Pathophysiology of Primary Sclerosing Cholangitis
Primary sclerosing cholangitis is an immune-mediated chronic liver disease characterized by progressive inflammation, fibrosis, and destruction of intrahepatic and/or extrahepatic bile ducts, leading to cholestasis, multifocal bile duct strictures, and hepatic fibrosis that ultimately progresses to cirrhosis, portal hypertension, and hepatic decompensation. 1, 2
Core Pathophysiological Mechanisms
Immune-Mediated Biliary Injury
The fundamental pathophysiology centers on immune-mediated destruction of biliary epithelial cells. The genetic associations with disease risk, presence of chronic inflammation in the portal tracts, and strong association with inflammatory bowel disease all point to PSC being an immune-mediated disease targeting the biliary epithelial cell. 1 The disease involves both genetic predisposition and immunological dysregulation, with environmental influences playing a contributory role. 3
Progressive Inflammatory and Fibrotic Process
The inflammatory process induces periductular fibrosis that creates the characteristic multifocal strictures and segmental ductal dilatations seen on cholangiography. 2 This periductal concentric ("onion-skin") fibrosis represents the classic histopathologic finding, though it is infrequently observed in liver biopsy specimens. 1 The fibro-obliterative inflammation affects both intra- and extrahepatic bile ducts, producing the typical "beaded" appearance on imaging. 4, 5
Cholestatic Consequences
Biochemical Manifestations
The biliary destruction and stricturing lead to cholestasis, which produces a characteristic biochemical profile of parallel elevation of alkaline phosphatase and γ-glutamyl transpeptidase. 2, 4 Aminotransferase levels are typically elevated 2-3 times the upper limit of normal, indicating hepatocellular injury secondary to the cholestatic process. 2
Metabolic Complications
Advanced cholestasis results in malabsorption of fat-soluble vitamins and predisposes patients to osteopenic bone disease. 2 Elevated serum bilirubin signals more advanced disease and is associated with significantly poorer prognosis. 1, 2
The Gut-Liver Axis
Association with Inflammatory Bowel Disease
Up to 80% of PSC patients have concurrent inflammatory bowel disease, most commonly ulcerative colitis. 2, 4 This strong association suggests shared pathogenic mechanisms involving the gut-liver axis. 6, 3 PSC-associated colitis frequently presents as extensive pancolitis (approximately 87% of cases) with higher rates of backwash ileitis and rectal sparing compared to ulcerative colitis alone. 2
Microbiome and Bacterial Factors
The pathogenesis involves disturbances in the gut-liver axis, including immune dysfunction in both the colon and liver, alterations in the fecal and biliary microbiome, and conjugation of bile acids into toxic species. 3 Bacterial colonization of bile ducts can occur at sites of dominant strictures, precipitating secondary cholangitis and potentially accelerating disease progression. 2
Compromised intestinal epithelial integrity due to colitis results in translocation of bacterial byproducts to the liver, contributing to ongoing inflammation. 3
Disease Progression and Complications
Natural History
The natural history is progressive in most patients, with the disease leading to biliary cirrhosis, hepatic failure, and sometimes cholangiocarcinoma. 7, 5 Progressive fibrosis culminates in biliary cirrhosis accompanied by portal hypertension, ascites, and risk of variceal hemorrhage. 2
Dominant Strictures
Dominant strictures (stenosis with diameter ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct) occur in 45-58% of patients during follow-up. 1 These strictures may cause acute cholestasis, bacterial cholangitis, and faster progression of liver disease. 2
Malignancy Risk
Patients with PSC have a markedly increased lifetime risk of cholangiocarcinoma and colorectal adenocarcinoma. 2 Cholangiocarcinoma develops in approximately 10-15% of PSC patients and often presents as a stenotic ductal lesion in the perihilar region. 1
Clinical Pitfalls
A common pitfall is attributing all symptoms to PSC when approximately half of patients are asymptomatic at diagnosis, with disease identified incidentally through elevated alkaline phosphatase. 2, 4 When symptomatic, typical manifestations include pruritus, right-upper-quadrant discomfort, fatigue, and weight loss, reflecting cholestatic injury. 2, 4
Fever and chills from bacterial cholangitis are uncommon at initial presentation unless the patient has undergone prior biliary instrumentation, so their presence should prompt evaluation for secondary causes or complications. 2, 4