In response to the RFA-AA-12-007, Indiana University (IU), Mayo Clinic (Mayo), and Virginia Commonwealth University (VCU) have formed a consortium """"""""Translational Research and Evolving Alcoholic Hepatitis Treatments""""""""(TREAT). Central hypotheses of this application are: (a) a large cohort of patients with well-characterized acute alcoholic hepatitis (AH) and matched controls greatly enhances our ability to conduct translational studies in humans to better understand its pathogenesis and to develop novel treatments, and (b) alcohol-induced impairment of signaling via bile salt receptors impairs gut integrity, permits activation of Kupffer cells, enhances oxidative stress in the liver, stimulates fatty liver, and sensitizes hepatocytes to cytokine-induced necroapoptosis, and that these abnormalities can be reversed with the FXR agonist, obeticholic acid (OCA). We will address these hypotheses by conducting the following patient- oriented studies.
Specific Aim 1 : To conduct a prospective multicenter observational study of patients with well-characterized AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. A robust central bio-repository of serum/plasma, peripheral mononuclear cells, genomic DNA, urine, stool samples, and liver tissue (where available) will be developed from both cases and controls.
Specific Aim 2 : To test the hypothesis that alcohol-induced impairment of signaling via farnesoid X receptor (FXR, the bile salt nuclear receptor) interrupts normal bile salt homeostasis, and that this will be reversed with an FXR agonist, obeticholic acids (OCA). A secondary hypothesis is that altered FXR signaling impairs gut integrity, promotes activation of the innate immune response, enhances hepatic oxidative stress, and sensitizes hepatocytes to cytokine-induced necroapoptosis. . To address these hypotheses, we will conduct a study of bile salt metabolism and effects of OCA in heavy drinkers without liver disease (n=15), moderate drinkers (n=15), and non-drinkers (n=15).
Specific Aim 3 : To test the hypothesis that FXR agonists are effective in treating AH by correcting multiple abnormalities implicated in its pathogenesis. We will test this hypothesis by conducting a proof-of-concept multicenter, placebo-controlled randomized controlled trial of OCA in patients with moderately severe AH. Sixty adults with AH of moderate severity will be randomized to receive either obeticholic acid (10 mg once daily by mouth) or placebo for 4 weeks. Primary efficacy end point is change in MELD score at 4 weeks  and the primary safety end point is the incidence of serious adverse events (SAE) at 4 weeks.
Specific aim 4 : To participate in the two other proof-of-concept studies proposed by the other two members of the TREAT consortium.
Alcoholic Hepatitis is a major public health problem and it causes significant morbidity and mortality. It is not known why some individuals develop acute alcoholic hepatitis and also there are no effective treatments. In this application, investigators are proposing to conduct studies to better understand its pathogenesis and to develop novel treatments.
|Yang, Zhihong; Ross, Ruth A; Zhao, Shi et al. (2017) LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis. Hepatol Commun 1:513-523|
|Jinjuvadia, Raxitkumar; Antaki, Fadi; Lohia, Prateek et al. (2017) The Association Between Nonalcoholic Fatty Liver Disease and Metabolic Abnormalities in The United States Population. J Clin Gastroenterol 51:160-166|
|Jinjuvadia, Chetna; Jinjuvadia, Raxitkumar; Mandapakala, Chaitanya et al. (2017) Trends in Outcomes, Financial Burden, and Mortality for Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) in the United States from 2002 to 2010. COPD 14:72-79|
|Beaudoin, James J; Long, Nanye; Liangpunsakul, Suthat et al. (2017) An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis. Scand J Gastroenterol 52:1263-1269|
|Li, Wei; Amet, Tohti; Xing, Yanyan et al. (2017) Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study. Hepatology 66:575-590|
|Puri, Puneet; Liangpunsakul, Suthat; Christensen, Jeffrey E et al. (2017) The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis. Hepatology :|
|Peng, Jennifer L; Patel, Milan Prakash; McGee, Breann et al. (2017) Management of alcohol misuse in patients with liver diseases. J Investig Med 65:673-680|
|Comerford, Megan; Lourens, Spencer; Liangpunsakul, Suthat et al. (2017) Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium. Alcohol Clin Exp Res 41:2000-2006|
|Jinjuvadia, Raxitkumar; Jinjuvadia, Chetna; Puangsricharoen, Pimpitcha et al. (2017) Concomitant Psychiatric and Nonalcohol-Related Substance Use Disorders Among Hospitalized Patients with Alcoholic Liver Disease in the United States. Alcohol Clin Exp Res :|
|Shen, Huafeng; Peng, Jennifer L; Tayarachakul, Sucharat et al. (2017) Association between serum cotinine level and prevalence of non-alcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey. J Investig Med 65:43-48|
Showing the most recent 10 out of 23 publications