What are the guidelines for testing and managing hemochromatosis?

Testing and Management of Hemochromatosis

The diagnosis of hemochromatosis requires both transferrin saturation and serum ferritin measurements as initial laboratory tests, followed by HFE genetic testing if either is abnormal, with C282Y homozygosity confirming hereditary hemochromatosis. 1, 2

Initial Diagnostic Testing

• Transferrin saturation (TS) and serum ferritin should always be measured together as the initial laboratory tests for diagnosing hemochromatosis 1, 2
• A TS ≥45% has high sensitivity for detecting C282Y homozygotes but lower specificity, meaning it will also identify persons with minor secondary iron overload 2
• Serum ferritin provides additional confirmation of iron overload and has prognostic value for advanced fibrosis and cirrhosis 2
• Fasting specimens for TS are no longer absolutely necessary, though confirming an elevated TS with a second determination is advisable 3

Diagnostic Algorithm

• If either TS ≥45% or ferritin is above the upper limit of normal, proceed to HFE mutation analysis for C282Y and H63D mutations 1
• Genetic interpretation:
  • C282Y homozygosity (C282Y/C282Y): Confirms hereditary hemochromatosis 1
  • Compound heterozygosity (C282Y/H63D): May have mild iron overload, especially with additional risk factors 1
  • H63D homozygosity with confirmed iron overload: Requires further investigation for other causes 1

Disease Severity Assessment

• Serum ferritin >1000 μg/L is associated with increased risk of cirrhosis and should prompt consideration of liver biopsy 1, 2
• A serum ferritin level >1000 μg/L with elevated liver enzymes and platelet count <200 predicts cirrhosis in approximately 80% of C282Y homozygotes 2
• Liver biopsy is indicated in C282Y homozygotes with serum ferritin above 1,000 μg/L, elevated liver enzymes, hepatomegaly, or age over 40 years to assess for cirrhosis 1

Management

• Phlebotomy is the mainstay of treatment for confirmed hemochromatosis with iron overload 1, 4
• Standard protocol involves removing one unit (approximately 500 mL) of blood weekly or biweekly 1
• Monitor hemoglobin/hematocrit during treatment and serum ferritin every 10-12 phlebotomies 1
• Target serum ferritin level is 50-100 μg/L 1
• Phlebotomy can improve heart function, reduce abnormal skin pigmentation, and reduce risk of liver complications 4
• Significant hepatic fibrosis is frequently found in asymptomatic subjects and can be reversed by iron removal, except when cirrhosis is present 5

Family Screening

• HFE genetic testing should be offered to first-degree relatives of patients with confirmed HFE-related hemochromatosis 1, 4
• Genetic testing should be offered after 18 years of age to first-degree relatives 4
• Both phenotype testing (ferritin and TS) and genotype testing are recommended for first-degree relatives 1

Common Pitfalls and Caveats

• Serum ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 1, 2
• Before proceeding with genetic testing, exclude common causes of hyperferritinemia including chronic alcohol consumption, inflammatory conditions, cell necrosis, malignancy, and metabolic syndrome 1
• A normal TS with elevated ferritin should prompt investigation for other causes of hyperferritinemia or non-HFE hemochromatosis 2
• Approximately 20% of patients with clinical hemochromatosis have no disease-associated genotype, underlining the importance of clear phenotypic criteria 6
• Non-HFE forms of hemochromatosis (Types 2-4) are rare but should be considered when clinical iron overload is present without the typical HFE mutations 7
• Patients with confirmed hemochromatosis should avoid alcohol and raw seafood due to increased risk of infections and liver damage 1
• Vitamin C supplements should be avoided as they can accelerate iron mobilization and potentially increase toxicity 1

Screening Recommendations

• Universal screening for hereditary hemochromatosis is not recommended 8
• Testing should be performed in:
  • First-degree relatives of patients with classical HFE-related hemochromatosis 8
  • Patients with evidence of active liver disease 8
  • Patients with abnormal iron study results 8
  • All patients with abnormal liver function tests should have iron studies performed 3
• Screening for hepatocellular carcinoma is recommended for patients with hemochromatosis and cirrhosis 8