What additional tests should be ordered to diagnose and manage suspected hereditary hemochromatosis (HH)?

Diagnostic Tests for Suspected Hereditary Hemochromatosis

For suspected hereditary hemochromatosis, a complete diagnostic workup should include transferrin saturation, serum ferritin, HFE genetic testing, and liver function tests, with consideration of liver biopsy in specific high-risk cases. 1, 2

Initial Laboratory Tests

• Transferrin saturation and serum ferritin should be the essential initial laboratory tests for diagnosing hemochromatosis, with transferrin saturation ≥45% being the most sensitive early marker 1, 2
• Serum iron concentration and total iron binding capacity provide additional information for differential diagnosis 2
• Before proceeding with genetic testing, common causes of hyperferritinemia should be excluded, including:
  • Chronic alcohol consumption 1
  • Inflammation (check C-reactive protein) 1
  • Cell necrosis (check AST, ALT, CK) 1
  • Malignancy 1
  • Non-alcoholic fatty liver disease 1
  • Metabolic syndrome (check blood pressure, BMI, cholesterol, triglycerides, serum glucose) 1

Genetic Testing

• HFE testing for the C282Y and H63D polymorphisms should be performed in all patients with unexplained increased serum ferritin and increased transferrin saturation 1, 2
• Genetic testing should not be performed in isolation; evidence of increased iron stores is required for diagnosis 1
• For C282Y homozygotes with increased iron stores, liver biopsy is no longer necessary to diagnose hemochromatosis 1
• For C282Y/H63D compound heterozygotes and H63D homozygotes with elevated iron indices, further investigation for other causes of hyperferritinemia is needed 2

Additional Testing Based on Initial Results

• Liver function tests (AST, ALT) should be performed to assess for hepatic involvement 2
• Complete blood count and platelet count should be checked, as a platelet count <200 with elevated liver enzymes and ferritin >1000 μg/L predicts cirrhosis in approximately 80% of C282Y homozygotes 2
• Liver biopsy should be considered in C282Y homozygous patients with:
  • Serum ferritin above 1000 μg/L 1
  • Elevated AST/ALT 1
  • Hepatomegaly 1
  • Age over 40 years 1

Testing for Non-HFE Hemochromatosis

• If C282Y homozygosity is excluded but iron overload is confirmed by direct assessment (MRI or liver biopsy), testing for other hemochromatosis genes may be considered 1
• Genetic testing for "other hemochromatosis genes" (TFR2, SLC40A1, HAMP, HJV) should be considered when:
  • Iron excess has been proven by direct assessment (MRI or liver biopsy) 1
  • Other hepatic and hematological disorders have been ruled out 1
• HJV p.Gly320Val mutation testing should be the molecular test of choice in suspected patients with juvenile hemochromatosis under 30 years with cardiac or endocrine manifestations 3

Imaging Studies

• MRI should be used to quantify hepatic iron concentrations in patients with:
  • Unclear cause of hyperferritinemia 2
  • Biochemical iron overload 2
  • Positive liver iron staining 2
• Cardiac MRI can be performed in patients with signs of heart disease or juvenile forms of hemochromatosis 2

Family Screening

• Genetic testing of siblings of individuals with HFE-HC should be carried out due to the 25% chance of being susceptible 1
• Serum ferritin and transferrin saturation should be assessed in first-degree relatives 1
• For children of affected individuals, HFE genotyping of the unaffected spouse can help establish the likelihood of genetic susceptibility 1

Important Pitfalls to Avoid

• Do not diagnose HFE hemochromatosis based on C282Y homozygosity alone; evidence of increased iron stores is required 1
• Do not overlook other causes of hyperferritinemia before genetic testing 1
• Serum ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 2
• A normal transferrin saturation with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis 2
• General population screening for HH is not recommended 1