Risk factors for hepatocellular carcinoma: an umbrella review of systematic review and meta-analysis

Abstract

Background: Numerous meta-analyses have identified various risk factors for hepatocellular carcinoma (HCC), prompting a comprehensive study to synthesize evidence quality and strength.

Methods: This umbrella review of meta-analyses was conducted throughout PubMed, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews. Evidence strength was evaluated according to the evidence categories criteria.

Results: We identified 101 risk factors throughout 175 meta-analyses. 31 risk factors were classified as evidence levels of class I, II, or III. HBV and HCV infections increase HCC risk by 12.5-fold and 11.2-fold, respectively. These risks are moderated by antiviral treatments and virological responses but are exacerbated by higher HBsAg levels, anti-HBc positivity, and co-infection. Smoking, obesity, non-alcoholic fatty liver disease, diabetes, low platelet, elevated liver enzymes and liver fluke infection increase HCC risk, while coffee consumption, a healthy diet, and bariatric surgery lower it. Medications like metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), aspirin, statins, and selective serotonin reuptake inhibitors reduce HCC risk, while acid suppressive agents, particularly proton pump inhibitors, elevate it. Blood type O reduces the risk of HCC, while male gender and older age increase the risk.

Conclusions: HBV and HCV are major HCC risk factors, with risk mitigation through antiviral treatments. Lifestyle habits such as smoking and alcohol use significantly increase HCC risk, highlighting the importance of cessation. Certain drugs like aspirin, statins, GLP-1 RAs, and metformin may reduce HCC occurrence, but further research is needed to confirm these effects.

Keywords: Hepatocellular carcinoma; incidence; risk factor; umbrella review.

Figure 1.

Flowchart of systematic search and selection process.

Figure 2.

Associations between virus-related risk factors (Class I, Class II, and Class III) and hepatocellular carcinoma incidence. CI, confidence interval; T, total No. of studies; R, randomized controlled trials; C, cohort studies; P, population-based case-control and/or cross-sectional studies; AMSTAR, a measurement tool to assess systematic reviews; anti-HBc, Hepatitis B core antibody; HCV, Hepatitis C virus; HBsAg, Hepatitis B surface antigen; HBV, Hepatitis B virus; NA, not available; *, the data was the result of the original data divided by 10.

Figure 3.

Associations between non-virus-related risk factors (Class I, Class II, and Class III) and hepatocellular carcinoma incidence. CI, confidence interval; T, total No. of studies; R, randomized controlled trials; C, cohort studies; P, population-based case-control and/or cross-sectional studies; AMSTAR, a measurement tool to assess systematic reviews; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; NAFLD, non-alcoholic fatty liver disease; PPI, proton pump inhibitor; NA, not available.