Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a progressive chronic inflammation of both the intrahepatic and extrahepatic bile ducts. While the exact etiology is unknown, there is a strong association with autoimmune diseases, particularly ulcerative colitis (UC). In the early stages, PSC is usually asymptomatic. Later in the course of the disease, patients present with symptoms of cholestasis (e.g., pruritus, jaundice). Laboratory abnormalities include elevated liver function tests and autoantibodies (pANCA in up to 80% of cases). Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) is performed to confirm the diagnosis. 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 PSC patients have IBD (from these patients, ∼ 87% have ulcerative colitis (UC) and ∼ 13% have Crohn's disease.
    • However, only ∼ 5% of patients with UC and < 5% of patients with Crohn's disease develop PSC.
  • Presence of HLA-B8 and HLA-DR3
  • Other autoimmune conditions (e.g., hypergammaglobulinemia IgM)

The majority of PSC patients 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]

Laboratory findings

• Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are present in up to 80% of cases
• ↑ Cholestasis parameters (ALP, GGT, conjugated bilirubin)
• Transaminases (AST/ALT) are within normal limits or slightly elevated (< 300 U/L).
• ↑ Cholesterol
• ↑ IgM

Imaging

• Cholangiography
  • Method of choice: magnetic resonance cholangiopancreatography (MRCP)
  • Alternatives
    • Endoscopic retrograde cholangiopancreatography (ERCP)
      • More invasive but also more accurate than MRCP
      • Good alternative for patients who cannot undergo MRI testing (e.g., patients with pacemaker)
    • Percutaneous transhepatic cholangiography (PTC)
      • Most invasive test
      • For patients who cannot undergo ERCP
  • Findings: multifocal strictures alternating with dilation and beading of bile ducts
• Ultrasound
  • Irregular diameter of the bile duct
  • Diffuse thickening of the wall of the common hepatic and bile ducts
• Other: colonoscopy (to assess for ulcerative colitis)

Liver biopsy

• Not an essential part of the workup; usually done if small duct PSC is suspected, which is not always detectable via cholangiography
• Typical finding: concentric "onion skin" scarring and fibrosis of bile ducts

If a patient with pre-existing chronic inflammatory bowel disease displays increased ALP, GGT, and conjugated bilirubin, always consider PSC.References:^[1][2]

• 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.

• Symptomatic
  • Ursodeoxycholic acid and immunosuppressives (e.g., tacrolimus): may decrease transaminases, ALP, and serum bilirubin, but do not prevent disease progression
  • Treatment of pruritus (e.g., cholestyramine, rifampicin, naltrexone)
  • Supplementation of fat-soluble vitamins (see “Complications” below)
  • In the case of bile duct stenosis: ERCP with duct dilation; potentially, stent placement
• Surgical: Liver transplantation is the only curative option and is performed in the case of advanced liver cirrhosis. ^[5]

References:^[6][7][8][9]

• Steatorrhea and deficiency of fat-soluble vitamins
• Liver cirrhosis
• Malignancy
  • Cholangiocarcinoma (∼ 10–15% of cases) ^[10]
    • Screening for cholangiocarcinoma with ultrasonography and cholangiopancreatography (e.g., MRCP, ERCP) with or without serum CA 19-9 levels is recommended every 6–12 months.
  • Gallbladder carcinoma
    • Perform annual screening for gallbladder polyps or carcinoma with ultrasonography.
  • Colorectal carcinoma ^[10][11]
    • In patients with PSC and inflammatory bowel disease (e.g., evidence of ulcerative colitis on the initial colonoscopy): Perform a colonoscopy every 1–2 years.
    • In patients with PSC without inflammatory bowel disease: Perform a colonoscopy every 5 years.
  • Hepatocellular carcinoma (HCC) ^[10]
    • Perform screening for HCC in patients with advanced (stage 3) cirrhosis or fibrosis with ultrasonography with or without serum CA 19-9 levels every 6 months.
  • Pancreatic carcinoma

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

• Five-year survival rate after liver transplantation: ∼ 85% ^[12]

1. Abdalian R, Heathcote EJ. Sclerosing cholangitis: A focus on secondary causes. Hepatology. 2006; 44 (5): p.1063-1074. doi: 10.1002/hep.21405 . | Open in Read by QxMD
2. Ruemmele P, Hofstaedter F, Gelbmann CM. Secondary sclerosing cholangitis. Nature Reviews Gastroenterology & Hepatology. 2009; 6 (5): p.287-295. doi: 10.1038/nrgastro.2009.46 . | Open in Read by QxMD
3. Kowdley KV. Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/primary-sclerosing-cholangitis-in-adults-clinical-manifestations-and-diagnosis.Last updated: January 4, 2016. Accessed: December 26, 2016.
4. Kowdley KV. Primary sclerosing cholangitis: Epidemiology and pathogenesis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/primary-sclerosing-cholangitis-epidemiology-and-pathogenesis.Last updated: January 13, 2015. Accessed: December 26, 2016.
5. Visseren T, Darwish Murad S. Recurrence of primary sclerosing cholangitis, primary biliary cholangitis and auto-immune hepatitis after liver transplantation. Best Practice & Research Clinical Gastroenterology. 2017; 31 (2): p.187-198. doi: 10.1016/j.bpg.2017.04.004 . | Open in Read by QxMD
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7. Van thiel DH, Carroll P, Abu-elmagd K, et al.. Tacrolimus (FK 506), a treatment for primary sclerosing cholangitis: results of an open-label preliminary trial. The American Journal of Gastroenterology. 1995; 90 (3): p.455-9.
8. Poropat G, Giljaca V, Stimac D, Gluud C. Bile acids for primary sclerosing cholangitis. The Cochrane Database of Systematic Reviews . 2011 : p.CD003626.
9. Kremer AE, Namer B, Bolier R et al. Pathogenesis and Management of Pruritus in PBC and PSC. Digestive Diseases. 2015; 33 (Suppl 2): p.164-75. doi: 10.1159/000440829 . | Open in Read by QxMD
10. Gochanour E,Jayasekera C, Kowdley K. Primary Sclerosing Cholangitis: Epidemiology, Genetics, Diagnosis, and Current Management. Clinical Liver Disease. 2020; VOL 15 (NO 3).
11. Diagnosis and Management of Primary Sclerosing Cholangitis. https://www.aasld.org/sites/default/files/2019-06/PrimarySclerosingCholangitis2010.pdf. Updated: August 31, 2009. Accessed: January 13, 2021.
12. Ponsioen C. Diagnosis, prognosis, and management of primary sclerosing cholangitis. Gastroenterology & Hepatology. 2013; 9 (7): p.453-65.