From the Guidelines
Macrocytic anemia is primarily caused by vitamin B12 or folate deficiency, which impairs DNA synthesis and leads to the production of abnormally large red blood cells. The most common causes of megaloblastic, macrocytic anemia are vitamin B12 and folate deficiency, as stated in the British Obesity and Metabolic Surgery Society guidelines 1. Vitamin B12 deficiency can result from inadequate dietary intake, malabsorption conditions, or after gastric surgery. Folate deficiency typically stems from poor nutrition, alcoholism, increased requirements during pregnancy, or certain medications like methotrexate and phenytoin.
Some key points to consider in the diagnosis of macrocytic anemia include:
- Vitamin B12 deficiency should be treated immediately, especially if there is possible neurological involvement, with hydroxocobalamin 1 mg intramuscularly administered on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly administered every 2 months 1.
- Folic acid deficiency may indicate non-adherence with the daily multivitamin and mineral supplement or malabsorption, and treatment with oral folic acid 5 mg daily should be given for a minimum of 4 months 1.
- Other causes of macrocytic anemia include liver disease, alcoholism, certain medications, and myelodysplastic syndromes, as outlined in the European consensus on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases 1.
- Hypothyroidism can also slow red blood cell production, resulting in macrocytic anemia, and should be evaluated and treated accordingly, as suggested in the management and prevention of anemia in adult critical care patients guidelines 1.
In terms of treatment, identifying and addressing the underlying cause of macrocytic anemia is crucial, such as vitamin supplementation for deficiencies, reducing alcohol consumption, or adjusting medications under medical supervision. It is essential to note that folate supplementation may mask severe vitamin B12 depletion, and therefore, vitamin B12 deficiency should be treated immediately before initiating additional folic acid 1.
From the FDA Drug Label
Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. The cause of macrocytic anemia is thought to be related to folic acid deficiency, which impairs thymidylate synthesis and leads to defective DNA synthesis, resulting in megaloblast formation and macrocytic anemias 2.
- Key factors include:
- Folic acid deficiency
- Impaired thymidylate synthesis
- Defective DNA synthesis
From the Research
Causes of Macrocytic Anemia
Macrocytic anemia can be caused by various factors, which can be broadly classified into megaloblastic and nonmegaloblastic causes. The main causes of macrocytic anemia include:
- Vitamin B12 deficiency 3, 4, 5
- Folate deficiency 3, 4, 5
- Alcoholism 6, 7, 5
- Liver disease 6, 7, 5
- Hypothyroidism 7, 5
- Myelodysplastic syndrome (MDS) 4, 7, 5
- Certain drugs 4, 7
- Inherited disorders of DNA synthesis 4
Megaloblastic vs Nonmegaloblastic Anemia
Megaloblastic anemia is caused by impaired DNA synthesis, leading to the release of megaloblasts, which are large nucleated red blood cell precursors with chromatin that is not condensed 5. Nonmegaloblastic anemia, on the other hand, entails normal DNA synthesis and is typically caused by chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders 5.
Diagnosis and Treatment
Diagnosis of macrocytic anemia involves a carefully obtained history and examination, evaluation of a peripheral blood smear and reticulocyte count, and measurement of serum vitamin B12 and folate levels, serum thyroid studies, liver function studies, and bone marrow aspirate and biopsy with cytogenetic analysis 7. Treatment of macrocytic anemia is specific to the etiology identified through testing and patient evaluation 5.