Non-invasive biomarkers in chronic liver disease

Liver fibrosis is the final common pathway following chronic insult to the liver. Progression to cirrhosis is mostly asymptomatic, but the end stages of disease result in clinical events such as ascites, bleeding, infection, hepatocellular cancer and death. Liver biopsy has been regarded as the gold-standard for assessing fibrosis and whilst it provides useful information it is hazardous for patients and subject to inaccuracy. Many serum markers of liver fibrosis have been evaluated as tests for severity of fibrosis on biopsy, as a surrogate for prediction of clinical outcomes. Their performance as direct predictors of clinical outcomes as the reference standard would be ideal. This thesis focused on serum biomarkers and had two broad aims. Firstly, the evaluation of published literature on the diagnostic accuracy of serum markers in identification of fibrosis in the three main causes of chronic liver disease (CLD) in the UK (chronic Hepatitis C (CHC), Non-alcoholic fatty liver disease (NAFLD), and Alcoholic liver disease (ALD). Secondly, the exploration of the diagnostic accuracy of a particular panel of markers (Enhanced Liver Fibrosis (ELF) in the diagnosis of fibrosis severity in external independent populations of patients with CLD. Thirdly the evaluation of the performance of ELF in prediction of clinical outcomes. The systematic reviews highlighted the breadth of serum markers, found that markers performed better at identifying serious fibrosis than milder disease, and marked the evolution from single markers to panels of marker. One such marker panel was ELF, whose components are part of the fibrotic process, which was derived and validated in a cohort of patients recruited in 1998-2000. The performance of ELF was externally validated in eight studies in patients with CHC, NAFLD, Primary Biliary Cirrhosis (PBC) and HCV-HIV co-infection. ELF maintained its performance in all studies with AUC values >0.80 and >0.85 in identification of significant fibrosis and cirrhosis respectively. It performed particularly well in NAFLD. In the final part of the thesis, two studies were conducted to explore the accuracy of ELF in predicting clinical outcomes. One study involved follow-up of the patients in the original ELF cohort for liver related outcomes and all-cause mortality. Analyses showed that baseline ELF score can predict liver outcomes and all-cause mortality, with those people having highest ELF scores being significantly more likely to have clinical outcomes than those with lower scores. A unit change in ELF was associated with a doubling ofthe risk of having a liver-related outcome at 6 years. In the second prognostic study 161 patients with PBC were followed up for 8 years. The results confirmed the findings in the first study. ELF was found to be better than other markers currently used for prognosis of clinical events in PBC. Serum markers have a role in the assessment of patient with CLD both predicting fibrosis and clinical outcomes. More research is needed to assess performance of these markers in different settings, such as Primary Care.