Primary sclerosing cholangitis (PSC) is characterized by idiopathic inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, leading to multifocal bile duct strictures. Clinically, it primarily manifests as chronic cholestasis. PSC predominantly affects middle-aged males, with a male-to-female ratio of 2:1. Approximately 50–70% of PSC patients have coexisting ulcerative colitis.
Etiology and Pathogenesis
A specific HLA genetic background plays a significant role in the pathogenesis of PSC. Autoimmune factors, infections, dysbiosis of the gut microbiota, or other unknown causes may attack biliary epithelial cells, resulting in bile duct injury.
Clinical Manifestations
PSC has an insidious onset. Between 15% and 55% of patients are asymptomatic at the time of diagnosis, which is often made incidentally during routine health examinations due to elevated ALP levels or during evaluation for inflammatory bowel disease. Typical symptoms include jaundice and pruritus, while other manifestations may include fatigue, weight loss, and hepatosplenomegaly. Jaundice is often intermittent and recurrent. Complications such as cholangitis, bile duct stones, or cholangiocarcinoma may present with right upper quadrant pain, moderate to high fever, and chills. Severe bile duct strictures and obstruction can lead to acute liver injury and may progress to liver failure. Chronic cholestasis is often associated with bile duct strictures or cirrhosis and may present with symptoms of portal hypertension, fat-soluble vitamin deficiencies, and metabolic bone disease.
PSC can be classified into three subtypes based on the location of bile duct involvement:
- Large bile duct type: Affects the larger extrahepatic bile ducts, accounting for approximately 90% of PSC cases.
- Small bile duct type: Involves smaller bile ducts without abnormalities detectable on imaging.
- Diffuse type: Involves both intrahepatic and extrahepatic bile ducts of varying sizes.
Laboratory Tests
Serum Biochemistry
PSC is typically associated with elevated ALP and γ-GT levels, while ALT and AST are usually normal. Significant elevations in ALT and AST may indicate acute biliary obstruction or overlap with autoimmune hepatitis (AIH).
Immunological Tests
No PSC-specific autoantibodies have been identified. Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are positive in 33–85% of PSC patients. Approximately 50% of patients exhibit mild to moderate elevations in serum IgM, increased immune complexes, and decreased complement C3 levels. Circulating CD8+ T cell counts are reduced, with an increased CD4/CD8 ratio.
Imaging Studies
Imaging is the primary modality for diagnosing PSC.
Endoscopic Retrograde Cholangiopancreatography (ERCP)
ERCP is considered the "gold standard" for diagnosing PSC. It reveals multifocal, short-segment, annular strictures of the intrahepatic and extrahepatic bile ducts. The bile duct walls appear rigid and lack elasticity, resembling a "lead pipe." Dilated bile ducts proximal to the strictures often display a "beaded" appearance. Severe cases may show long-segment strictures with cystic or diverticulum-like dilations of the bile ducts. When the intrahepatic bile ducts are extensively involved, a "pruned tree" appearance may be observed.
Magnetic Resonance Cholangiopancreatography (MRCP)
Due to its non-invasive nature, MRCP is the preferred imaging modality for suspected PSC. The imaging findings are similar to those of ERCP, showing discontinuous or "dotted-line" intrahepatic bile ducts, irregular and inhomogeneously thickened extrahepatic bile ducts, and rough, unsmooth bile duct margins.
Abdominal Ultrasound
Ultrasound may show scattered hyperechoic areas within the liver, thickened walls of the common bile duct, irregular bile duct strictures and dilations, thickened gallbladder walls, and bile stasis.
Histopathology
While PSC diagnosis primarily relies on imaging, liver biopsy is not routinely required. However, liver tissue examination is necessary when small intrahepatic bile ducts are involved. Histological findings typically show extensive fibrosis of the intrahepatic bile ducts, with the characteristic "onion-skin" concentric fibrosis being a hallmark feature.
Diagnosis and Differential Diagnosis
The diagnosis of PSC is primarily based on abnormalities in ALP and γ-GT levels, along with biliary imaging that shows multifocal strictures of the intrahepatic and extrahepatic bile ducts. When small intrahepatic bile ducts are involved, characteristic histopathological changes of PSC may be observed.
It is important to differentiate PSC from secondary sclerosing cholangitis (SSC). SSC refers to a group of diseases with clinical features similar to PSC but with identifiable causes. Common causes include common bile duct stones, biliary surgical trauma, recurrent pyogenic cholangitis, biliary neoplasms (such as cholangiocarcinoma, hepatocellular carcinoma involving the bile ducts, ampullary carcinoma, or compression from metastatic lymph nodes near the common bile duct), and IgG4-related sclerosing cholangitis. Atypical cases of PSC may also need differentiation from primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), drug-induced liver injury, chronic active hepatitis, and alcoholic liver disease.
Treatment
Medications
Moderate doses of ursodeoxycholic acid (UDCA) [17–23mg/(kg⋅d)] can improve liver biochemical parameters, reduce liver fibrosis, and improve biliary imaging findings. Patients with acute bacterial cholangitis should be treated with effective broad-spectrum antibiotics. In late-stage PSC, complications such as steatorrhea, fat-soluble vitamin malabsorption syndrome, and osteoporosis may occur, and supplementation with fat-soluble vitamins such as vitamin D may be necessary. Severe pruritus may be managed with cholestyramine.
Endoscopic Intervention
PSC-related biliary obstruction often involves multiple levels of the biliary tree. For significant strictures of the extrahepatic bile ducts and large intrahepatic bile ducts, ERCP with balloon dilation or stent placement may be used to alleviate pruritus and complications such as cholangitis.
Interventional or Surgical Approaches
Percutaneous Transhepatic Cholangial Drainage (PTCD)
PTCD may be performed when ERCP is not feasible. PTCD can also be used to place a guidewire percutaneously into the ampulla, followed by stent placement via ERCP.
Palliative Surgery
Palliative surgery is suitable for non-cirrhotic PSC patients with significant strictures at the hepatic hilum or extrahepatic bile ducts, who have severe cholestasis or recurrent cholangitis that cannot be resolved through minimally invasive procedures.
Liver Transplantation
Liver transplantation is indicated for end-stage PSC patients. The 5-year survival rate after transplantation is 80–85%, but approximately 20% of PSC cases may recur within 10 years after transplantation.
Prognosis
In the absence of effective treatment for PSC, the median time from diagnosis to death or liver transplantation is approximately 12–18 years. Cholangiocarcinoma is the leading cause of death in PSC patients. Among symptomatic PSC patients, the cumulative incidence of liver failure, cholangiocarcinoma, and other complications reaches up to 41% after six years of follow-up.