Safety and efficacy of resmetirom in the treatment of patients with non-alcoholic steatohepatitis and liver fibrosis: a systematic review and meta-analysis
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SUBMITTER: Raja A
PROVIDER: S-EPMC11230798 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
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Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty liver disease, including non-alcoholic fatty liver (NAFL) and its more progressive form, non-alcoholic steatohepatitis (NASH). The prevalence of NAFLD/NASH along with type 2 diabetes and obesity is rising worldwide. In those who develop NASH, unlike those with bland steatosis (NAFL), lipotoxic lipids drive hepatocyte injury, inflammation and stellate cell activation leading to progressive accumulation of collagen or fibrosis, ultimately leading to cirrhosis and increased risk of hepatocellular carcinoma. Hypothyroidism is associated with NAFLD/NASH; specifically, intrahepatic hypothyroidism drives lipotoxicty in preclinical models. Agonists of thyroid hormone receptor (THR)-β, which is primarily found in the liver, can promote lipophagy, mitochondrial biogenesis and mitophagy, stimulating increased hepatic fatty acid β-oxidation, and thereby decreasing the burden of lipotoxic lipids, while promoting low-density lipoprotein (LDL) uptake and favourable effects on lipid profiles. A number of THR-β agonists are currently being investigated for NASH. This review focuses on resmetirom, an orally administered, once-daily, small-molecule, liver-directed, ß-selective THR agonist, as it is furthest along in development. Data from completed clincal studies outlined in this review demonstrate that resmetirom is effective in reducing hepatic fat content as measured by magnetic resonance imaging-derived proton density fat fraction, reduces liver enzymes, improves non-i nvasive markers of liver fibrogenesis and decreases liver stiffness, while eliciting a favourable cardiovascular profile with a reduction in serum lipids, including LDL cholesterol. Topline phase III biopsy data showed resolution of NASH and/or fibrosis improvement after 52 weeks of treatment, with more detailed peer-reviewed findings anticipated in order to certify these findings. Longer term clinical outcomes from both MAESTRO-NASH and MAESTRO-NASH OUTCOMES will be a pivotal juncture in the drug's road towards being approved as a NASH therapeutic.
| S-EPMC10258622 | biostudies-literature
Project description:Thiazolidinediones (TZDs) have been used in the treatment of non-alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically.To conduct a meta-analysis of randomised, placebo-controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH.Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters.Four good quality RPCTs derived from three continents were included. The meta-analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33-3.36), 2.58 (95% CI, 1.68-3.97) and 3.39 (95% CI, 2.19-5.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03-14.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.02-2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment.Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo-controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis.
| S-EPMC3488596 | biostudies-literature
Project description:Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.
| S-EPMC8106094 | biostudies-literature
Project description:Background and aimThe progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is believed to be the driver for future development of fibrosis and cirrhosis. Nevertheless, there remains a clear deficit in non-invasive methods for the diagnosis of NASH. The aim of the present study was to evaluate the prevalence of portal lymphadenopathy (PL) in biopsy- proven NAFLD patients and to determine whether PL correlates with NAFLD stage and severity.MethodsA retrospective study included biopsy-proven NAFLD patients with up to date (within one year) abdominal imaging by computed tomography (CT) and/or magnetic resonance imaging (MRI). Patients were clustered into three groups based on their NAFLD Activity Score (NAS): NAS1-2 (mild), NAS3-4 (moderate) and NAS≥5 (advanced). We Assessed for association between PL and other clinical and laboratory findings with NAS, NAS components and fibrosis.ResultsSeventy-five patients with NAFLD and no other competing etiologies for liver diseases or PL were included. The mean age was 50.7±14.84 years with male predominance (N = 47, 62.7%). Twenty-five (33.3%), 37 (49.3%) and 13 (17.3%) patients had mild, moderate and advanced NAS, respectively. PL significantly correlated with advanced NAS ≥ 5 (Fisher's (F) 9.5, P = 0.009). Correlation was driven mainly by a link to hepatocytes ballooning (F of 5.9, P = 0.043). In addition, PL significantly correlated with portal inflammation (F 4.29, P = 0.038). As for hepatic fibrosis, the F test wasn't significant, though spearman's coefficient (SC) was significant (0.277, P = 0.012). On multivariate analysis, PL was identified as a sole predictor of advanced NAS score (Odds ratio of 2.68, P = 0.002). Incorporation of PL into noninvasive fibrosis scores improved their diagnostic yield.ConclusionPL predicts severity of NAFLD. Its presence may serve as a novel radiological marker for NAFLD/NASH differentiation and disease progression.
| S-EPMC6267957 | biostudies-literature
Project description:IntroductionNon-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder over the last four decades, more evidence shows a high prevalence of sarcopenia in NAFLD that may influence disease severity. This meta-analysis aims to determine the association of sarcopenia with liver fibrosis and steatohepatitis in NAFLD.Methods and analysisWe will conduct the literature search using Medline (via PubMed), Web of Science databases, EMBASE, Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews (from the date of inception to 1 May 2022). There will be no restriction to the publication year. Two reviewers will independently screen the articles and abstract key study characteristics. The outcome of this meta-analysis is the strength of association of sarcopenia with liver fibrosis and steatohepatitis in NAFLD. The STATA (V.14, StataCorp, 2015) will be used to carry out the statistical analysis. Comprehensive evaluation of bias risk and heterogeneity will be performed before data synthesis. Also, consistency and evidence quality will be assessed.Ethics and disseminationThere will be no need of ethics approval as this systematic review is summary and analysis of existing literature. Final results may be presented in international conferences or a peer-reviewed journal.Prospero registration numberCRD42022322685.
| S-EPMC9900053 | biostudies-literature
Project description:BackgroundSeveral studies have emerged indicating that sarcopenia is associated with nonalcoholic fatty liver disease, we aimed to systematically review and quantify the association between sacropenia and the histological severity of nonalcoholic fatty liver disease.MethodsPubmed, the Cochrane Library and EMBASE were searched (until August 2017) for studies examining the relationship of sarcopenia with steatohepatitis and advanced liver fibrosis in nonalcoholic fatty liver disease. Pooled odds ratios were estimated by fixed effects models.ResultsThree articles met our inclusion criteria, with a total of 3226 individuals. Two of the studies examined the association between sacropenia and steatohepatitis, a significant association was documented between sarcopenia and steatohepatitis (OR = 2.35, 95%CI 1.45, 3.81). All of the three studies assessed the association between sacropenia and advanced liver fibrosis, a significant association between sarcopenia and advanced liver fibrosis (OR = 2.41, 95%CI 1.94, 2.98). No significant heterogeneity was detected among studies in all comparisons. These results remained essentially unchanged after excluding any of the studies in the sensitivity analysis.ConclusionsSarcopenia in patients with nonalcoholic fatty liver disease is associated with a higher likelihood of having steatohepatitis or advanced liver fibrosis. Demonstration of the role of sarcopenia in nonalcoholic fatty liver disease development in future studies could have important therapeutic implications.
| S-EPMC5907709 | biostudies-literature
Project description:BackgroundNon-alcoholic fatty liver (NAFL) can progress to the severe subtype non-alcoholic steatohepatitis (NASH) and/or fibrosis, which are associated with increased morbidity, mortality, and healthcare costs. Current machine learning studies detect NASH; however, this study is unique in predicting the progression of NAFL patients to NASH or fibrosis.AimTo utilize clinical information from NAFL-diagnosed patients to predict the likelihood of progression to NASH or fibrosis.MethodsData were collected from electronic health records of patients receiving a first-time NAFL diagnosis. A gradient boosted machine learning algorithm (XGBoost) as well as logistic regression (LR) and multi-layer perceptron (MLP) models were developed. A five-fold cross-validation grid search was utilized for hyperparameter optimization of variables, including maximum tree depth, learning rate, and number of estimators. Predictions of patients likely to progress to NASH or fibrosis within 4 years of initial NAFL diagnosis were made using demographic features, vital signs, and laboratory measurements.ResultsThe XGBoost algorithm achieved area under the receiver operating characteristic (AUROC) values of 0.79 for prediction of progression to NASH and 0.87 for fibrosis on both hold-out and external validation test sets. The XGBoost algorithm outperformed the LR and MLP models for both NASH and fibrosis prediction on all metrics.ConclusionIt is possible to accurately identify newly diagnosed NAFL patients at high risk of progression to NASH or fibrosis. Early identification of these patients may allow for increased clinical monitoring, more aggressive preventative measures to slow the progression of NAFL and fibrosis, and efficient clinical trial enrollment.
| S-EPMC8938756 | biostudies-literature
Project description:Background & aimsLiver fibrosis is the most worrisome feature of non-alcoholic steatohepatitis (NASH). Growing evidence supports a link between hepatocyte apoptosis and liver fibrogenesis. Our aim was to determine the therapeutic efficacy and safety of liver Bid, a key pro-apoptotic molecule, suppression using RNA interference (RNAi) for the treatment of fibrosis.MethodsFirst, we optimized the delivery system for Bid siRNA in mice using ten different stealth RNAi siRNAs and two lipid formulations -Invivofectamine2.0 and a newly developed Invivofectamine3.0 - that have been designed for high efficacy accumulation in the liver, assessed via real-time PCR of Bid mRNA. Next, C57BL/6 mice were placed on a choline-deficient L-amino acid defined (CDAA) diet. After 19weeks of the CDAA diet, a time point that results in severe fibrotic NASH, mice were injected with the selected Bid siRNA-Invivofectamine3.0 biweekly for three weeks. Additionally hepatocyte-specific Bid deficient (Bid(Δhep)) mice were placed on CDAA diet for 20weeks.ResultsA maximum Bid knockdown was achieved at 1.5mg/kg siRNA with Invivofectamine3.0, whereas it was at 7mg/kg with Invivofectamine2.0. In NASH mice, after 3weeks of treatment, BID protein was reduced to 10% and this was associated with an improvement in liver fibrosis and inflammation associated with a marked reduction in TUNEL positive cells, caspase 3 activation, and a reduction in mitochondrial BAX and BAK. Bid(Δhep) mice showed similar protection from fibrotic changes.ConclusionOur data demonstrate that liver Bid suppression by RNAi technology, as well as hepatocyte-specific Bid deficiency, improves liver fibrosis coupled with a reduction of inflammation in experimental NASH. These findings are consistent with existing evidence that hepatocyte apoptosis triggers hepatic stellate cell activation and liver fibrosis and suggest that Bid inhibition may be useful as an antifibrotic NASH therapy.
| S-EPMC4761314 | biostudies-literature
Project description:The incidence of non-alcoholic fatty liver disease (NAFLD) is rising across the globe, with the presence of steatohepatitis leading to a more aggressive clinical course. Currently, the diagnosis of non-alcoholic steatohepatitis (NASH) is based on histology, though with the high prevalence of NAFLD, a non-invasive method is needed. The 13C-aminopyrine breath test (ABT) evaluates the microsomal liver function and could be a potential candidate. We aimed to evaluate a potential change in liver function in NASH patients and to evaluate the diagnostic power of ABT to detect NASH. We performed a retrospective analysis on patients suspected of NAFLD who underwent a liver biopsy and ABT. 440 patients were included. ABT did not decrease in patients with isolated liver steatosis but decreased significantly in the presence of NASH without fibrosis and decreased even further with the presence of significant fibrosis. The predictive power of ABT as a single test for NASH was low but improved in combination with ALT and ultrasonographic steatosis. We conclude that microsomal liver function of patients with NASH is significantly decreased, even in the absence of fibrosis. The ABT is thus a valuable tool in assessing the presence of NASH; and could be used as a supplementary diagnostic tool in clinical practice.
| S-EPMC7760673 | biostudies-literature
Project description:ObjectiveClinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis.DesignThis multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16- monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis.ResultsThe algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography.ConclusionsThe proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers.Clinical trialsDiscovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.
| S-EPMC9872242 | biostudies-literature