Megaloblastic and macrocytic anemias

15 DOH Abu Dhabi (HAAD) lab licensing practice questions on Megaloblastic and macrocytic anemias, part of Hematology. The first 15 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

1. Question 1 · Hard

   A 63-year-old man who lives alone and eats little besides bread and tea has hemoglobin 86 g/L (8.6 g/dL), MCV 116 fL, hypersegmented neutrophils and macro-ovalocytes. He takes no medicines or supplements and does not drink alcohol. A fasting sample gives: serum B12 320 pmol/L (434 pg/mL; reference 150-650 pmol/L), methylmalonic acid 0.22 µmol/L (reference below 0.40), total homocysteine 41 µmol/L (reference 5-15) and serum folate 21 nmol/L (9.3 ng/mL; reference 7-45 nmol/L). The analyzer reports a hemolysis index of 3+ on the folate sample. What best explains the normal serum folate?

   1. AFolate trapping from vitamin B12 deficiency
   2. BA folate-rich meal before the sample
   3. CImpaired folate use due to methotrexate
   4. DFolate released from lysed red cells

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   Answer: D · Folate released from lysed red cells

   Megaloblastic changes with a raised homocysteine but a normal B12 and normal methylmalonic acid point to folate deficiency, because methylmalonic acid rises only when B12 is lacking. Red cells hold many times more folate than serum, so even moderate hemolysis releases enough folate to lift a low serum result into the reference range. B12 deficiency can trap folate as methyltetrahydrofolate and raise serum folate, but the normal B12 and methylmalonic acid exclude it. The sample was fasting and he takes no drugs, so a recent meal and methotrexate do not explain the result. The hemolyzed sample should be rejected for folate, and a fresh, unhemolyzed sample (or a red cell folate) collected before any folic acid is given.

   • A: A normal B12 and normal methylmalonic acid exclude B12 deficiency.
   • B: The sample was taken fasting.
   • C: He takes no medicines.

2. Question 2 · Hard

   A 30-year-old woman from South India, a lifelong vegetarian who eats no meat, fish or eggs, has fatigue, mild jaundice and tingling feet. Results: hemoglobin 58 g/L (5.8 g/dL), MCV 114 fL, WBC 3.0 × 10^9/L, platelets 46 × 10^9/L, reticulocytes 0.9% (absolute 15 × 10^9/L; reference 25-100), LD 4,200 U/L (reference 125-220), indirect bilirubin 52 µmol/L (3.0 mg/dL), haptoglobin undetectable and DAT negative. Creatinine, PT and APTT are normal. The film shows macro-ovalocytes, hypersegmented neutrophils and 2% schistocytes. A possible thrombotic microangiopathy has been flagged, and ADAMTS13 activity is pending. The most likely diagnosis is:

   1. AParoxysmal nocturnal hemoglobinuria
   2. BThrombotic thrombocytopenic purpura
   3. CVitamin B12 deficiency
   4. DMyelodysplastic neoplasm

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   Answer: C · Vitamin B12 deficiency

   The hemolysis markers here come from ineffective erythropoiesis: megaloblasts die in the marrow, releasing LD and bilirubin and using up haptoglobin, and the LD is often very high. The low absolute reticulocyte count shows that the marrow is not responding, which does not fit TTP, where red cells are destroyed in the circulation and the reticulocytes rise; PNH does not cause macro-ovalocytes, hypersegmented neutrophils or neuropathy. Macro-ovalocytes, hypersegmented neutrophils, pancytopenia and neuropathy in a lifelong vegetarian point to vitamin B12 deficiency, and the few schistocytes are fragments of fragile megaloblastic red cells (pseudo-thrombotic microangiopathy). Myelodysplasia causes macrocytosis but typically with hyposegmented (pseudo-Pelger) neutrophils, and it does not cause neuropathy. Measuring B12, with methylmalonic acid if it is borderline, before treatment avoids needless plasma exchange.

   • A: PNH does not cause macro-ovalocytes, hypersegmented neutrophils or neuropathy.
   • B: TTP raises the reticulocyte count and does not cause macro-ovalocytes or hypersegmented neutrophils.
   • D: Myelodysplasia shows hyposegmented, not hypersegmented, neutrophils and no neuropathy.

3. Question 3 · Hard

   A 10-month-old girl has been fed only goat's milk since 4 months of age. Hemoglobin is 76 g/L (7.6 g/dL), MCV 108 fL, WBC 4.1 × 10^9/L, platelets 120 × 10^9/L, and the film shows hypersegmented neutrophils. Serum B12 and methylmalonic acid are normal and homocysteine is raised. The most likely cause is:

   1. ADiamond-Blackfan red cell aplasia
   2. BInherited transcobalamin deficiency
   3. CFolate deficiency from a goat's milk diet
   4. DIron deficiency from a milk-only diet

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   Answer: C · Folate deficiency from a goat's milk diet

   Goat's milk contains much less folate than human or cow's milk, and infants fed on it alone can develop megaloblastic anemia within months. A raised homocysteine with normal MMA and normal B12 is the pattern of folate deficiency, because only the folate-dependent step is blocked. Infants have small folate stores and grow fast, so deficiency develops quickly. Folic acid and a suitable formula correct the anemia.

   • A: Diamond-Blackfan anemia is a pure red cell aplasia without hypersegmented neutrophils or a low WBC.
   • B: Transcobalamin deficiency raises methylmalonic acid as well as homocysteine, often with a normal serum B12.
   • D: Iron deficiency gives microcytic, not macrocytic, red cells.

4. Question 4 · Hard

   A 36-year-old woman had gastric bypass surgery 4 years ago and takes no supplements. Hemoglobin is 88 g/L (8.8 g/dL), MCV 87 fL (reference 80-100), RDW 22% (reference 11.5-14.5%), ferritin 5 µg/L (reference 15-150) and B12 95 pmol/L (129 pg/mL; reference above 150 pmol/L). The film shows hypochromic microcytes, oval macrocytes and hypersegmented neutrophils. What best explains the normal MCV?

   1. ACombined iron and vitamin B12 deficiency
   2. BEarly iron deficiency on its own
   3. CAcute blood loss with reticulocytosis
   4. DAnemia of inflammation after surgery

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   Answer: A · Combined iron and vitamin B12 deficiency

   Gastric bypass reduces acid and intrinsic factor and bypasses the duodenum, so iron and B12 deficiency often develop together. Small hypochromic cells and large oval cells average out to a normal MCV, while the RDW is very high because the two populations differ so much in size. Hypersegmented neutrophils and the low B12 show the megaloblastic part, and the low ferritin shows the iron deficiency. The MCV alone can mislead, so the RDW and the film must always be checked.

   • B: Iron deficiency alone does not explain the macrocytes, hypersegmentation and low B12.
   • C: Acute blood loss gives polychromasia, not hypochromic microcytes with hypersegmented neutrophils.
   • D: Anemia of inflammation does not give a ferritin of 5 µg/L or hypersegmented neutrophils.

5. Question 5 · Easy

   Neutrophil hypersegmentation on a blood film is commonly defined as:

   1. AMore than 5% of neutrophils with three lobes
   2. BAny neutrophil with four separate lobes
   3. CMore than 5% with two lobes joined by a strand
   4. DMore than 5% with five lobes, or any with six

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   Answer: D · More than 5% with five lobes, or any with six

   Normal mature neutrophils have two to five lobes, and most have three. Hypersegmentation is usually defined as more than 5% of neutrophils with five lobes, or any neutrophil with six or more. It is an early and sensitive sign of megaloblastic anemia from B12 or folate deficiency, and it can appear before the MCV rises. Two-lobed cells joined by a strand suggest a Pelger-Huët anomaly instead.

   • A: Three lobes is the most common normal pattern.
   • B: Four lobes is within the normal range of two to five lobes.
   • C: Bilobed neutrophils suggest a Pelger-Huët anomaly, not hypersegmentation.

6. Question 6 · Hard

   A 58-year-old man with diabetes is admitted with glucose 48 mmol/L (865 mg/dL). The impedance analyzer reports hemoglobin 138 g/L (13.8 g/dL), RBC 4.50 × 10^12/L, MCV 112 fL (reference 80-100), hematocrit 0.50 L/L and MCHC 274 g/L (reference 320-360). The film shows normocytic red cells. What best explains the MCV?

   1. AMegaloblastic change from metformin-related low B12
   2. BRed cells swell in the analyzer's isotonic diluent
   3. CRed cell agglutination caused by a cold autoantibody
   4. DDehydration that concentrates the circulating red cells

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7. Question 7 · Hard

   An 82-year-old woman with eGFR 18 mL/min/1.73 m² has hemoglobin 102 g/L (10.2 g/dL), MCV 91 fL and no hypersegmented neutrophils. Serum B12 is 190 pmol/L (257 pg/mL; borderline range 150-220 pmol/L) and methylmalonic acid is 0.9 µmol/L (reference below 0.4). How should the methylmalonic acid be interpreted?

   1. AIt confirms pernicious anemia as the cause
   2. BIt is invalid unless the serum B12 is low
   3. CIt confirms that she has folate deficiency
   4. DPoor kidney function can raise it on its own

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8. Question 8 · Easy

   Long-term use of which diabetes drug is a known cause of low vitamin B12?

   1. AGliclazide
   2. BMetformin
   3. CInsulin glargine
   4. DEmpagliflozin

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9. Question 9 · Easy

   Vitamin B12 bound to intrinsic factor is absorbed in the:

   1. ADuodenum
   2. BTerminal ileum
   3. CAscending colon
   4. DProximal jejunum

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10. Question 10 · Medium

    Round macrocytes, no hypersegmented neutrophils, and normal serum B12 and folate fit best with:

    1. AHypothyroidism
    2. BDietary folate deficiency
    3. CPernicious anemia
    4. DFish tapeworm infection

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11. Question 11 · Medium

    In megaloblastic anemia, marrow erythroblasts show nuclear-cytoplasmic asynchrony. What does this mean?

    1. AThe cells contain two separate nuclei
    2. BThe cytoplasm looks immature for the nucleus
    3. CThe nucleus looks immature for the cytoplasm
    4. DThe nucleus is small, dense and pyknotic

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12. Question 12 · Medium

    Which test measures the fraction of plasma vitamin B12 that body cells can take up?

    1. AHaptocorrin-bound B12
    2. BHolotranscobalamin
    3. CIntrinsic factor antibody
    4. DTotal serum B12

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13. Question 13 · Medium

    Severe vitamin B12 deficiency often lowers the white cell and platelet counts as well as hemoglobin. Why?

    1. AAutoantibodies destroy all three cell lines
    2. BDNA synthesis fails in all dividing marrow cells
    3. CAn enlarged spleen traps all the cell types
    4. DMarrow fibrosis replaces the blood-forming cells

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14. Question 14 · Medium

    Methotrexate causes megaloblastic changes by inhibiting which enzyme?

    1. AMethionine synthase
    2. BDihydrofolate reductase
    3. CRibonucleotide reductase
    4. DMethylmalonyl-CoA mutase

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15. Question 15 · Hard

    Both methylmalonic acid and homocysteine are raised in a patient with macrocytic anemia. Which deficiency does this point to?

    1. AVitamin B12 deficiency
    2. BVitamin B6 deficiency
    3. CFolate deficiency
    4. DIron deficiency

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