Alcoholic Hepatitis Clinical Trial
Official title:
Adipose Tissue Involvement in Alcohol-induced Liver Inflammation in Human : Study of Pro- and Anti-inflammatory Cytokines and ADIPOKINES..
The histological characteristics of alcoholic liver disease (ALD) and non-alcoholic
steatohepatitis (NASH) related to overweight and obesity suggest the presence of partly
common physiopathological mechanisms. We reported that the ponderal overload was an
independent risk factor of alcoholic cirrhosis. The adipose tissue was considered for a long
time as a simple place of storage of fat. However, it is now recognized that the adipose
tissue can secrete cytokines called ADIPOKINES.
The adipose tissue can secrete others cytokines such as TNF-alpha, IL6, IL10 and IL1-Ra.
Increase in the production of the leptin and TNF-alpha by the adipose tissue after alcohol
administration in the rat, as well as the role of leptin in inflammation and liver
fibrogenesis in the murine model of chemical hepatotoxicity strongly suggest that activation
of adipocytes by alcohol can explain the strong correlation observed between the body mass
index (BMI) and the severity of ethanol-induced liver injury. Conversely, it was suggested
in a murine model that the reduction in adiponectin production would sensitize the liver
with the toxicity of alcohol. The PPAR alpha and gamma are the receptors which play a role
both in inflammation and glucide and lipid metabolism. Taking into account the inhibiting
role of PPAR alpha on the proliferation of the hepatic stellate cells, responsible for the
fibrosis, the PPAR could also be implied in the relation between the overweight and the
hepatic fibrosis in the alcoholic.
The aim of this project is to demonstrate that ADIPOKINES, as well as the PPAR alpha and
gamma are implied in the intensity of the steatosis and in the regulation of the
inflammatory process and the hepatic fibrogenesis in alcoholic liver disease. In order to
prove this hypothesis, we will study among patients having a ALD at various stages of
histological severity: 1) the hepatic and subcutaneous abdominal adipose tissue expression
of the PPAR alpha and PPAR gamma, 2) the hepatic and subcutaneous abdominal adipose tissue
expression of the TNF alpha, the IL1Ra, the IL6 and the IL10, 3) the hepatic and
subcutaneous abdominal adipose tissue expression of the ADIPOKINES (leptin, adiponectin,
resistin), 4) the serum ADIPOKINES values, the cyanotic of the mRNA expression and of the
serum ADIPOKINES values after 7 days of alcohol withdrawal 50 patients will be studied (25
having ALD without cirrhosis, with or without acute alcoholic hepatitis (AAH) and 25 having
alcoholic cirrhosis with or without AAH). A part of liver biopsy will be frozen in a dry
tube. The percutaneous adipose tissue will be obtained with a punction on the abdominal
level at the time of inclusion of the patients having AAH and, for the second time, after 7
days of alcohol withdrawal, than will be frozen. The TNF alpha, the IL1Ra, the IL6, the
IL10, the leptin, the adiponectin and the resistin expression as well as the hepatic and
adipose tissue PPAR alpha and gamma will be evaluated by PCR in real time. The serum
concentration of the ADIPOKINES (leptin, adiponectin, resistin) will be measured by ELISA or
RIA.
If our hypothesis is true, severity of liver lesions (steatosis, AAH, fibrosis) could be
positively correlated with the expression in the liver and the adipose tissue and / or the
serum values of the anti-inflammatory cytokines and ADIPOKINES (TNF alpha, IL6, leptin,
resistin) and negatively with the cytokines and ADIPOKINES which are potentially
anti-inflammatory (IL1Ra, IL10, adiponectin). We also expect to find a negative correlation
between the amount of hepatic and adipose tissue PPAR-alpha and PPAR-gamma mRNA and the
severity of the liver disease.
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Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
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