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Marqueurs diagnostiques et pronostiques de la stéatohépatite métabolique

Abstract : Obesity is a major public health problem in France since 50% of the population has overweight. Several hepatic complications of obesity exist including NASH, pathology characterized by the combination of histological lesions of hepatic steatosis and hepatitis, liver test abnormalities and the absence of known liver disease, particularly toxic (alcohol) or virus. In one third of patients, NASH leads to fibrosis and then cirrhosis. It also promotes the development of hepatocellular carcinoma.The pathophysiology of NASH is characterized by a deregulation of lipid metabolism that leads to the accumulation of lipids in the hepatocytes. This accumulation of lipids is toxic and one of the causes of insulin resistance and the development of diabetes mellitus. All stages of lipid metabolism are affected by an accumulation of triglycerides, an increase in hepatic lipogenesis and a decrease in ß-oxidation. The composition and the role of lipids as a promoter of NASH is being increasingly studied.The first part of the thesis concerns the detection of diagnostic markers of NASH. In this study, we established for the first time a lipid signature of nonalcoholic steatohepatitis by quantification of 32 lipids. The overall lipid signature allowed distinguishing controls from NAFL and NASH. We have also demonstrated a deregulation of the metabolic pathway involved in the synthesis of fatty acids in NASH. This deregulation has been observed in both humans and animal models in our study.The second part aimed to identify new hepatic prognostic markers of NASH. Microarray analysis of gene expression showed 1549 genes discriminating patients with NAFL or NASH, healthy obese or controls. Among them, 58 genes discriminated NASH from simple steatosis. These genes were involved in extracellular matrix remodeling and inflammation. The most discriminating gene was FABP4 (fatty acid binding protein 4). Among genes strongly associated with high expression of FABP4, matrix metalloproteinase-9 (MMP9) was overexpressed in 55% of NASH patients. We identified a total of 330 differentially regulated genes, of which 229 genes were overexpressed in NASH patients with high levels of MMP9 expression. Using the gene expression levels of the liver FABP4 and MMP9 genes as indicators of disease progression in an independent cohort of NAFLD patients, we identified patients with NAFL and NASH who may have a poor prognosis.Finally, in the third part, we looked at the diagnostic and prognostic value of steatosis of liver grafts, measured by FTIR (Infrared Fourier Transform Microspectroscopy). Indeed, steatosis, when it exceeds 60% and is macrovacuolar, is known to significantly impact the function and survival of liver grafts. In our study, among 58 graft samples, the average percentage of macrovacuolar steatosis and microvesicular steatosis assessed by the pathologist was 2% to 30%, respectively. The average concentration of liver triglycerides measured by gas chromatography-spectrometry was 214 [10-1045] nmol/mg liver tissue. The FTIR triglyceride content estimate was significantly correlated (r2=0.812) with the results of the average hepatic triglyceride concentration measured by gas chromatography-spectrometry. Thirty-four (58%) patients had complications defined by a Dindo-Clavien stage ≥2, including 2 non-primary graft function and 5 deaths. The most discriminating threshold between triglyceride level and TH failure was 59.29 and 54.02 nmol/mg hepatic tissue obtained by spectrometry and FTIR, respectively. Quantification of hepatic triglyceride content by GC/MS was significantly associated with patient survival at the end of follow-up (p <0.0001) and failure of transplantation (p <0.0001). Estimating hepatic triglyceride content using FTIR was significantly associated with one-year post-transplant survival (p <0.0001).
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Audrey Coilly. Marqueurs diagnostiques et pronostiques de la stéatohépatite métabolique. Hépatologie et Gastroentérologie. Université Paris Saclay (COmUE), 2019. Français. ⟨NNT : 2019SACLS211⟩. ⟨tel-02906575⟩

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