Browsing by Author "Shah, Vijay"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study
    (Wiley, 2017) Li, Wei; Amet, Tohti; Xing, Yanyan; Yang, Dennis; Liangpunsakul, Suthat; Puri, Puneet; Kamath, Patrick; Sanyal, Arun; Shah, Vijay; Katz, Barry; Radaeva, Svetlana; Crabb, David; Chalasani, Naga; Yu, Qigui; Department of Microbiology and Immunology, IU School of Medicine
    Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma–induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. Conclusion: AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities.
  • Thumbnail Image
    Item
    Blood Biomarkers of Intestinal Epithelium Damage Regenerating Islet-derived Protein 3α and Trefoil Factor 3 Are Persistently Elevated in Patients with Alcoholic Hepatitis
    (Wiley, 2021) Yang, Jing; Syed, Fahim; Xia, Ying; Sanyal, Arun; Shah, Vijay; Chalasani, Naga; Zheng, Xiaoqun; Yu, Qigui; Lou, Yongliang; Li, Wei; Microbiology and Immunology, School of Medicine
    Background: Heavy alcohol consumption disrupts gut epithelial integrity, leading to increased permeability of the gastrointestinal tract and subsequent translocation of microbes. Regenerating islet-derived protein 3α (REG3α) and Trefoil factor 3 (TFF3) are mainly secreted to the gut lumen by Paneth and Goblet cells, respectively, and are functionally linked to gut barrier integrity. Circulating levels of REG3α and TFF3 have been identified as biomarkers for gut damage in several human diseases. We examined whether plasma levels of REG3α and TFF3 were dysregulated and correlated with conventional markers of microbial translocation (MT) and pro-inflammatory mediators in heavy drinkers with and without alcoholic hepatitis (AH). Methods: Cross-sectional and longitudinal studies were performed to monitor plasma levels of REG3α and TFF3 in 79 AH patients, 66 heavy drinkers without liver disease (HDC), and 46 healthy controls (HC) at enrollment and at 6- and 12-month follow-ups. Spearman correlation was used to measure the relationships of REG3α and TFF3 levels with MT, disease severity, inflammation, and effects of abstinence from alcohol. Results: At enrollment, AH patients had significantly higher levels of REG3α and TFF3 than HDC and HC. The elevated REG3α levels were positively correlated with the 30-day fatality rate. Plasma levels of REG3α and TFF3 in AH patients differentially correlated with conventional MT markers (sCD14, sCD163, and LBP) and several highly up-regulated inflammatory cytokines/chemokines/growth factors. At follow-ups, although REG3α and TFF3 levels were decreased in AH patients with alcohol abstinence, they did not fully return to baseline levels. Conclusions: Circulating levels of REG3α and TFF3 were highly elevated in AH patients and differentially correlated with AH disease severity, MT, and inflammation, thereby serving as potential biomarkers of MT and gut epithelial damage in AH patients.
  • Thumbnail Image
    Item
    Design of a multicenter randomized clinical trial for treatment of Alcohol-Associated Hepatitis
    (Elsevier, 2023-01-18) Tu, Wanzhu; Gawrieh, Samer; Dasarathy, Srinivasan; Mitchell, Mack C.; Simonetto, Douglas A.; Patidar, Kavish R.; McClain, Craig J.; Bataller, Ramon; Szabo, Gyongyi; Tang, Qing; Barton, Bruce A.; Radaeva, Svetlana; Sanyal, Arun J.; Shah, Vijay; Alcoholic Hepatitis Network (AlcHepNet) Investigators; Biostatistics, School of Public Health
    Background: Mortality is high for severe alcohol-associated hepatitis (AH). Corticosteroids are the standard of care for patients without contraindications. Recent data showed that interleukin-1β receptor antagonist anakinra attenuated inflammation and liver damage. We designed a multicenter, double-blind, randomized controlled trial to assess the safety and efficacy of anakinra compared to prednisone. Methods: Patients meeting the clinical and biochemical criteria for severe AH with MELD scores between 20 and 35 were recruited at eight clinical sites. Eligible patients enrolled in the study were randomized to anakinra, 100 mg subcutaneous injection for 14 days, plus zinc sulfate 220 mg for 90 days, vs. prednisone 40 mg PO daily for 30 days. Matching placebos for anakinra, zinc, and prednisone were provided to mask the treatment. Participants were followed for 180 days. The primary outcome was overall survival at 90 days. An unadjusted log-rank test was used to compare the survival of the two treatments in the first 90 days. Between July 10, 2020, and March 4, 2022, we screened 1082 patients with severe AH, and 147 eligible patients were enrolled and randomized. The average baseline MELD score was 25 [range 20-35], Maddrey discriminant function (MDF) was 59.4 [range 20.2-197.5]. The mean aspartate transaminase (AST)-to-alanine transaminase (ALT) ratio was 3.5. The baseline characteristics were not statistically different between the two treatment groups. Conclusions: The study provided a direct comparison of the survival benefits and safety profiles of anakinra plus zinc vs. prednisone in patients with severe AH.
  • Thumbnail Image
    Item
    Effects of Age, Sex, Body Weight, and Quantity of Alcohol Consumption on Occurrence and Severity of Alcoholic Hepatitis
    (Elsevier, 2016-12) Liangpunsakul, Suthat; Puri, Puneet; Shah, Vijay; Kamath, Patrick; Sanyal, Arun; Urban, Thomas; Ren, Xiaowei; Katz, Barry; Radaeva, Svetlana; Chalasani, Naga; Crabb, David W.; Medicine, School of Medicine
    Background & Aims Only a minority of heavy drinking individuals develop alcoholic hepatitis (AH), for unclear reasons. We analyzed data from the Translational Research and Evolving Alcoholic Hepatitis Treatment cohort: subjects who drink heavily with normal results from liver tests (controls) and patients with AH. We examined risk factors for the development of AH including body mass index (BMI), drinking pattern and quantity, and sex. Methods We compared data from 145 patients with AH cases and 124 controls, based on BMI when they joined the cohort; groups were matched for sex and race. Drinking patterns were assessed using the time line follow back method, the Alcohol Use Disorders Identification Test, and National Institute of Alcohol Abuse and Alcoholism 6-question survey. We performed univariable and multivariable analyses we to assess effects of these factors and their interaction in increasing the risk for AH. We also explored the association between PNPLA3 variants and AH. Results Cases with AH were older (47 vs 44 years; P=.03). For nearly all measures of quantity of alcohol consumed or frequency of binge drinking, controls drank more heavily than cases with AH. We did not find an association between BMI, sex, drinking patterns, and the presence of AH. Age and BMI were independent predictors for severity of AH. When we analyzed cases and controls of European ancestry, the PNPLA3 single nucleotide polymorphism rs738409 was associated with risk for AH (odds ratio, 1.89; P=.007). Conclusion Compared with heavy drinkers without liver disease, subjects with AH consumed lower levels of alcohol and had less binge drinking, suggesting an increased sensitivity to the toxic effects of alcohol. The risk for AH may be associated with the PNPLA3 rs738409 polymorphism.
  • Thumbnail Image
    Item
    An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis
    (Taylor & Francis, 2017-11) Beaudoin, James J.; Long, Nanye; Liangpunsakul, Suthat; Puri, Puneet; Kamath, Patrick S.; Shah, Vijay; Sanyal, Arun J.; Crabb, David W.; Chalasani, Naga P.; Urban, Thomas J.; TREAT Consortium; Medicine, School of Medicine
    OBJECTIVES: To elucidate the genetic variability between heavy drinkers with and without alcoholic hepatitis (AH). MATERIALS AND METHODS: An exploratory genome-wide association study (GWAS; NCT02172898) was conducted comparing 90 AH cases with 93 heavy drinking matched controls without liver disease in order to identify variants or genes associated with risk for AH. Individuals were genotyped using the multi-ethnic genotyping array, after which the data underwent conventional quality control. Using bioinformatics tools, pathways associated with AH were explored on the basis of individual variants, and based on genes with a higher 'burden' of functional variation. RESULTS: Although no single variant reached genome-wide significance, an association signal was observed for PNPLA3 rs738409 (p = .01, OR 1.9, 95% CI 1.1-3.1), a common single nucleotide polymorphism that has been associated with a variety of liver-related pathologies including alcoholic cirrhosis. Using the improved gene set enrichment analysis for GWAS tool, it was shown that, based on the single variants' trait-association p-values, multiple pathways were associated with risk for AH with high confidence (false discovery rate [FDR] < 0.05), including several pathways involved in lymphocyte activation and chemokine signaling, which coincides with findings from other research groups. Several Tox Functions and Canonical Pathways were highlighted using Ingenuity Pathway Analysis, with an especially conspicuous role for pathways related to ethanol degradation, which is not surprising considering the phenotype of the genotyped individuals. CONCLUSION: This preliminary analysis suggests a role for PNPLA3 variation and several gene sets/pathways that may influence risk for AH among heavy drinkers.
  • Thumbnail Image
    Item
    Persistent Hyperactivation of Endothelial Cells in Patients with Alcoholic Hepatitis
    (Wiley, 2020-05) Xia, Ying; Yang, Jing; Sanyal, Arun; Shah, Vijay; Chalasani, Naga; Yu, Qigui; Zheng, Xiaoqun; Li, Wei; Microbiology and Immunology, School of Medicine
    Background: Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up-regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM-1, VCAM-1, and VEGF-A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH. Methods: ELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6-month follow-up, and 18 AH patients and 25 HDC at 12-month follow-up. Results: At baseline, the 4 soluble markers were significantly up-regulated in AH patients compared with HDC and HC, whereas only sVCAM-1 was elevated in HDC relative to HC. At follow-ups, plasma levels of CD146, VCAM-1, and VEGF-A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors. Conclusions: The levels of soluble CD146, ICAM-1, VCAM-1, and VEGF-A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.