Risk of Hepatocellular Carcinoma in Patients with Various HFE Genotypes

Background and aims: Hereditary hemochromatosis (HH) is associated with increased risk of hepatocellular carcinoma (HCC). However, HCC risk factors within this population and across various HFE genotypes remain unclear.

Methods: We conducted a retrospective cohort study of patients with ≥ 1 HFE genotype test in the Veterans Health Administration. We followed patients until HCC, death, or 6/30/19. We calculated incidence rates (IRs) and used Cox proportional hazards models to estimate HCC risk. In patients with type-1 HH genotypes (C282Y/C282Y or C282Y/H63D), we examined risk factors for HCC.

Results: We identified 5225 patients: 260 were C282Y/C282Y; 227 were C282Y/H63D; 436 were H63D heterozygous; 535 had other HFE mutations; 3767 without mutation. IR for C282Y/C282Y homozygotes (5.59/1000 PYs) and C282Y/H63D compound heterozygotes (4.12/1000 PYs) were significantly higher than controls (0.92/1000 PYs) with adjusted hazard ratio (adj HR), 95% CI 8.80, 4.17-18.54; and 5.25, 2.24-12.32, respectively. HCC risk was higher in H63D heterozygote than controls (adj HR = 2.82, 95% CI 1.21-6.58); cases were related to non-alcoholic fatty liver disease. Among patients with HH, age ≥ 65 (adj HR = 2.2, 95% CI 0.47-10.27), diabetes (adj HR 3.74, 95% CI 1.25-11.20) and high baseline aspartate-aminotransferase to platelet ratio-index (APRI, adj HR = 3.91, 95% CI 1.29-11.89) had higher risk. Among patients with high baseline ferritin, persistent ferritin > 250 ng/mL had higher risk.

Conclusion: HCC risk was high in C282Y homozygous and C282Y/H63D patients. These HFE genotypes, older age, diabetes, high APRI/ferritin levels were associated with increased risk. While H63D heterozygous genotype was associated with HCC risk, this association might be due to metabolic factors.