Biopsy-confirmed liver fibrosis is a prognostic factor for patients with nonalcoholic fatty liver disease (NAFLD). We performed a systematic review to quantify the prognostic value of fibrosis stage in patients with NAFLD and the subgroup of patients with nonalcoholic steatohepatitis (NASH) and to assess the evidence that change in fibrosis stage is a surrogate endpoint. We searched the MEDLINE, Embase, Cochrane Library, and trial registry databases through August 2018 for prospective or retrospective cohort studies of liver-related clinical events and outcomes in adults with NAFLD or NASH. We collected data on mortality (all cause and liver related) and morbidity (cirrhosis, liver cancer, and all liver-related events) by stage of fibrosis, determined by biopsy, for patients with NAFLD or NASH. Using fibrosis stage 0 as a reference population, we calculated fibrosis stage-specific relative risk (RR) and 95% confidence interval (CI) values for mortality and morbidities. We performed fixed-effect and random-effect model meta-analyses. Metaregression was used to examine associations among study design (prospective vs retrospective cohort), overall risk of bias (medium or high), and mean duration of follow-up (in years). Our meta-analysis included 13 studies, comprising 4428 patients with NAFLD; 2875 of these were reported to have NASH. Compared with no fibrosis (stage 0), unadjusted risk increased with increasing stage of fibrosis (stage 0 vs 4): all-cause mortality RR, 3.42 (95% CI, 2.63-4.46); liver-related mortality RR, 11.13 (95% CI, 4.15-29.84); liver transplant RR, 5.42 (95% CI, 1.05-27.89); and liver-related events RR, 12.78 (95% CI, 6.85-23.85). The magnitude of RR did not differ significantly after adjustment for confounders, including age or sex in the subgroup of NAFLD patients with NASH. Three studies examined the effects of increasing fibrosis on quality of life had inconsistent findings. In a systematic review and meta-analysis, we found biopsy-confirmed fibrosis to be associated with risk of mortality and liver-related morbidity in patients with NAFLD, with and without adjustment for confounding factors and in patients with reported NASH. Further studies are needed to assess the association between fibrosis stage and patient quality of life and establish that change in liver fibrosis stage is a valid endpoint for use in clinical trials.

The liver is an organ that is particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also during the biotransformation of xenobiotics. The disruption of redox balance causes oxidative stress, which affects liver function, modulates inflammatory pathways and contributes to disease. Thus, oxidative stress is implicated in acute liver injury and in the pathogenesis of prevalent infectious or metabolic chronic liver diseases such as viral hepatitis B or C, alcoholic fatty liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Moreover, oxidative stress plays a crucial role in liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Herein, we provide an overview on the effects of oxidative stress on liver pathophysiology and the mechanisms by which oxidative stress promotes liver disease.

The diagnostic assessment of liver injury is an important step in the management of patients with chronic liver disease (CLD). Although liver biopsy is the reference standard for the assessment of necroinflammation and fibrosis, the inherent limitations of an invasive procedure, and need for repeat sampling, have led to the development of several non-invasive tests (NITs) as alternatives to liver biopsy. Such non-invasive approaches mostly include biological (serum biomarker algorithms) or physical (imaging assessment of tissue stiffness) assessments. However, currently available NITs have several limitations, such as variability, inadequate accuracy and risk factors for error, while the development of a newer generation of biomarkers for fibrosis may be limited by the sampling error inherent to the reference standard. Many of the current NITs were initially developed to diagnose significant fibrosis in chronic hepatitis C, subsequently refined for the diagnosis of advanced fibrosis in patients with non-alcoholic fatty liver disease, and further adapted for prognostication in CLD. An important consideration is that despite their increased use in clinical practice, these NITs were not designed to reflect the dynamic process of fibrogenesis, differentiate between adjacent disease stages, diagnose non-alcoholic steatohepatitis, or follow longitudinal changes in fibrosis or disease activity caused by natural history or therapeutic intervention. Understanding the strengths and limitations of these NITs will allow for more judicious interpretation in the clinical context, where NITs should be viewed as complementary to, rather than as a replacement for, liver biopsy.

Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Its staging is critical for the management and prognosis of chronic hepatitis C (CHC) patients, whose number is expected to rise over the next decades, posing a major health care challenge. This review provides a brief update on HCV epidemiology, summarizes basic mechanistic concepts of HCV-dependent liver fibrogenesis, and discusses methods for assessment of liver fibrosis that are routinely used in clinical practice. Liver biopsy was until recently considered as the gold standard to diagnose and stage liver fibrosis. However, its invasiveness and drawbacks led to the development of non-invasive methods, which include serum biomarkers, transient elastography and combination algorithms. Clinical studies with CHC patients demonstrated that non-invasive methods are in most cases accurate for diagnosis and for monitoring liver disease complications. Moreover, they have a high prognostic value and are cost-effective. Non-invasive methods for assessment of liver fibrosis are gradually being incorporated into new guidelines and are becoming standard of care, which significantly reduces the need for liver biopsy.