Screening for Hemochromatosis in Asymptomatic Subjects With or Without a Family History

Abstract

Background: Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. Methods:We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years.Results: Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2-4) in 18.4% and 5.4%; and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic.Conclusions: Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.

Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

“…Although we did not find a significantly higher prevalence of self-reported arthritis in C282Y homozygotes than in controls, arthritis is one of the most common clinical conditions in hemochromatosis patients and often is the first to develop (39)(40)(41)(42). In the current study, the prevalence of joint stiffness or pain in newly diagnosed C282Y homozygotes with normal SF was similar to that in previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF (Table 2).…”

“…Although we did not find a significantly increased prevalence of self-reported liver disease in C282Y homozygotes relative to controls in the current study, this could have been an effect of the selection of controls for the clinical examination or differential recall bias between the time of initial screening and the subsequent clinical examination. Hepatic fibrosis and cirrhosis in hemochromatosis patients can also be silent, and a recent report documents comparable prevalences of fibrosis and cirrhosis on liver biopsy in apparently healthy Australian C282Y homozygotes identified either by screening during health checks (19% fibrosis and 12% cirrhosis in males) or because there was a family history of hemochromatosis (23% and 6%, respectively) (40). In a Norwegian population-screening study, similar but slightly lower prevalences of fibrosis (11%) and cirrhosis (4%) were found in male C282Y homozygotes undergoing biopsy (44).…”

“…Whether, or the rate at which, such individuals will develop clinical symptoms related to iron overload in the future is unknown (50). However, a longitudinal study (40) has shown that in the absence of therapeutic phlebotomy, a progressive increase in SF occurs in a majority of C282Y homozygotes. Three other longitudinal studies have assessed morbidity.…”

Reversibility of hepatic fibrosis in treated genetic hemochromatosis: A study of 36 cases

“…However, among the 15 patients who either maintained (n ϭ 13) or developed (n ϭ 2) cirrhosis, 5 were regular excessive drinkers, 9 presented with at least one feature of metabolic syndrome (of whom 4 were also excessive drinkers), and 1 was infected with human immunodeficiency virus. This could suggest, despite the absence of statistical significance in the current series, that alcohol consumption and development of metabolic abnormalities may impair regression of fibrosis in treated GH patients, as recently pointed out by Powell et al 34 The current data as well as those from Powell et al 35 show that fibrosis in the absence of cirrhosis may regress along venesection therapy in a large number of hemochromatotic patients. However, the question of the complete reversal of cirrhosis, which is clinically and basically relevant, remains debated.…”

Impact of hemochromatosis screening in patients with indeterminate results: The hemochromatosis and iron overload screening study

“…10 Survival is dependent on the prevalence of cirrhosis which is low in population screening studies (1-4%) 11,12 but as high as 15% in referred patients. 13,14 Patients with cirrhosis have a 5.5-fold relative risk of death compared to the noncirrhotic hemochromatosis patients. 15,16 HH can cause other complications such as primary liver cancer, diabetes mellitus or other endocrinopathy, arthropathy, cardiomyopathy, and reduced longevity, 17,18 but timely treatment can prevent many of these complications.…”