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Experimental Pharmacological Agents for the Treatment of Primary Biliary Cholangitis.

ABSTRACT: The standard therapy for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA) which has shown to improve hepatic biochemistry, delay histological progression and improve transplant-free survival. Approximately 30-40% of patients do not respond or are intolerant to UDCA. Obeticholic acid, a farnesoid X receptor (FXR) agonist is the only agent approved by the Food and Drug Administration for patients who do not respond to UDCA. Recently, combination therapy with UDCA and bezafibrate has been shown to improve biochemistry and both GLOBE and UK-PBC score in patients with an inadequate response to UDCA. More recently, new pharmacological agents have been included in Phase 2 and Phase 3 trials: PPAR agonists, non-bile acid FXR agonists, anti-NOX agents, immunomodulators and mesenchymal stem cells transplantation. This review gives an overview on the current experimental pharmacological agents employed in the treatment of PBC.

SUBMITTER: Floreani A

PROVIDER: S-EPMC7751712 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Experimental Pharmacological Agents for the Treatment of Primary Biliary Cholangitis.

Floreani Annarosa A

Journal of experimental pharmacology 20201217

The standard therapy for primary biliary cholangitis (PBC) is ursodeoxycholic acid (UDCA) which has shown to improve hepatic biochemistry, delay histological progression and improve transplant-free survival. Approximately 30-40% of patients do not respond or are intolerant to UDCA. Obeticholic acid, a farnesoid X receptor (FXR) agonist is the only agent approved by the Food and Drug Administration for patients who do not respond to UDCA. Recently, combination therapy with UDCA and bezafibrate ha ...[more]

PMID: 33364858

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Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Dataset Information

Experimental Pharmacological Agents for the Treatment of Primary Biliary Cholangitis.

Publications

Experimental Pharmacological Agents for the Treatment of Primary Biliary Cholangitis.

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