Primary sclerosing cholangitis (PSC) is patchy inflammation, fibrosis, and strictures of the bile ducts that has no known cause. However, 80% of patients with PSC also have inflammatory bowel disease, most often ulcerative colitis. Other associated conditions include connective tissue disorders, autoimmune disorders, and immunodeficiency syndromes, sometimes complicated by opportunistic infections. Fatigue and pruritus develop insidiously and progressively. Diagnosis is by cholangiography (magnetic resonance cholangiopancreatography [MRCP] or endoscopic retrograde cholangiopancreatography [ERCP]). Liver transplantation is indicated for advanced disease.
(See also Overview of Biliary Function.)
PSC is the most common form of sclerosing cholangitis. Most (70%) patients with PSC are men. Mean age at diagnosis is 40 years.
Etiology of Primary Sclerosing Cholangitis
Although the cause is unknown, primary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease, which is present in 70% of patients (1). About 5% of patients with ulcerative colitis and about 1% with Crohn disease develop primary sclerosing cholangitis (PSC). This association and the presence of several autoantibodies (eg, antinuclear antibodies [ANA] and perinuclear antineutrophilic antibodies [pANCA]) suggest immune-mediated mechanisms. T cells appear to be involved in the destruction of the bile ducts, implying disordered cellular immunity. A genetic predisposition is suggested by a tendency for the disorder to develop in multiple family members and a higher frequency in people with HLAB8 and HLADR3, which are often correlated with autoimmune disorders. An unknown trigger (eg, bacterial infection, ischemic duct injury) presumably precipitates development of PSC in genetically predisposed people.
Etiology reference
1. Bowlus CL, Arrivé L, Bergquist A, et al: AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 77(2):659-702, 2023. doi: 10.1002/hep.32771
Symptoms and Signs of Primary Sclerosing Cholangitis
Onset is usually insidious, with progressive fatigue and then pruritus. Up to 40% of patients can present with symptoms including abdominal pain, pruritis, diarrhea, jaundice, fatigue, and fevers (1). Steatorrhea and deficiencies of fat-soluble vitamins can develop. Persistent jaundice harbingers advanced disease. Symptomatic gallstones and choledocholithiasis tend to develop in about 75% of patients (1).
Some patients, asymptomatic until late in the course, first present with hepatosplenomegaly or cirrhosis. Primary sclerosing cholangitis (PSC) tends to slowly and inexorably progress. The terminal phase involves decompensated cirrhosis, portal hypertension, ascites, and liver failure.
Despite the association between PSC and inflammatory bowel disease, the two diseases tend to run separate courses. Ulcerative colitis may appear years before PSC and tends to have a milder course when associated with PSC. Similarly, total colectomy does not change the course of PSC.
The presence of both PSC and inflammatory bowel disease increases the risk of colorectal carcinoma, regardless of whether a liver transplantation has been done for PSC. Cholangiocarcinoma develops in 10 to 15% of patients (2).
Symptoms and signs references
1. Kaplan GG, Laupland KB, Butzner D, et al: The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol 102(5):1042-1049, 2007. doi: 10.1111/j.1572-0241.2007.01103.x
2. Tabibian JH, Ali AH, Lindor KD: Primary sclerosing cholangitis, part 2: Cancer risk, prevention, and surveillance. Gastroenterol Hepatol (NY). 14(7):427-432, 2018. PMID: 30166959
Diagnosis of Primary Sclerosing Cholangitis
Magnetic resonance cholangiopancreatography (MRCP)
Primary sclerosing cholangitis (PSC) is suspected in patients with unexplained abnormalities in liver tests, particularly in those with inflammatory bowel disease. A cholestatic pattern is typical: elevated alkaline phosphatase and gamma-glutamyltransferase (GGT) rather than aminotransferases. Gamma globulin and IgM levels tend to be increased. Antinuclear antibodies and pANCA are usually positive. Antimitochondrial antibody, positive in primary biliary cholangitis, is characteristically negative.
Imaging of the hepatobiliary system begins with ultrasonography to exclude extrahepatic biliary obstruction. Although ultrasonography or CT can show ductal dilation, diagnosis requires cholangiography to show multiple strictures and dilations in the intrahepatic and extrahepatic bile ducts. Cholangiography should begin with magnetic resonance cholangiopancreatography (MRCP). Endoscopic retrograde cholangiopancreatography (ERCP) is usually a 2nd choice because it is invasive. Liver biopsy is usually not required for diagnosis; when done, it shows bile duct proliferation, periductal fibrosis, inflammation, and loss of bile ducts. With disease progression, periductal fibrosis extends from the portal regions and eventually leads to secondary biliary cirrhosis.
Adults with PSC, even in the absence of cirrhosis, should undergo abdominal imaging (ultrasound, abdominal computed tomography, or magnetic resonance imaging/magnetic resonance cholangiopancreatography) every 6 to 12 months to screen for gallbladder cancer and cholangiocarcinoma. Serum levels of carbohydrate antigen (CA) 19-9 should be monitored regularly (1).
Colonoscopy with biopsies should be done in patients without pre-existing inflammatory bowel disease (IBD) at the time of diagnosis of PSC and should be carried out annually in patients with PSC and IBD from the time of diagnosis of PSC due to the increased risk of colorectal adenocarcinoma.
Diagnosis reference
1. Bowlus CL, Lim JK, Lindor KD: AGA Clinical practice update on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis: Expert review. Clin Gastroenterol Hepatol 17(12):2416-2422, 2019. doi: 10.1016/j.cgh.2019.07.011
Treatment of Primary Sclerosing Cholangitis
Supportive care
Endoscopic retrograde cholangiopancreatography (ERCP) dilation for major (dominant) strictures
Transplantation for recurrent bacterial cholangitis or complications of liver failure
Asymptomatic patients usually require only monitoring (eg, physical examination and liver tests twice/year) and, if adults, periodic imaging and measurement of CA 19-9 for gallbladder cancer and cholangiocarcinomaERCP as needed (1). If a single stricture appears to be the major cause of obstruction (a dominant stricture may develop in up to 45% of patients) (2), ERCP dilation (with brush cytology and fluorescence in situ hybridization [FISH] to screen for cholangiocarcinoma) and stenting can relieve symptoms.
Liver transplantation is the only treatment that improves life expectancy in patients with primary sclerosing cholangitis and that offers a cure. Recurrent bacterial cholangitis, complications of end-stage liver disease (eg, intractable ascites, portosystemic encephalopathy, bleeding esophageal varices), or cholangiocarcinoma (in appropriately selected patients) are indications for liver transplantation.
Treatment references
1. Aabakken L, Karlsen TH, Albert J, et al: Role of endoscopy in primary sclerosing cholangitis: European Society of Gastrointestinal Endoscopy (ESGE) and European Association for the Study of the Liver (EASL) Clinical Guideline. Endoscopy 49(6):588-608, 2017. doi: 10.1055/s-0043-107029
2. Bowlus CL, Arrivé L, Bergquist A, et al: AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 77(2):659-702, 2023. doi: 10.1002/hep.32771
Key Points
Most (80%) patients with PSC have IBD, usually ulcerative colitis, and many have autoantibodies.
Suspect PSC if patients, particularly those with inflammatory bowel disease, have an unexplained cholestatic pattern of abnormalities in liver tests.
Exclude extrahepatic biliary obstruction by ultrasonography, then do MRCP (or, as a second choice, ERCP).
Monitor patients with periodic liver testing, screen regularly for gallbladder cancer and cholangiocarcinoma, and treat symptoms and complications (eg, ERCP to evaluate and treat dominant strictures).
Consider liver transplantation if recurrent cholangitis or complications of liver failure develop.
