Flow chart for hemochromatosis diagnosis based on genotype at risk and liver iron content. Starting from abnormal iron parameters (which should be obtained at least twice) and after exclusion of conditions leading to secondary iron overload, the genetic test is performed. The approach for HFE-positive and -negative genotypes is shown. Assessment of liver iron is useful for subsequent therapeutic decision: liver biopsy can be done on an individual basis; superconducting quantum interference device (SQUID) and magnetic resonance imaging (MRI) can be done if available. If liver iron concentration is normal, only follow-up is proposed in all genotypes. When liver iron content is high, clinical complications should be assessed and phlebotomy is recommended in all genotypes. Selected cases of C282Y or C282Y/H63D with a severe phenotype could be screened for mutations in other genes. Among patients with HFE-negative genotypes, screening for other gene mutations is advisable only if iron overload is present. Family screening is indicated when causal mutations are recognized either in HFE or in other hemochromatosis-associated genes. TS indicates transferrin saturation; SF, serum ferritin. Illustration by Kenneth Probst.