Primary sclerosing cholangitis: causes
Last reviewed: 23.04.2024
All iLive content is medically reviewed or fact checked to ensure as much factual accuracy as possible.
We have strict sourcing guidelines and only link to reputable media sites, academic research institutions and, whenever possible, medically peer reviewed studies. Note that the numbers in parentheses ([1], [2], etc.) are clickable links to these studies.
If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please select it and press Ctrl + Enter.
The cause of primary sclerosing cholangitis is unknown. With primary sclerosing cholangitis, all parts of the biliary tree can be involved in a chronic inflammatory process with the development of fibrosis, leading to obliteration of the biliary tract and eventually to biliary cirrhosis. The involvement of different sections of the biliary tract is not the same. The disease can be confined to intra- or extrahepatic bile ducts. Over time, interlobular, septal and segmental bile ducts are replaced by fibrous strands. Involvement of the smallest ducts of portal tracts (zone 1) is called pericholangitis or primary sclerosing cholangitis of small ducts.
Almost 70% of patients with primary sclerosing cholangitis have concomitant nonspecific ulcerative colitis and very rarely - regional ileitis. At the same time, of the 10-15% cases of liver damage in case of ulcerative colitis, the proportion of patients with sclerosing cholangitis accounts for approximately 5%. The development of cholangitis can precede colitis for up to 3 years. Primary sclerosing cholangitis and ulcerative colitis in rare cases can be familial. Persons with haplotypes Al, B8, DR3, DR4 and DRW52A of the HLA system are more sensitive to them. In hepatitis of streets with haplotype DR4, the disease appears to progress more rapidly.
There are signs of a violation of immune regulation. Circulating antibodies to tissue components are not detected or are detected in a low titer. At least two-thirds of the cases show perinuclear antineutrophil cytoplasmic antibodies. After liver transplantation, they do not disappear. Probably, these antibodies do not participate in pathogenesis, but are an epiphenomenon. In addition, the serum detects autoantibodies to the cross-reacting peptide produced by the colon and bile duct epithelium. Primary sclerosing cholangitis can be combined with other autoimmune diseases, including thyroiditis and type 1 diabetes mellitus.
The content of circulating immune complexes may be increased and their excretion reduced. The complement exchange is accelerated.
Also disturbed are cellular immune mechanisms. The number of T-lymphocytes decreases in the blood, but increases in the portal tracts. The ratio of CD4 / CD8 lymphocytes in the blood increases, as does the absolute and relative amount of B-lymphocytes.
It is unclear whether these immune shifts indicate a primary autoimmune disease or whether they are secondary to bile duct damage.
Similar cholangiographic and histological changes in the liver are found in some infections, for example, cryptosporidiosis, and in immunodeficient conditions. This serves as an argument in favor of the assumption that the primary sclerosing cholangitis is of an infectious nature. If this assumption is correct, one might think that the frequent combination of primary sclerosing cholangitis with ulcerative colitis is the result of bacteremia, but this has not yet been proved. Perhaps, the products of the vital activity of bacteria matter. When rats with experimentally induced colitis of anti-inflammatory bacterial peptides were introduced into the large intestine, their content in the bile and the development of pericholangitis increased. Moreover, in rats with a hereditary predisposition to the formation of a blind loop of the intestine with dysbacteriosis, liver damage developed as a result of proliferation and fibrosis of the bile ducts and inflammatory changes in zone 1. Finally, in rabbits, the introduction of killed nonpathogenic microorganisms of Escherichia coli into the portal vein caused changes in the liver, partly resembling pericholangitis, developing in humans.
With nonspecific ulcerative colitis, the permeability of the intestinal epithelium increases, facilitating the penetration of endotoxin and toxic bacterial products into the portal vein and then into the liver.
Infectious theory does not allow to explain why ulcerative colitis is not detected in all cases of primary sclerosing cholangitis and why the severity of the disease does not depend on the severity of colitis. In addition, it remains unclear why primary sclerosing cholangitis can precede colitis, why antibiotics are ineffective and why there is no improvement after proctocolectomy.
Pathomorphology. For primary sclerosing cholangitis, the following pathomorphological changes are characteristic:
- nonspecific inflammation and fibrous thickening of the walls of the intrahepatic and extrahepatic bile ducts, narrowing of the lumen;
- Inflammatory infiltration and fibrosis are localized in the subserous and submucosa layers of the inflamed bile duct wall;
- proliferation of bile ductulae in significantly fibrotic portal tracts;
- obliteration of a large part of the bile ducts;
- expressed signs of cholestasis, dystrophy and necrobiotic changes in hepatocytes;
- in the late stage - a picture typical of biliary cirrhosis.
[