Viral Infection and Hepatocellular Carcinoma

Much of liver pathology is related to infection with HBV and HCV and it is important to define factors associated with clinical behavior of disease following infection with these viruses. Thus in this thesis I first focus on the natural history of chronic viral diseases associated with HBV or HCV infection, also in relation to HIV coinfection. Problem is that disease progression and its effects on liver physiology can be difficult to monitor and often reliable determination of liver health currently involves highly invasive liver biopsies.
Evidently, serum based markers would bring disease monitoring forward and thus allow more precise analysis of disease course and thus also aids delineation of risk factors associated with alternative outcome. To address this void I first explore a potential clinically useful biomarker, cytokeratin-18. Its potential in monitoring chronic hepatitis is documented in Chapter 2. Concomitantly, however, I also tried to characterize the general beneficial effects of antiretroviral therapy in patients with HIV infection. To this end a big cohort from Yunnan province in China was analyzed for identification of the factors associated with overall survival and the results, described in Chapter 3, show that especially CD4 counts are important, but only in the early course of disease. This highlights the care that should be taken when interpreting biological information in chronic disease and highlights the importance of defining novel markers specifically aimed at assessing disease course in chronic patients (as I attempted in chapter 2) but also in general show that care of epidemiological data is necessary and one should be careful not to over-extrapolate results obtained, a theme that will also emerge from other parts of this thesis. Indeed, prevalence of coinfection with hepatitis virus and its impact on clinical outcome of patients with HIV infection were explored in Chapter 4 and also show this: no negative impact of coinfection was found on the overall survival of these patients treated with HAART and thus the notion that more infection means more disease is simplistic.
Due to the fact that chronic HBV/HCV infection is associated with developing HCC, I subsequently focus in this thesis is on the clinical outcome of patients with HCC. In particular, because of the existing racial disparity in overall survival for American patients with HCC, I aimed to identify the actual contributors to such disparity based on the Surveillance, Epidemiology, and End Results (SEER) database (Chapter 5). Again the result show a surprising correlation to the time domain: even many years after diagnosis racial disparity is maintained. The notion that racial disparity is driven access to health care thus appears an oversimplification and highlights the importance of studies exactly dissecting the contribution of different factors to disease course and the necessity of careful study of their relationship to continuous variables in the study cohort, especially the time domain.
These lessons were taken into account in the last experimental chapter (Chapter 6) in which I study a potentially effective anti-HCC treatment, metformin, which was systematically analyzed via the meta-analysis method.
The relationship between these findings and their place in the contemporary body of literature are presented in a general discussion (Chapter 7). In conjunction I hope my studies will contribute to better clinical management of liver disease.