Fibrosis progression rate in a systematic review of placebo-treated nonalcoholic steatohepatitis.

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 rates of ineligibility for participation in trials of new therapies in non-alcoholic steatohepatitis: a systematic review.

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.

Surveillance for hepatocellular cancer.

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 ultrasound scans is recommended by many expert bodies including the National Institute for Health and Care Excellence (NICE). This surveillance is not supported by high-quality evidence and there is an increasing appreciation of the associated harms. In this review the likely benefits of surveillance are discussed together with recommendations to increase the effectiveness of surveillance overall.

The effect of eccentric and concentric calf muscle training on Achilles tendon stiffness.

OBJECTIVE: To compare in vivo effects of eccentric and concentric calf muscle training on Achilles tendon stiffness, in subjects without tendinopathy. METHODS: Thirty-eight recreational athletes completed 6 weeks eccentric (6 males, 13 females, 21.6 ± 2.2 years) or concentric training (8 males, 11 females, 21.1 ± 2.0 years). Achilles tendon stiffness, tendon modulus and single-leg jump height were measured before and after intervention. Exercise adherence was recorded using a diary. RESULTS: All data are reported as mean ± SD. Groups were matched for height and weight but the eccentric training group were more active at baseline (P < 0.05). Tendon stiffness was higher in the eccentrically trained group at baseline compared to the concentrically trained group (20.9 ± 7.3 N/mm v 13.38 ± 4.66 N/mm; P = 0.001) and decreased significantly after eccentric training (to 17.2 ( ± 5.9) N/mm (P = 0.035)). There was no stiffness change in the concentric group (P = 0.405). Stiffness modulus showed similar changes to stiffness. An inverse correlation was found between initial, and subsequent, reduction in stiffness (r = -0.66). Jump height did not change and no correlation between stiffness change and adherence was observed in either group (r = 0.01). CONCLUSIONS: Six weeks of eccentric training can alter Achilles tendon stiffness while a matched concentric programme shows no similar effects. Studies in patients with Achilles tendinopathy are warranted.