Search

Objective Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. Design The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. Results When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18‒/‒ and CD1d‒/‒ mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. Conclusion Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis. [ABSTRACT FROM AUTHOR]

Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH). We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%−1.9%; P =.002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P =.10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P =.20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov , Number: NCT02443116. [ABSTRACT FROM AUTHOR]

Summary: Background: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is common in people with HIV (PWH). The morphological spectrum of MASLD compared to matched controls and of the correlation between the NAFLD activity score (NAS) and fibrosis stage in PWH remains unknown. Methods: Overall, 107 liver biopsies from PWH with MASLD (MASLD‐PWH) were matched to 107 biopsies from individuals with MASLD and without HIV (MASLD controls) on age at biopsy, race/ethnicity, sex, type 2 diabetes, body mass index (BMI) and alanine aminotransferase (ALT) level. Biopsies were scored using NAS. Results: Compared to MASLD‐controls, MASLD‐PWH had lower steatosis grade (OR: 0.65, 95% CI: (0.47–0.90), p = 0.01), lower lobular inflammation grade (OR: 0.55, 95% CI: (0.34–0.89), p = 0.02), less portal inflammation (OR: 0.42, 95% CI: (0.25–0.72), p = 0.002) and less ballooned hepatocytes (OR: 0.60, 95% CI: (0.41–0.88), p = 0.01). Thus, NAS was lower in MASLD‐PWH (OR: 0.69, 95% CI: (0.56–0.85), p < 0.001) than in MASLD controls. There was a trend towards lower prevalence of steatohepatitis in MASLD‐PWH (OR: 0.84, 95% CI: (0.68–1.03), p = 0.09). A multivariate analysis demonstrated that MASLD‐PWH cases had significantly less steatosis (OR: 0.66, p = 0.03), portal inflammation (OR: 0.34, p = 0.001) and ballooned hepatocytes (OR: 0.55, p = 0.01), yet higher stage fibrosis (OR: 1.42, p = 0.03) compared to MASLD controls. Conclusion: The NAS and histological drivers of fibrosis (e.g. inflammation and hepatocyte ballooning) are less pronounced in MASLD‐PWH, and yet fibrosis stage was generally higher when compared to matched controls with MASLD without HIV. This suggests HIV‐specific factors beyond hepatic necroinflammation may contribute to fibrosis progression in MASLD‐PWH. [ABSTRACT FROM AUTHOR]

We analyzed markers of fibrosis in serum samples from patients with nonalcoholic fatty liver disease (NAFLD), assessed by liver biopsy. We used serum levels of markers to develop an algorithm to discriminate patients with advanced fibrosis from those with mild or moderate fibrosis and validated its performance in 2 independent cohorts of patients with NAFLD. We performed a retrospective analysis of serum samples from 396 patients with NAFLD and different stages of fibrosis (F0–F4), collected from 2007 through 2017 on the day of liver biopsy (training cohort 1). We measured serum concentrations of alpha-2 macroglobulin (A2M), hyaluronic acid (HA), and TIMP metallopeptidase inhibitor 1 (TIMP1), and used measurements to develop an algorithm that could discriminate patients with NAFLD with advanced fibrosis (F3–F4; 24.1% of cohort) from those with mild or moderate fibrosis (F0–F2; 79.5% of cohort). We validated the algorithm using serum samples collected from a separate 396 patients from the same time period and location (validation cohort 1), as well as 244 patients with NAFLD evaluated at a separate location, from 2011 through 2017, within a median of 11 days of liver biopsy (cohort 2). The algorithm identified patients with advanced fibrosis vs mild or moderate fibrosis in training cohort 1 with an area under the receiver operating characteristic (AUROC) curve of 0.867 (95% CI, 0.827–0.907), 84.8% sensitivity (95% CI, 75.5%–91.0%), and 72.3% specificity (95% CI, 66.9%–77.3%), at a cutoff score of 17. The AUROC for the combined validation cohorts 1 and 2 (n=640) was 0.856 (95% CI, 0.820–0.892), identifying patients with 79.7% sensitivity (95% CI, 71.9%–86.2%) and 75.7% specificity (95% CI, 71.8%–79.4%) at the predetermined cutoff score of 17. The algorithm had negative predictive values that ranged from 92.5% to 94.7% in the validation cohorts; it correctly classified 90.0% of F0 samples, 75.0% of F1 samples, 77.4% of F3 samples, and 94.4% of F4 samples. We developed an algorithm that identifies patients with advanced fibrosis from those with mild to moderate fibrosis in patients with NAFLD with an AUROC value of approximately 0.86, based on levels of serum biomarkers. We validated the findings in 2 separate sets of patients with biopsy-proven NAFLD. The algorithm can be used non-invasively to determine risk of advanced fibrosis in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Findings: 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.Interpretation: 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.Funding: Madrigal Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background & Aims Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. Methods We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. Results Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than postmenopausal women ( P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory-Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women ( P < .05). Conclusions Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress. [ABSTRACT FROM AUTHOR]

Background: NAFLD is highly prevalent with limited treatment options. Bile acids (BAs) increase in the systemic circulation and liver during NAFLD progression. Changes in plasma membrane localization and zonal distribution of BA transporters can influence transport function and BA homeostasis. However, a thorough characterization of how NAFLD influences these factors is currently lacking. This study aimed to evaluate the impact of NAFLD and the accompanying histologic features on the functional capacity of key hepatocyte BA transporters across zonal regions in human liver biopsies., Methods: A novel machine learning image classification approach was used to quantify relative zonal abundance and plasma membrane localization of BA transporters (bile salt export pump [BSEP], sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide [OATP] 1B1 and OATP1B3) in non-diseased (n = 10), NAFL (n = 9), and NASH (n = 11) liver biopsies. Based on these data, membrane-localized zonal abundance (MZA) measures were developed to estimate transporter functional capacity., Results: NAFLD diagnosis and histologic scoring were associated with changes in transporter membrane localization and zonation. Increased periportal BSEPMZA (mean proportional difference compared to non-diseased liver of 0.090) and decreased pericentral BSEPMZA (-0.065) were observed with NASH and also in biopsies with higher histologic scores. Compared to Non-diseased Liver, periportal OATP1B3MZA was increased in NAFL (0.041) and NASH (0.047). Grade 2 steatosis (mean proportional difference of 0.043 when compared to grade 0) and grade 1 lobular inflammation (0.043) were associated with increased periportal OATP1B3MZA., Conclusions: These findings provide novel mechanistic insight into specific transporter alterations that impact BA homeostasis in NAFLD. Changes in BSEPMZA likely contribute to altered BA disposition and pericentral microcholestasis previously reported in some patients with NAFLD. BSEPMZA assessment could inform future development and optimization of NASH-related pharmacotherapies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis., Methods: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score., Results: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group., Conclusions: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.)., (Copyright © 2024 Massachusetts Medical Society.)

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification., Competing Interests: Declaration of interests Manal F. Abdelmalek consults, advises, and received grants from Bristol Myers Squibb, Hanmi, Intercept, Inventiva, and Madrigal. She consults and advises 89Bio, Merck, NGM Bio, Novo Nordisk, Sonic Incytes, and Theratechnologies. She is on the speakers’ bureau for the Chronic Liver Disease Foundation, Clinical Care Options, Fishawack, Medscape, and Terra Firma. She received grants from Allergan, Boehringer Ingelheim, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Novo Nordisk, Poxel, Target NASH, and Viking. Quentin M. Anstee, on behalf of Newcastle University, consults for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, GENFIT, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Pharmanest, Prosciento, Poxel, RTI, Resolution Therapeutics, Ridgeline Therapeutics, Roche, Shionogi, and Terns. He is on the speakers’ bureau for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare. He received grants from AstraZeneca, Boehringer Ingelheim, and Intercept. He holds intellectual property rights with Elsevier, Ltd. Ramon Bataller is on the speakers’ bureau for Abbvie and Gilead. Ulrich Beuers consults for CSL Behring. He is on the speakers’ bureau for Abacus and Zambon. Elisabetta Bugianesi advises Boehringer Ingelheim, MSD, and Novo Nordisk. Helena Cortez-Pinto consults and received grants from Novo Nordisk and Roche. She received grants from Eisai, Gilead, GMP-Orphan, and Intercept. Kenneth Cusi Consults for Aligos, Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Covance, Lilly, Madrigal, Myovant, Novo Nordisk, Prosciento, Sagimet, and Siemens. He received grants from Echosens, Inventiva, LabCorp, Nordic Biosciences, and Target NASH. Sven M. Francque consults and received grants from Astellas, Falk, GENFIT, Gilead, Glympse Bio, Janssen, Inventiva, Merck, Pfizer, and Roche. He consults for AbbVie., Actelion, Aelin Therapeutics, Allergan, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Coherus, CSL Behring, Echosens, Eisai, ENYO, Galapagos, Galmed, Genetech, Intercept, Julius Clinical, Madrigal, Medimmune, NGM Bio, Novartis, Novo Nordisk, and Promethera. Samer Gawrieh consults for Pfizer and TransMedics. He received grants from LiverIncytes, Viking, and Zydus. Manuel Romero-Gómez advises and received grants from Novo Nordisk and Siemens. He advises AbbVie., Alpha-sigma, Allergan, AstraZeneca, Axcella, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Intercept, Inventia, Kaleido, MSD, Pfizer, Prosciento, Rubió, Shionogi, Sobi, and Zydus. He received grants from Echosens and Theratechnologies. Cynthia D. Guy consults for 89Bio, CymaBay, HistoIndex, Madrigal, and NGM. Stephen Harrison consults, advises, is involved with trials, received grants, and owns stock in Akero, Galectin, GENFIT, Hepion, and NGM Bio. He consults, advises, is involved with trials, and received grants from Axcella, Gilead, Intercept, Madrigal, and Poxel. He consults, advises, received grants, and owns stock in NorthSea Therapeutics. He consults, advises, and is involved with trials for Terns. He consults, advises, and received grants from HighTide, Novartis, Novo Nordisk, and Sagimet. He consults, advises, and owns stock in HistoIndex, Metacrine, and Sonic Incytes. He consults, received grants, and owns stock in Cirius. He consults, is involved with trials, and received grants from ENYO and Viking. He is involved with trials and received grants from Genentech. He consults and is involved with trials for Ionis. He consults and received grants from CiVi, CymaBay, Galmed, and Pfizer. He consults and owns stock in Hepta Bio. He consults and advises for Altimmune, Echosens North America, Foresite Labs, and Medpace. He advises and owns stock in ChronWell. He consults for AgomAb, Alentis, Aligos Therapeutics, Alimentiv, Blade, Bluejay, Boston Pharmaceuticals, Boxer Capital, CanFite BioPharma, the Chronic Liver Disease Foundation (CLDF), CohBar, Corcept, Fibronostics, Fortress Biotech, Galecto, Gelesis, GSK, GNS Healthcare, GRI Bio, Hepagene, Indalo, Inipharm, Innovate Biopharmaceuticals, Kowa Research Institute, Merck, MGGM, NeuroBo, Nutrasource, Perspectum, Piper Sandler, Prometic (now Liminal BioSciences), Ridgeline Therapeutics, Silverback, and Zafgen (now Larimar). He advises Arrowhead BVF Partners, Humana, and Pathai. He received grants from Bristol Myers Squibb, Conatus, Immuron, and Second Genome. Samuel Klein advises Alnylam, Altimmune, and Merck. Kris V. Kowdley advises, is on the speakers’ bureau, and received grants from Gilead and Intercept. He advises, received grants, and owns stock in Inipharm. He advises and received grants from 89bio, CymaBay, GENFIT, Ipsen, Madrigal, Mirum, NGM Bio, Pfizer, Pliant, and Zeds. He advises Enact, HighTide, and Protagonist. He is on the speakers’ bureau for AbbVie. He received grants from Boston Pharmaceuticals, Corcept, GSK, Hanmi, Janssen, Novo Nordisk, Terns, and Viking. Jeffrey V. Lazarus consults for Novavax. He received grants from AbbVie, Gilead, MSD, and Roche Diagnostics. Rohit Loomba consults and received grants from Arrowhead, AstraZeneca, Bristol Myers Squibb, Galmed, Gilead, Intercept, Inventiva, Ionis, Janssen, Lilly, Madrigal, Merck, NGM Bio, Novo Nordisk, Pfizer, and Terns. He consults and owns stock in 89Bio and Sagimet. Consults for Altimmune, Anylam, Amgen, CohBar, Glympse Bio, HighTide, Inipharm, Metacrine, Novartis, Regeneron, Theratechnologies, and Viking. He received grants from Boehringer Ingelheim, Galectin Therapeutics, Hanmi, and Sonic Incytes. He cofounded and owns stock in LipoNexus. Phillip N. Newsome consults, advises, is on the speakers’ bureau, and received grants from Novo Nordisk. He consults and advises Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GSK, Intercept, Madrigal, Pfizer, Poxel, and Sun Pharma. He is on the speakers’ bureau for AiCME. Elizabeth E. Powell advises and received grants from Novo Nordisk. Vlad Ratziu consults and received grants from Intercept. He consults for Boehringer Ingelheim, Eny, Madrigal, NorthSea, Novo Nordisk, E. Poxel, and Sagimet. He received grants from Gilead. Mary E. Rinella consults for Boehringer Ingelheim, CytoDyn, GSK, Novo Nordisk, HistoIndex, Intercept, Madrigal, NGM Bio, and Sonic Incytes. Michael Roden consults and received grants from Boehringer Ingelheim and Novo Nordisk. He consults for Lilly. He is on the speakers’ bureau for AstraZeneca. Arun J. Sanyal consults and advises Avant Santé and AstraZeneca. He consults and received grants from Akero, Bristol Myers Squibb, Intercept, Lilly, Madrigal, and Novo Nordisk. He consults and owns stock in Rivus. He consults for AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelhiem, 89Bio, Echosense, Genentech, Gilead, GSK, HistoIndex, Malinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns, and Zydus. He owns stock in Durect, Exhalenz, GENFIT, Indalo, Inversago, and Tiziana. He received royalties from Elsevier and Wolters Kluwer. Marcelo Silva consults, advises, and received grants from Zydus. He received grants from Inventiva and MSD. Dina Tiniakos consults for Clinnovate Health, ICON, Ionis, Inventiva, Merck, and Verily. Luca Valenti consults and received grants from Gilead. He consults for AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Pfizer, and Resalis Therapeutics. Miriam B. Vos consults and advises Thiogenesis. She consults and received grants from Target Real World Evidence. She consults and owns stock in Intercept. She consults for Albireo, Boehringer Ingelheim, Lilly, Novo Nordisk, and Takeda. She received grants from Bristol Myers Squibb, Quest, and Sonic Incytes. Vincent Wai-Sun Wong consults and received grants from Gilead. He consults for AbbVie, Boehringer Ingelheim, Echosens, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet, and TARGET PharmaSolutions. He owns stock in Illuminatio Medical Technology. Yusuf Yilmaz consults for Zydus. He advises Novo Nordisk. He is on the speakers’ bureau for Echosens. Zobair Younossi consults for Bristol Myers Squibb, Gilead, Intercept, Madrigal, Merck, Novartis, Novo Nordisk, Quest, Siemens, and Terns. The remaining authors have no conflicts to report., (Copyright © 2023 Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu, Sven M. Francque, Arun J. Sanyal, Fasiha Kanwal, Diana Romero, Manal F. Abdelmalek, Quentin M. Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher D. Byrne, Graciela E. Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D. Guy, Stephen A. Harrison, Seung Up Kim, Bart Koot, Marko Korenjak, Kris Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R. Morgan, Elisabeth Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C. Sookoian, C. Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B. Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N. Newsome (senior), NAFLD Nomenclature consensus group. Published by Elsevier España, S.L.U. All rights reserved.)

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification., (Copyright © 2023 Mary E. Rinella, Jeffrey V. Lazarus, Vlad Ratziu, Sven M. Francque, Arun J. Sanyal, Fasiha Kanwal, Diana Romero, Manal F. Abdelmalek, Quentin M. Anstee, Juan Pablo Arab, Marco Arrese, Ramon Bataller, Ulrich Beuers, Jerome Boursier, Elisabetta Bugianesi, Christopher Byrne, Graciela E. Castro Narro, Abhijit Chowdhury, Helena Cortez-Pinto, Donna Cryer, Kenneth Cusi, Mohamed El-Kassas, Samuel Klein, Wayne Eskridge, Jiangao Fan, Samer Gawrieh, Cynthia D. Guy, Stephen A. Harrison, Seung Up Kim, Bart Koot, Marko Korenjak, Kris Kowdley, Florence Lacaille, Rohit Loomba, Robert Mitchell-Thain, Timothy R. Morgan, Elisabeth Powell, Michael Roden, Manuel Romero-Gómez, Marcelo Silva, Shivaram Prasad Singh, Silvia C. Sookoian, C. Wendy Spearman, Dina Tiniakos, Luca Valenti, Miriam B. Vos, Vincent Wai-Sun Wong, Stavra Xanthakos, Yusuf Yilmaz, Zobair Younossi, Ansley Hobbs, Marcela Villota-Rivas, Philip N. Newsome, NAFLD Nomenclature consensus group. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin-protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH., Approach and Results: We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed "undead") hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl 4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of 'undead' senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress., Conclusion: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, and injury, and is associated with an increased risk of liver transplantation and death. NASH affects more than 16 million people in the USA, and there is no approved therapy. The aim of this study was to evaluate the safety and efficacy of aldafermin, an engineered analogue of the gut hormone fibroblast growth factor 19 (FGF19)., Methods: In this randomised, double-blind, placebo-controlled, phase 2b study (ALPINE 2/3) in patients with biopsy-confirmed NASH and stage 2 or 3 fibrosis, we randomly assigned patients stratified by fibrosis stage in a 1:1:1:1 ratio to receive placebo, aldafermin 0·3 mg, 1·0 mg, or 3·0 mg once daily for 24 weeks at 30 study sites in the USA. Patients, investigators, the funder, and all other staff, were masked to treatment assignment throughout the study. The primary endpoint was an improvement in liver fibrosis of at least one stage with no worsening of NASH at week 24. Analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT03912532, and has been completed., Findings: Between May 16, 2019, and Sept 4, 2020, 786 patients were screened, of whom 171 were randomly assigned to a treatment group and included in the intention-to-treat population: 43 in the 0·3 mg aldafermin group, 42 in the 1·0 mg group, 43 in the 3·0 mg group, and 43 in the placebo group. In total, 145 (85%) of patients completed treatment. At week 24, among patients with biopsies at both baseline and week 24, was seven (19%) of 36 patients in the placebo group, 11 (31%) of 36 in the 0·3 mg aldafermin group (difference 90% CI 12% [-9 to 33]; p=0·11), five (15%) of 34 patients in the 1·0 mg group (difference -5% [-24 to 13]; p=0·80), and 11 (30%) of 37 patients in the 3·0 mg group (difference 10% [-9 to 30]; p=0·12) had an improvement in liver fibrosis of at least one stage with no worsening of NASH, without meeting the prespecified significance for dose response (p=0·55). Adverse events were mostly mild or moderate in severity. Diarrhoea occurred in six (14%) of 43 patients in the placebo group, three (7%) of 43 patients in the 0·3 mg aldafermin group, five (12%) of 41 patients in the 1·0 mg group, and ten (23%) of 43 patients in the 3·0 mg group. Incidences of serious adverse events and discontinuations owing to adverse events were similar between groups., Interpretation: Aldafermin was generally well tolerated but did not produce a significant dose response on fibrosis improvement of at least one stage with no worsening of NASH, despite positive effects on a number of secondary endpoints. The findings of this trial may have implications for the design of future NASH trials., Funding: NGM Biopharmaceuticals., Competing Interests: Declaration of interests SAH reports grant and research support from Akero, Axcella, Bristol-Myers Squibb, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet, Viking, and 89 Bio; is a scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Bristol-Myers Squibb, Echosens, Forest Labs, Galectin, Gilead, Hepion, Hepagene, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Sagimet, Sonic Incytes, Terns, and Viking; and has stock options in Akero, Cirius, Chronwell, Galectin, Genfit, Hepion, HistoIndex, Metacrine, NGM, and Northsea. MFA reports grant and research support from Allergan, Bristol-Myers Squibb, Boeringher Ingelheim, Celgene, Genentech, Hanmi, Intercept, Inventiva, Magrigal, NGM, NovoNordisk, and Viking; is a consultant for Hanmi and Madrigal; and serves on an advisory committee for 89Bio, Bristol-Myers Squibb, Hanmi, NGM, Novo Nordisk, and Thera. CDG reports grant and research support from 89Bio, CymaBay, Madrigal, and NGM; and is a consultant for 89Bio, CymaBay, Madrigal, and NGM. NA reports serving on advisory boards for 89Bio, Gilead, Intercept, LG Chem, NGM, Novo Nordisk, Pfizer, Terns, and Zydus; is a speaker for AbbVie, Alexion, Echosens, Gilead, Intercept, Perspectum, and Simply Speaking; and has received research support from 89Bio, Akero, Albireo, Allergan, Axcella, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Corcept, Gilead, Galmed, Galectin, Genfit, Enanta, Enyo, Fibronostics, Hanmi, Hepagene, Inventiva, Madrigal, Merck, Metacrine, Northsea, Noom, Novartis, Novo Nordisk, Pfizer, Poxel, and Zydus. MRB reports grant and research support from the National Institutes of Health (5U01-DK061713-19, 1R01CA249765-01) as well as Carmot, Corcept, CymaBay, Diabetes & Endocrinology Consultants, Madrigal, Metacrine, NGM, Pinnacle Clinical Research, Polarean Imaging, and Siemens Healthineers. MER reports consulting for Alnylam, Amgen, AMRA, Bristol-Myers Squibb, Boehringer Ingelheim, Centara, Coherus, Enanta, Galecto, Intercept, Madrigal, NGM, Novo Nordisk, Pfizer, Fractyl, Gelesis, Siemens, Thetis, Terns, Rivus, 3vBio (Sagimet), 89Bio, and Novartis. MSS reports consulting for Pfizer and serves on an advisory committee for AMRA. MK reports research grants from Medtronic, SARO, Pfizer, Dexcom, Abbott, Regenacy, Metacrine, Lumos, Ascendis, Sagimet, MannKind, Aeterna-Zentaris, 89Bio, Gilead, Senseonics, KOWA, Allergan, NGM, Tolerion, and Lilly, and is on an advisory board for Quest Diagnostics. ZHY reports grant and research support from Gilead, Bristol-Myers Squibb, Cymabay, HighTide, Madrigal, NGM, Conatus, Novartis, Allergan, Intercept, and Novo Nordisk, and is a consultant for Gilead. MB reports grant support from the National Institutes of Health. SJB reports serving on a scientific advisory board for Altimmune, Amgen, AstraZeneca, Axcella, Boehringer Ingelheim, Eli Lilly, Esperion, Novartis, Regeneron, and Sanofi, and is a consultant for Altimmune, Amgen, Madrigal, Novartis, Regeneron, and Sanofi. BB reports research support from Akero, Axcella, Bristol-Myers Squibb, Conatus, Cymabay, Enyo, Galectin, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, NGM, Novartis, Novo Nordisk, Northsea, Viking, AbbVie, Gynkotex, GlaxoSmithKline, Arena, Protagonist, Mirum, Eli Lilly, Ionis, and Poxel. PJR reports serving as speaker and adviser for Gilead Sciences and ViiV. PJT reports grant and research support from AbbVie, Allergan, Bayer, Bristol-Myers Squibb, Cara, Celgene, Cirius, Conatus, Cymabay, Dova, Eisai, Eli Lilly, Elobix, Enanta, Enyo, Exelixis, Gilead, HighTide, Intercept, Mallinckrodt, Novo Nordisk, Pfizer, Sillajen, and Targ, and is a consultant for Mallinckrodt. MG, MK, CC, LM-K, WC, AMD, LL, and HDL report being employees and stockholders of NGM. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Primary hepatic neoplasms with neuroendocrine differentiation are extremely rare. Their clinicopathological features and molecular genetic basis are largely unknown. We identified four cases of primary hepatic neoplasms with neuroendocrine differentiation. Electronic medical records were reviewed for clinical history, imaging findings, laboratory results, and follow-up. Pathology slides, immunohistochemistry, and ancillary studies were reviewed. There were two females and two males with age ranging from 52 to 74 years. There was one amphicrine carcinoma with tumor cells simultaneously demonstrating both hepatocellular and neuroendocrine differentiation, one mixed hepatocellular-neuroendocrine carcinoma (NEC) with hepatocellular component intermingled with neuroendocrine component, one small cell NEC, and one well-differentiated neuroendocrine tumor. Next- generation sequencing of the mixed hepatocellular-NEC and small cell NEC showed molecular/genetic alterations commonly seen in hepatocellular carcinoma (HCC). All four cases arose in a background of cirrhosis. Primary hepatic neoplasms arising in cirrhotic livers can have a spectrum of neuroendocrine differentiation. Presence of a NEC component may be an indicator of aggressiveness. In addition, primary hepatic carcinomas with neuroendocrine differentiation likely share the same molecular pathways as HCC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The diagnosis of invasive adenocarcinoma of the gallbladder can sometimes be challenging. The presence of true desmoplastic reaction facilitates the diagnosis of invasion. However, desmoplasia-like changes can be observed in benign gallbladder conditions, and recognition of desmoplasia may be challenging based on morphology. In this study, we tested the expression pattern of microfibril-associated protein 5 (MFAP5), a promising immunohistochemical marker for desmoplasia, in benign gallbladders with desmoplasia-like reaction and gallbladders with invasive adenocarcinoma. We also evaluated the diagnostic utility of MFAP5 in challenging cases with an interobserver agreement study. The results showed that all benign cases retained intact/positive MFAP5 staining pattern in periglandular connective tissue, whereas 79.3% (23 out of 29) of cases of adenocarcinomas demonstrated diffuse and complete loss of MFAP5 staining in the tumor stroma. Interobserver agreement was improved by 2.66 times when images of MFAP5 immunohistochemistry were provided. In conclusion, MFAP5 expression is downregulated in the desmoplastic stroma of gallbladder adenocarcinoma and may provide a useful diagnostic marker in difficult cases.

Cases of new pseudotumors of the liver were collected from multiple medical centers. Four resection and 4 biopsy specimens were collected, including 4 women and 4 men at an average age of 48 ± 15 years (range: 28-73 years). The lesions were visible on imaging but were either ill-defined or had indeterminate features for characterization. They ranged in size from 2 to 9 cm and were multiple in five cases. The resection specimens showed lesions that had vague borders but were visible in juxtaposition to the normal liver on gross examination. Histologically, the lesions also had ill-defined borders and were composed of benign reactive liver parenchyma. Central vein thrombi were seen in 5 cases, and portal vein thrombi, in 2 cases. These vascular changes were associated reactive parenchymal changes including sinusoidal dilation, patchy bile ductular proliferation, and portal vein abnormalities. All lesions lacked the histological findings of hepatic adenomas, focal nodular hyperplasia, or other known tumors and pseudotumors of the liver. In summary, this study provides a detailed description of a new pseudotumor of the liver: a reactive, hyperplastic mass-like lesion that forms in association with localized vascular thrombi, for which we propose the term regenerative hepatic pseudotumor. This lesion can closely mimic other benign or malignant hepatic tumors on imaging and histology., (Copyright © 2020. Published by Elsevier Inc.)