Background & Aims: Liver fibrosis is the critical determinant of liver-related outcomes in persons with nonalcoholic fatty liver disease. The rate that fibrosis develops determines the time taken to reach cirrhosis and consequent clinical outcomes.Estimates of the fibrosis progression rate (FPR) are uncertain having been defined in small observational series that rely largely on nonstandardised repeat biopsy in selected patients. The aim of this study was to evaluate the FPR in placebo-treated participants with nonalcoholic steatohepatitis (NASH) in randomised controlled trials (RCTs).Methods: Systematic review and meta-analysis of RCTs in NASH with data on fibrosis change extracted. Calculated fibrosis progression rates were pooled in meta-analysis.The pooled estimate was then used to model the proportion of hypothetical cohorts starting with no fibrosis at the age of 30 who develop cirrhosis.Results: A total of 35 trials including 1419 placebo-treated participants who underwent repeat liver biopsy were evaluated. Considering all trials, the overall FPR was 0.00 stages per year, increasing to 0.03 stages per year in both trials at low risk of bias and trials including >50 placebo-treated participants. This estimate was markedly lower than the value derived from previously pooled analyses of observational data.Using a FPR of 0.03 resulted in a substantial reduction in the proportion of patients developing cirrhosis compared with the FPR derived from observational studies (13% vs 28%). Conclusions:The FPR in placebo-treated participants in RCTs is lower than that described from observational data. Slower fibrosis progression predicts fewer persons with NASH will progress to cirrhosis than previously estimated.

high in patients with cirrhosis who develop HCC. 8 Mortality data from the UK for HCC demonstrates that this is rising in parallel with the incidence rates of HCC such that in 2015 there were approximately 1,700 deaths due to HCC. Since cirrhosis is readily identified and the risk of HCC is known, regular surveillance testing using ultrasound scanning is proposed to identify HCC early and to facilitate curative treatment.9 This rationale is supported by many international guidelines for the management of patients with cirrhosis including the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), as well as by recent guidance issued by the National Institute for Health and Care Excellence (NICE). 10-12 However, the recommendation that patients with cirrhosis have regular surveillance for HCC is not universally accepted and the majority of patients do not receive surveillance. 13-15The imperative for surveillanceMany international authorities, including the AASLD and the EASL recommend that high risk groups are entered into surveillance programmes. This includes the majority of patients with cirrhosis but not those with advanced liver failure unless they are on the transplant waiting list. Patients with non-cirrhotic HBV infection and patients with HCV infection and advanced fibrosis (defined as fibrosis stage 3 [out of 4, where 4 is cirrhosis]) are also recommended to have surveillance due to the increased incidence of HCC in these groups. 11 Surveillance of individuals without cirrhosis will not be discussed further in this article. Surveillance relies on the ideal that if we detect early asymptomatic cancers, curative treatment options are available to these patients. These treatments include resection, transplantation and radiofrequency ablation, each of which can achieve 5-year survival rates near 70% for small lesions, <2.5 cm in diameter.9 Recurrent HCC is frequently observed after liver resection and ablation since the development of HCC is associated with the underlying cirrhosis and that cirrhosis is not treated or targeted by local therapies. Liver transplantation offers a real prospect of cure for these patients; however, in practice this option is limited in applicability due to comorbidity and limited in availability due to a shortage of donor organs. Current provision of surveillanceReports of HCC surveillance in patients with cirrhosis consistently show poor uptake and adherence to the published guidance. A UK survey confirmed these international findings and showed that current surveillance for HCC is poor, provision is ad hoc and there Hepatocellular carcinoma (HCC) is a common complication of cirrhosis. The incidence of HCC is rising and HCC-related mortality is rising in parallel such that there were more than 1,700 deaths in the UK in 2015. Since cirrhosis is a known risk factor for the development of HCC and early diagnosis is associated with improved outcomes, surveillance for the development of HCC using regular ultrasou...

Background and aims: Non-alcoholic fatty liver disease is common and there are a number of treatments in development. Patients with non-alcoholic steatohepatitis (NASH) and significant fibrosis are thought to be the population most in need of treatment. Identification of this group requires liver biopsy. The aim of this study was to identify the proportion of patients screened for phase 2 randomised controlled trials who subsequently entered these studies. Methods: Large, multicentre, phase 2 randomised controlled trials of pharmacological therapies for NASH were identified by systematic review. The pooled proportion of potential participants who entered the trials was estimated by meta-analysis. The reasons for trial ineligibility were separately extracted and analysed. Results: Thirteen reports of 14 trials were included. Overall, there were 4014 screened individuals included in the quantitative analyses and 53% were subsequently enrolled in a trial. Considering trials in which the entry criteria matched the current paradigm for treatment, that is, the presence of NASH and significant fibrosis, only 35% of screened individuals were eligible for trial entry. More than half of ineligible individuals were excluded on the basis of liver histology most often due to insufficient disease activity with or without insufficient fibrosis. Conclusion: The majority of patients considered at risk of NASH and fibrosis sufficient for treatment in randomised controlled trials are ineligible for trial entry. Most often, this is due to ineligible liver histology. These findings have implications for the design of future trials in NASH and for the applicability of treatments after licensing.

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