What is the further workup for hemoglobin issues in a patient with a low Hemoglobin A1c (HbA1c) and macrocytosis?

From the Guidelines

For a patient with low A1c and macrocytosis, further workup should include vitamin B12 and folate levels, thyroid function tests, liver function tests, reticulocyte count, and serum methylmalonic acid and homocysteine levels, as these tests can help identify underlying causes of macrocytosis and hemoglobinopathies that may affect A1c accuracy 1.

Key Considerations

• A peripheral blood smear should be examined for morphological abnormalities to identify potential hemoglobinopathies or other red blood cell disorders.
• Medication review is crucial, as certain drugs like metformin, anticonvulsants, and chemotherapeutic agents can cause macrocytosis.
• Testing for alcohol use disorder with gamma-glutamyl transferase (GGT) and carbohydrate-deficient transferrin (CDT) may also be necessary.
• If initial tests are inconclusive, bone marrow examination may be necessary to rule out myelodysplastic syndrome or other bone marrow disorders.

Rationale

The low A1c with macrocytosis suggests increased red blood cell turnover, which can artificially lower A1c values despite normal or elevated blood glucose levels 1. This pattern is common in conditions with shortened red cell lifespan, such as hemolytic anemia, recent blood loss, or certain hemoglobinopathies. Macrocytosis (elevated MCV) often indicates impaired DNA synthesis in red blood cell precursors, commonly due to B12/folate deficiency, alcoholism, liver disease, or certain medications, which can all affect the accuracy of A1c as a measure of glycemic control.

Additional Testing

Consider evaluating for other potential causes of hemolysis, such as autoimmune hemolytic anemia, using tests like direct antibody test (Coombs test), haptoglobin, and LDH, as recommended in recent guidelines 1. However, the primary focus should be on identifying underlying causes of macrocytosis and hemoglobinopathies that may affect A1c accuracy.

From the Research

Macrocytosis and Hemoglobin Issues

• Macrocytosis is generally defined as a mean corpuscular volume greater than 100 fL, and it can be caused by various factors such as alcoholism, vitamin B12 and folate deficiencies, and medications 2, 3.
• A low A1c level with macrocytosis may require further workup to determine the underlying cause of the macrocytosis.
• The initial evaluation of macrocytosis should include a history and physical examination, vitamin B12 level, reticulocyte count, and a peripheral smear 2, 3.

Differential Diagnosis of Macrocytic Anemia

• The most common causes of macrocytic anemias in adults are:
  • Alcoholism
  • Liver diseases
  • Hemolysis or bleeding
  • Hypothyroidism
  • Folate or vitamin B12 deficiency
  • Exposure to chemotherapy and other drugs
  • Myelodysplasia 3, 4
• A carefully obtained history and examination with evaluation of a peripheral blood smear and reticulocyte count should be performed in most patients with macrocytosis 3.

Further Workup for Hemoglobin Issues

• Serum vitamin B12 and folate levels, serum thyroid studies, liver function studies, and bone marrow aspirate and biopsy with cytogenetic analysis may be required to confirm a diagnosis suspected on the basis of the initial evaluation 3, 4.
• If myelodysplastic syndrome (MDS) is suspected, a hematology consultation may be appropriate, especially if there is leukocytopenia and/or thrombocytopenia with anemia 4.
• There is no direct evidence in the provided studies to suggest that a low A1c level with macrocytosis is specifically related to hemoglobin issues, but further workup may be necessary to rule out underlying conditions that could be contributing to the macrocytosis 2, 3, 4.