A 23-year-old man presents to the office complaining of weight loss and fatigue for the past 2 months. He states that he has been experiencing foul-smelling, light-colored stools but thinks it is because he hasn’t been eating well, recently. He has a past medical history significant for cystic fibrosis, which is well-controlled medically. He denies any shortness of breath, chest or abdominal pain, nausea, vomiting, or melena. On physical examination, his skin is pale and dry. Which of the following would be the most likely etiology of a malabsorption syndrome giving rise to this patient’s current condition?

Decreased recycling of bile acids

Autoimmune damage to parietal cells

Chronic damage to intestinal mucosa

Damage to intestinal brush border

A 15-year-old girl is brought to the physician because of an 8-month history of fatigue, intermittent postprandial abdominal bloating and discomfort, foul-smelling, watery diarrhea, and a 7-kg (15-lb) weight loss. She developed a pruritic rash on her knees 3 days ago. Physical examination shows several tense, excoriated vesicles on the knees bilaterally. The abdomen is soft and nontender. Her hemoglobin concentration is 8.2 g/dL and mean corpuscular volume is 76 μm3. Further evaluation of this patient is most likely to show which of the following findings?

IgA tissue transglutaminase antibodies

Elevated serum amylase concentration

Intraluminal esophageal membrane

Periodic acid-Schiff-positive macrophages

A 29-year-old man presents to clinic with a complaint of fatigue that has developed over the past 6 months. Upon questioning, he endorses abdominal pain, non-bloody diarrhea, and decreased appetite over the past year. He denies recent travel outside of the country or eating uncooked meats. On exam, his temperature is 99.0°F (37.2°C), blood pressure is 126/78 mmHg, pulse is 93/min, and respirations are 12/min. Notably, the abdominal exam is unremarkable aside from some tenderness to palpation near the umbilicus. His colonoscopy demonstrates perianal inflammation with a normal rectum, and biopsies of suspicious lesions in the transverse colon reveal transmural inflammation. Which one of the following is most strongly associated with the patient’s condition?

Positive serum transglutaminase antibodies

A 19-year-old woman with a known history of malabsorption presents with a painful red tongue, red eyes, and cracked lips. She says her symptoms gradually began 4 months ago after moving away from home for college. She also complains of photophobia, spontaneous lacrimation, and itchy dermatitis. Past medical history is significant for a long-standing malabsorption syndrome, which she says that she hasn't been able to maintain her normal diet or take her vitamins regularly due to her busy schedule. The patient is afebrile and vital signs are within normal limits. On physical examination, she has a malnourished appearance with significant pallor. Conjunctival injection is present bilaterally. Which of the following diagnostic tests will be most helpful to support the diagnosis of the most likely vitamin deficiency in this patient?

Measurement of erythrocyte glutathione reductase activity

Measurement of erythrocyte folate levels

Measurement of erythrocyte glutamic oxaloacetic transaminase activity

Measurement of erythrocyte transketolase activity

Measurement of serum methylmalonic acid levels

A 54-year-old man comes to the physician because of diarrhea that has become progressively worse over the past 4 months. He currently has 4–6 episodes of foul-smelling stools per day. Over the past 3 months, he has had fatigue and a 5-kg (11-lb) weight loss. He returned from Bangladesh 6 months ago after a year-long business assignment. He has osteoarthritis and hypertension. Current medications include amlodipine and naproxen. He appears pale and malnourished. His temperature is 37.3°C (99.1°F), pulse is 76/min, and blood pressure is 140/86 mm Hg. Examination shows pale conjunctivae and dry mucous membranes. Angular stomatitis and glossitis are present. The abdomen is distended but soft and nontender. Rectal examination shows no abnormalities. Laboratory studies show: Hemoglobin 8.9 g/dL Leukocyte count 4100/mm3 Platelet count 160,000/mm3 Mean corpuscular volume 110 μm3 Serum Na+ 133 mEq/L Cl- 98 mEq/l K+ 3.3 mEq/L Creatinine 1.1 mg/dL IgA 250 mg/dL Anti-tissue transglutaminase, IgA negative Stool culture and studies for ova and parasites are negative. Test of the stool for occult blood is negative. Fecal fat content is 22 g/day (N < 7). Fecal lactoferrin is negative and elastase is within normal limits. Which of the following is the most appropriate next step in diagnosis?

PAS-stained biopsy of small bowel

IgG against deamidated gliadin peptide

A 42-year-old woman presents with exertional dyspnea and fatigue for the past 3 months. Her past medical history is significant for multiple episodes of mild diarrhea for many years, which was earlier diagnosed as irritable bowel syndrome (IBS). She denies any current significant gastrointestinal symptoms. The patient is afebrile and vital signs are within normal limits. Physical examination reveals oral aphthous ulcers and mild conjunctival pallor. Abdominal examination is unremarkable. There is a rash present on the peripheral extremities bilaterally (see image). Laboratory findings are significant for evidence of microcytic hypochromic anemia. FOBT is negative. Which of the following is the most likely diagnosis in this patient?

Small intestinal bacterial overgrowth

A previously healthy 20-year-old woman comes to the physician because of recurrent abdominal cramps, bloating, and diarrhea for 4 months. She describes her stools as greasy, foul-smelling, and difficult to flush. During this time she has had a 6-kg (13.2-lb) weight loss. She has no personal or family history of serious illness. Physical examination shows pallor and cheilitis. Laboratory studies show a hemoglobin concentration of 11 g/dL. Serum concentrations of electrolytes, urea nitrogen, and creatinine are within the reference range. Test of the stool for occult blood is negative and stool microscopy reveals no pathogens and no leukocytes. Analysis of a 24-hour stool sample shows 12 g of fat. The patient is asked to consume 25 g of d-xylose. Five hours later, its concentration is measured in urine at 2 g (N = > 4 g/5 h). The test is repeated after a two-week course of rifaximin, but the urinary concentration of d-xylose remains the same. Which of the following is the most likely diagnosis?

Exocrine pancreatic insufficiency

Bacterial overgrowth in the small intestine

Malabsorption syndromes for USMLE Step 1: High-Yield Internal Medicine Lessons

Malabsorption - The Leaky Pipeline

Pathophysiology: Impaired intestinal absorption of nutrients, leading to nutritional deficiencies & GI symptoms.
Hallmark Sign: Steatorrhea (fatty, foul-smelling stools), weight loss, abdominal distension.
Classification:
- Pre-mucosal: Defective digestion (e.g., pancreatic insufficiency).
- Mucosal: Damaged absorptive surface (e.g., Celiac disease, Whipple's disease).
- Post-mucosal: Impaired nutrient transport (e.g., lymphatic obstruction).
Key Diagnostics:
- Qualitative stool fat (Sudan III stain).
- D-xylose test to differentiate mucosal from pancreatic causes.

⭐ D-xylose Test: A monosaccharide absorbed without pancreatic enzymes. A low urinary D-xylose level suggests mucosal damage (e.g., Celiac disease), as the intestine cannot absorb it.

Pathogenesis of Celiac Disease

Diagnostic Workup - Following the Clues

Initial Labs: CBC (anemia), iron studies, folate, vitamin B12, albumin, prothrombin time (PT).
Stool Studies:
- Qualitative: Sudan III stain for fecal fat.
- Quantitative: 72-hour fecal fat collection is the gold standard (abnormal: >7 g/day).

⭐ The D-xylose test is key: it's a monosaccharide absorbed in the proximal intestine without pancreatic enzymes. A low urinary/serum level after an oral dose points to mucosal defects (e.g., celiac disease), not pancreatic insufficiency.

Celiac Disease - Gluten's Gut Grudge

Pathophysiology: Autoimmune reaction to gliadin (a gluten protein) in individuals with HLA-DQ2/DQ8 haplotypes, leading to inflammation and damage of the small bowel mucosa.

Celiac disease histology: normal vs. affected villi

Clinical Features:
- GI: Chronic diarrhea/steatorrhea, bloating, weight loss.
- Extra-intestinal: Dermatitis herpetiformis (pruritic papulovesicular rash on extensor surfaces), iron deficiency anemia, fatigue.
Diagnosis:
- Serology: ↑ IgA anti-tissue transglutaminase (tTG) is the preferred initial test.
- Biopsy: Duodenal biopsy is the gold standard, showing villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis.

⭐ Associated Malignancy: Patients have an increased risk of developing enteropathy-associated T-cell lymphoma (EATL) and small bowel adenocarcinoma.

Other Syndromes - The Rogues' Gallery

Whipple Disease
- Systemic infection with Tropheryma whipplei.
- Presents with migratory polyarthritis, abdominal pain, diarrhea, and weight loss. May have CNS or cardiac signs.
- 📌 Mnemonic: "Foamy WHIPPed cream" for Foamy macrophages in Whipple disease.
- ⭐ Biopsy reveals PAS-positive, diastase-resistant macrophages in the lamina propria.
Tropical Sprue
- Acquired syndrome in tropical regions, likely infectious.
- Chronic diarrhea and megaloblastic anemia (↓ folate/B12) after travel.
- Responds to antibiotics (e.g., tetracycline) and folic acid.
Short Bowel Syndrome
- Malabsorption post-surgical resection. Severity depends on length/site.
- Loss of ileum is most critical (↓ bile salt and B12 absorption).
Small Intestinal Bacterial Overgrowth (SIBO)
- Excess bacteria deconjugate bile acids, causing malabsorption.
- Presents with bloating, flatulence, watery diarrhea.

High-Yield Points - ⚡ Biggest Takeaways

Celiac disease is strongly associated with HLA-DQ2/DQ8, villous atrophy, and dermatitis herpetiformis.

Whipple disease presents with a classic triad of diarrhea, weight loss, and arthralgia; look for PAS-positive macrophages on biopsy.

Pancreatic insufficiency (e.g., chronic pancreatitis, cystic fibrosis) is a primary cause of steatorrhea and fat-soluble vitamin deficiencies.

The D-xylose test helps distinguish mucosal defects (abnormal result) from pancreatic causes (normal result).

Lactose intolerance causes osmotic diarrhea and bloating after dairy intake.

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