PSC is not caused by any single factor. Its exact etiology and pathogenesis are not known, but genetic, environmental and immunological causes appear to interact, and two broad explanations — a response to gut-derived bacterial products and an injury from altered bile — are used to make sense of the disease.
The leaky-gut hypothesis
One of the most accepted hypotheses is that PSC begins with a trigger event, such as an environmental or toxic exposure, in a person who is genetically susceptible. The idea is that lipopolysaccharide (LPS), a component of the outer membrane of some gram-negative bacteria, enters the portal circulation from the gut of a patient whose IBD is inflamed — the so-called leaky gut — and reaches the liver in the portal blood.
Genetic susceptibility supports this model. There is a strong relation between PSC and certain HLA haplotypes, the inherited clusters of immune-recognition genes: HLA-B8 and HLA-DR3. Beyond the HLA genes, several other, minor genes have been identified, and most of them are also associated with ulcerative colitis and Crohn disease, which fits the close epidemiological link between PSC and IBD.
Once LPS reaches the liver, the hypothesis holds that natural killer (NK) cells are recruited and lymphocytes are activated in response to the inflammation the NK cells cause. This part of the model is supported by studies that found CD8+ memory T cells carrying biomarkers of the epithelial barrier of the gut — gut-derived immune cells that appear to have trafficked to the liver.
A second strand concerns the co-stimulatory molecule CD28, which is needed for the activation, proliferation and survival of T cells. The gene encoding CD28 has been genetically associated with PSC, and CD4+CD28− T cells — helper T cells that have lost CD28 — are abundant in the liver of patients with PSC compared with the periphery. Patients with PSC are also reported to have a lower count of T regulatory (Treg) cells, the cells that normally restrain immune responses.
The toxic bile theory
A second, less well-supported hypothesis is the toxic bile theory. Here a change in the composition of bile, together with decreased biliary flow and increased biliary pressure, damages the bile ducts directly. The accumulation of bile in the ducts that is typical of PSC can be caused by genetic abnormalities in genes related to the anion transporters — the proteins that move bicarbonate and other ions into bile — which change the composition of bile and leave it stagnant in the ducts. This is a different starting point from the leaky-gut hypothesis: injury begins in the bile rather than in the immune response to the gut.