Diagnosis and Management of Primary Sclerosing Cholangitis

This guideline has been approved by the American Association for the Study of Liver Diseases and represents the position of the Association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recently-published world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).3 The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C). AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; CCA, cholangiocarcinoma; ERC, endoscopic retrograde cholangiography; FISH, fluorescent in situ hybridization; IBD, inflammatory bowel disease; IgG, immunoglobulin G; MRC, magnetic resonance cholangiography; OLT, orthotopic liver transplantation; OR, odds ratio; PET, positron emission tomography; PSC, primary sclerosing cholangitis; SSC, secondary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodeoxycholic acid. Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts,4 leading to the formation of multifocal bile duct strictures. PSC is likely an immune mediated, progressive disorder that eventually develops into cirrhosis, portal hypertension and hepatic decompensation, in the majority of patients.5 Small duct PSC is a disease variant which is characterized by typical cholestatic and histological features of PSC but normal bile ducts on cholangiography.6 PSC overlap syndromes are conditions with diagnostic features of both PSC and other immune mediated liver diseases including autoimmune hepatitis and autoimmune pancreatitis.7 Secondary sclerosing cholangitis (SSC) is characterized by a similar multifocal biliary stricturing process due to identifiable causes such as long-term biliary obstruction, infection, and inflammation which in turn leads to destruction of bile ducts and secondary biliary cirrhosis.8 Immunoglobulin G4 (IgG4)-positive sclerosing cholangitis might represent a separate entity.9 A diagnosis of PSC is made in patients with a cholestatic biochemical profile, when cholangiography (e.g., magnetic resonance cholangiography [MRC], endoscopic retrograde cholangiography [ERC], percutaneous transhepatic cholangiography) shows characteristic bile duct changes with multifocal strictures and segmental dilatations, and secondary causes of sclerosing cholangitis have been excluded.8 Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC.6 Clinical and cholangiographic findings resembling PSC have been described in patients with choledocholithiasis, surgical trauma of the biliary tree, intra-arterial chemotherapy, and recurrent pancreatitis.8 Other conditions reported to mimic PSC are listed in Table 2. Distinguishing primary from SSC may be challenging because PSC patients may have undergone bile duct surgery or have concomitant intraductal stone disease or even cholangiocarcinoma (CCA). The clinical history, distribution of cholangiographic findings, and the presence or absence of inflammatory bowel disease (IBD), have to be taken into consideration when determining if an abnormal cholangiogram is due to PSC or secondary processes.8 The clinical presentation is variable; typical symptoms include right upper quadrant abdominal discomfort, fatigue, pruritus, and weight loss.10 Episodes of cholangitis (i.e., fever and chills) are very uncommon features at presentation, in the absence of prior biliary surgery or instrumentation such as ERC.11 Physical examination is abnormal in approximately half of symptomatic patients at the time of diagnosis; jaundice, hepatomegaly, and splenomegaly are the most frequent abnormal findings. Many patients with PSC are asymptomatic with no physical abnormalities at presentation. The diagnosis is made incidentally when persistently cholestatic liver function tests are investigated. Approximately 60%–80% of patients with PSC have concomitant IBD, most often ulcerative colitis (UC).12 Serum biochemical tests usually indicate cholestasis; elevation of serum alkaline phosphatase is the most common biochemical abnormality in PSC.5, 10, 13 However, a normal alkaline phosphatase activity does not exclude the diagnosis. Serum aminotransferase levels are elevated in the majority of patients (2–3 times upper limits of normal), but like the alkaline phosphatase can also be in the normal range. Serum bilirubin levels are normal at diagnosis in the majority of patients. IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of normal).14 A wide range of autoantibodies can be detected in the serum of patients with PSC indicating an altered state of immune responsiveness or immune regulation.15 Most are present at low prevalence rates and at relatively low titers (Table 3). They have no role in the routine diagnosis of PSC including the perinuclear antineutrophil cytoplasmic antibody which is nonspecific, although it may draw attention to colon involvement in a cholestatic syndrome. Transabdominal ultrasound (US) is usually nondiagnostic and may even be normal, although bile duct wall thickening and/or focal bile duct dilatations are often identified. However, gallbladder abnormalities, including wall thickening, gallbladder enlargement,16 gallstones, cholecystitis, and mass lesions, are identified in up to 41% of patients with PSC who undergo US examinations.17 The findings on computed tomography (CT) cross-sectional or coronal imaging of the upper abdomen are also nonspecific. CT imaging can detect thickening of the bile ducts with contrast enhancement consistent with inflammation, saccular dilatations of the intrahepatic ducts, heterogenous bile duct dilatation, document the presence of portal hypertension (i.e., varices, splenomegaly, and ascites), and identify mass lesions.18-22 It should be noted that lymphadenopathy in the abdomen is common in PSC and should not be over interpreted as metastases or a lymphoproliferative disorder.22 No information exists on the emerging technology of CT cholangiography for the diagnosis or evaluation of PSC. Traditionally, ERC was regarded as the gold standard in diagnosing PSC.23, 24 However, ERC is an invasive procedure associated with potentially serious complications such as pancreatitis and bacterial cholangitis. Indeed, ERC is associated with hospitalization in up to 10% of PSC patients undergoing the procedure25 MRC, which is non-invasive and avoids radiation exposure, has become the diagnostic imaging modality of choice when PSC is suspected. ERC and MRC have comparable diagnostic accuracy, although the visualization of bile ducts may be less than optimal for certain patients with MRC.26 Sensitivity and specificity of MRC is ≥80% and ≥87%, respectively, for the diagnosis of PSC.26, 27 However, it should be noted that that patients with early changes of PSC may be missed by MRC, and ERC still has a useful role in excluding large duct PSC where MRC views may not be optimal. A cholangiographic assessment of the extrahepatic and intrahepatic biliary tree is required to establish a diagnosis of large duct PSC.24 The characteristic cholangiographic findings include multifocal, short, annular strictures alternating with normal or slightly dilated segments producing a "beaded" pattern.23, 24 Long, confluent strictures may also be observed although these are worrisome for the development of superimposed cholangiocarcinoma.23 Both the intra- and extrahepatic bile ducts are usually involved, although a subset of patients (<25%) may only have intrahepatic disease. Conversely, lesions confined to the extrahepatic ducts are quite unusual (usually <5%) and should only be diagnosed in the presence of adequate filling of the intrahepatic ducts. The gallbladder, cystic duct and pancreatic duct may also be involved in PSC patients.23 Liver histological findings maybe compatible with a diagnosis of PSC, but in general the changes at an early stage are non-specific although usually indicating some form of biliary disease. Periductal concentric ("onion-skin") fibrosis is a classic histopathologic finding of PSC, but this observation is infrequent in PSC liver biopsy specimens and may also be observed in SSC. A retrospective study in 138 patients with cholangiographic features of PSC suggested that liver biopsy rarely adds useful diagnostic information.28 In the presence of an abnormal cholangiogram, a liver biopsy is therefore not required to establish a diagnosis of large duct PSC, although is essential in suspected small duct PSC, and for the assessment of possible overlap syndromes. In PSC patients with disproportionately elevated serum aminotransferase values, especially if the antinuclear antigen and/or smooth muscle antigen is positive and/or serum IgG levels are elevated, a liver biopsy may identify features of a PSC–autoimmune hepatitis (AIH) overlap syndrome. PSC-AIH overlap syndrome is a disorder mainly described in children and young adults.29-37 It is characterized by the clinical, biochemical, and histological features of AIH in the presence of cholangiographic findings identical to PSC.38, 39 Diagnosis of an overlap syndrome by use of the modified AIH score was established in 8% of 113 PSC patients from the Netherlands,40 in 1.4% of 211 PSC patients from the United States,41 in 17% of 41 PSC patients from Italy,42 and in 6.1% of 264 patients with AIH from England.37 Autoimmune pancreatitis (AIP) is a clinical entity characterized by stricturing of the pancreatic duct, focal or generalized pancreatic enlargement, a raised serum immunoglobulin G4 (IgG4) level, a lymphoplasmacytic infiltrate on biopsy, and a response to corticosteroid therapy.43 AIP in association with intrahepatic and extrahepatic bile duct stricturing similar to those present in PSC is termed autoimmune pancreatitis–sclerosing cholangitis (AIP-SC). Pancreatic abnormalities are not universally found, suggesting that IgG4-associated cholangitis (IAC) may be a more appropriate term to describe the condition.44 A recent study found an elevated serum IgG4 level (>140 mg/dL) in 9% of a cohort of 127 patients with PSC.45 In comparison to patients with PSC with normal IgG4 concentrations, the former group had significantly higher levels of alkaline phosphatase and bilirubin, in addition to higher PSC Mayo risk scores. An association with IBD was less likely in those with elevated IgG4 levels, although biliary and pancreatic involvement were similar in both groups.45 Whether PSC and AIP represent different ends of the same disease spectrum or are separate clinical entities is of debate, although current evidence favors the latter. In patients with cholestatic biochemical profile, we recommend indirect (MRC) or direct cholangiography (ERCP) for making the diagnosis of PSC (1A). We recommend against routine liver biopsy for the diagnosis of PSC in patients with typical cholangiographic findings (1B). In patients with a normal ERC or MRC, we recommend a liver biopsy to diagnose small duct PSC (1B). In patients with disproportionately elevated aminotransferases, we recommend performing a liver biopsy to diagnose or exclude overlap syndrome (1B). In all patients with possible PSC, we suggest measuring serum IgG4 levels to exclude IgG4-associated sclerosing cholangitis (2C). Algorithm for the diagnosis of PSC. A "dominant stricture" has been defined as a stenosis with a diameter of ≤1.5 mm in the common bile duct or of ≤1 mm in the hepatic duct.46, 47 It is a frequent finding and occurs in 45% to 58% of patients during follow up.5, 46, 48 It should always raise the suspicion of the presence of a cholangiocarcinoma (CCA), because this malignant complication of PSC occurs frequently as a stenotic ductal lesion in the perihilar region. Although CCA may develop in approximately 10%–15% of PSC patients, stenotic lesions are far more often benign than malignant in nature.49 The distinction between a dominant stricture and CCA is difficult; the diagnosis of CCA is discussed below in this guideline. The goal of an endoscopic or percutaneous therapeutic approach to the management of patients with PSC is to relieve biliary obstruction. The stricturing disease of PSC may cause extrahepatic ductal obstruction and therefore lead to symptoms and decompensation of liver function. Some 15%–20% of patients will experience obstruction from discrete areas of narrowing within the extrahepatic biliary tree.24, 50, 51 It is generally agreed that patients with symptoms from dominant strictures such as cholangitis, jaundice, pruritus, right upper quadrant pain or worsening biochemical indices, are appropriate candidates for therapy. The percutaneous approach is associated with increased morbidity but similar efficacy as the endoscopic approach and is reserved for patients who have proximal dominant strictures with a failed endoscopic approach.52, 53 Before any attempt at endoscopic therapy, brush cytology and/or endoscopic biopsy should be obtained to help exclude a superimposed malignancy. The best therapeutic endoscopic approach is still debated; multiple techniques have been utilized such as sphincterotomy, catheter or balloon dilatation, and stent placement.51-54 Of these, only endoscopic biliary sphincterotomy and balloon dilatation with or without stent placement have been found to be of value.51-59 Because injecting contrast agent into an obstructed duct may precipitate cholangitis, perioperative antibiotics should be administered. Sphincterotomy alone has been performed in small subsets of patients, usually when stent placement was unsuccessful. In these small uncontrolled groups, bilirubin and alkaline phosphatase levels did improve.54 Indeed, the biliary sphincter of Oddi may be involved by the sclerosing process and therefore contribute to biliary obstruction. Nevertheless, sphincterotomy is rarely used alone, but rather to facilitate balloon dilatation, stent placement or stone extraction.55 Stricture dilatation can be accomplished through balloons or coaxial dilators. Balloon dilatation has been shown to be effective alone.52, 56, 57 It may be performed periodically with or without stenting. However, biliary stenting has been shown to be associated with increased complications when compared to endoscopic dilatation only and should be reserved for strictures that are refractory to dilatation.52-57 At this time there has not been a randomized controlled study to evaluate the effectiveness of endoscopic therapy. Still, much indirect evidence by large retrospective studies, suggest that endoscopic therapy results in clinical improvement and prolonged survival. Baluyut et al. evaluated their population of patients with PSC and dominant strictures who underwent endoscopic balloon dilatation and found that the observed 5-year survival rate was significantly better than that predicted by the Mayo Risk Score (83% versus 65%, P = 0.027).58 This is the first study to suggest that therapy may actually impact the natural history of the disease. More recently, Gluck et al. described a 20 year experience with endoscopic therapy for 84 symptomatic patients with PSC.59 Similar to the Baluyut study, observed patient survival was higher than expected by the Mayo Risk Score.59 All therapeutic endoscopy comes with risk. In the two largest reported series of patients with long follow-up, the risk of complications was 7.3%–20%. The complications were mild without need for surgical intervention.58, 59 The most common complications were pancreatitis, cholangitis, biliary tract perforation and hemorrhage. Focal biliary tract obstruction, whether benign or malignant, has been the primary indication for the nontransplant surgical management of PSC. Despite limitations of the accuracy of current diagnostic modalities for malignancy in PSC, diagnostic laparotomy has little clinical value. The rationale for surgical management in PSC is bypass of an obstruction caused by a dominant stricture. Non-transplant surgical approaches include biliary bypass by cholangio-enterostomy or resection of the extrahepatic biliary stricture and Roux Y hepaticojejunostomy.60, 61 Biliary bypass alone has been employed infrequently because dominant strictures are typically hilar. Moreover, the intrahepatic ducts are variably involved which limits the access and quality of these ducts for bypass.60 Biliary bypass has no role in PSC patients with cirrhosis. Extrahepatic bile duct resection and Roux Y hepaticojejunostomy with or without stenting for dominant strictures is controversial.53, 61 Current evidence suggests that selected patients with non-cirrhotic stage PSC have an overall survival of 83% at 5 years and 60% at 10 years and a readmission free rate from cholangitis of 57% at 3 years for such an approach.62 Bilirubin levels > 2 mg/dL and cirrhosis are associated with decreased survival. No data regarding surgical management have shown that either bypass or resection of a dominant stricture affect natural history or disease progression. Most patients, who have not had biliary tree instrumented, have negative microbial bile cultures.63, 64 However, dominant strictures can induce stagnation of bile resulting in bacterial colonization and secondary cholangitis. This can be the first presentation of the disease occurring in 6.1% of PSC patients in one recent study.65 Furthermore, severe recurrent cholangitis may play a role in the progression of the disease. The relevance of a bile duct stricture was demonstrated by documenting bacterial infection of the bile in 15 out of 37 PSC patients (40.5%) with a dominant stricture but not in the absence of such stenosis; short-course antibiotic treatment proved not very effective in eradicating bacteria from the bile ducts of patients with dominant strictures.66 However, most patients respond to therapeutic drainage of the obstruction plus antibiotics. Occasional patients with recurrent bacterial cholangitis may benefit from prophylactic long term antibiotics. Rarely, recurrent cholangitis can be so severe as to become the primary indication for OLT.67 The management of in PSC patients should consideration of a dominant stricture. In the absence of a dominant the management of is similar to that for in primary biliary cirrhosis. the AASLD Guidelines on the of In patients with in serum bilirubin and/or worsening progressive bile duct dilatation on imaging studies, and/or cholangitis, we recommend performing an ERC to exclude a dominant stricture (1B). In patients with dominant strictures from PSC, we recommend management with endoscopic dilatation with or without stenting (1B). In patients with dominant strictures from PSC in an endoscopic approach is biliary tract dilatation by percutaneous cholangiography with or without stenting should be (1B). We recommend performing brush cytology and/or endoscopic biopsy to exclude a superimposed malignancy prior to endoscopic therapy for dominant strictures (1B). In patients with dominant strictures refractory to endoscopic and/or percutaneous we recommend surgical therapy in selected patients without cirrhosis (1B). We recommend therapy with of bile duct obstruction in dominant strictures to cholangitis (1A). In patients with recurrent bacterial cholangitis, we recommend the use of prophylactic long-term antibiotics (1B). In patients with refractory bacterial cholangitis, we recommend evaluation for liver (1B). cirrhosis is present in a patient with PSC, portal hypertension will develop because it of the natural history of all patients with cirrhosis. is the with cirrhosis in the is a of the presence of also in PSC. Of PSC patients diagnosed at Mayo = had varices, of which had and had of and of were level, and disease. for the presence of stage and levels, the odds of less than for the presence of was Similar were in in a hypertension be present in patients with PSC who not have cirrhosis, but this is Of liver performed during for biliary tract underwent in the of had PSC. Of the patients with portal hypertension as the indication for OLT, was in and portal in at may contribute as an indication for OLT.67 The management of portal hypertension in patients with PSC does not from patients and has been discussed in prior AASLD is the term used for the associated with liver The diagnosis is made by is characterized by a between and standard below the observed in young normal and as a The of in PSC is between and The with mass with of the with and with of the although this was not should be for in all diagnosed patients with PSC. Although information is it is to for at year and to is in patients with and in of may be therapy a improvement in in have been associated with which be in patients with in these patients therapy is an approach. We recommend to exclude or at diagnosis at year (1B). In patients with hepatic we suggest the use of and for therapy (2C). In patients with hepatic we suggest the use of therapy in addition to and (2C). In patients with and varices, we suggest the use of of therapy rather than (2C). PSC is associated with In most series of patients from and the prevalence of IBD in PSC has been in the range 50, The most frequent of IBD in PSC is UC, which is diagnosed in the patients with to have disease which usually the Conversely, PSC has been diagnosed in between and of patients with and was found in a large group of The prevalence of PSC IBD patients is to because data that cholangiography is out in of patients. The diagnosis and classification of IBD in PSC are based on diagnostic including findings on with multiple Because is a common a is Moreover, as IBD in PSC may be present with little or no clinical evidence of bowel disease and a diagnosis of IBD has in of follow-up, a with multiple is in all PSC patients at the with is negative for IBD, it is if a in the absence of symptoms should be over IBD may be diagnosed at any time during the of PSC. In the majority of the diagnosis of IBD that of PSC, even by IBD and PSC are diagnosed of IBD can also some years the diagnosis of PSC, and IBD may present liver for PSC may be diagnosed at any time during the of IBD, and may present years clinical and endoscopic features of IBD in PSC from those of IBD without evidence of disease (Table et compared patients with PSC who had IBD with a group of patients with the PSC patients, had UC, had and had The PSC patients more frequently had versus versus and versus than the It is a general experience that the colitis associated with PSC usually is This observation also in PSC, that typically as confined to the small bowel is not associated with it has been noted that the colitis may not always have features of 84 A classification of the IBD in PSC may be and can between The presence of or involvement may for be interpreted by some as or rather than 84 IBD in children with PSC is also characterized by often with and mild clinical Although symptoms of IBD in PSC be from those of IBD without the bowel disease in PSC to a more The IBD can also have a prolonged In a study of 27 PSC patients with IBD, patients reported disease activity during the first time diagnosis of IBD, followed by a patients had disease mild or disease in the majority of patients had some complication of IBD during the observation PSC patients who have an have an increased risk of compared to patients with without for this complication are Although one suggests that patients with PSC and an increased risk of development of in the compared with patients without PSC and that these patients should undergo in of patients should be out to the findings. is associated with an increased risk of Indeed, a including studies, that patients with and PSC are at an increased risk of and compared with patients with alone, with In a recent study, PSC patients with IBD and were found to be at of IBD than patients who had IBD and without PSC versus P = The time from of colitis diagnosis of similar in the two versus 20 P = the increased risk of in patients with PSC, at one to two year from the time of diagnosis of PSC in patients with as by associated with PSC to have a for the proximal with up to a A is therefore during to the increased risk of in patients with PSC who have are to be to patients with has been suggested to the risk of in patients with PSC and with was associated with a decreased prevalence