Incidence of liver complications with hemochromatosis-associated HFE p.C282Y homozygosity: The role of central adiposity.

BACKGROUND AND AIMS

The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but the combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort.

APPROACH AND RESULTS

Baseline WHR data available in 1297 male and 1602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient-diagnosed liver fibrosis/cirrhosis ( p = 2.4 × 10 -5 ), liver cancer ( p = 0.007), non-alcoholic fatty liver disease ( p = 7.7 × 10 -11 ), and type 2 diabetes ( p = 5.1 × 10 -16 ). The hazard ratio for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was 4.13 for liver fibrosis/cirrhosis (95% CI: 2.04-8.39, p = 8.4 × 10 -5 vs. normal WHR); cumulative age 80 incidence 15.0% (95% CI: 9.8%-22.6%) versus 3.9% (95% CI: 1.9%-7.6%); for liver cancer, cumulative incidence was 9.2% (95% CI: 5.7%-14.6%) versus 3.6% (95% CI: 1.9%-6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (hazard ratio = 9.17, 95% CI: 2.51-33.50, p = 3.8 × 10 -7 ) and Non-alcoholic fatty liver disease (hazard ratio = 5.17, 95% CI: 2.48-10.78, p = 1.2 × 10 -5 ). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses.

CONCLUSIONS

In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.