Overview and Risk Factors
Megaloblastic anemia is characterized by enlarged and oval shaped red blood cells and is frequently caused by vitamin B12 (cobalamin) or folate deficiency. Numerous hematologic and neurologic abnormalities can result from the impaired DNA processes due to inadequate B12 or folate concentrations.
Vitamin B12 deficiency causes subacute combined neurologic degeneration, which can be severe and sometimes irreversible. Neurologic defects may occur with or without anemia. The signs and symptoms include:
- Paresthesias of the hands and feet.
- Symmetrical and progressive spastic and ataxic weakness.
- Loss of deep tendon reflexes.
- Irritability and mental status changes (megaloblastic madness).
Other symptoms of vitamin B12 or folate deficiency may include fatigue, weakness, glossitis, gastrointestinal problems (eg, diarrhea), decreased appetite, changes in taste, and weight loss. These symptoms sometimes precede anemia. However, megaloblastic anemia is often asymptomatic until the condition is quite severe.
Vitamin B12 deficiency may result from:
Intrinsic factor deficiency. Intrinsic factor is required for vitamin B12 absorption. A deficiency can occur congenitally or through chronic gastritis, gastrectomy, or autoimmune processes directed at intrinsic factor or the gastric parietal cells that produce it. When anemia results from an intrinsic factor deficiency, it is called pernicious anemia.
Malabsorption. Small bowel and pancreatic disease and alcohol abuse contribute to poor B12 absorption. Elderly persons may also have reduced B12 absorption.
Other gastric disease. Occasionally, individuals with H. pylori gastritis, total or partial gastrectomy, or gastric bypass may develop a B12 deficiency.
Medications. Metformin (reversible with calcium supplements), proton pump inhibitors, H2-blockers, antacids, and antibiotic use (with subsequent bacterial overgrowth) may inhibit B12 absorption.
HIV infection. Weight loss and diarrhea in HIV/AIDS are associated with B12 deficiency.1
Fish tapeworm. Fish tapeworm competes for available B12.
Dietary deficiency. See Nutritional Considerations.
Folate deficiency may result from:
Alcohol abuse. Alcohol interferes with the enterohepatic cycle and absorption of folate.
Malabsorption. Malabsorptive diseases, such as inflammatory bowel disease and sprue, decrease folate absorption.
Pregnancy and breast-feeding. Because fetal and infant growth requires increased folate, pregnancy and breast-feeding may deplete a woman's folate stores. In turn, an exclusively breast-fed infant whose mother is folate-deficient will not receive adequate folate.
Medications. Intake of certain medications, such as methotrexate, phenytoin, and trimethoprim, may lead to folate deficiency.
Hemolysis and exfoliative dermatitis. Both conditions increase the demand for folate.
Vitamin B12 deficiency. Because Vitamin B12 is responsible for the formation of the metabolically active form of folic acid, its deficiency can lead to folate deficiency.
Dietary deficiency. See Nutritional Considerations.
Diagnosis and Treatment
The complete hematologic picture includes:
- Large bone marrow precursor cells of neutrophils and erythrocytes (macro-ovalocytes) with an elevated mean corpuscular volume (MCV). Note: An elevated MCV may not be present if iron deficiency is concurrent.
- Hypersegmented neutrophil nuclei (6 lobes or greater or several 5-lobed cells).
- A complete blood count showing anemia. Severe anemia is possible with occasional hemoglobin values less than 5.0 g/dL.
- Normal or depressed reticulocyte counts.
- Marked lactate dehydrogenase (LDH) elevation (in the thousands) due to ineffective red blood cell production.
- Thrombocytopenia and neutropenia.
Bone marrow biopsy is usually not necessary for diagnosis, but typically shows megaloblastosis and hypercellularity with erythroid and myeloid hyperplasia.
Additional tests must be conducted to distinguish between folate and vitamin B12 deficiencies, because the hematologic indices revealed by blood smear review and bone marrow aspirate are similar for both deficiency types.
Serum B12 and folate and/or red blood cell folate concentration should be measured. Serum folate can be acutely elevated after a folate-rich meal, whereas red blood cell folate more accurately measures actual stores.
If the serum B12 and folate results are not diagnostic, additional testing can be performed. Note that serum folate and vitamin B12 assays may be rendered unreliable by pregnancy, alcohol intake, acute nutrition change, or medication use. In these instances, additional tests may aid diagnosis.
Serum methylmalonic acid is elevated in vitamin B12 deficiency and is usually normal in folate deficiency.
Deficiency of vitamin B12 or folate will elevate homocysteine.
Identification of the underlying cause of vitamin B12 or folate deficiency is necessary to ensure adequate long-term treatment.
Vitamin B12 injections (1000 µg) are usually given daily for 1 week, then weekly for 4 weeks, and then monthly until hematologic indices have stabilized. Patients with continued risk of deficiency should remain on monthly injections. Oral B12 (1000-2000 µg/day) may be substituted in highly compliant patients. At high intakes, the vitamin enters the body through diffusion. Vitamin B12 sublingual preparations and a nasal gel are also available for maintenance therapy when compliance is ensured.
Oral folate (1 mg) taken daily for several months usually corrects the deficiency.
Doses up to 5 mg may be used, if indicated.
Concomitant B12 deficiency must be ruled out, as folate supplementation can mask the hematologic signs of B12 deficiency, leading to irreversible neurological injury if not treated. This masking is more likely to occur in patients routinely prescribed folate for other medical reasons (eg, sickle cell anemia).2
In individuals following omnivorous diets, dietary vitamin B12 is usually adequate. However, elderly persons often have poorer B12 absorption due to atrophic gastritis and hypochlorhydria. These individuals may be able to prevent B12 deficiency by taking low-dose crystalline B12 supplements. However, if intrinsic factor deficiency is present, intramuscular injections or high-dose supplements (1 mg/day) will suffice to prevent or treat pernicious anemia.3
Persons who have had gastric bypass surgery are at risk for B12 deficiency,4,5 as are individuals who have followed vegan diets for many years without taking B12 supplements and their exclusively breast-fed infants. In these groups, the risk for vitamin B12 deficiency is easily eliminated with supplementation.4 Individuals who abuse alcohol and those with celiac disease are also at higher risk for deficiency.6,7
Due to fortification of grain products with folic acid, anemia resulting from folate deficiency is becoming less frequent. However, alcoholism often leads to poor folate intake and, combined with alcohol's anti-folate effect, may lead to deficiency.8
An autosomal-recessive inborn error of metabolism causes thiamine-responsive megaloblastic anemia (also known as Rogers Syndrome).9 Pharmacologic doses of thiamine (25-200 mg/day) correct the hematologic abnormalities associated with this condition.10
Restrict alcohol use. A psychiatric referral, along with substance abuse counseling and Alcoholics Anonymous meetings or other community-based support, may be necessary.
Vitamin B12 supplementation, intramuscular or oral as indicated.
Oral folate supplementation (rule out B12 deficiency prior to treatment).
What to Tell the Family
Megaloblastic anemia is typically caused by a vitamin B12 or folate deficiency and can be easily treated. Appropriate supplementation, increased consumption of folate-rich foods, and reduction of alcohol use can help prevent recurrence. In vegan diets, oral Vitamin B12 supplementation is necessary. If the primary cause of deficiency is alcohol use, the patient will likely need multilevel support facilitated through the primary care provider.
1. Balt CA. An investigation of the relationship between vitamin B12 deficiency and HIV infection. J Assoc Nurses AIDS Care. 2000;11:24-28, 31-35.
7. Quigley EM, Carmichael HA, Watkinson G. Adult celiac disease (celiac sprue), pernicious anemia and IgA deficiency: case report and review of the relationships between Vitamin B12 deficiency, small intestinal mucosal disease and immunoglobulin deficiency. J Clin Gastroenterol. 1986;8:277-281.
9. Singleton CK, Martin PR. Molecular mechanisms of thiamine utilization. Curr Mol Med. 2001;1:197-207.
10. Bappal B, Nair R, Shaikh H, et al. Five years followup of diabetes mellitus in two siblings with thiamine responsive megaloblastic anemia. Indian Pediatrics. 2001;38:1295-1298.