Megaloblastic anemia

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Megaloblastic Anemia

Megaloblastic anemia is a disorder of impaired DNA synthesis in hematopoietic (and other rapidly dividing) cells, resulting in abnormally large, nuclear-cytoplasmic asynchronous precursors and a characteristic peripheral blood picture. The two principal causes are vitamin B12 (cobalamin) deficiency and folate (folic acid) deficiency.

Pathogenesis

Both vitamin B12 and folate are required for synthesis of thymidine (dTMP), one of the four DNA bases. The key pathway:

Folate (as FH4) acts as a one-carbon carrier. Its derivative N5,10-methylene-FH4 is needed to convert dUMP → dTMP for DNA synthesis.
Vitamin B12 (as methylcobalamin) acts as cofactor for methionine synthase, converting homocysteine → methionine. In this reaction, N5-methyl-FH4 (the circulating form of folate) is converted back to FH4. Without B12, folate is "trapped" as N5-methyl-FH4 and unavailable for DNA synthesis - the "methyl-folate trap."
A second B12-dependent reaction: adenosylcobalamin is required by methylmalonyl-CoA mutase to convert methylmalonyl-CoA → succinyl-CoA. Deficiency raises methylmalonic acid (MMA) levels, which is diagnostically useful.

The net result in either deficiency: deranged DNA synthesis → delayed nuclear maturation while cytoplasmic maturation proceeds normally → nuclear-cytoplasmic asynchrony → most precursors undergo apoptosis in the marrow (ineffective hematopoiesis) → pancytopenia.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 608-609

Causes

Vitamin B12 Deficiency

Category	Examples
Decreased intake	Strict vegetarianism/veganism
Impaired absorption - Intrinsic factor (IF) deficiency	Pernicious anemia, total/partial gastrectomy
Impaired absorption - Ileal disease	Ileal resection, Crohn's ileitis
Diffuse intestinal disease	Lymphoma, systemic sclerosis
Competitive parasitic uptake	Fish tapeworm (Diphyllobothrium latum), bacterial overgrowth (blind loops)
Medications	Metformin, proton pump inhibitors, nitrous oxide
Pancreatic insufficiency	Reduced proteases → B12 not released from haptocorrin

B12 stores (hepatic) last 3-5 years, so deficiency develops insidiously.

Folate Deficiency

Category	Examples
Decreased intake	Alcoholism, poverty, elderly, psychiatric patients
Impaired absorption	Celiac disease, bariatric surgery
Drug-induced	Methotrexate, trimethoprim, pyrimethamine, phenytoin, sulfasalazine, ethanol, OCP
Increased requirement	Pregnancy (3-4x increase), hemolytic anemias (e.g., sickle cell), disseminated cancer
Increased loss	Hemodialysis

Folate stores are limited - deficiency can develop within weeks to months.

Washington Manual of Medical Therapeutics, p. 803; Robbins p. 608

Normal Vitamin B12 Absorption (Key for Pernicious Anemia)

Stomach: Pepsin releases B12 from food proteins; B12 binds salivary haptocorrin
Duodenum: Pancreatic proteases cleave B12 from haptocorrin; B12 binds intrinsic factor (IF) secreted by gastric parietal cells
Terminal ileum: B12-IF complex binds cubilin receptor on ileal enterocytes → endocytosed
Bloodstream: B12 bound to transcobalamin II → delivered to liver and bone marrow

Daily requirement: 2-3 µg. Animal products (meat, fish, eggs, dairy) are the only dietary sources; plants contain negligible amounts.

Robbins p. 609

Pernicious Anemia (Major Cause of B12 Deficiency)

Pernicious anemia (PA) is an autoimmune gastritis destroying parietal cells, impairing IF production.

Key features:

Mean age of onset: 60 years; typically >40 years
Up to 30% have positive family history
Associated autoimmune conditions: Graves disease (~30%), Hashimoto thyroiditis (~11%), Addison disease (5-10%)
Antibodies: Anti-parietal cell antibodies (90% of PA patients); anti-IF antibodies (60%, highly specific)
Pathology: Chronic atrophic gastritis with loss of parietal and chief cells, lymphocytic/plasma cell infiltrate; intestinal metaplasia
Increased risk of gastric carcinoma (mucosa atrophy/metaplasia is irreversible with B12 therapy)
Washington Manual p. 803; Robbins p. 609-610

Morphology

Peripheral Blood Smear

Megaloblastic anemia - hypersegmented neutrophil with 6-lobed nucleus, macro-ovalocytes on peripheral smear

Fig. 14.15: Peripheral blood smear showing a hypersegmented neutrophil (6 lobes) and macro-ovalocytes. (Robbins)

Macro-ovalocytes: Large, oval RBCs without central pallor - pathognomonic
Anisocytosis and poikilocytosis
Hypersegmented neutrophils: ≥5 nuclear lobes (normal: 3-4); even a single neutrophil with 6+ lobes is highly significant
Low reticulocyte count (ineffective erythropoiesis)
Pancytopenia in severe cases

Bone Marrow

Fig. 14.16: Bone marrow aspirate showing megaloblasts (A-C) with nuclear-cytoplasmic asynchrony. (Robbins)

Hypercellular marrow (erythroid hyperplasia in response to elevated EPO)
Megaloblasts: Large erythroid precursors with finely distributed ("open") chromatin despite cytoplasmic hemoglobinization (nuclear-cytoplasmic asynchrony)
Giant metamyelocytes and band forms (granulocyte precursors also affected)
Bizarre, multilobate megakaryocytes
Robbins p. 608-609

Clinical Features

Hematologic

Symptoms of anemia: fatigue, pallor, dyspnea, palpitations
Jaundice (mild, from intramedullary hemolysis - elevated indirect bilirubin + LDH)
Splenomegaly (extramedullary hematopoiesis in severe cases)
Glossitis (beefy red, smooth tongue) - due to mucosal cell damage
Skin/nail pigmentation

Neurologic (B12 deficiency only - NOT folate deficiency)

Subacute combined degeneration (SCD) of the spinal cord: demyelination of dorsal and lateral columns
Peripheral neuropathy, paresthesias, loss of vibratory and positional sense
Ataxia, positive Romberg sign
Confusion, dementia, behavioral changes
Neurologic symptoms can occur without anemia and may not fully reverse with treatment
Duration/severity before treatment inversely correlates with reversibility
Washington Manual p. 803-804; Goldman-Cecil p. 1734-1735

Diagnosis

Laboratory Tests

Test	Findings
CBC	Macrocytic anemia (↑MCV), leukopenia, thrombocytopenia
Peripheral smear	Macro-ovalocytes, hypersegmented neutrophils
Serum B12	Low (<200 pg/mL; borderline 100-400)
Serum/RBC folate	Low in folate deficiency
Methylmalonic acid (MMA)	Elevated in B12 deficiency; normal in folate deficiency
Homocysteine	Elevated in both B12 and folate deficiency
LDH	Markedly elevated (ineffective erythropoiesis)
Indirect bilirubin	Elevated
Anti-IF antibodies	Highly specific for pernicious anemia (60% sensitivity)
Anti-parietal cell antibodies	Sensitive (90%) but less specific for PA

Key differentiator: MMA elevated = B12 deficiency; MMA normal + homocysteine elevated = folate deficiency.

Bone Marrow Biopsy

May be needed to exclude MDS or AML, which can mimic megaloblastic anemia with hypercellular marrow and immature cells
Washington Manual p. 803-804; Robbins p. 1276

Treatment

Vitamin B12 Deficiency

Cyanocobalamin IM: 1 mg/day IM for 7 days, then 1 mg/week for 4 weeks, then 1 mg/month for life (for pernicious anemia or chronic malabsorption)
High-dose oral B12 (1000-2000 µg/day): Effective even in PA because ~1% absorbed by passive diffusion (bypasses IF). An option for compliant patients without severe neurologic disease.
Monitor: Reticulocytosis begins within 5-7 days; Hgb normalizes by 1-2 months

Folate Deficiency

Folic acid 1 mg PO daily until corrected
High-dose folic acid (5 mg/day) for malabsorption syndromes
5 mg/day periconceptionally for women at high risk of neural tube defects

Important Treatment Considerations

Potassium monitoring: Transient hypokalemia at initiation due to rapid hematopoiesis - potentially life-threatening arrhythmias; supplement as needed
Coexisting iron deficiency: Present in ~1/3 of patients - blunts response (MCV may fall into microcytic range with treatment)
Do NOT give folate alone in B12 deficiency: Corrects anemia but does NOT halt neurologic deterioration - and may even worsen it
Neurologic recovery: Paresthesias and behavioral changes respond best; established spinal cord lesions often do not fully reverse
Pernicious anemia: B12 therapy is lifelong; gastric mucosal changes and carcinoma risk are unaffected by treatment

Washington Manual p. 803-804; Goldman-Cecil p. 1734-1735

B12 vs. Folate Deficiency: Key Differences

Feature	Vitamin B12 Deficiency	Folate Deficiency
Time to deficiency	Years (large hepatic stores)	Weeks-months (limited stores)
Common causes	PA, gastrectomy, ileal disease, veganism	Alcoholism, malnutrition, pregnancy, drugs
Neurologic disease	Yes (SCD, peripheral neuropathy)	No
Methylmalonic acid	Elevated	Normal
Homocysteine	Elevated	Elevated
Treatment	Cyanocobalamin IM or high-dose oral	Folic acid 1 mg PO daily

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 608-610; Washington Manual of Medical Therapeutics, pp. 803-804; Goldman-Cecil Medicine, pp. 1734-1735

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