What are the recommendations for managing macrocytosis if vitamin B12 (cobalamin) and B9 (folate) levels are normal?

From the Guidelines

When managing macrocytosis with normal vitamin B12 and folate levels, the primary recommendation is to identify and address the underlying cause, considering factors such as medication use, alcohol consumption, thyroid function, liver disease, and potential myelodysplastic syndrome. To approach this condition, several key steps can be taken.

• Evaluate medication use, as certain drugs can cause macrocytosis, such as thiopurine treatment (azathioprine or 6-mercaptopurine) as indicated by 1.
• Assess alcohol consumption and reduce or eliminate it if it's contributing to the condition.
• Perform thyroid function tests to rule out hypothyroidism, which can also lead to macrocytosis.
• Conduct liver function tests to identify liver disease as a potential cause.
• If myelodysplastic syndrome is suspected, particularly in older patients, a bone marrow biopsy may be necessary. For patients with reticulocytosis, it's essential to investigate hemolysis or recent blood loss, considering indicators such as serum concentrations of haptoglobin, lactate dehydrogenase, and bilirubin as suggested by 1. In some cases, macrocytosis may be a normal variant, especially if mild (MCV 100-110 fL) and stable over time with no other abnormalities. Regular monitoring with complete blood counts every 3-6 months is recommended for unexplained stable macrocytosis, tailoring the approach to the patient's clinical presentation, as macrocytosis can result from various conditions beyond B12 and folate deficiencies.

From the Research

Managing Macrocytosis with Normal Vitamin B12 and B9 Levels

If vitamin B12 (cobalamin) and B9 (folate) levels are normal, the following recommendations can be considered for managing macrocytosis:

• Evaluate for other causes of macrocytosis, such as alcoholism, liver disease, hypothyroidism, and primary bone marrow dysplasias 2
• Perform a complete medical history, red cell parameters, and peripheral blood smear to identify the underlying cause of macrocytosis 3
• Consider measuring serum methylmalonic acid and total homocysteine levels to rule out vitamin B12 deficiency 4
• Assess for drug-related causes of macrocytosis, as drug therapy is a common cause of macrocytosis 4
• Evaluate liver function tests and thyroid function tests to rule out liver disease and hypothyroidism as causes of macrocytosis 2, 3

Diagnostic Evaluation

The diagnostic evaluation of macrocytosis should include:

• Complete blood counts (CBC) to evaluate for anemia and other blood cell abnormalities
• Peripheral blood smear to evaluate for morphological abnormalities, such as macro-ovalocytes and hyper-segmented neutrophils
• Reticulocyte count to evaluate for reticulocytosis
• Liver function tests and thyroid function tests to rule out liver disease and hypothyroidism
• Serum vitamin B12 and folate levels to rule out deficiency 5, 2, 3

Underlying Causes

The underlying causes of macrocytosis can be diverse, and may include:

• Alcoholism 2, 6, 3
• Liver disease 2, 3, 4
• Hypothyroidism 2
• Primary bone marrow dysplasias, such as myelodysplasia and myeloproliferative disorders 2
• Drug-related causes 4
• Vitamin B12 and folate deficiency, although these are less likely if levels are normal 5, 2, 3