Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a progressive chronic inflammation of both the intrahepatic and extrahepatic bile ducts. The exact etiology is unknown but there is a strong association with autoimmune diseases, particularly ulcerative colitis (UC). In the early stages, PSC is often asymptomatic. As the disease progresses, patients may present with right upper quadrant abdominal pain, pruritus, fatigue, and weight loss. Laboratory tests show findings of cholestasis, including elevated alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). While not recommended for diagnosis, pANCA is positive in up to 80% of cases. Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) is used for diagnostic confirmation. Management is primarily symptomatic, with liver transplantation reserved for end-stage liver disease.

• Sex: : ♂ > ♀ (2:1)
• Age: : The median age at diagnosis is ∼ 40.

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• The exact cause is unknown.
• Associations
  • Chronic inflammatory bowel diseases (IBD)
    • ∼ 90% of patients with PSC have IBD (approx. 87% of these patients have ulcerative colitis) and ∼ 13% have Crohn disease.
    • However, only approx. 5% of patients with UC and < 5% of patients with Crohn disease develop PSC.
  • Presence of HLA-B8 and HLA-DR3
  • Other autoimmune conditions (e.g., hypergammaglobulinemia IgM)

The majority of patients with PSC also have ulcerative colitis.References:^[1][2]

• Often initially asymptomatic
• Signs of cholestasis
  • Jaundice/scleral icterus
  • Pruritus
  • Pale stool, dark urine
  • Fatigue
  • Can lead to acute cholangitis (fever, chills, right upper quadrant pain)
• Later stages: signs of cirrhosis
  • Hepatosplenomegaly
  • Portal hypertension
  • Liver failure
• Symptoms of chronic inflammatory bowel disease, which is frequently associated with PSC, or other associated comorbidities

References:^[2]

Approach ^[3][4]

• Suspect PSC in patients with persistently elevated cholestatic enzymes.
• Obtain abdominal imaging (e.g., ultrasound) to evaluate for biliary obstruction.
• Obtain further studies for diagnostic confirmation.
  • No biliary obstruction: MRCP
  • Biliary obstruction: therapeutic ERCP
  • Consider liver biopsy in select patients.

The diagnosis of PSC is based on persistently elevated cholestatic enzymes, characteristic bile duct strictures seen on MRCP or ERCP, and the exclusion of secondary sclerosing cholangitis. ^[3]

Laboratory studies ^[3][4][5]

Routine studies

• Cholestatic enzymes
  • ↑ ALP
  • ↑ GGT
  • Normal or ↑ conjugated bilirubin
• Transaminases: normal or moderately elevated (approx. 2–3× ULN) AST and ALT ^[3]
• Lipid profile: ↑ total cholesterol ^[6]
• CBC: Thrombocytopenia may be a sign of cirrhosis.

Suspect PSC in patients with a history of inflammatory bowel disease and elevated cholestatic enzymes (ALP, GGT, and conjugated bilirubin).

Serological studies

Findings are typically nonspecific but may help support the diagnosis or differential diagnoses.

All patients should be tested for elevated IgG4 at least once, as findings may influence management. ^[3][4]

Imaging ^[3][4][7]

Initial imaging

Obtain abdominal imaging for all patients to evaluate for biliary obstruction.

• Modalities: ultrasound, CT scan with contrast, MRI
• Supportive findings
  • Diffuse thickening of the bile duct walls
  • Focal bile duct dilatations
  • Possibly gallbladder abnormalities, e.g., thickening, enlargement

Advanced imaging

Obtain for all patients for diagnostic confirmation.

• Magnetic resonance cholangiopancreatography
  • Method of choice (if there is no biliary obstruction)
  • Supportive findings: multifocal intrahepatic and extrahepatic bile duct strictures alternating with dilatation and beading of bile ducts
• Endoscopic retrograde cholangiopancreatography
  • Should not be used for diagnosis of PSC except in the following scenarios:
    • Need for simultaneous therapeutic intervention for biliary obstruction
    • Contraindications to MRI
  • Supportive findings: similar to MRCP

Liver biopsy ^[4]

• Not routinely indicated as part of the workup for PSC
• Consider in select patients to evaluate for:
  • Small-duct PSC
  • Autoimmune hepatitis-PSC overlap syndrome
• Finding: concentric periductal onion skin fibrosis (typical but rare)

• Stage I: inflammatory infiltrate of portal triads and degeneration of the bile duct epithelium
• Stage II: periportal inflammation, bridging fibrosis, periportal fibrosis
• Stage III: septal fibrosis (from portal triad to another) and bridging necrosis; intrahepatic cholestasis
• Stage IV: biliary liver cirrhosis

The differential diagnoses listed here are not exhaustive.

General principles ^[3][4]

• Management is primarily supportive and includes:
  • Management of cholestasis-associated pruritus, e.g., with cholestyramine
  • Interventional treatment as needed to relieve obstructions
  • Monitoring for commonly associated conditions and complications
• No medications currently prevent disease progression (e.g., reduced time to liver transplantation). ^[10]
• Liver transplantation is the only curative treatment but has a significant risk of disease recurrence.

Pharmacological management ^[3][4][5]

• Ursodeoxycholic acid (UDCA)
  • Widely used, but evidence of benefit is mixed. ^[3][4]
  • May decrease transaminases, ALP, and serum bilirubin
• Immunosuppressants (e.g., glucocorticoids); usually reserved for patients with overlap syndromes: ^[3][4]
  • IgG4-associated cholangitis
  • Autoimmune hepatitis-PSC overlap syndrome

Interventional treatment ^[3][4][5]

Perform as needed in patients with relevant strictures. ^[3]

• ERCP with dilation of stenoses
  • Indications
    • To relieve symptoms caused by stenosis, e.g., pruritus and/or cholangitis
    • To exclude cholangiocarcinoma
  • Stenting may be necessary for severe strictures.
  • Provide prophylactic antibiotics to prevent post-ERCP cholangitis .
• Percutaneous cholangiography
  • Indication: patients who cannot undergo ERCP
  • Requires placement of a percutaneous drain

Patients with PSC are at increased risk for post-ERCP cholangitis. ^[4]

Liver transplantation ^[4][11]

• Refer patients with decompensated cirrhosis and a MELD score > 14.
• Additional MELD points may be offered to patients with:
  • Recurrent cholangitis with recurrent bacteremia (> 2 episodes) or sepsis (> 1 episode)
  • Cholangiocarcinoma < 3 cm in diameter without metastasis
  • Intractable pruritus

Screening and monitoring ^[3][4][7]

Patients with PSC are at increased risk of IBD, progression of liver disease to cirrhosis, osteoporosis, and malignancy.

Patients with both PSC and UC have a 4–5 times higher risk of developing colorectal dysplasia or cancer than those with UC alone. ^[4][11]

• Steatorrhea and deficiency of fat-soluble vitamins
• Liver cirrhosis
• Bacterial cholangitis
• Malignancy
  • Cholangiocarcinoma (∼ 10–15% of cases) ^[7]
  • Gallbladder carcinoma
  • Colorectal carcinoma ^[7][13]
  • Hepatocellular carcinoma ^[7]
  • Pancreatic carcinoma

We list the most important complications. The selection is not exhaustive.

• Five-year survival rate after liver transplantation: ∼ 85% ^[14]