Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is the largest cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is not certain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore we performed a systematic review and meta-analysis to seek evidence for significant associations. Methods: MEDLINE, Embase and Web of Science databases were searched from 1st January 2000 to 24th June 2020 for English studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection. We extracted data for meta-analysis and report pooled effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present. Results: We identified 40 observational studies reporting on associations of diabetes mellitus, hypertension, dyslipiaemia and obesity with HCC risk. Meta-analysis was possible for only diabetes mellitus due to the limited number of studies. Diabetes mellitus was associated with >25% increase in hazards of HCC (fixed effects Hazards Ratio [HR] 1.26, 95% CI 1.20-1.32, random effects HR 1.36, 95% CI 1.23-1.49). This association was attenuated towards the null in sensitivity analysis restricted to studies adjusted for metformin use. Conclusions: In adults with chronic HBV infection, diabetes mellitus is a significant risk factor for HCC, but further investigation of how antidiabetic drug use and glycaemic control influence this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.

Hepatitis B virus–induced hepatocarcinogenesis: A virological and oncological perspective

“…Other factors could not be evaluated by meta-analysis, but based on the studies evaluated, the effects of hypertension or dyslipidaemia on HCC risk are not relevant. 54 In conclusion, the relationship between hepatitis B virus and HCC is a controversial issue that has not been fully elucidated yet, apart from their epidemiological correlation. Many metabolic pathways seem to be affected by HBV replication, but further investigations to establish a clear relationship between viral replication and HCC occurrence are needed, also in light of antivirals therapies currently available.…”

“…Based on the results reported by the authors, only DM could be investigated by meta‐analysis and was associated with a 25% increase in terms of risk, when the effect of metformin was not included in the analysis. Other factors could not be evaluated by meta‐analysis, but based on the studies evaluated, the effects of hypertension or dyslipidaemia on HCC risk are not relevant 54 …”

Cohort Profile: National Institute for Health Research Health Informatics Collaborative: Hepatitis B Virus (NIHR HIC HBV) Research Dataset

“…As the prevalence of HBV infection is low across the United Kingdom (UK) overall, there are limited data describing population characteristics and disease burden (5, 6). Chronic HBV (CHB) nevertheless presents a concern in certain populations, either as a result of increased prevalence, and/or risk factors for the development of long-term liver disease (e.g., chronic coinfection with HIV (7) or other hepatitis viruses (8, 9), diabetes mellitus or metabolic syndrome (10, 11), alcohol abuse (11), migrants from countries/regions with a high prevalence of HBV (12, 13)). Chronic infection can lead to pathology which has a major impact on quality of life and life expectancy, including cirrhosis, end-stage-liver failure, and hepatocellular carcinoma (HCC).…”

Effects of genetic polymorphisms in INTS10 and their interaction with environmental factors on progression from persistent HBV infection to hepatocellular carcinoma

“…However, the clinical course of HBV infection greatly differs among individuals, and only a fraction of persistent HBV‐infected persons would develop HCC in their lifespan. Driving forces in hepatocyte transformation and tumor development involve the interaction of virus, environmental factors, and host genetic factors 5,6 . The genetic mechanisms underlying development of HCC from persistent HBV infection have a critical preparedness against HBV‐related HCC.…”