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 μg/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 Mitomycin C mouse for both normal and moderately elevated SF concentrations. The maximum BIBW2992 supplier 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 μg/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 homozygotes. HEPATOLOGY 2010 Hereditary hemochromatosis (HH) refers to symptoms and signs of disease that result from an inherited predisposition to iron overload. Iron overload is preventable, but can lead to significant health problems, including arthritis, hepatic cirrhosis, hepatocellular carcinoma, fatigue, and diabetes mellitus, if it is left untreated.1 More than 80% of patients presenting with symptomatic iron overload2, 3 are homozygous for the 845GA mutation in the hemochromatosis (HFE) gene, which leads to the Cys282Tyr (C282Y) substitution in the HFE protein.4 The prevalence of C282Y homozygotes is at least 1 in 200 for people
of northern European descent.5, 6 The majority of C282Y homozygotes have elevated iron indices7, 8 but the serum click here ferritin (SF) concentration threshold at which there is an increased risk of developing HH-associated signs and symptoms other than cirrhosis is not known. We have recently shown that at least 28% of male C282Y homozygotes develop iron overload–related disease (as defined by both the presence of documented iron overload9 and one of the following five objective HH features: hepatocellular carcinoma, cirrhosis/fibrosis, physician-diagnosed symptomatic HH, elevated liver enzymes, or evidence of HH-associated arthritis),7 with onset in the majority by age 55 years. Other studies have shown that individuals with SF concentrations >1000 μg/L are at significantly increased risk of cirrhosis.