In a 65-year-old woman, what are the possible causes of an elevated mean corpuscular hemoglobin, macrocytic mean corpuscular volume, and increased ferritin level?

Elevated MCH, MCV, and Ferritin in a 65-Year-Old Woman

The combination of mild macrocytosis (MCV 101 fL), elevated MCH (34.9 pg), and normal-to-high ferritin (127 ng/mL) most likely reflects either early vitamin B12 or folate deficiency, medication-induced macrocytosis, or early myelodysplastic syndrome—but the normal ferritin effectively rules out iron deficiency and points toward a macrocytic process that requires systematic evaluation for nutritional deficiencies and bone marrow disorders. 1

Understanding the Laboratory Pattern

• MCH of 34.9 pg is mildly elevated (normal range approximately 27–33 pg), indicating that each red blood cell contains more hemoglobin than usual, which typically accompanies macrocytosis. 1

• MCV of 101 fL places the patient in the macrocytic category (normal range approximately 80–100 fL), though only mildly elevated, and this combination with elevated MCH narrows the differential to macrocytic processes without concurrent iron deficiency. 1

• Ferritin of 127 ng/mL is within the normal-to-high range and makes absolute iron deficiency extremely unlikely; in the absence of inflammation, ferritin >100 µg/L essentially excludes iron deficiency. 2

• This triad—macrocytosis, elevated MCH, and normal ferritin—distinguishes the patient from iron-deficiency anemia, which would show microcytosis (low MCV), low MCH, and low ferritin. 2, 3

Primary Differential Diagnoses

1. Vitamin B12 or Folate Deficiency

• Megaloblastic anemia remains the most common cause of macrocytosis even at MCV 101 fL, particularly in elderly patients with malabsorption, dietary insufficiency, or prior gastric surgery. 1

• Serum vitamin B12 and folate levels are mandatory first-line tests to confirm or exclude this diagnosis. 1, 3

• A peripheral blood smear should be examined for hypersegmented neutrophils (≥5 lobes), which are the hallmark of megaloblastic anemia and can appear before severe macrocytosis develops. 1, 3

2. Medication-Induced Macrocytosis

• Common culprits include hydroxyurea, methotrexate, azathioprine, anticonvulsants (phenytoin), and antiretroviral medications, all of which interfere with DNA synthesis and produce homogeneous macrocytosis. 1

• A thorough medication review is essential, as drug-induced macrocytosis can occur independently of nutritional deficiencies and may persist as long as the medication is continued. 1

3. Early Myelodysplastic Syndrome (MDS)

• MDS must be considered in elderly patients with unexplained macrocytosis, although it typically presents with other cytopenias (anemia, thrombocytopenia, or leukopenia) or more severe MCV elevation. 1

• Hematology consultation and possible bone marrow examination are warranted if initial workup is nondiagnostic, if MCV continues to rise, or if other cytopenias develop. 1

4. Chronic Alcohol Use

• Alcohol causes macrocytosis independent of folate deficiency through direct toxic effects on erythropoiesis, and should be assessed in the clinical history. 1

5. Hemochromatosis (Less Likely but Relevant)

• Hereditary hemochromatosis (HFE C282Y homozygosity) is associated with elevated MCV, MCH, and MCHC due to increased iron uptake and hemoglobin synthesis by immature erythroid cells. 4, 5

• However, ferritin of 127 ng/mL is relatively modest for hemochromatosis, which typically presents with ferritin >300–500 ng/mL in symptomatic patients; transferrin saturation >45% would be more suggestive. 4, 5

• If transferrin saturation is elevated (>45%), HFE genetic testing should be considered, particularly in patients of Northern European ancestry. 4, 5

Recommended Diagnostic Workup

First-Line Laboratory Tests

• Obtain serum vitamin B12 and folate levels immediately to confirm or exclude megaloblastic anemia. 1, 3

• Order a reticulocyte count to distinguish between ineffective erythropoiesis (low/normal reticulocytes, suggesting B12/folate deficiency or MDS) and hemolysis or recent blood loss (elevated reticulocytes). 1, 3

• Perform a peripheral blood smear to look for hypersegmented neutrophils (megaloblastic), oval macrocytes, or dysplastic changes (MDS). 1, 3

• Measure transferrin saturation (serum iron ÷ total iron-binding capacity × 100) to assess for hemochromatosis if ferritin is in the upper normal range; a value >45% warrants HFE genetic testing. 4, 5

• Check thyroid-stimulating hormone (TSH) to rule out hypothyroidism, a common reversible cause of macrocytosis in elderly patients. 3

Interpretation of Ferritin in Context

• Ferritin of 127 ng/mL is normal-to-high and excludes iron deficiency, but it can be falsely elevated by inflammation, chronic disease, malignancy, or liver disease. 2, 3

• If C-reactive protein (CRP) is elevated, ferritin up to 100 µg/L may still be compatible with iron deficiency; however, the macrocytic MCV makes iron deficiency extremely unlikely in this case. 2, 3

• Complete iron studies (ferritin, transferrin saturation, total iron-binding capacity) are essential to rule out combined deficiencies, as iron deficiency can coexist with B12 or folate deficiency and mask macrocytosis. 1, 3

Additional Considerations

• Review all medications for agents known to cause macrocytosis (see Section 2 above). 1

• Assess for gastrointestinal symptoms (diarrhea, malabsorption, prior gastric surgery) that raise the risk of vitamin B12 deficiency. 1

• If initial investigations are nondiagnostic, repeat CBC every 3–6 months and reassess B12/folate levels periodically, as deficiencies may develop later. 1

Common Pitfalls to Avoid

• Do not assume that normal ferritin excludes all forms of anemia; macrocytic anemia from B12/folate deficiency or MDS can coexist with normal or elevated ferritin. 1, 3

• Do not overlook combined deficiencies: iron deficiency can coexist with B12 or folate deficiency, and the two may neutralize each other's effect on MCV while producing an elevated red-cell distribution width (RDW). 1, 3

• Do not delay hematology referral if the cause remains unclear after initial workup, if MCV continues to rise, or if other cytopenias develop, as these findings raise concern for MDS. 1

• Do not attribute macrocytosis solely to alcohol use without measuring B12 and folate, as nutritional deficiencies are common in this population and require specific treatment. 1

Practical Diagnostic Algorithm

1. Order serum vitamin B12, folate, reticulocyte count, peripheral blood smear, and TSH immediately. 1, 3

2. If B12 or folate is low, initiate replacement therapy (oral B12 1000 µg daily or intramuscular B12 1000 µg weekly for 4 weeks, then monthly; oral folate 1 mg daily). 3

3. If B12 and folate are normal, review medications for macrocytosis-inducing agents and assess alcohol intake. 1

4. If transferrin saturation is >45%, order HFE genetic testing to evaluate for hemochromatosis. 4, 5

5. If all initial tests are normal, refer to hematology for possible bone marrow examination to exclude MDS or other primary marrow disorders. 1

6. Monitor CBC every 3–6 months even if no cause is identified, as a significant percentage of patients with unexplained macrocytosis develop primary bone marrow disorders or worsening cytopenias over time. 1