Pathology USMLE Questions: Anemias – Beta-Thalassemia Minor, Vitamin B12 Deficiency and Hereditary Spherocytosis

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Anemia questions on USMLE Step 1 start with the MCV (microcytic, normocytic or macrocytic) and then ask you to pick the right lab finding or underlying defect. Here are three practice questions. Pick your answer first, then open the explanation.

Question 1: Very small red cells with normal iron studies

A 24-year-old woman of Mediterranean descent is found to have mild anemia on routine testing. She feels well. Hemoglobin is 10.9 g/dL, MCV is 64 fL, and the red blood cell count is 5.8 million/mm³ (high). Serum ferritin and iron are normal. Her anemia did not improve with a previous course of iron supplements. Which of the following findings is most likely on further testing?

A. Decreased serum ferritin
B. Increased hemoglobin A2 on hemoglobin electrophoresis
C. Ringed sideroblasts in the bone marrow
D. Hemoglobin S on electrophoresis
E. Coarse basophilic stippling from lead

Correct answer: B. Increased hemoglobin A2 on hemoglobin electrophoresis

A very low MCV with only mild anemia, a high RBC count, normal iron studies and no response to iron suggests beta-thalassemia minor (trait). Reduced beta-globin production leads to a relative increase in hemoglobin A2 (α2δ2), which is the key finding on electrophoresis. Target cells are often seen on the smear. No treatment is needed, but avoid unnecessary iron, and offer genetic counseling.

Why the other options are wrong:

  • Decreased ferritin indicates iron deficiency; her iron studies are normal.
  • Ringed sideroblasts indicate sideroblastic anemia (e.g., alcohol, lead, isoniazid, or B6 deficiency).
  • Hemoglobin S indicates sickle cell disease or trait, which is not microcytic in this way.
  • Basophilic stippling with lead points to lead poisoning, which usually comes with exposure history and neurologic or GI symptoms.

Question 2: Numb feet and large red cells in a strict vegan

A 45-year-old man who has followed a strict vegan diet for 10 years has fatigue and numbness and tingling in both feet. Examination shows decreased vibration and position sense in the lower extremities. Hemoglobin is 9.2 g/dL and MCV is 114 fL. A blood smear shows hypersegmented neutrophils. Which of the following sets of laboratory findings is most likely?

A. Normal methylmalonic acid, elevated homocysteine
B. Normal methylmalonic acid, normal homocysteine
C. Elevated methylmalonic acid, normal homocysteine
D. Elevated methylmalonic acid, elevated homocysteine
E. Decreased methylmalonic acid, decreased homocysteine

Correct answer: D. Elevated methylmalonic acid, elevated homocysteine

This is vitamin B12 (cobalamin) deficiency, which can occur in strict vegans because B12 comes from animal foods. B12 is a cofactor for two enzymes: methionine synthase (homocysteine → methionine) and methylmalonyl-CoA mutase (methylmalonyl-CoA → succinyl-CoA). Deficiency therefore raises both homocysteine and methylmalonic acid. The buildup of methylmalonic acid is linked to the neurologic damage (subacute combined degeneration of the dorsal columns and lateral corticospinal tracts). In folate deficiency, only homocysteine is elevated and there are no neurologic findings.

Why the other options are wrong:

  • Normal MMA with elevated homocysteine is the pattern of folate deficiency.
  • Both normal would argue against B12 and folate deficiency.
  • Elevated MMA alone does not occur in B12 deficiency, because homocysteine also rises.
  • Decreased levels are not a feature of either deficiency.

Question 3: Jaundice, a large spleen and round red cells without central pallor

A 12-year-old boy has had episodes of jaundice since early childhood. His father had his spleen removed as a young adult. Examination shows mild scleral icterus and splenomegaly. Hemoglobin is 10.1 g/dL, the reticulocyte count is elevated, and the MCHC is increased. A blood smear shows small, round red cells without central pallor. A direct Coombs test is negative. The underlying defect most likely involves which of the following?

A. Glucose-6-phosphate dehydrogenase
B. Pyruvate kinase
C. Beta-globin chain (glutamic acid → valine)
D. GPI-anchored complement regulatory proteins
E. Red cell membrane skeleton proteins such as spectrin or ankyrin

Correct answer: E. Red cell membrane skeleton proteins such as spectrin or ankyrin

This is hereditary spherocytosis, usually autosomal dominant. Defects in red cell membrane skeleton proteins (most commonly ankyrin, spectrin, band 3 or protein 4.2) cause loss of membrane, producing spherocytes that are trapped and destroyed in the spleen (extravascular hemolysis). Clues: family history, splenomegaly, increased MCHC and a negative Coombs test (which separates it from autoimmune hemolytic anemia). The EMA binding test confirms the diagnosis. Patients are at risk of aplastic crisis with parvovirus B19 and of pigment gallstones; splenectomy can help in severe cases.

Why the other options are wrong:

  • G6PD deficiency is X-linked and causes episodic hemolysis after oxidant stress, with bite cells and Heinz bodies.
  • Pyruvate kinase deficiency is autosomal recessive and does not cause spherocytes or increased MCHC.
  • Beta-globin glutamic acid → valine is sickle cell disease.
  • GPI-anchor defects (CD55/CD59) cause paroxysmal nocturnal hemoglobinuria, with intravascular hemolysis.

Key takeaways

  • Microcytosis with high RBC count, normal iron studies and increased HbA2 = beta-thalassemia minor.
  • B12 deficiency: elevated MMA and homocysteine, with neurologic findings; folate deficiency: homocysteine only.
  • Hereditary spherocytosis: spherocytes, increased MCHC, negative Coombs; defects in ankyrin or spectrin.

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Written and reviewed by Dr. Ray Makar, MD, dermatologist with 20 years of clinical practice. Last reviewed: October 2026. For exam preparation only, not medical advice.

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