Browsing by Subject "Hepatology"
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Item Attendance at a Transitional Liver Clinic May Be Associated with Reduced Readmissions for Patients with Liver Disease(Elsevier, 2022) Yoder, Lindsay; Mladenovic, Andrea; Pike, Francis; Vuppalanchi, Raj; Hanson, Haleigh; Corbito, Laura; Desai, Archita P.; Chalasani, Naga; Orman, Eric S.; Medicine, School of MedicineIntroduction: Patients with liver disease have high rates of early hospital readmission, but there are no studies of effective, scalable interventions to reduce this risk. In this study, we examined the impact of a Physician Assistant (PA)-led post-discharge Transitional Liver Clinic (TLC) on hospital readmissions. Methods: We performed a cohort study of all adults seen by a hepatologist during admission to a tertiary care center in 2019 (excluding transplant patients). We compared those who attended the TLC with those who did not, with respect to 30-day readmission and mortality. Propensity score-adjusted modeling was used to control for confounding. Results: Of 498 patients, 98 were seen in the TLC; 35% had alcoholic liver disease and 58% had cirrhosis. Attendees were similar to non-attendees with respect to demographics, liver disease characteristics and severity, comorbidities, and discharge disposition. Thirty-day cumulative incidence of readmissions was 12% in TLC attendees, compared with 22% in non-attendees (P = .02), while 30-day mortality was similar (2.0% vs 4.3%; P = .29). In a model using propensity score adjustment, TLC attendance remained associated with reduced readmissions (subhazard ratio 0.52; 95% confidence interval, 0.27-0.997; P = .049). The effect of TLC was greater in women compared with men (P = .07) and in those without chronic kidney disease (P = .02), but there were no differences across other subgroups. Conclusions: Patients with liver disease seen in a PA-led TLC may have a significant reduction in the 30-day readmission rate. Randomized trials are needed to establish the efficacy of PA-led post-discharge transitional care for this population.Item Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms(American Society for Clinical Investigation, 2020-06-16) Ma, Jing; Cao, Haixia; Rodrigues, Robim M.; Xu, Mingjiang; Ren, Tianyi; He, Yong; Hwang, Seonghwan; Feng, Dechun; Ren, Ruixue; Yang, Peixin; Liangpunsakul, Suthat; Sun, Jian; Gao, Bin; Medicine, School of MedicineAlcohol-associated liver disease is a spectrum of liver disorders with histopathological changes ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Recent data suggest that chronic-plus-binge ethanol intake induces steatohepatitis by promoting release by hepatocytes of proinflammatory mitochondrial DNA–enriched (mtDNA-enriched) extracellular vesicles (EVs). The aim of the present study was to investigate the role of the stress kinase apoptosis signal–regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38) in chronic-plus-binge ethanol–induced steatohepatitis and mtDNA-enriched EV release. Microarray analysis revealed the greatest hepatic upregulation of metallothionein 1 and 2 (Mt1/2), which encode 2 of the most potent antioxidant proteins. Genetic deletion of the Mt1 and Mt2 genes aggravated ethanol-induced liver injury, as evidenced by elevation of serum ALT, neutrophil infiltration, oxidative stress, and ASK1/p38 activation in the liver. Inhibition or genetic deletion of Ask1 or p38 ameliorated ethanol-induced liver injury, inflammation, ROS levels, and expression of phagocytic oxidase and ER stress markers in the liver. In addition, inhibition of ASK1 or p38 also attenuated ethanol-induced mtDNA-enriched EV secretion from hepatocytes. Taken together, these findings indicate that induction of hepatic mtDNA-enriched EVs by ethanol is dependent on ASK1 and p38, thereby promoting alcoholic steatohepatitis.Item Hepatitis B Virus Reactivation in Cancer Patients Receiving Direct-Acting Antivirals for Hepatitis C Virus Infection(Wiley, 2021) Pritchard, Haley; Hwang, Jessica P.; Angelidakis, Georgios; Yibirin, Marcel; Wang, Lan; Miller, Ethan; Torres, Harrys A.; Medicine, School of MedicineDirect-acting antivirals (DAAs) against hepatitis C virus (HCV) infection can cause hepatitis B virus (HBV) reactivation in HBV/HCV co-infected patients. Cancer patients undergoing immunosuppressant treatment or chemotherapy are at risk for HBV reactivation. To our knowledge, no prospective studies have examined the risk of HBV reactivation during DAA treatment for HCV infection in cancer patients with HBV/HCV co-infection. Here, we report the results of one such study. In a prospective observational study, we enrolled HCV-infected cancer patients undergoing DAA treatment at The University of Texas MD Anderson Cancer Center between January 2015 and March 2018. Data regarding demographics, cancer history, and prior HCV treatment history were collected. Patients were assessed for HBV status before DAA treatment and for HBV-related outcomes, including HBV reactivation, hepatitis flare, and HBV-associated hepatitis, during DAA treatment. Demographic and treatment variables were analyzed using descriptive statistics. One hundred sixty-six patients were analyzed. Forty-eight patients received systemic chemotherapy within 6 months before to 6 months after treatment with DAAs. Ledipasvir plus sofosbuvir was the most common DAA regimen, administered to 88 patients (53%). Fifty-one patients (31%) had past HBV infection, and 4 (2.4%) had chronic HBV infection. No patient experienced HBV reactivation, hepatitis flare, or HBV-associated hepatitis induced by DAA treatment. In HCV-infected cancer patients, DAA treatment is safe regardless of whether patients have past or chronic HBV infection. However, HBV screening is still recommended before the initiation of and during DAA treatment, as is anti-HBV prophylactic treatment in selected cases.Item HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers(American Society for Clinical Investigation, 2018-06-01) Khambu, Bilon; Huda, Nazmul; Chen, Xiaoyun; Antoine, Daniel J.; Li, Yong; Dai, Guoli; Köhler, Ulrike A.; Zong, Wei-Xing; Waguri, Satoshi; Werner, Sabine; Oury, Tim D.; Dong, Zheng; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of MedicineAutophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.Item The impact of mTOR, TFEB and Bid on non-alcoholic fatty liver disease and metabolic syndrome(2015-05-18) Zhang, Hao; Yin, Xiao-Ming; Chalasani, Naga P.; Konger, Raymond Lloyd; Murrell, Jill R.Non-alcoholic fatty liver disease and metabolic syndrome induced by high nutrient status have increasingly become a global health concern as it cause multiple complications. The mTOR complex is central in regulating anabolic reactions within cells under growth factors or under high nutrients stimulation. Constitutive and persistent activation of mTOR can impair cellular functions. In the first part of this study, we demonstrate a damping oscillation of mTOR activity during a long-term treatment of high fat diet. TFEB translocation and lysosomal enzyme activity also oscillate, but in an opposite direction. TFEB controls the lysosomal activity, autophagic degradation and lipid metabolism. Overexpression of wild type and mutant TFEB could inhibit NAFLD development in mice. In addition, TFEB location in nucleus inversely correlates with NAFLD severity in patients. mTOR activation under hypernutrition status suppresses TFEB translocation, inhibits lysosomal functions and autophagic degradation of lipid droplets. Inhibition of mTOR activity by rapamycin reverse the above phenotypes. Because mTOR activation also requires normal lysosomal function, the inhibition of TFEB by mTOR leads to decreased lysosomal function and mTOR downregulation. This negative feedback may explain the oscillation pattern of mTOR activation in long term high fat diet regimen and is a novel mechanism for inhibition of mTOR. In the second part of study, we report that Bid protein, previously known for its pro-apoptosis function in promoting mitochondrial permeability, plays an unexpected role in regulating fatty acid beta oxidation. Deletion of Bid in mice reprograms the body's response to hyper-nutrition caused by high fat diet, leading to the resistance to the development of obesity, liver steatosis and metabolic syndrome. These mice present a higher oxygen consumption, a lower respiratory quotient, and an increased beta-oxidation rate. Mechanistically, the high fat diet regimen triggers translocation of the full length Bid molecule to mitochondrial membrane. Genetic deletion of Bid also affects the stability of its binding protein, MTCH2 in the mitochondrial membrane. In summary, we describe in this study a mTOR-TFEB-lysosome feedback loop, which can regulate NAFLD development, and a novel Bid-mediated regulatory mechanism in beta-oxidation, which limits energy expenditure and promotes obesity development.Item Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity(American Society for Clinical Investigation, 2017-07-20) Cai, Yan; Xu, Ming-Jiang; Koritzinsky, Erik H.; Zhou, Zhou; Wang, Wei; Cao, Haixia; Yuen, Peter S.T.; Ross, Ruth A.; Star, Robert A.; Liangpunsaku, Suthat; Gao, Bin; Medicine, School of MedicineOver the last several years, one of the major advances in the field of alcoholic liver disease research was the discovery that binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically ethanol-fed mice and human subjects with excessive alcohol use (EAU); however, the underlying mechanisms remain obscure. Here, we demonstrated that chronic EAU patients with a history of recent excessive drinking (EAU + RD) had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than EAU without recent drinking (EAU - RD) and healthy controls, which correlated positively with circulating neutrophils. Similarly, mice with chronic-plus-binge (E10d + 1B) ethanol feeding also had markedly elevated serum levels of mtDNA-enriched MPs, with activation of hepatic ER stress and inflammatory responses. Inhibition of ER stress by gene KO or inhibitors attenuated ethanol-induced elevation of mtDNA-enriched MPs, neutrophilia, and liver injury. The data from the study of hepatocyte-specific deletion of the protein kinase RNA-like ER kinase (Perk) gene in mice and of cultured hepatocytes demonstrated that hepatocytes were the main source of mtDNA-enriched MPs after ethanol feeding. Finally, administration of mtDNA-enriched MPs isolated from E10d+1B-fed mice caused neutrophilia in mice. In conclusion, E10d + 1B ethanol consumption activates hepatic ER stress-dependent mtDNA-enriched MP release, leading to neutrophilia and liver injury.Item Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir Mini-Tabs Plus Ribavirin for Children Aged 3–11 Years with Hepatitis C Genotype 1a(Springer, 2020-05-25) Rosenthal, Philip; Narkewicz, Michael R.; Yao, Betty B.; Jolley, Christopher D.; Lobritto, Steven J.; Wen, Jessica; Molleston, Jean P.; Hsu, Evelyn K.; Jonas, Maureen M.; Zha, Jiuhong; Liu, Li; Leung, Daniel H.; Pediatrics, School of MedicineIntroduction To assess the safety, efficacy, and pharmacokinetics of mini-tablet formulations of ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) with or without ribavirin for 12 weeks in children infected with chronic hepatitis C virus (HCV) genotype (GT) 1. Methods This is an ongoing, open-label, Phase 2/3 study in children 3–11 years old infected with HCV GT1 who were HCV treatment-naïve and non-cirrhotic. Pediatric mini-tablet formulations of OBV, PTV, ritonavir, and DSV plus ribavirin oral solution were administered for 12 weeks based on body weight. Endpoints included SVR12, adverse events (AEs), and pharmacokinetic parameters. Results Overall, 26 children received OBV, PTV, ritonavir, and DSV plus ribavirin; 14 were 3–8 years old and 12 were 9–11 years old; 35% were male; and all had chronic HCV GT1a infection. The SVR12 rate was 96% (25/26; 95% CI 81.1–99.3), with 1 child failing to achieve SVR12 due to non-adherence and treatment discontinuation. Treatment-emergent AEs of Grade ≥ 3 occurred in 3 children; 2 events in 1 child were considered serious; and none were considered treatment-related. No AEs led to discontinuation of study treatment. The most common AEs were headache (27%), fatigue (23%), pyrexia (19%), and vomiting (19%). Pharmacokinetic results showed mini-tablet formulations of OBV, PTV, DSV, and ritonavir drug exposures were comparable to the adult formulation. Conclusion The mini-tablet combination of OBV, PTV, ritonavir, and DSV plus ribavirin to treat HCV GT1a infection for 12 weeks was highly effective and suitable in children 3–11 years of age.Item Portal vein thrombosis, mortality and hepatic decompensation in patients with cirrhosis: A meta-analysis(Baishideng Publishing Group Co (World Journal of Hepatology), 2015-11-28) Stine, Jonathan G.; Shah, Puja M.; Cornella, Scott L.; Rudnick, Sean R.; Ghabril, Marwan S.; Stukenborg, George J.; Northup, Patrick G.; Department of Medicine, IU School of MedicineAIM: To determine the clinical impact of portal vein thrombosis in terms of both mortality and hepatic decompensations (variceal hemorrhage, ascites, portosystemic encephalopathy) in adult patients with cirrhosis. METHODS: We identified original articles reported through February 2015 in MEDLINE, Scopus, Science Citation Index, AMED, the Cochrane Library, and relevant examples available in the grey literature. Two independent reviewers screened all citations for inclusion criteria and extracted summary data. Random effects odds ratios were calculated to obtain aggregate estimates of effect size across included studies, with 95%CI. RESULTS: A total of 226 citations were identified and reviewed, and 3 studies with 2436 participants were included in the meta-analysis of summary effect. Patients with portal vein thrombosis had an increased risk of mortality (OR = 1.62, 95%CI: 1.11-2.36, P = 0.01). Portal vein thrombosis was associated with an increased risk of ascites (OR = 2.52, 95%CI: 1.63-3.89, P < 0.001). There was insufficient data available to determine the pooled effect on other markers of decompensation including gastroesophageal variceal bleeding or hepatic encephalopathy. CONCLUSION: Portal vein thrombosis appears to increase mortality and ascites, however, the relatively small number of included studies limits more generalizable conclusions. More trials with a direct comparison group are needed.Item The role of SHP/REV-ERBα/CYP4A axis in the pathogenesis of alcohol-associated liver disease(The American Society for Clinical Investigation, 2021-08-23) Yang, Zhihong; Smalling, Rana V.; Huang, Yi; Jiang, Yanchao; Kusumanchi, Praveen; Bogaert, Will; Wang, Li; Delker, Don A.; Skill, Nicholas J.; Han, Sen; Zhang, Ting; Ma, Jing; Huda, Nazmul; Liangpunsakul, Suthat; Medicine, School of MedicineAlcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp-/- mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp-/- mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα-/- hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.