Pathophysiology of Primary Sclerosing Cholangitis
Core Pathophysiologic Mechanisms
PSC is fundamentally an immune-mediated disease targeting biliary epithelial cells, driven by genetic susceptibility, chronic portal tract inflammation, and a strong association with inflammatory bowel disease (present in up to 80% of cases), indicating that the biliary epithelium is under sustained immune attack. 1
The disease process begins with cholangiocyte activation triggered by bacterial pathogen-associated molecular patterns (PAMPs) that reach the liver via the portal vein from the gut, stimulating innate immune responses and initiating a cascade of inflammation. 2, 3
Activated cholangiocytes upregulate adhesion molecules, antigen-presenting molecules, and aberrantly express gut-specific chemokines (such as CCL25 and MAdCAM-1), which recruit gut-primed memory T lymphocytes from the intestinal circulation into the portal tracts and peribiliary spaces. 4, 2, 3
Progressive periductal concentric ("onion-skin") fibrosis develops around bile ducts as a result of sustained inflammation, production of proinflammatory cytokines (TNF-α, IL-1β, IL-6), and release of fibrogenic mediators by activated cholangiocytes, stellate cells, and recruited immune cells. 4, 5, 2
The inflammatory and fibrotic process creates multifocal strictures and segmental dilatations of both intrahepatic and extrahepatic bile ducts, which are the pathognomonic imaging features of PSC. 1, 4
Consequences of Biliary Obstruction and Cholestasis
Bile duct strictures cause bile stasis, leading to cholestasis with accumulation of toxic bile acids that directly injure hepatocytes and cholangiocytes, perpetuating inflammation and cellular damage. 4, 6, 7
Bacterial colonization occurs at sites of dominant strictures (bile duct lumen ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct), precipitating recurrent episodes of secondary bacterial cholangitis that accelerate disease progression. 4, 7
Chronic cholestasis produces malabsorption of fat-soluble vitamins (A, D, E, K) and predisposes to metabolic bone disease (osteopenia and osteoporosis), while elevated serum bilirubin signals advanced disease with poor prognosis. 4, 8
Disease Progression and End-Stage Complications
Progressive hepatic fibrosis culminates in biliary cirrhosis, portal hypertension, ascites, variceal hemorrhage, and hepatic decompensation, representing the natural history of untreated PSC. 1, 4
Patients with PSC have a markedly elevated lifetime risk of cholangiocarcinoma (10-15% develop CCA, most often as perihilar stenotic lesions) and colorectal adenocarcinoma, likely related to chronic inflammation, bile acid toxicity, and shared immunopathogenic mechanisms with inflammatory bowel disease. 4, 5, 7