What is the differential diagnosis for a patient with macrocytic anemia, normal iron studies, and elevated ferritin level?

Differential Diagnosis: Mild Hyponatremia with Borderline Macrocytosis and Elevated Ferritin

The most likely diagnosis is early vitamin B12 or folate deficiency, potentially masked by concurrent iron overload or inflammation, given the borderline macrocytic MCV (99.1 fL) and elevated ferritin (203 ng/mL) with otherwise normal iron studies. 1, 2

Primary Diagnostic Considerations

Vitamin B12 Deficiency

• MCV of 99.1 fL represents borderline macrocytosis (threshold for true macrocytosis is ≥100 fL), suggesting early megaloblastic changes 2
• Ferritin levels can be paradoxically elevated in untreated megaloblastic anemia, with levels comparable to those seen in hemochromatosis 3
• Measure serum vitamin B12 immediately, with deficiency defined as <150 pmol/L or <203 ng/L 1, 2
• If borderline B12 levels, obtain methylmalonic acid (>271 nmol/L confirms deficiency) 1, 2

Folate Deficiency

• Also causes macrocytosis with elevated ferritin in untreated cases 3
• Check serum folate and RBC folate levels, with deficiency indicated by serum folate <10 nmol/L or RBC folate <305 nmol/L 1, 2
• Critical: Never initiate folate supplementation before ruling out and treating B12 deficiency, as this can precipitate subacute combined degeneration of the spinal cord—an irreversible neurological complication 1, 2

Mixed Deficiency States

• Combined iron deficiency and B12/folate deficiency can neutralize each other, resulting in normal or borderline MCV when both microcytosis and macrocytosis coexist 4
• A wide red cell distribution width (RDW) helps identify this mixed picture 4, 2
• The elevated ferritin (203 ng/mL) may represent true iron overload coexisting with vitamin deficiency 3

Secondary Diagnostic Considerations

Medication-Induced Macrocytosis

• Thiopurines (azathioprine, 6-mercaptopurine), methotrexate, or hydroxyurea commonly cause macrocytosis without true vitamin deficiency 4, 1
• Review current medications as part of the workup 1, 2

Hypothyroidism

• Can cause macrocytosis independent of vitamin deficiencies 4
• Measure TSH and free T4 to exclude this diagnosis 1, 2

Alcohol Use

• Causes isolated macrocytosis, often without anemia 4
• May also contribute to true folate deficiency 4

Anemia of Chronic Disease with Functional Iron Deficiency

• Ferritin 203 ng/mL with normal iron studies suggests possible inflammation 4
• Check CRP to assess for inflammatory conditions that may falsely elevate ferritin despite true iron deficiency 1, 2
• In the presence of inflammation, ferritin up to 100 μg/L may still indicate iron deficiency; ferritin >100 μg/L with transferrin saturation <20% suggests anemia of chronic disease 4

Myelodysplastic Syndrome

• Less likely given the clinical presentation, but should be considered if other causes are excluded 4, 1
• Presents with macrocytic anemia and normal/low reticulocyte count 4

Essential Diagnostic Algorithm

Step 1: Reticulocyte Count

• Low or normal reticulocytes indicate inability to respond properly to anemia, suggesting deficiency states or primary bone marrow disease 4
• Elevated reticulocytes exclude deficiencies and suggest hemolysis or hemorrhage 4, 2

Step 2: If Reticulocytes Low/Normal

• Measure vitamin B12, methylmalonic acid (if B12 borderline), serum folate, and RBC folate 1, 2
• Check TSH and free T4 1, 2
• Measure CRP and creatinine to assess for inflammation or renal failure 1
• Obtain RDW to identify mixed micro/macrocytosis 4, 2

Step 3: If Reticulocytes Elevated

• Evaluate for hemolysis with haptoglobin, lactate dehydrogenase, and bilirubin 4, 2

Critical Management Pitfall

The elevated ferritin (203 ng/mL) in the setting of borderline macrocytosis is characteristic of untreated megaloblastic anemia and should not be interpreted as excluding vitamin deficiency 3. Red cell ferritin levels in untreated B12 or folate deficiency can reach levels comparable to idiopathic hemochromatosis and normalize after vitamin replacement 3.

Hyponatremia Consideration

The mild hyponatremia (Na 132) is likely unrelated to the hematologic findings but warrants separate evaluation for SIADH, hypothyroidism (already part of workup), or other causes 1.