Megaloblastic Anemias¶

Chapter 104 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 104

Key Clinical Points¶

Megaloblastic anemias result from impaired DNA synthesis due to cobalamin (B12) or folate deficiency, leading to ineffective erythropoiesis.
Key hematologic hallmarks include macrocytosis (MCV >100 fL) and hypersegmented neutrophils (>5 lobes).
Neurologic symptoms (e.g., neuropathy, dementia) occur only with cobalamin deficiency and involve spinal cord demyelination.
Pernicious anemia is the leading cause of severe B12 deficiency in Western countries due to intrinsic factor deficiency from gastric atrophy.
Folic acid supplementation (0.4 mg/day) reduces neural tube defects (NTDs) by ~80% when initiated preconception.
MTHFR C677T polymorphism increases homocysteine levels and risk for NTDs, colorectal cancer, and vascular disease.
Diagnosis relies on serum cobalamin (200–900 pg/mL), methylmalonic acid (MMA), homocysteine, and intrinsic factor antibodies.
Vegans require B12 supplementation; deficiency is inevitable after total gastrectomy.
Cobalamin deficiency may cause vascular disease, cognitive decline, and increased thrombosis risk via hyperhomocysteinemia.
Ineffective erythropoiesis in the marrow results in megaloblasts with asynchronous nuclear-cytoplasmic maturation.

1. DEFINITION & OVERVIEW¶

Megaloblastic anemias are characterized by ineffective erythropoiesis and abnormal red cell morphology in the bone marrow. The marrow is typically hypercellular, with megaloblasts (large, immature erythroblasts) showing asynchronous nuclear-cytoplasmic maturation.

Pathophysiology: • Impaired DNA synthesis due to reduced dNTP availability. ◦ Failure of dUMP to dTMP conversion → uracil misincorporation into DNA → cell cycle arrest.

1.1 Classification¶

Megaloblastic anemias are categorized by the underlying cause of impaired DNA synthesis:

• Cobalamin deficiency (e.g., pernicious anemia, food malabsorption) • Folate deficiency (e.g., dietary, malabsorptive, drug-induced) • Antifolate drugs (e.g., methotrexate) • DNA synthesis inhibitors (e.g., cytarabine, hydroxyurea, 6-mercaptopurine, azidothymidine [AZT]) • Orotic aciduria (responds to uridine) • Thiamine-responsive anemia

2. ETIOLOGY & PATHOPHYSIOLOGY¶

Cobalamin is synthesized by microorganisms and absorbed in the ileum via intrinsic factor binding. Folate is obtained from diet (liver, leafy greens) and absorbed through intestinal mucosa.

Key Mechanisms: 1. Cobalamin deficiency: ◦ Impairs methylmalonyl-CoA mutase → elevated MMA. ◦ Inhibits methionine synthase → homocysteine accumulation. ◦ "Methylfolate trap" → THF starvation → reduced intracellular folate coenzymes. 2. Folate deficiency: ◦ Blocks dTMP synthesis → DNA replication arrest. ◦ Impairs purine/pyrimidine synthesis. ◦ Reduces SAM production → affects methylation reactions.

2.1 Causes of Cobalamin Deficiency¶

Severe Cobalamin Deficiency (Table 104-3): • Nutritional: Vegans, malnutrition. • Malabsorption: ◦ Pernicious anemia (autoimmune gastritis). ◦ Intestinal stagnant loop syndrome: jejunal diverticulosis, ileocolic fistula, anatomic blind loop, intestinal stricture, etc. ◦ Ileal resection and Crohn's disease. ◦ Selective malabsorption with proteinuria. ◦ Tropical sprue. ◦ Transcobalamin II deficiency. ◦ Fish tapeworm (Diphyllobothrium latum).

Mild Cobalamin Malabsorption (Table 104-4): Note: These conditions are not usually sufficient to cause megaloblastosis. • Gastric causes: Simple atrophic gastritis, Zollinger-Ellison syndrome, gastric bypass or bariatric surgery, use of proton pump inhibitors. • Intestinal causes: Gluten-induced enteropathy (celiac disease), severe pancreatitis, HIV infection. • Other factors: Radiotherapy, graft-versus-host disease, various medications (colchicine, neomycin, metformin, etc.), alcohol.

2.2 Causes of Folate Deficiency (Table 104-5)¶

• Dietary: Especially in old age, infancy, poverty, alcoholism; may be associated with scurvy or kwashiorkor. • Malabsorption: ◦ Major: Tropical sprue, gluten-induced enteropathy, intestinal megaloblastosis (due to severe cobalamin or folate deficiency). ◦ Minor: Extensive jejunal resection, Crohn's disease, partial gastrectomy, congestive heart failure, Whipple's disease, scleroderma, amyloid, diabetic enteropathy, systemic bacterial infection, lymphoma, sulfasalazine. • Excess utilization or loss: ◦ Physiologic: Pregnancy and lactation, prematurity. ◦ Pathologic: ◦ Hematologic: Chronic hemolytic anemias, sickle cell anemia, thalassemia major, myelofibrosis. ◦ Malignant: Carcinoma, lymphoma, leukemia, myeloma. ◦ Inflammatory: Tuberculosis, Crohn's disease, psoriasis, exfoliative dermatitis, malaria. ◦ Metabolic: Homocystinuria. ◦ Other: Congestive heart failure, active liver disease, Hemodialysis, peritoneal dialysis. • Antifolate drugs: ◦ Anticonvulsant drugs (phenytoin, primidone, barbiturates), sulfasalazine, Nitrofurantoin, tetracycline.

3. CLINICAL FEATURES¶

• General Presentation: ◦ Early stages: Often asymptomatic (detected by serum cobalamin or elevated MCV). ◦ Anemia symptoms: Fatigue, pallor, glossitis, angular cheilosis, diarrhea/constipation. ◦ Epithelial changes: Macrocytic mucosal cells in mouth, GI tract, cervix. • Neurologic Manifestations (Cobalamin Deficiency Only): ◦ Mechanism: Myelination impairment → spinal cord demyelination (cervical/thoracic tracts). ◦ MRI finding: "Spongy" degeneration. ◦ Symptoms: Paresthesias, gait ataxia, dementia, visual loss. ◦ Autonomic dysfunction: Postural hypotension, impotence. ◦ Infants: Intellectual disability, seizures. • Pregnancy & Development: ◦ Neural Tube Defects (NTDs): Risk reduced by ~80% with 0.4 mg/day folic acid preconception. ◦ MTHFR C677T polymorphism → increased NTD risk in mothers.

3.1 Clinical Summary¶

• Cobalamin Deficiency: Unique for causing neurological symptoms and spinal cord demyelination. • Folic Acid: Essential for preventing NTDs; deficiency leads to increased risk of colorectal cancer, breast cancer, and vascular disease.

4. HEMATOLOGIC FINDINGS¶

• Peripheral Blood: ◦ Macrocytosis (MCV >100 fL). ◦ Hypersegmented neutrophils (>5 lobes). ◦ Presence of nucleated red blood cells (nRBCs) in severe cases. • Bone Marrow: ◦ Megaloblasts: Large, immature erythroblasts with "open" or "S-shaped" nuclei. ◦ Ineffective erythropoiesis: High number of polychromatic and orthochromatic precursors; elevated reticulocytes; low hemoglobin.

5. INVESTIGATIONS & DIAGNOSIS¶

• Serum Cobalamin: Normal range 200–900 pg/mL. • Methylmalonic Acid (MMA): Elevated in cobalamin deficiency. • Homocysteine: Elevated in both cobalamin and folate deficiencies. • Intrinsic Factor Antibodies: Diagnostic for pernicious anemia. • Folate Assessment: Use red cell folate; serum folate is unreliable.

5.1 Diagnostic Criteria for Pernicious Anemia¶

Serum cobalamin < 200 pg/mL.
Positive intrinsic factor antibodies.
Evidence of gastric atrophy (low pepsinogen I, high gastrin).
Clinical response to B12 therapy.

6. MANAGEMENT & TREATMENT¶

Cobalamin Deficiency: • Parenteral cyanocobalamin (1000 µg IM weekly) OR hydroxocobalamin.
Folate Deficiency: • Oral folic acid 1–5 mg/day.
Pregnancy Management: • Folic acid 0.4–0.8 mg/day preconception and during pregnancy (Note: 0.4 mg/day specifically cited for NTD reduction).
Post-Gastrectomy Protocol: • Monthly B12 injections (1000 µg IM) to prevent deficiency. • Monitor serum cobalamin, MMA, and homocysteine levels.

7. PROGNOSIS & COMPLICATIONS¶

• Early Treatment: Prevents irreversible neurologic damage and NTDs. • Untreated Cobalamin Deficiency: Dementia, neuropathy, myelopathy. • Folate Deficiency: Increased risk of cancer (colorectal, breast) and vascular disease. • Cobalamin Deficiency: Risk of thrombosis via hyperhomocysteinemia.

8. SPECIAL CONSIDERATIONS¶

• Vegans: Require B12 supplementation due to lack of animal-derived foods. • Pregnancy: High risk for NTDs; requires folic acid (0.4 mg/day) preconception. • Elderly: Higher risk of deficiency due to malabsorption and dietary insufficiency. • HIV: Increased folate requirements and absorption issues.

9. KEY PEARLS & HIGH-YIELD POINTS¶

• Differentiation Rule: MMA is the key differentiator; it is elevated in B12 deficiency but normal in isolated folate deficiency. • Morphology: Hypersegmented neutrophils are a hallmark of megaloblastic anemia and can be seen before severe anemia develops. • Folate Biochemistry (Table 104-2): ◦ Formate activation: THF → 10-formyl-THF. ◦ Purine synthesis: 5,10-Methylene-THF → purines. ◦ Pyrimidine synthesis: 10-Formyl (CHO)THF → formylation of AICAR. ◦ dTMP synthesis: 5,10-Methylene-THF → dTMP (Rate limiting in DNA synthesis). ◦ Methionine synthase: 5-Methyl(M)THF → Homocysteine to methionine. ◦ Serine-glycine interconversion: THF → entry of single carbon units into active pool. • Pernicious Anemia: Characterized by autoimmune-mediated gastric atrophy and IF antibodies.

Reference Tables¶

TABLE 104-1 Causes of Megaloblastic Anemia Cobalamin deficiency or abnormalities of cobalamin metabolism (see Tables…¶

Harrison's 22e, p.781

Cobalamin deficiency or abnormalities of cobalamin metabolism
(see Tables 104-3, 104-4)
Folate deficiency or abnormalities of folate metabolism (see Table 104-5)
Therapy with antifolate drugs (e.g., methotrexate)
Independent of either cobalamin or folate deficiency and refractory to cobalamin
and folate therapy:
Some cases of acute myeloid leukemia, myelodysplasia
Therapy with drugs interfering with synthesis of DNA (e.g., cytosine
arabinoside, hydroxyurea, 6-mercaptopurine, azidothymidine [AZT])
Orotic aciduria (responds to uridine)
Thiamine-responsive

TABLE 104-2 Biochemical Reactions of Folate Coenzymes REACTION Formate activation Purine synthesis¶

Harrison's 22e, p.782

REACTION	COENZYME FORM OF FOLATE INVOLVED	SINGLE CARBON UNIT TRANSFERRED	IMPORTANCE
Formate activation	THF	−CHO	Generation of 10-formyl-THF
	5,10-Methylene-THF 10-Formyl (CHO)THF	−CHO
Pyrimidine synthesis
Methylation of deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP)	5,10-Methylene-THF	−CH 3	Rate limiting in DNA synthesis Oxidizes THF to DHF Some breakdown of folate at the C-9–N-10 bond
	THF 5-Methyl(M)THF THF	=CH 2 −CH 3 −HN−CH=

TABLE 104-3 Causes of Cobalamin Deficiency Sufficiently Severe to Cause Megaloblastic Anemia NUTRITIONAL Malabsorption…¶

Harrison's 22e, p.785

NUTRITIONAL	VEGANS
Malabsorption	Pernicious anemia
Intestinal causes	Intestinal stagnant loop syndrome: jejunal diverticulosis, ileocolic fistula, anatomic blind loop, intestinal stricture, etc.
	Ileal resection and Crohn’s disease
	Selective malabsorption with proteinuria
	Tropical sprue
	Transcobalamin II deficiency
	Fish tapeworm

TABLE 104-4 Malabsorption of Cobalamin May Occur in the Following Conditions but Is Not Usually Sufficiently Severe and…¶

Harrison's 22e, p.786

Gastric causes
Simple atrophic gastritis (food cobalamin malabsorption)
Zollinger-Ellison syndrome
Gastric bypass or bariatric surgery
Use of proton pump inhibitors
Intestinal causes
Gluten-induced enteropathy
Severe pancreatitis
HIV infection
Radiotherapy
Graft-versus-host disease
Deficiencies of cobalamin, folate, protein,? riboflavin,? nicotinic acid
Therapy with colchicine, para-aminosalicylate, neomycin, slow-release
potassium chloride, anticonvulsant drugs, metformin,a cytotoxic drugs
Alcohol

TABLE 104-5 Causes of Folate Deficiency Dietary a¶

Harrison's 22e, p.787

Dietarya
Particularly in: old age, infancy, poverty, alcoholism, chronic invalids, and the
psychiatrically disturbed; may be associated with scurvy or kwashiorkor
Malabsorption
Major causes of deficiency
Tropical sprue, gluten-induced enteropathy in children and adults, and in
association with dermatitis herpetiformis, specific malabsorption of folate,
intestinal megaloblastosis caused by severe cobalamin or folate deficiency
Minor causes of deficiency
Extensive jejunal resection, Crohn’s disease, partial gastrectomy, congestive
heart failure, Whipple’s disease, scleroderma, amyloid, diabetic enteropathy,
systemic bacterial infection, lymphoma, sulfasalazine (Salazopyrin)
Excess utilization or loss
Physiologic
Pregnancy and lactation, prematurity
Pathologic
Hematologic diseases: chronic hemolytic anemias, sickle cell anemia,
thalassemia major, myelofibrosis
Malignant diseases: carcinoma, lymphoma, leukemia, myeloma
Inflammatory diseases: tuberculosis, Crohn’s disease, psoriasis, exfoliative
dermatitis, malaria
Metabolic disease: homocystinuria
Excess urinary loss: congestive heart failure, active liver disease
Hemodialysis, peritoneal dialysis
Antifolate drugsb
Anticonvulsant drugs (phenytoin, primidone, barbiturates), sulfasalazine
Nitrofurantoin, tetracycline, antituberculosis (less well documented)
Mixed causes
Liver diseases, alcoholism, intensive care units