Hemochromatosis is a common cause of chronic liver disease and HFE genotyping 
allows decisive and non-invasive diagnosis. Molecular and clinical genetic 
studies have led to the identification of genes other than HFE in patients with 
inherited diseases associated with increased hepatic iron storage that can cause 
hemochromatosis, which adds complexity to a diagnostic approach to patients with 
suspected hemochromatosis. Despite major advances in genetics, hepatic iron 
quantification by non-invasive methods therefore remains the key to the 
diagnosis of hemochromatosis. Although associated with homozygosity for the 
C282Y polymorphism in the HFE gene in >80% of patients, hemochromatosis is a 
complex genetic disease with strong environmental disease modifiers. Testing for 
mutations in the non-HFE hemochromatosis genes transferrin receptor 2, 
hemojuvelin, HAMP and SLC40A1 is complex, costly and time-consuming. 
Demonstration of hepatic iron overload by liver biopsy or MRI is therefore 
required before such complex tests are carried out. The pathogenesis of chronic 
liver disease in hemochromatosis is mainly attributed to the redox potential of 
tissue iron, and only the more recent studies have focused on the toxic 
properties of circulating iron. Considering the fact that an increased 
saturation of transferrin and high iron in plasma are the hallmark of all 
hemochromatosis forms, an alternative view would be that toxic iron in the 
circulation is involved in the pathogenesis of hemochromatosis. Recent studies 
have shown an increased concentration of redox-active iron in plasma in patients 
with increased transferrin saturation. This finding supports the hypothesis that 
tissue iron may be the 'smoking gun' of iron-induced organ damage. Taken 
together, caring for patients with suspected or established hemochromatosis 
still remains a challenge, where understanding the genetics, biochemistry and 
cell biology of hemochromatosis will aid better diagnosis and treatment of 
affected individuals.