Review article: the genetic basis of haemochromatosis

Summary Background  Since the seminal discovery of the HFE gene a decade ago, considerable further progress in unravelling the genetic basis of haemochromatosis has been made. Novel genes and iron overload phenotypes have been described with potential insights into the molecular pathophysiology of human iron metabolism. Aim  To review recent key advances in the field of inherited iron overload and assess their impact on clinical practice and on our understanding of iron regulation. Methods  A PubMed search was undertaken predominantly using ‘haemochromatosis’, ‘HFE’, ‘hepcidin’ and ‘ferroportin’. Illustrative cases were sought. Results  The impact of HFE mutation analysis on the management of haemochromatosis is significant and allows early accurate diagnosis. HFE is also implicated in the siderosis associated with other liver pathologies. Non‐ HFE genes underpinning other forms of haemochromatosis are now recognized and genotype–phenotype interactions result in a spectrum of disease. These novel gene products interact with HFE in a common pathway for iron homeostasis. Conclusions  Further identification of non‐ HFE genes associated with iron homeostasis will enhance our diagnostic certainty of primary haemochromatosis and may explain the variable expression seen in HFE ‐related disease. Improving our understanding of the mechanisms of iron regulation may lead to novel therapeutic strategies for the management of iron overload.