Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is an inflammatory disease that causes fibrosis and strictures of the bile ducts. The exact etiology is unknown, but there is a strong association with inflammatory bowel disease (IBD). Patients typically present with an insidious onset of fatigue, pruritus, and jaundice, which can progress to cirrhosis and complications related to biliary obstruction. The diagnosis is established with magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). Liver transplantation is the only definitive treatment and is indicated in patients with advanced liver disease.

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Overview

Epidemiology

  • Prevalence is approximately 6.3 cases per 100,000
  • Higher rate in Scandinavian countries
  • 70% of patients are men.
  • Age at diagnosis is around 30–50 years.
  • Predominantly seen in non-smokers

Etiology

The cause of primary sclerosing cholangitis (PSC) is unknown, but the disease is associated with:

  • Inflammatory bowel disease (IBD):
    • Approximately 80% of patients
    • Ulcerative colitis > Crohn’s disease
  • Genetic predisposition:
    • HLA-B8
    • HLA-DR3

Pathophysiology

  • Environmental insult in susceptible individuals → cholangiocyte activation → cytokine production → perpetual inflammatory response
  • Chronic periductal inflammation leads to:
    • Cholangiocyte damage → peribiliary gland proliferation (accessory glands containing biliary stem cells) 
    • Portal myofibroblast activation → periductal fibrosis (“onion skin”) → biliary strictures and interlobular duct loss
    • Hepatic stellate cell activation → hepatic fibrosis → cirrhosis
    • Potential malignant transformation of cholangiocytes
Pathophysio of primary sclerosing cholangitis

Progression of cholangiocyte activation, inflammation, and fibrosis in PSC. This starts with a predisposed phenotype, and may be triggered by a stressor.

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Clinical Presentation

Though many patients are asymptomatic, others may present with:

  • Insidious onset of:
    • Fatigue
    • Pruritus
    • Jaundice (later in the course)
  • Later development of:
    • Hepatomegaly
    • Splenomegaly 
    • Cirrhosis
  • Evidence of biliary obstruction (approximately 75% of patients):
    • Acute cholangitis (15%–20% of patients):
      • Fever 
      • Right upper quadrant abdominal pain 
    • Gallstones
    • Choledocholithiasis
  • Associated IBD:
    • Chronic diarrhea
    • Colicky abdominal pain
    • Tenesmus
Psc symptoms and related diseases

Common presentations in PSC are fatigue, pruritis, jaundice, and cirrhosis. Patients may have concurrent IBD, and PSC is associated with an increased risk of cholangiocarcinoma.

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Diagnosis

  • Laboratory testing: 
    • Usually the 1st step in the workup
    • Evidence of cholestasis:
      • ↑ Alkaline phosphatase
      • ↑ Gamma-glutamyl transferase (GGT)
      • ↑ Conjugated bilirubin
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may be slightly ↑ (typically < 300 IU/L).
    • Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) are positive in about 75% of cases.
    • Antimitochondrial antibodies (AMAs) are negative.
    • Immunoglobulin M (IgM) levels may be ↑.
  • Magnetic resonance cholangiopancreatography (MRCP):
    • Investigation of choice
    • Findings:
      • Stricturing and dilation of intrahepatic and/or extrahepatic bile ducts
      • Appears as “beading” (diagnostic for PSC)
  • Endoscopic retrograde cholangiopancreatography (ERCP): 
    • 2nd choice for diagnosis in patients who cannot undergo MRCP (patients with implanted devices, such as a pacemaker)
    • Similar findings to MRCP
  • Ultrasonography (US):
    • Not diagnostic
    • Usually performed during the initial workup to exclude biliary obstruction
    • Thickening of the wall of the common bile and hepatic ducts are potential findings.
  • Liver biopsy:
    • Rarely required for the diagnosis
    • Will show:
      • Peribiliary duct proliferation
      • Periductal fibrosis (“onion skin”)
      • Inflammation
      • Loss of bile ducts
      • Potential biliary cirrhosis

Complications and Management

Complications

Primary sclerosing cholangitis is a progressive and chronic disease that causes inflammation in the bile ducts, which can lead to several complications:

  • Biliary cirrhosis → portal hypertension:
    • Varices
    • Ascites
    • Hepatic encephalopathy
  • Incidence of malignancy:
    • Cholangiocarcinoma 
    • Colorectal adenocarcinoma
    • Gallbladder cancer
    • Hepatocellular carcinoma
  • Cholelithiasis, choledocholithiasis, and acute cholangitis
  • Fat-soluble vitamin deficiencies (A, D, E, K):
    • Rare, generally seen in advanced disease
    • Due to ↓ secretion of conjugated bile acids
  • Osteopenia or osteoporosis: Mechanism is unclear.

Management

  • Medical management:
    • Ursodeoxycholic acid:
      • May slow progression of the disease and delay transplantation
      • Does not improve survival
      • Still under investigation
    • Other immunosuppressive and anti-inflammatory agents have not shown a benefit.
  • ERCP:
    • Duct dilation and stenting for biliary strictures
    • Screening for cholangiocarcinoma
  • Liver transplantation: 
    • The only definitive treatment
    • Indications:
      • Recurrent acute cholangitis
      • End-stage liver disease complications (intractable ascites, hepatic encephalopathy, esophageal varices)
  • Cancer screening:
    • Gallbladder cancer and cholangiocarcinoma:
      • Serial imaging (US, abdominal computed tomography (CT), or MRCP) every 6–12 months
      • Periodic cancer antigen 19-9 (CA 19-9)
    • Colorectal cancer:
      • Colonoscopy with biopsy at the time of diagnosis, and annually for patients with IBD
    • Hepatocellular carcinoma:
      • Performed in patients with cirrhosis
      • Abdominal US and alpha-fetoprotein (AFP) every 6 months
  • General health maintenance:
    • Screening and treatment for osteoporosis
    • Screening and supplementation for fat-soluble vitamin deficiencies in advanced disease

Prognosis

  • Median survival (without liver transplantation) is 10–12 years.
  • Prognosis is worse in patients with concurrent IBD.

Differential Diagnosis

Primary sclerosing cholangitis should be differentiated from primary biliary cholangitis (PBC), because the 2 conditions are similar in presentation:

Table: Primary sclerosing cholangitis compared to primary biliary cholangitis
PBC PSC
Predominantly women Predominantly men
Associated with autoimmune diseases Associated with IBD
Intrahepatic involvement only Intra- and extrahepatic involvement
Absence of bile duct narrowing on MRCP MRCP shows narrowing and dilation of bile ducts.
AMA positive in 95% of cases.
  • P-ANCA in up to 80% of cases
  • AMA negative
IBD: inflammatory bowel disease
MRCP: magnetic resonance cholangiopancreatography
P-ANCA: perinuclear anti-neutrophil cytoplasmic antibodies
AMA: antimitochondrial antibody
  • PBC: autoimmune destruction of the intrahepatic bile ducts. Patients are typically women, and may present with pruritus, fatigue, and evidence of cholestasis or cirrhosis. Diagnosis is made with elevated liver enzymes, AMAs, and liver biopsy, which will differentiate PBC from PSC. Management includes ursodeoxycholic acid, vitamin supplementation, and liver transplantation for advanced disease.
  • Bile duct obstruction: an obstruction of the biliary system that may be due to gallstones, malignancy, or trauma. Patients present with acute jaundice and right upper abdominal pain. Diagnosis will show elevated liver enzymes, and imaging (US or MRCP) will differentiate bile duct obstruction from PSC. Treatment is based on the etiology. 
  • Autoimmune hepatitis: an autoimmune disease causing chronic inflammation of the liver. The clinical presentation ranges from asymptomatic, to symptoms of acute liver failure. Serum anti-smooth muscle antibodies and liver biopsy will determine the diagnosis and differentiate autoimmune hepatitis from PSC. Treatment is with corticosteroids and azathioprine. With early treatment, the prognosis is favorable.
  • Acute cholangitis: a life-threatening condition characterized by fever, jaundice, and abdominal pain that develops as a result of stasis and infection of the biliary tract. Biliary strictures from PSC may precipitate acute cholangitis. The diagnosis is confirmed with elevated liver tests, leukocytosis, and an US showing dilation of the common bile duct or gallstones. Treatment includes hemodynamic stabilization, broad-spectrum antibiotics, urgent biliary drainage, and cholecystectomy to prevent recurrence.

References

  1. Longo, D.L., Fauci, A.S., Kasper, D.L., Hauser, S.L., Jameson, J., & Loscalzo, J. (Eds.) (2018). Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill. 2060-2062. 
  2. Kowdley, K. (2020). Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis. UpToDate. Retrieved November 10, 2020, from: https://www.uptodate.com/contents/primary-sclerosing-cholangitis-in-adults-clinical-manifestations-and-diagnosis
  3. Kowdley, K.V. (2020). Primary sclerosing cholangitis in adults: Management. In Grover, S. (Ed.), Uptodate. Retrieved December 5, 2020, from https://www.uptodate.com/contents/primary-sclerosing-cholangitis-in-adults-management
  4. Mendes, F., & Lindor, K.D. (2010). Primary sclerosing cholangitis: overview and update. Nat Rev Gastroenterol Hepatol. Nov; 7(11):611-9. 
  5. Lindor, K.D., Kowdley, K.V., & Harrison, M.E. (2015). American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol; 110:646.
  6. Khurana, V., Singh, T., & Roy, P.K. (2019). Primary sclerosing cholangitis. In Kapoor, V.K. (Ed.), Medscape. Retrieved December 5, 2020, from https://emedicine.medscape.com/article/187724-overview
  7. Lindenmeyer, C.C. (2020). Primary sclerosing cholangitis (PSC). [online] MSD Manual Professional Version. Retrieved December 5, 2020, from https://www.msdmanuals.com/professional/hepatic-and-biliary-disorders/gallbladder-and-bile-duct-disorders/primary-sclerosing-cholangitis-psc

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