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

Authors

Aaron P Thrift
Fasiha Kanwal
Hyeyeun Lim
Hao Duong
Yanhong Liu
Amit G Singal
Saira Khaderi
Sumeet K Asrani
Christopher I Amos
Hashem B El-Serag

Publication Date

9-1-2024

Journal

Clinical Gastroenterology and Hepatology

DOI

10.1016/j.cgh.2024.04.006

PMID

38729396

PMCID

PMC11615715

PubMedCentral® Posted Date

12-4-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Male, Middle Aged, Carcinoma, Hepatocellular, Female, Liver Neoplasms, Lipase, Membrane Proteins, Obesity, Prospective Studies, Liver Cirrhosis, Aged, United States, Risk Factors, Alcohol Drinking, Risk Assessment, Genetic Predisposition to Disease, Acyltransferases, Phospholipases A2, Calcium-Independent

Abstract

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 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs/m2), 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 59.6 years, 64.3% were male, 28.7% were Hispanic, 18.3% were non-Hispanic Black, 50.9% were obese, 6.2% had current heavy alcohol consumption, and 58.4% harbored at least 1 PNPLA3 G-allele. One hundred sixteen patients developed HCC. Compared with 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 with 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.

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