The overall clinical penetrance in terms of iron overload-related clinical symptoms is less than 30% in HFE-associated hereditary hemochromatosis. Ferritin is the most reliable biomarker to quantify iron load but may be falsely elevated during an acute phase response as in inflammation, stress, or infections. In the investigation of clinical hereditary hemochromatosis, don’t order HFE C282Y testing unless BOTH the ferritin and the transferrin saturation are elevated. A normal ferritin rules out a clinically treatable hemochromatosis syndrome and is therefore an appropriate first line test. Transferrin saturation can be added on to the same blood sample if the ferritin is elevated.
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