What is the initial work‑up and management for an adult with a hemoglobin of 14.5 g/dL and an elevated mean corpuscular volume?

Initial Work-up for Hemoglobin 14.5 g/dL with Elevated MCV

Order a complete blood count with red cell indices including reticulocyte count, peripheral blood smear examination, serum vitamin B12 and folate levels, serum ferritin, transferrin saturation, and thyroid function tests to identify the underlying cause of macrocytosis. 1, 2

Immediate Laboratory Evaluation

The initial work-up must include:

• Complete blood count with red cell indices and reticulocyte count to assess bone marrow response and confirm the MCV elevation 1, 2
• Peripheral blood smear examination to identify morphologic abnormalities such as megaloblastic changes, hypersegmented neutrophils, or other red cell abnormalities 1, 2
• Serum vitamin B12 and folate levels, particularly critical when MCV exceeds 100 fL, as vitamin B12 or folate deficiency is the most common cause of megaloblastic macrocytosis (often with MCV >120 fL) 1, 2
• Serum ferritin and transferrin saturation to rule out concurrent iron deficiency or hemochromatosis, as elevated MCV can occur in hemochromatosis with increased iron availability for erythropoiesis 3, 1, 4
• Red blood cell distribution width (RDW) to assess for mixed deficiency states, as lower hemoglobin with higher RDW correlates with more severe disease in megaloblastic anemia 1, 2

Critical Differential Diagnosis Considerations

The combination of normal-to-high hemoglobin with elevated MCV narrows the differential significantly 2:

• Hemochromatosis: Reports show increased hemoglobin levels, hematocrit, and MCV in hemochromatosis patients related to increased iron availability for erythropoiesis 3. Mean MCV in C282Y homozygotes is significantly elevated (94.4-95.3 fL) compared to controls, largely associated with increased transferrin saturation and serum ferritin 4
• Medication effects: Hydroxyurea, azathioprine, 6-mercaptopurine, or thiopurines cause macrocytosis that resembles megaloblastic changes but is not vitamin-related 1, 2
• Alcohol use: A common cause of macrocytosis that must be assessed through history 2
• Hypothyroidism or liver disease: Both can cause macrocytosis and should be evaluated 2
• Vitamin B12 or folate deficiency: Less likely with normal hemoglobin but must be excluded 1, 2

Management Algorithm Based on Initial Results

If Transferrin Saturation and Ferritin are Elevated:

• Suspect hemochromatosis and proceed with HFE genetic testing (C282Y and H63D mutations) 3, 4
• If confirmed, initiate phlebotomy as the treatment of choice when hemoglobin and hematocrit support it 3
• Note that anemia is NOT characteristic of hemochromatosis; finding anemia should prompt investigation of other unrelated causes 3

If Vitamin B12 or Folate Levels are Low:

• Initiate appropriate vitamin replacement therapy 1
• In patients with inflammatory bowel disease, extensive small bowel disease, or resection, annual monitoring of vitamin B12 and folate is required 1, 2

If Medication-Related:

• Macrocytosis from hydroxyurea or thiopurines is expected and may not require extensive work-up if the patient is otherwise stable 1, 2
• Continue monitoring but recognize this as a medication effect rather than nutritional deficiency 1

If Thyroid or Liver Function Abnormal:

• Address the underlying endocrine or hepatic disorder 2

Common Pitfalls to Avoid

• Do not assume macrocytosis with normal hemoglobin is benign: The combination requires systematic evaluation as it may indicate early hemochromatosis, medication effects, or subclinical deficiency states 2, 4
• Do not overlook alcohol use: This is a frequent cause of isolated macrocytosis and should be specifically queried 2
• Do not miss hemochromatosis: Elevated MCV with normal-to-high hemoglobin is characteristic of iron overload states, and early detection prevents organ damage 3, 4
• Do not perform therapeutic phlebotomy without confirming iron overload: Inappropriate phlebotomy can cause iron deficiency and microcytic anemia 3

Special Population Considerations

• Patients on thiopurines or hydroxyurea: Macrocytosis is an expected finding; distinguish drug effect from nutritional deficiency by checking vitamin levels 1, 2
• Patients with inflammatory bowel disease: Require annual vitamin B12 and folate monitoring, especially with extensive small bowel involvement 1, 2
• Older patients: Increasing age is associated with macrocytic anemia and comorbidities that may contribute 5