he term 'hemochromatosis' refers to an autosomal recessive disorder of iron metabolism associated with two mutant alleles of the HFE gene (usually leading to a Cys282Tyr mutation in the gene product) and characterized by a slow and progressive increase in plasma iron content, which, in adults, may lead to systemic iron loading of parenchymal cells (particularly hepatocytes) and, eventually, to organ disease. In rare cases, mutations in other iron-loading genes may result in a similar syndrome. The term was coined by von Recklinghausen in 1889 to describe the association at autopsy of widespread tissue injury, usually cirrhosis, with increased tissue staining for iron. 1 Sheldon, in his review of all published cases, linked this term to an inherited disorder of iron metabolism that is overwhelmingly more common in males and sometimes has a familial incidence. 2 A breakthrough in the history of the disease came with the recognition of its autosomal recessive nature and the location of the pathogenic gene on the short arm of chromosome 6. 3,4 These observations preceded the identification of an iron-regulating gene, now named HFE, 5 that is mutated in hemochromatosis.
Once the HFE gene was identified, it immediately appeared to be clear that not all patients with an inherited hemochromatosis-like phenotype carried pathogenic mutations in the HFE gene. This was particularly evident in southern European countries. 6,7 Therefore, the term 'non-HFE hemochromatosis' was coined to define hereditary iron overload in patients without pathogenic mutations in the HFE gene. 8 Like 'non A-non B hepatitis', 'non-HFE hemochromatosis' was mainly a negative term, based on the ignorance of the genetic basis of the underlying disorders. Since then, unprecedented progress in animal and human iron genetics has led to the identifica-Abbreviations: RE, reticuloendothelial; mRNA, messenger RNA; IRE, iron-responsive element.