What does a normal Mean Corpuscular Volume (MCV) and rising Red Cell Distribution Width (RDW) indicate in a patient with Bechet's disease on Imuran (azathioprine) and low-dose prednisone?

Normal MCV with Rising RDW in Behçet's Patient on Azathioprine and Prednisone

A normal MCV with rising RDW in this clinical context most likely indicates early iron deficiency anemia or a mixed deficiency state where microcytosis and macrocytosis are canceling each other out, though azathioprine-induced bone marrow suppression with abnormal erythropoiesis must also be considered and ruled out urgently. 1

Primary Diagnostic Considerations

Early or Mixed Iron Deficiency (Most Likely)

• Rising RDW with normal MCV is a classic pattern for early iron deficiency where the RDW increases before MCV drops, as it reflects the heterogeneous red cell population with both normal and newly-formed microcytic cells. 1

• The European Crohn's and Colitis Organisation specifically notes that a wide RDW range can identify iron deficiency when microcytosis and macrocytosis coexist, resulting in a falsely normal MCV. 1

• This pattern may indicate deficiency of iron early in its course, or combined deficiencies (iron plus B12/folate) where the opposing effects on cell size mask each individual deficiency. 1

Azathioprine-Induced Myelosuppression (Must Exclude)

• Azathioprine causes dose-dependent bone marrow suppression that can manifest as abnormal erythropoiesis with elevated RDW, and this can occur late in therapy, not just early. 2

• The FDA label specifically warns that delayed hematologic suppression may occur with azathioprine, and macrocytic anemia has been reported as an adverse effect. 2

• Patients with TPMT or NUDT15 deficiency are at increased risk for severe myelotoxicity from azathioprine, which could manifest as abnormal RBC production with elevated RDW. 2

Chronic Inflammation from Behçet's Disease

• Elevated RDW occurs in inflammatory conditions due to erythrocyte membrane injury and abnormal erythropoiesis. 1

• However, chronic inflammation alone typically produces anemia of chronic disease with normal or only mildly elevated RDW, making this less likely as the sole explanation for a rising RDW. 1

Immediate Diagnostic Workup

Order the following tests immediately to differentiate these possibilities:

• Complete blood count with differential to assess hemoglobin level, other cell lines (looking for pancytopenia suggesting azathioprine toxicity), and confirm the RDW trend. 1, 2

• Reticulocyte count - Low reticulocyte count suggests bone marrow suppression from azathioprine; elevated count suggests hemolysis or appropriate response to deficiency. 1

• Serum ferritin and transferrin saturation - Ferritin <30 μg/L confirms iron deficiency in absence of inflammation; with inflammation present (likely in Behçet's), ferritin <100 μg/L can still indicate iron deficiency. 1

• C-reactive protein (CRP) to assess current inflammatory state, which is critical for interpreting ferritin levels. 1

• Vitamin B12 and folate levels to identify potential combined deficiencies. 1

• Peripheral blood smear to assess red cell morphology, look for macrocytes (suggesting azathioprine effect or B12/folate deficiency) versus microcytes (iron deficiency), and evaluate for other abnormalities. 3

• Consider TPMT and NUDT15 testing if severe myelosuppression develops, as deficiency in these enzymes increases risk of azathioprine toxicity. 2

Management Algorithm

If Iron Deficiency is Confirmed:

• Initiate iron supplementation (oral or IV depending on severity and tolerance) while simultaneously investigating the source of blood loss, particularly gastrointestinal. 1

• Do not delay iron replacement while searching for the source, but the source must be identified. 1

• Monitor CBC weekly initially to assess response and ensure no worsening of other cell lines. 2

If Azathioprine Toxicity is Suspected:

• Reduce azathioprine dose or temporarily discontinue if there is evidence of bone marrow suppression (falling white blood cells, platelets, or hemoglobin). 2

• The FDA label recommends weekly CBC monitoring during the first month of azathioprine therapy, then twice monthly for months 2-3, then monthly - this patient should return to more frequent monitoring given the rising RDW. 2

• Do not intentionally increase azathioprine dose to lower white blood cell count, as leukopenia does not correlate with therapeutic effect. 2

If Combined or Unclear Etiology:

• Treat confirmed deficiencies while reducing azathioprine dose if any evidence of myelosuppression exists. 1, 2

• Avoid empirical iron supplementation without confirmation, as it may be ineffective and potentially harmful if the primary issue is drug toxicity. 1

Critical Monitoring Points

• Weekly CBC monitoring is warranted in this situation until the cause is identified and the RDW trend stabilizes or reverses. 2

• Prompt dose reduction of azathioprine may be necessary if rapid fall in leukocyte count or other evidence of bone marrow depression occurs. 2

• Re-evaluate iron studies after 4-6 weeks of iron supplementation if deficiency was confirmed and treated. 1

• If anemia persists despite appropriate treatment or transfusion dependence develops, consider hematology consultation. 3

Common Pitfalls to Avoid

• Do not assume normal MCV rules out iron deficiency - the rising RDW is the key finding that suggests evolving pathology. 1

• Do not ignore the possibility of azathioprine toxicity even if the patient has been on stable doses for extended periods, as delayed hematologic suppression can occur. 2

• Do not interpret ferritin in isolation - inflammatory states in Behçet's can elevate ferritin, masking iron deficiency; use the <100 μg/L threshold in the presence of inflammation. 1

• Do not empirically treat with iron without confirming deficiency, as this may delay recognition of drug toxicity. 1