SAT0036 IMPACT OF RHEUMATOID ARTHRITIS IN LIVER DAMAGE. INVOLVEMENT OF ANTI-CITRULLINATED PROTEIN ANTIBODIES

Abstract

Background: Liver damage in rheumatoid arthritis (RA) is most common in the form of asymptomatic abnormal liver biopsies. It is difficult to differentiate between hepatic manifestations of the primary disease and potential hepatotoxicity of the therapies. Inflammation, oxidative stress, apoptosis and loss of lipid droplets are involved in the hepatic fibrogenesis Objectives: 1)To analyze the impact of RA in the liver function and 2)To evaluate the direct effect of anti-citrullinated protein antibodies (ACPAs) in the liver fibrosis. Methods: 150 RA patients and 100 healthy donors (HD) were included. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), phosphatase alkaline (ALP), albumin and levels of autoantibodies and inflammatory markers were evaluated in serum. In vitro studies: Hep G2 cells were treated with IgG-ACPAs isolated from RA patients. Molecules involved in lipid metabolism, insulin resistance, oxidative stress and inflammation were analyzed by RT-PCR and Western blot. Activation of intracellular pathways involved in fibrogenesis were analyzed. Lipid accumulation was evaluated by fluorescence microscopy. Mouse model: 20 CB57J/BL mice were used; 5 mice were used as non-diseased group, and 15 were used in CIA modelling. Liver samples were collected. Genes involved in insulin signal, lipid accumulation, macrophage infiltration and polarization and inflammation were evaluated. Activation of intracellular pathways related to fibrogenesis were analyzed. Immunohistochemistry was used to evaluate the percentage of fibrotic cells. Results: Within the normal range of hepatic enzymes, the percentage of RA patients with levels of AST, ALT and ALP above the mean was significantly higher compared to HD. In contrast, percentage of RA patients displaying levels of albumin bellow the mean was significantly elevated compared to HD. Differences remained significant after adjusting for potential confounders (treatment). Moreover, high levels of AST and ALT were associated with ACPAs and inflammatory markers. IgG-ACPAs induced the expression of inflammatory and oxidative stress markers and decreased genes involved in insulin signal and lipid accumulation in Hep G2 cells. In addition, lipid content decreased after IgG-ACPAs treatment. The phosphorylation of intracellular pathways involved in fibrogenesis was modulated by Ig-ACPAs.The induction of arthritis in mice elevated inflammatory cytokines and markers of macrophages presence and polarization state M1 and reduced genes related to lipid droplets in the liver. Phosphorylation of ERK and mTOR was increased in the liver of CIA mice. Additionally, the percentage of cells positive for α-smoth muscle antibody was increased in the liver of CIA mice. Conclusion: (1) RA patients displayed a subclinical alteration of the hepatic enzymes levels associated with levels of autoantibodies ACPAs, which may suggest that RA is associated with an abnormal liver function induced by autoantibodies. (2) ACPAs may induce alterations in hepatic cells, increasing inflammation and oxidative stress, reducing lipid accumulation and activating intracellular pathways, processes closely involved in fibrogenesis. (3) In a CIA mice, arthritis induced inflammation, infiltration of macrophages, reduction of genes involved in lipid accumulation and activation of intracellular pathways involved in fibrogenesis Acknowledgement: Funded by ISCIII (CP15/00158 and PI17/01316) co-funded with FEDER. Disclosure of Interests: None declared