Etiology and Pathogenesis
The exact causes of the disease are not fully understood, but its non-infectious nature is well established. Genetic predisposition plays an important role: familial cases occur in 1–7% of situations, and patients often carry specific genotypes (HLA-DR3, DR4, or DR2). Congenital or acquired deficiency of the immunosuppressive system contributes to the development of the disease.
The pathogenesis is based on autoimmune cellular reactions that resemble graft-versus-host disease in their character and morphology.
- Target of aggression: human leukocyte antigens (HLA) located on the epithelium of intrahepatic bile ducts. Their abnormally high density makes the biliary epithelium vulnerable to immune attack.
- Immune imbalance: increased concentration and activity of T-helper cells with a simultaneous decrease in T-suppressor function. T-helper cells along with B-lymphocytes accumulate in the portal tracts, maintaining chronic inflammation.
- Cross-reactivity: the destruction of ducts triggers autoimmune reactions against other tissues. This is why the pathology is frequently combined with Hashimoto thyroiditis, scleroderma, rheumatoid arthritis, and systemic lupus erythematosus.
Clinical Presentation and Systemic Manifestations
The disease develops gradually. In the early stages, the most characteristic sign is pruritus. At first, it is intermittent, then becomes constant. Due to the absence of jaundice at disease onset, patients may undergo long and unsuccessful treatments by dermatologists.
Other early symptoms include:
- Dark brown skin pigmentation (starting in the scapular region due to melanin deposition).
- Appearance of xanthelasmas.
- Hepatomegaly and splenomegaly.
- Elevated blood levels of gamma-glutamyl transferase (GGT), alkaline phosphatase, and specific antimitochondrial antibodies (AMA-M2).
In the established stage, jaundice, fever, and weight loss join the clinical picture. The skin becomes coarse, and vitiligo-like depigmentation foci may appear. The liver significantly enlarges, occupying both hypochondria.
The disease rarely occurs in isolation and is accompanied by multiple extraphepatic manifestations:
- Sjögren syndrome: involvement of salivary and lacrimal glands occurs in 70–100% of patients.
- Gastrointestinal and pancreatic involvement: duodenitis, papillitis, as well as exocrine pancreatic insufficiency leading to steatorrhea.
- Renal involvement: development of glomerulonephritis or tubulointerstitial nephritis.
- Bone changes: bone resorption, systemic osteoporosis, and osteomalacia.
- Pulmonary involvement: excessive connective tissue proliferation (associated with $\alpha_1$-antitrypsin deficiency).
- Endocrine disorders: ovarian dysfunction in women (amenorrhea, dysmenorrhea).
Pathology
Macroscopically, the liver is somewhat enlarged and acquires a greenish tint due to pronounced cholestasis. In late stages, its surface becomes finely granular. Lymph nodes in the porta hepatis are usually enlarged.
The microscopic picture progresses through four sequential stages:
- Stage I: non-suppurative destructive cholangitis. Inflammation destroys the bile ducts, leading to ductopenia (progressive reduction in their number).
- Stage II: compensatory proliferation of small bile ducts amidst connective tissue proliferation around portal tracts (periportal sclerosis).
- Stage III: formation of septal fibrosis, which disrupts the normal lobular architecture of the organ.
- Stage IV: formation of true liver cirrhosis.
Complications and Prognosis
The disease progresses slowly — from the onset of first symptoms to severe impairment takes an average of 10–12 years. Major complications include liver failure, bone fractures secondary to osteoporosis, gallstone formation, and hemorrhages.
Men have an increased risk of developing cholangiocellular carcinoma. Additionally, against the background of immunodeficiency (including from immunosuppressive therapy), the likelihood of extrahepatic malignancies increases.
In the terminal stage, signs of liver failure worsen, ascites appears (which is atypical for early stages), along with encephalopathy and hepatorenal syndrome. Death most frequently results from esophageal variceal bleeding, hepatic coma, or septicemia.