An update on drug development for the treatment of nonalcoholic fatty liver disease – from ongoing clinical trials to future therapy

Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.

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Systematic Review with Meta-Analysis: The Effects of Probiotics in Nonalcoholic Fatty Liver Disease

Gastroenterology Research and Practice ◽

10.1155/2019/1484598 ◽

2019 ◽

Vol 2019 ◽

pp. 1-19 ◽

Cited By ~ 4

Author(s):

Meng-Wei Xiao ◽

Shi-Xin Lin ◽

Zhao-Hua Shen ◽

Wei-Wei Luo ◽

Xiao-Yan Wang

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Meta Analysis ◽

Free Text ◽

Model Assessment ◽

Nonalcoholic Fatty Liver

Background and Aims. Probiotics was considered as a potential therapy for nonalcoholic fatty liver disease (NAFLD) without approval and comprehensive assessment in recent years, which call for a meta-analysis. Methods. We performed electronic and manual searches including English and Chinese databases published before April 2019, with the use of mesh term and free text of “nonalcoholic fatty liver disease” and “probiotics.” Clinical trials evaluating the efficacy of probiotic therapy in NAFLD patients were included according to the eligibility criteria. With the use of random effects models, clinical outcomes were presented as weighted mean difference (WMD) with 95% confidence interval (CI), while heterogeneity and meta-regression were also assessed. Results. 28 clinical trials enrolling 1555 criterion proven NAFLD patients with the use of probiotics from 4 to 28 weeks were included. Overall, probiotic therapy had beneficial effects on body mass index (WMD: -1.46, 95% CI: [-2.44, -0.48]), alanine aminotransferase (WMD: -13.40, 95% CI: [-17.03, -9.77]), aspartate transaminase (WMD: -13.54, 95% CI: [-17.86, -9.22]), gamma-glutamyl transpeptidase (WMD: -9.88, 95% CI: [-17.77, -1.99]), insulin (WMD: -1.32, 95% CI: [-2.43, -0.21]), homeostasis model assessment-insulin resistance (WMD: -0.42, 95% CI: [-0.73, -0.12]), and total cholesterol (WMD: -15.38, 95% CI: [-26.50, -4.25]), but not in fasting blood sugar, lipid profiles, or tumor necrosis factor-alpha. Conclusion. The systematic review and meta-analysis support that probiotics are superior to placebo in NAFLD patients and could be utilized as a common complementary therapeutic approach.

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Efficacy of resveratrol supplementation in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis of clinical trials

Complementary Therapies in Clinical Practice ◽

10.1016/j.ctcp.2020.101281 ◽

2021 ◽

Vol 42 ◽

pp. 101281

Author(s):

Sahar Rafiee ◽

Hamed Mohammadi ◽

Abed Ghavami ◽

Erfan Sadeghi ◽

Zahra Safari ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Meta Analysis ◽

Nonalcoholic Fatty Liver

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A Comprehensive Systematic Review of the Effects of Naringenin, a Citrus-Derived Flavonoid, on Risk Factors for Nonalcoholic Fatty Liver Disease

Advances in Nutrition ◽

10.1093/advances/nmaa106 ◽

2020 ◽

Cited By ~ 1

Author(s):

Fatemeh Naeini ◽

Zahra Namkhah ◽

Alireza Ostadrahimi ◽

Helda Tutunchi ◽

Mohammad Javad Hosseinzadeh-Attar

Keyword(s):

Risk Factors ◽

Systematic Review ◽

Clinical Trials ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Therapeutic Effects ◽

Nonalcoholic Fatty Liver ◽

Promising Therapeutic Approach

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver dysfunction worldwide. Recently, some natural compounds have attracted growing interest in the treatment of NAFLD. In this context, most attention has been paid to natural products derived from fruits, vegetables, and medicinal herbs. Naringenin, a natural flavanone, has been revealed to have pharmacological effects in the treatment of obesity and associated metabolic disorders such as NAFLD. The aim of this study was to examine the therapeutic effects of naringenin and its possible mechanisms of action in the management of NAFLD and related risk factors. The current systematic review was performed according to the guidelines of the 2015 PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statements. We searched PubMed/Medline, Science Direct, Scopus, ProQuest, and Google Scholar databases up until February 2020. Of 1217 full-text articles assessed, 36 studies met the inclusion criteria. The evidence reviewed in the present study indicates that naringenin modulates several biological processes related to NAFLD including energy balance, lipid and glucose metabolism, inflammation, and oxidative stress by different mechanisms. Overall, the favorable effects of naringenin along with its more potency and efficacy, compared with other antioxidants, indicate that naringenin may be a promising therapeutic approach for the management of NAFLD and associated complications. However, due to the lack of clinical trials, future robust human randomized clinical trials that address the effects of naringenin on NAFLD and other liver-related diseases are crucial. Further careful human pharmacokinetic studies are also needed to establish dosage ranges, as well as addressing preliminary safety and tolerability of naringenin, before proceeding to larger-scale endpoint trials.

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How to Diagnose Nonalcoholic Fatty Liver Disease

Digestive Diseases ◽

10.1159/000447277 ◽

2016 ◽

Vol 34 (Suppl. 1) ◽

pp. 19-26 ◽

Cited By ~ 6

Author(s):

Nimantha M.W. de Alwis ◽

Quentin M. Anstee ◽

Christopher P. Day

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Liver Biopsy ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Acoustic Radiation Force Impulse ◽

Nonalcoholic Fatty Liver ◽

Blood Tests ◽

Nafld Fibrosis Score

Patients with nonalcoholic fatty liver disease (NAFLD) are asymptomatic and present with either unexplained abnormal liver blood tests or a bright liver on ultrasonography. Some patients will have normal liver blood tests raising the issue of whether patients with risk factors for NAFLD (diabetes and/or metabolic syndrome [MS]) should be screened for its presence with biomarkers, such as the fatty liver index (FLI). The diagnosis of NAFLD requires the exclusion of other causes of chronic liver disease and steatosis, especially heavy alcohol consumption and viral hepatitis particularly HCV genotype 3. Diagnostic work-up should include evaluation of family and personal history of components of the MS and assessment of liver tests, fasting blood glucose, triglycerides and HDL levels. A drug history is important due to a number being associated with steatosis. To confirm the diagnosis of NAFLD and quantify steatosis, ultrasound (US) and MRI-based techniques are available but none are in routine use outside clinical trials. Standard US is no more accurate than biomarkers such as FLI. The accurate staging of NAFLD requires liver biopsy; however, this is clearly impractical for such a prevalent disease. Accordingly, a number of imaging and blood-based biomarker tests have been evaluated. While none have proved reliable for the diagnosis of nonalcoholic steatohepatitis, several have proved accurate in diagnosing the presence of stage 3 or 4 fibrosis, including the NAFLD fibrosis score, fibrosis-4 and the enhanced liver fibrosis test. Of the imaging techniques, elastography has received the most attention and is being used in routine clinical practice. US acoustic radiation force impulse imaging, and MR-based elastography have recently been described but none are sufficiently accurate to replace liver biopsy for clinical trials as yet or are cost effective for use in routine clinical settings.

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