Chronic Liver Diseases: With a Focus on Hepatitis B, Type 2 Diabetes and Statins

Abstract

Chronic liver disease, and its advanced state – liver cirrhosis causes significant cirrhosis complications and mortality globally. However, the epidemiology and aetiology of liver cirrhosis are not well defined and the liver disease burden in NZ is unknown. In the era of obesity epidemic and increasing prevalence of diabetes mellitus (DM), it is unknown if the risk of cirrhosis and hepatocellular carcinoma (HCC) among hepatitis B (HBV) patients with metabolic syndrome (MetS) is related through delayed HBeAg seroclearance. In addition, the data on whether pre-existing DM prior to the onset of cirrhosis diagnosis will increase the risk of morbidity and mortality is lacking. Finally, there is insufficient data to support the use of statin for its anti-tumour effect in the HBV patients with a high risk of developing HCC. This thesis examines these unanswered questions and found that:  The study of the epidemiology of liver cirrhosis in South Auckland, NZ showed that the age- and ethnicity-adjusted incidence rate ratio (IRR) of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) cirrhosis were rising. Furthermore, the IRR of HCC incidence, liver- and HCC-related mortality have increased in the last 12 years. Some predictors associated with liver-related mortality were older age, male gender, high MELD score, low albumin and low platelet count. Certain ethnic groups such as Maori and Pacific people were also at much higher risk of HCC-related mortality possibly related to obesity.  The presence of MetS may delay HBeAg seroclearance in Chinese HBV patients, providing a plausible mechanism of which MetS could increase the risk of HCC and cirrhosis by affecting the virological response of the host. Neither the presence of NASH nor hepatic steatosis influenced the HBV HBeAg seroclearance. Type 2 DM at baseline was a predictor of delayed HBeAg seroclearance after adjusted for viral, host and metabolic factors. The presence of DM prior to the onset of liver cirrhosis was also associated with a two-fold risk in the development of HCC, cirrhosis complications, liver-related mortality or OLT and overall mortality or OLT. In addition, those with poor DM control at cirrhosis diagnosis had a two-fold increased risk of liver-related complications, almost four-fold increased risk in HCC development and a two-fold increased risk of death or OLT in multivariate analysis.  Statin use could reduce HCC risk during follow-up by 32% (if statin was started in HBV patients who were alive and event-free for two years) using landmark analysis, propensity score weighting and data imputations to adjust for confounders and missing data. There was a synergistic 59% effect on HCC risk reduction among those who used NA and statin concurrently, compared to NA users alone. This thesis provided important findings on liver cirrhosis epidemiology and disease burden in South Auckland, NZ. Further analysis also showed that MetS and DM could potentially affect specific HBV outcomes such as virological response, and cirrhosis outcomes, respectively. Finally, statin use in chronic HBV infection, particularly with the concurrent use of antiviral therapy, suggested its importance in HCC risk reduction.