Megaloblastic anemia
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Megaloblastic anemia Merck Manual diagnosis treatment vitamin B12 folate
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Megaloblastic anemia
Megaloblastic anemia is a macrocytic anemia caused by impaired DNA synthesis. Nuclear maturation lags behind cytoplasmic maturation, producing abnormally large erythroid precursors in marrow and ineffective production of blood cells. It can therefore cause anemia alone or pancytopenia. The usual causes are vitamin B12 (cobalamin) or folate deficiency. Goldman-Cecil Medicine, p. 1117.
Causes
-
Vitamin B12 deficiency
- Pernicious anemia, due to intrinsic-factor deficiency
- Gastrectomy or bariatric surgery
- Ileal disease or resection, such as Crohn disease
- Dietary deficiency, particularly without B12-fortified foods or supplements
- Drugs or exposures, including metformin and nitrous oxide
-
Folate deficiency
- Poor nutrition or alcohol use
- Increased requirement: pregnancy, hemolysis
- Malabsorption: celiac disease, small-bowel disease
- Drugs that impair folate metabolism: methotrexate, trimethoprim, phenytoin, some anticonvulsants
-
Other causes
- Antimetabolite chemotherapy
- Rare inherited disorders of DNA synthesis
Clinical features
- Fatigue, weakness, pallor, exertional dyspnea, palpitations
- Glossitis, sore mouth, mild jaundice
- Leukopenia and thrombocytopenia in severe disease
- B12 deficiency specifically: paresthesia, numbness, gait imbalance, impaired vibration/position sense, cognitive or mood changes. These neurologic manifestations do not occur in isolated folate deficiency.
Investigations
| Test | Typical finding |
|---|---|
| CBC | High MCV, often markedly elevated; anemia, sometimes pancytopenia |
| Peripheral smear | Macro-ovalocytes, anisopoikilocytosis, hypersegmented neutrophils |
| Reticulocyte count | Low |
| LDH and indirect bilirubin | Elevated due to ineffective erythropoiesis/intramedullary cell breakdown |
| Serum B12 and folate | Identifies likely deficiency |
| Homocysteine | Raised in both B12 and folate deficiency |
| Methylmalonic acid | Raised in B12 deficiency, typically normal in folate deficiency |
| If B12 deficiency suspected | Anti-intrinsic-factor antibody testing for pernicious anemia; assess diet, gastric and ileal disease |
The characteristic smear is macro-ovalocytes with hypersegmented neutrophils. Frameworks for Internal Medicine, p. 336.
Treatment
- Identify and correct the cause.
- Vitamin B12 deficiency: replace B12, orally or by injection depending on cause and severity. Parenteral treatment is often favored when malabsorption or neurologic involvement is present.
- Folate deficiency: oral folic acid and correction of nutritional deficiency, alcohol use, malabsorption, or causal drugs.
- Review medications that interfere with folate or B12 metabolism.
Important: do not give folic acid alone until B12 deficiency has been excluded or is being treated concurrently. Folate may correct the anemia while B12-related neurologic injury continues or worsens, as emphasized in the Merck diagnostic guidance.
Distinguishing B12 from folate deficiency
| Feature | B12 deficiency | Folate deficiency |
|---|---|---|
| Neurologic signs | May occur | Absent |
| Methylmalonic acid | Increased | Normal |
| Homocysteine | Increased | Increased |
| Common cause | Pernicious anemia or malabsorption | Dietary deficiency, alcohol, increased demand, drugs |
Seek prompt medical review for new neurologic symptoms, severe breathlessness, chest pain, syncope, or suspected severe anemia.
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