** - This patient presents with the classic pentad of **Thrombotic Thrombocytopenic Purpura (TTP)**: **fever, neurologic deficits, renal impairment, microangiopathic hemolytic anemia (schistocytes, low Hb), and thrombocytopenia (low platelets)**. - **Plasmapheresis** (plasma exchange) is the definitive treatment for TTP, as it removes antibodies targeting **ADAMTS13** and replaces deficient ADAMTS13 with healthy plasma. *A platelet transfusion should be given.* - **Platelet transfusions are generally contraindicated in TTP** because they can worsen thrombosis by adding more platelets to an already hypercoagulable state. - This can exacerbate the microvascular occlusions responsible for organ damage. *Bleeding time will be normal.* - The patient has severe **thrombocytopenia (43 × 1000/mm³)** which directly impairs primary hemostasis. - **Bleeding time** is a measure of platelet function and will be **prolonged** significantly in patients with such low platelet counts. *The condition is caused by the deficiency of a sodium transporter.* - TTP is caused by a severe deficiency or inhibition of the **ADAMTS13 enzyme**, which is a metalloprotease responsible for cleaving **ultralarge von Willebrand factor (vWF)** multimers. - A deficiency in a sodium transporter is unrelated to TTP and would be associated with conditions like certain renal tubular disorders. *Splenectomy should be performed as early as possible.* - **Splenectomy** is not a primary or early treatment for TTP. - While it may be considered in rare, refractory cases of TTP that do not respond to plasmapheresis and rituximab, it is not the initial or preferred approach due to its invasiveness and potential complications.

Question 307: A 43-year-old woman comes to the office with a 5-day history of a rash. She's had a rash across her neck, shoulders, and the palms of her hands for the past five days. She's also had large-volume watery diarrhea for the same period of time. Past medical history is notable for acute myeloid leukemia, for which she received a stem cell transplant from a donor about two months prior. Physical exam reveals a faint red maculopapular rash across her neck, shoulders, and hands, as well as an enlarged liver and spleen. Labs are notable for a total bilirubin of 10. Which of the following is the mechanism of this patient's pathology?

A. Drug hypersensitivity reaction
B. Host CD8+ T cells against graft antigens
C. Graft T cells against host antigens (Correct Answer)
D. Pre-existing host antibodies against graft antigens
E. Host antibodies that have developed against graft antigens

Explanation: ***Graft T cells against host antigens*** - This patient's symptoms (rash, diarrhea, hepatosplenomegaly, elevated bilirubin) occurring after a stem cell transplant are classic for **graft-versus-host disease (GVHD)**. - GVHD occurs when **donor T cells** from the graft recognize the recipient's (host's) tissues as foreign and mount an immune attack against them. *Drug hypersensitivity reaction* - While drug rashes can occur, the widespread nature, severe GI involvement (large-volume watery diarrhea), and liver dysfunction, especially in the context of a recent stem cell transplant, point away from a simple **hypersensitivity reaction**. - A drug reaction would typically not cause such severe systemic effects or splenomegaly. *Host CD8+ T cells against graft antigens* - This describes **host-versus-graft rejection**, where the recipient's immune system attacks the transplanted cells. - In a stem cell transplant setting, the host's immune system is typically severely suppressed to prevent this, and the clinical picture here is characteristic of the donor cells attacking the host. *Pre-existing host antibodies against graft antigens* - Pre-existing antibodies would cause a **hyperacute or acute rejection** much earlier after transplantation, often within minutes to days. - This patient's symptoms developed two months post-transplant, which is more typical for acute GVHD, mediated by T cells. *Host antibodies that have developed against graft antigens* - The development of host antibodies against graft antigens would lead to **humoral rejection**, which typically manifests differently and less commonly causes the specific constellation of symptoms seen here (skin rash, severe diarrhea, cholestatic hepatitis in the context of stem cell transplant). - T-cell-mediated responses are the primary drivers of GVHD in this scenario.

Question 308: A 29-year-old African American woman presents with incidentally noted bilateral hilar lymphadenopathy on a recent chest radiograph for the evaluation of pneumonia 1 month earlier. Upon questioning, she reports a cough and dyspnea. The report provided by a previous ophthalmologic consultation did not demonstrate any eye abnormalities. Clinical laboratory pathologic analysis reveals an elevated level of angiotensin-converting enzyme. Her physical examination reveals no obvious abnormalities. Her vital signs show a heart rate of 76/min, respiratory rate of 16/min, and blood pressure of 123/73 mm Hg. Of the following options, which is the mechanism of the reaction causing hilar adenopathy in this patient?

A. Type III and IV–mixed immune complex and cell-mediated hypersensitivity reactions
B. Type I–anaphylactic hypersensitivity reaction
C. Type II–cytotoxic hypersensitivity reaction
D. Type IV–cell-mediated (delayed) hypersensitivity reaction (Correct Answer)
E. Type III–immune complex-mediated hypersensitivity reaction

Explanation: ***Type IV–cell-mediated (delayed) hypersensitivity reaction*** - Sarcoidosis, characterized by **bilateral hilar lymphadenopathy**, cough, dyspnea, and elevated **angiotensin-converting enzyme (ACE)** levels, is a classic example of a **Type IV hypersensitivity reaction**. - This reaction involves the accumulation of **T lymphocytes** and macrophages, leading to the formation of **non-caseating granulomas** in affected tissues. *Type III and IV–mixed immune complex and cell-mediated hypersensitivity reactions* - While sarcoidosis involves a chronic inflammatory process and granuloma formation (Type IV), there isn't significant evidence pointing towards **immune complex deposition** (Type III) as a primary mechanism in its pathogenesis. - This option incorrectly suggests a mixed mechanism when the predominant feature aligns with a single, specific type of hypersensitivity. *Type I–anaphylactic hypersensitivity reaction* - This type involves **IgE-mediated mast cell degranulation**, leading to immediate allergic reactions such as **anaphylaxis** or asthma, which is not consistent with the patient's presentation. - Clinical signs like **hives, angioedema, and bronchospasm** are characteristic, none of which are described. *Type II–cytotoxic hypersensitivity reaction* - This reaction involves **antibody-mediated destruction of cells** or tissues, typically seen in conditions like **autoimmune hemolytic anemia** or **Goodpasture syndrome**. - There is no indication of direct antibody-mediated cellular destruction in sarcoidosis. *Type III–immune complex-mediated hypersensitivity reaction* - This reaction involves the formation and deposition of **antigen-antibody immune complexes** in tissues, leading to inflammation, as seen in **serum sickness** or certain vasculitides. - While inflammation is present in sarcoidosis, the primary mechanism of tissue damage is not due to widespread immune complex deposition.

Question 309: A 47-year-old woman presents to her physician for difficulty swallowing. She states that she intentionally delayed seeing a physician for this issue. She says her primary issue with swallowing is that her mouth always feels dry so she has difficulty chewing food to the point that it can be swallowed. On physical examination, her oral mucosa appears dry. Both of her eyes also appear dry. Several enlarged lymph nodes are palpated. Which of the following patterns of reactive lymphadenitis is most commonly associated with this patient’s presentation?

A. Sinus hyperplasia
B. Follicular hyperplasia (Correct Answer)
C. Diffuse hyperplasia
D. Mixed B and T cell hyperplasia
E. Paracortical hyperplasia

Explanation: ***Follicular hyperplasia*** - The patient's symptoms of **dry mouth (xerostomia)** and **dry eyes (xerophthalmia)** strongly suggest **Sjögren syndrome**. This autoimmune disease selectively affects **exocrine glands**, particularly the salivary and lacrimal glands. - Lymphoid hyperplasia, especially **follicular hyperplasia**, is a common feature in Sjögren syndrome due to chronic B-cell activation, which is linked to a higher risk of developing **MALT lymphoma**. *Sinus hyperplasia* - **Sinus hyperplasia**, also known as **reticular hyperplasia**, is characterized by an increase in the number and size of macrophages within the subcapsular and medullary sinuses of lymph nodes. - It is typically associated with **lymph nodes draining a site of malignancy** or conditions involving histiocytic proliferation. *Diffuse hyperplasia* - **Diffuse hyperplasia** involves a generalized expansion of all lymphoid components within the lymph node, without a predominance of any specific area. - This pattern is less specific and can be seen in various **chronic inflammatory conditions** or reactive processes, but it is not the most characteristic pattern for Sjögren syndrome. *Mixed B and T cell hyperplasia* - While both B and T cells are involved in immune responses, **mixed B and T cell hyperplasia** refers to the expansion of both populations in a less defined pattern than follicular or paracortical types. - Conditions like **toxoplasmosis** can present with mixed hyperplasia, but it is not the classic pattern seen in Sjögren syndrome. *Paracortical hyperplasia* - **Paracortical hyperplasia** involves the expansion of the paracortical areas of the lymph node, which are rich in T-lymphocytes. - This pattern is typically seen in response to **viral infections** (e.g., infectious mononucleosis) or certain drug reactions, where T-cell activation is a prominent feature.

Question 310: A 37-year-old man who had undergone liver transplantation 7 years ago, presents to the physician because of yellowish discoloration of the skin, sclera, and urine. He is on regular immunosuppressive therapy and is well-adherent to the treatment. He has no comorbidities and is not taking any other medication. He provides a history of similar episodes of yellowish skin discoloration 6–7 times since he underwent liver transplantation. Physical examination shows clinical jaundice. Laboratory studies show: While blood cell (WBC) count 4,400/mm3 Hemoglobin 11.1 g/dL Serum creatinine 0.9 mg/dL Serum bilirubin (total) 44 mg/dL Aspartate transaminase (AST) 1,111 U/L Alanine transaminase (ALT) 671 U/L Serum gamma-glutamyl transpeptidase 777 U/L Alkaline phosphatase 888 U/L Prothrombin time 17 seconds A Doppler ultrasound shows significantly reduced blood flow into the transplanted liver. A biopsy of the transplanted liver is likely to show which of the following histological features?

A. Ballooning degeneration of hepatocytes
B. Normal architecture of bile ducts and hepatocytes
C. Irregularly shaped nodules of regenerating hepatocytes with peripheral halo
D. Broad fibrous septations with formation of micronodules
E. Interstitial cellular infiltration with parenchymal fibrosis, obliterative arteritis (Correct Answer)

Explanation: ***Interstitial cellular infiltration with parenchymal fibrosis, obliterative arteritis*** - The patient's history of **repeated jaundice episodes** after liver transplantation, coupled with **elevated liver enzymes** and **significantly reduced transplanted liver blood flow** on Doppler, points to **chronic rejection**. - **Chronic rejection** is histologically characterized by **interstitial cellular infiltration**, **parenchymal fibrosis**, and hallmark **obliterative arteritis**, which describes the progressive luminal narrowing and obliteration of hepatic arteries due to intimal proliferation. *Ballooning degeneration of hepatocytes* - This feature is typically associated with **acute hepatitis**, often viral or alcoholic, and indicates **hepatocyte swelling and necrosis**. - While reflecting liver injury, it doesn't specifically point to **chronic rejection** in a transplanted liver with repeated episodes and vascular changes. *Normal architecture of bile ducts and hepatocytes* - This finding would suggest a **healthy liver** or a successful response to treatment, which contradicts the patient's symptoms of **jaundice**, highly elevated **liver enzymes**, and **reduced blood flow**. - The presence of clinical symptoms and abnormal lab values rules out a normal liver architecture. *Irregularly shaped nodules of regenerating hepatocytes with peripheral halo* - This description is characteristic of **biliary hamartomas** (von Meyenburg complexes) or focal nodular hyperplasia, which are typically benign lesions and not indicative of the **severe liver injury** seen here. - It does not align with the progressive nature of the patient's recurrent jaundice and vascular compromise identified. *Broad fibrous septations with formation of micronodules* - This histological pattern is typical of **cirrhosis**, a condition characterized by diffuse **fibrosis** and the formation of **regenerative nodules**, often resulting from chronic liver diseases like hepatitis or alcohol abuse. - While fibrosis is part of chronic rejection, the description does not capture the specific **vascular and inflammatory changes** of **obliterative arteritis** that are central to chronic rejection.

Question 311: A 4-year-old male is evaluated for frequent epistaxis and mucous membrane bleeding. Physical examination shows diffuse petechiae on the patient’s distal extremities. Peripheral blood smear shows an absence of platelet clumping. An ELISA binding assay reveals that platelet surfaces are deficient in GIIb/IIIa receptors. Serum platelet count is normal. Which of the following is the most likely diagnosis?

A. Idiopathic thrombocytopenic purpura
B. Thrombotic thrombocytopenic purpura
C. Bernard-Soulier disease
D. Hemophilia A
E. Glanzmann’s thrombasthenia (Correct Answer)

Explanation: ***Glanzmann’s thrombasthenia*** - This condition is characterized by a **deficiency of GIIb/IIIa receptors** on platelets, leading to impaired platelet aggregation despite a normal platelet count. - The patient's symptoms of **epistaxis**, **mucous membrane bleeding**, and **diffuse petechiae** are consistent with a primary hemostasis disorder. *Idiopathic thrombocytopenic purpura* - This autoimmune disorder causes **isolated thrombocytopenia** (low platelet count) due to antibody-mediated destruction of platelets. - The patient's **normal platelet count** makes ITP an unlikely diagnosis. *Thrombotic thrombocytopenic purpura* - TTP is characterized by the **pentad of symptoms**: thrombocytopenia, microangiopathic hemolytic anemia, renal failure, neurological symptoms, and fever. - The patient does not present with **anemia** or the other systemic features typical of TTP, and their platelet count is normal. *Bernard-Soulier disease* - This is a rare inherited disorder involving a **deficiency of GPIb-IX-V receptor** complex on platelets, which affects platelet adhesion to von Willebrand factor. - While it causes bleeding symptoms and often **giant platelets** on smear, the specific defect mentioned (GIIb/IIIa deficiency) is not consistent with Bernard-Soulier. *Hemophilia A* - Hemophilia A is an **X-linked recessive bleeding disorder** caused by a deficiency of factor VIII. - It primarily affects **secondary hemostasis**, leading to deep tissue bleeding (e.g., hemarthroses, hematomas) rather than petechiae and mucous membrane bleeding, and platelet function is normal.

Question 312: An otherwise healthy 27-year-old man presents to the Emergency Department with dark urine and left flank pain. He has had a fever, sore throat, and malaise for the last 2 days. Vital signs reveal a temperature of 38.1°C (100.5°F), blood pressure of 120/82 mm Hg, and a pulse of 95/min. His family history is noncontributory. Physical examination reveals enlarged tonsils with tender anterior cervical lymphadenopathy. Urinalysis shows pink urine with 20–25 red cells/high power field and 2+ protein. This patient’s condition is most likely due to which of the following?

A. Immune complex deposition
B. C3 nephritic factor
C. Diffuse mesangial IgA deposition (Correct Answer)
D. Inherited abnormalities in type IV collagen
E. Autoantibodies against alpha-3 chain of type IV collagen

Explanation: ***Diffuse mesangial IgA deposition*** - The patient's presentation with **dark urine**, **flank pain**, and a recent **upper respiratory infection** (pharyngitis, fever, malaise, enlarged tonsils) followed by **hematuria** and **proteinuria** is highly suggestive of **IgA nephropathy** (Berger's disease). - In IgA nephropathy, **IgA immune complexes** deposit in the glomerular mesangium, triggering inflammation and kidney damage. *Immune complex deposition* - While IgA nephropathy involves immune complex deposition, this option is too general; it does not specify the type of immune complex or its location, which is crucial for diagnosis. - Other conditions like post-streptococcal glomerulonephritis also involve immune complex deposition, but they typically have a longer latent period after infection and often involve C3 complement activation. *C3 nephritic factor* - **C3 nephritic factor** is associated with **dense deposit disease** (a form of C3 glomerulopathy) and some cases of membranoproliferative glomerulonephritis, leading to persistent activation of the alternative complement pathway. - This condition is characterized by distinctive electron-dense deposits within the glomerular basement membrane and presents differently from the acute, infection-associated nephritis described. *Inherited abnormalities in type IV collagen* - **Inherited abnormalities in type IV collagen** are characteristic of **Alport syndrome**, a genetic disorder. - Alport syndrome typically presents with progressive **hematuria**, sensorineural **hearing loss**, and ocular abnormalities, which are not mentioned in this patient's acute presentation. *Autoantibodies against alpha-3 chain of type IV collagen* - **Autoantibodies against the alpha-3 chain of type IV collagen** are the hallmark of **Goodpasture syndrome** (anti-GBM disease). - Goodpasture syndrome typically presents with rapidly progressive glomerulonephritis, often accompanied by **pulmonary hemorrhage**, symptoms not seen in this patient.

Question 313: A 63-year-old man presents to the emergency department with periorbital swelling. He states that he was gardening, came inside, looked in the mirror, and then noticed his eyelids were swollen. He denies pain, pruritus, or visual disturbances. He states that he was drinking “a lot of water" to prevent dehydration, because it was hot outside this morning. His medical history is significant for rheumatoid arthritis. He takes methotrexate and acetaminophen as needed. The patient’s temperature is 98°F (36.7°C), blood pressure is 168/108 mmHg, and pulse is 75/min. Physical examination is notable for periorbital edema, hepatomegaly, and bilateral 1+ pitting lower extremity edema. Labs and a urinalysis are obtained, as shown below: Leukocyte count: 11,000/mm^3 Hemoglobin: 14 g/dL Serum: Na: 138 mEq/L K+: 4.3 mEq/L Cl-: 104 mEq/L HCO3-: 25 mEq/L Urea nitrogen: 26 mg/dL Creatinine: 1.4 mg/dL Glucose: 85 mg/dL Aspartate aminotransferase (AST, GOT): 15 U/L Alanine aminotransferase (ALT, GPT): 19 U/L Albumin: 2.0 g/dL Urine: Protein: 150 mg/dL Creatinine: 35 mg/dL An abdominal ultrasound reveals an enlarged liver with heterogeneous echogenicity and enlarged kidneys with increased echogenicity in the renal parenchyma. A biopsy of the kidney is obtained. Which of the following biopsy findings is associated with the patient’s most likely diagnosis?

A. Apple green birefringence with Congo red staining (Correct Answer)
B. Subepithelial dense deposits
C. Tubulointerstitial fibrosis
D. Kimmelstiel-Wilson nodules
E. Glomerular basement membrane splitting

Explanation: ***Apple green birefringence with Congo red staining*** - The patient's presentation with **periorbital and pitting edema**, **hepatomegaly**, **renal dysfunction** (elevated creatinine, proteinuria), and **low serum albumin** in the setting of chronic **rheumatoid arthritis** suggests **AA amyloidosis**. - **Congo red staining** followed by examination under polarized light revealing **apple green birefringence** is the classic diagnostic finding for amyloidosis on tissue biopsy. *Subepithelial dense deposits* - **Subepithelial dense deposits** are characteristic of **post-streptococcal glomerulonephritis** (PSGN) or other forms of immune-complex glomerulonephritis. - PSGN typically presents with a recent history of infection and often hematuria, which is not described in this patient. *Tubulointerstitial fibrosis* - **Tubulointerstitial fibrosis** is a non-specific finding that can occur in various chronic kidney diseases, including those caused by long-term use of certain medications like **methotrexate** or chronic hypertension. - While it might be present, it does not explain the widespread systemic findings or the specific cause of the present nephropathy in this case. *Kimmelstiel-Wilson nodules* - **Kimmelstiel-Wilson nodules** are pathognomonic for **diabetic nephropathy**, characterized by specific nodular glomerulosclerosis. - The patient's glucose levels are normal, and there is no mention of diabetes mellitus in his history. *Glomerular basement membrane splitting* - **Glomerular basement membrane splitting** is a key feature of **Alport syndrome** and some forms of **membranoproliferative glomerulonephritis**. - Alport syndrome is a genetic disorder typically presenting earlier in life with hematuria, hearing loss, and ocular abnormalities, none of which are detailed here.

Question 314: A 24-year-old male was in a motor vehicle accident that caused him to fracture his femur and pelvis. After 2 days in the hospital, the patient became delirious, tachypneic, and a petechial rash was found in his upper extremities. Which of the following is most likely responsible for this patient’s symptoms?

A. Thrombotic clot in the pulmonary artery
B. Aspiration of oropharyngeal contents
C. Alveolar foamy exudates with disc shaped cysts seen with methenamine silver stain
D. Fat microglobules in the microvasculature (Correct Answer)
E. Type I and type II pneumocyte damage due to neutrophils

Explanation: ***Fat microglobules in the microvasculature*** - This scenario describes **fat embolism syndrome (FES)**, often triggered by trauma to long bones (like the femur) or the pelvis. - The classic triad of FES includes **respiratory distress (tachypnea)**, **neurological symptoms (delirium)**, and a **petechial rash**, which perfectly matches the patient's presentation. *Thrombotic clot in the pulmonary artery* - A **pulmonary embolism (PE)** can cause tachypnea and delirium, but it typically does not present with a **petechial rash**. - PE is usually due to a **venous thromboembolism** from deep leg veins, though trauma can increase risk, the rash points away from a simple thrombotic PE. *Aspiration of oropharyngeal contents* - **Aspiration pneumonia** can cause respiratory distress, but it doesn't typically lead to **delirium or a petechial rash** in this timeframe. - The symptoms would likely include fever, cough, and infiltrates on chest X-ray. *Alveolar foamy exudates with disc-shaped cysts seen with methenamine silver stain* - This description is characteristic of **Pneumocystis pneumonia** (*Pneumocystis jirovecii*), an opportunistic infection typically seen in immunocompromised individuals. - It would not manifest acutely after trauma with a petechial rash. *Type I and type II pneumocyte damage due to neutrophils* - This describes **acute respiratory distress syndrome (ARDS)**, which can be a complication of severe trauma. - While ARDS could cause respiratory distress and potentially delirium, it generally doesn't present with a **petechial rash** as a hallmark symptom in this context.

Question 315: A 19-year-old man comes to the physician for the evaluation of progressive difficulty climbing stairs over the last 2 years. During this period, he has also had problems with running, occasional falls, and standing from a chair. He has not had any vision problems or muscle cramping. There is no personal or family history of serious illness. Neurological examination shows deep tendon reflexes are 2+ bilaterally and sensation to pinprick and light touch is normal. Musculoskeletal examination shows enlarged calf muscles bilaterally. He has a waddling gait. Laboratory studies show a creatine kinase level of 1700 U/L. Which of the following is the most appropriate next step to confirm the diagnosis?

A. Tensilon test
B. Anti-Jo-1 antibodies measurement
C. CT scan of the chest
D. Electromyography
E. Genetic analysis (Correct Answer)

Explanation: ***Genetic analysis*** - The patient's presentation with **progressive proximal muscle weakness**, **calf pseudohypertrophy**, **waddling gait**, and a significantly elevated **creatine kinase** level is highly suggestive of a **dystrophinopathy**. - Given the patient's **age (19 years) and ambulatory status**, this presentation is most consistent with **Becker muscular dystrophy (BMD)** rather than Duchenne (DMD), as DMD patients typically become wheelchair-bound by age 12-13. - **Genetic analysis**, specifically testing for **dystrophin gene mutations** (e.g., deletions, duplications, point mutations), is the most definitive method to confirm these diagnoses and distinguish between DMD and BMD based on mutation type and dystrophin expression. *Tensilon test* - The **Tensilon test** (edrophonium test) is used to diagnose **myasthenia gravis**, a disorder affecting the neuromuscular junction. - The patient's symptoms (e.g., progressive onset over years, calf pseudohypertrophy) are not typical of myasthenia gravis, which often presents with **fluctuating weakness** and ocular symptoms. *Anti-Jo-1 antibodies measurement* - **Anti-Jo-1 antibodies** are associated with **polymyositis** and dermatomyositis, autoimmune inflammatory myopathies. - While these conditions cause proximal muscle weakness and elevated CK, they typically have an **inflammatory pattern** and do not cause **calf pseudohypertrophy** or a waddling gait in the same manner as muscular dystrophies. *CT scan of the chest* - A **CT scan of the chest** is typically used to investigate conditions such as lung pathology, thymoma (associated with myasthenia gravis), or sarcoidosis. - It is not a primary diagnostic tool for primary muscle disorders like muscular dystrophy. *Electromyography* - **Electromyography (EMG)** can help differentiate between **myopathic** and neuropathic conditions by showing characteristic patterns of muscle fiber degeneration. - While EMG can support a diagnosis of myopathy, it is not as definitive as **genetic analysis** in confirming a specific muscular dystrophy like BMD, especially given the clear clinical picture.

Question 316: A 34-year-old man with AIDS comes to the physician because of a 2-day history of decreasing vision and seeing black spots in his right eye. He has no pain and the left eye is asymptomatic. He was treated for fungal esophagitis 6 months ago with fluconazole. He was diagnosed with Kaposi's sarcoma 2 years ago. Current medications include efavirenz, tenofovir, emtricitabine, azithromycin, trimethoprim-sulfamethoxazole, multivitamins, and a nutritional supplement. He is 170 cm (5 ft 7 in) tall and weighs 45 kg (99 lbs); BMI is 15.6 kg/m2. His temperature is 37°C (98.6°F), pulse is 89/min, and blood pressure is 110/70 mm Hg. Examination shows cervical lymphadenopathy. There are multiple violaceous plaques seen over his trunk and extremities. Fundoscopic examination shows granular yellow-white opacities around the retinal vessels and multiple areas of dot-blot hemorrhages. His CD4+ T-lymphocyte count is 36/mm3. Which of the following is the most likely diagnosis?

A. Cytomegalovirus retinitis (Correct Answer)
B. Toxoplasma retinitis
C. Herpes simplex keratitis
D. Varicella zoster retinitis
E. HIV retinopathy

Explanation: ***Cytomegalovirus retinitis*** - The patient's **severely immunocompromised state** (CD4+ count of 36/mm3), along with the characteristic fundoscopic findings of **"pizza pie" retinopathy** (granular yellow-white opacities around retinal vessels, hemorrhage, and dot-blot hemorrhages), are pathognomonic for CMV retinitis. - **CMV retinitis** typically causes painless, progressive vision loss and is a common opportunistic infection in advanced AIDS. *Toxoplasma retinitis* - While possible in immunocompromised patients, **Toxoplasma retinitis** usually presents with well-demarcated, intensely white, cottony or fluffy lesions often associated with a darker, scarred choroidal lesion, and significant vitreal inflammation, which are not described here. - The **"pizza pie" appearance** with hemorrhage is more classic for CMV. *Herpes simplex keratitis* - **Herpes simplex keratitis** primarily affects the **cornea**, causing symptoms like pain, redness, photophobia, and blurred vision, often with a characteristic dendritic ulcer. - The patient's symptoms are painless and fundoscopic findings point to a **retinal infection**, not a corneal one. *Varicella zoster retinitis* - **Varicella zoster virus (VZV) retinitis** can occur in immunocompromised patients and typically causes acute retinal necrosis, leading to rapid, severe vision loss and often circumferential, peripheral retinal necrosis. - While VZV retinitis causes retinal damage, the specific fundoscopic description in the patient (granular yellow-white opacities and dot-blot hemorrhages) is more consistent with **CMV**. *HIV retinopathy* - **HIV retinopathy** is a microvascular complication of HIV infection, often causing cotton wool spots, retinal hemorrhages, and microaneurysms, but typically **does not cause significant vision loss** or the extensive opacities described. - The severe changes mentioned, including yellow-white opacities and significant vision loss, are more indicative of an **opportunistic infection** like CMV rather than HIV retinopathy itself.

Question 317: A 65-year-old man was picked up by the security personnel for voiding urine and defecating at an inappropriate place in the community. On questioning, he was making offensive remarks and behaving inappropriately. On physical examination, the physician observed signs of cognitive impairment and amnesia. Initial urine drug screen is negative for any drugs of abuse. Which is the most likely pathological finding present in this patient?

A. Drug abuse
B. Amyloid plaques
C. Lewy bodies
D. Pick bodies (Correct Answer)
E. PrPSC Sheets

Explanation: ***Pick bodies*** - The patient presents with **disinhibition** (inappropriate voiding, defecating in public), **offensive remarks**, and **inappropriate behavior**, which are hallmarks of **frontotemporal dementia (FTD)**, specifically the behavioral variant. - **Pick bodies** are aggregates of **tau protein** found in neurons of the frontal and temporal lobes, characteristic of Pick's disease, a subtype of FTD. - Behavioral variant FTD characteristically presents with **personality changes**, **loss of social awareness**, and **executive dysfunction** before significant memory impairment. *Drug abuse* - While drug abuse can lead to inappropriate behavior and neuropsychiatric symptoms, the **negative urine drug screen** makes this diagnosis unlikely. - Drug abuse typically doesn't present with the progressive cognitive decline and specific behavioral pattern seen here. *Amyloid plaques* - **Amyloid plaques** (along with neurofibrillary tangles) are characteristic pathological findings in **Alzheimer's disease**, which typically presents with **memory impairment** as the predominant initial symptom. - Although Alzheimer's disease can lead to behavioral changes in later stages, the **prominent early disinhibition** and preserved memory (relative to behavioral changes) are more typical of FTD than Alzheimer's. *Lewy bodies* - **Lewy bodies** are associated with **dementia with Lewy bodies (DLB)** and **Parkinson's disease dementia**. - DLB is characterized by **fluctuating cognition**, **visual hallucinations**, and **parkinsonism** (rigidity, bradykinesia), which are not the predominant features in this patient's presentation. *PrPSC Sheets* - **PrPSC sheets** refer to the misfolded prion protein found in **prion diseases** such as Creutzfeldt-Jakob disease (CJD). - CJD typically manifests with **rapidly progressive dementia** (over weeks to months), **myoclonus**, and **cerebellar signs**, with a much faster progression than the clinical picture suggested here.

Question 318: A 54-year-old woman comes to the physician because of a painful skin lesion on her right leg for 1 month. It initially started out as a small red spot but has rapidly increased in size during this period. She remembers an ant bite on her leg prior to the lesion occurring. She was treated for anterior uveitis 8 months ago with corticosteroids. She has Crohn's disease, type 2 diabetes mellitus, and hypertension. Current medications include insulin, mesalamine, enalapril, and aspirin. She returned from Wisconsin after visiting her son 2 months ago. Her temperature is 37.6°C (98°F), pulse is 98/min, and blood pressure is 126/88 mm Hg. Examination shows pitting pedal edema of the lower extremities. There is a 4-cm tender ulcerative lesion on the anterior right leg with a central necrotic base and purplish irregular borders. There are dilated tortuous veins in both lower legs. Femoral and pedal pulses are palpated bilaterally. Which of the following is the most likely diagnosis?

A. Pyoderma gangrenosum (Correct Answer)
B. Basal cell carcinoma
C. Squamous cell carcinoma
D. Ecthyma gangrenosum
E. Blastomycosis

Explanation: ***Pyoderma gangrenosum*** - The patient's history of **Crohn's disease**, **anterior uveitis**, and a rapidly progressing, **tender ulcerative lesion** with a **necrotic base** and **purplish irregular borders** are highly characteristic of pyoderma gangrenosum. - The phenomenon of **pathergy** (exacerbation of lesions after minor trauma like a bug bite) further supports this diagnosis. *Basal cell carcinoma* - Typically presents as a **slow-growing lesion** with **pearly borders** and **telangiectasias**, not a rapidly enlarging, tender ulcer with a necrotic base. - It is often associated with sun exposure and rarely presents with the systemic associations seen in this case. *Squamous cell carcinoma* - Usually appears as a **scaly, erythematous patch** or an **indurated nodule** that may ulcerate, but it is generally a chronic lesion and less acutely painful or rapidly progressing. - While it can be aggressive, the clinical presentation and rapid progression with a necrotic center and systemic associations point away from this diagnosis. *Ecthyma gangrenosum* - This condition is caused by **Pseudomonas aeruginosa bacteremia** and is characterized by a central necrotic area surrounded by an erythematous halo, typically in immunocompromised patients. - While there is some overlap in appearance, ecthyma gangrenosum is usually associated with **sepsis** and systemic signs of infection, which are not prominent here. *Blastomycosis* - A **fungal infection** endemic to the Great Lakes region (including Wisconsin), which can cause skin lesions that may be verrucous, ulcerative, or plaque-like. - However, the description of a rapidly progressing, deeply ulcerative lesion with purplish, undermined borders and strong association with inflammatory bowel disease is more consistent with pyoderma gangrenosum.

Question 319: A 51-year-old man presents to his dermatologist because of severe stomatitis and superficial skin erosions over his trunk. His condition started 2 months ago and was unresponsive to oral antibiotics and antiherpetic medications. He has no history of a similar rash. His medical history is remarkable for type 2 diabetes mellitus and essential hypertension. The physical examination reveals numerous flaccid blisters and bullae which rupture easily. Nikolsky's sign is positive. Which of the following best represents the etiology of this patient’s condition?

A. Dermatophyte infection
B. Cutaneous T cell lymphoma
C. Increased mitotic activity of basal and suprabasal cells
D. Anti-hemidesmosome antibodies
E. Anti-desmoglein-3 antibodies (Correct Answer)

Explanation: ***Anti-desmoglein-3 antibodies*** - The patient's presentation with **flaccid blisters**, widespread **erosions** (including oral mucosa), **positive Nikolsky's sign**, and **unresponsiveness to antibiotics/antivirals** is highly suggestive of **Pemphigus Vulgaris**. - **Pemphigus Vulgaris** is an autoimmune blistering disease characterized by the production of **autoantibodies against desmoglein 3** (and sometimes desmoglein 1), which are components of desmosomes responsible for keratinocyte adhesion. *Dermatophyte infection* - **Dermatophyte infections** (tinea) typically present as **erythematous, scaly, pruritic plaques** with peripheral spreading, often without blistering, and are usually responsive to antifungal treatments. - They do not cause flaccid blisters, extensive erosions, or a positive Nikolsky's sign. *Cutaneous T cell lymphoma* - **Cutaneous T-cell lymphoma (CTCL)**, such as Mycosis Fungoides, typically manifests as **patches, plaques, or tumors** in the skin, often with a chronic, relapsing course, and is not characterized by the acute onset of flaccid blisters and erosions. - It involves proliferation of malignant T-cells in the skin and does not present with positive Nikolsky's sign or widespread bullae. *Increased mitotic activity of basal and suprabasal cells* - **Increased mitotic activity** is a general feature of various proliferative conditions, including hyperplastic states or malignancies like squamous cell carcinoma, but it does not directly explain the formation of **flaccid blisters and erosions** due to loss of keratinocyte adhesion. - This finding would be a histological observation, not the primary immunological etiology of blister formation in pemphigus. *Anti-hemidesmosome antibodies* - **Anti-hemidesmosome antibodies** are characteristic of **Bullous Pemphigoid**, another autoimmune blistering disease. - Unlike **Pemphigus Vulgaris**, **Bullous Pemphigoid** typically presents with **tense bullae** that are less prone to rupture, usually spares the oral mucosa, and a negative Nikolsky's sign.

Question 320: A 7-month old boy, born to immigrant parents from Greece, presents to the hospital with pallor and abdominal distention. His parents note that they recently moved into an old apartment building and have been concerned about their son's exposure to chipped paint from the walls. On physical exam, the patient is found to have hepatosplenomegaly and frontal skull bossing. Hemoglobin electrophoresis reveals markedly increased HbF and HbA2 levels. What would be the most likely findings on a peripheral blood smear?

A. Microcytosis and hypochromasia of erythrocytes (Correct Answer)
B. Sickling of erythrocytes
C. Basophilic stippling of erythrocytes
D. Macrocytosis of erythrocytes with hypersegmented neutrophils
E. Schistocytes and normocytic erythrocytes

Explanation: ### ***Microcytosis and hypochromasia of erythrocytes*** - This patient presents with **β-thalassemia major**, as evidenced by **Greek ancestry** (Mediterranean population at high risk), **markedly elevated HbF and HbA2 levels** on hemoglobin electrophoresis, **frontal skull bossing** from bone marrow expansion, and **hepatosplenomegaly** from extramedullary hematopoiesis. - The peripheral blood smear in β-thalassemia major characteristically shows **severe microcytic, hypochromic anemia** with target cells, nucleated RBCs, and marked anisocytosis and poikilocytosis. - The inadequate β-globin chain production leads to ineffective erythropoiesis and severe hemolysis, resulting in the microcytic, hypochromic pattern. ### *Basophilic stippling of erythrocytes* - While **basophilic stippling** can be seen in β-thalassemia, it is not the **most characteristic** finding and is more commonly associated with **lead poisoning**. - The chipped paint exposure in this case is a distractor; **lead poisoning does NOT cause elevated HbF/HbA2, frontal bossing, or this degree of organomegaly** in a 7-month-old. - The hemoglobin electrophoresis findings definitively point to thalassemia, not lead toxicity. ### *Sickling of erythrocytes* - **Sickling** is pathognomonic for **sickle cell disease**, which presents with elevated HbS (not HbF and HbA2) on electrophoresis. - While both are hemoglobinopathies affecting Mediterranean populations, the electrophoresis pattern and clinical features clearly indicate thalassemia, not sickle cell disease. ### *Schistocytes and normocytic erythrocytes* - **Schistocytes** indicate **microangiopathic hemolytic anemia** (e.g., TTP, HUS, DIC), which involves mechanical RBC fragmentation in damaged microvasculature. - The patient's chronic presentation, organomegaly, skeletal changes, and hemoglobin electrophoresis findings are inconsistent with microangiopathic hemolysis. ### *Macrocytosis of erythrocytes with hypersegmented neutrophils* - **Macrocytic anemia with hypersegmented neutrophils** is characteristic of **megaloblastic anemia** from vitamin B12 or folate deficiency. - β-thalassemia causes **microcytic** anemia due to deficient hemoglobin synthesis, not macrocytic anemia from impaired DNA synthesis.

Question 321: A 27-year-old woman with sickle cell disease and at 39-weeks' gestation is brought to the emergency department in active labor. She has had multiple episodes of acute chest syndrome and has required several transfusions in the past. She has a prolonged vaginal delivery complicated by postpartum bleeding, and she receives a transfusion of 1 unit of packed red blood cells. One hour later, the patient experiences acute flank pain. Her temperature is 38.7°C (101.6°F), pulse is 115/min, respirations are 24/min, and blood pressure is 95/55 mm Hg. Foley catheter shows dark brown urine. Further evaluation of this patient is most likely to show which of the following?

A. Positive blood cultures
B. Serum antibodies against class I HLA antigens
C. Low levels of serum IgA immunoglobulins
D. Positive direct Coombs test (Correct Answer)
E. Bilateral pulmonary infiltrates on chest x-ray

Explanation: ***Positive direct Coombs test*** - The patient's symptoms (flank pain, fever, tachycardia, hypotension, dark brown urine) following a blood transfusion are highly suggestive of an acute hemolytic transfusion reaction (AHTR). - A **positive direct Coombs test** (direct antiglobulin test) confirms AHTR by detecting antibodies or complement components bound to the surface of the patient's red blood cells, indicating immune-mediated destruction. *Positive blood cultures* - While fever is present, the constellation of symptoms, especially **flank pain** and **dark brown urine** immediately post-transfusion, points away from a primary bacterial infection. - Blood cultures would be relevant for a **septic transfusion reaction**, but the rapid onset and hematologic signs are more consistent with immune hemolysis. *Serum antibodies against class I HLA antigens* - **HLA antibodies** are primarily associated with **febrile nonhemolytic transfusion reactions** or **transfusion-related acute lung injury (TRALI)**. - While fever is present, the severe **hemolytic signs** (flank pain, dark urine) are not typical for these reactions. *Low levels of serum IgA immunoglobulins* - **IgA deficiency** can lead to severe **anaphylactic transfusion reactions** in patients who receive IgA-containing blood products and have anti-IgA antibodies. - Anaphylactic reactions typically present with sudden **hypotension**, **bronchospasm**, and **angioedema**, not primarily with flank pain and dark urine from hemolysis. *Bilateral pulmonary infiltrates on chest X-ray* - **Bilateral pulmonary infiltrates** on chest X-ray are characteristic of **transfusion-related acute lung injury (TRALI)**. - While TRALI can cause acute respiratory distress and hypoxemia, the patient's predominant symptoms of flank pain and dark brown urine point specifically to **hemolysis**, not primarily lung injury.

Question 322: A 71-year-old man presents to his primary care physician because he is increasingly troubled by a tremor in his hands. He says that the tremor is worse when he is resting and gets better when he reaches for objects. His wife reports that he has been slowing in his movements and also has difficulty starting to walk. His steps have been short and unsteady even when he is able to initiate movement. Physical exam reveals rigidity in his muscles when tested for active range of motion. Histology in this patient would most likely reveal which of the following findings?

A. Intracellular hyperphosphorylated tau
B. Large intracellular vacuoles
C. Amyloid beta plaques
D. Perivascular inflammation
E. Alpha-synuclein (Correct Answer)

Explanation: ***Alpha-synuclein*** - The patient's symptoms of a **resting tremor** that improves with action, **bradykinesia** (slowed movements, difficulty initiating walking, short steps), and **rigidity** are classic for **Parkinson's disease**. - Histologically, Parkinson's disease is characterized by the presence of **Lewy bodies**, which are intracellular inclusions comprised primarily of aggregated **alpha-synuclein** protein, particularly in the substantia nigra. *Intracellular hyperphosphorylated tau* - **Hyperphosphorylated tau protein** forms **neurofibrillary tangles** and is characteristic of **Alzheimer's disease** and other tauopathies (e.g., frontotemporal dementia), which typically present with cognitive decline rather than primarily motor symptoms as seen here. - While Parkinson's disease can have co-existing tau pathology, it is not the primary histological hallmark for the motor symptoms described. *Large intracellular vacuoles* - The presence of **large intracellular vacuoles** within neurons is characteristic of **spongiform encephalopathies** (e.g., Creutzfeldt-Jakob disease), which present with rapidly progressive dementia, myoclonus, and ataxia. - This finding is not associated with the classic motor symptoms of Parkinson's disease. *Amyloid beta plaques* - **Amyloid beta plaques** (extracellular deposits of amyloid-beta protein) are a hallmark of **Alzheimer's disease**, which primarily manifests with progressive cognitive impairment and memory loss. - These plaques are not the primary histological feature of Parkinson's disease. *Perivascular inflammation* - **Perivascular inflammation** is typically seen in **inflammatory or demyelinating diseases** of the central nervous system, such as **multiple sclerosis** or **encephalitis**. - This finding is not characteristic of neurodegenerative disorders like Parkinson's disease, which are instead marked by protein aggregation and neuronal loss.

Question 323: A 28-year-old man presents for severe abdominal pain and is diagnosed with appendicitis. He is taken for emergent appendectomy. During the procedure, the patient has massive and persistent bleeding requiring a blood transfusion. The preoperative laboratory studies showed a normal bleeding time, normal prothrombin time (PT), an INR of 1.0, and a normal platelet count. Postoperatively, when the patient is told about the complications during the surgery, he recalls that he forgot to mention that he has a family history of an unknown bleeding disorder. The postoperative laboratory tests reveal a prolonged partial thromboplastin time (PTT). Which of the following is the most likely diagnosis in this patient?

A. von Willebrand disease
B. Bernard-Soulier syndrome
C. Thrombotic thrombocytopenic purpura
D. Hemophilia A (Correct Answer)
E. Glanzmann thrombasthenia

Explanation: ***Hemophilia A*** - The patient's presentation with **severe, persistent bleeding** during surgery despite normal preoperative coagulation studies (PT, INR, platelet count) and a subsequent **prolonged PTT** strongly indicates a **factor deficiency in the intrinsic pathway**. - **Hemophilia A**, an X-linked recessive disorder, is caused by a deficiency of **Factor VIII**, leading to a prolonged PTT and deep tissue bleeding, which fits the clinical picture and family history. *von Willebrand disease* - This condition typically presents with **mucocutaneous bleeding** (e.g., nosebleeds, menorrhagia) and can have a prolonged bleeding time, but the primary defect is in **platelet adhesion**, not usually massive operative bleeding with normal platelet count. - While **von Willebrand factor (vWF)** carries Factor VIII, a primary deficiency of vWF would affect factor VIII levels but the presentation and normal bleeding time here make it less likely than direct factor VIII deficiency. *Bernard-Soulier syndrome* - This is a **platelet disorder** characterized by defective **glycoprotein Ib/IX/V complex**, leading to impaired platelet adhesion and often **thrombocytopenia** with unusually large platelets. - The patient had a **normal platelet count** and a subsequent prolonged PTT, which points away from a primary platelet adhesion defect. *Thrombotic thrombocytopenic purpura* - This is a microangiopathic hemolytic anemia characterized by a **pentad of symptoms**: fever, neurologic symptoms, renal dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia. - It involves widespread **thrombosis** and **low platelet count**, which does not align with the patient's presentation of massive bleeding with normal platelet counts. *Glanzmann thrombasthenia* - This is a rare **platelet aggregation disorder** caused by a defect in **glycoprotein IIb/IIIa**, leading to impaired fibrinogen binding and platelet aggregation. - While it causes severe bleeding, it would be associated with a **prolonged bleeding time** and normal PTT, which contradicts the patient's normal bleeding time and prolonged PTT.

Question 324: A previously healthy 40-year-old woman comes to the physician because of a 3-day history of fever, headaches, and fatigue. She also reports a persistent tingling sensation in her right hand and numbness in her right arm that started this morning. Physical examination shows pallor, mild scleral icterus, and petechiae on her forearms and legs. On mental status examination, she appears confused and is only oriented to person. Laboratory studies show: Hemoglobin 11.1 g/dL Platelet count 39,500/mm3 Bleeding time 9 minutes Prothrombin time 14 seconds Partial thromboplastin time 35 seconds Serum Creatinine 1.7 mg/dL Total bilirubin 2.1 mg/dL A peripheral blood smear shows fragmented erythrocytes. Which of the following is the most likely underlying cause of this patient's condition?

A. Antibodies against double-stranded DNA
B. Mutation of the PIGA gene
C. Antibodies against GpIIb/IIIa
D. Antibodies against ADAMTS13 (Correct Answer)
E. Absence of platelet GpIIb/IIIa receptors

Explanation: ***Antibodies against ADAMTS13*** - This patient presents with a classic pentad of symptoms: **fever**, **neurologic symptoms** (confusion, tingling, numbness), **renal failure** (creatinine 1.7 mg/dL), **thrombocytopenia** (platelet count 39,500/mm3), and **microangiopathic hemolytic anemia** (pallor, scleral icterus, fragmented erythrocytes on smear). This constellation of findings is highly suggestive of **Thrombotic Thrombocytopenic Purpura (TTP)**. - TTP is primarily caused by a deficiency of the **ADAMTS13 enzyme**, often due to **autoantibodies** that inhibit its activity. ADAMTS13 is responsible for cleaving large **von Willebrand factor (vWF) multimers**, and its deficiency leads to the accumulation of these large multimers, promoting platelet aggregation and microthrombi formation. *Antibodies against double-stranded DNA* - Antibodies against double-stranded DNA (**anti-dsDNA antibodies**) are characteristic of **Systemic Lupus Erythematosus (SLE)**, which can present with various systemic symptoms. - While SLE can cause thrombocytopenia and renal involvement, it typically does not cause the severe **microangiopathic hemolytic anemia** with schistocytes or the combination of symptoms seen in this patient to the extent of TTP. *Mutation of the PIGA gene* - A **mutation of the *PIGA* gene** is responsible for **Paroxysmal Nocturnal Hemoglobinuria (PNH)**, a clonal stem cell disorder characterized by hemolytic anemia, thrombosis, and bone marrow failure. - While PNH involves hemolysis, it typically lacks the prominent neurological symptoms, severe thrombocytopenia with microangiopathic features, and renal failure seen in TTP. *Antibodies against GpIIb/IIIa* - **Antibodies against GpIIb/IIIa** (glycoprotein IIb/IIIa) receptors are the hallmark of **Immune Thrombocytopenic Purpura (ITP)**, causing accelerated platelet destruction. - ITP primarily causes **isolated thrombocytopenia** and mucocutaneous bleeding, but it does not cause microangiopathic hemolytic anemia, renal failure, or neurological symptoms that are prominent in this patient. *Absence of platelet GpIIb/IIIa receptors* - The **absence of platelet GpIIb/IIIa receptors** is characteristic of **Glanzmann's thrombasthenia**, a rare inherited disorder of platelet function. - Glanzmann's thrombasthenia leads to **mucocutaneous bleeding** due to impaired platelet aggregation, but it does not cause thrombocytopenia, hemolytic anemia, renal failure, or neurological symptoms.

Question 325: A 12-year-old boy presents to your office with facial swelling and dark urine. He has no other complaints other than a sore throat 3 weeks ago that resolved after 6 days. He is otherwise healthy, lives at home with his mother and 2 cats, has no recent history of travel, and no sick contacts. On physical examination his temperature is 99°F (37.2°C), blood pressure is 130/85 mmHg, pulse is 80/min, respirations are 19/min, and pulse oximetry is 99% on room air. Cardiopulmonary and abdominal examinations are unremarkable. There is mild periorbital and pedal edema. Urinalysis shows 12-15 RBC/hpf, 2-5 WBC/hpf, and 30 mg/dL protein. Which additional finding would you expect to see on urinalysis?

A. Fatty casts
B. RBC casts (Correct Answer)
C. WBC casts
D. Granular casts
E. Hyaline casts

Explanation: ***RBC casts*** - The patient's presentation with **facial swelling**, **dark urine**, and a history of a recent **sore throat** points toward **post-streptococcal glomerulonephritis (PSGN)**. - **RBC casts** are a hallmark microscopic finding in **glomerulonephritis**, indicating **glomerular inflammation** and bleeding. *Fatty casts* - **Fatty casts** are characteristic of **nephrotic syndrome**, which primarily involves heavy proteinuria and generalized edema. - While there is some proteinuria and edema, the dark urine and history of recent infection are more consistent with nephritic syndrome. *Hyaline casts* - **Hyaline casts** are composed of Tamm-Horsfall proteins and can be found in healthy individuals, or in conditions like **dehydration** or **fever**. - They are a non-specific finding and do not indicate specific renal pathology like glomerulonephritis. *WBC casts* - **WBC casts** are typically seen in **pyelonephritis** (kidney infection) or **interstitial nephritis**, indicating inflammation within the renal tubules. - The patient's primary symptoms and lab findings are more consistent with glomerular disease rather than an infection of the renal parenchyma. *Granular casts* - **Granular casts** are formed from degenerated cellular casts or protein aggregates and are often seen in **acute tubular necrosis (ATN)** or **chronic kidney disease**. - While they suggest renal parenchymal injury, they are not as specific for glomerulonephritis as RBC casts, especially in a subacute presentation like this.

Question 326: A 61-year-old man with a history of stage IIIa lung adenocarcinoma that has been treated with wedge resection and chemotherapy presents to the primary care clinic. He is largely asymptomatic, but he demonstrates a persistent microcytic anemia despite iron supplementation. Colonoscopy performed 3 years earlier was unremarkable. His past medical history is significant for diabetes mellitus type II, hypertension, acute lymphoblastic leukemia as a child, and hypercholesterolemia. He currently smokes 1 pack of cigarettes per day, drinks a glass of pinot grigio per day, and currently denies any illicit drug use. His vital signs include: temperature, 36.7°C (98.0°F); blood pressure, 126/74 mm Hg; heart rate, 87/min; and respiratory rate, 17/min. On physical examination, his pulses are bounding, complexion is pale, but breath sounds remain clear. Oxygen saturation was initially 91% on room air, with a new oxygen requirement of 2 L by nasal cannula. Which of the following lab values would suggest anemia of chronic disease as the underlying etiology?

A. Decreased serum iron and transferrin, decreased ferritin, normal serum transferrin receptor
B. Increased serum iron and transferrin, increased ferritin, normal serum transferrin receptor
C. Decreased serum iron, increased transferrin, decreased ferritin, increased serum transferrin receptor
D. Decreased serum iron and transferrin, increased ferritin, normal serum transferrin receptor (Correct Answer)
E. Decreased serum iron, decreased transferrin, increased ferritin, increased serum transferrin receptor

Explanation: ***Decreased serum iron and transferrin, increased ferritin, normal serum transferrin receptor*** - In **anemia of chronic disease (ACD)**, inflammation leads to increased **hepcidin** levels, which blocks iron release from stores and reduces iron absorption, resulting in **decreased serum iron and transferrin** (which reflects transferrin saturation). - The inflammatory state also causes **ferritin** (an acute phase reactant and iron storage protein) to be **increased** or normal, as iron is sequestered. **Serum transferrin receptor** levels are typically normal, differentiating it from iron deficiency anemia. *Decreased serum iron and transferrin, decreased ferritin, normal serum transferrin receptor* - This pattern, particularly the **decreased ferritin**, is more indicative of **iron deficiency anemia**, where the body's iron stores are depleted. - In iron deficiency, the body attempts to increase iron absorption and mobilization, thus ferritin would be low. *Increased serum iron and transferrin, increased ferritin, normal serum transferrin receptor* - This combination is not typical for any common anemia. **Increased serum iron and transferrin** might suggest iron overload conditions, but not iron-restricted erythropoiesis. - While ferritin can be increased in chronic disease, the increased serum iron and transferrin are contradictory to ACD. *Decreased serum iron, increased transferrin, decreased ferritin, increased serum transferrin receptor* - This constellation, especially the **increased transferrin** and **decreased ferritin**, is characteristic of **iron deficiency anemia**. - **Increased serum transferrin receptor** is a hallmark of iron deficiency, as cells upregulate receptors to capture more iron when deficient. *Decreased serum iron, decreased transferrin, increased ferritin, increased serum transferrin receptor* - While **decreased serum iron, decreased transferrin** (low transferrin saturation), and **increased ferritin** can be seen in ACD, the presence of an **increased serum transferrin receptor** is inconsistent. - An increased serum transferrin receptor is usually a marker for increased erythropoietic activity or iron deficiency, which is not the primary mechanism of ACD.

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Systemic Pathology — MCQs

Systemic Pathology — MCQs

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