Aetiology

PSC represents a multifactorial disease driven by the interplay between genetic susceptibility and environmental triggers, culminating in an aberrant immune-mediated attack on the bile ducts.

A strong epidemiologic association links PSC with inflammatory bowel disease, particularly ulcerative colitis. IBD occurs in approximately 60% to 80% of patients with PSC, whereas only 2% to 8% of patients with ulcerative colitis and 1% to 2% of patients with Crohn disease develop PSC. (1)

Genome-wide association studies have identified over 20 susceptibility loci, with the strongest associations located in the HLA region, along with several non-HLA risk loci involved in immune-regulatory pathways, including the IL2/IL21 cytokine gene region and FUT2. (2)

Other conditions associated with PSC include:

• retroperitoneal fibrosis
• sarcoidosis
• Riedel's thyroiditis

PSC is frequently associated with HLA-B8 and HLA-DR3.

The cellular immune system appears to play a part in primary sclerosing cholangitis. There is a decrease in the total number of circulating T cells, whereas the number of T cells in the portal tracts is increased. The ratio of CD4 to CD8 lymphocytes in the circulation is increased, as are the number and percentage of B cells. It is unknown whether these immunologic abnormalities are primary events or are due to the underlying disease.

Reference

1. Mertz A et al. Primary sclerosing cholangitis and inflammatory bowel disease comorbidity: an update of the evidence. Ann Gastroenterol. 2019 Mar-Apr;32(2):124-133
2. Goode EC et al. Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nat Commun. 2024 Nov 06;15(1):9594