Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials

AbstractNon-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. However, the treatment is limited. The aim of this meta-analysis was to evaluate the effects and safety of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4 (DPP-4I), in treating NAFLD. Studies were sourced from electronic databases including PubMed, CENTRAL (Cochrane Controlled Trials Register), Embase, Medline, Web of Science, Clinical Trials, and CNKI to identify all randomized controlled clinical trials (RCTs) and non-RCTs in adult patients with NAFLD. Key outcomes were changes in serum levels of liver enzymes and improvement in hepatic histology and fat content measured by imaging or liver biopsy. Stata14.0 and RevMan5.3 were used for the meta-analysis. Seven studies with 269 NAFLD patients were included. Compared to the control group, sitagliptin treatment improved serum gamma-glutamyl transpeptidase (GGT) levels in the RCT subgroup (SMD = 0.79, 95% CI: 0.01–1.58). However, there was no significant improvement in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels following sitagliptin treatment. Four of the included studies performed liver imaging, but sitagliptin treatment did not result in a significant reduction in liver fat content. Only five participants developed sitagliptin-related gastrointestinal discomfort. Our study suggests that sitagliptin effects individuals with NAFLD by improving serum GGT. Although sitagliptin is safe and well tolerated in NAFLD patients, it exerts no beneficial effects on liver transaminase and liver fat content in these patients.

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Quantifying and monitoring fibrosis in non-alcoholic fatty liver disease using dual-photon microscopy

Gut ◽

10.1136/gutjnl-2019-318841 ◽

2019 ◽

Vol 69 (6) ◽

pp. 1116-1126 ◽

Cited By ~ 3

Author(s):

Yan Wang ◽

Grace Lai-Hung Wong ◽

Fang-Ping He ◽

Jian Sun ◽

Anthony Wing-Hung Chan ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Fibrosis Stage ◽

Research Network ◽

Operating Characteristics ◽

Collagen Fibres ◽

Alcoholic Fatty Liver ◽

Liver Biopsies ◽

Alcoholic Fatty Liver Disease

ObjectiveFibrosis stage is strongly associated with liver-related outcomes and is a key surrogate endpoint in drug trials for non-alcoholic steatohepatitis. Dual-photon microscopy allows automated quantification of fibrosis-related parameters (q-FPs) and may facilitate large-scale histological studies. We aim to validate the performance of q-FPs in a large histological cohort.Design344 patients with non-alcoholic fatty liver disease (NAFLD) underwent 428 liver biopsies (240 had paired transient elastography examination). Fibrosis stage was scored using the NASH Clinical Research Network system, and q-FPs were measured by dual-photon microscopy using unstained slides. Patients were randomly assigned to the training and validation cohorts to test the performance of individual q-FPs and derive optimal cut-offs.ResultsOver 25 q-FPs had area under the receiver-operating characteristics curves >0.90 for different fibrosis stages. Among them, the perimeter of collagen fibres and number of long collagen fibres had the highest accuracy. At the best cut-offs, the two q-FPs had 88.3%–96.2% sensitivity and 78.1%–91.1% specificity for different fibrosis stages in the validation cohort. q-FPs and histological scoring had nearly identical correlations with liver stiffness measurement, suggesting that the accuracy of q-FPs approached that of histological assessment. Among patients with paired liver biopsies, changes in the same q-FPs were associated with changes in fibrosis stage. At a median follow-up of 5.6 years, baseline q-FPs predicted liver-related events.Conclusionq-FP is highly accurate in the assessment of fibrosis in NAFLD patients. This automated platform can be used in future studies as objective and reliable evaluation of histological fibrosis.

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Vitamin D supplementation and non-alcoholic fatty liver disease: A critical and systematic review of clinical trials

Critical Reviews in Food Science and Nutrition ◽

10.1080/10408398.2017.1389693 ◽

2017 ◽

Vol 59 (4) ◽

pp. 693-703 ◽

Cited By ~ 6

Author(s):

Nasrin Sharifi ◽

Reza Amani

Keyword(s):

Systematic Review ◽

Vitamin D ◽

Clinical Trials ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Vitamin D Supplementation ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis

Gut ◽

10.1136/gutjnl-2021-324243 ◽

2021 ◽

pp. gutjnl-2021-324243

Author(s):

Ferenc Emil Mózes ◽

Jenny A Lee ◽

Emmanuel Anandraj Selvaraj ◽

Arjun Narayan Ajmer Jayaswal ◽

Michael Trauner ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Individual Patient Data ◽

Meta Analysis ◽

Advanced Fibrosis ◽

Alcoholic Fatty Liver ◽

Liver Biopsies ◽

Alcoholic Fatty Liver Disease ◽

Rule Out

ObjectiveLiver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.DesignIndividual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.ResultsData were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (<1.3; ≥2.67) followed by LSM-VCTE cut-offs (<8.0; ≥10.0 kPa) to rule-in or rule-out advanced fibrosis had sensitivity and specificity (95% CI) of 66% (63–68) and 86% (84–87) with 33% needing a biopsy to establish a final diagnosis. FIB-4 cut-offs (<1.3; ≥3.48) followed by LSM cut-offs (<8.0; ≥20.0 kPa) to rule out advanced fibrosis or rule in cirrhosis had a sensitivity of 38% (37–39) and specificity of 90% (89–91) with 19% needing biopsy.ConclusionSequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

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Perspective strategies for non-alcoholic fatty liver disease therapy: from trial to practice

Experimental and Clinical Gastroenterology ◽

10.31146/1682-8658-ecg-170-10-18-25 ◽

2020 ◽

Vol 1 (10) ◽

pp. 18-25

Author(s):

I. G. Bakulin ◽

L. N. Belousova ◽

L. I. Nazarenko ◽

A. G. Sushilova

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Randomized Clinical Trials ◽

Intestinal Microbiome ◽

Good Effect ◽

Growth Trend ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common diseases all over the world, but there is no so much approved medicines treating liver fibrosis, which is a predictor of total and hepatic mortality in this group of patients. Innovation methods of treating the NAFLD/NASH include several ways: decrease fat accumulation in the liver; influence on oxidative stress; inflammation and apoptosis; impact on the intestinal microbiome and metabolic endotoxemia; antifibrotic drugs. A few drugs which have recommended to use in treating other diseases (for example GLP-1RA for diabetes), demonstrated the good effect of treating NAFLD in clinical trials. There is a big number of drugs from different pharmacological groups, which are on the second and third stage of international multicenter randomized clinical trials, reviewed in this article. Probably, versions of treating NAFLD, which will reduce the growth trend of NAFLD-associated diseases, will be proposed in the near future.

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The role of the gut microbiome and exercise in non-alcoholic fatty liver disease

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820941745 ◽

2020 ◽

Vol 13 ◽

pp. 175628482094174

Author(s):

Veera Houttu ◽

Ulrika Boulund ◽

Aldo Grefhorst ◽

Maarten R. Soeters ◽

Sara-Joan Pinto-Sietsma ◽

...

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Fatty Liver ◽

Gut Microbiome ◽

Fatty Liver Disease ◽

Inflammatory Responses ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

In recent years, the human gut microbiome has been found to influence a multitude of non-communicable diseases such as cardiovascular disease and metabolic syndrome, with its components type 2 diabetes mellitus and obesity. It is recognized to be mainly influenced by environmental factors, such as lifestyle, but also genetics may play a role. The interaction of gut microbiota and obesity has been widely studied, but in regard to non-alcoholic fatty liver disease (NAFLD) as a manifestation of obesity and insulin resistance, the causal role of the gut microbiome has not been fully established. The mechanisms by which the gut microbiome influences lipid accumulation, inflammatory responses, and occurrence of fibrosis in the liver are a topic of active research. In addition, the influence of exercise on gut microbiome composition is also being investigated. In clinical trials, exercise reduced hepatic steatosis independently of weight reduction. Other studies indicate that exercise may modulate the gut microbiome. This puts forward the question whether exercise could mediate its beneficial effects on NAFLD via changes in gut microbiome. Yet, the specific mechanisms underlying this potential connection are largely unknown. Thus, associative evidence from clinical trials, as well as mechanistic studies in vivo are called for to elucidate the relationship between exercise and the gut microbiome in NAFLD. Here, we review the current literature on exercise and the gut microbiome in NAFLD.

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