What is primary sclerosing cholangitis (PSC) and how is it treated?

Primary Sclerosing Cholangitis: Overview and Management

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

Definition and Pathophysiology

PSC is characterized by:

• Inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts
• Formation of multifocal bile duct strictures and segmental dilatations
• Progressive disease course leading to cirrhosis, portal hypertension, and hepatic decompensation 1

The exact etiology remains unclear, but evidence suggests it is an immune-mediated disease with:

• Strong genetic associations
• Chronic inflammation in portal tracts
• Strong association with inflammatory bowel disease (IBD) 1

Epidemiology

• Incidence: 0.9-1.3 per 100,000 person-years (may be increasing)
• Small duct PSC incidence: 0.15 per 100,000 person-years
• Higher incidence in populations of northern European descent
• Male predominance 1, 2
• Strong association with IBD (60-80% of PSC patients), most commonly ulcerative colitis 1

Clinical Presentation

Patients may present in several ways:

1. Asymptomatic: Incidental finding of abnormal liver biochemistry
2. Biochemical screening: In patients with newly diagnosed or pre-existing IBD
3. Symptomatic presentation:
   • Right upper quadrant pain
   • Fatigue
   • Pruritus
   • Jaundice
   • Weight loss 1

Episodes of cholangitis (fever and chills) are uncommon at presentation unless there has been prior biliary surgery or instrumentation 1.

Diagnostic Approach

Laboratory Findings

• Elevated alkaline phosphatase (most common biochemical abnormality)
• Elevated serum aminotransferases (2-3 times upper limits of normal)
• Normal serum bilirubin at diagnosis in most patients
• Modestly elevated IgG serum levels in approximately 60% of patients 1

Imaging

1. First-line imaging:

   • Magnetic resonance cholangiography (MRC) - recommended as initial diagnostic test 1, 3
   • Shows characteristic bile duct changes with multifocal strictures and segmental dilatations

2. Endoscopic retrograde cholangiography (ERC):

   • Alternative when MRC is unavailable or inconclusive
   • Allows for therapeutic intervention for dominant strictures 1

Diagnostic Criteria

A diagnosis of PSC is made when:

• Cholestatic biochemical profile is present
• Cholangiography shows characteristic bile duct changes
• Secondary causes of sclerosing cholangitis have been excluded 1

Additional Testing

• Liver biopsy:

  • Not routinely recommended when cholangiographic findings are typical
  • Recommended for diagnosing small duct PSC when ERC/MRC is normal
  • Recommended when disproportionately elevated aminotransferases suggest overlap syndrome 1

• Serum IgG4 levels:

  • Should be measured in all patients with possible PSC to exclude IgG4-associated sclerosing cholangitis
  • Elevated in approximately 9% of PSC patients 1

Complications

Major complications include:

1. Dominant strictures:

   • Occur in 45-58% of patients during follow-up
   • Defined as stenosis with diameter ≤1.5 mm in common bile duct or ≤1 mm in hepatic duct 1

2. Cholangiocarcinoma:

   • Develops in 10-15% of PSC patients
   • Must be considered when dominant strictures are present 1, 4

3. Other complications:

   • Metabolic bone disease
   • Colorectal neoplasia (in patients with IBD)
   • Hepatic decompensation
   • Gallbladder polyps and cancer 5, 6

Management

Medical Therapy

Currently, no medical therapy has been proven to halt disease progression or improve transplant-free survival 2, 4. Treatment options include:

• Ursodeoxycholic acid (UDCA):

  • Widely used as it improves biochemical parameters of cholestasis
  • Safe at low doses
  • However, not shown to improve overall survival 2

• Antibiotics:

  • Used for episodes of cholangitis
  • Should include those with broad antimicrobial activity and good penetration into bile ducts (e.g., third-generation cephalosporins, fluoroquinolones) 1

Endoscopic Management of Dominant Strictures

For symptomatic dominant strictures:

1. Obtain brush cytology/endoscopic biopsy before therapy to exclude malignancy
2. Administer perioperative antibiotics
3. Consider balloon dilatation with or without stenting
   • Note that stenting has increased complications compared to dilatation alone 1, 3

The goal is to relieve biliary obstruction in patients with symptoms such as:

• Cholangitis
• Jaundice
• Pruritus
• Right upper quadrant pain
• Worsening biochemical indices 1

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 2, 4

Emerging Therapies

Several novel therapeutic strategies are in development:

• Bile acid transporter inhibitors
• Integrin inhibitors
• Peroxisome proliferator-activated receptor agonists
• Farnesoid X receptor bile acid receptor agonists
• Nor-ursodeoxycholic acid
• Manipulation of gut microbiome (including fecal microbiota transplantation) 2

Surveillance

Regular monitoring is essential for:

1. Disease progression:

   • Regular liver biochemistry and imaging

2. Cholangiocarcinoma:

   • Vigilance for dominant strictures
   • Brush cytology and/or endoscopic biopsy for suspicious strictures

3. Colorectal cancer (in patients with IBD):

   • Regular colonoscopy surveillance

Prognosis

• Median survival without liver transplantation: 12-15 years after diagnosis 6
• Progressive disease in most patients, leading to cirrhosis and need for liver transplantation 4

Clinical Pearls

• Always consider PSC in patients with IBD and elevated liver enzymes 5
• Dominant strictures should always raise suspicion for cholangiocarcinoma, though they are more often benign than malignant 1
• Conventional brush cytology has limited sensitivity (18-40%) for cholangiocarcinoma in PSC patients 3
• Up to 20% of patients undergoing surgery for suspected biliary malignancy may have benign pathology 3
• Episodes of cholangitis are uncommon at presentation unless there has been prior biliary instrumentation 1