What is the initial workup for a patient suspected of having hemochromatosis?

Initial Workup for Suspected Hemochromatosis

The first step in testing for hemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin. 1, 2

Initial Laboratory Evaluation

• Transferrin saturation (TSAT) - calculated from serum iron and transferrin or total iron binding capacity (TIBC) - is the most sensitive initial test with a diagnostic threshold of ≥45% 1, 2
• Serum ferritin should be measured simultaneously with transferrin saturation to increase diagnostic accuracy 1, 2
• Full blood count with reticulocytes should be obtained to exclude anemia and red cell disorders 1
• Liver function tests (ALT, AST) should be performed as part of the initial evaluation 1

Diagnostic Thresholds

• Transferrin saturation >45% in females or >50% in males is considered elevated 1, 2
• Serum ferritin >200 μg/L in females or >300 μg/L in males is considered elevated 1
• It is advisable to confirm an elevated transferrin saturation with a second determination, preferably on a fasting specimen 1

Genetic Testing

• If transferrin saturation is elevated (>45%) and/or serum ferritin is elevated, genetic testing for the HFE gene 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 1
• In patients of non-European origin with clinical suspicion of hemochromatosis and elevated transferrin saturation and ferritin, direct sequencing of HFE and non-HFE genes may be considered 1

Additional Testing Based on Initial Results

• If serum ferritin is >1000 μg/L with elevated liver enzymes and platelet count <200, there is approximately 80% risk of cirrhosis in C282Y homozygotes 2
• Non-invasive scores such as APRI (aspartate aminotransferase-to-platelet ratio index) and FIB-4 can be used to assess for advanced fibrosis, though thresholds are lower than in other chronic liver diseases 1
• MRI should be used to quantify hepatic iron concentrations in patients with unclear cause of hyperferritinemia or confirmed iron overload 1, 2

Cardiac and Joint Evaluation

• Patients with severe iron overload should be evaluated for arrhythmia and cardiac dysfunction with ECG and echocardiography 1
• Cardiac MRI should be performed in patients with signs or symptoms of heart disease or juvenile forms of hemochromatosis 1
• Joint assessment should be considered as arthropathy is common in hemochromatosis and typically affects the 2nd and 3rd metacarpophalangeal joints and ankles 1

Common Pitfalls and Considerations

• Serum ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 1, 3
• A normal transferrin saturation with elevated ferritin should prompt investigation for other causes of hyperferritinemia besides hemochromatosis 3
• Before proceeding with genetic testing, common causes of hyperferritinemia should be excluded, including chronic alcohol consumption, inflammatory conditions, cell necrosis, malignancy, and metabolic syndrome 2
• Measuring hepcidin is not recommended for diagnosing hemochromatosis 1

Next Steps After Diagnosis

• If genetic testing confirms hemochromatosis, family screening of first-degree relatives is recommended 2
• Adult first-degree relatives of patients with p.C282Y homozygous hemochromatosis should be tested for the p.C282Y variant in HFE 1
• Liver biopsy may be considered in C282Y homozygotes with serum ferritin above 1,000 μg/L, elevated liver enzymes, hepatomegaly, or age over 40 years to assess for cirrhosis 2