What laboratory tests should be ordered to diagnose hemochromatosis?

Laboratory Tests for Diagnosing Hemochromatosis

The first step in testing for hemochromatosis should include transferrin saturation and serum ferritin, which are the essential initial laboratory tests for diagnosis. 1, 2

Initial Laboratory Evaluation

• Transferrin saturation (calculated as serum iron/total iron binding capacity × 100) is the most sensitive marker and should be measured with a diagnostic threshold of ≥45% 2, 3
• Serum ferritin should be measured simultaneously to increase diagnostic accuracy 2
• Serum iron concentration and transferrin or total iron binding capacity can provide additional information for differential diagnosis 1
• Unsaturated iron binding capacity (UIBC) can be used as an alternative to transferrin saturation with equal reliability (optimal threshold of 143 μg/dL or 25.6 μmol/L) 4

Follow-up Testing Based on Initial Results

• If transferrin saturation is elevated (>45% in females, >50% in males) and/or serum ferritin is elevated (>200 μg/L in females, >300 μg/L in males), genetic testing should be performed 1, 2
• Genetic testing should focus on the C282Y mutation in the HFE gene, which is present in approximately 90% of patients with hereditary hemochromatosis 2, 3
• Testing for the H63D mutation should also be included, as compound heterozygosity (C282Y/H63D) can be associated with iron overload, particularly when other risk factors are present 1
• Measuring hepcidin is not recommended 1

Additional Testing for Disease Severity

• Liver function tests (ALT, AST) should be performed to assess for liver involvement 2, 3
• Complete blood count to evaluate for anemia or elevated hemoglobin 5
• Fasting blood glucose or HbA1c to screen for diabetes mellitus 6, 3
• If ferritin is >1000 μg/L with elevated liver enzymes, further evaluation for cirrhosis is warranted 2, 3

Imaging and Invasive Testing

• MRI should be used to quantify hepatic iron concentrations in patients with unclear cause of hyperferritinemia, biochemical iron overload, or positive liver iron staining 1
• Cardiac MRI can be performed in patients with signs of heart disease or juvenile forms of hemochromatosis 1
• Liver biopsy may be considered in patients with serum ferritin >1000 μg/L, elevated liver enzymes, or when the diagnosis remains unclear despite other testing 2, 3

Important Considerations and Pitfalls

• Normal transferrin saturation with elevated ferritin should prompt investigation for other causes of hyperferritinemia besides hemochromatosis, such as inflammation, liver disease, or metabolic syndrome 2, 7
• Ferritin can be falsely elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 2, 7
• During phlebotomy treatment, regular monitoring of hemoglobin and ferritin is essential to prevent iron deficiency 5
• First-degree relatives of patients with confirmed hemochromatosis should undergo both genetic testing and phenotypic assessment (ferritin and transferrin saturation) 2, 3

Testing Algorithm

1. Order transferrin saturation and serum ferritin as initial tests 1, 2
2. If transferrin saturation is elevated (>45%) or ferritin is above normal, proceed with HFE genetic testing for C282Y and H63D mutations 1, 2
3. If genetic testing confirms C282Y homozygosity or C282Y/H63D compound heterozygosity with elevated iron studies, the diagnosis is established 2, 3
4. For patients with confirmed hemochromatosis, assess for end-organ damage with liver function tests, glucose metabolism tests, and cardiac evaluation if indicated 2, 6, 3
5. Consider MRI for iron quantification if the diagnosis remains unclear or to assess organ involvement 1