Primary Sclerosing Cholangitis – PSC

Primary sclerosing cholangitis (PSC) is a progressive autoimmune liver disease (ALD) that often leads to cirrhosis and may eventually require liver transplantation.  There is a strong association between PSC and inflammatory bowel disease (IBD), and the two conditions often occur together.  Many patients are diagnosed incidentally due to abnormal liver biochemistry or after an IBD diagnosis and subsequent biochemical screening suggestive of PSC.  Because of this, many patients are asymptomatic at diagnosis. Symptoms, when present, include pruritus, fatigue, jaundice, and gastrointestinal bleeding.  Laboratory testing and liver biopsy may assist in diagnosis; however, there are no autoantibodies or liver biochemistry profiles that are specific to PSC.   Magnetic resonance cholangiopancreatography (MRCP) is the primary method of diagnosis for PSC, although diagnosis also involves exclusion of other causes of liver disease (eg, toxic or infectious etiologies).  

Quick Answers for Clinicians

Which other diagnoses should be considered alongside primary sclerosing cholangitis?

Primary sclerosing cholangitis (PSC) is a diagnosis of exclusion and thus should only be diagnosed when other potential toxic, infectious, or inflammatory causes of the characteristic bile duct injury pattern are not present.  Causes of secondary sclerosing cholangitis (eg, previous biliary surgery and cholangiolithiasis) should be ruled out.  

Other potential diagnoses include primary biliary cholangitis (PBC), immunoglobulin G4 (IgG4)-related cholangitis, cholangiocarcinoma, HIV cholangiopathy, and autoimmune hepatitis (AIH).   These potential diagnoses should be evaluated during the diagnostic workup.  

What is the role of biopsy in a workup for primary sclerosing cholangitis?

Liver biopsies are rarely recommended for the diagnosis of primary sclerosing cholangitis (PSC).   However, a liver biopsy should be considered when the diagnosis or treatment might be altered by histopathologic results.  A liver biopsy is necessary to diagnose small-duct PSC and should be performed in patients with normal imaging results who have unexplained cholestatic liver tests.   A liver biopsy should also be performed if a PSC-autoimmune hepatitis (AIH) variant form or immunoglobulin G4 (IgG4)-related sclerosing cholangitis is suspected.   

The characteristic histologic feature of PSC is concentric periductal “onion skin” fibrosis, but this pattern is not often seen, and the results of the liver biopsy are usually interpreted as “compatible” with PSC. 

What is the significance of the association between primary sclerosing cholangitis and inflammatory bowel disease?

Approximately 80% of patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC).   The prevalence of PSC among patients with IBD is about 5%.  Most often, the IBD diagnosis precedes the PSC diagnosis, although IBD may also appear years after an initial diagnosis of PSC.  The pathophysiology linking the two disorders is unclear, but it is most likely influenced by altered gut microbiota, genetic predisposition, and immune-mediated processes.  Perinuclear antineutrophil cytoplasmic antibodies (pANCAs) are detected in both patients with PSC and in patients with UC.

The presence and severity of IBD does not appear to be associated with long-term outcomes of PSC, including the need for liver transplantation and likelihood of PSC recurrence after transplantation.  However, concomitant IBD is associated with a higher risk of rejection posttransplant.  

Because of the frequent overlap between the diseases, patients with a diagnosis of IBD should be screened for liver disease annually,  and patients with PSC should be screened for IBD at diagnosis and every 3-5 years thereafter.  PSC with concomitant IBD is associated with certain premalignancies and malignancies (eg, colorectal dysplasia, colorectal cancer [CRC], cholangiocarcinoma [CCA]), and patients with PSC-IBD should be routinely screened for these cancers.   For more information, see Screening for Related Disorders.

What algorithms are associated with this topic?

Indications for Testing

PSC should be considered in patients with elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT), symptoms of liver disease (eg, jaundice, pruritus, cholangitis), variceal bleeding, or cholangiocarcinoma (CCA). 

Laboratory Testing

Diagnosis

Liver Biochemistry Tests

Although there is no specific biochemical profile for PSC,  liver biochemistry is abnormal in 75% of patients with PSC, and a biochemical profile may be useful in the diagnostic process.  The table below lists results for several biomarkers that may assist in either diagnosing or ruling out PSC.

Serum Biomarkers in PSC
Biomarker Diagnostic Significance

ALP

Elevated ALP is the most common biomarker

Sensitive, but unspecific

GGT Generally high
Bilirubin Generally normal at diagnosis
Albumin Generally normal at diagnosis
AST

Often slightly elevated

Not necessarily indicative of AIH or PSC-AIH variant form

Immunoglobulins

Hypergammaglobulinemia is not common in PSC

IgM levels are elevated in approximately 50% of patients

AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IgM, immunoglobulin M

Source: BSG 2019 ; ACG 2015 

Autoantibody Tests

In certain studies, autoantibodies have been found in more than 50% of patients with PSC; however, due to a lack of specific autoantibodies associated with PSC, they play only a minor role in diagnosis.   Smooth muscle antibodies (SMAs), antinuclear antibodies (ANAs), and perinuclear antineutrophil cytoplasmic antibodies (pANCAs) are often detected in patients with PSC  ; however, these antibodies are also commonly found in other ALDs (ie, primary biliary cholangitis [PBC] or AIH).  

Because antimitochondrial antibodies (AMAs) are a hallmark of PBC but are absent in PSC, AMA testing may be useful to differentiate between the two ALDs. 

For more information on the use of autoantibodies in the diagnosis of PSC and other ALDs, see the Autoimmune Liver Disease Testing algorithm.

Prognosis

Although there are no established prognostic tools for PSC,  a patient’s biochemical profile at the time of diagnosis may inform prognosis.  Elevated serum bilirubin is a marker of poor prognosis.  An increased AST:ALT ratio may be an indicator of cirrhosis and poor prognosis; other indications of cirrhosis include elevated prothrombin time, low albumin, and low platelets.  A serum ALP of <1.5 times the upper limit of normal (ULN) has been associated with improved survival, whereas a serum ALP of ≥2.4 times the ULN has been associated with a higher likelihood of death or liver transplantation. 

An increased serum immunoglobulin G4 (IgG4) may correlate with a more severe disease course.  Approximately 10% of patients present with elevated serum IgG4, and these patients tend to have a more aggressive disease course with no treatment.  However, it is not certain whether elevated IgG4 levels indicate a distinct subset of PSC or misdiagnosed cases of IgG4 sclerosing cholangitis. 

Various prognostic models for PSC have been devised. The most commonly used model is the revised Mayo natural history model for PSC, which uses age, bilirubin level, albumin level, AST level, and history of variceal bleeding to predict a patient’s probability of survival.   

Monitoring

Liver biochemistry should be assessed every 3-4 months in patients with PSC with the aim of identifying signs of strictures, tumors, or AIH.  An MRCP should be performed if any changes or additional symptoms are observed. 

Screening for Related Disorders

Regular screening should be performed for other disorders commonly associated with PSC. Bone mineral density screening should be performed every 2-4 years, and in cases of advanced disease, patients should be monitored for fat-soluble vitamin deficiencies.  Because of the high prevalence of IBD in patients with PSC, patients should undergo a full colonoscopy with biopsies at the time of diagnosis to screen for associated IBD.   In patients without IBD at the time of diagnosis, screening should be repeated every 3-5 years. 

Patients with PSC have a higher likelihood of developing several different types of cancer, so regular cancer screenings are an important part of managing PSC.  

Cancer Surveillance in PSC
Cancer Type Tests Used Frequency
Cholangiocarcinoma US, MRCP, ERCP, serum CA 19-9 (optional) Every 6-12 mos
CRC Colonoscopy Every 1-2 yrs in patients with concurrent IBD
Gallbladder polyps and cancer US Every 12 mos
Hepatocellular carcinoma US, CT, or MRI, serum AFP (optional) Every 6 mos, if advanced liver fibrosis or cirrhosis is present

AFP, alpha fetoprotein; CA, cancer antigen; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRI, magnetic resonance imaging; US, ultrasound

Source: Gochanour, 2020 

ARUP Laboratory Tests

Liver Biochemistry Tests

Initial screening for hepatobiliary inflammation

ALP, AST, and ALT may assist in diagnosis of PSC

ALP, bilirubin, and albumin may assist in prognosis in PSC

Components: albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total

May assist in diagnosis of PSC

Autoantibody Tests

Recommended first-line panel for the evaluation of ALD

Components: AMA, IgG; liver-kidney microsome-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG; SMA, IgG titer; soluble liver antigen antibody, IgG; ANA with HEp-2 substrate, IgG

Use to detect ANA

May assist in diagnosis of PSC

Use to detect SMA

May assist in diagnosis of PSC

Use to detect pANCAs

May assist in diagnosis of PSC

Immunoglobulin Test

Use to detect IgG4 antibodies

May assist in prognosis in PSC

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