Expression of pro-inflammatory and hepatoprotective factors at early stages of alcoholic liver disease in humans and the impact of short term abstinence.

Starkel, Peter;De Saeger, Christine;Lanthier, Nicolas;de Timary, Philippe;Leclercq, Isabelle
(2016) European Association for the Study of the Liver (EASL) international congress — Location: Barcelona (13.April.2016)

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Abstract
Background and Aims: Animal models imperfectly mimic the spectrum of alcoholic liver disease (ALD) seen in humans. Some studies have investigated late stages and severe forms of human ALD, but little is known about the pathophysiological mechanisms occurring in the human liver at early stages of the disease. Here,we investigated inflammatory mechanisms in alcohol dependent patients undergoing a standardized inpatient alcohol withdrawal program. Methods: Patients with suspicion of significant ALD (ALT, AST increase, fibroscan >7.8 kPa) were randomly assigned to undergo liver biopsy either in the active drinking phase or after 2 weeks of abstinence. Patients without significant fibrosis on histology were included in the study (n = 40). Liver tissue (n = 6) from size-reduced liver grafts was used as normal controls. Expression and cellular localization of various factors was assessed by Western-blotting, qPCR and immunohistochemistry and immunofluorescence. Results: the active drinking phase, a strong activation of the Kupffer cell (KC) compartment was found with KCs forming clusters adjacent to ballooned, steatotic hepatocytes. KC showed a pro-inflammatory M1 phenotype with activation of NFkB and increased expression of TNF , IL-1 and iNOS. After 2 weeks of abstinence, the staining pattern of KC returned to normal and NFkB, IL-1 and iNOS levels but not TNF decreased to almost control levels. In addition, abstinence induced a partial shift to a M2 phenotype with increased production of the anti-inflammatory cytokine IL-10. Interestingly,we did not find activation of TLR4 since TLR4, CD14, and LBP levels remained at control values in active drinkers. By contrast, we found a strong and persistent upregulation of the intracellular TLR3 and TLR7 which correlated with high production of interferon beta and gamma principally located to hepatocytes and bile ducts. Moreover, the hepatoprotective factors IL-6, IL-22, MCP-1 and Stat3 DNA-binding were strongly down-regulated in active drinkers and did not recover after short term abstinence. Hepatocyte Ki67 proliferation index was low in active drinkers and increased modestly but significantly after 2 weeks of abstinence. Conclusions: At early stages of ALD, a strong pro-inflammatory, KC-dependent response is observed which rapidly reversed upon abstinence. By contrast, down-regulation of hepatoprotective factors is more long lasting and might significantly impair liver repair mechanisms in sustained drinkers.
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Starkel, P. (2016). Expression of pro-inflammatory and hepatoprotective factors at early stages of alcoholic liver disease in humans and the impact of short term abstinence. Journal of Hepatology, 64(2), S239. https://hdl.handle.net/2078.5/186038 (Original work published 2016)