IU Indianapolis ScholarWorks :: Browsing by Author "Shah, Vijay H."

Browsing by Author "Shah, Vijay H."

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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 Health
Objective: 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.
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 Medicine
OBJECTIVES: 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.
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 Medicine
Background & 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.
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 Medicine
The 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.
Changes in Serum Myostatin Levels in Alcoholic Hepatitis Correlate with Improvement in MELD
(Springer Nature, 2021) Shamseddeen, Hani; Madathanapalli, Abhishek; Are, Vijay S.; Shah, Vijay H.; Sanyal, Arun J.; Qing, Tang; Liang, Tiebing; Gelow, Kayla; Zimmers, Teresa A.; Chalasani, Naga; Desai, Archita P.; Medicine, School of Medicine
Background: Alcoholic hepatitis (AH) is a serious clinical syndrome often associated with muscle wasting. Myostatin, a member of the transforming growth factor-β superfamily, has been studied in diseases with muscle wasting; however, the role of myostatin in AH is unknown. Aims: To investigate the association between myostatin, clinical variables, and outcomes in AH. Methods: We analyzed data for cases of AH and controls of heavy drinkers (HD) in TREAT001 (NCT02172898) with serum myostatin levels (AH: n = 131, HD: n = 124). We compared characteristics between the two groups at baseline, 30, and 90 days and explored correlations between myostatin and clinical variables. We then modeled the relationship of myostatin to other variables, including mortality. Results: Baseline median myostatin was lower in AH compared to HD (males: 1.58 vs 3.06 ng/ml, p < 0.001; females: 0.84 vs 2.01 ng/ml, p < 0.001). In multivariable linear regression, bilirubin, WBC, and platelet count remained negatively correlated with myostatin in AH. AH females who died at 90 days had significantly lower myostatin, but in a multivariable logistic model with MELD and myostatin, only MELD remained significantly associated with 90-day mortality. During 1-year follow-up, AH cases (n = 30) demonstrated an increase in myostatin (mean, 1.73 ng/ml) which correlated with decreasing MELD scores (ρ = - 0.42, p = 0.01). Conclusions: Myostatin levels are significantly lower in AH compared to HD and are negatively correlated with total bilirubin, WBC, and platelet count. Myostatin increased as patients experienced decreases in MELD. Overall, myostatin demonstrated a dynamic relationship with AH outcomes and future studies are needed to understand the prognostic role of myostatin in AH.
Circulating Extracellular Vesicles Carrying Sphingolipid Cargo for the Diagnosis and Dynamic Risk Profiling of Alcoholic Hepatitis
(Wolters Kluwer, 2021) Sehrawat, Tejasav S.; Arab, Juan P.; Liu, Mengfei; Amrollahi, Pouya; Wan, Meihua; Fan, Jia; Nakao, Yasuhiko; Pose, Elisa; Navarro-Corcuera, Amaia; Dasgupta, Debanjali; Liao, Chieh-Yu; He, Li; Mauer, Amy S.; Avitabile, Emma; Ventura-Cots, Meritxell; Bataller, Ramon A.; Sanyal, Arun J.; Chalasani, Naga P.; Heimbach, Julie K.; Watt, Kymberly D.; Gores, Gregory J.; Gines, Pere; Kamath, Patrick S.; Simonetto, Douglas A.; Hu, Tony Y.; Shah, Vijay H.; Malhi, Harmeet; Medicine, School of Medicine
Background and aims: Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. Approach and results: EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end-stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol-associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 1011 /mL) compared to healthy controls (4.38 × 1010 /mL; P < 0.0001), heavy drinkers (1.28 × 1011 /mL; P < 0.0001), ESLD (5.35 × 1010 /mL; P < 0.0001), and decompensated AC (9.2 × 1010 /mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End-Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high-EV group and 90.0% in the low-EV group (log-rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. Conclusions: Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90-day survival permitting dynamic risk profiling.
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 Medicine
Intestinal 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.
Clinical Characteristics and Outcomes of Mild to Moderate Alcoholic Hepatitis
(Wiley, 2019) Samala, Niharika; Gawrieh, Samer; Tang, Qing; Lourens, Spencer G.; Shah, Vijay H.; Sanyal, Arun J.; Liangpunsakul, Suthat; Chalasani, Naga; Medicine, School of Medicine
Introduction & Aim Much is known about alcoholic hepatitis (AH) that is severe enough to require hospitalisation. The characteristics of individuals with alcoholic hepatitis presenting with mild to moderate severity are not well understood. In this study, we investigated the risk factors, characteristics and outcomes of mild to moderate AH (M‐AH). Methods A total of 255 individuals with AH enrolled into a multicenter, prospective, observational study between 12/2014 and 4/2018 was included. Participants were seen at enrollment, 6 and 12 months. M‐AH was defined as MELD ≤20 at presentation, whereas severe AH as MELD ≥21. Results In total, 100 individuals had M‐AH, whereas 155 had severe AH. Individuals with M‐AH were older (49 vs 44 years, P = 0.01), had lower BMI (27 vs 31 kg/m2, P = 0.0007) and more likely to be male (68% vs 55%, P = 0.046) compared to the severe AH group. A higher proportion in the M‐AH group consumed coffee in the last 5 years compared to the severe AH group (29% vs 18%, P = 0.03), and fewer had PNPLA3 risk allele G (P = 0.019) compared to the severe AH group. Average drinks per drinking day (12.9 vs 10.7, P = 0.13) and total number of drinks in last 30‐day period (331 vs 280, P = 0.14) were not different between two groups. Compared to severe AH, patients with M‐AH had significantly lower mortality at 30 days (2% vs 13.6%), 90 days (3% vs 22.6%) and 12 months (10.4% vs 31.4%) (P < 0.001 for all). Conclusions Individuals with M‐AH were older, less obese, drank coffee more often and carried more favourable PNPLA3 genotype compared to severe AH, despite similar alcohol consumption. M‐AH had substantial mortality with one in ten dying by 12 months.
Coordinated signaling of activating transcription factor 6α and inositol-requiring enzyme 1α regulates hepatic stellate cell-mediated fibrogenesis in mice
(American Physiological Society, 2021) Xue, Fei; Lu, Jianwen; Buchl, Samuel C.; Sun, Liankang; Shah, Vijay H.; Malhi, Harmeet; Maiers, Jessica L.; Medicine, School of Medicine
Liver injury and the unfolded protein response (UPR) are tightly linked, but their relationship differs with cell type and injurious stimuli. UPR initiation promotes hepatic stellate cell (HSC) activation and fibrogenesis, but the underlying mechanisms are unclear. Despite the complexity and overlap downstream of UPR transducers inositol-requiring protein 1α (IRE1α), activating transcription factor 6α (ATF6α), and protein kinase RNA-like ER kinase (PERK), previous research in HSCs primarily focused on IRE1α. Here, we investigated the fibrogenic role of ATF6α or PERK in vitro and HSC-specific UPR signaling in vivo. Overexpression of ATF6α, but not the PERK effector activating transcription factor 4 (ATF4), promoted HSC activation and fibrogenic gene transcription in immortalized HSCs. Furthermore, ATF6α inhibition through Ceapin-A7, or Atf6a deletion, disrupted transforming growth factor β (TGFβ)-mediated activation of primary human hepatic stellate cells (hHSCs) or murine hepatic stellate cells (mHSCs), respectively. We investigated the fibrogenic role of ATF6α in vivo through conditional HSC-specific Atf6a deletion. Atf6aHSCΔ/Δ mice displayed reduced fibrosis and HSC activation following bile duct ligation (BDL) or carbon tetrachloride (CCl4)-induced injury. The Atf6aHSCΔ/Δ phenotype differed from HSC-specific Ire1a deletion, as Ire1aHSCΔ/Δ mice showed reduced fibrogenic gene transcription but no changes in fibrosis compared with Ire1afl/fl mice following BDL. Interestingly, ATF6α signaling increased in Ire1aΔ/Δ HSCs, whereas IRE1α signaling was upregulated in Atf6aΔ/Δ HSCs. Finally, we asked whether co-deletion of Atf6a and Ire1a additively limits fibrosis. Unexpectedly, fibrosis worsened in Atf6aHSCΔ/ΔIre1aHSCΔ/Δ mice following BDL, and Atf6aΔ/ΔIre1aΔ/Δ mHSCs showed increased fibrogenic gene transcription. ATF6α and IRE1α individually promote fibrogenic transcription in HSCs, and ATF6α drives fibrogenesis in vivo. Unexpectedly, disruption of both pathways sensitizes the liver to fibrogenesis, suggesting that fine-tuned UPR signaling is critical for regulating HSC activation and fibrogenesis. NEW & NOTEWORTHY: ATF6α is a critical driver of hepatic stellate cell (HSC) activation in vitro. HSC-specific deletion of Atf6a limits fibrogenesis in vivo despite increased IRE1α signaling. Conditional deletion of Ire1α from HSCs limits fibrogenic gene transcription without impacting overall fibrosis. This could be due in part to observed upregulation of the ATF6α pathway. Dual loss of Atf6a and Ire1a from HSCs worsens fibrosis in vivo through enhanced HSC activation.
Development of Alcohol-Associated Hepatitis Is Associated With Specific Changes in Gut-Modified Bile Acids
(Wolters Kluwer, 2022) Muthiah, Mark D.; Smirnova, Ekaterina; Puri, Puneet; Chalasani, Naga; Shah, Vijay H.; Kiani, Calvin; Taylor, Stephanie; Mirshahi, Faridoddin; Sanyal, Arun J.; Medicine, School of Medicine
The perturbations in bile acids (BAs) in alcohol-associated hepatitis (AH) and its relationship to disease severity is not well defined. The aims of this study were to define (1) the effects of heavy alcohol consumption on BAs and related microbiome, (2) the additional changes with AH, and (3) the relationship of these changes to disease severity. In this multicenter study, plasma and fecal BAs and related microbiome were interrogated in healthy individuals, heavy drinking controls (HDCs) without overt liver disease, and AH. Compared to healthy controls, HDCs had increased glycine-conjugated 7α and 27α primary BAs and increased secondary BA glycocholenic sulfate (multiple-comparison adjusted P < 0.05 for all). Plasma-conjugated cholic and chenodeoxycholic acid increased in AH along with the secondary BAs ursodeoxycholic and lithocholic acid (P < 0.001 for all), whereas deoxycholic acid decreased; however fecal concentrations of both deoxycholic acid and lithocholic acid were decreased. Glycocholenic acid further increased significantly from HDCs to AH. HDCs and AH had distinct plasma and fecal BA profiles (area under the curve, 0.99 and 0.93, respectively). Plasma taurochenodeoxycholic acid and tauroursodeoxycholic acid were directly related to disease severity, whereas fecal ursodeoxycholic acid was inversely related. The fecal abundance of multiple taxa involved in formation of secondary BAs, especially deoxycholic acid (Clostridium cluster XIVa) was decreased in AH. Multiple genera containing taxa expressing 3α, 3β, 7α, and 7β epimerases were decreased with concordant changes in fecal BAs that required these functions for formation. Conclusion: There are distinct changes in BA-transforming microbiota and corresponding BAs in AH that are related to disease severity.

Browsing by Author "Shah, Vijay H."

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