What lab tests should be drawn to diagnose hemochromatosis in a patient with elevated ferritin levels?

Diagnostic Testing for Hemochromatosis in Patients with Elevated Ferritin

For patients with elevated ferritin levels, the first step in testing for hemochromatosis should be assessment of both transferrin saturation and serum ferritin, followed by HFE genotyping if either is abnormal (transferrin saturation ≥45% or ferritin above upper limit of normal). 1, 2

Initial Laboratory Evaluation

• Transferrin saturation (TS) and serum ferritin should be obtained simultaneously as the initial laboratory tests rather than relying on a single test 1, 2
• Serum iron concentration and total iron binding capacity (TIBC) or transferrin can provide additional information for differential diagnosis 1
• Measuring hepcidin is not recommended 1
• Common causes of hyperferritinemia should be excluded before genetic testing, including:
  • Chronic alcohol consumption
  • Inflammation (check CRP)
  • Cell necrosis (check AST, ALT, CK)
  • Malignancy
  • Non-alcoholic fatty liver disease and metabolic syndrome 1, 2

Interpretation of Initial Iron Studies

• Transferrin saturation ≥45% is the earliest and most sensitive marker of hemochromatosis 2
• Normal ranges for serum ferritin vary by sex:
  • Men: 20-200 μg/L (normal), 150-1000 μg/L (asymptomatic HH), 500-6000 μg/L (symptomatic HH)
  • Women: 15-150 μg/L (normal), 120-1000 μg/L (asymptomatic HH), 500-6000 μg/L (symptomatic HH) 1
• A serum ferritin level >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 1

Genetic Testing

• If either transferrin saturation ≥45% or ferritin is above the upper limit of normal, HFE genotyping for C282Y and H63D mutations should be performed 1, 2
• Genotyping for p.C282Y in HFE should be carried out in individuals of European origin with biochemical evidence of iron overload:
  • Females with transferrin saturation >45% and serum ferritin >200 μg/L
  • Males with transferrin saturation >50% and ferritin >300 μg/L 1
• Approximately 91% of patients with hemochromatosis are C282Y homozygotes 3

Interpretation of Genetic Testing Results

• C282Y homozygosity (C282Y/C282Y) confirms the diagnosis of HFE-related hemochromatosis 2
• For compound heterozygotes (C282Y/H63D) or H63D homozygotes with confirmed iron overload, investigate for other causes of iron overload 1
• Management of patients with p.C282Y/p.H63D compound heterozygosity or p.H63D homozygosity should be guided by their phenotypic presentation and presence of additional risk factors, not the genotype alone 1

Additional Testing When Indicated

• Liver biopsy may be considered in C282Y homozygotes with serum ferritin above 1000 μg/L, elevated AST, hepatomegaly, or age over 40 years to assess for cirrhosis 1, 2
• MRI should be used to quantify hepatic iron concentrations and assess extrahepatic organ involvement in patients with unclear cause of hyperferritinemia, biochemical iron overload, or positive liver iron staining 1
• Cardiac MRI can be performed in patients with hemochromatosis and signs of heart disease 1

Family Screening

• Once a patient with hemochromatosis has been identified (proband), family screening should be recommended for all first-degree relatives 1
• For children of an identified proband, HFE testing of the other parent is generally recommended 1
• Adult first-degree relatives of patients with p.C282Y homozygous hemochromatosis should be tested for the p.C282Y variant in HFE 1

Common Pitfalls

• Isolated elevated ferritin with normal transferrin saturation is an unusual pattern for classic HFE-related hemochromatosis 2, 4
• Serum ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 2, 5
• Iron loading HFE mutations are unlikely to be the most common cause of mild hyperferritinemia (ferritin <1000 μg/L) 5, 6
• Not all C282Y homozygotes develop clinical disease due to low penetrance of the mutation 7, 6