[1734] Steatohepatitis: Distinct Pathway(s) to Cirrhosis?

Nora E Joseph, Heewon Aimee Kwak, John Hart. University of Chicago, Chicago, IL

Background: Steatohepatitis is divided into two major categories: alcohol induced fatty liver disease (AFLD) and non-alcohol induced fatty liver disease (NAFLD) which are essentially indistinguishable on H&E. Recent literature proposes that AFLD and NAFLD result from distinct mechanisms of injury although the details are essentially unknown. Lipid accumulation and subsequent injury related to excessive alcohol use is believed to result, in part, from intrahepatic lipid synthesis following an ER stress response. In contrast, accumulation of lipids in NAFLD has been reported to result from both the diet as well as made within the liver. Several proteins within these various pathways have been implicated to be differentially expressed in AFLD and NAFLD; however, much of the literature is overlapping and unclear. Delineating the molecular details of these pathways would be of great clinical benefit as distinguishing AFLD from NAFLD is currently not possible by pure morphologic features.
Design: Pathology databases from the University of Chicago were searched from 2010-2011 for biopsies and explants containing a final diagnosis of steatohepatitis. All grades and stages were included. Clinical history provided within the pathology report was used to choose 10 AFLD and 10 NAFLD cases. Immunohistochemistry on FFPE tissue for SAFB and SREBP-1 (transcription factors involved in regulation of fatty acid synthesis), CD36 (fatty acid translocase which brings circulating fatty acids into the hepatocyte) and FAS (fatty acid synthesis) was performed and graded independently for intensity (0-3) and location by 2 pathologists. Scores of 2 and 3 were considered positive.
Results: Immunostaining for SREBP-1 showed significantly increased nuclear expression in 70% of AFLD vs 30% of NAFLD liver specimens (p=0.02). This increased nuclear expression was independent of steatohepatitis grade, stage or percentage of steatosis. Antibodies against SAFB, FAS and CD36 did not distinguish AFLD from NAFLD.
Conclusions: Significantly increased nuclear expression of transcription factor SREBP-1 in ALFD is independent of grade and stage. This may reflect distinct molecular pathways responsible for ongoing injury leading to cirrhosis in steatohepatitis. Further investigation into the mechanisms behind increased SREBP-1 expression may unveil differential expression of additional proteins within these pathways. These findings may provide the initial step to definitively distinguish AFLD from NAFLD.
Category: Liver

Wednesday, March 21, 2012 9:30 AM

Poster Session V # 235, Wednesday Morning

 

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