Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the hemochromatosis and iron overload screening study

Abstract

Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE (High Iron) 282 Cys → Tyr (C282Y) homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload resulting from hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99,711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and HFE genotyping. In this HEIRS substudy, serum hepatic transaminases activities (e.g., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) were compared between 162 C282Y homozygotes and 1,367 nonhomozygotes with serum ferritin levels >300 μg/L in men and >200 μg/L in women and transferrin saturation >45% in women and 50% in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges. Mean ALT and AST activities were significantly lower in C282Y homozygotes than nonhomozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased.

Conclusion: Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics.

Figure 1A

Serum alanine transaminase (ALT) in male C282Y homozygotes (●) (r=0.44, p < .0001) and non-homozygotes ( ○ )(r = 0.22, p < .0001). Data displayed are excerpted from observations in participants with a serum ferritin < 1000 μg/L and ALT < 300 IU/L. The solid line represents the upper limit of the reference range (40 IU/L). The numbers above the bar represent the number of participants in each group.

Figure 1B

Serum alanine transaminase (ALT) in female C282Y homozygotes (●)(r = 0.63, p < .0001) and non-homozygotes ( ○ )(r = 0.31, p < .0001). Data displayed are excerpted from observations in participants with a serum ferritin < 1000 μg/L and ALT < 300 IU/L. The solid line represents the upper limit of the reference range (40 IU/L). The numbers above the bar represent the number of participants in each group.

Figure 2

The probability of being a C282Y homozygotes in 6 groups according to serum alanine transaminase (ALT) in men( ■ ) and women (□ ) . Chi-square test for linear test for trend in proportions was 0.036 in men and 0.00017 in women.