Since the discovery of HFE gene in 1996, considerable progress has been made 
concerning the iron-metabolism and its major abnormalities. Five types of 
hereditary hemochromatosis are actually known: type 1 (HFE gene), type 2A (HJV 
gene), type 2B (HAMP gene), type 3 (TfR2 gene), type 4 (SLC40A1 gene). The HFE 
C282Y +/+ mutation is responsible for the most frequent type of hemochromatosis 
in France. Various secondary causes can lead to iron-overload: associated 
genetic diseases, exogenous iron intake, thalassaemia and refractory anaemia, 
hepatic siderosis, alcoholic hepatitis, cutaneous porphyria and cirrhosis. The 
deleterious consequences of iron-overload are due to the interactions of the 
environmental factors. The role of HFE heterozygote mutations is still 
discussed. In clinical practice, the interpretation of a serum ferritin increase 
is a frequent problem that needs a careful evaluation based on the tranferrin 
saturation measurement. Significant increase of both these factors is in favour 
of an HFE C282Y +/+ hemochromatosis, after exclusion of a hepatocellular 
insufficiency or a refractory anaemia. Nevertheless, high ferritin is not always 
a marker of iron-overload. Thus, there are many disorders increasing the serum 
ferritin levels without iron overload : cytolysis (hepatic...), inflammatory or 
infectious syndromes, high alcohol intake, neoplasia... Looking for HFE 
mutations help to separate type 1 hemochromatosis from other conditions mainly 
hepatic siderosis (metabolic disorders). The identification of rare types of 
hemochromatosis (types 2-4) is only required in particular cases. The evaluation 
of the iron overload is now based on hepatic MRI determination rather than liver 
biopsy. Repeated phlebotomies remain the essential way to decrease the iron 
overload in HFE hemochromatosis and to prevent the occurrence of severe and 
irreversible complications (cirrhosis, arthropathies, cardiac failure, and 
diabetes). Because of the link established between the amount of iron-overload 
and the occurrence of complications and the mortality over-risk in HFE C282Y +/+ 
hemochromatosis, venesections must be started when serum ferritin is higher than 
300 microg/l in man and 200 microg/l in woman, whatever the clinical 
manifestations are and obviously before the symptomatic phase of the disease.