Non-alcoholic steatohepatitis is a disease without a single, specific, diagnostic marker, hence multiple indicators are required to measure therapeutic efficacy. Moreover, drug candidates for ...non-alcoholic steatohepatitis target many distinct mechanisms that are believed to promote hepatic injury. Therefore, a wide range of endpoints must be reached, sequentially, as required by the drug development process. Some of these endpoints validate the mechanism of action, others are used to anticipate histological efficacy. Histological endpoints are still considered the best predictors of clinical outcome, but they can only be reliably tested in larger, late phase trials. Herein, we will review the rationale and clinical data supporting the use of specific endpoints at different stages of therapeutic trials. We will also discuss the validity and limitations of current phase IIb histological endpoints, particularly a one stage reduction in fibrosis, for their ability to predict progression to cirrhosis, which is the ultimate outcome measure in therapeutic trials.
Patients with nonalcoholic steatohepatitis were randomly assigned to receive subcutaneous semaglutide or placebo. The incidence of NASH resolution was significantly higher with semaglutide than with ...placebo, but the between-group difference in the incidence of an improvement in fibrosis stage was not significant.
Initially a condition that received limited recognition and whose clinical impact was controversial, non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease. Although ...there are no approved therapies, major breakthroughs, which will be reviewed here, have paved the way for future therapeutic successes. The unmet medical need in NASH is no longer disputed, and progress in the understanding of its pathogenesis has resulted in the identification of many pharmacological targets. Key surrogate outcomes for therapeutic trials are now accepted by regulatory agencies, thus creating a path for drug registration. A set of non-invasive measurements enabled early-stage trials to be conducted expeditiously, thus providing early indications on the biological and possibly clinical actions of therapeutic candidates. This generated efficacy results for a number of highly promising compounds that are now in late-stage development. Intense research aimed at further improving the assessment of histological endpoints and in developing non-invasive predictive biomarkers is underway. This will help improve the design and feasibility of successful trials, ultimately providing patients with therapeutic options that can change the course of the disease.
Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with ...wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics - from epidemiology, awareness, care and treatment to public health policies and leadership - that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.
Nonalcoholic fatty liver disease（NAFLD）has been recognized as a major health burden.The high prevalence of NAFLD is probably due to the contemporary epidemics of obesity,unhealthy dietary pattern,and ...sedentary lifestyle.The efficacy and safety profile of pharmacotherapy in the treatment of NAFLD remains uncertain and obesity is strongly associated with hepatic steatosis;therefore,the first line of treatment is lifestyle modification.The usual management of NAFLD includes gradual weight reduction and increased physical activity（PA）leading to an improvement in serum liver enzymes,reduced hepatic fatty infiltration,and,in some cases,a reduced degree of hepatic inflammation and fibrosis.Nutrition has been demonstrated to be associated with NAFLD and Non-alcoholic steatohepatitis（NASH）in both animals and humans,and thus serves as a major route of prevention and treatment.However,most human studies are observational and retrospective,allowing limited inference about causal associations.Large prospective studies and clinical trials are now needed to establish a causal relationship.Based on available data,patients should optimally achieve a 5%-10%weight reduction.Setting realistic goals is essential for long-term successful lifestyle modification and more effort must be devoted to informing NAFLD patients of the health benefits of even a modest weight reduction.Furthermore,all NAFLD patients,whether obese or of normal weight,should be informed that a healthy diet has benefits beyond weight reduction.They should be advised to reduce saturated/trans fat and increase polyunsaturated fat,with special emphasize on omega-3 fatty acids.They should reduce added sugar to its minimum,try to avoid soft drinks containing sugar,including fruit juices that contain a lot of fructose,and increase their fiber intake.For the heavy meat eaters,especially those of red and processed meats,less meat and increased fish intake should be recommended.Minimizing fast food intake will also help maintain a healthy diet.PA should be integrated into behavioral therapy in NAFLD,as even small gains in PA and fitness may have significant health benefits.Potentially therapeutic dietary supplements are vitamin E and vitamin D,but both warrant further research.Unbalanced nutrition is not only strongly associated with NAFLD,but is also a risk factor that a large portion of the population is exposed to.Therefore,it is important to identify dietary patterns that will serve as modifiable risk factors for the prevention of NAFLD and its complications.
Summary This review of the literature consists of three sections. First, papers concerning non-alcoholic fatty liver disease (NAFLD) awareness among the general population, general practitioners, and ...liver and non-liver specialists were retrieved and analyzed to highlight the perception of disease, verify knowledge of current recommendations, and identify the main difficulties experienced in clinical practice. Next, position papers and clinical practice guidelines issued by International and National Hepatological Scientific Societies were identified and critically assessed in order to pinpoint the areas of convergence/difference. Finally, practical suggestions on NAFLD diagnosis and management in daily practice are provided and the open questions highlighted.
Despite a well‐documented increase in the prevalence of subclinical atherosclerosis in patients with steatosis, the relationship among steatosis and atherosclerosis, specific atherosclerotic sites, ...multiple‐site atherosclerosis, and cardiovascular risk prediction is incompletely understood. We studied the relationship among steatosis, atherosclerosis site, multiple‐site atherosclerosis, coronary artery calcification (CAC), and 10‐year Framingham Risk Score (FRS) in 2,554 patients with one or more cardiovascular risk factors (CVRF), free of cardiovascular events and other chronic liver diseases, and drinking less than 50 g alcohol/day. All patients underwent arterial ultrasound (carotid CP and femoral FP plaques defined as intima‐media thickness (IMT) > 1.5 mm), coronary computed tomography scan (severe CAC if ≥ 100), 10‐year FRS calculation, and steatosis detection by the fatty liver index (FLI, present if score ≥ 60). Patients with steatosis (36% of total) had higher prevalence of CP (50% versus 45%, P = 0.004) and higher CAC (181 ± 423 versus 114 ± 284, P < 0.001) but similar prevalence of FP (53% versus 50%, P = 0.099) than patients without steatosis. Steatosis was associated with carotid IMT and CAC, but not with FP, independent of age, diabetes, hypertension, and tobacco use (P < 0.001). Fifty‐three percent of patients had at least 2‐site atherosclerosis and steatosis was associated with at least 2‐site atherosclerosis independent of age and CVRF (odds ratio = 1.21, 95% confidence interval 1.01‐1.45, P = 0.035). Sixty‐four percent of patients with steatosis had a FRS score of 10% or more. FLI was associated with FRS beyond the CVRF or the number of atherosclerosis sites (P < 0.001). Adding FLI to CVRF predicted an FRS greater than or equal to 10% better than CVRF alone (area under the receiver operating characteristic curve = 0.848 versus 0.768, P < 0.001). Conclusion: Steatosis is associated with carotid and coronary, but not femoral atherosclerosis, and with cardiovascular mortality risk. The multiple‐site involvement and quantitative tonic relationship could reinforce the prediction of cardiovascular mortality or events over classical CVRF or imaging‐based detection of atherosclerosis.
Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and ...validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD.
Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36-45 (n=96), 46-55 (n=197), 56-64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3-F4) for each group was assessed using liver biopsy as the standard.
Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77-0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%).
The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.
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