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?

Deposition of an extracellular fibrillar protein that stains positive for Congo red in the myocardium

Thickening of the parietal pericardium with dystrophic calcification

Calcification of the aortic valve orifice with obstruction of the left ventricular outflow tract

Concentric hypertrophy of the myocytes with thickening of the interventricular septum

Diastolic cardiac dysfunction with reciprocal variation in ventricular filling with respiration

A 65-year-old man comes to the physician because of increasing swelling of the legs and face over the past 2 months. He has a history of diastolic heart dysfunction. The liver and spleen are palpable 4 cm below the costal margin. On physical examination, both lower limbs show significant pitting edema extending above the knees and to the pelvic area. Laboratory studies show: Serum Cholesterol 350 mg/dL (<200 mg/dL) Triglycerides 290 mg/dL (35–160 mg/dL) Calcium 8 mg/dL Albumin 2.8 g/dL Urea nitrogen 54 mg/dL Creatinine 2.5 mg/dL Urine Blood 3+ Protein 4+ RBC 15–17/hpf WBC 1–2/hpf RBC casts Many Echocardiography shows concentrically thickened ventricles with diastolic dysfunction. Skeletal survey shows no osteolytic lesions. Which of the following best explains these findings?

Monoclonal gammopathy of undetermined significance

Waldenstrom’s macroglobulinemia

A 79-year-old homeless man is brought to the emergency department by ambulance 30 minutes after being found unresponsive by the police. On arrival, he is apneic and there are no palpable pulses. Despite appropriate life-saving measures, he dies. Examination of the heart during autopsy shows normal ventricles with a sigmoid-shaped interventricular septum. A photomicrograph of a section of the heart obtained at autopsy is shown. Which of the following is the most likely underlying cause for the structure indicated by the arrow?

Deposition of wild-type transthyretin

Clumping of defective mitochondria

Oxidation of phospholipid molecules

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?

Apple green birefringence with Congo red staining

Glomerular basement membrane splitting

A 55-year-old man comes to the physician because of a 3-day history of decreased urine output, progressively worsening bilateral pedal edema, and fatigue. He has a 4-month history of persistent lower back pain. He has hypercholesterolemia and stable angina pectoris. Current medications include atorvastatin, aspirin, and ibuprofen. His pulse is 80/min, respirations are 16/min, and blood pressure is 150/100 mm Hg. Examination shows periorbital and pedal edema and pallor. There is tenderness of the lumbar spinal vertebrae. Straight leg raise test is negative. The remainder of the examination shows no abnormalities. Laboratory studies show: Hemoglobin 8.9 g/dl Serum Urea nitrogen 20 mg/dl Creatinine 2.4 mg/dl Calcium 11.2 mg/dl Alkaline phosphatase 140 U/L X-ray of the spine shows diffuse osteopenia and multiple lytic lesions. Which of the following is most likely to confirm the diagnosis?

Congo red stain of renal tissue

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?

Intimal thickening and medial hypertrophy

Thinning of the intima and media

A 51-year-old African American man with a history of poorly controlled hypertension presents to the emergency room with blurry vision and dyspnea. He reports rapid-onset blurred vision and difficulty breathing 4 hours prior to presentation. He takes lisinopril, hydrochlorothiazide, and spironolactone but has a history of poor medication compliance. He has a 50 pack-year smoking history and drinks 4-6 shots of vodka per day. His temperature is 99.2°F (37.3°C), blood pressure is 195/115 mmHg, pulse is 85/min, and respirations are 20/min. On exam, he is ill-appearing and pale. He is intermittently responsive and oriented to person but not place or time. Fundoscopic examination reveals swelling of the optic disc with blurred margins. A biopsy of this patient’s kidney would most likely reveal which of the following?

Concentrically thickened arteriolar tunica media with abundant nuclei

Calcific deposits in the arterial media without luminal narrowing

Fibrous atheromatous plaques in the arterial intima

Endothelial proliferation and luminal narrowing with a chronic inflammatory infiltrate

A 62-year-old man comes to the physician because of a swollen and painful right knee for the last 3 days. He has no history of joint disease. His vital signs are within normal limits. Examination shows erythema and swelling of the right knee, with limited range of motion due to pain. Arthrocentesis of the right knee joint yields 7 mL of cloudy fluid with a leukocyte count of 29,000/mm3 (97% segmented neutrophils). Compensated polarized light microscopy of the aspirate is shown. Which of the following is the most likely underlying mechanism of this patient's knee pain?

Calcium pyrophosphate deposition

Immune complex-mediated cartilage destruction

Bacterial infection of the joint

Amyloidosis for USMLE Step 3: High-Yield Pathology Lessons

Amyloidosis Basics - The Misfolded Mess

Core Defect: Normally soluble proteins misfold, adopting an insoluble $β$-pleated sheet secondary structure.
- These abnormal fibrils aggregate extracellularly in various tissues.
- Resistant to native proteolysis, leading to progressive accumulation.
Mechanism of Injury: Physical deposition causes tissue compression and disruption, ultimately leading to organ dysfunction.
- Common targets include kidneys (nephrotic syndrome), heart (restrictive cardiomyopathy), and nerves (neuropathy).

⭐ Histological Hallmark: Diagnosis requires tissue biopsy showing Congo Red staining, which produces a pathognomonic apple-green birefringence under polarized light.

Amyloidosis: Congo Red Stain with Apple-Green Birefringence

Classification - The Protein Rogues Gallery

Systemic vs. Localized: Amyloid can deposit throughout the body or in a single organ.
Primary vs. Secondary: Primary (AL) arises from immunoglobulin light chains. Secondary (AA) results from chronic inflammation or infection.

Fibril Protein	Precursor Protein	Associated Conditions
AL (Amyloid Light-chain)	Ig Light Chain (λ > κ)	Multiple Myeloma, Plasma Cell Dyscrasias
AA (Amyloid-Associated)	Serum Amyloid A (SAA)	Chronic Inflammation (RA, IBD, FMF)
Aβ (Beta-amyloid)	Amyloid Precursor Protein (APP)	Alzheimer Disease, Down Syndrome
ATTR (Transthyretin)	Transthyretin (TTR)	Senile Systemic Amyloidosis (wild-type), Familial Amyloid Polyneuropathies (mutant)
Aβ₂M (Beta-2 microglobulin)	β₂-microglobulin	Dialysis-Related Amyloidosis (esp. joints)

⭐ Congo Red Staining: Regardless of the protein type, all amyloid deposits show characteristic apple-green birefringence under polarized light after staining with Congo red. This is a pathognomonic finding.

Clinical Picture & Dx - Spotting the Gunk

Presentation is vague; depends on organ + protein type.
- Kidney (most common): Nephrotic syndrome (proteinuria, edema).
- Heart: Restrictive cardiomyopathy, arrhythmias. Macroglossia is a classic clue for AL type.
- GI: Malabsorption, hepatosplenomegaly.
- Nerves: Peripheral neuropathy, autonomic dysfunction (e.g., orthostatic hypotension).

Amyloidosis: Apple-Green Birefringence with Congo Red

Diagnostic Workflow:

⭐ The pathognomonic finding is apple-green birefringence of Congo Red-stained tissue when viewed under polarized light. Without this, it's not amyloidosis.

Amyloidosis is the extracellular deposition of misfolded fibrillar proteins, leading to tissue damage.

The pathognomonic finding is Congo red staining that reveals apple-green birefringence under polarized light.

AL (Primary) amyloidosis is caused by immunoglobulin light chains and is associated with plasma cell dyscrasias like multiple myeloma.

AA (Secondary) amyloidosis is derived from serum amyloid A (SAA) and is linked to chronic inflammatory conditions.

Transthyretin (TTR) is implicated in senile systemic amyloidosis.

β2-microglobulin is the culprit in dialysis-related amyloidosis.

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Amyloidosis

Amyloidosis

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Amyloidosis Basics - The Misfolded Mess

Classification - The Protein Rogues Gallery

Clinical Picture & Dx - Spotting the Gunk

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