52 INCREASED MORTALITY ON THE LIVER TRANSPLANT WAITING LIST IN FEMALES UNDER THE MELD ALLOCATION SYSTEM: UTILITY OF REVISED MELD INCORPORATING ESTIMATED GLOMERULAR FILTRATION RATE

Background and Aims: Liver fibrosis in chronic hepatitis C progresses with menopause while postmenopausal women with hormone replacement therapy have lower degrees of liver fibrosis.Moreover, estrogen treatment leads to improvement of liver injury in CCl4-induced liver fibrosis in rats.On the other hand, mutations in MDR3 (ABCB4) gene are associated with increased risk for intrahepatic cholestasis in pregnancy (ICP).The pathogenesis of ICP may be linked to the effects of estrogen and progesterone metabolites on bile secretion.Therefore, we aimed to test the effects of pregnancy on development of liver fibrosis and cholangitis in Mdr2-/-mice, known to develop liver injury due to abnormal biliary composition.Methods: Pregnant (18.5 days) Mdr2-/-mice were compared with age-matched Mdr2-/-and wild-type control.Liver injury was evaluated using serum liver enzymes and liver histology.Markers of hepatic fibrosis, ductular proliferation and inflammation were studied using Q-PCR and Western blotting.Bile flow and biliary composition were determined.Anti-inflammatory effects of estrogen and progesterone were studied in vitro in female mouse macrophage cell line (RAW264) and bile duct epithelial cell line (BEC) upon activation with LPS and TNF-a respectively.Results: Pregnancy led to reduction of ALT, AP and bile acid levels in Mdr2-/-mice and improved liver histology.Moreover, reduction of liver fibrosis correlated with decreased hydroxyproline content, mRNA expression of Tgf-1b, Col1a1, Col1a2 and protein expression of a-SMA in pregnant Mdr2-/-mice.In addition, hepatic inflammatory response was lowered during pregnancy resulting in down-regulation of Tnf-a, Il-6, Mcp-1 mRNA.No changes in biliary bile acid, cholesterol or phospholipid content were observed between pregnant and non-pregnant mice.Estrogen and progesterone directly reduced Tnf-a, Mcp-1 and iNos production in LPS and Tnf-a treated RAW264 and BEC cells.Conclusions: Pregnancy ameliorates liver injury in Mdr2-/-mice without having striking effects on bile acid homeostasis.Direct antiinflammatory and anti-fibrotic effects of estrogen and progesterone on hepatic inflammatory cells and reactive cholangiocytes may explain the unexpected improvement of sclerosing cholangitis and cholestatic liver injury in Mdr2-/-mice.