Pathogenesis of primary sclerosing cholangitis

Abstract

Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis.The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.

Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

“…An important pathogenic component of cholestatic liver disease involves toxic bile exposure to hepatocytes 4, 5. Injury to biliary epithelium results in local inflammation, loss of cholangiocyte tight junctions, and extravasation of bile salts, which induce local hepatocyte death and periductular fibrosis.…”

Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis ‐ a pilot study

“…One hypothesis is that enterohepatic circulation of (as of yet undetermined) bacterially derived molecules plays a critical role in eliciting pro-inflammatory, pro-fibrotic hepatobiliary responses that lead to the development of PSC (hereinafter 'PSC microbiota hypothesis'). [16][17][18] The entry of such molecules into the enterohepatic circulation may, in some patients, be related to the enteric dysbiosis and increased intestinal permeability associated with inflammatory bowel disease (IBD), a condition diagnosed in 75% of those with PSC. [19][20][21][22][23] Further supporting the PSC microbiota hypothesis is the observation, for example, that patients with PSC often have a leucocyte differential exhibiting increased neutrophils, even in the absence of signs or symptoms of acute cholangitis, suggesting circulation of endotoxins or other immunoactive molecules.…”

Current research on the treatment of primary sclerosing cholangitis

“…Several animal experiments demonstrated a link between the gut microbiota and development of PSC (52)(53)(54)(55)(56)(57)(58)(59). Induction of small bowel bacterial overgrowth by ligating the jejunum in rats resulted in development of hepatic lesions compatible with PSC (53,55,56).…”