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

Disclosures

J Viral Hepat. 2021;28(3):493-507. 

In This Article

Discussion

Our meta-analysis suggests that DM is a risk factor for HCC in CHB-infected individuals, with hazards of HCC substantially higher in the presence of DM; however, we report significant between-study heterogeneity. This association did not materially change after restriction to studies adjusting for relevant confounders, but did suggest a favourable impact of DM treatment with metformin. Pooled effect estimates remained significant in sensitivity analyses. Few studies investigated other comorbidities, and some comorbidity search terms included in our systematic literature search returned few or no results. This highlights the need for future investigation of these comorbidities, as antiviral treatment cannot eliminate the risk of HCC entirely and therefore significant risk factors must be identified in order to inform interventions. Although EASL[10] and APASL[24] guidelines recognize this association, it does not inform surveillance, and is not currently consistently described in other recommendations (eg AASLD guidelines[23] do not list DM as a risk factor for HCC).

Some studies investigating comorbidities and their metabolic risk factors, specifically dyslipidaemia, reported significantly reduced hazards of HCC in participants with these conditions compared to those without. This finding was unexpected, and observed associations may be confounded by statin use, as only two of the seven studies reporting significantly reduced hazards of HCC associated with dyslipidaemia adjusted for statin use. Alternatively, CHB treatment in secondary care may be confounding the analysis, with CHB-infected individuals receiving treatment and HCC screening being potentially more likely to have comorbid dyslipidaemia diagnosed. However, further investigation of this association is warranted to minimize the influence of confounding factors.

Findings from case-control and cohort studies were not consistent; while the majority of cohort studies reported increased hazards of HCC associated with DM, case-control findings were inconsistent, and indeed three studies reported a significant reduction of HCC risk in association with DM. Explanations for such findings include confounding, selection bias associated with the study of hospital control groups that enrich for DM,[31,32] and chance, especially in small studies.[31–34]

Our findings are consistent with a previous meta-analysis;[35] we provide a comprehensive review of all cohort studies and include a larger number of studies. We restricted our analysis to studies reporting HRs minimally adjusted for age and sex. However, adjustment for covariates and inclusion criteria varied considerably between studies, and this may explain some of the between-study heterogeneity. Substantial heterogeneity remained in sensitivity analyses restricted to studies adjusting for additional key confounders, as adjustment for confounders was variable within these studies and populations may not have been comparable. Although baseline age and sex characteristics were comparable across studies, there was variability regarding exclusion of those with additional comorbidities and those on antiviral treatment.

We noted variable definitions of DM, with some studies restricting investigation to type 2 DM, whereas others included participants with unspecified DM. Risk factors for types 1 and 2 diabetes mellitus vary, and heterogeneity in DM definitions could therefore contribute to variable study populations and outcomes. Global prevalence and incidence estimates for specific DM types do not exist, as distinguishing between types often requires expensive laboratory resources that are not available in many settings. However, most cases of type 1 DM are found in Europe and North America, and the large majority of studies included in this systematic review and meta-analysis were conducted in Asian countries.[36]

Although HRs did not significantly vary with length of follow-up in sensitivity analysis, it is possible that variable lengths of follow-up also contributed to between-study heterogeneity. Generally, cancer is a chronic disease with a slow development, and preclinical disease can be present for many years before clinical manifestation; follow-up periods <10 years may be insufficient to detect HCC outcomes. We were unable to provide effect estimates across most potential patient subgroups because the subgroups contained small numbers of studies, putting subgroup analyses at greater risk of chance findings as well as being subject to the influence of multiple testing.

The association of DM with HCC we report in this meta-analysis is weaker than those observed in patients with chronic HCV infection. In studies of individuals with chronic HCV infection, risk of HCC was elevated ~twofold in the presence of DM.[37,38] Previous studies also report increased risks of DM in HCV-infected individuals as compared to noninfected individuals.[39–42] However, this may be due to the various extra-hepatic manifestations of HCV which are not so clearly associated in HBV infection.[43,44]

In sensitivity analysis restricted to studies adjusting for cirrhosis, the observed association of DM with HCC was attenuated towards the null. This may be explained by a confounding of the association by cirrhosis, accounted for by an independent association of cirrhosis with both DM and HCC, and the absence of cirrhosis from the causal pathway that associates DM with HCC. However, if cirrhosis is located along this causal pathway, then it can be characterized as a mediator rather than a confounder. If cirrhosis is a mediator, then adjusting for it would be incorrect.

Past studies support a positive association of DM with HCC risk in non-CHB patients,[6,7,45] and aetiological investigation has suggested that DM can lead to cirrhosis and thereby HCC via fatty liver disease,[46] as a result of accumulation of fatty acids causing oxidative stress driving inflammation and tissue necrosis,[47,48] and longer-term fibrosis and cirrhosis, thereby increasing HCC risk. However, alternative pathways causally associating DM with HCC have been suggested, including increased hepatocyte proliferation induced by hyperinsulinaemia[49,50] and production of pro-inflammatory cytokines that increase cell survival via apoptosis inhibition.[51–53] It is possible that multiple disease pathways associating DM with HCC operate simultaneously. Elucidation of the aetiological mechanisms underpinning this association will inform future epidemiological studies and disease management. Characterizing the impact of glycaemic control on HCC risk is also an important question for future research.

Three studies adjusted for metformin use,[54–56] and in sensitivity analysis restricted to these studies, the association between DM and HCC remained significant but was attenuated towards the null. It is not known the extent to which this is a result of glucoregulation by metformin, accomplished by inhibition of hepatic gluconeogenesis and improvement of insulin sensitivity in tissues leading to reduced oxidative stress in the liver,[57] and/or a direct impact of metformin in reducing cancer risk via regulation of cellular signalling. Evidence from observational studies[58–60] and randomized controlled trials (RCTs)[61] supports a protective effect of metformin against the development and progression of cancer in diabetic individuals. There is also some RCT evidence for protective effects of metformin against progression of certain cancer types in nondiabetic individuals[62] although this is not consistent. Multiple large-scale phase III RCTs are currently underway[63–66] and will provide further information regarding the roles of DM and metformin in cancer development.

We included all studies investigating the association of comorbidities with risk of CHB progression to HCC that minimally adjusted for age and sex in order to provide a comprehensive review of available evidence. However, few studies investigated non-DM comorbidities, preventing meta-analysis for these comorbidities. Additionally, we were unable to restrict our meta-analysis of DM and HCC to studies adjusting for further confounders in addition to age and sex, as few studies minimally adjusted for all relevant factors. Publication bias may influence the outcome, as we restricted our search to the peer-reviewed English-language literature, and studies that do not report an association of DM with HCC may be less likely to be published. Our results may not be generalizable to the global CHB population, as there were a limited number of studies from non-Asian countries. The lack of studies from any African countries is of concern, given that the region carries both the highest HBV prevalence[67] and largest mortality burdens for cirrhosis and HCC.[68,69]

Our finding that DM is a risk factor for HCC in CHB-infected individuals suggests that enhanced cancer surveillance may be justified in patients with CHB and DM to enable early detection and treatment. Improvements in guidelines could help to inform more consistent approaches to risk reduction. After adjustment for metformin use, this association remained significant but was attenuated, suggesting a potential benefit of metformin that warrants further study. Ongoing investigation is required in order to identify and characterize risk factors for HCC, to extend these analyses to diverse global populations and to elucidate disease mechanisms in order to inform prevention, screening and therapeutic intervention.

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