What is the workup and management for mild macrocytosis (large red blood cell size) without anemia?

From the Guidelines

The workup for mild macrocytosis without anemia should begin with a thorough history and physical examination, focusing on alcohol use, medication review, and dietary habits, as recommended by recent guidelines 1. Initial laboratory testing should include a complete blood count with peripheral smear, reticulocyte count, liver function tests, thyroid function tests, vitamin B12 and folate levels, and serum methylmalonic acid if B12 deficiency is suspected despite normal B12 levels. Some key points to consider in the workup include:

• Evaluation of reticulocyte count and MCV to assess for underlying causes of macrocytosis, such as vitamin B12 or folate deficiency 1
• Assessment of liver function tests and thyroid function tests to rule out underlying liver disease or hypothyroidism as a cause of macrocytosis
• Consideration of medication-induced causes of macrocytosis, such as certain antibiotics or anticonvulsants, and evaluation for alternative medications if necessary
• Evaluation of dietary habits and potential nutritional deficiencies, such as vitamin B12 or folate deficiency, and supplementation as needed Management depends on the underlying cause:
• If medication-induced, consider alternatives when possible
• If alcohol-related, recommend reduction or cessation
• If nutritional, supplement with vitamin B12 (1000 mcg daily or weekly) or folate (1-5 mg daily) as needed For B12 deficiency, initial treatment often involves 1000 mcg intramuscularly daily for one week, then weekly for four weeks, followed by monthly maintenance, as recommended by recent guidelines 1. Mild isolated macrocytosis without anemia may require only monitoring with periodic CBC checks every 3-6 months if no cause is identified and the patient remains asymptomatic, as the risk of progression to anemia or neurological complications is low 1. However, it is essential to identify and treat underlying causes of macrocytosis to prevent potential complications, such as neurological damage from B12 deficiency, which can occur even in the absence of anemia 1.

From the Research

Causes of Mild Macrocytosis without Anemia

• The most common etiologies of macrocytosis are alcoholism, vitamin B12 and folate deficiencies, and medications 2
• Other possible causes include hypothyroidism, liver disease, and primary bone marrow dysplasias (including myelodysplasia and myeloproliferative disorders) 2
• Approximately 10% of patients will have unexplained macrocytosis after laboratory evaluation 3

Workup for Mild Macrocytosis without Anemia

• History and physical examination, vitamin B12 level, reticulocyte count, and a peripheral smear are helpful in delineating the underlying cause of macrocytosis 2
• Serum vitamin B12 and folate levels, serum thyroid studies, liver function studies, and bone marrow aspirate and biopsy with cytogenetic analysis are frequently required to confirm a diagnosis suspected on the basis of the initial evaluation 4
• A strategy of follow-up with blood cell counting every 6 months is suggested, and bone marrow biopsy should be performed when cytopenias are present 3

Management of Mild Macrocytosis without Anemia

• Management of macrocytic anemia is specific to the etiology identified through testing and patient evaluation 5
• Patients with unexplained macrocytosis still require close follow-up, and the probability of a bone marrow biopsy to establish a diagnosis of a primary disorder is lower in patients with macrocytosis without anemia compared to those with anemia 3
• The outcomes of patients with unexplained macrocytosis were not significantly different when comparing patients with or without anemia upon diagnosis 3