DSpace Angular :: Browsing by Author "Shah, Vijay H."

Browsing by Author "Shah, Vijay H."

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Alcohol-associated liver disease in the United States is associated with severe forms of disease among young, females and Hispanics
(2021) Singal, Ashwani K.; Arsalan, Arshad; Dunn, Winston; Arab, Juan P.; Wong, Robert J.; Kuo, Yong-Fang; Kamath, Patrick S.; Shah, Vijay H.
Background Alcohol use and alcohol-associated liver disease (ALD) burden are increasing in young individuals. Aim To assess host factors associated with this burden. Methods National Health and Nutrition Examination Survey (NHANES), National Inpatient Sample (NIS), and United Network for Organ Sharing (UNOS) databases (2006-2016) were used to identify individuals with harmful alcohol use, ALD-related admissions, and ALD-related LT listings respectively. Results Of 15 981 subjects in NHANES database, weighted prevalence of harmful alcohol use was 17.7%, 29.3% in <35 years (G1) versus 16.9% in 35-64 years (G2) versus 5.1% in >= 65 years (G3). Alcohol use was about 11 and 4.7 folds higher in G1 and G2 versus G3, respectively. Male gender and Hispanic race associated with harmful alcohol use. Of 593 600 ALD admissions (5%, 77%, and 18% in G1-G3 respectively), acute on chronic liver failure (ACLF) occurred in 7.2%, (7.2 in G2 vs 6.7% in G1 and G3, P < 0.001). After controlling for other variables, ACLF development among ALD hospitalizations was higher by 14% and 10% in G1 and G2 versus G3, respectively. Female gender and Hispanic race were associated with increased ACLF risk by 8% and 17% respectively. Of 20,245 ALD LT listings (3.4%, 84.4%, and 12.2% in G1-G3 respectively), ACLF occurred in 28% candidates. Risk of severe (grade 2 or 3) ACLF was higher by about 1.7 fold in G1, 1.5 fold in females and 20% in Hispanics. Conclusion Young age, female gender, and Hispanic race are independently associated with ALD-related burden and ACLF in the United States. If these findings are validated in prospective studies, strategies will be needed to reduce alcohol use in high risk individuals to reduce burden from ALD.
An artificial intelligence-generated model predicts 90-day survival in alcohol-associated hepatitis: A global cohort study
(2024) Dunn, Winston; Li, Yanming; Singal, Ashwani K.; Simonetto, Douglas A.; Díaz Piga, Luis Antonio; Idalsoaga Ferrer, Francisco Javier; Ayares, Gustavo; Arnold Alvaréz, Jorge Ignacio; Ayala-Valverde, Maria; Perez, Diego; Gomez, Jaime; Escarate, Rodrigo; Fuentes López, Eduardo; Ramirez-Cadiz, Carolina; Morales-Arraez, Dalia; Zhang, Wei; Qian, Steve; Ahn, Joseph C.; Buryska, Seth; Mehta, Heer; Dunn, Nicholas; Waleed, Muhammad; Stefanescu, Horia; Bumbu, Andreea; Horhat, Adelina; Attar, Bashar; Agrawal, Rohit; Cabezas, Joaquin; Echavaria, Victor; Cuyas, Berta; Poca, Maria; Soriano, German; Sarin, Shiv K.; Maiwall, Rakhi; Jalal, Prasun K.; Higuera-de-la-Tijera, Fatima; Kulkarni, Anand V.; Rao, P. Nagaraja; Guerra-Salazar, Patricia; Skladany, Lubomir; Kubanek, Natalia; Prado, Veronica; Clemente-Sanchez, Ana; Rincon, Diego; Haider, Tehseen; Chacko, Kristina R.; Romero, Gustavo A.; Pollarsky, Florencia D.; Restrepo, Juan C.; Toro, Luis G.; Yaquich, Pamela; Mendizabal, Manuel; Garrido, Maria L.; Marciano, Sebastian; Dirchwolf, Melisa; Vargas, Victor; Jimenez, Cesar; Hudson, David; Garcia-Tsao, Guadalupe; Ortiz, Guillermo; Abraldes, Juan G.; Kamath, Patrick S.; Arrese, Marco; Shah, Vijay H.; Bataller, Ramon; Arab, Juan P.
Background and Aims: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model. Approach and Results: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30 d) and 27.9% (90 d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores (p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts. Conclusions: Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/.
Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes
(Elsevier B.V., 2023) Diaz Piga, Luis Antonio; Fuentes, López Eduardo; Idalsoaga Ferrer, Francisco Javier; Ayares Campos, Gustavo Ignacio; Corsi Sotelo, Oscar Felipe; Arnold Alvarez, Jorge Ignacio; Cannistra Cadiz, Macarena Rossella; Vio Quiroz, Danae Fernanda; Marquez Lomas, Andrea; Ramirez Cadiz, Carolina Andrea; Medel Salas, María Paz; Hernández Tejero, María; Ferreccio Readi, Fresia Catterina; Lazo Bravo, Mariana Carolina; Roblero Cum, Juan Pablo; Cotter, Thomas G.; Kulkarni ,Anand V.; Kim, Won; Brahmania, Mayur; Louvet, Alexandre; Tapper, Elliot B.; Dunn, Winston; Simonetto, Douglas; Shah, Vijay H.; Kamath, Patrick S.; Lazarus, Jeffrey V.; Singal, Ashwabi K.; Bataller, Ramón; Arrese Jimenez, Marco Antonio; Arab Verdugo, Juan Pablo
© 2023 The Author(s)Background & Aims: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. Methods: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010–2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. Results: The median API in the 169 countries was 54 [IQR 34.9–76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03–0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03–0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02–0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02–0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02–0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). Conclusions: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. Impact and implications: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.
Comparison Between Dynamic Models for Predicting Response to Corticosteroids in Alcohol-Associated Hepatitis: A Global Cohort Study
(WILEY, 2025) Idalsoaga Ferrer, Francisco Javier; Díaz Piga, Luis Antonio; Guizzetti, Leonardo; Dunn, Winston; Mehta, Heer; Arnold, Jorge; Ayares Campos, Gustavo Ignacio; Mortuza, Rokhsana; Mahli, Gurpreet; Islam, Alvi H.; Sarin, Shiv K.; Maiwall, Rakhi; Zhang, Wei; Qian, Steve; Simonetto, Douglas; Singal, Ashwani K.; Elfeki, Mohamed A.; Ramirez-Cadiz, Carolina; Cabezas, Joaquin; Echavarria, Victor; Cots, Meritxell Ventura; La Tijera, Maria Fatima Higuera-De; Abraldes, Juan G.; Al-Karaghouli, Mustafa; Jalal, Prasun K.; Ali Ibrahim, Mohamad; Garcia-Tsao, Guadalupe; Goyes, Daniela; Skladany, Lubomir; Havaj, Daniel J.; Sulejova, Karolina; Selcanova, Svetlana Adamcova; Rincon, Diego; Shah, Vijay H.; Kamath, Patrick S.; Arrese, Marco; Bataller, Ramon; Arab, Juan Pablo
Several dynamic models predict mortality and corticosteroid response in alcohol-associated hepatitis (AH), yet no consensus exists on the most effective model. This study aimed to assess predictive models for corticosteroid response and short-term mortality in severe AH within a global cohort. We conducted a multi-national study of patients with severe AH treated with corticosteroids for at least 7 days, enrolled between 2009 and 2019. Dynamic models-Lille-4, Lille-7, trajectory of serum bilirubin (TSB), and neutrophil-to-lymphocyte ratio (NLR)-were used to estimate 30- and 90-day mortality. Lille-7 demonstrated the highest accuracy for both 30- and 90-day mortality.
Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
(2019) Argemie, Josepmaria; Latasa, Maria U.; Atkinson, Stephen R.; Blokhin, Ilya O.; Massey, Verónica; Gue, Joel P.; Cabezas, Joaquín; Lozano, Juan J.; Van Booven, Derek; Arab Verdugo, Juan Pablo; Bell, Aaron; Cao, Sheng; Vernetti, Lawrence A.; Ventura Cots, Maritxell; Edmunds, Lia R.; Fondevilla, Constantino; Starkel, Peter; Dubuquoy, Laurent; Louvet, Alexandre; Odena, Gemma; Gómez, Juan L.; Aragón, Tomás; Altamirano, José; Caballeria, Juan; Jurczak, Michael J.; Taylor, D. Lansing; Berasain, Carmen; Wahlestedt, Claes; Monga, Satdaeshan P.; Morgan, Marsha Y.; Sancho Bru, Pau; Mathurin, Philippe; Furuya, Shinji; Lackner, Carolin; Rusyn, Ivan; Shah, Vijay H.; Thursz, Mark R.; Mann, Jelena; Ávila, Matías A.; Bataller, Ramón
Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-beta Dependent Hepatic Stellate Cell Activation and Liver Fibrosis
(2019) Martin Mateos, Rosa; De Assuncao, Thiago M.; Arab Verdugo, Juan Pablo; Jalan Sakrikar, Nidhi; Yagoob, Usman; Greuter, Thomas; Verma, Vikas K.; Mathison, Angela J.; Cao, Sheng; Lomberk, Gwen; Mathurin, Philippe; Urrutia, Raúl; Huebert, Robert C.; Shah, Vijay H.
Gut–liver axis, cirrhosis and portal hypertension: the chicken and the egg
(2018) Arab Verdugo, Juan Pablo; Martin-Mateos, Rosa M.; Shah, Vijay H.
Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12
(2020) Arab, Juan P.; Cabrera, Daniel; Sehrawat, Tejasav S.; Jalan-Sakrikar, Nidhi; Verma, Vikas K.; Simonetto, Douglas; Cao, Sheng; Yaqoob, Usman; Leon, Jonathan; Freire, Mariela; Vargas, Jose, I; De Assuncao, Thiago M.; Kwon, Jung H.; Guo, Yi; Kostallari, Enis; Cai, Qing; Kisseleva, Tatiana; Oh, Youngman; Arrese, Marco; Huebert, Robert C.; Shah, Vijay H.
Background & Aims: Steatohepatitis drives fibrogenesis in alcohol-related liver disease. Recent studies have suggested that hepatic stellate cells (HSCs) may regulate the parenchymal cell injury and inflammation that precedes liver fibrosis, although the mechanism remains incompletely defined. Neuropilin-1 (NRP-1) and synectin are membrane proteins implicated in HSC activation. In this study, we disrupted NRP-1 and synectin as models to evaluate the role of HSC activation on the development of steatohepatitis in response to alcohol feeding in mice.
Identifying Alcohol Use Disorder in Patients With Cirrhosis Reduces 30-Days Readmission Rate
(2022) Singal, Ashwani K.; DiMartini, Andrea; Leggio, Lorenzo; Arab, Juan P.; Kuo, Yong-Fang; Shah, Vijay H.
Aims Readmission is frequent among patients with cirrhosis and is a complex multifactorial process. To examine the association of alcohol use disorder (AUD) and risk of readmission in patients with alcohol-associated cirrhosis. Methods and Results National Readmission Dataset (2016-2017) was used to extract a retrospective cohort of 53,348 patients with primary or secondary discharge diagnosis code of alcohol-associated cirrhosis with their first admission (26,674 patients with vs. propensity matched 26,674 without a primary or secondary discharge diagnosis code of AUD). Readmission within 30-day was lower (43.9 vs. 48%, P < 0.001) among patients identified to have AUD at the time of discharge. In a conditional logistic regression model, a diagnosis of AUD was associated with 15% reduced odds of 30-day readmission, 0.85 (0.83-0.88). Furthermore, the reason for readmission among patients identified vs. not identified to have AUD was less likely to be liver disease complication. The findings remained similar in a matched cohort of patients where the AUD diagnosis at discharge was listed as one of the secondary diagnoses only. Conclusion Although, our study findings suggest that identification of AUD at the time of discharge among patients hospitalized for alcohol-associated cirrhosis reduces the risk of 30-day readmission, unavailable information on patient counseling, referral for mental health specialist and treatment received for AUD limit the causality assessment. Future studies are needed overcoming the inherent limitations of the database to establish the role of identification and treatment of AUD in reducing readmission and liver decompensation in patients with alcohol-associated cirrhosis.
MELD 3.0 adequately predicts mortality and renal replacement therapy requirements in patients with alcohol-associated hepatitis
(Elsevier B.V., 2023) Diaz Piga, Luis Antonio; Fuentes Lopez, Eduardo; Ayares Campos, Gustavo Ignacio; Idalsoaga Ferrer, Francisco Javier; Arnold Álvarez, Jorge Ignacio; Valverde, María Ayala; Perez, Diego; Gómez, Jaime; Escarate, Rodrigo; Villalon Friedrich, Alejandro Andrés; Ramírez, Carolina A.; Hernández-Tejero, María; Zhang, Wei; Qian, Steve; Simonetto, Douglas; Ahn, Joseph C.; Buryska, Seth; Dunn, Winston; Mehta, Heer; Agrawal, Rohit; Cabezas, Joaquín; Garcia Carrera, Inés; Cuyas, Berta; Poca, Maria; Soriano, German; Sarin, Shiv K.; Maiwall, Rakhi; Jalal, Prasun K.; Abdulsada, Saba; Higuera de la Tijera, Fátima; Kulkarni, Anand V.; Rao, P. Nagaraja; Guerra Salazar, Patricia; Skladany, Lubomir; Bystrianska, Natália; Clemente Sánchez, Ana; Villaseca Gómez, Clara; Haider, Tehseen; Chacko, Kristina R.; Romero, Gustavo A.; Pollarsky Florencia D.; Restrepo, Juan Carlos; Castro Sánchez, Susan; Toro, Luis G.; Yaquich, Pamela; Mendizabal, Manuel; Garrido, María Laura; Marciano, Sebastián; Dirchwolf, Melisa; Vargas, Víctor; Jimenez, César; Louvet, Alexandre; Garcia Tsao, Guadalupe; Roblero, Juan Pablo; Abraldes, Juan G.; Shah, Vijay H.; Kamath, Patrick S.; Arrese Jimenez, Marco Antonio; Singal, Ashwani K.; Bataller, Ramón; Arab Verdugo, Juan Pablo
© 2023 The Author(s)Background & Aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. Results: A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20–33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732–0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713–0.775; p = 0.042) and Maddrey's discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691–0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723–0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727–0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724–0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708–0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687–0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805–0.883). Conclusions: MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Impact and implications: Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.
Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group
(2021) Im, Gene Y.; Mellinger, Jessica L.; Winters, Adam; Aby, Elizabeth S.; Lominadze, Zurabi; Rice, John; Lucey, Michael R.; Arab, Juan P.; Goel, Aparna; Jophlin, Loretta L.; Sherman, Courtney B.; Parker, Richard; Chen, Po-Hung; Devuni, Deepika; Sidhu, Sandeep; Dunn, Winston; Szabo, Gyongyi; Singal, Ashwani K.; Shah, Vijay H.
BACKGROUND & AIMS: While abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease.
Racial and ethnic disparities in the natural history of alcohol-associated liver disease in the United States
(WILEY, 2024) Ayares Campos, Gustavo Ignacio; Diaz Piga, Luis Antonio; Fuentes Lopez, Eduardo; Idalsoaga Ferrer, Francisco Javier; Cotter, Thomas G.; Dunn, Winston; Simonetto, Douglas; Shah, Vijay H.; Kamath, Patrick S.; Lazarus, Jeffrey V.; Bataller, Ramon; Arrese, Marco; Wong, Robert J.; Singal, Ashwani K.; Arab, Juan Pablo
Background: Outcomes in alcohol-associated liver disease (ALD) are influenced by several race and ethnic factors, yet its natural history across the continuum of patients in different stages of the disease is unknown.MethodsWe conducted a retrospective cohort study of U.S. adults from 2011 to 2018, using three nationally representative databases to examine potential disparities in relevant outcomes among racial and ethnic groups. Our analysis included logistic and linear regressions, along with competing risk analysis.ResultsBlack individuals had the highest daily alcohol consumption (12.6 g/day) while Hispanic participants had the largest prevalence of heavy episodic drinking (33.5%). In a multivariable-adjusted model, Hispanic and Asian participants were independently associated with a higher ALD prevalence compared to Non-Hispanic White interviewees (OR: 1.4, 95% CI: 1.1-1.8 and OR: 1.5 95% CI:1.1-2.0, respectively), while Blacks participants had a lower ALD prevalence (OR: .7 95% CI: .6-.9), and a lower risk of mortality during hospitalization due to ALD (OR: .83 95% CI: .73-.94). Finally, a multivariate competing-risk analysis showed that Hispanic ethnicity had a decreased probability of liver transplantation if waitlisted for ALD (SHR: .7, 95% CI: .6-.8) along with female Asian population (HR: .40, 95% CI: .26-.62).ConclusionsAfter accounting for key social and biological health determinants, the Hispanic population showed an increased risk of ALD prevalence, even with lower alcohol consumption. Additionally, Hispanic and Asian female patients had reduced access to liver transplantation compared to other enlisted patients., image
Statins and portal hypertension : a tale of two models
(2016) Arab Verdugo, Juan Pablo; Shah, Vijay H.
Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
(2021) Liu, Mengfei; Cao, Sheng; He, Li; Gao, Jinhang; Arab, Juan P.; Cui, Huarui; Xuan, Weixia; Gao, Yandong; Sehrawat, Tejasav S.; Hamdan, Feda H.; Ventura-Cots, Meritxell; Argemi, Josepmaria; Pomerantz, William C. K.; Johnsen, Steven A.; Lee, Jeong-Heon; Gao, Fei; Ordog, Tamas; Mathurin, Philippe; Revzin, Alexander; Bataller, Ramon; Yan, Huihuang; Shah, Vijay H.
Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNF alpha with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNF alpha /NF-kappa B signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment. Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.
The Mortality Index for Alcohol-Associated Hepatitis: A Novel Prognostic Score
(2022) Kezer, Camille A.; Buryska, Seth M.; Ahn, Joseph C.; Harmsen, William S.; Dunn, Winston; Singal, Ashwani K.; Arab, Juan P.; Diaz, Luis A.; Arnold, Jorge; Kamath, Patrick S.; Shah, Vijay H.; Simonetto, Douglas A.
Objective: To develop a new scoring system that more accurately predicts 30-day mortality in patients with alcohol-associated hepatitis (AH).
Use of Statins in Patients with Chronic Liver Disease and Cirrhosis: Current Views and Prospects
(2017) Vargas Domínguez, José Ignacio; Arrese Jiménez, Marco; Shah, Vijay H.; Arab Verdugo, Juan Pablo
XIAP Knockdown in Alcohol-Associated Liver Disease Models Exhibits Divergent in vitro and in vivo Phenotypes Owing to a Potential Zonal Inhibitory Role of SMAC
(2021) He, Li; Sehrawat, Tejasav S.; Verma, Vikas K.; Navarro-Corcuera, Amaia; Sidhu, Guneet; Mauer, Amy; Luo, Xin; Katsumi, Tomohiro; Chen, Jingbiao; Shah, Soni; Arab, Juan Pablo; Cao, Sheng; Kashkar, Hamid; Gores, Gregory J.; Malhi, Harmeet; Shah, Vijay H.
Alcohol-associated liver disease (ALD) has been recognized as the most common cause of advanced liver disease worldwide, though mechanisms of pathogenesis remain incompletely understood. The X-linked inhibitor of apoptosis (XIAP) protein was originally described as an anti-apoptotic protein that directly binds and inhibits caspases-3, 7, and 9. Here, we investigated the function of XIAP in hepatocytes in vitro using gain and loss-of-function approaches. We noted an XIAP-dependent increase in caspase activation as well as increased inflammatory markers and pro-inflammatory EV release from hepatocytes in vitro. Primary hepatocytes (PMH) from Xiap(Alb.Cre) and Xiap(loxP) mice exhibited higher cell death but surprisingly, lower expression of inflammation markers. Conditioned media from these isolated Xiap deleted PMH further decrease inflammation in bone marrow-derived macrophages. Also, interestingly, when administered an ethanol plus Fas-agonist-Jo2 model and an ethanol plus CCl4 model, these animals failed to develop an exacerbated disease phenotype in vivo. Of note, neither Xiap(Alb).(Cre) nor Xiap(AAV8.Cre) mice presented with aggravated liver injury, hepatocyte apoptosis, liver steatosis, or fibrosis. Since therapeutics targeting XIAP are currently in clinical trials and caspase-induced death is very important for development of ALD, we sought to explore the potential basis of this unexpected lack of effect. We utilized scRNA-seq and spatially reconstructed hepatocyte transcriptome data from human liver tissue and observed that XIAP was significantly zonated, along with its endogenous inhibitor second mitochondria-derived activator of caspases (SMAC) in periportal region. This contrasted with pericentral zonation of other IAPs including cIAP1 and Apollon as well as caspases 3, 7, and 9. Thus providing a potential explanation for compensation of the effect of Xiap deletion by other IAPs. In conclusion, our findings implicate a potential zonallydependent role for SMAC that prevented development of a phenotype in XIAP knockout mice in ALD models. Targeting SMAC may also be important in addition to current efforts of targeting XIAP in treatment of ALD.

Browsing by Author "Shah, Vijay H."

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