Macrocytic megaloblastic anemia with neurologic features from cobalamin deficiency.
Also known as: B12 deficiency, cobalamin deficiency, pernicious anemia, megaloblastic anemia
Overview
Anemia and neurologic disease resulting from deficiency of vitamin B12 (cobalamin), a cofactor for methionine synthase and methylmalonyl-CoA mutase. Pernicious anemia is the autoimmune subtype caused by loss of intrinsic factor from gastric parietal cell destruction.
Epidemiology
Affects 6% of adults over 60 in the US. Pernicious anemia is the most common cause of severe B12 deficiency in adults; prevalence ~2% over age 60, more common in northern European and African ancestry, and associated with other autoimmune disease.
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Question 1HematologyMedium
A 58-year-old vegetarian woman has fatigue. Labs: Hgb 9.4, MCV 108 fL, normal reticulocyte count, low B12 level, elevated methylmalonic acid and homocysteine. Peripheral smear shows hypersegmented neutrophils. Which is the next best step in workup?
AUpper endoscopy with gastric body and antral biopsies
BAnti-intrinsic factor and anti-parietal cell antibodies
CBone marrow aspirate and biopsy with cytogenetic analysis
DSerum iron, total iron-binding capacity, and ferritin levels
Reveal answer & full explanation
Correct answer: B — Anti-intrinsic factor and anti-parietal cell antibodies
AUpper endoscopy with gastric body and antral biopsies
BAnti-intrinsic factor and anti-parietal cell antibodies✓
CBone marrow aspirate and biopsy with cytogenetic analysis
DSerum iron, total iron-binding capacity, and ferritin levels
Why Anti-intrinsic factor and anti-parietal cell antibodies is correct
This is megaloblastic macrocytic anemia from B12 deficiency
Elevated methylmalonic acid (MMA) AND homocysteine differentiates B12 deficiency from folate deficiency, which elevates only homocysteine
Causes of B12 deficiency: pernicious anemia (autoimmune anti-intrinsic factor (anti-IF)/parietal cell antibodies — MOST COMMON cause in adults), strict vegetarianism, terminal ileal disease, gastric bypass, atrophic gastritis
Anti-IF antibodies are highly specific for pernicious anemia; anti-parietal cell antibodies are sensitive but less specific
Serology is sent regardless of dietary history: a vegetarian diet does not exclude coexisting pernicious anemia, and a positive result changes management (lifelong parenteral or high-dose oral B12 rather than dietary correction, plus increased gastric cancer risk)
Why the others are wrong
Upper endoscopy with gastric body and antral biopsies — can document atrophic gastritis, but it is invasive and follows rather than precedes noninvasive serologic testing; it is reserved for confirmed pernicious anemia or alarm symptoms
Bone marrow aspirate and biopsy with cytogenetic analysis — unnecessary when B12 deficiency is already established as the cause; reserved for cytopenias that persist despite repletion or suspected myelodysplastic syndrome
Serum iron, total iron-binding capacity, and ferritin levels — appropriate for microcytic anemia workup; this patient has macrocytic anemia from B12 deficiency
Question 2HematologyMedium
A 62-year-old woman has fatigue, macrocytosis, paresthesias, and positive intrinsic factor antibodies. Which of the following best explains the anemia?
ADefective heme group production
BImpaired nuclear DNA synthesis
CReduced erythropoietin release
DIncreased red-cell membrane loss
Reveal answer & full explanation
Correct answer: B — Impaired nuclear DNA synthesis
ADefective heme group production
BImpaired nuclear DNA synthesis✓
CReduced erythropoietin release
DIncreased red-cell membrane loss
Why Impaired nuclear DNA synthesis is correct
Intrinsic factor antibodies block B12 absorption (pernicious anemia), and B12 is a cofactor for thymidine synthesis.
Stalled DNA synthesis with continued cytoplasmic growth yields megaloblastic, macrocytic red cells.
The paresthesias point to B12 rather than folate, since only B12 causes the neuropathy.
Why the others are wrong
Defective heme group production — Sideroblastic or lead-related heme defects are microcytic, not macrocytic; this is a size-pattern trap.
Increased red-cell membrane loss — Membrane defects give spherocytic hemolysis with high reticulocytes, not megaloblastosis.
Reduced erythropoietin release — Low EPO from kidney disease gives normocytic anemia and no neurologic findings.
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Nitrous oxide exposure (recreational or anesthesia in marginal patients)
Pathophysiology
Dietary B12 binds R-factor in the stomach, is released by pancreatic enzymes in the duodenum, and then complexes with intrinsic factor (from gastric parietal cells) for absorption in the terminal ileum. In pernicious anemia, autoantibodies destroy parietal cells and/or intrinsic factor, blocking absorption. B12 deficiency impairs DNA synthesis (megaloblastic erythropoiesis) and myelin maintenance (subacute combined degeneration of dorsal columns and lateral corticospinal tracts).
Low serum B12 (<200 pg/mL) OR borderline B12 with elevated MMA, plus clinical/laboratory features consistent with deficiency. Pernicious anemia confirmed by positive anti-intrinsic factor antibody.
Labs
CBC — macrocytic anemia (MCV often >110 fL), pancytopenia in advanced cases
Peripheral smear — oval macrocytes, hypersegmented neutrophils (>5 lobes or any 6-lobed), anisopoikilocytosis
Distinguishing B12 from folate deficiency — methylmalonic acid is the most specific discriminator.
Treatment
First-line
Cyanocobalamin or hydroxocobalamin IM — 1000 mcg IM daily for 1 week, then weekly for 4 weeks, then monthly for life (pernicious anemia) or until cause corrected
High-dose oral cyanocobalamin 1000-2000 mcg daily — alternative for non-PA causes and stable PA patients; ~1% absorbed passively independent of intrinsic factor
Sublingual and intranasal formulations available
Treat concurrent iron deficiency (often unmasked after B12 repletion)
Second-line / adjunct
Address underlying cause: discontinue offending drugs when possible, treat H. pylori, manage Crohn disease, screen for celiac
Monitor potassium — refeeding hypokalemia can occur in first 48 hours of treatment
Lifelong replacement in pernicious anemia, post-gastrectomy, terminal ileum resection
Complications
Permanent neurologic deficits if untreated >6 months (dorsal column and corticospinal tract damage)
Increased gastric adenocarcinoma and carcinoid risk in pernicious anemia (EGD surveillance debated; baseline endoscopy recommended)
Severe pancytopenia with risk of bleeding and infection
Hyperhomocysteinemia — associated with arterial/venous thrombosis
Refeeding hypokalemia after starting therapy
PANCE pearls
Neurologic deficits can occur with normal hemoglobin — do not exclude B12 deficiency in a patient with paresthesias and ataxia just because the CBC is normal.
Folate replacement WITHOUT B12 in a B12-deficient patient corrects the anemia but allows neurologic disease to progress — always check B12 before treating presumed folate deficiency.
Methylmalonic acid is more reliable than serum B12 for diagnosis; serum B12 has high false-negative and false-positive rates.
Schilling test is obsolete (radioisotope and intrinsic factor unavailable); diagnosis now relies on antibody testing.
Nitrous oxide irreversibly oxidizes cobalamin and can precipitate fulminant deficiency — important in recreational use ('whippets') and in marginal patients undergoing anesthesia.
Hypersegmented neutrophils on smear are a clue even before macrocytosis develops.
References
BSH 2014 — British Society for Haematology Guidelines for the diagnosis and treatment of cobalamin and folate disorders (Devalia et al., Br J Haematol 2014)
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