PNPLA3, Obesity, and Heavy Alcohol Use in Cirrhosis Patients May Exert a Synergistic Increase Hepatocellular Carcinoma Risk

Background & Aims In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors. Methods We analyzed data from 1911 patients in two multicenter prospective cohort studies in the U.S. We classified patients according to alcohol consumption (current heavy vs. not current heavy), obesity (body mass index [BMI] ≥30 vs. <30), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs. noncarrier). We examined the independent and joint effects of these risk factors on risk of developing HCC using Cox regression with competing risks. Results Mean age was 59.6y, 64.3% male, 28.7% Hispanic, 18.3% non-Hispanic Black, 50.9% were obese, 6.2% had current heavy alcohol consumption, and 58.4% harbored at least one PNPLA3 G-allele. 116 patients developed HCC. Compared to PNPLA3 noncarriers without heavy alcohol consumption, HCC risk was 2.65-fold higher (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.20-5.86) for carriers who had current heavy alcohol consumption. Compared to noncarrier patients without obesity, HCC risk was higher (HR, 2.40; 95%CI, 1.33-4.31) for carrier patients who were obese. PNPLA3 and alcohol consumption effect was stronger among patients with viral etiology of cirrhosis (HR, 3.42; 95% CI, 1.31-8.90). PNPLA3 improved 1-year risk prediction for HCC when added to a clinical risk model. Conclusions The PNPLA3 variant may help refine risk stratification for HCC in patients with cirrhosis with heavy alcohol consumption or obesity who may need specific preventive measures.