What is the next step in managing a patient with elevated ferritin and macrocytosis?

Elevated Ferritin with Macrocytosis: Next Steps

The next step is to check transferrin saturation (TS) to differentiate between iron overload disorders and other causes of hyperferritinemia, followed by targeted evaluation based on the TS result. 1

Initial Diagnostic Approach

Given the presentation of ferritin 203 μg/L with MCV 99.1 fL, normal TSH, B12, folate, and no alcohol use, you need to systematically evaluate both the elevated ferritin and macrocytosis:

Step 1: Measure Transferrin Saturation

• Order fasting transferrin saturation immediately to determine if this represents true iron overload versus other causes of hyperferritinemia 1
• If TS ≥45%, proceed with HFE genetic testing (C282Y and H63D mutations) to evaluate for hereditary hemochromatosis 1
• If TS <45% with ferritin 203 μg/L, iron overload is unlikely and alternative causes should be investigated 1

Step 2: Evaluate for Common Causes of Hyperferritinemia

Before pursuing genetic testing, the 2022 EASL guidelines mandate excluding common causes of elevated ferritin 1:

• Check inflammatory markers: CRP and ESR to assess for inflammation (ferritin is an acute phase reactant) 1
• Assess liver function: AST, ALT to evaluate for hepatocellular injury or non-alcoholic fatty liver disease 1
• Screen for metabolic syndrome: Blood pressure, BMI, lipid panel, fasting glucose (NAFLD commonly causes hyperferritinemia) 1
• Consider malignancy screening if clinically indicated, as malignancy is the most common cause of markedly elevated ferritin in tertiary care settings 2

Step 3: Address the Macrocytosis

The macrocytosis (MCV 99.1) with normal B12 and folate requires additional evaluation:

• Review medication list for drugs causing macrocytosis (though patient reports no medications) 1
• Check reticulocyte count to assess bone marrow response 1
• Consider peripheral blood smear to evaluate for dysplastic features or other morphologic abnormalities 3
• Measure lactate dehydrogenase (LDH) and haptoglobin to exclude hemolysis, though less likely with macrocytosis 1, 3

Clinical Context and Pitfalls

Important Considerations:

• Ferritin 203 μg/L is only mildly elevated and does not suggest severe iron overload or conditions like Adult-onset Still's disease (which typically shows ferritin >1000 μg/L) 1, 2
• The combination of mild hyperferritinemia with macrocytosis is unusual for classic hereditary hemochromatosis, which typically presents with microcytosis or normocytosis 1
• Hyponatremia (Na 132) may be incidental but warrants evaluation for underlying systemic illness 1

Common Pitfalls to Avoid:

• Do not proceed directly to HFE genetic testing without checking transferrin saturation first - this violates guideline recommendations and may lead to misdiagnosis 1
• Do not assume iron overload based on ferritin alone - over 90% of hyperferritinemia cases are due to inflammation, alcohol, cytolysis, tumors, or metabolic syndrome rather than true iron overload 1
• Do not overlook the macrocytosis - while B12 and folate are normal, other causes including bone marrow disorders must be considered 1, 3

If Transferrin Saturation is Elevated (≥45%):

• Proceed with HFE mutation analysis for C282Y and H63D polymorphisms 1
• If C282Y homozygous with ferritin <1000 μg/L: Liver biopsy is not necessary; initiate therapeutic phlebotomy 1
• If compound heterozygote (C282Y/H63D): Investigate other cofactors before attributing hyperferritinemia to hemochromatosis 1
• Screen first-degree relatives if hereditary hemochromatosis is confirmed 1

If Transferrin Saturation is Normal (<45%):

• Focus on identifying secondary causes of hyperferritinemia as outlined above 1
• Consider bone marrow examination if ferritin continues to rise, unexplained cytopenias develop, or peripheral smear shows dysplastic features 3
• Monitor ferritin levels every 3-6 months if no clear cause is identified and patient remains asymptomatic 1