Hepatic Iron Overload: Direct HLA-HMutation AnalysisvsQuantitative Iron Assays for the Diagnosis of Hereditary Hemochromatosis

Abstract

Among patients with hepatic iron overload, the distinction between hereditary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discovery of a specific homozygous mutation (C282Y) in a novel major histocompatibility complex class I-like gene (named HLA-H or HFE) in 80% to 100% of well-characterized cases of HH suggests that direct DNA-based mutation analysis may help resolve this dilemma. To assess the clinical utility of direct HLA-H mutation analysis in a typical diagnostic setting, we measured genotypic and phenotypic parameters of iron overload in 37 subjects with biopsy-proven hepatic siderosis (2+ or greater) and in 127 healthy control subjects. The prevalence of C282Y homozygotes was significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozygous mutation and hepatic iron overload. In the hepatic siderosis group, C282Y homozygotes had significantly higher hepatic iron and ferritin levels, a significantly lower prevalence of hepatitis C virus or alcoholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HII) in the previously defined "hemochromatosis range" (>1.9), 9 (45%) were C282Y homozygotes. Of the 11 nonhomozygous subjects with an HII greater than 1.9 (presumed false-positive HIIs), 10 (91%) had hepatic cirrhosis compared with 3 of 9 (33%) homozygotes with an HII greater than 1.9 who had cirrhosis (P<.02). The HII thus has poor diagnostic specificity for predicting genotypic HH in patients with cirrhosis. We conclude that direct determination of the HLA-H C282Y genotype may be the single best diagnostic test for HH, particularly in patients with cirrhosis, for whom the HII is quite nonspecific.

A retrospective anonymous pilot study in screening newborns forHFE mutations in Scandinavian populations

“…There is currently considerable debate concerning how and when to screen for GH [Bassett et al, 1997;Adams, 1998;Brissot et al, 1998;Edwards et al, 1998;Press et al, 1998]. There have been observations of nonexpressing C282Y homozygotes [Rhodes et al, 1997;Crawford et al, 1998].…”

Hepatic Iron Overload in the Age of Hereditary Hemochromatosis Mutation Analysis

“…1 Distinguishing hereditary hemochromatosis (HH) from other causes of liver iron deposition and cirrhosis has important implications for the treatment of the individual patient and for advising the patient's family of their risk of iron overload. In this issue of the Journal, Press et al 2 examine cases of hepatic siderosis for the presence of a mutation commonly seen in patients with H H and compare the results of this DNA-based test to those of conventional iron studies in the diagnosis of H H in this selected population. The advent of a molecular diagnostic test for HH has been a long time coming.…”