InTEAM Consortium - Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we describe the transcriptional programs involved in disease progression. We uncovered that development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). The PPARG predicted activation state was found increased in early forms of ALD, while AH was associated by a marked decrease in HNF4A-dependent gene expression along with a marked expression of the fetal HNF4A isoform (P2). TGFB1, a key upstream transcriptome regulator in AH, induced the use of HNF4a P2 promoter in hepatocytes, which resulted in abnormal bile acid synthesis and defective metabolic and synthetic functions. PPARG agonists partially prevented this effect. We conclude that targeting TGFB1 and epigenetic drivers that modulate HNF4A-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. The study was conducted thanks to a multicenter collaboration under the National Institute of Alcohol Abuse and Alcoholism (NIAAA)-funded consortium: Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTEAM).]]>
Patients with Alcoholic hepatitis: Inclusion criteria Patients with a previous probable or possible AH episode will be defined following the guidelines proposed by the NIAAA. Biopsy proven or Probable AH: Patients without a histological confirmation but with a recent-onset of jaundice (<8 weeks) before hospitalization and a total bilirubin level ≥3mg/dL at admission AST/ALT ratio >1.5, AST ≥50 IU/L and maximum AST and ALT values <400 IU/L. Actively drinking and long-term alcoholism (>40 grams of alcohol/day for females, >60 grams of alcohol/day for males) for 6 months or more, with less than 60 days of abstinence prior to the onset of jaundice) Absence of other possible liver diseases (HCV and HBV negative, ANA's < 1:160, ASMA < 1:80) Absence of sepsis, cocaine use and shock at inclusion and use of new hepatotoxic drugs as a probable cause for liver injury during the previous 30 days. Patients older than 18 years Signed informed consent Exclusion criteria Terminal liver disease (e.g. advanced hepatocellular carcinoma) Patients who are pregnant or breast-feeding Complete portal vein thrombosis (PVT) Previous liver transplant recipient Alcoholic liver disease with compensated never-decompensated liver disease (Early ASH) Inclusion criteria Patients diagnosed with an alcohol use disorder identification test (AUDIT) total scores of 8 or more OR Patients with a score lower than 8 in the AUDIT test but for whom there is a high suspicion of current or recent (within one year) AUD based on medical history, self-reported history of excessive alcohol use, stigmata of alcohol use on physical exam, liver chemistry abnormalities, or alcohol-induced organ involvement other than decompensated liver disease. Patients who admit having a persistent alcohol intake of more than 40 g/daily for women and 60 g/daily for men. 18 years of age or older Signed informed consent Any stage of liver disease: from simple elevation of transaminases to any METAVIR or Ishack score assess by liver biopsy or by any validated non-invasive methods (Fibroscan®, Fibrotest®, Fibrosis-4®). Patients without a pre-existent liver fibrosis assessment for whom there is a high suspicion of liver disease according to clinical and/or analytic and/or radiological criteria will also be included. Exclusion criteria Patients with a past history of decompensated advanced liver disease (i.e. jaundice episodes, ascites, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome) or known hepatocellular carcinoma. Patients with severe extrahepatic disease or terminal illness Patients who are pregnant or breast-feeding These groups were compared with fragments of non-diseased human livers (N=10), patients with non-alcoholic fatty liver disease (NAFLD) according to Keiner's Crieria and without alcohol abuse (N=9) and from patients with non-cirrhotic HCV infection (N=10) and compensated HCV-related cirrhosis (N=9).]]>