Diagnosis and Management of Hemochromatosis

Initial Laboratory Evaluation

The European Association for the Study of the Liver recommends that the first step in testing for hemochromatosis is the assessment of serum iron parameters, which should include transferrin saturation and serum ferritin 1, 2, 3
Transferrin saturation, calculated from serum iron and transferrin or total iron binding capacity, is the most sensitive initial test with a diagnostic threshold of ≥45% 1, 4
Serum ferritin should be measured simultaneously with transferrin saturation to increase diagnostic accuracy 5, 3
A full blood count with reticulocytes should be obtained to exclude anemia and red cell disorders 1
Liver function tests, including ALT and AST, should be performed as part of the initial evaluation 5, 4

The American Association for the Study of Liver Diseases considers transferrin saturation >45% in females or >50% in males to be elevated 1, 3
Serum ferritin >200 μg/L in females or >300 μg/L in males is considered elevated 1, 6
It is advisable to confirm an elevated transferrin saturation with a second determination, preferably on a fasting specimen 4

The European Association for the Study of the Liver recommends that if transferrin saturation is elevated (>45%) and/or serum ferritin is elevated, genetic testing for the HFE gene should be performed 2, 3
Genotyping for p.C282Y in HFE should be carried out in individuals of European origin with biochemical evidence of iron overload 2
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

Non-invasive scores such as APRI 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 2, 3

Patients with severe iron overload should be evaluated for arrhythmia and cardiac dysfunction with ECG and echocardiography 1, 6
Cardiac MRI should be performed in patients with signs or symptoms of heart disease or juvenile forms of hemochromatosis 2, 6
Joint assessment should be considered as arthropathy is common in hemochromatosis and typically affects the 2nd and 3rd metacarpophalangeal joints and ankles 1, 6

If genetic testing confirms hemochromatosis, family screening of first-degree relatives is recommended 3
Adult first-degree relatives of patients with p.C282Y homozygous hemochromatosis should be tested for the p.C282Y variant in HFE 2
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 3