HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis

Allen KJB, N. A.; Osborne, N. J.; Constantine, C. C.; Delatycki, M. B.; Nisselle, A. E.; Nicoll, A. J.; Gertig, D. M.; McLaren, C. E.; Giles, G. G.; Hopper, J. L.; Anderson, G. J.; Olynyk, J. K.; Powell, L. W.; Gurrin, L. C. (2010) HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis. Hepatology 52:925-933

Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease that potentially affects approximately 80,000 persons in Australia and almost 1 million persons in the United States. Most clinical cases are homozygous for the Cys282Tyr (C282Y) mutation in the HFE gene, with serum ferritin (SF) concentration >1000 microg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 microg/l="" is="" unknown.="" we="" assessed="" hfe="" mutations="" in="" a="" prospective="" cohort="" of="" 31,192="" participants="" of="" northern="" european="" descent,="" aged="" 40-69="" years.="" an="" hfe-stratified="" random="" sample="" of="" 1438="" participants="" including="" all="" c282y="" homozygotes="" with="" iron="" studies="" 12="" years="" apart="" were="" examined="" by="" physicians="" blinded="" to="" participants'="" hfe="" genotype.="" all="" previously="" undiagnosed="" c282y="" homozygotes="" (35="" male,="" 67="" female)="" and="" all="" hfe="" wild-types="" (131="" male,="" 160="" female)="" with="" baseline="" and="" follow-up="" sf="" concentrations=""><1000 microg/l="" were="" assessed="" for="" hh-associated="" signs="" and="" symptoms="" including="" abnormal="" second/third="" metacarpophalangeal="" joints="" (mcp2/3),="" raised="" liver="" enzymes,="" hepatomegaly,="" and="" self-reported="" liver="" disease,="" fatigue,="" diabetes="" mellitus,="" and="" use="" of="" arthritis="" medication.="" the="" prevalence="" of="" hh-associated="" signs="" and="" symptoms="" was="" similar="" for="" c282y="" homozygotes="" and="" hfe="" wild-types="" for="" both="" normal="" and="" moderately="" elevated="" sf="" concentrations.="" the="" maximum="" prevalence="" difference="" between="" hfe="" genotype="" groups="" with="" moderately="" elevated="" sf="" was="" 11%="" (mcp2/3,="" 95%="" confidence="" interval="-6%," 29%;="" p="0.22)" and="" for="" normal="" sf="" was="" 6%="" (arthritis="" medicine="" use,="" 95%="" confidence="" interval="-3%," 16%;="" p="0.11)." conclusion:="" previously="" undiagnosed="" c282y="" homozygotes="" with="" sf="" concentrations="" that="" remain="" below="" 1000="" microg/l="" are="" at="" low="" risk="" of="" developing="" hh-associated="" signs="" and="" symptoms="" at="" an="" age="" when="" disease="" would="" be="" expected="" to="" have="" developed.="" these="" observations="" have="" implications="" for="" the="" management="" of="" c282y="">