Aetiology

The aetiology is not well understood, with multiple mechanisms thought to be involved in its development and progression.[3]​ The frequent presence of serum auto-antibodies, the increased frequency of autoimmune diseases, the association with inflammatory bowel disease, and the over-representation of certain HLA haplotypes suggests that PSC is an immune-mediated disorder.[16][17][18] However, PSC is not a classic autoimmune disease, as it occurs predominantly in males and does not respond to immunosuppressive treatment. The association with certain HLA haplotypes and the increased risk of PSC in first-degree relatives of patients with PSC indicate that genetic factors are important, with non-HLA loci also being implicated.[3]​[19]​​​ An impaired gut barrier and dysbiosis are also proposed to play a role.[3] Beyond a possible link with non-smoking, less is known about the environmental risk factors for PSC.[3]

The trigger of the immune response in a genetically susceptible individual is unknown. Factors that have been hypothesised to play a role include: translocation of lymphocytes activated in the colon of patients with colitis to the liver via the enterohepatic circulation, and bacterial infection of the bile.[20][21]

Pathophysiology

Inflammation and injury of the medium- and large-sized bile ducts, leading to fibrosis and multi-focal stricturing of the ducts, characterise the pathological process. Gross and histological specimens of the extrahepatic bile ducts demonstrate a diffusely thickened, fibrotic duct wall.[22] Obstruction of the medium- and large-sized bile ducts leads to progressive fibrosis and ultimately obliteration of the smaller ducts (ductopenia) and bile stasis (cholestasis). Bile stasis above strictures predisposes patients to primary bile duct stones, and retained bile salts may further contribute to bile duct damage. The biliary strictures of PSC, both intrahepatic and extrahepatic, contribute to jaundice, pruritus, episodes of bacterial cholangitis, and progression to biliary cirrhosis. Ongoing injury and continued destruction of the bile ducts results in secondary parenchymal damage, fibrosis, cirrhosis, and end-stage liver disease.[23]

Classification

PSC variants[1][2]​[3]​

Large-duct PSC

  • The more common, 'classic' PSC, involving the large ducts (intra- and extrahepatic ducts that can be seen by cholangiography)

  • Defined as PSC that can be seen cholangiographically

  • Diagnosis established by characteristic clinical, biochemical, and cholangiographic findings.

Small-duct PSC

  • Less common variant of PSC, affecting only the small bile ducts (intrahepatic bile ducts that can only be seen microscopically; they are too small to be seen by cholangiography)

  • Defined as PSC that can be identified only by microscopy

  • Diagnosis established by characteristic clinical, biochemical, and histological findings, but normal cholangiography.

PSC-autoimmune hepatitis overlap syndrome

  • Serological and histological features of autoimmune hepatitis but cholangiographic abnormalities characteristic of PSC

  • More common in children; accounts for 35% of paediatric cases of PSC and 5% of adult cases.[3]​

Use of this content is subject to our disclaimer