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The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 2·2, 95% CI 1·4 to 3·3; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH. MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1–3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260. 348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (−32·9% resmetirom vs −10·4% placebo; least squares mean difference −22·5%, 95% CI −32·9 to −12·2; p<0·0001) and week 36 (−37·3% resmetirom [n=74] vs −8·5 placebo [n=34]; −28·8%, −42·0 to −15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom. Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging. Madrigal Pharmaceuticals.

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study ( NCT03248882 ) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging–proton density fat fraction. Dose-dependent reductions in liver fat reached 50–65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was −7.2 (−13.9, 0.0), −17.1 (−22.7, −11.1), −49.9 (−53.3, −46.2), −55.9 (−59.0, −52.4) and −64.8 (−67.5, −62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) −44.6% (−54.8, −32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was −44.5% (−55.0, −31.7) and −35.4% (−47.4, −20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone. Two phase 2a trials demonstrate the efficacy of a new ACC inhibitor (PF 05221304) for reducing liver fat in patients with NAFLD, with co-administration of a DGAT2 inhibitor (PF-06865571) mitigating ACC inhibitor-mediated increases in serum triglycerides.

Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis. In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis. A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P = 0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range. In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality. Normothermic machine perfusion of the liver improved early graft function, demonstrated by reduced peak serum aspartate transaminase levels and early allograft dysfunction rates, and improved organ utilization and preservation times, although no differences were seen in graft or patient survival.

A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD. A randomized, parallel controlled, open-label clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR. As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression. BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism. ClinicalTrials.gov NCT00633282.

BackgroundFatty acid translocase CD36 (FAT/CD36) mediates uptake and intracellular transport of long-chain fatty acids in diverse cell types. While the pathogenic role of FAT/CD36 in hepatic steatosis in rodents is well-defined, little is known about its significance in human liver diseases.ObjectiveTo examine the expression of FAT/CD36 and its cellular and subcellular distribution within the liver of patients with non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection.Patients34 patients with non-alcoholic steatosis (NAS), 30 with non-alcoholic steatohepatitis (NASH), 66 with HCV genotype 1 (HCV G1) and 32 with non-diseased liver (NL).MethodsReal-time PCR and western blot analysis were used to assess hepatic FAT/CD36 expression. Computational image analysis of immunostained liver biopsy sections was performed to determine subcellular distribution and FAT/CD36 expression index.ResultsCompared with NL, hepatic mRNA and protein levels of FAT/CD36 were significantly higher in patients with NAS (median fold increase 0.84 (range 0.15–1.61) and 0.66 (range 0.33–1.06), respectively); NASH (0.91 (0.22–1.81) and 0.81 (0.38–0.92), respectively); HCV G1 without steatosis (0.30 (0.17–1.59) and 0.33 (0.29–0.52), respectively); and HCV G1 with steatosis (0.85 (0.15–1.98) and 0.87 (0.52–1.26), respectively). In contrast to NL, FAT/CD36 was predominantly located at the plasma membrane of hepatocytes in patients with NAFLD and HCV G1 with steatosis. A significant correlation was observed between hepatic FAT/CD36 expression index and plasma insulin levels, insulin resistance (HOMA-IR) and histological grade of steatosis in patients with NASH (r=0.663, r=0.735 and r=0.711, respectively) and those with HCV G1 with steatosis (r=0.723, r=0.769 and r=0.648, respectively).ConclusionsHepatic FAT/CD36 upregulation is significantly associated with insulin resistance, hyperinsulinaemia and increased steatosis in patients with NASH and HCV G1 with fatty liver. Translocation of this fatty acid transporter to the plasma membrane of hepatocytes may contribute to liver fat accumulation in patients with NAFLD and HCV.

Aims/hypothesisIn addition to beneficial effects on glycaemia and cardiovascular death, empagliflozin improves adiposity indices. We investigated the effect of empagliflozin on aminotransferases (correlates of liver fat) in individuals with type 2 diabetes.MethodsChanges from baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in the EMPA-REG OUTCOME® trial (n = 7020), pooled data from four 24-week placebo-controlled trials (n = 2477) and a trial of empagliflozin vs glimepiride over 104 weeks (n = 1545). Analyses were performed using data from all participants and by tertiles of baseline aminotransferases.ResultsIn the EMPA-REG OUTCOME® trial, mean ± SE changes from baseline ALT at week 28 were −2.96 ± 0.18 and −0.73 ± 0.25 U/l with empagliflozin and placebo, respectively (adjusted mean difference: −2.22 [95% CI −2.83, −1.62]; p < 0.0001). Reductions in ALT were greatest in the highest ALT tertile (placebo-adjusted mean difference at week 28: −4.36 U/l [95% CI −5.51, −3.21]; p < 0.0001). The adjusted mean difference in change in ALT was −3.15 U/l (95% CI −4.11, −2.18) with empagliflozin vs placebo at week 24 in pooled 24-week data, and −4.88 U/l (95% CI −6.68, −3.09) with empagliflozin vs glimepiride at week 28. ALT reductions were largely independent of changes in weight or HbA1c. AST changes showed similar patterns to ALT, but the reductions were considerably lower.Conclusions/interpretationThese highly consistent results suggest that empagliflozin reduces aminotransferases in individuals with type 2 diabetes, in a pattern (reductions in ALT>AST) that is potentially consistent with a reduction in liver fat, especially when ALT levels are high.