Primary Sclerosing Cholangitis - Causes

The cause of primary sclerosing cholangitis is unknown. In primary sclerosing cholangitis, all parts of the biliary tree may be involved in a chronic inflammatory process with the development of fibrosis, leading to obliteration of the bile ducts and ultimately to biliary cirrhosis. The involvement of different parts of the bile ducts is not the same. The disease may be limited to the intra- or extrahepatic bile ducts. Over time, the interlobular, septal, and segmental bile ducts are replaced by fibrous cords. Involvement of the smallest ducts of the 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. However, of the 10-15% of cases of liver damage in nonspecific ulcerative colitis, patients with sclerosing cholangitis account for approximately 5%. The development of cholangitis can precede colitis by up to 3 years. Primary sclerosing cholangitis and nonspecific ulcerative colitis can rarely be familial. Individuals with the Al, B8, DR3, DR4, and DRW52A haplotypes of the HLA system are more sensitive to them. In hepatitis Utes with the DR4 haplotype, the disease apparently progresses faster.

There are signs of immune regulation disorder. Circulating antibodies to tissue components are not detected or are detected in low titer. Perinuclear antineutrophil cytoplasmic antibodies are detected in at least two-thirds of cases. They do not disappear after liver transplantation. Probably, these antibodies are not involved in pathogenesis, but are an epiphenomenon. In addition, autoantibodies to a cross-reacting peptide produced by the epithelium of the colon and bile ducts are detected in the serum. Primary sclerosing cholangitis can be combined with other autoimmune diseases, including thyroiditis and type 1 diabetes mellitus.

The content of circulating immune complexes may increase and their elimination may decrease. Complement exchange is accelerated.

Cellular immune mechanisms are also disrupted. The number of T-lymphocytes decreases in the blood, but increases in the portal tracts. The CD4/CD8 lymphocyte ratio in the blood increases, as does the absolute and relative number of B-lymphocytes.

It is unclear whether these immune shifts represent a primary autoimmune disease or are secondary to bile duct damage.

Similar cholangiographic and histological changes in the liver are found in some infections, such as cryptosporidiosis, and in immunodeficiency states. This serves as an argument in favor of the assumption that primary sclerosing cholangitis has an infectious nature. If this assumption were true, one might think that the frequent combination of primary sclerosing cholangitis with nonspecific ulcerative colitis is the result of bacteremia, but this has not yet been proven. It is possible that bacterial waste products are important. When anti-inflammatory bacterial peptides were introduced into the colon of rats with experimentally induced colitis, an increase in their content in the bile and the development of pericholangitis were observed. Moreover, in rats with a hereditary predisposition to the formation of a blind loop of the intestine, liver damage developed during dysbacteriosis, manifested by proliferation and fibrosis of the bile ducts and inflammatory changes in zone 1. Finally, in rabbits, the introduction of killed non-pathogenic Escherichia coli microorganisms into the portal vein caused changes in the liver that partly resembled pericholangitis developing in humans.

In ulcerative colitis, the permeability of the intestinal epithelium increases, facilitating the penetration of endotoxin and toxic bacterial products into the portal vein and further into the liver.

The infectious theory does not explain why nonspecific 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. The following pathomorphological changes are characteristic of primary sclerosing cholangitis:

• non-specific 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 submucosal layers of the inflamed wall of the bile ducts;
• proliferation of bile ducts in significantly fibrotic portal tracts;
• obliteration of a large part of the bile ducts;
• pronounced signs of cholestasis, dystrophy and necrobiotic changes in hepatocytes;
• in the late stage - a picture characteristic of biliary cirrhosis of the liver.

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