From the Guidelines
Macrocytosis with normal Vitamin B12 and folate levels is most likely caused by alcohol use disorder, liver disease, medications, myelodysplastic syndromes, hypothyroidism, or reticulocytosis, and requires further investigation to determine the underlying cause. The diagnostic work-up should include a thorough history and physical examination, focusing on alcohol consumption patterns, medication use, and symptoms of liver or thyroid dysfunction, as recommended by the American Society of Clinical Oncology clinical practice guideline 1. Laboratory testing should include liver function tests, thyroid function tests, reticulocyte count, and peripheral blood smear examination.
Common Etiologies
- Alcohol use disorder
- Liver disease
- Medications (such as methotrexate, phenytoin, or zidovudine)
- Myelodysplastic syndromes
- Hypothyroidism
- Reticulocytosis If these initial investigations are inconclusive, consider bone marrow examination, particularly in older patients or those with other cytopenias, as suggested by the European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases 1. Treatment depends on addressing the underlying cause: alcohol cessation for alcohol-related macrocytosis, medication adjustment if drug-induced, thyroid hormone replacement for hypothyroidism, or appropriate management for liver disease. It is also important to note that folate status can be assessed by measuring levels of folate in serum/plasma or RBC, and plasma homocysteine concentrations can be measured as a functional marker of folate status, as discussed in the ESPEN micronutrient guideline 1.
From the FDA Drug Label
While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy The cause of macrocytosis with normal Vitamin B12 (Cobalamin) and folate levels is not directly stated in the drug label.
- Key points:
- Macrocytosis has occurred in patients taking phenytoin.
- The condition usually responds to folic acid therapy, implying that folate deficiency may be a cause.
- However, the label does not provide information on causes of macrocytosis when folate and Vitamin B12 levels are normal 2.
From the Research
Causes of Macrocytosis with Normal Vitamin B12 and Folate Levels
The causes of macrocytosis with normal Vitamin B12 and folate levels can be attributed to several factors, including:
- Alcoholism, as identified in 3 and 4
- Medications, as mentioned in 3
- Hypothyroidism, as noted in 3 and 5
- Liver disease, as discussed in 3, 4, and 6
- Primary bone marrow dysplasias, including myelodysplasia and myeloproliferative disorders, as mentioned in 3 and 5
- Hemolysis or hemorrhage, as indicated in 3
- Chronic renal failure and Aplastic anemia, as identified in 4
- Myelodysplastic syndrome, as noted in 4 and 5
Prevalence of Causes
According to 4, alcoholism was identified as the etiological factor in 36.5% of cases, while liver disease and myelodysplastic syndrome were less common causes. In 6, macrocytosis was found to be more frequent in patients with alcoholic liver cirrhosis. In 5, 10% of patients had unexplained macrocytosis after laboratory evaluation, and some of these patients developed primary bone marrow disorders or worsening cytopenias over time.
Diagnostic Approach
As suggested in 3 and 4, a complete medical history, red cell parameters, and peripheral blood smear can be helpful in identifying the underlying cause of macrocytosis. Additionally, 5 recommends a strategy of follow-up with blood cell counting every 6 months and performing a bone marrow biopsy when cytopenias are present.