Megaloblastic Anemia

Megaloblastic anemia is one form of macrocytic anemia in which red blood cells become enlarged and oval shaped. The most common causes are deficiencies of vitamin B12 (cobalamin) or folate. Numerous hematologic and neurologic abnormalities can result from the impaired DNA synthesis caused by these deficiencies.[1]

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, loss of proprioception, and loss of vibratory sense.
  • Symmetrical and progressive spastic and ataxic weakness.
  • Loss of deep tendon reflexes.
  • Irritability and mental status changes (megaloblastic madness).
  • Memory disturbances.

Folate deficiency is a leading cause of megaloblastic anemia during pregnancy in developing countries. Folate requirements may increase by 5- to 10-fold during the perinatal period. Folate deficiency can cause congenital malformations, most notably neural tube defects. The practice of fortifying foods with folate has led to a reduction in the incidence of neural tube defects by as much as 50% in North America.[2]

Other symptoms of vitamin B12 or folate deficiency may include fatigue, weakness, glossitis, gastrointestinal problems (e.g., diarrhea), decreased appetite, changes in taste and smell, and weight loss. These symptoms sometimes precede anemia, in some cases by many years. Megaloblastic anemia, however, is often asymptomatic until the condition is quite severe.

Risk Factors

Vitamin B12 deficiency may result from:

Age. Ten percent to 30% of people 50 years or older may be unable to absorb naturally occurring vitamin B12.[3]

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. Pancreatic disease, small bowel disease (especially Crohn’s disease), and alcohol abuse contribute to poor B12 absorption.

Other gastric disease. Occasionally, individuals with Helicobacter 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) inhibit B12 absorption.

HIV infection. Weight loss and diarrhea in HIV/AIDS are associated with B12 deficiency.[4]

Fish tapeworm. Fish tapeworm competes for available B12.

Congenital transcobalamin deficiency. Transcobalamin I and II are glycoproteins that function to bring B12 into cells.[5]

Dietary deficiency. See Nutritional Considerations below.

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 celiac disease, decrease folate absorption.

Pregnancy and breastfeeding. Because fetal and infant growth requires increased folate, pregnancy and breastfeeding may deplete a woman’s folate stores. In turn, an exclusively breastfed 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 below.


The complete hematologic picture includes:

  • A complete blood count showing anemia. Severe anemia is possible with occasional hemoglobin values < 5.0 g/dL. Absence of depressed hemoglobin or hematocrit levels does not rule out B12 or folate deficiency.
  • Erythrocytes with an elevated mean corpuscular volume (MCV). Note: An elevated MCV may not be present if iron deficiency is concurrent. However, a normal MCV does not rule out B12 or folate deficiency.
  • Normal or depressed reticulocyte counts.
  • Possible thrombocytopenia and neutropenia (may be present but rarely cause a clinical problem).
  • Marked lactate dehydrogenase elevation (in the thousands) and elevated bilirubin levels caused by both ineffective red blood cell production and increased peripheral breakdown.
  • Blood smear examination revealing typical oval macrocytes as well as hypersegmented neutrophil nuclei (6 lobes or greater or several 5-lobed cells).

Bone marrow biopsy is usually not necessary for diagnosis, but typically shows megaloblastic erythroid precursors, which are larger than normal with a lack of synchronous maturation of the nucleus and cytoplasm. Megaloblastic features in granulocyte precursors include giant metamyelocyte and band forms containing large horseshoe-shaped nuclei.

Additional tests must be conducted to distinguish between folate and vitamin B12 deficiencies because the hematologic indices, 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 the diagnosis. In addition, a normal vitamin B12 level does not exclude deficiency and a low vitamin B12 level does not confirm deficiency. This is in part due to the fact vitamin B12 is bound to 2 main plasma proteins, 1 that is functional and can deliver the vitamin B12 to cells and another that cannot.

Serum methylmalonic acid is elevated in vitamin B12 deficiency but is usually normal in folate deficiency.

Deficiency of vitamin B12 or folate will elevate homocysteine.

Once B12 deficiency is confirmed, a cause should be sought. If there is not an obvious reason for the deficiency (e.g., B12-deficient diet without supplementation, history of gastric surgery), then consider testing for pernicious anemia with antiparietal cell antibodies or anti-IF antibodies. Because hypothyroidism can be associated with macrocytic anemia and is also associated with pernicious anemia, screening with a thyroid-stimulating hormone level should be considered in patients with B12 deficiency.


Identification of the underlying cause of vitamin B12 or folate deficiency is necessary to ensure adequate long-term treatment.

Vitamin B12

In patients who are symptomatic or have significant hematologic abnormalities, vitamin B12 injections (1000 μg) are usually given on alternate days for 2 weeks, then weekly for 4 weeks, and then monthly until hematologic indices have stabilized. Patients with continued risk of deficiency should remain on maintenance therapy, which consists of injections monthly or every 3 months, depending on the formulation. In highly compliant patients, high-dose oral B12 (1000-2000 μg/day) is an option because 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, but there is less information on long-term effectiveness of these treatment routes.

In patients with asymptomatic B12 deficiency, treatment with high-dose daily oral supplementation or monthly injections is usually adequate to reverse hematologic indices. Serum B12 or methylmalonic acid levels should be monitored and normalized before stopping treatment. Patients at continued risk of deficiency should remain on maintenance therapy for as long as risk factors are present.


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 neurologic injury if not treated. This masking is particularly likely to occur in patients routinely prescribed folate for other medical reasons (e.g., sickle cell anemia).[6]

Nutritional Considerations

Vitamin B12

In individuals following omnivorous diets, dietary vitamin B12 is usually adequate. However, some people, particularly elderly persons, have poorer B12 absorption due to atrophic gastritis or hypochlorhydria, and prevalence of these conditions appears to increase with age.[7] The Food and Nutrition Board advises everyone older than age 50 to meet their recommended dietary allowance with B12-fortified foods or a supplement.[3]

The use of histamine H2 receptor blockers or proton pump inhibitors, usually for 12 months or longer, or daily use of metformin for 4 months or longer may also interfere with the breakdown of vitamin B12 from food and interfere with its absorption. In these situations, low-dose crystalline B12 supplements may prevent B12 deficiency. In cases of intrinsic factor deficiency, intramuscular injections or high-dose supplements (1 mg/day) will prevent or treat pernicious anemia.[8]

Persons who have had gastric bypass surgery are at risk for B12 deficiency.[9],[10] Individuals who have followed vegan diets for many years without taking B12 supplements and their exclusively breastfed infants are also at risk.[11] In these groups, the risk for vitamin B12 deficiency is easily eliminated with supplementation.[12]

Individuals who abuse alcohol and those with celiac disease are also at higher risk for deficiency.[13],[14] Individuals infected with Helicobacter pylori may also be at risk.[15]


Thanks to fortification of grain products with folic acid in some countries such as the US, anemia resulting from folate deficiency is becoming less frequent. However, alcoholism often leads to poor folate intake and, combined with alcohol’s antifolate effect, may lead to deficiency.[16]

An autosomal-recessive inborn error of metabolism causes thiamine-responsive megaloblastic anemia (also known as Rogers syndrome).[17] Pharmacologic doses of thiamine (25-200 mg/day) correct the hematologic abnormalities associated with this condition.[18]

Caution is necessary in prescribing folate supplements. As noted above, folic acid can mask signs of vitamin B12 deficiency.


See Basic Diet Orders chapter.

Restrict alcohol use. When appropriate, a psychiatric referral, along with substance abuse counseling and Alcoholics Anonymous meetings or other community-based support, may be helpful.

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 can be easily treated. Appropriate supplementation, increased consumption of folate-rich foods, and reduction of alcohol use can help prevent recurrence. For people following 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.


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Last updated: May 6, 2022