Novel observations in hereditary hemochromatosis: potential implications for clinical strategies

Remarkable advances in understanding the pathogenesis of hereditary hemochromatosis have been made since 1996, the year in which the HFE gene, which is responsible for the vast majority of cases, was discovered.1 The recognition of the central role of the iron regulatory hormone hepcidin in the pathogenesis of hereditary hemochromatosis has been particularly significant. In addition to HFE, defects in four additional genes have been found to cause hereditary hemochromatosis: hepcidin, transferrin receptor 2 (TFR2), hemojuvelin (HJV), and ferroportin.2 Interestingly, these genes each encode for a protein that affects pathways influencing liver hepcidin synthesis or its interaction with the cellular iron export protein ferroportin. It is now clear that inadequate production of hepcidin or response to it is responsible for the excess dietary iron absorption and excess iron release from macrophages stores, and consequent hyperferremia, which characterize the classical hereditary hemochromatosis phenotype. For clinicians, the challenge is to diagnose hereditary hemochromatosis before this hyperferremia leads to irreversible tissue damage. At the same time the clinician must have ways to distinguish progressive heritable forms of iron overload from increasingly common acquired diseases with only moderately increased iron body stores, such as the metabolic syndrome. This challenge has raised interest in the possibility that recent bench top discoveries might lead to novel bedside laboratory tests. Two publications in this issue of Haematologica are relevant to this possibility.3,4 In one study, serum hepcidin levels were used to characterize the response of patients with HFE- or TFR2-associated hereditary hemochromatosis to an oral iron challenge.3 The other study identifed several clinically significant orphan mutations in the HFE gene.4 The contribution of each of these studies to a better understanding of the pathogenesis of hereditary hemochromatosis and the possible ways they might influence the future diagnostic work-up and monitoring of iron overload disorders are discussed.