PRACTICAL GASTROENTEROLOGY • JULY 2011 30 Diagnostic and Therapeutic Endoscopy of Biliary Diseases DISEASES OF THE BILIARY TRACT, SERIES #6 Rad Agrawal, M.D., Series Editor by Yamini Subbiah, Shyam Thakkar, Elie Aoun The therapeutic approach to biliary diseases has undergone a paradigm shift over the past decade toward minimally invasive endoscopic interventions. This paper reviews the advances and different diagnostic and therapeutic endoscopic approaches to common biliary diseases including choledocholithiasis, benign and malignant biliary strictures and bile leaks. INTRODUCTION W ith the introduction of innovative endoscopic implements and options allowing for unprece- dented access to the biliary tree, the therapeutic approach to biliary diseases has undergone a significant paradigm shift over the past decade toward minimally invasive endoscopic interventions. The days where bil- iary diseases were exclusively managed surgically are long gone, and much has changed since the first reported biliary sphincterotomies in 1974. The recent developments in peroral cholangioscopy and new modalities of anchoring high resolution nasogastric scopes in the bile duct offer the opportunity of direct visualization of the bile duct lumen, which allows for not only better identification of the underlying disease process but also for targeting of biopsies and directed lithotripsy. Other modalities that add to the growing world of biliary luminal imaging include endoscopic ultrasound (EUS) and intraductal ultrasound, which enable the endoscopist to assess extrabiliary disorders. EUS-assisted fine needle aspiration (FNA) tissue sam- pling and immediate preliminary histopathologic analy- sis also assist in immediate decision making and therapeutics. Other recent advances include cutting- edge molecular imaging technology that allows the endoscopist to differentiate between benign and malig- nant features, thus guiding decision making in real time. COMMON BILE DUCT STONES Over 98% of biliary disorders are linked to gallstones. Stones are found in the common bile duct (CBD) in up to 18% of patients with symptomatic cholelithiasis (1). The vast majority of gallstones are cholesterol-rich, form in the gallbladder and gain access to the CBD via the cystic duct. De novo CBD stone formation is also well described and is more common in patients of Asian descent. These primary duct stones typically have a higher bilirubin and a lower cholesterol content and biliary stasis; further, bacterial infections have been implicated in their pathogenesis (2,3). CBD stones can lead to several complications including bil- iary colic, obstructive jaundice and cholangitis. Diagnostic Imaging Tests While a minority of patients with a straight-forward clinical presentation consistent with choledocholithia- sis may immediately be treated with ERCP, the vast majority will benefit from diagnostic imaging studies to confirm the diagnosis. Performing a diagnostic ERCP with no prior imaging is not optimal due to the potential risks associated with the procedure. Current imaging modalities available for this purpose include transabdominal ultrasound, regular- and high-resolu- Yamini Subbiah, MD; Shyam Thakkar, MD; Elie Aoun, MD, MS, West Penn Allegheny Health System, Divi- sion of Gastroenterology, Hepatology and Nutrition, Pittsburgh, PA. (continued on page 32)
Transcript
PRACTICAL GASTROENTEROLOGY • JULY 201130
Diagnostic and TherapeuticEndoscopy of Biliary Diseases
DISEASES OF THE BILIARY TRACT, SERIES #6
Rad Agrawal, M.D., Series Editor
by Yamini Subbiah, Shyam Thakkar, Elie Aoun
The therapeutic approach to biliary diseases has undergone a paradigm shift over the past decade toward minimally invasive endoscopic interventions. This paperreviews the advances and different diagnostic and therapeutic endoscopic approachesto common biliary diseases including choledocholithiasis, benign and malignant biliarystrictures and bile leaks.
INTRODUCTION
With the introduction of innovative endoscopicimplements and options allowing for unprece-dented access to the biliary tree, the therapeutic
approach to biliary diseases has undergone a significantparadigm shift over the past decade toward minimallyinvasive endoscopic interventions. The days where bil-iary diseases were exclusively managed surgically arelong gone, and much has changed since the firstreported biliary sphincterotomies in 1974. The recentdevelopments in peroral cholangioscopy and newmodalities of anchoring high resolution nasogastricscopes in the bile duct offer the opportunity of directvisualization of the bile duct lumen, which allows fornot only better identification of the underlying diseaseprocess but also for targeting of biopsies and directedlithotripsy. Other modalities that add to the growingworld of biliary luminal imaging include endoscopicultrasound (EUS) and intraductal ultrasound, whichenable the endoscopist to assess extrabiliary disorders.EUS-assisted fine needle aspiration (FNA) tissue sam-pling and immediate preliminary histopathologic analy-sis also assist in immediate decision making andtherapeutics. Other recent advances include cutting-edge molecular imaging technology that allows the
endoscopist to differentiate between benign and malig-nant features, thus guiding decision making in real time.
COMMON BILE DUCT STONESOver 98% of biliary disorders are linked to gallstones.Stones are found in the common bile duct (CBD) in upto 18% of patients with symptomatic cholelithiasis (1).The vast majority of gallstones are cholesterol-rich,form in the gallbladder and gain access to the CBD viathe cystic duct. De novo CBD stone formation is alsowell described and is more common in patients ofAsian descent. These primary duct stones typicallyhave a higher bilirubin and a lower cholesterol contentand biliary stasis; further, bacterial infections havebeen implicated in their pathogenesis (2,3). CBDstones can lead to several complications including bil-iary colic, obstructive jaundice and cholangitis.
Diagnostic Imaging TestsWhile a minority of patients with a straight-forwardclinical presentation consistent with choledocholithia-sis may immediately be treated with ERCP, the vastmajority will benefit from diagnostic imaging studiesto confirm the diagnosis. Performing a diagnosticERCP with no prior imaging is not optimal due to thepotential risks associated with the procedure. Currentimaging modalities available for this purpose includetransabdominal ultrasound, regular- and high-resolu-
Yamini Subbiah, MD; Shyam Thakkar, MD; Elie Aoun,MD, MS, West Penn Allegheny Health System, Divi-sion of Gastroenterology, Hepatology and Nutrition,Pittsburgh, PA. (continued on page 32)
tion computed tomography (CT) scans, magnetic reso-nance cholangiopancreatography (MRCP) and EUS.
A transabdominal ultrasound remains the initialtest of choice in suspected cases of choledocholithiasisbecause of its wide-spread availability and relativelylower costs. Dilated ducts seen on ultrasound arehighly suggestive of biliary obstruction; however, normal caliber ducts do not exclude a CBD stone. Furthermore, differentiating between causes ofobstruction may also be difficult using this imagingmodality. Even still, while the transabdominal ultra-sound’s sensitivity in detecting choledocholithiasis islow (ranging between 25% and 58%), its specificitycan be greater than 95% (4–6).
MRCP has catapulted to the frontlines of diagnos-tic imaging and is typically the next test physicians perform following an indeterminate transabdominalultrasound. Its sensitivity and specificity is 95% and97%, respectively, in detecting the presence and levelof biliary obstruction. However, its sensitivity in detect-ing stones is a function of stone size. While it rangesfrom 67%–100% for stones larger than 1 cm, it can beas low as 33%–71% in stones less than 6 mm (7–9).
Conventional CT scans have relatively good accu-racy (70%–94%) when it comes to identifying both thepresence and the cause of biliary obstruction (10,11).A newer technique, the helical CT cholangiography(hCTC), is yet another diagnostic option and allowsfor three-dimensional reconstitution of images throughthe use of volumetric data after the administration ofboth oral and intravenous (IV) contrast. It has provento be beneficial in detecting CBD stones with a sensi-tivity of ~87% and a high specificity of 97%, account-ing for an overall accuracy of 95% (12,13). However,
hCTC remains underused due to its limited availabilityas compared with MRCP.
Over the past few years, the use of EUS as a diag-nostic imaging modality for CBD stones has gainedsignificant momentum. While more invasive than theabove methods, its associated risks and complicationsare lower than those with ERCP. The sensitivity andspecificity at detecting CBD stones are 95% and 98%,respectively, with a total accuracy of 96% (14,15).Furthermore, studies have shown that in cases withmoderate or low clinical suspicion for choledocholithi-asis, the use of EUS may prevent up to 30% of unnec-essary ERCPs (16). Figure 1A illustrates an EUSshowing a stone in the CBD.
Endoscopic TherapyPrior to the introduction of ERCP with sphincterotomyin the 1970s, choledocholithiasis was mainly managedwith surgical extraction and open bile duct exploration(17). Now, endoscopic techniques are first-line therapyfor CBD stones.
ERCP should be reserved for patients in whom atherapeutic intervention is likely to occur. Neverthe-less, in certain rare situations where the diagnosisremains uncertain despite multiple imaging modalities,ERCP may be required. Once the diagnosis is sus-pected or established, stone extraction and ductalclearance become the therapeutic goals. Using a side-viewing scope which allows direct visualization andeasy access to the papilla, cannulation of the bile ductcan be performed using a variety of available instru-ments including cannulas and sphincterotomes. In thehands of an experienced endoscopist, cannulation suc-cess rates average ~95% (18). Once ductal access isestablished, contrast can be used to opacify and visu-alize the lumen. Typically stones are identified on thecholangiogram as filling defects around which the con-trast flows. Opacification of the ducts also allows formeasurement of the severity of the dilation proximal tothe stone if any. Frey et al quote the accuracy of ERCPat detecting CBD stones to be at 96% (19).
Once the stone is identified, the focus shifts toextracting it from the duct. Figure 1B shows gallstoneextraction during ERCP. In the majority of cases, a bil-iary sphincterotomy is needed prior to stone removal.
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Figure 1. Endoscopic ultrasound showing stone in the common bile duct; B) Gallstone extraction during ERCP.
(continued from page 30)
In certain cases where such a cut may be problematic,such as in patients on anticoagulation, the endoscopistmay elect to balloon dilate the sphincter area. It shouldbe noted though that there are reports of higher risks ofpost-ERCP pancreatitis in cases where balloon dilationhas been used (20). In cases where cannulation is diffi-cult to achieve, a needle knife papillotome can be usedin a technique known as “precutting” to establish directaccess into the bile duct. Once access is achieved, avariety of instruments are available to attempt ductalclearance. Most stones up to 15 mm in size can beremoved by sweeping the ducts with an extraction bal-loon, or alternatively by using a Dormia basket pro-vided that a large enough sphincterotomy has beenperformed (21). In certain instances, though, the stonesize may be too large to extract, and as such, alternativemethods such as lithotripsy should be considered.
Different lithotripsy modalities are availableincluding mechanical, electrohydraulic, laser and extra-corporeal shock wave (22,23). Mechanical lithotriptorsare widely available. They consist of a basket with twosheaths: plastic and metal. Once the stone is caught inthe basket wires, the metal sheath is advanced over theplastic sheath, and the stone is crushed into smallerpieces against the metal. Mechanical lithotripsy hashigh success rates but can be limited in the setting ofstone impaction (24). Most tertiary care centers havethe capability of performing intraductal lithotripsythrough the use of a SpyGlass® choledochoscope(Boston Scientific Corp, Natick, MA, USA), whichallows for direct visualization of the ductal lumen (25).Laser lithotripsy amplifies light energy to break up thestone, while the electrohydraulic method relies onshock waves produced by a power generator and trans-mitted through a bipolar electrode (22,26).
Under certain circumstances, only partial ductalclearance is achieved, and a repeat ERCP is needed. Insuch situations, it is typical to insert a temporary bil-iary stent to secure ductal patency while the patientawaits the second procedure (27). In most cases, theERCP can be performed on an outpatient basis anddoes not require an overnight hospital stay unless earlypost-procedure complications are suspected.
The readmission rates following biliary sphinctero-tomy and same day discharge are approximately 6%,with the majority of cases being readmitted for post-
ERCP pancreatitis. Readmission is more likely to occurin patients who have one or more of the following riskfactors: suspected sphincter of Oddi dysfunction, cir-rhosis, difficult bile duct cannulation, precut sphinctero-tomy, or combined percutaneous-endoscopic procedure.The majority of complications requiring readmissionoccur within six hours following the procedure (28).
PREVENTING RECURRENCERecurrent CBD stones occur most frequently in patientswith concurrent choledocholithiasis and cholelithiasis(29). A study of 371 patients who underwent an ERCPwith sphincterotomy but who did not undergo subse-quent cholecystectomy over a span of 7.7 years found a10% recurrence rate of choledocholithiasis (30). Asmaller study of 120 patients who had undergone a bil-iary sphincterotomy for CBD stones and who were ran-domized to laparoscopic cholecystectomy or a “waitand see” policy found that recurrent biliary events wereobserved more frequently over the next 2 years in thewatchful waiting group as compared to the treated group(47% versus 2%, respectively) (31). It is therefore rec-ommended that an elective cholecystectomy be per-formed as soon as possible following ductal clearance ifthe patient is deemed to be a surgical candidate.
BILIARY STRICTURESBiliary strictures can be benign or malignant. The gen-eral approach to treatment is based on the need to re-establish bile flow through the narrowed area in orderto avoid complications including biliary stasis, jaun-dice and infections. A wide spectrum of clinical pre-sentations has been described with biliary stricturesranging from asymptomatic patients with mild liverfunction test abnormalities to full blown obstructivejaundice, hyperbilirubinemia and recurrent episodes ofcholangitis. Many classifications have been generatedfor biliary strictures. However, the Bismuth classifica-tion is the most widely used. It subdivides stricturesinto five groups depending on the stricture locationwithin the biliary tree (Table 1) (32).
Differentiating between benign and malignant eti-ologies is of high clinical importance. A full discussionabout the clinical indices of possible malignancy isbeyond the scope of this review; however, certain ele-
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ments in the patient history such as recent biliary surgi-cal interventions, liver transplantation, pancreatitis,inflammatory bowel disease, unexplained weight loss,and presence of palpable lymph nodes may point to thelikely etiology. Lower alkaline phosphatase (ALP) andaspartate aminotransferase (AST) levels have been notedin benign strictures while elevated tumor markers levelssuch as Ca19-9 and carcinoembryonic antigen (CEA)increase the suspicion of a malignant process (33,34).
Non-invasive Imaging in Biliary StricturesA wide array of noninvasive imaging modalities areavailable for evaluation of biliary strictures includingultrasonography, CT, cholangiogram, MRCP, andpositron emission tomography (PET). More invasiveimaging including EUS with FNA may be used to fur-ther investigate the nature of the stricture.
The transabdominal ultrasound is usually the firstimaging investigation performed to evaluate possiblebiliary obstruction with a 78%–98% accuracy atdetecting an extrahepatic biliary obstruction; however,it fails at accurately determining the level and etiologyof such an obstruction (14). HIDA scans are of littlevalue beyond pointing out that an actual obstruction ispresent (35). MRCP is currently the best noninvasiveimaging study available and has an overall sensitivityof 95% and a specificity of 97% in demonstrating boththe presence and the level of a stricture. Furthermore,the cholangiogram obtained can serve as a roadmapwhich will help plan and guide endoscopic interven-tions. Ampullary lesions and pancreatic cancers withno pancreatic duct dilations may not be detected by anMRCP (14). In certain instances, a PET study may beused to help differentiate malignant etiologies such ascholangiocarcinoma and metastatic lesions frombenign processes (36).
Endoscopic Diagnostic ApproachesMore invasive diagnostic modalities allow for betterimaging and tissue sampling. They include EUS,ERCP and intraductal ultrasonography (IDUS).
EUS with FNA can help determine the nature ofthe stricture. The sensitivity of EUS-FNA in diagnos-ing malignant strictures by a trained advanced endo-scopist can be as high as 86% (37). Furthermore, EUShas been shown to be superior to CT scan imaging indetecting distal biliary malignant processes (38). Addi-tionally, EUS can be used for staging purposes if amalignancy is suspected or established.
ERCP is both diagnostic and therapeutic in its appli-cation to strictures. It allows for the application of a basicapproach to this disease process including dilation andstenting to allow bile flow through the narrowed portionof the duct (Figure 2). In addition, ERCP techniquesallow direct visualization of the strictured segmentthrough the use of cholangioscopy, therefore improvingdiagnostic outcomes through the use of targeted brushingand biopsies. In general, biliary brush cytology has a rel-atively low sensitivity ranging from 35%–70% in detect-ing a malignancy (39, 40). The addition of fluorescencein situ hybridization (FISH) analysis to routine brush
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Table 1. Bismuth Classification
Stricture Type Description
Benign stricturesType 1 Low common bile duct stricture
>2 cm distal to the bifurcation Type 2 Mid common bile duct stricture
<2 cm distal to the bifurcationType 3 Hilar Stricture Type 4 Hilar stricture extending into both
left and right hepatic ductsType 5 Hilar stricture extending into either
the right or the left hepatic duct
Malignant StricturesType 1 Low common bile duct stricture
>2 cm distal to the bifurcation Type 2 Mid common bile duct stricture
<2 cm distal to the bifurcationType 3a Hilar stricture extending into the
right hepatic ductType 3b Hilar stricture extending into the
left hepatic ductType 4 Multifocal tumor, or tumors
extending into the right and lefthepatic ducts
PRACTICAL GASTROENTEROLOGY • JULY 201136
cytology improves the brushing’s diagnostic accuracy(41). Targeted intraductal forceps biopsies through theuse of a cholangioscope can improve the sensitivity to ashigh as 96% (42). The use of SpyGlass® cholangioscopyresults in a sensitivity of 71% and specificity of 100% indiagnosing malignancy in an indeterminate stricture(43). IDUS is a relatively newer technique which canbetter evaluate and distinguish between benign andmalignant lesions when coupled with ERCP, increasingthe diagnostic accuracy to up to 90% (14).
Image-enhanced cholangioscopy techniquesinclude chromocholangioscopy, autofluorescence imag-ing (AFI) and narrow band imaging (NBI). These mayfurther enhance the ability to detect malignancies inindeterminate lesions but have a limited availability andrequire a high level of training (44). Confocal electro-microscopy has been recently introduced as an addi-tional imaging modality. The miniprobe is used inconjunction with a cholangioscope, and it allows for thedetection of specific vasculature patterns. The presenceof irregular vessels predict a neoplastic process with anaccuracy of 86%, a sensitivity of 83%, with a specificityof 88%. Further investigative studies are ongoing to bet-ter determine its future application (44–46).
Managing Malignant StricturesCommon etiologies of malignant biliary stricturesinclude pancreatic carcinoma, ampullary carcinoma,cholangiocarcinoma, gallbladder cancer, hepatocellu-lar carcinoma and metastatic lesions. Once a malig-nancy has been established, the focus switches todetermine the extent of the disease and its resectability.
Patients should be referred for surgical and oncologicevaluation. Immediate relief of the obstruction shouldbe established if possible. The use of temporary plas-tic stents is favored in patients who may be surgicalcandidates or in cases where the diagnosis is unclear.Self expanding metal stents (SEMS) are usuallyreserved for patients with unresectable disease and alife expectancy exceeding five to six months (47).
Special Patient Populations: Chronic Pancreatitis, Primary Sclerosing Cholangitis and Liver Transplant RecipientsChronic pancreatitis related distal bile duct stricturesdeserve special attention as they account for up to 10%of all CBD strictures and carry a significant amount ofmorbidity. Inflammation and fibrosis can make it diffi-cult to establish adequate access during an ERCP, andendoscopic management can therefore be limited. Stud-ies suggest that the use of multiple stents may be supe-rior to single stents in this patient population. In casesrefractory to repeated stenting and endoscopic therapy,surgery may be required and is usually complicatedbecause this patient population typically suffers fromcomorbid conditions and additional complications suchas vascular thrombosis and liver involvement (43).
In patients with primary sclerosing cholangitis(PSC), chronic inflammation leads to multiple fibroticstrictures of the entire biliary tree and eventually resultsin significant liver disease and cirrhosis (Figure 3).Medical therapy has not proven to be of benefit, and theuse of ursodeoxycholic acid is no longer recommended.Liver transplantation is the only long-term option for
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Figure 3. Cholangiogram showing significant extrahepatic(thick arrow) and intrahepatic (thinner arrows) structuringconsistent with primary sclerosing cholangitis.
Figure 2. Ischemic common bile duct stricture seen oncholangiogram with dilation of the proximal bile duct.
severe cases. Dominant extrahepatic strictures are com-mon in PSC patients occurring in up to 50% of cases.They may lead to cholangitis, which in turn can worsenthe extent of damage to the liver. Their presence is typ-ically suspected clinically based on worsening jaundiceand pruritis and increasing liver function test abnormal-ities. It is important to rule out a malignant process inthese patients in view of the substantially increased riskof cholangiocarcinoma (8%-14% of patients) (48).Endoscopic therapy consists of dilation of the dominantstricture and extraction of any stones or sludge that maybe lodged above the strictured area. Short-term stentingmay be effective in a small number of patients. Howeverstent occlusion remains a problem. Repeat dilations maybe required in many cases. Stenting after balloon dila-tion may not have any additional benefit (49).
Anastomotic strictures are common post orthotopicliver transplantation (OLT) with an incidence around5%–10%. These typically are short segment stricturesand occur within one year of the transplant with earlystrictures resulting from technical complications of thesurgery and later ones from vascular insufficiency andfibrosis (50). Risk factors include tension at the anasto-mosis, caliber mismatch between donor and recipientducts, and excessive use of electrocauterization for con-trol of intra-operative bleeding (51). Endoscopic man-agement with repeated dilation and stenting remains thetreatment of choice. Newer data suggest that the use offully covered metal stents may be beneficial in thesepatients by spacing out the ERCPs needed and thereforedecreasing costs and associated risks (52).
BILE LEAKSBile leaks occur mainly as a complication of biliarysurgery, including laparoscopic cholecystectomy (upto 1.1% of cases) and cadaveric OLT. The leak canoccur at the cystic duct stump or can involve thesmaller ducts of Luschka. The presentation is typicallyacute within the first few days following surgery butmay be delayed with a few cases presenting up to onemonth later. Imaging studies, such as an ultrasound orCT scan of the abdomen, are usually diagnostic, butthe absence of a biloma on imaging does not excludethe diagnosis. Endoscopic cholangiography can estab-lish the diagnosis in the vast majority of patients and
can provide therapeutic means in the same setting (53).Figure 4 shows a cholangiogram illustrating a bile leakin a patient with a recent cholecystectomy.
The therapeutic goal is to establish an area of lowerresistance for the bile to flow through. This is usuallyachieved by the insertion of a short temporary biliarystent, therefore relieving the high transpapillary pres-sure gradient. A biliary sphincterotomy may be enoughin certain milder cases. Response is typically measuredby the clinical improvement and decreased outputsfrom percutaneous surgical drains. Stents are typicallyleft in place for about four to six weeks. Bile leaksrefractory to endoscopic treatment typically requiresurgical interventions to correct the defect (54).
CONCLUSIONSIn summary, much progress has been made over recentyears in diagnosing and treating biliary tract disorders.Endoscopic therapy has become the predominantmodality used in both the diagnosis and treatment ofthese disorders. The future of therapeutic endoscopypromises to be quite interesting as it continues toevolve and offer more innovative new techniques. n
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DISEASES OF THE BILIARY TRACT, SERIES #6
Diagnostic and Therapeutic Endoscopy of Biliary Diseases
