Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTeam)
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Purpose: To improve the diagnosis and assessment of severity of acute alcoholic hepatitis Participants: Patients admitted to one of ten centers with acute alcoholic hepatitis Procedures (methods): Consecutive patients admitted with acute alcoholic hepatitis will be enrolled in an NIH U01 study of acute alcoholic hepatitis where liver tissue, blood and stool will be collected to discover and validate factors associated with diagnosis, severity of disease and survival.
Condition or disease
The development of new targeted therapies for alcoholic hepatitis (AH) is one of the more urgent needs in clinical hepatology. To reach this goal, large multidisciplinary networks are required. The proposed initiative "Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis" (InTeam) will coordinate a multidisciplinary group composed of clinicians, physician-scientists, basic scientists and bioinformatics experts. The overarching hypothesis of InTeam is that the most rational way to provide a useful framework for future clinical trials in (AH) consists of the (i) determination of key drivers of the disease process, (ii) classification of molecular profiles and subtypes of AH, and (iii) identification of "druggable" targets based on both key drivers and molecular classification. Moreover, mouse models for AH are lacking making it impossible to evaluate promising targets in preclinical mouse studies in a meaningful manner. For this purpose, InTeam will integrate data obtained from molecular pathology studies in human AH and functional studies of key pathways in animal models. The proposed InTeam consortium includes three research projects, ten clinical centers, a Human Biorepository and a Mouse Models Core. The Human Biorepository Core will generate the to-date largest collection of samples from patients with AH from 10 academic liver centers and a comprehensive database that will serve as a basis for the proposed translational studies and be a valuable asset for the broader scientific community. The Mouse Models core will conduct murine studies after establishing and evaluating mouse models of AH based on the pathophysiology and molecular drivers of human AH determined by this consortium.
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Ages Eligible for Study:
18 Years to 70 Years (Adult, Senior)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Patients with an episode of alcoholic hepatitis fulfilling the inclusion criteria will be eligible to participate in the study. Those patients who meet one or more exclusion criteria will not be included. We will prospectively include patients with the following inclusion criteria
Patients ≥18 and <70 years of age.
Active alcohol abuse defined according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM IV) and excessive alcohol consumption prior to admission (> 60 g per day for men and> 40 g per day for women).
Moderate elevation of aminotransferases (usually less than 300 U / L) with a characteristic pattern of AST/ ALT ratio of 2:1.
Elevated serum GGT and bilirubin levels.
Absence of prior autoimmune liver disease (ANA<1/80, SMA<1/80, LKM1 neg, AMA neg).
Absence of hepatitis B and C and HIV infection (anti-HCV, surface HBV antigen and anti-HIV neg).
Patients with decompensated alcoholic cirrhosis will be suitable for inclusion (eg, acute gastrointestinal bleeding, acute renal failure, hepatic encephalopathy and bacterial infections).
Because there are no non-diagnostic tools to diagnose alcoholic hepatitis, histological confirmation is required in all patients (preferably through a transjugular biopsy): alcoholic hepatitis will be diagnosed on the presence of the following histologic features:
Steatosis (either macro or microvesicular).
Hepatocellular damage (eg, hepatocyte ballooning and presence of Mallory-Denk bodies).