What is primary sclerosing cholangitis (PSC)?

Primary Sclerosing Cholangitis (PSC)

Primary sclerosing cholangitis is a chronic, immune-mediated liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to multifocal bile duct strictures, progressive cholestasis, and eventual cirrhosis with no effective medical therapy to halt disease progression. 1

Definition and Pathophysiology

PSC is defined as a chronic cholestatic liver disease with the following key characteristics:

• Inflammation and fibrosis of intrahepatic and/or extrahepatic bile ducts
• Formation of multifocal bile duct strictures and segmental dilatations
• Progressive disease course leading to cirrhosis, portal hypertension, and hepatic decompensation 2

The disease is likely immune-mediated, with genetic associations, chronic inflammation in portal tracts, and a strong association with inflammatory bowel disease (IBD) suggesting an abnormal immune response in genetically susceptible individuals 2, 3.

Epidemiology

• Incidence: 0.9-1.3 per 100,000 person-years, with higher rates in northern European populations 2, 1
• Small duct PSC incidence: 0.15 per 100,000 person-years 1
• Male predominance 1
• Typically diagnosed between ages 30-40 3
• Strong association with IBD: 60-80% of PSC patients have IBD, most commonly ulcerative colitis 1

Clinical Presentation

Patients with PSC may present in several ways:

1. Asymptomatic (common in early disease)

   • Incidental finding of abnormal liver biochemistry
   • Detected during screening of patients with IBD

2. Symptomatic presentation (more established disease)

   • Right upper quadrant abdominal pain
   • Pruritus
   • Fatigue
   • Jaundice
   • Weight loss 2

3. Complications-related presentation

   • Cholangitis (uncommon at initial presentation without prior biliary instrumentation)
   • Jaundice from liver failure
   • Variceal bleeding or ascites from portal hypertension
   • Cholangiocarcinoma 2

Diagnostic Approach

A diagnosis of PSC is established based on:

1. Biochemical profile:

   • Cholestatic pattern with elevated alkaline phosphatase (ALP) and γ-glutamyl transpeptidase
   • Mildly elevated AST and ALT (typically 2-3 times upper limit of normal)
   • Elevated serum bilirubin in 28-40% of cases (marker of poor prognosis)
   • Modestly elevated IgG levels in approximately 60% of patients 2, 1

2. Imaging:

   • Magnetic resonance cholangiography (MRC) is the first-line diagnostic test, showing characteristic multifocal bile duct strictures and segmental dilatations 1
   • Endoscopic retrograde cholangiography (ERC) is an alternative when MRC is unavailable or inconclusive 1

3. Exclusion of secondary causes of sclerosing cholangitis (e.g., choledocholithiasis, surgical trauma, intra-arterial chemotherapy, recurrent pancreatitis) 2

4. Variant forms:

   • Small duct PSC: normal cholangiography but typical biochemical and histological features
   • PSC overlap syndromes: features of both PSC and other immune-mediated liver diseases like autoimmune hepatitis 2

Complications

PSC is associated with several serious complications:

1. Dominant strictures: Occur in 45-58% of patients during follow-up 1

   • Defined as stenosis with diameter ≤1.5 mm in common bile duct or ≤1 mm in hepatic duct

2. Malignancy risk:

   • Cholangiocarcinoma: 10-15% lifetime risk 1, 3
   • Colorectal cancer (in patients with IBD)
   • Gallbladder polyps and cancer 1

3. Progressive liver disease:

   • Cirrhosis
   • Portal hypertension
   • Hepatic decompensation 2, 1

4. Metabolic bone disease 1

Management

Currently, no medical therapy has been proven to halt disease progression or improve transplant-free survival 1, 4:

1. Medical therapy:

   • Ursodeoxycholic acid (UDCA) improves biochemical parameters but has not shown to improve overall survival 1
   • Antibiotics for episodes of cholangitis (third-generation cephalosporins, fluoroquinolones) 1

2. Management of dominant strictures:

   • Obtain brush cytology/endoscopic biopsy to exclude malignancy
   • Administer perioperative antibiotics
   • Consider balloon dilatation with or without stenting 1

3. Liver transplantation:

   • Only definitive treatment for advanced disease
   • Indicated for end-stage liver disease with decompensation
   • Recurrence of PSC after transplantation occurs in up to 38% of patients 1

Monitoring and Surveillance

Regular monitoring is essential for:

1. Disease progression: Regular liver biochemistry and imaging 1

2. Cholangiocarcinoma surveillance:

   • Vigilance for dominant strictures
   • Brush cytology and/or endoscopic biopsy for suspicious strictures
   • Conventional brush cytology has limited sensitivity (18-40%) 1

3. Colorectal cancer surveillance: Regular colonoscopy in patients with IBD 1

Prognosis

• Median survival without liver transplantation: 12-15 years after diagnosis 1
• Progressive disease leads to cirrhosis and need for liver transplantation in most patients 1
• Up to 20% of patients undergoing surgery for suspected biliary malignancy may have benign pathology 1

Key Clinical Considerations

• PSC is a heterogeneous disease with variable clinical course, making clinical trials and treatment development challenging 4, 5
• The strong association with IBD requires monitoring for both hepatic and intestinal complications 1, 3
• Vigilance for cholangiocarcinoma is crucial as it accounts for a large proportion of mortality in PSC 3
• Liver transplantation is ultimately required in approximately 40% of patients 3