In contrast to the conventional view of haemochromatosis as a monogenic disease with autosomal recessive inheritance, more recent evidence form genetic, epidemiological, cell biological and clinical studies, challenges this view. The concept that haemochromatosis is an endocrine disorder of mixed etiology embraces the poylgenic nature of the disease, the low penetrance and the similarities in phenotype of genetic and acquired forms of iron overload. Key to understanding haemochromatosis as an endocrine disorder is that iron overload is caused by a deficiency of the iron hormone hepcidin.
Accordingly, haemochromatosis can be viewed the diabetes of iron metabolism, where hepcidin and iron have a functional relationship comparable to insulin and glucose. Studies in mice defective for the genes encoding the hemochromatosis protein HFE, transferrin receptor two, and bone morphogenic protein six provide first insight into the iron sensor, which signals directly to the hepcidin promoter and thus control its transcription rate. Studies on the iron export protein ferroportin and its direct negative regulator hepcidin have shown that plasma iron is regulated via controlled release of iron from recycling macrophages, duodenal enterocytes and hepatocytes. This closes a feedback-loop, where hepcidin tightly controls plasma iron for sufficient delivery to cells utilizing the metal, while avoiding oxidative stress though uncontrolled release of iron into the circulation.
In patients with haemochromatosis, hepcidin production is inappropriately low which causes uncontrolled release of iron into the circulation that results in increased transferrin saturation, which is the principal clinical biochemical defect in hemochromatosis. Genetically hemochromatosis is associated with homozygosity for the common C282Y polymorphism of the HFE gene. Although the exact function of this protein is still unknown, studies in cell and animal models of the disease suggest that HFE is part of the iron sensor expressed in hepatocytes. Distribution of iron overload in HFE associated hemochromatosis is similar to other genetic iron overload disorders such as haemochromatosos associated with mutations in the transferrin receptor two gene, hemojuvelin gene or the hepcidin gene, which supports the role of these gene products in the iron sensing mechanism, that is being unravelled.