Hepatitis C infection in the west of Scotland : epidemiology, treatment and disease progression
After the discovery of and development of diagnostic tests for hepatitis A and B it became apparent that a parenterally transmissible agent was responsible for cases of non-A non-B hepatitis. It was not until 1989, a further fifteen years later, that the agent responsible for most cases, the hepatitis C virus (HCV), was identified. This virus was initially thought to cause a mild self-limiting hepatitis. With the introduction of serological screening tests for HCV, it was soon apparent that it caused a chronic asymptomatic hepatitis which could be accompanied by significant fibrosis and sometimes cirrhosis and hepatocellular carcinoma. Epidemiological studies have since revealed that up to eighty percent of those infected develop chronic infection and that in the developed world hepatitis C virus infection is widespread. An estimated 0.5% of the UK population and 1.8% of the population in the USA are infected. It is now accepted that HCV can cause an asymptomatic indolent infection that can progress over decades with the development of cirrhosis. Hepatitis C infection is now established as the single most common condition referred to hepatologists and the leading indication for hepatic transplantation in Europe and the USA.Since the discovery of the hepatitis C virus much research has focussed on the epidemiology, natural history and treatment of the condition. The first chapter provides an overview of HCV and places in context the research contained in this thesis. In western countries the role of the healthcare setting in transmitting hepatitis C virus is poorly understood. We performed a large retrospective serological survey of hepatitis C virus infection in healthcare workers from theWest of Scotland. This revealed the overall prevalence of HCY infection in healthcare workers to be low regardless of involvement in exposure-prone procedures. This indicates that the risk of acquisition of hepatitis C virus infection by healthcare workers in an area with a large HCY infected intravenous drug using population is small and that the risk posed to patients by contact with the HCY infected healthcare workers is also low. Liver biopsy is the gold standard for assessing the extent of liver injury and determining prognosis in chronic hepatitis C. Non-invasive markers of liver injury have proved disappointing such that serial liver biopsies are required to monitor disease progression. In this thesis the hepatocellular enzyme a-glutathione stransferase is studied as a non-invasive marker of liver injury and as a means of assessing response to treatment with a - interferon. Disappointingly a-glutathione s-transferase performed poorly as a non-invasive marker of liver injury but showed some promise as a marker of response to interferon therapy. Three chapters of this thesis then focus on factors that may influence the natural history of chronic hepatitis C virus infection and in particular account for the variable rates of progression of liver fibrosis observed in chronic HCY. The role of iron and polymorphisms in the haemochromatosis gene (HFE) were studied. Carriage of HFE mutations was not related to the serum and liver markers of iron accumulation or the progression of liver fibrosis. Elevated liver iron concentrations were rarely observed, occurring in patients with more severe liver disease, and whether this was the cause or result of hepatocellular injury was unclear. Carriage of genetic polymorphisms in the renin-angiotensin system, which are associated with increased systemic renin-angiotensin system activity, were studied. This novel study was designed to explore whether these polymorphisms, known to influence the progression of renal and cardiac fibrosis in a number of cardiovascular diseases, influenced the progression of liver fibrosis in chronic HCY. In this study no association between these functional renin-angiotensin polymorphisms and the progression of liver fibrosis was observed. Hepatitis G virus infection was sought in a cohort of hepatitis C virus infected blood donors to investigate whether coinfection with this virus influenced the severity of hepatitis C virus related liver injury. Although hepatitis G virus co-infection was frequently observed it did not effect the severity of liver injury assessed biochemically and histologically. The factors that account for the variable rates of progression of chronic hepatitis C virus infection remain to be elucidated. Finally in this thesis the role of a - interferon therapy in the management of asymptomatic blood donors found to have hepatitis C virus infection at blood donation is studied. Most patients detected in this manner have only mild hepatitis with minimal fibrosis and little data exists as to whether they are appropriate candidates for treatment. In a randomised crossover study these patients were observed to tolerate a. - interferon therapy and have comparable response rates to other patient groups with chronic hepatitis C infection. These patients appear to be suitable candidates for treatment, although more data are required to establish what the prognosis is for these individuals if chronic HCV is left untreated.