The penetrance of genetic hemochromatosis has decreased over time, while body weight has increased and alcohol consumption has decreased, according to results published in the Journal of Hepatology. Additionally, smoking tobacco continues to be a factor that can aggravate the disorder.
Genetic hemochromatosis results in progressive iron overload in the body. It is an inherited disorder most frequently related to homozygosity of the p.Cys282Tyr (C282Y) mutation in the HFE gene, which causes a deficiency in hepcidin, a protein that regulates iron metabolism. Hemochromatosis can result in cirrhosis, diabetes, arthritis, and chronic fatigue in adults.
Hemochromatosis has an estimated clinical penetrance of 30% among male C282Y homozygotes and 1% among female C282Y homozygotes. Overall, the severity of the disorder has declined over the previous 3 decades, even though patients now tend to be older at diagnosis. This trend could be associated with decreased alcohol consumption and increased body mass in the French population during this time span.
Researchers assessed clinical symptoms, markers of iron load, and risk factors, stratified by year of diagnosis, across 30 years from a cohort of C282Y homozygotes in France. The study population included a total of 2050 patients, of whom 1460 were probands (804 male, 656 female) and 542 were relatives (244 male, 346 female).
The ratio of probands to relatives remained stable over time, and the ratio of male to female patients among probands was approximately equal over the study period. Though age at diagnosis did not change in male probands across all 3 decades, the age at diagnosis increased in female probands.
The frequency of chronic fatigue and distal joint symptoms such as arthritis remained stable over the 30 years. The frequency of diabetes and hepatic fibrosis decreased, as did levels of serum ferritin, the amount of iron removed, and transferrin saturation. Excessive consumption of alcohol decreased over time while the proportion of overweight and obese patients increased. Tobacco smoking remained stable over time and was associated with increased saturation of ferritin.
Of note, genetic testing was not associated with age at diagnosis, which contrasts with the significant decrease in iron load observed over time. The low penetrance of hemochromatosis observed in this study and the changing phenotype of the disorder over time indicate that multiple nongenetic factors affect the expression of this disorder. Because alcohol consumption and body weight affect hepcidin production, researchers suggested that the changing prevalence of these factors could affect the incomplete penetrance of hemochromatosis in this population.
1. Deugnier Y, Morcet J, Lainé F, et al. Reduced phenotypic expression in genetic hemochromatosis with time: Role of exposure to non-genetic modifiers [published online September 20, 2018]. J Hepatol. doi: 10.1016/j.jhep.2018.09.009