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Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC), the two most common chronic liver diseases, are associated with liver steatosis, insulin resistance (IR) and type 2 diabetes. These distinct diseases can induce advanced liver fibrosis, end stage liver disease and hepatocellular cancer, which are influenced by increased IR and steatosis. The pathogenic mechanisms contributing to liver disease progression remain elusive and include an interplay between IR, excess fat, lipotoxicity, inflammation and adipokine disturbances which, in NAFLD, occur together with overnutrition and dysregulated energy balance. This thesis, using data from NAFLD and CHC subjects, explores the pathogenesis of IR in CHC and the interaction between IR, fat depots and circulating adipokines in disease progression in NAFLD; this has important implications for arresting long term metabolic and liver complications. CHC infection is associated with IR, demonstrated to be predominantly peripheral (in muscle and fat) and independent of liver steatosis. Despite higher liver steatosis in genotype 3, IR was similar to genotype 1; IR was associated with viral load and subcutaneous (not visceral) fat, suggesting interplay between the virus and peripheral adipocytes. Despite higher TNF-alpha and lipocalin-2 levels in CHC, adipocytokines do not appear to contribute to CHC IR. Antiviral eradication of CHC improves IR independent of changes in fat depots and adipokine levels, supporting a direct role of the virus inducing IR. In NAFLD visceral fat correlates with liver inflammation and fibrosis independent of IR and steatosis, and also with components of the metabolic syndrome. Adipokines, Adipocycte fatty acid-binding protein (AFABP) and Lipocalin-2, produced in adipocytes, macrophages and other tissues are elevated in NAFLD, with AFABP predicting liver inflammation and fibrosis independent of IR, liver steatosis and visceral adiposity. Conclusion: Here we demonstrated that in NAFLD, adipokines and visceral fat contribute independently and synergistically with IR and liver fat to liver disease progression. Despite hepatitis C being a hepatropic virus, it induces IR in the periphery, likely via adipocyte interaction. Visceral and liver fat appear not to be important determinants of IR in CHC; this remains the only human model of viral-induced IR and mechanisms of IR appear to differ from obesity and NAFLD related IR.

Chronic hepatitis C affects more than 170 million people worldwide and is one of the most common infectious diseases on earth. If untreated, it can lead to progressive liver injury, cirrhosis, liver failure and hepatocellular carcinoma. While curative antiviral therapy is currently available, it is far from 100% effective. The broad aim of this thesis is to examine factors influencing treatment response and liver injury in chronic hepatitis C virus. The first two studies examine treatment responses in ethnic groups where chronic hepatitis C is prevalent. A case-control study was conducted to compare the treatment responses between Arabic patients infected with genotype 4 with Caucasians infected with genotype 1 who were treated with interferon and ribavirin combination antiviral therapy, and found a superior sustained virological response rate of 64.0% , compared to that of 32.3% of genotype 1 infected patients, independent of other factors. Another retrospective case control study found Asians infected with chronic hepatitis C genotype 1 also had better sustained virological response rate of 73%, as compared to that of 36% of Caucasians infected with genotype 1. Findings of these two studies challenges the current clinical practice of extrapolating data from clinical trials originating from genotype 1 infected Caucasians, and treating different ethnic groups with same regimen, and prompted further research into treatment of different patient groups. The third study examined the role of two adipocytokines, namely adiponectin and retinal binding protein 4 in the pathogenesis of chronic hepatitis C by examining their serum levels and their expression at the genetic level in the liver, and contrasted that with non-alcoholic fatty liver disease. The study found that the relationship between insulin resistance and liver injury in chronic hepatitis C is probably independent from the effects of retinal binding protein 4. In addition, this study found the complex role of retinal binding protein 4 in non-alcoholic fatty liver disease, and prompted further research into identifying the pathways of adipocytokines in pathogenesis of chronic hepatitis C and non-alcoholic fatty liver disease.

A new serological assay to detect antibodies against hepatitis C, based on a recombinant protein (BHC10) which incorporates structural and non-structural viral antigens, was tested in 67 healthy subjects and 409 patients with various forms of liver disease. Results were compared with the current assay based on the recombinant non-structural viral antigen c100 and with the recently introduced second-generation assay, Ortho2. None of the healthy subjects was positive by any of the assays. In patients with chronic non-A, non-B hepatitis the prevalence of anti-BHC10 was 96.8%, higher than anti-c100 (83.3%, p less than 0.001) and similar to Ortho2 (94.3%). False-positive results were less frequently found when BHC10 was used. These findings show that assays incorporating structural and non-structural antigens provide higher sensitivity to detect hepatitis C virus infection and they define an almost exclusive role of hepatitis C virus in the genesis of chronic non-A, non-B hepatitis.