Risk Factors for the Development of Hepatocellular Carcinoma (HCC) in Chronic Hepatitis B Virus (HBV) Infection

A Systematic Review and Meta-analysis

Cori Campbell; Tingyan Wang; Anna L. McNaughton; Eleanor Barnes; Philippa C. Matthews


J Viral Hepat. 2021;28(3):493-507. 

In This Article

Abstract and Introduction


Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is a leading cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is uncertain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore, we performed a systematic literature review and meta-analysis to seek evidence for significant associations. MEDLINE, EMBASE and Web of Science databases were searched from 1 January 2000 to 24 June 2020 for studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection, written in English. We extracted data for meta-analysis and generated pooled effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present. We identified 40 observational studies reporting on associations of diabetes mellitus (DM), hypertension, dyslipidaemia and obesity with HCC risk. Only DM had a sufficient number of studies for meta-analysis. DM was associated with >25% increase in hazards of HCC (fixed-effects hazards ratio [HR] 1.26, 95% confidence interval (CI) 1.20–1.32, random-effects HR 1.36, 95% CI 1.23–1.49). This association was attenuated towards the null in a sensitivity analysis restricted to studies adjusted for metformin use. In conclusion, in adults with chronic HBV infection, DM is a significant risk factor for HCC, but further investigation of the influence of antidiabetic drug use and glycaemic control on this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.


Hepatitis B virus (HBV) is a hepatotropic virus responsible for substantial morbidity and mortality worldwide. Infection can be acute or chronic, with most of the HBV disease burden attributable to chronic disease. The World Health Organization (WHO) estimated a chronic HBV (CHB) global burden of 257 million CHB-infected individuals for 2015, with 887,000 HBV-attributable deaths reported in the same year,[1] making HBV one of the leading causes of morbidity and mortality from viral infection, for which the burden has increased in recent decades.[2]

CHB deathsdue to primary liver cancer and cirrhosis account for the majority of deaths attributable to viral hepatitis. A Global Burden of Disease study on the global hepatocellular carcinoma (HCC) burden reported a 42% increase in incident cases of HCC attributable to CHB infection between 1990 and 2015,[3] among which CHB infection was the largest contributor, responsible for more than 30% of incident cases in 2015.[3]

Multiple risk factors for HCC in CHB-infected individuals have been established, including sex, age, cirrhosis and co-infection with human immunodeficiency virus (HIV) or other hepatitis viruses (including hepatitis C and D). Previous studies have investigated associations of comorbidities, such as diabetes mellitus (DM)[4–7] and hypertension,[8,9] with risk of HCC in the general population, and The European Association for the Study of the Liver (EASL) recognizes DM as a risk factor for HCC in CHB.[10] As the global prevalence of comorbidities such as DM,[11] renal disease,[12] hypertension[13] and coronary heart disease (CHD)[14] continues to rise, these conditions are increasingly relevant to the development of HCC.

Various risk scores have been developed to predict HCC risk: the PAGE-B risk score was developed to predict HCC risk in Caucasian patients on antiviral treatment,[15] while the REACH-B,[16,17] GAG-HCC[18,19] and CU-HCC[18,20–22] risk scores apply to untreated Asian populations. Existing risk scores use age, sex and HBV DNA viral load (VL) to predict risk. CU-HCC and GAG-HCC include parameters for cirrhosis; however, no score accounts for comorbidities such as DM or hypertension. It is possible that risk prediction could be improved by incorporating these comorbid conditions.

Despite rises in the global prevalence of relevant comorbidities, evidence concerning associations of comorbidities with HCC risk in CHB is poor and heterogeneous. Neither EASL, the American Association of the Study of Liver Disease (AASLD)[23] nor the Asian Pacific Association for the Study of the Liver (APASL)[24] guidelines for HBV management include recommendations for enhanced screening or DM management in CHB, despite recent clinical interest in the potential utility of metformin in preventing and treating various cancers.[25,26] Furthermore, there are few studies investigating associations of other potentially relevant comorbidities (such as hypertension, CHD and renal disease) and their metabolic risk factors (such as obesity and dyslipidaemia) with HCC risk. Therefore, we undertook a systematic review, aiming to summarize and critically appraise studies investigating associations of relevant comorbidities and metabolic factors with risk of HCC in CHB-infected individuals.