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.
Try two board-style Vitamin B12 Deficiency / Pernicious Anemia questions
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Question 1NeurologyMedium
A 50-year-old male has 3 months of fatigue, bilateral lower extremity weakness, and electric shock sensations shooting down the spine into both legs when he flexes his neck. MRI cervical spine shows hyperintense T2 signal in the posterior columns at C3-C5. B12 level is 68 pg/mL. He has been taking omeprazole for 5 years and is a strict vegan. Which of the following is the most likely diagnosis?
ATabes dorsalis
BSubacute combined degeneration
CMultiple sclerosis
DSyringomyelia
ECompressive cervical myelopathy
Reveal answer & full explanation
Correct answer: B — Subacute combined degeneration
ATabes dorsalis
BSubacute combined degeneration✓
CMultiple sclerosis
DSyringomyelia
ECompressive cervical myelopathy
Why Subacute combined degeneration is correct
Subacute combined degeneration (SCD): B12 deficiency causes demyelination of the posterior columns and the lateral corticospinal tracts
Posterior column involvement: loss of vibration and proprioception, positive Romberg, sensory ataxia — MRI shows posterior column T2 hyperintensity (matches C3–C5 finding here)
Lateral corticospinal tract involvement: spasticity, hyperreflexia, Babinski — 'combined' refers to posterior column plus lateral corticospinal tract degeneration; a coexisting B12 peripheral neuropathy can depress ankle reflexes, so absent ankle jerks with a Babinski sign is a classic pairing
B12 level of 68 pg/mL confirms deficiency; long-term PPI use and strict vegan diet are both recognized causes
Why the others are wrong
Compressive cervical myelopathy — structural compression; would not explain the B12 deficiency or the vegan/PPI history — right-concept-wrong-setting given the biochemical context clinching SCD
Multiple sclerosis — also causes Lhermitte sign and posterior column changes, but is not explained by B12 deficiency; confused-with SCD, though onset at 50 and the metabolic history favor SCD
Syringomyelia — causes a cape-like dissociated sensory loss (pain/temperature > vibration/proprioception) and is linked to Chiari malformation; confused-with when fixating on cord signal but does not explain the B12 level
Tabes dorsalis — the other classic posterior column disease, and its lancinating pains can mimic shooting electric sensations, but tabes is a late complication of untreated syphilis that affects the dorsal roots and columns while sparing the corticospinal tracts (areflexia and sensory ataxia rather than weakness), and it does not explain a B12 of 68 pg/mL in a vegan on long-term PPI therapy
Additional high-yield points
Causes of B12 deficiency: vegans, pernicious anemia (anti-intrinsic factor (IF) antibodies — most common cause), proton pump inhibitor (PPI) use (acid/pepsin suppression impairs release of protein-bound B12 from food) and metformin (impairs calcium-dependent ileal uptake of the intrinsic factor-B12 complex), gastrectomy, terminal ileum disease (Crohn)
Treatment: IM B12 bypasses intrinsic factor; high-dose oral B12 1000–2000 mcg daily (passive absorption) is effective for dietary deficiency
Reversibility: improvement expected if treated within 3–6 months
Question 2HematologyMedium
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?
AAnti-intrinsic factor and anti-parietal cell antibodies
BUpper endoscopy with gastric body and antral biopsies
CSerum iron, total iron-binding capacity, and ferritin levels
DSchilling test with and without oral intrinsic factor
EBone marrow aspirate and biopsy with cytogenetic analysis
Reveal answer & full explanation
Correct answer: A — Anti-intrinsic factor and anti-parietal cell antibodies
AAnti-intrinsic factor and anti-parietal cell antibodies✓
BUpper endoscopy with gastric body and antral biopsies
CSerum iron, total iron-binding capacity, and ferritin levels
DSchilling test with and without oral intrinsic factor
EBone marrow aspirate and biopsy with cytogenetic analysis
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
Schilling test with and without oral intrinsic factor — the Schilling test once separated pernicious anemia from dietary deficiency and malabsorption by measuring urinary excretion of oral radiolabeled B12, but it is no longer available in the United States; intrinsic factor and parietal cell antibody testing has replaced it as the noninvasive way to confirm pernicious anemia
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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).
Copper deficiency — Myeloneuropathy that mimics subacute combined degeneration, with anemia and neutropenia; after gastric bypass, excess zinc intake, or malabsorption; low serum copper and ceruloplasmin with normal B12 and MMA
Diagnostic workup
Diagnostic criteria
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% of neutrophils with 5 lobes or any with ≥6 lobes), anisopoikilocytosis
Serum B12 — <200 pg/mL low and consistent with deficiency in the right clinical picture; 200-300 pg/mL borderline (confirm with MMA)
Methylmalonic acid (MMA) — elevated in B12 deficiency, normal in folate deficiency (most sensitive/specific test for tissue B12 deficiency)
Homocysteine — elevated in both B12 and folate deficiency
Anti-intrinsic factor antibody (specific for pernicious anemia, ~70% sensitive); anti-parietal cell antibody (more sensitive, less specific)
Reticulocyte count low (inappropriately)
Imaging
MRI cervical/thoracic spine — T2 hyperintensity in dorsal columns ('inverted V sign') in subacute combined degeneration
EGD with biopsies once pernicious anemia is confirmed by anti-intrinsic factor antibody (serology comes first) — atrophic gastritis; increased risk of gastric adenocarcinoma and type 1 gastric carcinoid
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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