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 [5] 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-JJ (07))
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Orosz, Andras
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Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
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