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


Study Characteristics

In total, our search identified 1,814 articles (899 from MEDLINE, 407 from EMBASE and 508 from Web of Science) (Figure 1). After deduplication, 1136 individual articles were screened by title/abstract, from which 140 full texts were identified for full-text assessment. After exclusion of ineligible articles and reference list searching of relevant articles, 40 articles were identified for inclusion in this review. Summary characteristics of included studies are reported in Table S2.

Figure 1.

Flow chart of study selection. MEDLINE, EMBASE and Web of Science databases were systematically searched using relevant terms to identify relevant human studies published in English from 1 January 2000 to 24 June 2020

All studies were observational in design, with 33 cohort and seven case-control studies included (Table S2). Thirty-two studies were conducted in Asian countries. Four studies were restricted to male cohorts, and 36 were undertaken in mixed-sex cohorts. All studies recruited participants from health centres, health care or prescription databases, or pre-existing cohorts or cancer screening programmes. All studies were undertaken in adults, with mean/median ages of cohorts ranging between 40 and 65 years in 33 studies. Thirty-three studies investigated DM/insulin resistance/fasting serum glucose, 11 investigated blood hypertension/blood pressure, seven investigated dyslipidaemia, five investigated obesity and cardiovascular disease. Fewer than five studies investigated other factors including renal disease, statin use and use of antidiabetic drugs.

In the 40 studies including 536,456 adults, >30,500 HCC events occurred (we are unable to report an exact number, because one study did not report a precise number of HCC cases[30]). Sample sizes of cohort studies varied widely, ranging from 102 to 214,167 (median 3090), with corresponding numbers of HCC cases ranging from seven (arising among 102 participants) to 11,241 (arising among 214,167 participants). Case-control sample sizes ranged from 182 to 6275 (median 1122) with corresponding numbers of HCC cases ranging from 73 (out of 182 participants) and 1105 (out of 6275 participants).

Quality Assessment

Among 40 studies, 39 had quality scores ≥5 (Tables S3 and S4). All 33 cohort studies were of sufficient quality with 13 of these being scored as high quality. Six out of seven case-control studies were of sufficient quality and one of poor quality. Inclusion criteria varied widely, and therefore, study populations were heterogeneous. In most studies, exposures and outcomes were ascertained using health assessment, imaging or record linkage. Twenty-three cohort studies and seven case-control studies accounted for age and sex. HCC typically arises after long durations of infection, and therefore, prolonged follow-ups enable the detection of more HCC events; among 23 cohort studies identified, only five cohort studies had lengths of follow-up ≥10 years.

Association of Diabetes Mellitus With HCC Risk

Thirty-six studies investigated the association of DM with risk of CHB progression to HCC, comprising seven case-control studies (Table 1a) and 29 cohort studies (Table 1b). Four studies were restricted to males and the others included both sexes (Table S2). Mean ages at baseline in all studies were ≥40 years, respectively. Study populations were heterogeneous with variable inclusion criteria, and definitions of DM were not consistent between studies. Four case-control and four cohort studies investigated type 2 DM/insulin resistance, three case-control and seven cohort studies investigated unspecified DM, and one case-control and three cohort studies investigated both type 1 and 2 DM as a composite potential risk factor.

Among the seven case-control studies that reported effect estimates there was directional inconsistency between effect estimates, with four studies reporting an increased risk of HCC in those with DM as compared to those without, three studies reporting a decreased risk of HCC in those with DM, and one study failing to provide an effect estimate. Odds ratios (ORs) and HRs >1 ranged from 1.35 to 2.04 and all were statistically significant. RRs <1 ranged from 0.19 to 0.80, of which two were statistically significant. Among 28 cohort studies providing effect estimates (27 HRs and 1 OR), there was directional consistency with 27 of the reported RRs >1. Effect sizes >1 ranged from 1.05 to 6.80, with 15 RRs being statistically significant. The single RR that was <1 was nonsignificant.

Minimal adjustment for confounders differed between case-control and cohort studies. Most case-control studies adjusted for age, sex, HCV coinfection, HIV coinfection and cirrhosis. Twenty cohort studies minimally adjusted for age and sex. Of these, 15 adjusted for HCV coinfection, 13 for cirrhosis, 12 for antiviral treatment, 10 for HIV coinfection, 9 for alcohol consumption, seven each for HBV viral DNA load and cigarette smoking and 6 for other liver disease (including alcoholic liver disease). Eight studies excluded participants who developed HCC within the first 3 to 12 months of follow-up in their main analyses. One study did so in a sensitivity analysis and found this did not modify associations observed.

Meta-analysis of Cohort Studies

DM was associated with increased hazards of progression to HCC by meta-analysis restricted to HRs minimally adjusted for age and sex (Figure 2). As there was significant heterogeneity (I 2 = 52%, p < 0.01), results from both fixed- and random-effects analyses are presented. In random-effects analysis, the hazards of HCC were 36% higher (summary HR 1.36; 95% CI 1.23–1.49) in those with DM as compared to those without DM.

Figure 2.

Forest plot of hazard ratios from longitudinal cohort studies investigating the association of diabetes mellitus with risk of progression of chronic hepatitis B infection to hepatocellular carcinoma (HCC). All studies included in meta-analysis were cohort or nested case-control studies reporting hazards ratios minimally adjusted for age and sex. The study by Yu et al 96 provided an odds ratio and was excluded from the meta-analysis. Dashed vertical lines represent HR based on meta-analysis of all studies by fixed-effect and random-effects models. The studies for pooling the HR had sufficient quality (quality scores ≥5). CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio

Subgroup and Sensitivity Analyses

We performed sensitivity analyses in order to investigate the robustness of pooled estimates to additional adjustment for HCV or HIV coinfection, cirrhosis and DM treatment. After restricting meta-analysis to 16 studies adjusting for HCV coinfection in addition to age and sex (Figure S1), pooled HRs did not change materially. Considering eight studies adjusting for HIV and antiviral treatment (Figure S2), pooled HR from the fixed-effects analysis was attenuated towards the null but remained significant. To investigate the robustness of the association of DM with HCC to adjustment for cirrhosis, a potential mediator, we restricted meta-analysis to studies adjusting for cirrhosis (Figure S3). This did not change pooled HRs materially.

To investigate heterogeneity between type 2 DM and unspecified DM, sensitivity analysis was performed whereby studies were stratified by DM type. Among studies investigating type 2 DM, heterogeneity was 33% (p = 0.18) (Figure S4). However, this HR did not differ substantially to that observed in the primary meta-analysis.

The association of DM with increased HCC risk was attenuated towards the null in studies that adjusted for metformin use, with risk of HCC 16% higher in DM participants as compared to non-DM (random-effects HR 1.16, 95% CI 1.04–1.29) in analysis restricted to studies adjusting for metformin use (Figure S5). After restricting to studies adjusting to DM treatment, pooled HRs remained statistically significant.

Association of Hypertension With Hepatocellular Carcinoma Risk

Eleven studies investigated the association of HT with risk of CHB progression to HCC, one case-control study and 10 cohort studies (Table 2). All studies were mixed-sex samples in which mean/median age at baseline was ≥40 years (Table S2). Definitions of HT were heterogeneous; most studies ascertained hypertension via record linkage, but others used health assessment or interview. Few studies defined clinical thresholds for hypertension classification. 'Higher' MAP was the primary exposure of interest in the case-control study, for which a threshold was not defined.

Among 10 studies reporting hazards of HCC associated with HT, only four HRs were minimally adjusted for age and sex. Out of three studies which reported significantly increased hazards of HCC associated with HT, two reported unadjusted HRs and one reported a HR adjusted for age and not sex. Another five studies reported an effect in the same direction, but effect sizes were not statistically significant. Adjusted HRs >1 ranged from 1.19 to 1.70 and <1 from 0.04 to 0.96. Adjustment for confounders was poor, with only four HRs minimally adjusted for age and sex.

Associations of Other Comorbidities With Hepatocellular Carcinoma Risk

Seven studies investigated the association of dyslipidaemia with HCC risk in CHB patients (Table 3). All studies reported reduced risks of HCC in participants with dyslipidaemia as compared to those without; however, only one HR was statistically significant. Clinical definitions of dyslipidaemia were often not reported, and only four studies minimally adjusted for age and sex. Six studies investigated the association of obesity with HCC risk. Clinical definitions of obesity varied greatly, and out of four studies reporting increased risks of HCC with obesity, only one HR was statistically significant.

Three studies investigated the association of statin use with HCC risk in CHB. All studies reported HRs <1, and two of these HRs were statistically significant. HRs reported in five studies for HCC risk associated with CVD varied, likely due to the variable definitions of CVD used across studies. Associations for other variables, including respiratory disease and renal disease, were reported by ≤2 studies each.