What is the approach to diagnose and manage hemochromatosis (iron overload disorder)?

Diagnostic Approach to Hemochromatosis

The initial approach to diagnosing hemochromatosis should begin with transferrin saturation (TS) and serum ferritin measurements, followed by genetic testing for HFE mutations in patients with elevated iron studies. 1, 2

Initial Laboratory Testing

• Transferrin saturation (TS) is the primary screening test, calculated as serum iron divided by total iron binding capacity × 100, with a diagnostic threshold of ≥45% offering high sensitivity for detecting C282Y homozygotes 2, 1
• Serum ferritin should be measured simultaneously with TS to increase diagnostic accuracy, as it correlates with body iron stores 2, 1
• Fasting is no longer absolutely necessary for these tests, though confirming an elevated TS with a second determination is advisable 1
• Normal ranges for serum ferritin vary by sex: 20-200 μg/L for men and 15-150 μg/L for women (non-iron overloaded), while symptomatic patients may have levels of 500-6000 μg/L 1

Follow-up Testing After Abnormal Iron Studies

• If TS ≥45% or ferritin is elevated above the upper limit of normal, HFE genetic testing should be performed to detect C282Y and H63D mutations 2, 1
• C282Y homozygosity is the most common genotype associated with hereditary hemochromatosis, while C282Y/H63D compound heterozygosity can also cause iron overload 1
• Patients with normal TS but elevated ferritin should be evaluated for other causes of hyperferritinemia, including inflammation, liver disease, or non-HFE hemochromatosis 3

Liver Assessment

• Liver function tests (ALT, AST) should be performed in all patients with suspected hemochromatosis 1
• 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 may be indicated in specific circumstances 2:
  • When iron markers are equivocal
  • To rule out significant iron overload
  • To investigate other possible causes of liver disease
  • In patients with serum ferritin >1000 μg/L to assess for cirrhosis

Screening High-Risk Populations

• First-degree relatives of patients with HFE-related hemochromatosis should undergo screening with iron studies and HFE mutation analysis 1
• All patients with evidence of liver disease should be evaluated for hemochromatosis 1
• Patients with unexplained symptoms consistent with hemochromatosis (fatigue, arthralgia, diabetes, cardiac abnormalities) should be screened 1

Management Considerations

• Therapeutic phlebotomy is the mainstay of treatment for hemochromatosis with iron overload 4
• For patients requiring iron chelation therapy, deferasirox can be considered, but requires careful monitoring of renal and hepatic function 5
• Serum ferritin and hemoglobin should be monitored during treatment to prevent iron deficiency from excessive phlebotomy 4

Pitfalls and Caveats

• Serum ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload, requiring careful interpretation 2, 3
• Lowering the TS threshold to 45% increases sensitivity but reduces specificity, potentially identifying patients with secondary iron overload (alcohol-induced liver disease, steatohepatitis, chronic hepatitis C) 1
• Population screening for hemochromatosis is not recommended, but targeted screening in high-risk populations is appropriate 1
• Non-HFE forms of inherited iron overload are rare (<5% of cases) but should be considered in patients with clinical iron overload and negative HFE testing 1

By following this systematic approach to diagnosis, hemochromatosis can be detected early, allowing for timely intervention to prevent complications such as cirrhosis, diabetes, cardiomyopathy, and arthropathy.