Diabetes Poses a Higher Risk of Hepatocellular Carcinoma and Mortality in Patients With Chronic Hepatitis B

A Population-based Cohort Study

Yu-Chiau Shyu; Ting-Shuo Huang; Cheng-Hung Chien; Chau-Ting Yeh; Chih-Lang Lin; Rong-Nan Chien


J Viral Hepat. 2019;26(6):718-726. 

In This Article

Abstract and Introduction


Diabetes mellitus may be a risk factor of HCC development in chronic hepatitis B infected patients and affect the all-cause mortality. This study aimed to examine whether DM was associated with the development of HCC with CHB and affected the all-cause mortality. A total of 2966 CHB patients newly diagnosed with DM in 2000 were retrieved from the Longitudinal Cohort of Diabetes Patients database and used propensity scores matching based on age, sex-gender, alcohol-related liver disease and baseline liver cirrhosis to compare with the non-DM patients from the Taiwanese National Health Insurance Research Database. The CHB patients with DM compared to the non-DM had significantly increased (3.3%) risk for HCC development and significantly increased (2.8%) risk of HCC-related mortality. Interestingly, the all-cause mortality was significantly higher in the DM cohort (16.9%) compared to the non-DM cohort (8.2%). In a multivariable transition-specific Cox model to investigate the adjusted hazard ratio of CHB patients with DM or non-DM during the transitions from start to HCC was 1.35; 95% CI (1.16-1.57) and from HCC to death was 1.31; 95% CI (1.06-1.62). All-cause mortality between CHB patients with DM or non-DM during the transitions from start to death was 2.32; 95% CI (1.84-2.92). Taken together, DM is an independent risk factor associated with increasing disease development of HCC, HCC-related mortality and all-cause mortality in CHB patients. This study may provide a clinical strategy for strict DM control in order to reduce the risk of disease development in CHB patients.


Chronic hepatitis B virus infection (CHB) is a major health problem that affects approximately 400 million people worldwide, more than 5% of the global population.[1] Patients with CHB are at an increased risk for developing hepatic cirrhosis, liver failure and primary hepatocellular carcinoma (HCC). Nearly one million people die every year from these HBV-associated complications.[2] The prevalence of CHB is variable throughout the world, with a significant burden (75%) in the Asia Pacific region.[3] An estimated 53% of HCC cases around the world have been attributed to CHB.[4] Furthermore, HCC is the fifth most common cancer in men and ninth in women, as well as the second most common cause of cancer-related death, with an annual incidence of 0.7 million worldwide.[5] Although HBV vaccination and antiviral CHB therapy have been implemented in recent decades, the incidence of hepatocellular carcinoma has still increased in many countries.[6] In addition to CHB, other factors have been suggested as causing HCC. Diabetes mellitus (DM), chronic hepatitis C virus infection (CHC), liver cirrhosis, obesity, fatty liver disease, hereditary hemochromatosis, alcohol, smoking, and other types of dietary and environmental exposure may contribute to the development of HCC.[7]

The increased incidence of HCC and DM over the past two decades has resulted in DM being suggested as a strong independent risk factor for HCC. In 2005, El-Serag et al reviewed 13 case-control studies and 13 cohort studies, which demonstrated that DM patients had a 2.5-fold greater risk of HCC compared to controls (pooled odds ratio [OR] 2.5; 95% confidence interval [CI] 1.8-3.5 in case-control studies; pooled relative risk [RR] 2.5 and 95% CI: 1.9-3.2 in cohort studies).[8] This finding was supported by Wang (2010), who reviewed 25 cohort studies that revealed DM patients had a 2.01-fold increased risk of HCC (RR = 2.01, 95% CI: 1.61-2.51) and a 1.56-fold higher HCC-related mortality rate (Summary RRs = 1.56, 95% CI: 1.30-1.87).[9] However, many of these studies were based on clinical series with discovery bias. Furthermore, the impact of DM on the development of HCC among hepatitis B patients remains inconclusive. Therefore, a population-based cohort study may be necessary to determine the exact nature of this effect.

In this study, we carried out a nationwide, population-based cohort study using the Taiwanese National Health Insurance Research Database (NHIRD) to investigate the effect of DM on the development of HCC. We also analysed the impact on the temporal transition from HCC to death, considering death a competing event in a multi-state model amongst HBV-infected patients. Causal diagrams were additionally used to evaluate the potential causal effects of DM on the development of HCC.