Stage F4 Research Articles

Comparison of Two-Dimensional Shear Wave Elastography Between Two Different Instruments for Hepatocellular Carcinoma Patients.

This study aimed to investigate and compare 2-dimensional shear wave elastography (2D-SWE) measurements and influencing factors among 2 different devices and to evaluate the ability and influencing factors of these measurements to assess liver fibrosis. From October 2022 to September 2023, 290 hepatocellular carcinoma (HCC) patients and 30 healthy volunteers were prospectively included. The 2D-SWE measurements were performed using AixPlorer V (SEmean) and APLIO i900 (CEmean). This study compared 2D-SWE measurements between instruments for evaluating the liver fibrosis stage and analyzed the potential influencing factors. The 2D-SWE measurements obtained by the 2 instruments were significantly different (P < .001), but the differences were significant only for patients with stage F4 liver fibrosis (P < .001) and not for volunteers or patients with stage F0-F3 liver fibrosis (all P > .050). Multivariate linear regression analysis revealed that the factors independently influencing the SEmean were alanine aminotransferase (ALT) (P = .034) and liver fibrosis stage (P < .001), while fibrosis stage (P = .028) was the only factor influencing the CEmean. Although 2D-SWE from the 2 different instruments was capable of detecting liver fibrosis, it yielded varying results in HCC patients. These discrepancies were predominantly observed in patients with F4 liver fibrosis but not in healthy adults or patients with F0-F3 liver fibrosis. One potential contributing factor to the differences between instruments could be ALT levels.

Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial.

Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis. This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment. Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related. Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development. Sagimet Biosciences.

Density of Limnoperna fortunei larval stages in a cascade of subtropical reservoirs: spatiotemporal variation and environmental influences.

The golden mussel (Limnoperna fortunei) is an invasive bivalve that has established itself in several South American river systems, impacting ecosystem functioning. Reservoir cascades provide their larvae with the means of rapid dispersal, but the relationship between environmental variables and larval stage structure remains unclear. In this study, the density of three L. fortunei larval stages and quantitative detection using DNA are analyzed in a cascade of five reservoirs in the upper Uruguay River Basin and associated with spatiotemporal variation in environmental parameters. The analysis of L. fortunei eDNA presence and absence in freshwater systems appears to be a valuable mapping tool; however, no significant link was found between the eDNA magnitude and the overall larval density. The increase in larval density was related to the fluctuation of environmental parameters over a year, with the highest average larval densities observed in the CN and ITA reservoirs, though no significant difference was observed between the five reservoirs, where D-shaped larvae predominated. During winter, larval density decreased significantly, however, other variables also contribute to species activity and development in the upper Uruguay River Basin reservoirs and may be considered limiting factors. The relationships between environmental parameters were evaluated using a multivariate model. The interaction between reservoir area and precipitation, water temperature, electrical conductivity, and dissolved oxygen had a significant effect on larval density but showed specific influences on each larval stage. Any increase in density was regulated by dissolved oxygen and electrical conductivity content at all larval stages. Furthermore, total phosphorus affected the density of F1 and F3 larvae. The interaction between reservoir area and precipitation, nitrate content, phosphate concentrations, and water temperature had the most influence on the density of F2 and F3 larval stages; the F1 stage was mainly affected by calcium concentrations. The isolated effect of precipitation also contributed to the density of F2 and F3 larvae. Our findings shed light on the interaction between different phases of golden mussel larvae and the main nutrients found in reservoirs, which may be a determining factor in the rise in density of the non-native species in these systems.

The impact of vildagliptin as an add-on therapy on matrix metalloproteinase-14 levels, liver stiffness and subclinical atherosclerosis in adolescents with type 1 diabetes and non-alcoholic steatohepatitis: A randomized controlled trial.

Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non-alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase-14 (MMP-14) is involved in cardiovascular disease and atherosclerosis. To assess the impact of oral dipeptidyl peptidase-4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP-14 levels and carotid intima media thickness (CIMT). Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP-14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT. By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP-14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post-therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well-tolerated. Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP-14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression.

Optimal cut-offs of vibration-controlled transient elastography and magnetic resonance elastography in diagnosing advanced liver fibrosis in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Opinions differ regarding vibration-controlled transient elastography and magnetic resonance elastography (VCTE/MRE) cut-offs for diagnosing advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD). We investigated the diagnostic performance and optimal cut-off values of VCTE and MRE for diagnosing AF. Literature databases, including Medline, EMBASE, Cochrane Library, and KoreaMed, were used to identify relevant studies published up to June 13, 2023. We selected studies evaluating VCTE and MRE regarding the degree of liver fibrosis using liver biopsy as the reference. The sensitivity, specificity, and area under receiver operating characteristics curves (AUCs) of the pooled data for VCTE and MRE for each fibrosis stage and optimal cut-offs for AF were investigated. A total of 19,199 patients from 63 studies using VCTE showed diagnostic AUC of 0.83 (95% confidence interval: 0.80-0.86), 0.83 (0.80-0.86), 0.87 (0.84-0.90), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. Similarly, 1,484 patients from 14 studies using MRE showed diagnostic AUC of 0.89 (0.86-0.92), 0.92 (0.89-0.94), 0.89 (0.86-0.92), and 0.94 (0.91-0.96) for ≥F1, ≥F2, ≥F3, and F4 stages, respectively. The diagnostic AUC for AF using VCTE was highest at 0.90 with a cut-off of 7.1-7.9 kPa, and that of MRE was highest at 0.94 with a cut-off of 3.62-3.8 kPa. VCTE (7.1-7.9 kPa) and MRE (3.62-3.8 kPa) with the suggested cut-offs showed favorable accuracy for diagnosing AF in patients with NAFLD. This result will serve as a basis for clinical guidelines for non-invasive tests and differential diagnosis of AF.

Budget impact of resmetirom for the treatment of adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis)

Aims This study assessed the budget impact of resmetirom as a treatment for adults with non-cirrhotic non-alcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis and estimated total costs for a hypothetical private payer in the United States. Materials and methods A three-year budget impact analysis based on an open cohort state transition model was developed for a hypothetical one-million-member private health plan. The comparator was Standard of Care (SOC), defined as routine care for non-cirrhotic NASH patients with moderate-to-advanced liver fibrosis. Each year, the number of resmetirom treatment-eligible patients was estimated through prevalent, incident, and diagnostic rate estimates. Costs included resources incurred by the medical and pharmacy benefits of private payers, including resmetirom drug acquisition costs, diagnosis and monitoring, other medical and other prescription costs stratified by disease progression status (i.e. non-cirrhotic vs. cirrhotic/advanced liver diseases). Resmetirom adverse event management costs were included in sensitivity analysis. Drug costs were estimated based on the average wholesale acquisition cost as of March 2024. Other costs were based on published sources and inflated to 2023 US dollars. Budget impact outcomes were presented in aggregate, net, and on a per-member per-month (PMPM) basis. Results Compared with a scenario without resmetirom, the introduction of resmetirom yielded results ranging from 50 to 238 treated patients, net budget impact of $2.2 to $9.5 million, and PMPM from $0.19 to $0.80 over years one and three. Net costs excluding resmetirom declined over time. In sensitivity analyses, results were most sensitive to diagnostic and epidemiologic inputs. Limitations Market shares are based on internal forecasts, a short time horizon, average treatment effects, and other limitations common to BIMs. Conclusion The adoption of resmetirom on the formulary for the treatment of non-cirrhotic NASH with moderate-to-advanced liver fibrosis resulted in a moderate increase in budget impact with declining costs related to NASH progression.

US Markers and Necroinflammation, Steatosis, and Fibrosis in Metabolic Dysfunction-associated Steatotic Liver Disease: The iLEAD Study.

Background Attenuation coefficient (AC) and shear-wave speed (SWS) are established US markers for assessing patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while shear-wave dispersion slope (DS) is not. Purpose To assess the relationship between the multiparametric US imaging markers DS, AC, and SWS and liver histopathologic necroinflammation in patients with MASLD. Materials and Methods This international multicenter prospective study enrolled consecutive patients with biopsy-proven MASLD between June 2019 and March 2023. Before biopsy, all participants underwent multiparametric US, and measurements of DS, AC, and SWS were obtained. Multivariable linear regression analyses were performed to assess the association of clinical variables and imaging markers with pathologic findings. The diagnostic performance of imaging markers for determining inflammation grade, steatosis grade, and fibrosis stage was assessed using the area under the receiver operating characteristic curve (AUC). Results A total of 124 participants (mean age, 53 years ± 15 [SD]; 62 males) were evaluated. In multivariable regression, lobular inflammation was associated with DS (regression coefficient, 0.06; P = .02), alanine aminotransferase level (regression coefficient, 0.002; P = .002), and Hispanic or Latino ethnicity (regression coefficient, -0.68; P = .047), while steatosis was associated with AC (regression coefficient, 3.66; P < .001) and fibrosis was associated with SWS (regression coefficient, 2.02; P < .001) and body mass index (regression coefficient, 0.05; P = .02). DS achieved an AUC of 0.72 (95% CI: 0.63, 0.82) for identifying participants with inflammation grade A2 or higher (moderate to severe inflammation). AC showed excellent performance for identifying participants with grade S1 (mild) or higher steatosis (AUC, 0.92 [95% CI: 0.87, 0.97]), while SWS showed excellent performance for identifying participants with fibrosis stage F2 or higher (clinically significant fibrosis) (AUC, 0.91 [95% CI: 0.86, 0.96]). Of the three US markers, SWS showed the highest AUC (0.81 [95% CI: 0.74, 0.89]) for the diagnosis of metabolic dysfunction-associated steatohepatitis. Conclusion Of the three US imaging markers (DS, AC, and SWS), DS was most associated with lobular inflammation grade at histologic examination and demonstrated fair diagnostic performance in distinguishing moderate to severe lobular inflammation. ClinicalTrials.gov Identifier: NCT04012242 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Yin in this issue.

Influence of Urea Foliar Nutrition and Leaf Harvesting Intensity on Growth, Yield Attributes and Yield in Cowpea [Vigna unguiculta (L.) Walp.

A field experiment was undertaken at Farming Systems Research Station (FSRS), Sadanandapuram, Kollam district, Kerala Agricultural University in summer 2022 for studying the effect of growth, yield attributes and yield of cowpea through foliar application of 2% urea and intensity of leaf harvesting. Experimental treatments comprised of 4 levels of foliar nutrition management (2% urea spray at vegetative stage (f1), 2% urea spray at flowering stage (f2), 2% urea spray at vegetative stage and flowering stage (f3), water spray control (f4) and 3 levels of leaf harvest (20% leaf harvest (l1), 40% leaf harvest (l2), and no leaf harvest (l3). Among the foliar nutrition management treatments, f3 showed significantly the taller plants (91.97 cm), more number of branches (15.13), leaves (34.76), leaf area/ plant (884.29 cm2), leaf area index (1.96) dry matter production (42.39 g) and chlorophyll content (3.544 mg/g) and were comparable with f1. The nodule parameters such as nodule number (37.44) and effective number of nodules (32.11) were the highest in treatment f3 and was on par with f1. Further, days to 50 per cent flowering (53.65 days), pod length (17.27 cm), 100 seed weight (12.40 g), pod number (24.58), foliage yield (1484.57 kg ha-1), grain yield (925.85 kg ha-1) and haulm yield (2722.70 kg ha-1) were the highest in treatment f3 and was on par with f1 except for pod weight (21.19 g). Among the leaf harvest intensity, treatment l3 recorded the taller plants (92.45 cm), leaf area per plant (902.71cm2) leaf area index (2.01), less days to 50% flowering (47.60 days) and haulm yield (2754.85 kg ha-1). It was on par with l1 pertaining to plant height. The number of branches (15.03), dry matter production per plant (40.78g), pod weight/plant (19.43 g), pod number/plant (23.59) and grain yield (925.85 kg ha-1) were the highest in treatment l1.

A Comparative Study of Novel Fibrosis Index and Other Non-invasive Serum Indices for Predicting Fibrosis in Patients of Chronic Liver Disease.

Introduction Chronic liver diseaseprogression leads to liver fibrosis/cirrhosis. Transient Elastography is used for staging liver fibrosis but ascites, obesity, and operator experience limit its applicability. In this study, we compared various non-invasive serum indices in predicting fibrosis in chronic liver disease patients. Materials and methods A total of 142 cases of confirmed Chronic Liver Disease were included. Quantitative determination of liver stiffness by Transient Elastography and relevant blood investigations was done. We compared the liver stiffness measurement by Transient Elastography and fibrosis indices, i.e., Aspartate Transaminase (AST) to Alanine Transaminase (ALT) Ratio (AAR), AST to Platelet Ratio Index (APRI), Fibrosis Index (FI), Fibrosis-4 (FIB-4) Index, Age-Platelet Index (API), Pohl score, and Fibrosis Cirrhosis Index (FCI) with Novel Fibrosis Index (NFI), to predict liver fibrosis stages. Results The optimum cutoff of NFI for the F4 stage was ≥ 6670 with a sensitivity of 75.8% and specificity of 81.8%, for the F3 stage was ≥ 2112 with a sensitivity of 63.6%and specificity of 72.7%, and for the F2 stage was ≥ 1334 with a sensitivity of 100% and specificity of 56.3%. The NFI had the maximum area under the curve compared to other indices in predicting fibrosis stages. Conclusion The Novel Fibrosis Index was the best in predicting fibrosis stages in Chronic Liver Disease patients, with good performance in predicting the F4 stage.

Diagnostic performance of two-dimensional shear wave elastography and attenuation imaging for fibrosis and steatosis assessment in chronic liver disease.

We investigated the diagnostic performance of two-dimensional shear wave elastography (2D-SWE) and attenuation imaging (ATI) in detecting fibrosis and steatosis in patients with chronic liver disease (CLD), comparing them with established methods. In 190 patients with CLD, 2D-SWE and vibration-controlled transient elastography (VCTE) were used for liver stiffness measurement (LSM), and ATI and controlled attenuation parameter (CAP) were used for steatosis quantification. The correlations between these new and established methods were analyzed. Significant correlations were found between 2D-SWE and VCTE (r = 0.78, P < 0.001), and between ATI and CAP (r = 0.70, P < 0.001). Liver stiffness tended to be lower with 2D-SWE compared with that with VCTE, especially in cases with higher LSM, and ATI was less influenced by skin-capsular distance than CAP. Area under the receiver-operating characteristics curves (AUCs) and optimal cut-offs of 2D-SWE for diagnosing liver fibrosis stages F2, F3, and F4 were 0.73 (8.7kPa), 0.79 (9.1kPa), and 0.88 (11.6kPa), respectively. The AUCs and optimal cut-offs of ATI for diagnosing hepatic steatosis grades S1, S2, and S3 were 0.91 (0.66dB/cm/MHz), 0.80 (0.79dB/cm/MHz), and 0.88 (0.86dB/cm/MHz), respectively. A subgroup analysis of 86 patients with metabolic dysfunction-associated steatotic liver disease also demonstrated good performance for 2D-SWE and ATI. 2D-SWE and ATI performed comparably with conventional VCTE and CAP in evaluating CLD, offering reliable alternatives for diagnosing liver fibrosis and steatosis.

Tirzepatide for Metabolic Dysfunction–Associated Steatohepatitis with Liver Fibrosis

BackgroundMetabolic dysfunction–associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.MethodsWe conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.ResultsAmong 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.ConclusionsIn this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.)

A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis

BackgroundDual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction–associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear.MethodsIn this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage.ResultsA total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose–response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo.ConclusionsSurvodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.)

Resmetirom: First Approval.

Resmetirom (Rezdiffra™) is an oral thyroid hormone receptor-β (THR-β) agonist being developed by Madrigal Pharmaceuticals, Inc., to target the key underlying causes of metabolic dysfunction associated steatohepatitis (MASH) [previously known as nonalcoholic steatohepatitis (NASH)]. In March 2024, resmetirom was approved for use (under accelerated approval) in conjunction with diet and exercise for the treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis) in the USA. Resmetirom is also under regulatory review in the EU for the treatment of MASH/NASH. This article summarizes the milestones in the development of resmetirom leading to this first approval for the treatment of adults with MASH/NASH.

The structure of liver damage in patients with acute decompensated heart failure, the prognostic role of steatosis and liver density

Abstract Funding Acknowledgements None. Aim To study the spectrum of liver damage in patients with acute decompensated heart failure (ADHF). Materials and methods Included were 566 patients hospitalized with ADHF, NYHA class II–IV, 66% men, mean age 72,4±11,4 years. All patients underwent laboratory and instrumental examination, the degree of steatosis and liver density were determined by transient elastometry methods, with an assessment of the controlled ultrasound attenuation parameter (CAP - Controlled Attenuation Parameter, S, dB/m) using a device according to standard methods. CAP values &amp;lt;294 dB/m with steatosis degree 0 - S0, 295-309 dB/m - S1, 310-330 dB/m - S2, ≥331 dB/m - S3. Liver density was used: ≤5,8 kPa – normal liver density, ≥5,9 – stage F1, ≥7,2 kPa – F2, ≥9,5 kPa – F3, ≥12,5 kPa – F4. Laboratory manifestations of liver damage were considered to be increased aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase and alkaline phosphatase. Results The incidence of hepatic steatosis (≥S1) among patients with ADHF was 29%. Among patients with liver steatosis, minimal steatosis (S1) was detected in 19% of cases, moderate steatosis (S2) - 28,6%, severe steatosis S3 - 52,4%. In patients with steatosis, the frequency of laboratory indicators of liver damage was 53%, and in patients without steatosis - 49,2%. Liver density ≥ F1 was observed in 79,5% of patients. Stage F1 was diagnosed in 10,4% of cases, F2 - in 11%, F3 - 12,7%, F4 - 44,5%. However, no relationship was found between the severity of steatosis and liver density (p&amp;gt;0,05). Multivariate Cox regression analysis showed that extremely low CAP values (&amp;lt;234 dB/m) were associated with a worse prognosis and higher risk of HF mortality during the 3-year follow-up period (adjusted hazard ratio (aHR) 1,57 95% confidence interval (CI) 1,08–2,31, p=0,019) after adjustment for established risk factors and potential confounders. The presence of increased liver density &amp;gt;15,9 kPa was also associated with a worse prognosis of the risk of death from HF during the 3-year follow-up period by Cox multivariate analysis (aHR 1,24, 95% CI 1,01–1,52, p= 0,040). Conclusion Thus, extremely low CAP values (&amp;lt;234 dB/m) and the presence of a marked increase in liver density (&amp;gt;15,9 kPa) were associated with a worse prognosis in patients with ADHF during the 3-year follow-up period.

Temporal variation in quality characteristics of nutritional constituents and bacterial community during dry salt-fermentation of hilsa (Tenualosa ilisha)

Nutritional constituents and bacterial community of hilsa (Tenualosa ilisha) at different stages of dry salt-fermentation; namely, F1 (after 2 days of salting), F2 (after 5 days of salting) and F3 (ripe product after 15 days of salting) was studied. Dry salt-fermentation did not negatively affect proximate biochemical composition. Total protein content in F1, F2 and F3 was 10.14, 22.30 and 16.21 mg/ml, respectively. With progression of ripening process, protein solubility gradually decreased. In all stages, about 98% protein digestibility was found. TBARS (Thiobarbituric acid reactive substances) values at F1, F2 and F3 stages was 0.30, 0.41 and 0.95 mg MDA/kg, respectively and within acceptable limit. A total of 3,248 OTUs were found. Of the identified 48 phyla, Proteobacteria (66%), Firmicutes (18%) and Bacteroidota (11%) were abundant at F1 stage but Firmicutes (82%) and Proteobacteria (9%) were dominant at F3 stage. Significant differences in the microbial β-diversity among initial, interim and ripe product were observed. There was no significant α-diversity difference at individual stages of dry salt-fermentation of hilsa. Functional gene profile revealed that, in the final product microbial genes related to organismal systems replaced human disease related genes found in initial and interim product. These findings provide new clues for in-depth characterization of salt-fermented foods from viewpoint of food chemistry and microbiology.Graphical

Validation study of age-independent fibrosis score (Fibrosis-3 index) in patients with metabolic dysfunction-associated steatotic liver disease.

Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60years (0.645 and 0.529, respectively; p<0.0001). The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

Indicators of cellular immunity and lymphocyte metabolism in children with type 1 autoimmune hepatitis at different stages of liver fibrosis

Autoimmune hepatitis (AIH) is a progressive hepatocellular inflammation of unknown etiology, accompanied by the process of liver fibrosis. Damage in the liver is associated with the formation of highly reactive molecules that contain unpaired electrons (free radicals), which in turn induce lipid peroxidation, leading to the development of mitochondrial dysfunction. Mitochondrial DAMPs released from damaged hepatocyte mitochondria (with mtDNA as the main active component) directly activate hepatic stellate cells and cause liver scarring. Assessing cellular metabolism can be done by examining the activity of succinate dehydrogenase (SDH), a key enzyme involved in both the tricarboxylic acid cycle and OXPHOS. Aim. to examine indicators of cellular immunity and succinate dehydrogenase activity in lymphocyte populations at different stages of liver fibrosis in children with type I AIH.. Materials and methods. During hospitalization, 69 children with AIH type I, aged 12 to 18 years, Me=15.5 [12.8;16.9], were examined. 62 healthy children made up the comparison group. The stage of liver fibrosis was assessed using the FibroScan F502. The subpopulation composition of lymphocytes and the activity of succinate dehydrogenase in them were assessed using flow cytometry. The following lymphocyte populations were evaluated: T-lymphocytes, activated T-cells, B-lymphocytes, NK cells, CD16/56+CD3+ lymphocytes, cytotoxic T-lymphocytes, T-helpers, including small populations: activated T-helpers, regulatory T-cells, Th17 lymphocytes. Statistica 10.0 (USA) program was used for statistical data processing. Results. The study included 47 girls and 22 boys. Children with AIH were on standard therapy with glucocorticosteroids for 2.6 [1.1;5.4] years. In 53 children, AIH occurred in combination with gastroduodenitis (76.8% of observations), in 12 children – with gastroesophageal reflux disease (17% of observations). 7 children had comorbid autoimmune diseases or a combination of them: 5 patients had autoimmune thyroiditis (7% of cases), 2 children had vitiligo (3% of cases), as well as type 1 diabetes mellitus, juvenile rheumatoid arthritis and celiac disease in one case (1.5%), 3 children (5% of cases) had multiple autoimmune syndrome. In children with AIH, an increase in the relative content of T cells and T helper cells was detected. The relative number of NK cells and B cells was reduced in all stages of AF relative to the comparison group. A significant increase in the absolute number of Thact and Tregs was obtained at all stages of fibrosis relative to the comparison group, while the relative number of Thact (% CD4+) was significantly higher only at stages F0, F3 and F4, and the relative number of Tregs (% CD4+) was significantly higher only at stages F0 and F4. The proportion of Th17 lymphocytes (% CD4+) was significantly reduced relative to the comparison group at stages F0 and F2. From the F0 to F3 stage, the relative number of B cells decreased, and then significantly increased by the F4 stage. The proportion of T helper cells, Tregs and Thact in most patients was higher than the comparison group, however, no significant differences were found between different stages. The proportion of Th17 lymphocytes increased with increasing stage of liver fibrosis, the maximum values were detected at stage F4. A study of SDH revealed a significant decrease in the activity of this enzyme in all populations of lymphocytes. The greatest decrease in activity was detected in double negative CD3+CD4-CD8- cells by 18.5% and NK cells by 17.5% relative to the comparison group. In the populations of Th17 and Treg lymphocytes, SDH activity was significantly lower in the state of exacerbation of the disease, relative to in the state of remission. Analysis of SDH activity indicators depending on the stage of liver fibrosis revealed a nonlinear relationship: in the populations of T-helpers, T-cytotoxic and Thact – an increase to stage F2-3, and then a decrease to stage F4. SDH activity in the population of Th17 lymphocytes increased maximally at the F1 stage and subsequently decreased to the F4 stage. With increasing stage of liver fibrosis, SDH activity significantly increased in the Treg population, but did not reach normative values. Children with autoimmune hepatitis need clinical observation and strict monitoring of the development of the disease. Conclusion. The subpopulation composition of peripheral blood lymphocytes and the activity of succinate dehydrogenase in lymphocyte populations objectively reflect the severity of the patient’s condition at the time of examination and can be used for additional laboratory assessment of the progression of liver fibrosis. The identified signs of mitochondrial dysfunction justify the use of correction of metabolic disorders as a therapy that improves the basic treatment of patients with type 1 AIH.

A281 CASE REPORT: STEATOTIC LIVER DISEASE DIAGNOSED IN A 24-YEAR-OLD FEMALE WITH RETT SYNDROME

Abstract Background Rett syndrome (RTT) is a rare, severe neurodevelopmental disorder seen almost exclusively in females that is caused by spontaneous loss-of-function mutations in the methyl CpG binding protein 2 (MECP2) gene. Girls with RTT typically demonstrate normal development for the first 6-18 months of life before displaying evidence of variable levels of developmental milestone regression and physical disability. Although perturbed lipid metabolism in the nervous system is the main contributor to the pathophysiology of RTT, mutations to the MECP2 gene also contribute to disease burden by causing perturbations to peripheral systems, leading to consequences such as dyslipidemia (DLD) and steatotic liver disease (SLD). Although DLD has been described in human cell lines and girls with RTT, SLD has only been described in RTT mouse models. Aims This report aims to present a case of a patient with RTT who was diagnosed with SLD on liver biopsy in the context of DLD but without insulin resistance or other comorbidities associated with metabolic syndrome. Methods Retrospective review of one patient. Results A 24-year-old woman with genetically proven RTT (T158M point mutation to MECP2) complicated by several physical disabilities was seen at a tertiary care center clinic for evaluation of abnormal liver enzymes (ALT 163, AST 51, ALP 258, total bilirubin 6). Abdominal ultrasound demonstrated moderately echogenic liver parenchyma consistent with hepatic steatosis. Additional investigations for an etiology were unremarkable and the patient had no history of alcohol misuse or the use of new medications or supplements. Regarding risk factors for SLD, her homeostatic model assessment for insulin resistance (HOMA-IR) score was 1.8, hemoglobin A1c was 4.8%, and her lipid profile demonstrated elevated triglycerides and LDL, in keeping with DLD. The decision was made to proceed with a liver biopsy. This demonstrated moderate steatosis and no ballooning, categorized as grade A1 and stage F1. Conclusions This case demonstrates that RTT patients have similar lipid metabolism perturbations to those seen in MECP2-null mouse models, resulting in similar metabolic abnormalities such as DLD and SLD. The absence of insulin resistance and other comorbidities associated with metabolic syndrome further support these perturbations are caused by a pathophysiologic mechanism specific to RTT. This demonstrates the importance of screening RTT patients for DLD and SLD despite their young age to detect these conditions before complications arise. It also demonstrates that MECP2-null mice can be used as reliable models to identify future therapies for RTT, such as ketogenic diet, ω-3 PUFAs supplementation, and lipid-lowering statin therapy. Funding Agencies None

Estimating utility values for non-alcoholic steatohepatitis health states: a discrete choice experiment.

Background: This study estimated utility values for non-alcoholic steatohepatitis (NASH). Previous studies have assumed that health-related quality of life does not vary between the early stages of NASH. Materials & Methods: Discrete choice experiment (DCE) surveys estimated the value of avoiding fibrosis progression. Patients also completed the EQ-5D-5L. Marginal rates of substitution estimated utility change associated with fibrosis progression. Results: DCE surveys were completed by the UK general public (n=520) and patients with NASH (n=154). The utility decline between fibrosis stages F1 and F4 decompensated was between -0.521 to -0.646 (depending on method). Conclusion: Three methods were used to estimate utilities for NASH, each one showed sensitivity to advancing fibrosis, including in the early stages, which is often considered asymptomatic.

Serum level of proteins involved in apoptosis and autophagy in patients with type 2 diabetes and non-alcoholic fatty liver disease

Aim of the study was to estimate the blood serum level of microtubule-associated protein 1 light chain 3 alpha (MAP1LC3alpha), beclin-1 (BECN-1), Bcl-2 (BCL-2), caspase-3 (CASP3) and autophagy related 5 (ATG-5) protein as potential markers of liver fibrosis in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD).Material and methods. A single center cross-sectional observational study was performed. Seventy four patients with T2D and NAFLD were included, 23 men and 51 women, aged 18 to 74 years. Transient elastography was used for the assessment of liver fibrosis. The severity of fibrosis was estimated using the Metavir sсore. In addition, indirect liver fibrosis indices APRI and FIB-4 were calculated. Serum concentration of MAP1LC3alpha, BECN-1, BCL-2, CASP and ATG-5 was measured by ELISA. We applied ROC analysis to assess the value of studied indicators in diagnosis of liver fibrosis.Results. Liver fibrosis stage F1 was verified in 16 subjects, stage F2 in 12, stage F3 in 7, and stage F4 in 19 individuals. Patients with advanced liver fibrosis (stage 3-4) when compared to those without fibrosis (stage 0–2) had higher content of MAP1LC3alpha (p = 0.01) and BECN-1 (p = 0.01). There were no significant differences in the level of BCL-2, CASP3 and ATG-5 between patients with different severity of fibrosis. In the ROC analysis, MAP1LC3alpha and BECN-1 showed significance for the diagnosis of severe liver fibrosis, which, however, did not exceed that of the APRI index.Conclusions. In patients with T2D and NAFLD, serum levels of MAP1LC3alpha and BECN-1 are associated with severe liver fibrosis.