Clinical expression of hemochromatosis gene ( HFE ) variants

Phenotypic expression of hereditary hemochromatosis (HH) related to the hemochromatosis gene HFE is generally defined by biochemical measures of iron overload coupled with either nonspecific or organ-specific clinical features. However, the clinical disease burden of HFE-related HH is difficult to ascertain due to interindividual variation of symptoms and signs, as well as differences in populations studied.1 Although C282Y homozygotes are genetically predisposed to events that may culminate in severe damage to susceptible organs, there is inadequate knowledge to predict the degree of phenotypic expression in individuals.1,2 HH is therefore more common when defined by genotype than by biochemical evidence of raised serum iron indices, which in turn is more common than documented hepatic iron overload; least common is symptomatic organ damage.2 Although the potential for liver disease with iron loading in C282Y homozygotes is well accepted, the risk of other organ involvement is more controversial. The association of other HFE variants with organ damage is even more contentious. Prior to the HFE-gene era, HH was defined based on clinical phenotypic expression and familial inheritance of the disorder. Clinical expression generally relied on detection of iron overload (raised iron indices and/or hepatic iron overload on liver biopsy) plus clinical features of iron overload, including cirrhosis, bronze pigmentation of the skin and diabetes mellitus (the so-called bronze diabetes phenotype), hepatocellular cancer, cardiomyopathy, destructive arthritis, and hypogonadism.3 The bronze diabetes phenotype is now relatively rare. With the advent of HFE gene mutation testing, it has been possible to diagnose “potential hemochromatosis”, that is, individuals at increased risk of clinically significant iron loading based on the finding of C282Y homozygosity. Although this has enabled diagnosis of preclinical and early HH, not all homozygotes will develop significant iron overload or disease. Many clinical symptoms and disorders have been attributed to HH but the degree of penetrance of these has been controversial. Several large cross-sectional cohort studies from North America, Europe, Australia, and the United Kingdom have reported a variable clinical penetrance of HH despite its relatively high genotypic prevalence and biochemical penetrance4-7 A recent comprehensive review of penetrance of HH described hepatic iron overload, hepatic fibrosis, and cirrhosis in 38%, 25%, and 6%, respectively, of all C282Y homozygotes identified from population screening.2 It was extrapolated that if all unevaluated homozygotes were unaffected, this would correspond to adjusted “minimal estimates” of 24%, 6%, and 1.4%, respectively. Homozygosity for the HFE C282Y variant has been estimated to have a penetrance of between 1.3% and 2.1% for hepatocellular carcinoma.8 Many symptoms and signs attributable to iron overload from HH are nonspecific, such as fatigue, abdominal pain, hepatomegaly, and arthralgia. Furthermore, features of advanced HH such as cirrhosis, diabetes, infertility, and arthritis are uncommon below the age of 40.9,10 Figure 1 illustrates the relative levels of penetrance of biochemical and clinical features of HH. In this issue of HEPATOLOGY, Ellervik and colleagues11 systematically explore the relationship between homozygous, heterozygous, and compound heterozygous HFE variants (C282Y/C282Y, H63D/H63D, C282Y/wild type, H63D/wild type, and C282Y/H63D) relative to the wild type for the risk of various disease endpoints. By conducting meta-analyses including 202 predominantly case-controlled studies, the authors have concluded that the presence of HFE variants alone does not confer an increased risk of type 2 diabetes mellitus, coronary artery disease, arthritis, stroke, and venous disease. Subgroup analysis did, however, detect an increased risk of liver disease (odds ratio 3.9) and type 2 diabetes (odds ratio 3.4) in clinically detected (as opposed to screening detected) C282Y homozygotes of Northern European origin. Disease association was strongest for the presence of any HFE variant with porphyria cutanea tarda (odds ratio 1.9-48). H63D homozygosity was associated with an increased risk of amyotrophic lateral sclerosis (odds ratio 3.9). Complications of HH such as hepatic fibrosis and cirrhosis, and patient prognosis in the presence of these, depend on the amount and duration of iron excess.12,13 Abbreviations: HFE, hemochromatosis gene; HH, hereditary hemochromatosis; NASH, nonalcoholic steatohepatitis. Address reprint requests to: John K. Olynyk, M.D., School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital Campus, P.O. Box 480, Fremantle 6959, Western Australia, Australia. E-mail: jolynyk@cyllene.uwa.edu.au; fax: (618) 94312977. Copyright © 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21957 Potential conflict of interest: Nothing to report.