Browsing by Author "Kamath, Patrick S."
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Item Acute Alcoholic Hepatitis: Natural History and Predictors of Mortality Using a Multicenter Prospective Study(Elsevier, 2017-04-28) Lourens, Spencer; Sunjaya, Dharma B.; Singal, Ashwani; Liangpunsakul, Suthat; Puri, Puneet; Sanyal, Arun; Ren, Xiaowei; Gores, Gregory J.; Radaeva, Svetlana; Chalasani, Naga; Crabb, David W.; Katz, Barry; Kamath, Patrick S.; Shah, Vijay H.; Biostatistics, School of Public HealthObjective: To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. Participants and Methods: We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. Results: Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; P<.001), and this association between regular coffee drinking and lower risk of AH persisted after controlling for relevant covariates (odds ratio=0.26; 95% CI, 0.15-0.46). Time-dependent receiver operating characteristic curve analysis revealed that Model for End-Stage Liver Disease; Maddrey Discriminant Function; age, serum bilirubin, international normalized ratio, and serum creatinine; and Child-Pugh scores all provided similar discrimination performance at 30 days (area under the curve=0.73-0.77). Conclusion: Alcoholic hepatitis remains highly fatal, with 1-year mortality of 25%. Regular coffee consumption was associated with lower risk of AH in heavy drinkers.Item Alcohol Abstinence Does Not Fully Reverse Abnormalities of Mucosal-Associated Invariant T Cells in the Blood of Patients With Alcoholic Hepatitis(Wolters Kluwer, 2019-06) Li, Wei; Lin, Edward L.; Liangpunsakul, Suthat; Lan, Jie; Chalasani, Sai; Rane, Sushmita; Puri, Puneet; Kamath, Patrick S.; Sanyal, Arun J.; Shah, Vijay H.; Radaeva, Svetlana; Crabb, David W.; Chalasani, Naga; Yu, Qigui; Microbiology & Immunology, IU School of MedicineOBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.Item Alcohol Rehabilitation Within 30 Days of Hospital Discharge Is Associated With Reduced Readmission, Relapse, and Death in Patients With Alcoholic Hepatitis(Elsevier, 2019) Peeraphatdit, Thoetchai (Bee); Kamath, Patrick S.; Karpyak, Victor M.; Davis, Brian; Desai, Vivek; Liangpunsakul, Suthat; Sanyal, Arun; Chalasani, Naga; Shah, Vijay H.; Simonetto, Douglas A.; Medicine, School of MedicineBackground & Aims Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and mortality. Methods We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge. Results Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios [AOR] 0.16; 95% CI, 0.04–0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02–0.53; P < .001), and death (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.05–0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09–0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01–0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01–0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73. Conclusions In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment.Item Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium(Wiley, 2017) Comerford, Megan; Lourens, Spencer; Liangpunsakul, Suthat; Chalasani, Naga P.; Sanyal, Arun J.; Shah, Vijay H.; Kamath, Patrick S.; Puri, Puneet; Katz, Barry P.; Radaeva, Svetlana; Crabb, David W.; Medicine, School of MedicineThe TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects’ demographics with their adherence to follow-up appointments were examined. Three hundred eight-seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two-thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two-thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6- and 12-month follow-up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis.Item The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis(Wiley, 2017) Puri, Puneet; Liangpunsakul, Suthat; Christensen, Jeffrey E.; Shah, Vijay H.; Kamath, Patrick S.; Gores, Gregory J.; Walker, Susan; Comerford, Megan; Katz, Barry; Borst, Andrew; Yu, Qigui; Kumar, Divya P.; Mirshahi, Faridoddin; Radaeva, Svetlana; Chalasani, Naga P.; Crabb, David W.; Sanyal, Arun J.; Medicine, School of MedicineIntestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate (n=18) or severe AH (n=19). These data were compared to heavy drinking controls (HDC) without obvious liver disease (n=19) and non-alcohol consuming controls (NAC, n=20). The data were related to endotoxin levels and markers of monocyte activation. Linear Discriminant Analysis (LDA) Effect Size (LEfSe) analysis, inferred metagenomics and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (p<0.01) and SAH (p<0.001) subjects. Compared to NAC, the relative abundance of phylum Bacteroidetes was significantly decreased in HDC, MAH, and SAH (p<0.001). In contrast, all alcohol consuming groups had enrichment with Fusobacteria; this was greatest for HDC and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (p=0.01). Compared to alcohol consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Also, both HDC and SAH showed activation of type III secretion system which has been linked to gram negative bacterial virulence. Metagenomics in SAH vs NAC predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram positive bacterial growth and biofilm production respectively. In conclusion, heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions.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 MedicineOBJECTIVES: 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.Item Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis(Wiley, 2017-11-11) Liangpunsakul, Suthat; Beaudoin, James J.; Shah, Vijay H.; Puri, Puneet; Sanyal, Arun J.; Kamath, Patrick S.; Lourens, Spencer G.; Tang, Qing; Katz, Barry P.; Crabb, David W.; Chalasani, Naga P.; Medicine, School of MedicineOnly a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well-characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P < 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation.Item Posttraumatic Stress Disorder in Patients with Heavy Alcohol Consumption and Alcoholic Hepatitis(Wiley, 2018) Samala, Niharika; Lourens, Spencer G.; Shah, Vijay H.; Kamath, Patrick S.; Sanyal, Arun J.; Crabb, David W.; Tang, Qing; Radaeva, Svetlana; Liangpunsakul, Suthat; Chalasani, Naga; Medicine, School of MedicineBackground Lifetime prevalence of posttraumatic stress disorder (PTSD) in the general population is reported to be 6.8%. Individuals with alcohol dependence and substance abuse have high prevalence of PTSD. However, the prevalence of PTSD in heavy drinkers with alcoholic hepatitis (AH) is not known.The study's aim was to determine the prevalence of PTSD in heavy drinkers with and without AH. Methods We screened for PTSD using the Primary Care‐PTSD questionnaire among heavy drinkers with (n = 115) and without (n = 64) AH participating in a multicenter observational study in which participants were followed up to 12 months following their enrollment. Results The prevalence of PTSD in heavy drinkers with AH was 34% and was not different from heavy drinking controls without liver disease (34%). In the entire group screened for PTSD, the presence of PTSD was associated with higher alcohol consumption as reported by average drinks per last 30 days and average grams of alcohol consumed per day (p = 0.047 for both tests), but not associated with relapse of heavy drinking or mortality. Similarly, patients with AH and PTSD did not have higher relapse rate or higher mortality compared to patients with AH but no PTSD. Conclusions Compared to previously reported prevalence in general population, heavy drinking individuals with or without AH have significantly higher prevalence of PTSD. However, PTSD was not associated with higher relapse rate or higher mortality in this population.Item Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia(Elsevier, 2016-04) Crabb, David W.; Bataller, Naga P.; Chalasani, Naga P.; Kamath, Patrick S.; Lucey, Michael; Mathurin, Philippe; McClain, Craig; McCullough, Arthur; Mitchell, Mack C.; Morgan, Timothy R.; Department of Medicine, IU School of MedicineHeavy drinkers are at risk for a spectrum of histologic alcohol-related liver injury: steatosis, alcoholic steatohepatitis (ASH), alcohol-related fibrosis, and cirrhosis. Alcoholic hepatitis (AH), the clinical entity associated with severe ASH, has high short-term mortality. The standard-of-care therapy, prednisolone, has limited efficacy and many side effects; no other treatment has consistently shown survival benefit. The National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded Alcoholic Hepatitis Consortia carry out translational research on pathophysiologic mechanisms, genetic and environmental risk factors, phase II clinical trials, and development of biomarkers. The consortia members were convened by the National Institutes of Health to address diagnostic criteria and practical issues related to clinical AH research, and to develop a set of common data elements to harmonize ongoing and future trials. This was accomplished through 3 face-to-face meetings of the investigators and representatives of the National Institutes of Health, and subsequent electronic communications over the course of 6 months. Evidence for the recommendations was based on published trials and observational data from several of the consortia members. A draft manuscript was iteratively reviewed by members of the consortia. The goal was to reach agreements on recommendations and definitions that could facilitate trial design, and simultaneously be tested by research groups pooling their data. The recommendations made here are specifically directed to achieve better uniformity in clinical trials, rather than serving as clinical practice guidelines.