HEPATIC IRON OVERLOAD - DIRECT HFE (HLA-H) MUTATION ANALYSIS VS QUANTITATIVE IRON ASSAYS FOR THE DIAGNOSIS OF HEREDITARY HEMOCHROMATOSIS

Among patients with hepatic iron overload, the distinction between her editary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discover y of a specific homozygous mutation (C282Y) in a novel major histocomp atibility 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 mut ation analysis may help resolve this dilemma. To assess the clinical u tility of direct HU-H mutation analysis in a typical diagnostic settin g, 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 w as significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozy gous mutation and hepatic iron overload. In the hepatic siderosis grou p, C282Y homozygotes had significantly higher hepatic iron and ferriti n levels, a significantly lower prevalence of hepatitis C virus or alc oholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HI I) 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 t han 1.9 who had cirrhosis (P<.02). The HII thus has poor diagnostic sp ecificity for predicting genotypic HH in patients with cirrhosis. We c onclude that direct determination of the HLA-H C282Y genotype may be t he single best diagnostic test for HH, particularly in patients with c irrhosis, for whom the HII is quite nonspecific.