Hepatology Communications最新文献

{"title":"Relationship between updated MELD and prognosis in alcohol-associated hepatitis: Opportunities for more efficient trial design.","authors":"Mustafa Al-Karaghouli, Meritxell Ventura-Cots, Yu Jun Wong, Joan Genesca, Francisco Bosques, Robert S Brown, Philippe Mathurin, Alexandre Louvet, Debbie Shawcross, Victor Vargas, Elizabeth C Verna, Bernd Schnabl, Joan Caballeria, Vijay J Shah, Patrick S Kamath, Michael R Lucey, Guadalupe Garcia-Tsao, Ramon Bataller, Juan G Abraldes","doi":"10.1097/HC9.0000000000000495","DOIUrl":"10.1097/HC9.0000000000000495","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium.</p><p><strong>Methods: </strong>Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs.</p><p><strong>Results: </strong>Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14-1.27) (p < 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12-1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention.</p><p><strong>Conclusion: </strong>We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversal of hepatic accumulation of nordeoxycholic acid underlines the beneficial effects of cholestyramine on alcohol-associated liver disease in mice.","authors":"Wei Guo, Wei Zhong, Liqing He, Xiaoyuan Wei, Liuyi Hao, Haibo Dong, Ruichao Yue, Xinguo Sun, Xinmin Yin, Jiangchao Zhao, Xiang Zhang, Zhanxiang Zhou","doi":"10.1097/HC9.0000000000000507","DOIUrl":"10.1097/HC9.0000000000000507","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism.</p><p><strong>Methods: </strong>BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study.</p><p><strong>Results: </strong>We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia.</p><p><strong>Conclusions: </strong>Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, implementation, and impact of a cirrhosis-specific remote patient monitoring program.","authors":"Daniel D Penrice, Kamalpreet S Hara, Beatriz Sordi-Chara, Camille Kezer, Kathryn Schmidt, Blake Kassmeyer, Ryan Lennon, Jordan Rosedahl, Daniel Roellinger, Puru Rattan, Katherine Williams, Sara Kloft-Nelson, Angela Leuenberger, Patrick S Kamath, Vijay H Shah, Douglas A Simonetto","doi":"10.1097/HC9.0000000000000498","DOIUrl":"10.1097/HC9.0000000000000498","url":null,"abstract":"<p><strong>Background: </strong>Remote patient monitoring (RPM) is an emerging focus in health care, and specialized programs may reduce medical costs, supplement in-office visits, and improve patient satisfaction. In this study, we describe the development, feasibility, and early outcomes of an RPM program for patients with decompensated cirrhosis.</p><p><strong>Methods: </strong>Forty-six patients were offered enrollment at the time of hospital discharge in the cirrhosis RPM program (CiRPM), of which 41 completed at least 30 days of monitoring. Participants were mailed remote monitoring equipment and a tablet to be used for patient-reported outcomes. Alerts were continuously monitored by virtual nursing staff who could perform targeted interventions. A cohort of historical controls (n = 74) was created for comparison using inverse probability of treatment weighting.</p><p><strong>Results: </strong>Patients were enrolled in the program for a mean of 83.9 days, with 28 (68%) completing the full 90-day program. Participants uploaded vital signs and responded to symptom-based questionnaires on 93% of the monitored days. On end-of-program surveys, over 75% of patients expressed satisfaction with the program. Gender, age, and MELD-Na were similar between CiRPM and weighted control groups. The 90-day readmission rate was 34% in CiRPM and 47% in weighted controls. In the CiRPM group, 12% of subjects had 2 or more admissions, compared to 37% in the weighted control group.</p><p><strong>Conclusion: </strong>This study demonstrates the feasibility of a cirrhosis-specific RPM program. Overall, patient satisfaction and utilization of the CiRPM was high. Future studies are needed to confirm the impact of RPM on the reduction of hospital readmissions in decompensated cirrhosis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In utero exposure to antihistamines and risk of hepatocellular carcinoma in a multigenerational cohort.","authors":"Caitlin C Murphy, Karim Seif El Dahan, Amit G Singal, Piera M Cirillo, Nickilou Y Krigbaum, Barbara A Cohn","doi":"10.1097/HC9.0000000000000497","DOIUrl":"10.1097/HC9.0000000000000497","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence suggests that liver disease originates in early life. Antihistamines cross the placenta and are frequently prescribed to pregnant women to treat nausea and vomiting, as well as allergy and asthma symptoms. Exposure to antihistamines in utero may impact the developing liver by reprogramming or inducing epigenetic changes in fetal hepatocytes.</p><p><strong>Methods: </strong>We examined in utero exposure to antihistamines and the risk of HCC in the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in the East Bay, CA, between 1959 and 1966 (n=14,507 mothers and 18,751 liveborn offspring). We reviewed mothers' medical records to identify those prescribed antihistamines during pregnancy, and diagnoses of HCC in adult (age ≥18 y) offspring were identified by linkage with a population-based cancer registry. Cox proportional hazard models were used to estimate adjusted hazard ratios, with follow-up accrued from birth through cancer diagnosis, death, or last contact.</p><p><strong>Results: </strong>About 15% of offspring (n=2759 of 18,751) were exposed in utero to antihistamines. Chlorpheniramine (51.8%) and diphenhydramine (15.4%) were the 2 most commonly prescribed antihistamines. Any in utero exposure was not associated with HCC (adjusted hazard ratio: 2.76, 95% CI: 0.70, 10.89), but the association differed by timing of exposure. Offspring exposed to antihistamines in the first or second trimester had a higher risk of HCC compared to offspring not exposed (adjusted hazard ratio: 4.64, 95% CI: 1.21, 17.78). Similarly, incidence rates were 4.3 per 100,000 (95% CI: 0.9, 12.6) for offspring exposed in the first or second trimester compared to 1.0 per 100,000 (95% CI: 0.3, 2.1) for offspring not exposed.</p><p><strong>Conclusions: </strong>In utero exposure to antihistamines in early pregnancy may increase the risk of HCC in adulthood.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.","authors":"Alexander Coukos, Chiara Saglietti, Christine Sempoux, Monika Haubitz, Thomas Greuter, Laureane Mittaz-Crettol, Fabienne Maurer, Elise Mdawar-Bailly, Darius Moradpour, Lorenzo Alberio, Jean-Marc Good, Gabriela M Baerlocher, Montserrat Fraga","doi":"10.1097/HC9.0000000000000500","DOIUrl":"10.1097/HC9.0000000000000500","url":null,"abstract":"<p><strong>Background: </strong>Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD).</p><p><strong>Methods: </strong>As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD.</p><p><strong>Results: </strong>This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel.</p><p><strong>Conclusions: </strong>Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medication burden and anticholinergic use are associated with overt HE in individuals with cirrhosis.","authors":"Jonathan A Montrose, Archita Desai, Lauren Nephew, Kavish R Patidar, Marwan S Ghabril, Noll L Campbell, Naga Chalasani, Yingjie Qiu, Matthew E Hays, Eric S Orman","doi":"10.1097/HC9.0000000000000460","DOIUrl":"10.1097/HC9.0000000000000460","url":null,"abstract":"<p><strong>Background: </strong>Polypharmacy and anticholinergic medications are associated with cognitive decline in elderly populations. Although several medications have been associated with HE, associations between medication burden, anticholinergics, and HE have not been explored. We examined medication burden and anticholinergics in patients with cirrhosis and their associations with HE-related hospitalization.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of patients aged 18-80 with cirrhosis seen in hepatology clinics during 2019. The number of chronic medications (medication burden) and anticholinergic use were recorded. The primary outcome was HE-related hospitalization.</p><p><strong>Results: </strong>A total of 1039 patients were followed for a median of 840 days. Thirty-seven percent had a history of HE, and 9.8% had an HE-related hospitalization during follow-up. The mean number of chronic medications was 6.1 ± 4.3. Increasing medication burden was associated with HE-related hospitalizations in univariable (HR: 1.09, 95% CI: 1.05-1.12) and multivariable (HR: 1.07, 95% CI: 1.03-1.11) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. Twenty-one percent were taking an anticholinergic medication. Anticholinergic exposure was associated with increased HE-related hospitalizations in both univariable (HR: 1.68, 95% CI: 1.09-2.57) and multivariable (HR: 1.71, 95% CI: 1.11-2.63) models. This relationship was maintained in those with baseline HE but not in those without baseline HE.</p><p><strong>Conclusions: </strong>Anticholinergic use and medication burden are both associated with HE-related hospitalizations, particularly in those with a history of HE. Special considerations to limit anticholinergics and minimize overall medication burden should be tested for potential benefit in this population.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estimating the economic impact of comorbidities in patients with MASH and defining high-cost burden in patients with noncirrhotic MASH.","authors":"Zobair M Younossi, Kamal Kant Mangla, Abhishek Shankar Chandramouli, Jeffrey V Lazarus","doi":"10.1097/HC9.0000000000000488","DOIUrl":"10.1097/HC9.0000000000000488","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is associated with high health care costs. This US study investigated the economic burden of MASH, particularly in patients without cirrhosis, and the impact of comorbidities on health care costs.</p><p><strong>Methods: </strong>This retrospective, observational study used data from patients diagnosed with MASH aged ≥18 years from October 2015 to March 2022 (IQVIA Ambulatory electronic medical record-US). Patients were stratified by the absence or presence of cirrhosis. Primary outcomes included baseline characteristics and annualized total health care cost after MASH diagnosis during follow-up. In addition, this study defined high costs for the MASH population and identified patient characteristics associated with increased health care costs among those without cirrhosis.</p><p><strong>Results: </strong>Overall, 16,919 patients (14,885 without cirrhosis and 2034 with cirrhosis) were included in the analysis. The prevalence of comorbidities was high in both groups; annual total health care costs were higher in patients with cirrhosis. Patients with a high-cost burden (threshold defined using the United States national estimated annual health care expenditure of $13,555) had a higher prevalence of comorbidities and were prescribed more cardiovascular medications. MASH diagnosis was associated with an increase in cost, largely driven by inpatient costs. In patients without cirrhosis, an increase in cost following MASH diagnosis was associated with the presence and burden of comorbidities and cardiovascular medication utilization.</p><p><strong>Conclusions: </strong>Comorbidities, such as cardiovascular disease and type 2 diabetes, are associated with a higher cost burden and may be aggravated by MASH. Prioritization and active management may benefit patients without cirrhosis with these comorbidities. Clinical care should focus on preventing progression to cirrhosis and managing high-burden comorbidities.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binge drinking at time of bariatric surgery is associated with liver disease, suicides, and increases long-term mortality.","authors":"Edilmar Alvarado-Tapias, David Martí-Aguado, Concepción Gómez-Medina, Andreu Ferrero-Gregori, Justyna Szafranska, Anna Brujats, Rubén Osuna-Gómez, Albert Guinart-Cuadra, Clara Alfaro-Cervelló, Elisa Pose, Meritxell Ventura-Cots, Ana Clemente, Carlos Fernández-Carrillo, Cynthia Contreras, Joaquin Cabezas, Hugo López-Pelayo, Juan Pablo Arab, Josepmaria Argemi, Ramon Bataller","doi":"10.1097/HC9.0000000000000490","DOIUrl":"10.1097/HC9.0000000000000490","url":null,"abstract":"<p><strong>Background and aims: </strong>Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up.</p><p><strong>Methods: </strong>A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk.</p><p><strong>Results: </strong>A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04-1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07-1.85)] and used other drugs (OR=2.65 [95% CI: 1.74-4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25-7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86-14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67-6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025).</p><p><strong>Conclusions: </strong>The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing of the analgesic Neurotropin for MASLD/MASH treatment.","authors":"Takashi Tsuchiya, So Yeon Kim, Michitaka Matsuda, Jieun Kim, Alexsandr Stotland, Mitsuru Naiki, Ekihiro Seki","doi":"10.1097/HC9.0000000000000480","DOIUrl":"10.1097/HC9.0000000000000480","url":null,"abstract":"<p><strong>Background: </strong>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased in recent decades. Approximately 25% of patients with MASLD progress to metabolic dysfunction-associated steatohepatitis, which is characterized by hepatic steatosis plus hepatocyte damage, inflammation, and fibrosis. We previously reported that Neurotropin (NTP), a drug used for relieving pain in Japan and China, inhibits lipid accumulation in hepatocytes by preventing mitochondrial dysfunction. We hypothesized that inhibiting hepatic steatosis and inflammation by NTP can be an effective strategy for treating MASLD and tested this hypothesis in a MASLD mouse model.</p><p><strong>Methods: </strong>Six-week-old C57BL/6NJ male mice were fed a normal diet and normal drinking water or a high-fat diet with high fructose/glucose water for 12 weeks. During the last 6 weeks, the mice were also given high-dose NTP, low-dose NTP, or control treatment. Histologic, biochemical, and functional tests were conducted. MitoPlex, a new proteomic platform, was used to measure mitochondrial proteins, as mitochondrial dysfunction was previously reported to be associated with MASLD progression.</p><p><strong>Results: </strong>NTP inhibited the development of hepatic steatosis, injury, inflammation, and fibrosis induced by feeding a high-fat diet plus high fructose/glucose in drinking water. NTP also inhibited HSC activation. MitoPlex analysis revealed that NTP upregulated the expression of mitochondrial proteins related to oxidative phosphorylation, the tricarboxylic acid cycle, mitochondrial dynamics, and fatty acid transport.</p><p><strong>Conclusions: </strong>Our results indicate that NTP prevents the development of hepatic steatosis, injury, and inflammation by preserving mitochondrial function in the liver and inhibits liver fibrosis by suppressing HSC activation. Thus, repurposing NTP may be a beneficial option for treating MASLD/metabolic dysfunction-associated steatohepatitis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic disease markers in primary sclerosing cholangitis and primary biliary cholangitis-methylomics of cholestatic liver disease.","authors":"Brian D Juran, Bryan M McCauley, Elizabeth J Atkinson, Erik M Schlicht, Jackie K Bianchi, Jason M Vollenweider, Hong Ye, Nicholas F LaRusso, Gregory J Gores, Zhifu Sun, Konstantinos N Lazaridis","doi":"10.1097/HC9.0000000000000496","DOIUrl":"10.1097/HC9.0000000000000496","url":null,"abstract":"<p><strong>Background: </strong>The epigenome, the set of modifications to DNA and associated molecules that control gene expression, cellular identity, and function, plays a major role in mediating cellular responses to outside factors. Thus, evaluation of the epigenetic state can provide insights into cellular adaptions occurring over the course of disease.</p><p><strong>Methods: </strong>We performed epigenome-wide association studies of primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) using the Illumina MethylationEPIC Bead Chip.</p><p><strong>Results: </strong>We found evidence of increased epigenetic age acceleration and differences in predicted immune cell composition in patients with PSC and PBC. Epigenetic profiles demonstrated differences in predicted protein levels including increased levels of tumor necrosis factor receptor superfamily member 1B in patients with cirrhotic compared to noncirrhotic PSC and PBC. Epigenome-wide association studies of PSC discovered strongly associated 5'-C-phosphate-G-3' sites in genes including vacuole membrane protein 1 and SOCS3, and epigenome-wide association studies of PBC found strong 5'-C-phosphate-G-3' associations in genes including NOD-like receptor family CARD domain containing 5, human leukocyte antigen-E, and PSMB8. Analyses identified disease-associated canonical pathways and upstream regulators involved with immune signaling and activation of macrophages and T-cells. A comparison of PSC and PBC data found relatively little overlap at the 5'-C-phosphate-G-3' and gene levels with slightly more overlap at the level of pathways and upstream regulators.</p><p><strong>Conclusions: </strong>This study provides insights into methylation profiles of patients that support current concepts of disease mechanisms and provide novel data to inspire future research. Studies to corroborate our findings and expand into other -omics layers will be invaluable to further our understanding of these rare diseases with the goal to improve and individualize prognosis and treatment.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11262819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}