Introduction: Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide through increasing obesity. It is not known whether HIV infection or its treatments, themselves associated with metabolic side effects such as dyslipidaemia and, historically, lipodystrophy, may potentiate the development and progression of NAFLD and its severe forms with NASH and fibrosis. The aim of this thesis is to explore in detail the clinical, histologic and metabolic phenotype of NAFLD in people living with HIV (PLWH), and the impact of the gut-liver axis in disease pathogenesis.
Methods: A systematic review and meta-analysis of the prevalence and risk factors of NAFLD, NASH and fibrosis was performed. An international collaboration of pooled liver histology in HIV mono-infection investigated the clinical features associated with biopsy- confirmed NAFLD and fibrosis. Laboratory assays including bacterial DNA polymerase- chain reaction, ELISA, stool metataxegenomics and immunohistochemistry characterised the impact of the gut microbiome, bacterial translocation and monocyte/macrophage activation on NAFLD and liver fibrosis development. Serum H1-nuclear magnetic resonance spectroscopy explored the metabolic profile of NAFLD in subjects with and without HIV.
Results: The clinical phenotyping supported the central role of obesity and insulin resistance in the development of NAFLD and particularly fibrosis in PLWH. HIV- specific factors were not associated with disease progression, and this was supported by the liver histology work. Monocyte/macrophage activation is evident in NAFLD with fibrosis, whereas changes to the microbiome or translocation were not clearly associated with the disease. Metabolic biomarkers were principally related to obesity rather than liver disease stage, although NAFLD in PLWH had a distinct lipid profile compared to NAFLD without HIV.
Conclusions: The clinical and pathophysiological mechanisms of NAFLD, NASH and fibrosis in HIV closely resemble that in the general population. Consideration should be given to including this group within the emerging clinical trials for therapeutics in NASH.