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Nandakumar
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
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.
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.
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.
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.
| 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 |
|
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 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 |
||
ARUP Laboratory Tests
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Quantitative Enzymatic Assay
Semi-Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)/Semi-Quantitative Indirect Fluorescent Antibody (IFA)
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
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot
Semi-Quantitative Indirect Fluorescent Antibody
Semi-Quantitative Indirect Fluorescent Antibody (IFA)
Quantitative Immunoturbidimetry
References
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Components: albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total