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Primary Sclerosing Cholangitis (PSC)

Introduction

Primary Sclerosing Cholangitis (PSC) is a chronic, progressive, immune-mediated disease characterized by fibrosis of the intrahepatic and/or extrahepatic biliary tree leading to inflammation and cholestatic liver disease. The exact cause is idiopathic, but it is considered an autoimmune process affecting the biliary tree.

  • Epidemiology:
    • More common in men.
    • Mean age at diagnosis is around 40 years.
    • Strongly associated with inflammatory bowel disease (IBD), especially ulcerative colitis (present in up to 82% of PSC patients).

Etiology and Pathogenesis

  • Autoimmune associations: PSC is associated with other autoimmune disorders such as:
    • Ulcerative colitis (in almost 70% of patients).
    • Crohn's disease (up to 13%).
    • Riedel thyroiditis.
    • Autoimmune pancreatitis.
  • Genetic and environmental factors are believed to play roles.
  • Disease progression:
    • Characterized by patchy inflammation leading to obliterative fibrosis.
    • Advances unpredictably to biliary cirrhosis and eventually liver failure.

Clinical Presentation

  • Symptoms:
    • Fatigue.
    • Pruritus (itching).
    • Jaundice.
    • Right upper quadrant pain.
    • Bouts of bacterial cholangitis accompanied by transient jaundice.
  • Signs:
    • Physical examination may reveal jaundice and xanthomata.
    • Signs of portal hypertension and liver failure may develop in advanced stages.

Laboratory Findings

  • Elevated liver enzymes:
    • Alkaline phosphatase (ALP) is typically elevated.
    • Gammaglobulin and serum immunoglobulin M (IgM) levels may be elevated.
  • Autoantibodies:
    • Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) are elevated in approximately 80% of patients.
      • Severity of disease does not correlate with antibody titer levels.
    • Antinuclear antibodies (ANA), antismooth muscle antibodies (ASMA), anticardiolipin, thyroperoxidase, and rheumatoid factor may be elevated.
    • Human leukocyte antigen (HLA) DRw52a is often present.
    • Antimitochondrial antibodies are generally negative (contrasts with primary biliary cholangitis).

Imaging Studies

  • Magnetic Resonance Cholangiopancreatography (MRCP):
    • Recommended as the first-line noninvasive imaging test.
    • Demonstrates multifocal diffuse dilation and stricturing of the intrahepatic and/or extrahepatic biliary trees.
    • Characteristic "beading" or "chain of lakes" appearance.
  • Endoscopic Retrograde Cholangiopancreatography (ERCP):
    • Reserved for treatment of dominant strictures and to exclude cholangiocarcinoma.
    • Cholangiography may show pseudodiverticula, mural irregularities, and biliary stones and sludge.

Histopathology

  • Liver biopsy findings:
    • Onion-skin concentric periductal fibrosis.
    • Progression to periportal fibrosis, bridging necrosis, and eventually biliary cirrhosis.
    • Histology may be nonspecific due to the segmental nature of the disease.

Complications

Cholangiocarcinoma

  • PSC is associated with a significant risk of developing cholangiocarcinoma:
    • Cumulative annual risk of approximately 1.5% per year.
    • Occurs in 9% to 15% of patients.
    • Risk is increased in patients with long-standing ulcerative colitis and cirrhosis.
  • Diagnosis challenges:
    • Early diagnosis is difficult due to lack of sensitive and specific markers.
    • Sudden worsening of jaundice, weight loss, and elevated CA19-9 levels should raise suspicion.
    • Tissue sampling during ERCP is indicated for any suspicious lesions.
  • Management:
    • Cholangiocarcinoma is generally a contraindication to liver transplantation.
    • Some centers use neoadjuvant chemotherapy and radiation followed by transplantation, showing survival rates up to 70% at 5 years.

Gallbladder Disease

  • Gallbladder polyps:
    • Adenomatous polyps have malignant potential.
    • Predictors of malignancy include:
      • Single polyp.
      • Size greater than 1 cm.
      • Age older than 50 years.
    • Cholecystectomy is recommended for polyps larger than 1 cm.
    • In PSC patients, the threshold for cholecystectomy should be lower due to increased cancer risk.

Other Complications

  • Cirrhosis and liver failure due to progressive fibrosis.
  • Recurrent bacterial cholangitis.
  • Portal hypertension.
  • Osteoporosis commonly develops in PSC patients.

Treatment

Medical Therapy

  • Ursodeoxycholic acid:
    • Commonly used, but its efficacy in altering disease progression is controversial.
    • High doses (28–30 mg/kg per day) have been found to lead to detrimental outcomes.
    • Standard doses (up to 15 mg/kg per day) may promote bile flow in patients with recurrent cholangitis.
  • Ongoing trials:
    • Investigating ursodeoxycholic acid homologs.
    • Antibiotics to alter the microbiome.
    • Interruption of the enterohepatic bile circulation.
  • No effective medication has been definitively proven to alter disease progression.

Endoscopic Therapy

  • Indications:
    • Treatment of dominant strictures.
    • Relief of jaundice and pruritus.
    • Management of symptomatic cholangitis.
    • Deteriorating liver function tests.
    • High concern for bile duct cancer.
  • Techniques:
    • Endoscopic sphincterotomy (ES).
    • Stone/sludge removal.
    • Stricture dilation with balloons or catheters.
    • Stent placement.
  • Outcomes:
    • Alleviates pruritus.
    • Reduces likelihood of cholangitis.
    • May prolong survival.
  • Procedural considerations:
    • Antibiotic prophylaxis is mandatory due to high risk of post-ERCP cholangitis.
    • Stents, if used, should be:
      • Single 10-Fr plastic stent for extrahepatic ducts.
      • Two 7-Fr stents for hilar strictures.
      • Removed within 1–2 weeks to prevent complications.

Surgical Therapy

  • Biliary reconstruction:
    • Considered in symptomatic patients with focal extrahepatic disease.
    • Use has decreased due to potential complications with future liver transplantation.
  • Hepaticojejunostomy:
    • May be considered for noncirrhotic patients with:
      • Severe cholestasis.
      • Recurrent bacterial cholangitis not amenable to endoscopic therapy.
  • Liver transplantation:
    • The only lifesaving option for patients with progressive hepatic dysfunction from PSC.
    • 5-year survival rates range from 75% to 85%.
    • Recurrent biliary strictures occur in 10% to 30% of patients post-transplant, suggestive of disease recurrence.

Management of Cholangiocarcinoma

  • Transplantation considerations:
    • Generally a contraindication in PSC patients with cholangiocarcinoma.
    • Some centers use neoadjuvant chemotherapy and radiation followed by transplantation.
  • Monitoring:
    • CA19-9 levels typically rise with the onset of cholangiocarcinoma and should be followed serially.

Prognosis

  • Disease progression is unpredictable.
  • PSC may advance to biliary cirrhosis and eventually death from liver failure.
  • Early diagnosis and management can improve outcomes.

PSC vs. Primary Biliary Cholangitis (PBC)

  • PSC:
    • Negative antimitochondrial antibodies.
    • Associated with IBD.
    • Affects both intrahepatic and extrahepatic bile ducts.
  • PBC:
    • Positive antimitochondrial antibodies (hallmark of the disease).
    • Granulomatous destruction of intralobar ducts.
    • Symptoms include fatigue, pruritus, jaundice, xanthomata.
    • Osteoporosis commonly develops.

PSC and IgG4-Associated Cholangitis

  • IgG4-Associated Cholangitis (IAC):
    • Immune-mediated systemic disorder affecting the pancreas and liver.
    • Causes autoimmune pancreatitis and cholangitis.
    • May mimic cholangiocarcinoma or pancreatic cancer.
  • Diagnosis of IAC:
    • Increased serum levels of total IgG and IgG4.
    • Presence of intrahepatic and extrahepatic biliary strictures on imaging.
    • Diffusely enlarged pancreas and narrowing of the main pancreatic duct in up to 90% of cases.
    • Histology: Infiltration of IgG4-positive lymphoplasmacytic cells.
  • Management:
    • Immunosuppression with steroids is highly effective.
    • Maintenance immunosuppression may be needed with azathioprine or mycophenolate mofetil.

Additional Associations

  • Autoimmune Pancreatitis:
    • PSC can be associated with autoimmune pancreatitis.
  • Risk Factors for Cholangiocarcinoma:
    • Choledochal cysts.
    • Choledocholithiasis.
    • Infections (e.g., Clonorchis sinensis, hepatitis B, hepatitis C).
    • Medications and chemicals (Thorotrast, oral contraceptives, asbestos, cigarette smoke).
  • Gallbladder Cancer:
    • PSC is a risk factor.
    • Type of gallstones does not correlate with incidence.
  • Gallbladder Polyps in PSC:
    • Lower threshold for cholecystectomy due to increased risk of malignancy.

Conclusion

Primary Sclerosing Cholangitis is a complex disease with significant implications for patient health due to its progressive nature and association with serious complications like cholangiocarcinoma. Early recognition, careful monitoring, and appropriate therapeutic interventions, including endoscopic therapies and consideration for liver transplantation, are crucial for managing PSC and improving patient outcomes.