Approach

Initial clinical manifestations are variable, ranging from lack of symptoms to complications of end-stage liver disease. An increasing proportion are identified through work-up of asymptomatic elevated liver enzymes detected on routine laboratory testing.[5][6] Diagnosis is based on a combination of clinical features, cholestatic liver tests, cholangiographic findings, and histological findings. However, it is often delayed from the time of presentation due to subtle symptoms and an insidious course.

Diagnosis requires exclusion of secondary sclerosing cholangitis (other conditions that may cause bile duct abnormalities and similar clinical and cholangiographic syndromes, e.g., surgical trauma to the bile duct, choledocholithiasis, recurrent pancreatitis, caustic injury from intra-arterial chemotherapy, or malignancy).[25]

Sudden and marked deterioration in clinical status or biochemical tests may indicate the presence of complications such as dominant/relevant stricture or cholangiocarcinoma.

Patients with advanced liver disease or cirrhosis should be referred to a liver transplantation centre for evaluation and management.

Historical factors

About half of patients are asymptomatic.[4] Common presenting symptoms include fatigue, upper abdominal pain, and pruritus. Fatigue is very non-specific but may be present at the time of diagnosis.[5][11] Abdominal pain is usually non-specific and located in the right upper quadrant or epigastrium.[5][8][11] Pruritus is usually generalised and intermittent, although it can also be severe and interfere with sleep and daily activities. Patients with liver disease may also complain of yellowing skin; pale, offensive-smelling stools that are difficult to flush; blood in vomit; confusion; and an increased abdominal girth.

Past medical history may reveal inflammatory bowel disease (typically ulcerative colitis but also Crohn's disease), with estimates indicating its presence in 50% to more than 80% of patients - it is estimated that 0.6% to 4.3% of patients with inflammatory bowel disease have PSC.[2][3][9][13] Inflammatory bowel disease may develop before or after PSC, and is frequently characterised by pancolitis with rectal sparing and backwash ileitis.[6][11][24]

Physical examination

Presenting signs may include excoriations (from pruritus), weight loss (from fat malabsorption, active inflammatory bowel disease, and/or advanced liver disease), jaundice, splenomegaly, ascites, encephalopathy, oesophageal variceal bleeding, and/or fever (from episodic bacterial cholangitis).

Routine laboratory testing

Although laboratory tests are not diagnostic of PSC, abnormalities (particularly elevated serum alkaline phosphatase) may suggest or support the diagnosis.

Liver function tests

  • Required for all patients presenting with the above symptoms and in patients with a history of inflammatory bowel disease, even if they are asymptomatic.

  • About 75% of patients demonstrate a cholestatic pattern.[3]

  • Serum alkaline phosphatase is derived from liver and bone and is elevated in the majority of patients with PSC, although it can be normal in up to 8.5% of patients, and is more often normal in children.[26][27] Elevated alkaline phosphatase is accompanied by elevated serum gamma-GT level in liver disorders. An elevated serum alkaline phosphatase with a normal gamma-GT should prompt evaluation for bone diseases.

  • Most patients have mild to moderate elevation in serum aminotransferase levels (typically 2-3 times the upper limit of normal). Predominant aminotransferase levels, or levels more than 5 times the upper limit of normal, may suggest overlapping autoimmune hepatitis, but precise criteria for PSC-autoimmune hepatitis overlap are not available.[3]

  • Bilirubin levels fluctuate in the early stages of disease and are more commonly persistently elevated in advanced disease.

  • Albumin and prothrombin times are usually within normal ranges because the majority of patients have intact liver synthetic function at the time of diagnosis (although albumin may be low due to concomitant active inflammatory bowel disease, and low in advanced liver disease).

  • Thrombocytopenia (platelet count <150,000 mm³) on FBC indicates advanced liver disease.[28]

Additional laboratory testing

Auto-antibodies

  • There are no auto-antibodies specific to (or diagnostic of) PSC. Serum autoantibodies should not, therefore, be routinely tested for in patients with possible PSC for diagnostic or risk-stratification purposes.[2]

  • Autoantibody testing may be appropriate when the following are considerations:

    • primary biliary cholangitis (antimitochondrial antibody is nearly always present in patients with primary biliary cholangitis, and is notably absent in patients with PSC)

    • PSC-autoimmune hepatitis overlap syndrome (anti-nuclear antibody [ANA] and anti-smooth muscle antibody).

  • The clinical significance of auto-antibodies that may be present in patients with PSC (e.g., atypical antineutrophil cytoplasmic auto-antibody (ANCA), ANA, anti-smooth muscle antibody, rheumatoid factor) is unclear.

  • ANA and anti-smooth muscle antibody are present in 8% to 77% and 0% to 83%, respectively, of patients with PSC.[16]

  • Presence of serum auto-antibodies should not exclude a diagnosis of PSC (or suggest an alternative diagnosis) in a patient whose clinical picture is otherwise consistent with PSC.

Immunoglobulins

  • Usually performed in patients with a clinical history and abnormal liver tests suggestive of autoimmune hepatitis or primary biliary cholangitis.

  • Not an essential part of laboratory evaluation for PSC, but if IgG or IgM is elevated and clinical suspicion is high, PSC should not be ruled out.

  • Elevated IgG is, however, more commonly associated with autoimmune hepatitis and elevated IgM is more commonly associated with primary biliary cholangitis.[29]

  • Elevated levels of IgG4 have been associated with a multi-organ lymphoplasmocytic sclerosing disease that can include a sclerosing cholangitis. IgG4-associated cholangitis is often associated with autoimmune pancreatitis and responds readily to corticosteroid immunosuppression. Up to 15% of patients with PSC have elevated IgG4 serum levels.[2][3] A diagnosis of IgG4-associated sclerosing cholangitis is suggested by an IgG4 >5.6 g/L, whereas it can be excluded by a serum IgG4 of 1.4 to 2.8 g/L in combination with a IgG4/IgG1 ratio of <0.24.[2][3] US guidance recommends testing all patients with possible PSC for IgG4, whereas European guidelines recommend determining serum IgG4 levels in all adults with large-duct PSC at the time of diagnosis.[2][3][30]

Copper

  • Urine copper levels are usually measured in patients with a clinical history and abnormal liver tests suggestive of Wilson's disease.

  • Not a routine part of laboratory evaluation of PSC, but as elevated levels can be seen in patients with any form of cholestatic liver disease, PSC should not be excluded if levels are elevated.

Ceruloplasmin

  • If urine copper is elevated, ceruloplasmin level may be helpful in differentiating PSC and Wilson's disease.

  • Ceruloplasmin has been reported to be high in patients with PSC, but is typically low in patients with Wilson's disease.

Imaging

Imaging of the biliary tree is essential for establishing diagnosis.

Abdominal ultrasound

  • Non-invasive initial test to investigate for abnormal (dilated) bile ducts and stones, and may also provide evidence of more advanced liver disease.[2]

  • Does not provide adequate evaluation of the biliary tree for diagnosis or exclusion of PSC.

Computed tomography (CT)

  • Abdominal CT scanning may reveal bile duct thickening, focal or saccular intrahepatic duct dilation, and lymphadenopathy. Mass lesions suggestive of cholangiocarcinoma may also be identified.[31][32][33]

  • CT scans are useful in patients with recurrent symptoms or laboratory findings indicating worsening disease suggestive of possible cholangiocarcinoma.

Cholangiography

  • Both magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) can establish a diagnosis and provide information on the distribution and extent of disease.

  • MRCP is the preferred diagnostic test for suspected PSC in adults and children.[2][3][34] MRCP is non-invasive; has comparable performance to ERCP, with high sensitivity and specificity for diagnosis; and is not associated with risk of pancreatitis, bleeding, cholangitis, or perforation.[30][35][36] MRCP can also be used to investigate the features of autoimmune hepatitis in children with PSC and to look for PSC in children with autoimmune hepatitis.[2] ERCP should be avoided for the diagnosis of PSC.[3]

  • A 3D magnetic resonance imaging (MRI) MRCP with T1- and T2-weighted axial images and contrast enhancement should be obtained.[3]

  • The characteristic cholangiographic features of PSC are minor ductal irregularities, decreased branching or narrowing of the intrahepatic biliary tree, and multi-focal stricturing of the intra- and extrahepatic bile ducts with areas of both normal calibre and dilated bile ducts, resulting in a 'beaded' appearance. However, decreased branching or 'diminution' of the intrahepatic biliary tree may also be present in patients with cirrhosis of any cause.[37][Figure caption and citation for the preceding image starts]: Typical endoscopic retrograde cholangiopancreatography findings in a patient with PSC: multi-focal strictures of the intra- and extrahepatic bile ductsDr Kris Kowdley's collection [Citation ends].com.bmj.content.model.Caption@4df71774[Figure caption and citation for the preceding image starts]: Normal endoscopic retrograde cholangiopancreatographyDr Michael Saunders' collection [Citation ends].com.bmj.content.model.Caption@48688ccb[Figure caption and citation for the preceding image starts]: Normal cholangiogram-pancreatogramDr Michael Saunders' collection [Citation ends].com.bmj.content.model.Caption@bc7b898

  • ERCP is indicated when MRCP is non-diagnostic or when therapeutic intervention is anticipated (e.g., brush cytology to evaluate for co-existing malignancy, extraction of bile duct stones, and dilation of prominent bile duct strictures).[2][3][30][35][36] Therapeutic ERCP should also be performed in patients with PSC if they have bacterial cholangitis that does not respond adequately to antibiotics.[2][3]

  • By definition, ‘dominant stricture’ is a stenosis with a diameter of ≤1.5 mm in the common bile duct or with a diameter of ≤1 mm in the hepatic duct by ERCP. The term ‘dominant stricture’ is used only with ERCP and not with MRI/MRCP, as MRI/MRCP has suboptimal spatial resolution. Common bile duct and hepatic duct strictures observed on MRI are termed ‘high-grade’ or ‘severe’ strictures.[2][3]

  • The term ‘relevant stricture’ is used to describe strictures of clinical relevance not meeting the ‘dominant’ and ‘high-grade’ criteria. The European Association for the Study of the Liver (EASL) defines ‘relevant stricture’ as a high-grade biliary stricture on imaging in the common bile duct or hepatic ducts with signs or symptoms of obstructive cholestasis and/or bacterial cholangitis (where a high-grade stricture is a biliary stricture on MRI/MRCP with >75% reduction of duct diameter in the common bile duct or hepatic ducts).[2] The American Association for the Study of Liver Diseases (AASLD) defines ‘relevant stricture’ as any biliary stricture of the common bile duct or hepatic duct associated with signs or symptoms of obstructive cholestasis and/or bacterial cholangitis.[3]

Bone mineral density scan

  • Bone mineral density scanning using dual energy x-ray absorptiometry (DEXA) is suggested in all patients at diagnosis and at 2- to 3- or 4-year intervals (based on risk factors) to detect osteoporosis.[2][3][30][34][38][39]

Colonoscopy

  • Patients newly diagnosed with PSC should undergo ileocolonoscopy with biopsies regardless of whether or not they already have a diagnosis of inflammatory bowel disease.

  • Ileocolonoscopy should be repeated (US guidance) or can be considered (European guidelines) every 5 years if inflammatory bowel disease is not present or whenever the patient has symptoms suggestive of inflammatory bowel disease.[2][3]

  • From the age of 15 years, all patients with co-existing inflammatory bowel disease should undergo high-definition surveillance colonoscopy regularly due to a high risk of colorectal cancer. US guidance suggests 1- to 2-year surveillance intervals, whereas European guidelines recommend surveillance annually, with 1- to 2-year intervals if there is no inflammatory activity.[2][3][30][34][40]​​​​

Staging of fibrosis

The AASLD suggests using imaging-based non-invasive testing to detect advanced fibrosis and cirrhosis in adults with PSC.[41]​ Either transient elastography or magnetic resonance elastography is recommended to stage fibrosis.[3][41]​ The AASLD advises against using imaging-based tests as standalone tests to assess regression or progression of liver fibrosis.[41]​​

Histology

Liver biopsy may support the diagnosis of PSC but is rarely diagnostic and is not necessary if clinical, laboratory, and radiographic findings already suggest PSC. There is evidence to suggest that liver biopsy in patients with cholangiographically diagnosed PSC adds new information or affects management in only 1.3% of patients.[42] However, liver biopsy should be considered (US guidance) and is recommended (European guidelines) to diagnose small-duct PSC (which should be suspected with, and is characterised by, laboratory and histological findings typical for PSC but with normal cholangiogram, especially in the presence of inflammatory bowel disease) or to evaluate for alternative or overlapping disorders, such as PSC-autoimmune hepatitis.[2][3]​​[34]​​​ Liver biopsy is also useful for staging disease (primarily for detecting cirrhosis, if not clinically apparent).[30]

The pathognomonic histological feature of PSC is fibro-obliterative cholangitis, which is found in <12% of patients with PSC who undergo liver biopsy.[43] Other histological findings are non-specific and include: periductal fibrosis and inflammation, absence of bile ducts in some portal tracts (referred to as focal ductopenia), and ductal proliferation in other portal tracts.[44]

During interventional procedures accessing the biliary tract, brush cytology should be performed to rule out cholangiocarcinoma, although yields are notably as low as 18%.[45] Diagnosis of cholangiocarcinoma remains difficult, and work-up should include tumour markers such as CA 19-9, imaging, and fluorescence in situ hybridisation (FISH) analysis of intraductal tissue samples obtained during ERCP.[2][3]​​[30][46]​​​

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