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Cholestatic liver diseases: new targets, new therapies.

ABSTRACT: Cholestatic liver diseases result from gradual destruction of bile ducts, accumulation of bile acids and self-perpetuation of the inflammatory process leading to damage to cholangiocytes and hepatocytes. If left untreated, cholestasis will lead to fibrosis, biliary cirrhosis, and ultimately end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the two most common chronic cholestatic liver diseases affecting adults, and their etiologies remain puzzling. While treatment with ursodeoxycholic acid (UDCA) has significantly improved outcomes and prolonged transplant-free survival for patients with PBC, treatment options for UDCA nonresponders remain limited. Furthermore, there is no available medical therapy for PSC. With recent advances in molecular biochemistry specifically related to bile acid regulation and understanding of immunologic pathways, novel pharmacologic treatments have emerged. In this review, we discuss the standard of care and emphasize the various emerging treatments for PBC and PSC.

SUBMITTER: Santiago P

PROVIDER: S-EPMC6109852 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cholestatic liver diseases: new targets, new therapies.

Santiago Priscila P Scheinberg Andrew R AR Levy Cynthia C

Therapeutic advances in gastroenterology 20180824

Cholestatic liver diseases result from gradual destruction of bile ducts, accumulation of bile acids and self-perpetuation of the inflammatory process leading to damage to cholangiocytes and hepatocytes. If left untreated, cholestasis will lead to fibrosis, biliary cirrhosis, and ultimately end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the two most common chronic cholestatic liver diseases affecting adults, and their etiologies remain puz ...[more]

PMID: 30159035

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Project description:Progress in development of prognostic and therapeutic options for the rare cholestatic liver diseases, primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), is hampered by limited knowledge of their pathogeneses. In particular, the potential role of hepatotoxic and/or metabolism-altering environmental chemicals in the pathogenesis of these diseases remains relatively unstudied. Moreover, the extent to which metabolic pathways are altered due to ongoing cholestasis and subsequent liver damage or possibly influenced by hepatotoxic chemicals is poorly understood. In this study, we applied a comprehensive exposomics-metabolomics approach to uncover potential pathogenic contributors to PSC and PBC. We used untargeted high-resolution mass spectrometry to characterize a wide range of exogenous chemicals and endogenous metabolites in plasma and tested them for association with disease. Exposome-wide association studies (EWAS) identified environmental chemicals, including pesticides, additives and persistent pollutants, that were associated with PSC and/or PBC, suggesting potential roles for these compounds in disease pathogenesis. Metabolome-wide association studies (MWAS) found disease-associated alterations to amino acid, eicosanoid, lipid, co-factor, nucleotide, mitochondrial and microbial metabolic pathways, many of which were shared between PSC and PBC. Notably, this analysis implicates a potential role of the 5-lipoxygenase pathway in the pathogenesis of these diseases. Finally, EWAS × MWAS network analysis uncovered linkages between environmental agents and disrupted metabolic pathways that provide insight into potential mechanisms for PSC and PBC. Conclusion: This study establishes combined exposomics-metabolomics as a generalizable approach to identify potentially pathogenic environmental agents and enumerate metabolic alterations that may impact PSC and PBC, providing a foundation for diagnostic and therapeutic strategies.

Dataset Information

Cholestatic liver diseases: new targets, new therapies.

Publications

Cholestatic liver diseases: new targets, new therapies.

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