Kaplan USMLE Step 1 prep: Higher risk of cancer in which organ?

If you’re preparing for the United States Medical Licensing Examination® (USMLE®) Step 1 exam, you might want to know which questions are most often missed by test-prep takers. Check out this example from Kaplan Medical, and read an expert explanation of the answer. Also check out all posts in this series.  

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A 39-year-old woman comes to the physician because of mild clumsiness when walking, tingling in her hands and feet, and persistent fatigue. She states that she maintains the same balanced diet. Her temperature is 36.9 °C (98.4 °F), pulse is 80 beats per minute, respirations are 14 a minute, and blood pressure is 128/76 mm Hg.

Physical examination shows a smooth, red tongue with loss of papillae, mild gait disturbance, and impaired position sense and vibration perception. Laboratory tests show an erythrocyte count of 3.0 million/mm³, hemoglobin of 10 g/dL, hematocrit of 30%, and MCV of 125 mum³. Serum folate level is normal and serum methylmalonic acid is elevated. Oral vitamin absorption studies demonstrate that the patient is unable to absorb vitamin B₁₂ in adequate amounts without added intrinsic factor.

This patient's condition is associated with an increased risk of developing cancer of which of the following organs?

A. Colon.

B. Duodenum.

C. Esophagus.

D. Ileum.

E. Stomach.

The correct answer is E.

Megaloblastic anemia with neuropathy suggests vitamin B₁₂ deficiency, which in this patient suggests pernicious anemia (PA). PA is associated with chronic gastritis, which leads to increased risk of gastric cancer.

Vitamin B₁₂ deficiency:  

• Subacute combined degeneration of the dorsal and lateral white matter tracts of the spinal cord due to demyelination.
• Stocking glove paresthesias, decreased sensation, gait disturbances.
• Glossitis, macrocytic RBCs with hypersegmented neutrophils.

Vitamin B₁₂ handling involves a complex, multistep process, which increases susceptibility to deficiencies.

• Vitamin B₁₂ (cobalamin) is ingested bound to proteins.
• Stomach proteases digest proteins to release vitamin B₁₂.
• Vitamin B₁₂ binds to haptocorrin, which protects it from stomach acid. Haptocorrin is produced by salivary glands and gastric glands.
• The Vitamin B₁₂-haptocorrin complex travels to the duodenum, where proteases digest haptocorrin, releasing vitamin B₁₂.
• Vitamin B₁₂ now binds to intrinsic factor (IF), which protects it from enzymatic degradation. IF is produced by gastric parietal cells.
• The Vitamin B₁₂-IF complex travels to the ileum where it binds to specific receptors on the apical surface of enterocytes. The receptor-Vitamin B₁₂-IF complex is then rapidly internalized by endocytosis.
• Vitamin B₁₂ dissociates from IF and binds to transcobalamin II, which allows it to leave the enterocyte and enter the enterohepatic circulation for delivery to tissues, or for storage by the liver. 

Causes of vitamin B₁₂ deficiency include:

• Pernicious anemia: Autoimmune gastritis that destroys parietal cells and leads to acid and IF deficiency.
• Nutritional: Pure plant-based diet; diet lacking meats, dairy, eggs.
• Surgery: Removal of stomach or ileum (source of IF or absorption of IF) or ileal bypass.
• Crohn disease: Inflammation of the ileum.
• Fish tapeworm Diphyllobothrium latum infection.
• Medications: Purine and pyrimidine antagonists.
• Blind loop syndrome: bacterial overgrowth.

Vitamin B₁₂ is required for DNA synthesis in blood cell precursors; deficiency produces megaloblastic anemia. Vitamin B₁₂ deficiency is associated with elevated levels of methylmalonic acid (MMA) and homocysteine. Recall, methylmalonyl CoA is converted to succinyl CoA and homocysteine is converted to methionine. Without vitamin B₁₂, these reactions cannot proceed, leading to substrate accumulation. In contrast, folate deficiency will only have an increase homocysteine level. Note: due to elevated levels of homocysteine, these patients have an increased risk of cardiovascular disease.

Choice A: Predisposing factors for colon cancer include familial polyposis syndromes, inflammatory bowel disease, isolated adenomatous polyps, and a diet high in animal fat.

Choice B and D: Duodenal and ileal cancers are uncommon.

Choice C: Predisposing factors for esophageal cancer include chronic exposure to hot foods/liquids, smoking, Barrett esophagus and Plummer-Vinson syndrome.

• Megaloblastic anemia with neuropathy equals vitamin B₁₂ deficiency.
• Pernicious anemia: antibodies against parietal cells or intrinsic factor.
• Chronic gastritis leads to gastric cancer.
• B₁₂ deficiency causes elevated levels of MMA and homocysteine.

For more prep questions on USMLE Steps 1, 2 and 3, view other posts in this series.