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Diagnosis and endoscopic management of primary sclerosing cholangitis
Author’s Accepted Manuscript Diagnosis and endoscopic management of primary sclerosing cholangitis Anthony Razzak, Richard Kozarek
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To appear in: Techniques in Gastrointestinal Endoscopy Received date: 7 March 2016 Accepted date: 27 May 2016 Cite this article as: Anthony Razzak and Richard Kozarek, Diagnosis and endoscopic management of primary sclerosing cholangitis, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2016.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Diagnosis and Endoscopic Management of Primary Sclerosing Cholangitis
Anthony Razzak, MD and Richard Kozarek, MD Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA
Corresponding author: Richard Kozarek, MD Digestive Disease Institute Virginia Mason Medical Center 1100 Ninth Ave. Seattle, WA 98101 Telephone: (206)223-6600 Fax: (206) 341-1405 Email: [email protected]
Abstract Primary sclerosing cholangitis (PSC) is a complex, chronic and progressive fibro-inflammatory destructive cholestatic biliary disease. The exact etiology and pathogenesis are unknown and possibly related to an enhanced immune-mediated response and reaction in the biliary system. PSC is closely associated with inflammatory bowel disease (IBD) and specifically, ulcerative colitis (UC). It is characterized by intrahepatic and/or extrahepatic bile duct stricturing and dilation. Clinical manifestations include abnormal liver tests, jaundice, pruritus and fatigue. At more advanced stages, PSC can progress to cirrhosis and post-transplant disease recurrence is not uncommon. PSC is associated with an increased risk of cholangiocarcinoma and is an independent risk factor for colorectal cancer in patients with concomitant inflammatory bowel disease. Cholangiography is the mainstay of PSC diagnosis. Improved non-invasive biliary imaging has shifted the role of endoscopic retrograde cholangiopancreatography (ERCP) from disease diagnosis to management of complications, including dominant biliary strictures, bile duct stones and assisting in the differentiation of benign versus malignant strictures. The role of additional endoscopic modalities, including endoscopic ultrasound (EUS), direct cholangioscopy and probe based confocal laser endomicroscopy (pCLE) is evolving. At the present time, medical treatment options are limited and the role of endoscopy is mainly supportive.
Keywords: Primary sclerosing cholangitis (PSC), endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), cholangiocarcinoma, fluorescence in situ hybridization (FISH)
Abbreviations: PSC – primary sclerosing cholangitis IBD – inflammatory bowel disease UC – ulcerative colitis ERCP – endoscopic retrograde cholangiopancreatography EUS – endoscopic ultrasound pCLE – probe based confocal laser endomicroscopy CCA – cholangiocarcinoma PTC – percutaneous transhepatic cholangiography MRCP –magnetic retrograde cholangiopancreatography AASLD – American Association for the Study of Liver Diseases FISH - fluorescence in situ hybridization FNA – fine needle aspiration SEMS – self-expandable metal stents uSEMS – uncovered self-expandable metal stents
Introduction Primary sclerosing cholangitis (PSC) is a complex, chronic and progressive fibro-inflammatory destructive cholestatic biliary disease of unclear etiology. Disease complications include recurrent cholangitis, bile duct stone formation, hepatic abscess formation, progression to cirrhosis and the development of cholangiocarcinoma (CCA). Endoscopic retrograde cholangiopancreatography (ERCP) is the most common endoscopic intervention to assist with disease diagnosis and management; however, the role of endoscopic ultrasound (EUS), direct cholangioscopy and probe based confocal laser endomicroscopy (pCLE) is evolving. At the present time, medical treatment options for PSC are limited and the role of endoscopy is mainly supportive.
Epidemiology, Pathogenesis and Clinical Presentation A majority of PSC disease burden is thought to occur in North America and Europe, though data on global disease distribution is lacking. A recent systematic review and meta-analysis evaluating North American and European population-based studies projected an incidence rate of 1.00 per 100,000 person years with a near two-fold increased risk in men as compared to women and a median age of diagnosis at 41 years (1). In a United States (US) specific population-based study, the overall incidence of PSC was 0.90 per 100,000 person years and the prevalence estimated at 13.6 per 100,000 persons (2). More than twice as many men were affected as women, the mean age at diagnosis was 40 years and a significantly lower rate of survival was noted in those with PSC when compared to age and gender matched controls (10 year survival of 65% versus 94%, respectively). It must be acknowledged that these US data are generated from a single geographic location and therefore, may not typify the PSC burden in the US as a whole.
PSC has a significant association with inflammatory bowel disease (IBD) with an estimated 70%-80% of affected individuals suffering concomitant ulcerative colitis (UC) or Crohn’s disease (2,3). While the true prevalence is unknown, the more common association is with UC and some data suggests a higher prevalence in those with more extensive colonic involvement (4). In contrast, approximately 4% of individuals with UC will develop PSC and the rate within the Crohn’s population is thought to be lower (3). The exact etiology of PSC remains unknown. Current theories suggest a complex multifactorial process, which includes both immune and non-immune mediated biliary injury in those with a genetic predisposition. This is supported by studies that have identified an increased risk of PSC in first-degree relatives and an increased association with autoantibodies (5,6). Non-immune mediated injury has been theorized from the association of PSC with IBD and the subsequent potential for bacterial translocation into portal circulation, cholangitis and ischemic injury (3,7); however, conclusive data to support this is limited. Approximately 50% of individuals are symptomatic at presentation with reported symptoms including jaundice, fatigue, pruritus, weight loss, right upper quadrant pain and fevers (2,3,8). Laboratory testing typically reveals a predominant cholestatic liver injury profile with elevated alkaline phosphatase. Complications from PSC and chronic cholestasis include fat-soluble vitamin deficiency, metabolic bone disease, cholangitis, progression to biliary cirrhosis, development of cholangiocarcinoma and an increased risk of colonic dysplasia and colorectal cancer in those with coexisting IBD (3,9). The lifetime risk of cholangiocarcinoma in PSC is approximately 10%. Up to 50% of individuals with cholangiocarcinoma will be diagnosed within 2 years of their PSC diagnosis. Cholangiocarcinoma screening is supported by multiple societies (9,10) but there remains no universal screening protocol or high quality data to suggest an impact on overall survival. Individual who are symptomatic at
presentation appear to have a significantly lower survival rate (11). Similarly, those with IBD appear to have a higher rate of malignancy, liver transplantation and death (12). At the present time, the median transplant free survival is approximately 10-12 years, and the post-transplant 5-year survival rates are 80-85%(9).
Diagnosis of PSC and Differential Diagnosis The diagnosis of PSC is based on visualization of the biliary system and identification of characteristic intrahepatic and extrahepatic cholangiographic features. The findings in classic PSC include multifocal strictures and dilations that create a beaded appearance and usually involve both the intrahepatic and extrahepatic biliary system. Less commonly, disease can be isolated to the intrahepatic or extrahepatic biliary system and involve the gallbladder and/or cystic duct (7). Small duct PSC, a less prevalent variant found in IBD patients, is characterized by normal cholangiography with cholestatic liver test abnormalities and typical PSC related histologic findings on liver biopsy. Some reports suggest a percentage of small duct patients will progress to classic PSC and this may represent an early disease state (13,14). ERCP had long been considered the gold standard for detecting PSC and favored over percutaneous transhepatic cholangiography (PTC) due to the technical difficulties of a percutaneous approach (7) (Fig 1). The availability of a non-invasive diagnostic tool, magnetic resonance cholangiopancreatography (MRCP) has been evaluated with multiple comparative studies that reveal equivalent diagnostic accuracy (80-90%) with higher interobserver agreement and a favorable cost effectiveness, relative to ERCP (15-17). Currently, MRCP is preferred over ERCP to establish the diagnosis of suspected PSC when there is no contraindication to magnetic resonance and no indication that would warrant an endoscopic biliary intervention (9) (Fig 2). Limited data is available on the effectiveness of EUS in the diagnosis of
PSC, but it may have a role in identifying extrahepatic PSC not identified on MRCP and offer a less invasive diagnostic alternative to ERCP (18). In patients with cholangiographic features suggesting PSC, a liver biopsy is not necessary to make the diagnosis (10). However, in the absence of typical imaging features and ongoing clinical suspicion, liver biopsy is indicated and required in cases of the small duct PSC variant. Classic histologic features include ductopenia and concentric periductal connective tissue fibrosis giving an onionskin type appearance (3,10). Liver biopsy provides the added benefit of staging underlying liver fibrosis in those with advanced disease. Evaluation to rule out secondary causes of sclerosing cholangitis must be undertaken to ensure the proper diagnosis (Table 1). Numerous conditions have been associated with secondary sclerosing cholangitis including, malignant and non-malignant causes of biliary obstruction, toxic biliary injury, biliary ischemia, immune-mediated processes such as IgG4 cholangiopathy, recurrent and chronic biliary infectious and genetic predispositions (19-34). A majority of these entities can be evaluated with clinical history, biliary imaging and a serologic assessment of autoimmune markers, including IgG4.
Endoscopic Management of PSC and related complications The pre-procedure evaluation of patients with PSC requires specific attention to patient safety and appropriateness of an endoscopic intervention. It is universally acknowledged that expert endoscopists should perform ERCP in patients with PSC. Periprocedural prophylactic antibiotics are recommended due to the risk of ERCP related cholangitis and typically continue post-procedurally (35-37). The approach to biliary cannulation remains similar to non-PSC cases; however, caution must be utilized when instrumenting and considering the intended duration and reversibility of an intervention.
To date, there is no data to suggest a contrast-free cannulation is superior or safer than a contrastassisted approach in the PSC population. In predominately non-PSC patient populations, wire-assisted biliary cannulation has been associated with low-rates of ERCP related complications (38,39). However, the presence of biliary epithelial ulcerations and severely narrowed distal multifocal strictures may increase the risk of guidewire-associated bile duct perforations and therefore, caution must be utilized when performing this technique in a PSC patient. Similarly, due to the stricturing nature of PSC and impaired bile drainage, avoidance of overfilling the biliary tree with contrast may reduce injection related bacterial inoculation and subsequent ERCP related cholangitis.
Bile duct stones The presence of biliary strictures contributes to bile stasis via impaired drainage and subsequent sludge and stone formation. The stone are characteristically calcium bilirubinate with a black pigment appearance. Brown pigment stones are noted in instances with bacterial colonization/biliary superinfection (19, 40) (Fig 3). In a review of 85 PSC patients, 22 (26%) endorsed biliary tract calculi with 15 (18%) having stone burden in the common bile duct. Stones were endoscopically removed with an 87% success rate and only 1 patient had recurrent calculi in the 25-month retrospective review period (41). To date, there is no data to directly compare the multiple stone extraction modalities in PSC and the approach undertaken must consider stone location and ductal diameter to avoid ductal injury and predisposition to infection.
Dominant strictures and Cholangiocarcinoma While no universal definition exists, dominant strictures have been defined as a biliary luminal stenosis ≤ 1.5 mm in the common bile duct or 1.0 mm in the right or left main intrahepatic ducts (42) (Fig 4). Identification is typically prompted by clinical symptoms to suggest a biliary obstruction, including symptomatic cholestasis and cholangitis. It is thought that a majority of patients with PSC will develop a dominant stricture during the course of their disease; however, the data on the optimal approach to manage this complication is limited by the lack of a universal strategy. Role of biliary endoscopic sphincterotomy The role and safety of sphincterotomy to facilitate stricture-related endoscopic interventions in PSC is controversial. In a retrospective review evaluating 185 procedures in 75 individuals over a 9-year review period, sphincterotomy significantly predicted a complication following ERCP (p=0.03) (43). A larger 14year retrospective review evaluating 657 ERCPs in 294 patients with PSC revealed a significant association between biliary sphincterotomy and any adverse event (OR 5.04 (95%CI 2.01-12.60, p=0.001)) (44). In contrast, a review of 441 ERCPs over a 2-year period for patients with PSC revealed a 7% post-ERCP related pancreatitis rate with prior biliary sphincterotomy identified as a protective factor (OR 0.28, p=0.02)(45). It must be acknowledged that pancreatic endoscopic sphincterotomy, an independent risk factor for pancreatitis, was utilized to facilitate biliary cannulation at a rate of approximately 12% and it is unclear if standard post-ERCP prophylaxis measures were utilized in these cases. A meta-analysis of randomized controlled trials evaluating the impact of biliary sphincterotomy on biliary stenting in malignant biliary obstruction revealed a significantly decreased risk of post-ERCP pancreatitis and a significantly increased risk of post-sphincterotomy bleeding (OR 0.34, 95%CI 0.12-0.93 and OR 9.70, 95%CI 1.21-77.75, p=0.03, respectively) (46).
The existing data for biliary sphincterotomy in PSC suggests an association with significant risk and there remains limited data to support sphincterotomy as required or protective in PSC related ERCP; thus, many do not advocate its routine use unless indicated by circumstance (47). When pursued, a biliary sphincterotomy should be limited by necessity to maintain some barrier function from refluxing enteric content and bacteria (48). Differentiating benign versus malignant strictures The identification of a dominant stricture introduces the difficult challenge of differentiating a benign process from cholangiocarcinoma. The baseline clinical and imaging characteristics are often similar and therefore, serologic, cytologic and direct endoscopic assessment are often required. Despite a multimodality approach, the diagnostic yield for malignancy is less than optimal and repeated testing is not uncommon. Tumor markers Tumor markers CA 19-9 and carcinoembryonic antigen (CEA) have been studied to determine their role in predicting the presence of cholangiocarcinoma. In a retrospective study evaluating 208 PSC patients, 14 with cholangiocarcinoma (6.7%), a CA 19-9 was significantly higher in those with cholangiocarcinoma (p<0.0001) and a cut-off of 129 U/ml was associated with a sensitivity and specificity of 78.6% and 98.5%, respectively (49). Another retrospective review of 333 PSC patients, 44 with cholangiocarcinoma (13%), a CEA cut-off of 5.2 ng/ml was associated with a sensitivity and specificity of 68.0% and 81.5%, respectively. A CA 19-9 cut-off of 180 U/ml was associated with a sensitivity and specificity of 66.7% and 97.7%, respectively (50). CA 19-9 is the more studied of the two markers and the American Association for the Study of Liver Diseases (AASLD) guidelines on PSC disease management suggest a cut off of 130 U/ml, which provides sensitivity and specificity of 79% and 98%, respectively (10). Due to the limited
predictive value of serologic testing alone, tumor markers are typically used in conjunction with other diagnostic modalities. Cross-sectional imaging The characteristic features of a malignant biliary lesion on abdominal imaging with delayed venous enhancement are highly suggestive of cholangiocarcinoma but often limited to late-stage presentations (Fig 5). In most instances, the stricture appears indeterminate and imaging alone is of limited predictive value. In a 6-year prospective evaluation of 230 PSC patients with a 10% incidence of cholangiocarcinoma (n=23), imaging alone was associated with a 38% to 48% positive predictive value (51). ERCP-based cytological sampling and fluorescent in situ hybridization (FISH) Cytologic sampling is made possible by direct biliary cannulation and tissue acquisition under fluoroscopic visualization. The two basic types of instruments used to perform these tasks are cytology brushes and intraductal biopsy forceps. Cytologic brushes can be advanced over a guidewire, while intraductal biopsy forceps require direct cannulation and reports of bile duct perforation have been reported (52). Numerous studies have evaluated the diagnostic yield of cytologic sampling, which demonstrates excellent specificity with suboptimal sensitivity. In a prospective evaluation of 61 patients with a PSC related strictures evaluated with brushings, 15 were identified to have high-grade dysplasia or cholangiocarcinoma (24.6%). The sensitivity and specificity of brush cytology for diagnosing cholangiocarcinoma was 73% and 95%, respectively (53). This appears to be somewhat of an overestimation as a recent meta-analysis, which included 11 studies with 747 patients, revealed a pooled sensitivity and specificity of 43% and 97%, respectively (54). The combination of cytology from brushings and forceps may increase the sensitivity for diagnosing cholangiocarcinoma; however, the data is limited. In a non-PSC population of 119 patients with pancreaticobiliary strictures, the sensitivity
of brushings, biopsy and the combination for diagnosing malignancy was 46.7%, 64.9% and 70.4%, respectively (55). Yet, in a prospective trial of non-PSC patients with pancreaticobiliary strictures, the improvement in sensitivity was less robust, 53% to 61%, by combining brush and biopsy cytology (52). To improve the diagnostic yield of cytology, gene and chromosome level assays have been developed. A number of studies have demonstrated an improved sensitivity with the use of fluorescent in situ hybridization (FISH) in detecting biliary malignancy. FISH utilizes fluorescent-labeled DNA probes to detect numerical chromosomal abnormalities. The presence of polysomy, or more chromosomal copies than normal, increases the detection of a malignant process (Fig 6). In a study evaluating 86 PSC patients with biliary strictures, cytology alone (positive or suspicious) was associated with 41% sensitivity for detecting cholangiocarcinoma, while the sensitivity of FISH was 70% (56). A small study retrospectively evaluating 30 PSC patients with identified polysomy and negative cytology and/or imaging suggested the presence of polysomy might in fact represent an early stage cancer. Diagnosis of cholangiocarcinoma from cytology and/or imaging occurred 1 to 2.7 years after the initial polysomy result (57). Cholangioscopy Cholangioscopy allows direct intraductal biliary visualization and targeted sampling (Fig 7). Since its initial introduction, the modern cholangioscope (SpyGlass tm, Boston Scientific) has evolved into a single operator, high-definition device with improved maneuverability and visualization. In a prospective study evaluating 36 indeterminate strictures, the visual impression was 89% accurate at differentiating malignant versus benign strictures (58). Another prospective study evaluating 26 indeterminate strictures revealed directly visualized cholangioscopic biopsies are significantly more accurate (85%) than standard ERCP cytology brushings (38%; P<0.001) or biopsy forceps (54%;P=0.0215) (59). In a study of 47 PSC patients, the technical success of cholangioscopic evaluation was 96% (n=45) and 9% of the
strictures (n=4) could only be reached with the additional maneuverability of direct visualization (60). While promising, more evidence is needed to support the routine use cholangioscopy directed evaluation in the PSC population. Endosonographic-based evaluation and fine needle aspiration Limited data exists to support the use of EUS as an additional tool to assist in the identification of cholangiocarcinoma when other modalities are unsuccessful. When stationed in the duodenum, EUS provides high quality extrahepatic bile duct evaluation and if indicated tissue sampling via transluminal fine needle aspiration (FNA) (Fig 8). Previous reports have estimated the sensitivity and specificity of EUS-FNA in the detection of cholangiocarcinoma ranging from 43% to 86% and 95% to 100%, respectively, with higher sensitivity noted in distal versus proximal extrahepatic biliary system (8,61). A significant concern exists over the potential for EUS-FNA related tumor seeding when diagnosing hilar cholangiocarcinoma. In a review of 191 patients, including 16 who underwent transperitoneal FNA (13 percutaneous, 3 EUS), 5/6 (83.3%) of those with positive cytology on FNA were noted to have peritoneal metastasis during operative staging compared to 14/175 (8%) without prior transperitoneal sampling (62). As such, those with EUS-FNA hilar sampling may be ineligible for liver transplantation at certain centers and it is advised against in individuals who may be eligible for curative transplantation. Probe based confocal laser endomicroscopy Probe based confocal laser endomicroscopy (pCLE) allows the passage of a microscopy probe directly into the biliary tree for real time microscopic imaging (Fig 9). A consensus definition of specific malignant pancreaticobiliary criteria was created, also termed the “Miami Classification” to assist in standardizing image interpretation (63). A prospective, multi-center study evaluating 112 patients with indeterminate strictures, revealed a sensitivity, specificity and accuracy of diagnosing cholangiocarcinoma from cytology alone as 56%, 100% and 72%, respectively. In comparison, the
sensitivity, specificity and accuracy of pCLE was 89%, 71% and 82% with an increase in accuracy of diagnosis to 88% when incorporating pCLE, ERCP and tissue sampling (64). While initially promising, additional studies on the cost-effectiveness and inter-observer variability issues will likely be required before pCLE becomes a common element in the indeterminate stricture pathway. Percutaneous sampling Multiple percutaneous sampling options exist when endobiliary access is not achievable. This includes transhepatic biliary tissue acquisition and transperitoneal fine needle aspiration. These approaches have unique challenges that differ from an endoscopic approach. The details regarding diagnostic yield and associated risks will not be discussed in further detail.
Role of balloon dilation, stenting and impact on disease progression After assessment for malignancy is complete, the decision to treat and the method of intervening on a dominant stricture is controversial. There are no randomized controlled trials to date to suggest a model of best practice. When pursued, treatment is intended to alleviate biliary obstruction, facilitate bile flow and minimize further risks of cholestasis and cholangitis. Current treatment strategies include balloon dilation over a guidewire, graduated dilating catheters, temporary biliary stenting or a combination of these; choosing the instrument size based on proximal and distal biliary caliber to avoid ductal injury and carefully determining the intended duration of the chosen intervention. As previously mentioned, periprocedural and post-procedural antibiotics are recommended and the use of biliary sphincterotomy is controversial (35-37,46).
A study evaluating 125 PSC patients, 56 of which (45%) suffered a dominant stricture, revealed no significant difference in cholestatic serologic parameters after up to 12 months and prompted the conclusion that treatment for dominant strictures not be routinely performed (42). A 10-year evaluation of 71 PSC patients compared balloon dilation to stenting and revealed significantly more complications in those treated with stents, including increased incidence of cholangitis and no additional improvement in cholestasis; questioning the routine role of stenting in PSC (65). A 20-year retrospective review of 117 patients with 84 suffering dominant strictures requiring at least one therapeutic endoscopic procedure, compared patient outcomes to that predicted by the Mayo Clinical Natural History Model for PSC, a survival-based estimator with good documented correlation between estimated and actual survival (66). The therapeutic interventions performed in the study included 64 biliary endoscopic sphincterotomies, 59 balloon dilations and 43 temporary stents. Those who underwent therapeutic interventions had a significantly higher rate of survival than that predicted by the model (p=0.021) with acceptable rates of all course adverse events (7.3%) and no procedure related mortality (67). Similarly, a prospective review of 106 PSC patients including 52 (49.1%) with dominant strictures treated endoscopically with repeated balloon dilations and 5 requiring temporary stenting were followed for a median of 5 years. The 3, 5 and 7 year liver transplant free survival rates were significantly higher than those predicted by the Mayo Clinic survival model (0.987, 0.931, 0.891 and 0.860, 0.775, 0.737, p<0.001, respectively). Complications associated with endoscopic interventions included pancreatitis (5.2%), cholangitis (3.3%) and biliary perforation (0.5%) (68). When biliary stenting is employed, most advocate for a short course of plastic stenting with the need for further endoscopic interventions based on the follow-up cholangiogram and clinical course (47). Some support routine stent placement after dilation with frequent exchanges in efforts to minimize stricture
re-formation, though the data on this approach is limited (48). There appears to be no role for selfexpandable metal stents (SEMS) in the treatment of benign PSC related strictures as the large caliber is a risk factor for infectious complications and the temporary nature of stenting is unlikely to make their use cost-effective. In contrast, SEMS in the management of PSC and cholangiocarcinoma may be beneficial with palliative intent and limited life expectancy (69). While early reports questioned the role of therapeutic interventions when managing PSC related dominant strictures, longitudinal studies suggest safety and beneficial impact from balloon dilation and temporary stenting on long-term, transplant-free survival with acceptable rates of procedure related adverse events. There remains no strong data to support routine use of biliary stenting post-dilation and the role of SEMS appear limited to palliative interventions in the context of limited life expectancy. Ultimately, the lack of randomized controlled trials limits the ability to create a standardized approach to endoscopic based dominant stricture therapy.
Complications of Endoscopic Interventions in PSC Reported overall complications from ERCP and endoscopic therapies in PSC patients are similar to those without PSC and may in part reflect the importance of understanding the underlying disease process and limiting the performance of ERCP to those with expertise in managing PSC. In a retrospective cross-sectional review of 30 PSC patients and 45 non-PSC controls, there was no significant difference in the overall complication rate (12.9% vs. 8.6%, p=0.45). However, the rate of complication was significantly higher in PSC patients with an acute indication for an ERCP compared to those without (29.2% vs. 6.6%, p=0.01). There was no difference in the complication rate for diagnostic and therapeutic procedure or those with balloon dilation and stenting (70).
In a larger retrospective review comparing 165 PSC patients to 981 non-PSC controls there was no overall difference in the rate of ERCP-related complications (11% vs. 8%, p=0.2), despite the PSC population having more biopsies, brushings, dilations and longer procedures. There was a significantly increased risk of cholangitis (4% vs. 0.2%, p<0.002) despite the use of antibiotics, but no difference in the rate of pancreatitis, perforation of hemorrhage (35). Despite studies demonstrating similar complication rates between PSC and non-PSC patients, the multifocal stricturing nature of PSC demands certain precautions be undertaken beyond what has been discussed thus far to avoid intervention related biliary injury, infection and unindicated endoscopic interventions. Figure 10 highlights an instance of an uncovered SEMS (uSEMS) placement for misdiagnosis of malignancy in a patient with PSC and a complex hilar stricture. The patient has been managed for a number of years and requires frequent balloon dilations and stent exchanges. The presence of the uSEMS increases the risk of cholangitis and thus prolonged antibiotics have been required. Bile duct perforation can occur with endoscopic management of PSC-related strictures and caution must be taken when maneuvering tight biliary strictures (Figure 11). As previously alluded to, direct visualization with cholangioscopy may have a role in these cases and allow for safer assessment. Ultimately, caution must be exercised when managing PSC and providers must be familiar with the complex nature of the underlying disease and ensure the appropriateness of any and all endoscopic interventions.
Summary PSC is a complex fibro-inflammatory cholestatic biliary condition with a progressive disease course commonly complicated by dominant biliary strictures and associated with an increased incidence of cholangiocarcinoma. There are numerous conditions that can present similarly and must be excluded in the initial evaluation. Cholangiography is the mainstay diagnostic technique in large duct disease. The role of ERCP has become increasingly supportive with data suggesting a beneficial impact on overall survival and comparable complication rates to that observed in non-PSC populations. Despite multiple endoscopic advancements, differentiating benign and malignant biliary strictures remains an obstacle.
Acknowledgements: We would like to give a special thanks to Diane E. Lee for her assistance with manuscript preparation, processing and submission. Conflicts of interest: Anthony Razzak (none); Richard Kozarek (none)
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35. Bangarulingam SY, Gossard AA, Petersen BT, et. al: Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis. Am J Gastroenterol 104:855-60, 2009 36. ASGE STANDARDS OF PRACTICE COMMITTEE, Banerjee S, Shen B, Baron TH, et. al: Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 67:791-8, 2008 37. ASGE Standards of Practice Committee, Khashab MA, Chithadi KV, Acosta RD, et. al: Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 81:81-9, 2015 38. Adler DG, Verma D, Hilden K, et. al: Dye-free wire-guided cannulation of the biliary tree during ERCP is associated with high success and low complication rates: outcomes in a single operator experience of 822 cases. J Clin Gastroenterol 44:e57-62, 2010 39. Cennamo V, Fuccio L, Zagari RM, et. al: Can a wire-guided cannulation technique increase bile duct cannulation rate and prevent post-ERCP pancreatitis?: A meta-analysis of randomized controlled trials. Am J Gastroenterol 104:2343-50, 2009 40. Wang DQH, Afdhal NH: Gallstone Disease, in Feldman M, Friedman LS, Bandt LJ (eds): Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management (ed 9). Philadelphia, PA, Saunders, 2010, pp. 1089-1120. 41. Kaw M, Silverman WB, Rabinovitz M, et. al: Biliary tract calculi in primary sclerosing cholangitis. Am J Gastroenterol 90:72-5, 1995 42. Björnsson E, Lindqvist-Ottosson J, Asztely M, et. al: Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol 99:502-8, 2004 43. Alkhatib AA, Hilden K, Adler DG: Comorbidities, sphincterotomy, and balloon dilation predict postERCP adverse events in PSC patients: operator experience is protective. Dig Dis Sci 56:3685-8, 2011 44. Navaneethan U, Jegadeesan R, Nayak S, et. al: ERCP-related adverse events in patients with primary sclerosing cholangitis. Gastrointest Endosc 81:410-9, 2015 45. Ismail S, Kylänpää L, Mustonen H, et. al: Risk factors for complications of ERCP in primary sclerosing
cholangitis. Endoscopy 44:1133-8, 2012 46. Cui PJ, Yao J, Zhao YJ, et. al: Biliary stenting with or without sphincterotomy for malignant biliary obstruction: a meta-analysis. World J Gastroenterol 20:14033-9, 2014 47. Ahmad J, Slivka A: Sclerosing Cholangitis, in Baron TH, Kozarek RA, Carr-Locke DL (eds): ERCP (ed 2). Philadelphia, PA, Saunders, 2013, pp. 430-436 48. Tharian B, George NE, Tham TC: What is the current role of endoscopy in primary sclerosing cholangitis? World J Gastrointest Endosc 7:920-7, 2015 49. Levy C, Lymp J, Angulo P, et. al: The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 50:1734-40, 2005 50. Siqueira E, Schoen RE, Silverman W, et. al: Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointest Endosc 56:40-7, 2002 51. Charatcharoenwitthaya P, Enders FB, Halling KC, et. al: Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 48:1106-17, 2008 52. Pugliese V, Conio M, Nicolò G, et. al: Endoscopic retrograde forceps biopsy and brush cytology of biliary strictures: a prospective study. Gastrointest Endosc 42:520-6, 1995 53. Boberg KM, Jebsen P, Clausen OP, et. al: Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 45:568-74, 2006 54. Trikudanathan G, Navaneethan U, Njei B, et. al: Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc 79:783-9, 2014 55. Schoefl R, Haefner M, Wrba F, et. al: Forceps biopsy and brush cytology during endoscopic retrograde cholangiopancreatography for the diagnosis of biliary stenoses. Scand J Gastroenterol 32:363-8, 1997
56. Moreno Luna LE, Kipp B, Halling KC, et. al: Advanced cytologic techniques for the detection of malignant pancreatobiliary strictures. Gastroenterology 131:1064-72, 2006 57. Barr Fritcher EG, Kipp BR, Voss JS, et. al: Primary sclerosing cholangitis patients with serial polysomy fluorescence in situ hybridization results are at increased risk of cholangiocarcinoma. Am J Gastroenterol 106:2023-8, 2011 58. Ramchandani M, Reddy DN, Gupta R, et. al: Role of single-operator peroral cholangioscopy in the diagnosis of indeterminate biliary lesions: a single-center, prospective study. Gastrointest Endosc 74:511-9, 2011 59. Draganov PV, Chauhan S, Wagh MS, et. al: Diagnostic accuracy of conventional and cholangioscopyguided sampling of indeterminate biliary lesions at the time of ERCP: a prospective, long-term follow-up study. Gastrointest Endosc 75:347-53, 2012 60. Arnelo U, von Seth E, Bergquist A: Prospective evaluation of the clinical utility of single-operator peroral cholangioscopy in patients with primary sclerosing cholangitis. Endoscopy 47:696-702, 2015 61. Mohamadnejad M, DeWitt JM, Sherman S, et. al: Role of EUS for preoperative evaluation of cholangiocarcinoma: a large single-center experience. Gastrointest Endosc 73:71-8, 2011 62. Eimbach JK, Sanchez W, Rosen CB, et. al: Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB (Oxford) 13:356-60, 2011 63. Meining A, Shah RJ, Slivka A, et. al: Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures. Endoscopy 44:251-7, 2012 64. Slivka A, Gan I, Jamidar P, et. al: Validation of the diagnostic accuracy of probe-based confocal laser endomicroscopy for the characterization of indeterminate biliary strictures: results of a prospective multicenter international study. Gastrointest Endosc 81:282-90, 2015 65. Kaya M, Petersen BT, Angulo P, et. al: Balloon dilation compared to stenting of dominant strictures in primary sclerosing cholangitis. Am J Gastroenterol 96:1059-66, 2001
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Table and Figure legend:
Table 1. Causes of secondary sclerosing cholangitis Description: Table outlining causes of secondary sclerosing cholangitis grouped by etiology subcategorization
Figure 1. ERCP cholangiogram in PSC Description: ERCP cholangiogram revealing Intra- and extra-hepatic multifocal biliary ductal stricturing and dilation (arrows highlighting areas of stricturing).
Figure 2. MRCP cholangiogram in PSC Description: MRCP cholangiogram in PSC revealing predominately intrahepatic multifocal bile duct stricturing and dilation (arrows highlighting areas of stricturing).
Figure 3. Bile ducts stones Description: Endoscopic view of a black pigment stone in PSC (left) and cholangiographic view of multiple mixed pigment stones in PSC (right)
Figure 4. Dominant strictures in PSC Description: A dominant common hepatic duct and hilar stricture with upstream biliary dilation in a patient with intra- and extra-hepatic duct PSC (arrows highlighting areas of stricturing).
Figure 5. Cross sectional abdominal imaging and corresponding cholangiogram in hilar cholangiocarcinoma Description: A contrast enhanced CT abdomen revealing a hypoenhancing hilar mass (left) with a corresponding ERCP cholangiogram demonstrating a Bismuth IV cholangiocarcinoma and multifocal intrahepatic PSC related strictures
Figure 6. Fluorescence in situ hybridization (FISH) with polysomy
Description: Reprinted with permission (56). Fluorescently labeled DNA revealing polysomy for three chromosomes (fluorescently labeled blue, green and red), a finding that suggests malignancy.
Figure 7. Cholangioscopy in cholangiocarcinoma Description: ERCP cholangiogram with a malignant appearing hilar stricture (top left) and cholangioscopy images ulcerated biliary epithelium and intraductal mass. Papillary fronds are noted (bottom right, arrows highlighting fronds) and highly concerning for cholangiocarcinoma.
Figure 8. Endosonographic FNA of a hilar cholangiocarcinoma Description: ERCP cholangiogram with a hilar cholangiocarcinoma (left) and corresponding EUS-FNA of the hilar mass (right) (arrow highlighting FNA).
Figure 9. Probe based confocal laser endomicroscopy (pCLE) in an indeterminate biliary stricture Description: ERCP cholangiogram with an indeterminate left main biliary stricture and upstream dilation (left) (arrow highlighting stricture). Cholangioscopy revealed non-specific scarring and fibrosis (top right). pCLE revealed dark clumps and thick white bands suggestive of malignancy (bottom right) (arrow highlighting thick white band).
Figure 10. Misdiagnosis of PSC and placement of an uSEMS Description: ERCP cholangiogram with a common bile duct uSEMS that was placed in the setting of a misdiagnosis of cholangiocarcinoma in a patient with PSC. There is evidence of right and left main dominant strictures that are treated with balloon dilation and short-term stenting.
Figure 11. Bile duct perforation Description: ERCP cholangiogram with evidence of a TIPS and uSEMS that was placed years prior percutaneously for a misdiagnosis of cholangiocarcinoma. Cholangiogram reveals left intrahepatic ductal dilation and a guidewire perforation with extra-luminal contrast extravasation while attempting wire advancement into the left biliary system (arrow).
Table 1. Causes of secondary sclerosing cholangitis
Secondary sclerosing cholangitis Malignant obstruction Cholangiocarcinoma Hepatocellular carcinoma Lymphoma Metastasisa Non-malignant obstruction Choledocholithiasis Chronic pancreatitis Portal hypertensive biliopathy Hepatic inflammatory pseudotumor Toxic & ischemic biliary injury Critical illness Iatrogenic and traumatic hepatic artery injury Hepatic artery thrombosis Critical illness Chemotherapyb Drug induced liver injuryc Allograft rejection Graft-versus-host disease Immune mediated IgG4-mediated cholangiopathy AIH overlap syndrome Sarcoidosis Behcet’s disease AIDS cholangiopathyd Hypereosinophilic syndrome Systemic mastocytosis and mast cell cholangiopathy Langerhan’s cell histiocytosis (Histiocytosis X) Combined immune deficiency Infectious Recurrent pyogenic cholangitis (Oriental cholangiohepatitis)e CMV Cryptosporidium/Microsporidium Echinococcus Mycosis Congenital/Genetic Cystic fibrosis Caroli’s disease
Progressive familial intrahepatic cholestasisf Alagille syndrome Biliary artresia a: including colorectal adenocarcinoma, melanoma, sarcoma, and breast carcinoma b: including floxuridine (FUDR, hepatic arterial infusion), paclitaxel, 5-fluorouracil, and yttrium 90 c: suspected agents include amoxicillin-clavulanate, green tea extract, sevoflurane, amiodarone, infliximab, venlafaxine, atorvastatin, and ketamine d: predisposition to cryptosporidium/microsporidium, CMV and other biliary opportunistic infections e: suspected pathogens include biliary parasitosis (including Ascaris, Clonorchis) and glucuronidase producing bacteria (including Escherichia coli, Bacteroides species, and Clostridium perfringens) f: mutations in APT8B1, ABCB11 or ABCB4(MRP3) genes
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S1096-2883(16)30008-0 http://dx.doi.org/10.1016/j.tgie.2016.05.003 YTGIE50488
To appear in: Techniques in Gastrointestinal Endoscopy Received date: 7 March 2016 Accepted date: 27 May 2016 Cite this article as: Anthony Razzak and Richard Kozarek, Diagnosis and endoscopic management of primary sclerosing cholangitis, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2016.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Diagnosis and Endoscopic Management of Primary Sclerosing Cholangitis
Anthony Razzak, MD and Richard Kozarek, MD Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA
Corresponding author: Richard Kozarek, MD Digestive Disease Institute Virginia Mason Medical Center 1100 Ninth Ave. Seattle, WA 98101 Telephone: (206)223-6600 Fax: (206) 341-1405 Email: [email protected]
Abstract Primary sclerosing cholangitis (PSC) is a complex, chronic and progressive fibro-inflammatory destructive cholestatic biliary disease. The exact etiology and pathogenesis are unknown and possibly related to an enhanced immune-mediated response and reaction in the biliary system. PSC is closely associated with inflammatory bowel disease (IBD) and specifically, ulcerative colitis (UC). It is characterized by intrahepatic and/or extrahepatic bile duct stricturing and dilation. Clinical manifestations include abnormal liver tests, jaundice, pruritus and fatigue. At more advanced stages, PSC can progress to cirrhosis and post-transplant disease recurrence is not uncommon. PSC is associated with an increased risk of cholangiocarcinoma and is an independent risk factor for colorectal cancer in patients with concomitant inflammatory bowel disease. Cholangiography is the mainstay of PSC diagnosis. Improved non-invasive biliary imaging has shifted the role of endoscopic retrograde cholangiopancreatography (ERCP) from disease diagnosis to management of complications, including dominant biliary strictures, bile duct stones and assisting in the differentiation of benign versus malignant strictures. The role of additional endoscopic modalities, including endoscopic ultrasound (EUS), direct cholangioscopy and probe based confocal laser endomicroscopy (pCLE) is evolving. At the present time, medical treatment options are limited and the role of endoscopy is mainly supportive.
Keywords: Primary sclerosing cholangitis (PSC), endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), cholangiocarcinoma, fluorescence in situ hybridization (FISH)
Abbreviations: PSC – primary sclerosing cholangitis IBD – inflammatory bowel disease UC – ulcerative colitis ERCP – endoscopic retrograde cholangiopancreatography EUS – endoscopic ultrasound pCLE – probe based confocal laser endomicroscopy CCA – cholangiocarcinoma PTC – percutaneous transhepatic cholangiography MRCP –magnetic retrograde cholangiopancreatography AASLD – American Association for the Study of Liver Diseases FISH - fluorescence in situ hybridization FNA – fine needle aspiration SEMS – self-expandable metal stents uSEMS – uncovered self-expandable metal stents
Introduction Primary sclerosing cholangitis (PSC) is a complex, chronic and progressive fibro-inflammatory destructive cholestatic biliary disease of unclear etiology. Disease complications include recurrent cholangitis, bile duct stone formation, hepatic abscess formation, progression to cirrhosis and the development of cholangiocarcinoma (CCA). Endoscopic retrograde cholangiopancreatography (ERCP) is the most common endoscopic intervention to assist with disease diagnosis and management; however, the role of endoscopic ultrasound (EUS), direct cholangioscopy and probe based confocal laser endomicroscopy (pCLE) is evolving. At the present time, medical treatment options for PSC are limited and the role of endoscopy is mainly supportive.
Epidemiology, Pathogenesis and Clinical Presentation A majority of PSC disease burden is thought to occur in North America and Europe, though data on global disease distribution is lacking. A recent systematic review and meta-analysis evaluating North American and European population-based studies projected an incidence rate of 1.00 per 100,000 person years with a near two-fold increased risk in men as compared to women and a median age of diagnosis at 41 years (1). In a United States (US) specific population-based study, the overall incidence of PSC was 0.90 per 100,000 person years and the prevalence estimated at 13.6 per 100,000 persons (2). More than twice as many men were affected as women, the mean age at diagnosis was 40 years and a significantly lower rate of survival was noted in those with PSC when compared to age and gender matched controls (10 year survival of 65% versus 94%, respectively). It must be acknowledged that these US data are generated from a single geographic location and therefore, may not typify the PSC burden in the US as a whole.
PSC has a significant association with inflammatory bowel disease (IBD) with an estimated 70%-80% of affected individuals suffering concomitant ulcerative colitis (UC) or Crohn’s disease (2,3). While the true prevalence is unknown, the more common association is with UC and some data suggests a higher prevalence in those with more extensive colonic involvement (4). In contrast, approximately 4% of individuals with UC will develop PSC and the rate within the Crohn’s population is thought to be lower (3). The exact etiology of PSC remains unknown. Current theories suggest a complex multifactorial process, which includes both immune and non-immune mediated biliary injury in those with a genetic predisposition. This is supported by studies that have identified an increased risk of PSC in first-degree relatives and an increased association with autoantibodies (5,6). Non-immune mediated injury has been theorized from the association of PSC with IBD and the subsequent potential for bacterial translocation into portal circulation, cholangitis and ischemic injury (3,7); however, conclusive data to support this is limited. Approximately 50% of individuals are symptomatic at presentation with reported symptoms including jaundice, fatigue, pruritus, weight loss, right upper quadrant pain and fevers (2,3,8). Laboratory testing typically reveals a predominant cholestatic liver injury profile with elevated alkaline phosphatase. Complications from PSC and chronic cholestasis include fat-soluble vitamin deficiency, metabolic bone disease, cholangitis, progression to biliary cirrhosis, development of cholangiocarcinoma and an increased risk of colonic dysplasia and colorectal cancer in those with coexisting IBD (3,9). The lifetime risk of cholangiocarcinoma in PSC is approximately 10%. Up to 50% of individuals with cholangiocarcinoma will be diagnosed within 2 years of their PSC diagnosis. Cholangiocarcinoma screening is supported by multiple societies (9,10) but there remains no universal screening protocol or high quality data to suggest an impact on overall survival. Individual who are symptomatic at
presentation appear to have a significantly lower survival rate (11). Similarly, those with IBD appear to have a higher rate of malignancy, liver transplantation and death (12). At the present time, the median transplant free survival is approximately 10-12 years, and the post-transplant 5-year survival rates are 80-85%(9).
Diagnosis of PSC and Differential Diagnosis The diagnosis of PSC is based on visualization of the biliary system and identification of characteristic intrahepatic and extrahepatic cholangiographic features. The findings in classic PSC include multifocal strictures and dilations that create a beaded appearance and usually involve both the intrahepatic and extrahepatic biliary system. Less commonly, disease can be isolated to the intrahepatic or extrahepatic biliary system and involve the gallbladder and/or cystic duct (7). Small duct PSC, a less prevalent variant found in IBD patients, is characterized by normal cholangiography with cholestatic liver test abnormalities and typical PSC related histologic findings on liver biopsy. Some reports suggest a percentage of small duct patients will progress to classic PSC and this may represent an early disease state (13,14). ERCP had long been considered the gold standard for detecting PSC and favored over percutaneous transhepatic cholangiography (PTC) due to the technical difficulties of a percutaneous approach (7) (Fig 1). The availability of a non-invasive diagnostic tool, magnetic resonance cholangiopancreatography (MRCP) has been evaluated with multiple comparative studies that reveal equivalent diagnostic accuracy (80-90%) with higher interobserver agreement and a favorable cost effectiveness, relative to ERCP (15-17). Currently, MRCP is preferred over ERCP to establish the diagnosis of suspected PSC when there is no contraindication to magnetic resonance and no indication that would warrant an endoscopic biliary intervention (9) (Fig 2). Limited data is available on the effectiveness of EUS in the diagnosis of
PSC, but it may have a role in identifying extrahepatic PSC not identified on MRCP and offer a less invasive diagnostic alternative to ERCP (18). In patients with cholangiographic features suggesting PSC, a liver biopsy is not necessary to make the diagnosis (10). However, in the absence of typical imaging features and ongoing clinical suspicion, liver biopsy is indicated and required in cases of the small duct PSC variant. Classic histologic features include ductopenia and concentric periductal connective tissue fibrosis giving an onionskin type appearance (3,10). Liver biopsy provides the added benefit of staging underlying liver fibrosis in those with advanced disease. Evaluation to rule out secondary causes of sclerosing cholangitis must be undertaken to ensure the proper diagnosis (Table 1). Numerous conditions have been associated with secondary sclerosing cholangitis including, malignant and non-malignant causes of biliary obstruction, toxic biliary injury, biliary ischemia, immune-mediated processes such as IgG4 cholangiopathy, recurrent and chronic biliary infectious and genetic predispositions (19-34). A majority of these entities can be evaluated with clinical history, biliary imaging and a serologic assessment of autoimmune markers, including IgG4.
Endoscopic Management of PSC and related complications The pre-procedure evaluation of patients with PSC requires specific attention to patient safety and appropriateness of an endoscopic intervention. It is universally acknowledged that expert endoscopists should perform ERCP in patients with PSC. Periprocedural prophylactic antibiotics are recommended due to the risk of ERCP related cholangitis and typically continue post-procedurally (35-37). The approach to biliary cannulation remains similar to non-PSC cases; however, caution must be utilized when instrumenting and considering the intended duration and reversibility of an intervention.
To date, there is no data to suggest a contrast-free cannulation is superior or safer than a contrastassisted approach in the PSC population. In predominately non-PSC patient populations, wire-assisted biliary cannulation has been associated with low-rates of ERCP related complications (38,39). However, the presence of biliary epithelial ulcerations and severely narrowed distal multifocal strictures may increase the risk of guidewire-associated bile duct perforations and therefore, caution must be utilized when performing this technique in a PSC patient. Similarly, due to the stricturing nature of PSC and impaired bile drainage, avoidance of overfilling the biliary tree with contrast may reduce injection related bacterial inoculation and subsequent ERCP related cholangitis.
Bile duct stones The presence of biliary strictures contributes to bile stasis via impaired drainage and subsequent sludge and stone formation. The stone are characteristically calcium bilirubinate with a black pigment appearance. Brown pigment stones are noted in instances with bacterial colonization/biliary superinfection (19, 40) (Fig 3). In a review of 85 PSC patients, 22 (26%) endorsed biliary tract calculi with 15 (18%) having stone burden in the common bile duct. Stones were endoscopically removed with an 87% success rate and only 1 patient had recurrent calculi in the 25-month retrospective review period (41). To date, there is no data to directly compare the multiple stone extraction modalities in PSC and the approach undertaken must consider stone location and ductal diameter to avoid ductal injury and predisposition to infection.
Dominant strictures and Cholangiocarcinoma While no universal definition exists, dominant strictures have been defined as a biliary luminal stenosis ≤ 1.5 mm in the common bile duct or 1.0 mm in the right or left main intrahepatic ducts (42) (Fig 4). Identification is typically prompted by clinical symptoms to suggest a biliary obstruction, including symptomatic cholestasis and cholangitis. It is thought that a majority of patients with PSC will develop a dominant stricture during the course of their disease; however, the data on the optimal approach to manage this complication is limited by the lack of a universal strategy. Role of biliary endoscopic sphincterotomy The role and safety of sphincterotomy to facilitate stricture-related endoscopic interventions in PSC is controversial. In a retrospective review evaluating 185 procedures in 75 individuals over a 9-year review period, sphincterotomy significantly predicted a complication following ERCP (p=0.03) (43). A larger 14year retrospective review evaluating 657 ERCPs in 294 patients with PSC revealed a significant association between biliary sphincterotomy and any adverse event (OR 5.04 (95%CI 2.01-12.60, p=0.001)) (44). In contrast, a review of 441 ERCPs over a 2-year period for patients with PSC revealed a 7% post-ERCP related pancreatitis rate with prior biliary sphincterotomy identified as a protective factor (OR 0.28, p=0.02)(45). It must be acknowledged that pancreatic endoscopic sphincterotomy, an independent risk factor for pancreatitis, was utilized to facilitate biliary cannulation at a rate of approximately 12% and it is unclear if standard post-ERCP prophylaxis measures were utilized in these cases. A meta-analysis of randomized controlled trials evaluating the impact of biliary sphincterotomy on biliary stenting in malignant biliary obstruction revealed a significantly decreased risk of post-ERCP pancreatitis and a significantly increased risk of post-sphincterotomy bleeding (OR 0.34, 95%CI 0.12-0.93 and OR 9.70, 95%CI 1.21-77.75, p=0.03, respectively) (46).
The existing data for biliary sphincterotomy in PSC suggests an association with significant risk and there remains limited data to support sphincterotomy as required or protective in PSC related ERCP; thus, many do not advocate its routine use unless indicated by circumstance (47). When pursued, a biliary sphincterotomy should be limited by necessity to maintain some barrier function from refluxing enteric content and bacteria (48). Differentiating benign versus malignant strictures The identification of a dominant stricture introduces the difficult challenge of differentiating a benign process from cholangiocarcinoma. The baseline clinical and imaging characteristics are often similar and therefore, serologic, cytologic and direct endoscopic assessment are often required. Despite a multimodality approach, the diagnostic yield for malignancy is less than optimal and repeated testing is not uncommon. Tumor markers Tumor markers CA 19-9 and carcinoembryonic antigen (CEA) have been studied to determine their role in predicting the presence of cholangiocarcinoma. In a retrospective study evaluating 208 PSC patients, 14 with cholangiocarcinoma (6.7%), a CA 19-9 was significantly higher in those with cholangiocarcinoma (p<0.0001) and a cut-off of 129 U/ml was associated with a sensitivity and specificity of 78.6% and 98.5%, respectively (49). Another retrospective review of 333 PSC patients, 44 with cholangiocarcinoma (13%), a CEA cut-off of 5.2 ng/ml was associated with a sensitivity and specificity of 68.0% and 81.5%, respectively. A CA 19-9 cut-off of 180 U/ml was associated with a sensitivity and specificity of 66.7% and 97.7%, respectively (50). CA 19-9 is the more studied of the two markers and the American Association for the Study of Liver Diseases (AASLD) guidelines on PSC disease management suggest a cut off of 130 U/ml, which provides sensitivity and specificity of 79% and 98%, respectively (10). Due to the limited
predictive value of serologic testing alone, tumor markers are typically used in conjunction with other diagnostic modalities. Cross-sectional imaging The characteristic features of a malignant biliary lesion on abdominal imaging with delayed venous enhancement are highly suggestive of cholangiocarcinoma but often limited to late-stage presentations (Fig 5). In most instances, the stricture appears indeterminate and imaging alone is of limited predictive value. In a 6-year prospective evaluation of 230 PSC patients with a 10% incidence of cholangiocarcinoma (n=23), imaging alone was associated with a 38% to 48% positive predictive value (51). ERCP-based cytological sampling and fluorescent in situ hybridization (FISH) Cytologic sampling is made possible by direct biliary cannulation and tissue acquisition under fluoroscopic visualization. The two basic types of instruments used to perform these tasks are cytology brushes and intraductal biopsy forceps. Cytologic brushes can be advanced over a guidewire, while intraductal biopsy forceps require direct cannulation and reports of bile duct perforation have been reported (52). Numerous studies have evaluated the diagnostic yield of cytologic sampling, which demonstrates excellent specificity with suboptimal sensitivity. In a prospective evaluation of 61 patients with a PSC related strictures evaluated with brushings, 15 were identified to have high-grade dysplasia or cholangiocarcinoma (24.6%). The sensitivity and specificity of brush cytology for diagnosing cholangiocarcinoma was 73% and 95%, respectively (53). This appears to be somewhat of an overestimation as a recent meta-analysis, which included 11 studies with 747 patients, revealed a pooled sensitivity and specificity of 43% and 97%, respectively (54). The combination of cytology from brushings and forceps may increase the sensitivity for diagnosing cholangiocarcinoma; however, the data is limited. In a non-PSC population of 119 patients with pancreaticobiliary strictures, the sensitivity
of brushings, biopsy and the combination for diagnosing malignancy was 46.7%, 64.9% and 70.4%, respectively (55). Yet, in a prospective trial of non-PSC patients with pancreaticobiliary strictures, the improvement in sensitivity was less robust, 53% to 61%, by combining brush and biopsy cytology (52). To improve the diagnostic yield of cytology, gene and chromosome level assays have been developed. A number of studies have demonstrated an improved sensitivity with the use of fluorescent in situ hybridization (FISH) in detecting biliary malignancy. FISH utilizes fluorescent-labeled DNA probes to detect numerical chromosomal abnormalities. The presence of polysomy, or more chromosomal copies than normal, increases the detection of a malignant process (Fig 6). In a study evaluating 86 PSC patients with biliary strictures, cytology alone (positive or suspicious) was associated with 41% sensitivity for detecting cholangiocarcinoma, while the sensitivity of FISH was 70% (56). A small study retrospectively evaluating 30 PSC patients with identified polysomy and negative cytology and/or imaging suggested the presence of polysomy might in fact represent an early stage cancer. Diagnosis of cholangiocarcinoma from cytology and/or imaging occurred 1 to 2.7 years after the initial polysomy result (57). Cholangioscopy Cholangioscopy allows direct intraductal biliary visualization and targeted sampling (Fig 7). Since its initial introduction, the modern cholangioscope (SpyGlass tm, Boston Scientific) has evolved into a single operator, high-definition device with improved maneuverability and visualization. In a prospective study evaluating 36 indeterminate strictures, the visual impression was 89% accurate at differentiating malignant versus benign strictures (58). Another prospective study evaluating 26 indeterminate strictures revealed directly visualized cholangioscopic biopsies are significantly more accurate (85%) than standard ERCP cytology brushings (38%; P<0.001) or biopsy forceps (54%;P=0.0215) (59). In a study of 47 PSC patients, the technical success of cholangioscopic evaluation was 96% (n=45) and 9% of the
strictures (n=4) could only be reached with the additional maneuverability of direct visualization (60). While promising, more evidence is needed to support the routine use cholangioscopy directed evaluation in the PSC population. Endosonographic-based evaluation and fine needle aspiration Limited data exists to support the use of EUS as an additional tool to assist in the identification of cholangiocarcinoma when other modalities are unsuccessful. When stationed in the duodenum, EUS provides high quality extrahepatic bile duct evaluation and if indicated tissue sampling via transluminal fine needle aspiration (FNA) (Fig 8). Previous reports have estimated the sensitivity and specificity of EUS-FNA in the detection of cholangiocarcinoma ranging from 43% to 86% and 95% to 100%, respectively, with higher sensitivity noted in distal versus proximal extrahepatic biliary system (8,61). A significant concern exists over the potential for EUS-FNA related tumor seeding when diagnosing hilar cholangiocarcinoma. In a review of 191 patients, including 16 who underwent transperitoneal FNA (13 percutaneous, 3 EUS), 5/6 (83.3%) of those with positive cytology on FNA were noted to have peritoneal metastasis during operative staging compared to 14/175 (8%) without prior transperitoneal sampling (62). As such, those with EUS-FNA hilar sampling may be ineligible for liver transplantation at certain centers and it is advised against in individuals who may be eligible for curative transplantation. Probe based confocal laser endomicroscopy Probe based confocal laser endomicroscopy (pCLE) allows the passage of a microscopy probe directly into the biliary tree for real time microscopic imaging (Fig 9). A consensus definition of specific malignant pancreaticobiliary criteria was created, also termed the “Miami Classification” to assist in standardizing image interpretation (63). A prospective, multi-center study evaluating 112 patients with indeterminate strictures, revealed a sensitivity, specificity and accuracy of diagnosing cholangiocarcinoma from cytology alone as 56%, 100% and 72%, respectively. In comparison, the
sensitivity, specificity and accuracy of pCLE was 89%, 71% and 82% with an increase in accuracy of diagnosis to 88% when incorporating pCLE, ERCP and tissue sampling (64). While initially promising, additional studies on the cost-effectiveness and inter-observer variability issues will likely be required before pCLE becomes a common element in the indeterminate stricture pathway. Percutaneous sampling Multiple percutaneous sampling options exist when endobiliary access is not achievable. This includes transhepatic biliary tissue acquisition and transperitoneal fine needle aspiration. These approaches have unique challenges that differ from an endoscopic approach. The details regarding diagnostic yield and associated risks will not be discussed in further detail.
Role of balloon dilation, stenting and impact on disease progression After assessment for malignancy is complete, the decision to treat and the method of intervening on a dominant stricture is controversial. There are no randomized controlled trials to date to suggest a model of best practice. When pursued, treatment is intended to alleviate biliary obstruction, facilitate bile flow and minimize further risks of cholestasis and cholangitis. Current treatment strategies include balloon dilation over a guidewire, graduated dilating catheters, temporary biliary stenting or a combination of these; choosing the instrument size based on proximal and distal biliary caliber to avoid ductal injury and carefully determining the intended duration of the chosen intervention. As previously mentioned, periprocedural and post-procedural antibiotics are recommended and the use of biliary sphincterotomy is controversial (35-37,46).
A study evaluating 125 PSC patients, 56 of which (45%) suffered a dominant stricture, revealed no significant difference in cholestatic serologic parameters after up to 12 months and prompted the conclusion that treatment for dominant strictures not be routinely performed (42). A 10-year evaluation of 71 PSC patients compared balloon dilation to stenting and revealed significantly more complications in those treated with stents, including increased incidence of cholangitis and no additional improvement in cholestasis; questioning the routine role of stenting in PSC (65). A 20-year retrospective review of 117 patients with 84 suffering dominant strictures requiring at least one therapeutic endoscopic procedure, compared patient outcomes to that predicted by the Mayo Clinical Natural History Model for PSC, a survival-based estimator with good documented correlation between estimated and actual survival (66). The therapeutic interventions performed in the study included 64 biliary endoscopic sphincterotomies, 59 balloon dilations and 43 temporary stents. Those who underwent therapeutic interventions had a significantly higher rate of survival than that predicted by the model (p=0.021) with acceptable rates of all course adverse events (7.3%) and no procedure related mortality (67). Similarly, a prospective review of 106 PSC patients including 52 (49.1%) with dominant strictures treated endoscopically with repeated balloon dilations and 5 requiring temporary stenting were followed for a median of 5 years. The 3, 5 and 7 year liver transplant free survival rates were significantly higher than those predicted by the Mayo Clinic survival model (0.987, 0.931, 0.891 and 0.860, 0.775, 0.737, p<0.001, respectively). Complications associated with endoscopic interventions included pancreatitis (5.2%), cholangitis (3.3%) and biliary perforation (0.5%) (68). When biliary stenting is employed, most advocate for a short course of plastic stenting with the need for further endoscopic interventions based on the follow-up cholangiogram and clinical course (47). Some support routine stent placement after dilation with frequent exchanges in efforts to minimize stricture
re-formation, though the data on this approach is limited (48). There appears to be no role for selfexpandable metal stents (SEMS) in the treatment of benign PSC related strictures as the large caliber is a risk factor for infectious complications and the temporary nature of stenting is unlikely to make their use cost-effective. In contrast, SEMS in the management of PSC and cholangiocarcinoma may be beneficial with palliative intent and limited life expectancy (69). While early reports questioned the role of therapeutic interventions when managing PSC related dominant strictures, longitudinal studies suggest safety and beneficial impact from balloon dilation and temporary stenting on long-term, transplant-free survival with acceptable rates of procedure related adverse events. There remains no strong data to support routine use of biliary stenting post-dilation and the role of SEMS appear limited to palliative interventions in the context of limited life expectancy. Ultimately, the lack of randomized controlled trials limits the ability to create a standardized approach to endoscopic based dominant stricture therapy.
Complications of Endoscopic Interventions in PSC Reported overall complications from ERCP and endoscopic therapies in PSC patients are similar to those without PSC and may in part reflect the importance of understanding the underlying disease process and limiting the performance of ERCP to those with expertise in managing PSC. In a retrospective cross-sectional review of 30 PSC patients and 45 non-PSC controls, there was no significant difference in the overall complication rate (12.9% vs. 8.6%, p=0.45). However, the rate of complication was significantly higher in PSC patients with an acute indication for an ERCP compared to those without (29.2% vs. 6.6%, p=0.01). There was no difference in the complication rate for diagnostic and therapeutic procedure or those with balloon dilation and stenting (70).
In a larger retrospective review comparing 165 PSC patients to 981 non-PSC controls there was no overall difference in the rate of ERCP-related complications (11% vs. 8%, p=0.2), despite the PSC population having more biopsies, brushings, dilations and longer procedures. There was a significantly increased risk of cholangitis (4% vs. 0.2%, p<0.002) despite the use of antibiotics, but no difference in the rate of pancreatitis, perforation of hemorrhage (35). Despite studies demonstrating similar complication rates between PSC and non-PSC patients, the multifocal stricturing nature of PSC demands certain precautions be undertaken beyond what has been discussed thus far to avoid intervention related biliary injury, infection and unindicated endoscopic interventions. Figure 10 highlights an instance of an uncovered SEMS (uSEMS) placement for misdiagnosis of malignancy in a patient with PSC and a complex hilar stricture. The patient has been managed for a number of years and requires frequent balloon dilations and stent exchanges. The presence of the uSEMS increases the risk of cholangitis and thus prolonged antibiotics have been required. Bile duct perforation can occur with endoscopic management of PSC-related strictures and caution must be taken when maneuvering tight biliary strictures (Figure 11). As previously alluded to, direct visualization with cholangioscopy may have a role in these cases and allow for safer assessment. Ultimately, caution must be exercised when managing PSC and providers must be familiar with the complex nature of the underlying disease and ensure the appropriateness of any and all endoscopic interventions.
Summary PSC is a complex fibro-inflammatory cholestatic biliary condition with a progressive disease course commonly complicated by dominant biliary strictures and associated with an increased incidence of cholangiocarcinoma. There are numerous conditions that can present similarly and must be excluded in the initial evaluation. Cholangiography is the mainstay diagnostic technique in large duct disease. The role of ERCP has become increasingly supportive with data suggesting a beneficial impact on overall survival and comparable complication rates to that observed in non-PSC populations. Despite multiple endoscopic advancements, differentiating benign and malignant biliary strictures remains an obstacle.
Acknowledgements: We would like to give a special thanks to Diane E. Lee for her assistance with manuscript preparation, processing and submission. Conflicts of interest: Anthony Razzak (none); Richard Kozarek (none)
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Table and Figure legend:
Table 1. Causes of secondary sclerosing cholangitis Description: Table outlining causes of secondary sclerosing cholangitis grouped by etiology subcategorization
Figure 1. ERCP cholangiogram in PSC Description: ERCP cholangiogram revealing Intra- and extra-hepatic multifocal biliary ductal stricturing and dilation (arrows highlighting areas of stricturing).
Figure 2. MRCP cholangiogram in PSC Description: MRCP cholangiogram in PSC revealing predominately intrahepatic multifocal bile duct stricturing and dilation (arrows highlighting areas of stricturing).
Figure 3. Bile ducts stones Description: Endoscopic view of a black pigment stone in PSC (left) and cholangiographic view of multiple mixed pigment stones in PSC (right)
Figure 4. Dominant strictures in PSC Description: A dominant common hepatic duct and hilar stricture with upstream biliary dilation in a patient with intra- and extra-hepatic duct PSC (arrows highlighting areas of stricturing).
Figure 5. Cross sectional abdominal imaging and corresponding cholangiogram in hilar cholangiocarcinoma Description: A contrast enhanced CT abdomen revealing a hypoenhancing hilar mass (left) with a corresponding ERCP cholangiogram demonstrating a Bismuth IV cholangiocarcinoma and multifocal intrahepatic PSC related strictures
Figure 6. Fluorescence in situ hybridization (FISH) with polysomy
Description: Reprinted with permission (56). Fluorescently labeled DNA revealing polysomy for three chromosomes (fluorescently labeled blue, green and red), a finding that suggests malignancy.
Figure 7. Cholangioscopy in cholangiocarcinoma Description: ERCP cholangiogram with a malignant appearing hilar stricture (top left) and cholangioscopy images ulcerated biliary epithelium and intraductal mass. Papillary fronds are noted (bottom right, arrows highlighting fronds) and highly concerning for cholangiocarcinoma.
Figure 8. Endosonographic FNA of a hilar cholangiocarcinoma Description: ERCP cholangiogram with a hilar cholangiocarcinoma (left) and corresponding EUS-FNA of the hilar mass (right) (arrow highlighting FNA).
Figure 9. Probe based confocal laser endomicroscopy (pCLE) in an indeterminate biliary stricture Description: ERCP cholangiogram with an indeterminate left main biliary stricture and upstream dilation (left) (arrow highlighting stricture). Cholangioscopy revealed non-specific scarring and fibrosis (top right). pCLE revealed dark clumps and thick white bands suggestive of malignancy (bottom right) (arrow highlighting thick white band).
Figure 10. Misdiagnosis of PSC and placement of an uSEMS Description: ERCP cholangiogram with a common bile duct uSEMS that was placed in the setting of a misdiagnosis of cholangiocarcinoma in a patient with PSC. There is evidence of right and left main dominant strictures that are treated with balloon dilation and short-term stenting.
Figure 11. Bile duct perforation Description: ERCP cholangiogram with evidence of a TIPS and uSEMS that was placed years prior percutaneously for a misdiagnosis of cholangiocarcinoma. Cholangiogram reveals left intrahepatic ductal dilation and a guidewire perforation with extra-luminal contrast extravasation while attempting wire advancement into the left biliary system (arrow).
Table 1. Causes of secondary sclerosing cholangitis
Secondary sclerosing cholangitis Malignant obstruction Cholangiocarcinoma Hepatocellular carcinoma Lymphoma Metastasisa Non-malignant obstruction Choledocholithiasis Chronic pancreatitis Portal hypertensive biliopathy Hepatic inflammatory pseudotumor Toxic & ischemic biliary injury Critical illness Iatrogenic and traumatic hepatic artery injury Hepatic artery thrombosis Critical illness Chemotherapyb Drug induced liver injuryc Allograft rejection Graft-versus-host disease Immune mediated IgG4-mediated cholangiopathy AIH overlap syndrome Sarcoidosis Behcet’s disease AIDS cholangiopathyd Hypereosinophilic syndrome Systemic mastocytosis and mast cell cholangiopathy Langerhan’s cell histiocytosis (Histiocytosis X) Combined immune deficiency Infectious Recurrent pyogenic cholangitis (Oriental cholangiohepatitis)e CMV Cryptosporidium/Microsporidium Echinococcus Mycosis Congenital/Genetic Cystic fibrosis Caroli’s disease
Progressive familial intrahepatic cholestasisf Alagille syndrome Biliary artresia a: including colorectal adenocarcinoma, melanoma, sarcoma, and breast carcinoma b: including floxuridine (FUDR, hepatic arterial infusion), paclitaxel, 5-fluorouracil, and yttrium 90 c: suspected agents include amoxicillin-clavulanate, green tea extract, sevoflurane, amiodarone, infliximab, venlafaxine, atorvastatin, and ketamine d: predisposition to cryptosporidium/microsporidium, CMV and other biliary opportunistic infections e: suspected pathogens include biliary parasitosis (including Ascaris, Clonorchis) and glucuronidase producing bacteria (including Escherichia coli, Bacteroides species, and Clostridium perfringens) f: mutations in APT8B1, ABCB11 or ABCB4(MRP3) genes