I. What every physician needs to know.
Primary sclerosing cholangitis (PSC) is a disorder of unknown etiology, likely autoimmune, which affects the biliary tree. It is characterized by progressive inflammation and sclerosis of the intra- and extrahepatic bile ducts. It is most commonly seen in association with inflammatory bowel disease (IBD), with ulcerative colitis being more closely associated than Crohn’s disease. Over time, bile duct strictures lead to cholestasis, recurrent biliary infections, and cirrhosis. These complications may ultimately necessitate liver transplantation.
II. Diagnostic Confirmation: Are you sure your patient has sclerosing cholangitis?
Patients with sclerosing cholangitis are most often asymptomatic at presentation and are identified on the basis of abnormal liver chemistry tests. Most commonly, patients present with elevations in alkaline phosphatase.
Diagnosis is based on both laboratory and imaging findings. Liver chemistries will show a cholestatic pattern of liver injury with elevated serum alkaline phosphatase, and serum aminotransferase levels usually less than 3 times the upper limit of normal. Bilirubin is often normal except in advanced stages of the disease. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) will show evidence of multifocal stricturing, along with intervening normal or dilated intrahepatic or extrahepatic bile ducts. This pattern is often termed the “beads on string” pattern.
A. History Part I: Pattern Recognition:
Patients with sclerosing cholangitis are most often asymptomatic. When they do present with symptoms, the most common are right upper quadrant abdominal pain, pruritus, and fatigue. Jaundice is rare except in late stages or in the presence of superimposed bacterial cholangitis.
B. History Part 2: Prevalence:
Sclerosing cholangitis is most closely associated with inflammatory bowel disease, particularly ulcerative colitis. It affects men more than women and presents most often in the 4th-5th decades of life. There may also be an overlap between primary sclerosing cholangitis and autoimmune hepatitis.
C. History Part 3: Competing diagnoses that can mimic sclerosing cholangitis.
The differential diagnosis of primary sclerosing cholangitis includes other etiologies of obstructive and cholestatic liver disease and bile duct injury.
1. Secondary sclerosing cholangitis: Chronic bile duct injury from recurrent biliary stone disease, surgical trauma to the biliary tree, recurrent pancreatitis, radiation, intra-aterial chemotherapy, and biliary ischemia can lead to radiographic and biochemical findings identical to primary sclerosing cholangitis.
2. Autoimmune pancreatitis: Autoimmune pancreatitis, leading to chronic pancreatitis, can be seen in association IgG-4 associated autoimmune cholangiopathy. In IgG4 mediated cholangiopathy, biliary strictures with obstructive jaundice and cholestatic liver chemistries similar to PSC can be seen. IgG-4 concentrations are elevated in >90% of cases, and unlike PSC, this form of sclerosing cholangitis, with or without pancreatitis, tends to be steroid-responsive.
3. Primary sclerosing cholangitis-autoimmune hepatitis (AIH-PSC) overlap syndrome: This entity has the characteristic imaging findings and liver chemistries of PSC, but with serologic features of autoimmune hepatitis. The liver biochemistry abnormalities in this condition respond well to immune suppressive regimens targeted towards autoimmune hepatitis.
4. Small duct primary sclerosing cholangitis: This is defined by the presence of liver chemistries consistent with primary sclerosing cholangitis (PSC), but without the characteristic findings of bile duct stricturing and dilatation of the intra and/or extrahepatic bile ducts on cholangiogram.
5. Acquired immunodeficiency syndrome (AIDS) cholangiopathy: This is distinguished from primary sclerosing cholangitis by the presence of HIV and the clinical syndrome of AIDS. Stricturing and dilation of the intra- and extrahepatic bile ducts can be seen in both conditions and can look identical on ERCP/MRCP. AIDS cholangiopathy has been linked to the following infections: Cryptosporidium, Mycobacterium avium-intracellulare, Cytomegalovirus, Microsporidia, and Isospora.
6. Recurrent bacterial cholangitis: This may have the liver chemistry profile resembling PSC, but with evidence of infection, whereas the majority of PSC patients are asymptomatic at the time of diagnosis. PSC can predispose patients to recurrent bacterial cholangitis, however, making this distinction difficult in some cases. Liver biochemical abnormalities typically improve with antibiotics in patients with pure bacterial cholangitis, unlike PSC alone.
D. Physical Examination Findings.
Physical exam findings for early PSC are non-specific. Progressive biliary obstruction can be associated with jaundice, and progression to cirrhosis can lead to findings of chronic liver disease.
E. What diagnostic tests should be performed?
There are no specific physical exam findings that confirm the diagnosis.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Liver chemistries including direct and total bilirubin, alkaline phosphatase, and aminotransferase levels should be ordered. IgG4 concentration can be helpful to distinguish PSC from IgG4 associated autoimmune cholangiopathy in patients with biliary strictures. Additionally, in patients with suspected cirrhosis, albumin, prothrombin time and serum electrolytes should be checked as a marker of disease severity. If there is concern for an AIH-PSC overlap syndrome, serologies including anti-nuclear antibody, serum immunoglobulins, and anti-smooth muscle or liver-kidney antibodies may be useful. In the absence of biliary structuring, anti-mitochondrial antibodies can differentiate PSC from primary biliary cholangitis (PBC). Serum and urine toxicology to assess for drug-induced liver disease may also be helpful in ruling out alternative diagnoses. In the absence of the AIH-PSC overlap syndrome, there are no particular laboratory tests or autoimmune markers that are specific to PSC.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Right upper quadrant ultrasound can be helpful to establish the presence of biliary dilatation or liver masses which can be associated with biliary obstruction and cholestatic liver chemistries. However, ultrasound can be normal in patients with PSC.
MRCP can be used to assess the biliary tree in a non-invasive manner. However, it is subject to motion artifact and may be limited by patients’ comfort with the MRI machine and body habitus. It also does not afford the ability to intervene should an intervenable lesion be found.
ERCP can be used to make the diagnosis, but is more invasive than MRCP. It carries the risks of cholangitis as well as pancreatitis in addition to the inherent risks of sedation used to perform the procedure. It does afford the opportunity to intervene in the event that the patient has another alternative diagnosis such as a focal extra-hepatic biliary stricture, gallstone, or obstructing mass.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
CT scan: This imaging modality can suggest the presence of biliary obstruction and rule out liver masses. However, it is more expensive than ultrasound and does not yield much additional information. It is less sensitive than MRCP and ERCP for evaluation of the biliary tree.
III. Default Management.
Primary sclerosing cholangitis is a progressive disease for which there are few treatment options available. No drug has yet shown efficacy in slowing disease progression. Management is centered on symptom management, monitoring for complications of infection and progression to end-stage liver disease, and liver transplant once cirrhosis has developed.
A. Immediate management.
There is no immediate management required once the diagnosis is made. Since bacterial cholangitis can complicate PSC, exclusion of this infection by clinical and laboratory means is appropriate depending on the clinical context.
B. Physical Examination Tips to Guide Management.
There are no specific physical examination maneuvers used to guide management. However, assessing for evidence of chronic liver disease and portal hypertension can be helpful in monitoring for decompensated cirrhosis.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
Liver chemistries can be followed to assess for the development of hyperbilirubinemia as this portends a worse prognosis. Additionally, labs for synthetic function can be used to calculate MELD scores in patients with cirrhosis who are awaiting transplant. However, there is no treatment known to be effective in the management of primary sclerosing cholangitis. Ursodeoxycholic acid (UDCA) has been shown to improve liver biochemical parameters, but there are no data that show this leads to an improvement in patient outcomes.
D. Long-term management.
There is no treatment known to be effective in the management of primary sclerosing cholangitis. Patients with cirrhosis and those with recurrent episodes of bacterial cholangitis should be referred for liver transplantation. Clinical trials investigating the role of antimicrobial therapy and synthetic bile acids are ongoing. PSC is associated with an increased risk of gallbladder carcinoma and cholangiocarcinoma. Patients with PSC should be screened for each on a yearly basis.
E. Common Pitfalls and Side-Effects of Management
There is no treatment known to be effective in the management of primary sclerosing cholangitis. Patients should be monitored closely for the presence of bacterial cholangitis.
IV. Management with Co-Morbidities
Since a large percentage of patients with PSC have concurrent IBD, an investigation into the presence of undiagnosed IBD may be indicated based on history, physical, and other laboratory and imaging data.
A. Transitions of Care
Dependent upon stage of liver disease and presence or absence of decompensated cirrhosis. See chapter on cirrhosis for further details.
D. Arranging for Clinic Follow-up
1. When should clinic follow up be arranged and with whom.
Follow-up care should be arranged with a liver specialist. Time period for follow-up should be based on the degree of liver disease and the acuity of the initial presentation to the hospital.
F. Prognosis and Patient Counseling.
PSC is associated with a lifetime risk of developing cholangiocarcinoma of approximately 8-15%, with the highest risk in patients with concurrent inflammatory bowel disease. PSC is associated with an increased risk of colon cancer and gallbladder cancer. The Mayo risk score can be used to determine prognosis in patients with PSC. Hyperbilirubinemia is felt to have a close association with progression to cirrhosis. Despite the presence of multiple prognostic scoring systems, predicting clinical outcomes for individual patients based on these models is imprecise.
IV. What's the Evidence?
Chapman, R, Fevery, J, Kalloo, A. “Diagnosis and management of primary sclerosing cholangitis”. Hepatology. vol. 51. 2010. pp. 660-78.
Mendes, FD, Jorgensen, R, Keach, J, Katzmann, JA, Smyrk, T, Donlinger, J. “Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis”. Am J Gastroenterol. vol. 101. 2006. pp. 2070-2075.
Karlsen, TH, Boberg, KM. “Update on primary sclerosing cholangitis”. J Hepatol. vol. 59. 2013. pp. 571-82.
Tabibian, JH, Weeding, E, Jorgensen, RA, Petz, JL, Keach, JC, Talwalkar, JA, Lindor, KD. “Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis – a pilot study”. Aliment Pharmacol Ther.. vol. 37. 2013. pp. 604-12.
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has sclerosing cholangitis?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic sclerosing cholangitis.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- A. Transitions of Care
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom.
- F. Prognosis and Patient Counseling.