Endoscopic Management of Hepatobiliary Complications of Inflammatory Bowel Disease





List of Abbreviations


AASLD


The American Association of Study for Liver Disease


CC


Cholangiocarcinoma


CD


Crohn’s disease


DC


Direct cholangioscopy


DIA


Digital image analysis


EASL


The European Association for the Study of the Liver


EIM


Extraintestinal manifestations


ERCP


Endoscopic retrograde cholangiopancreatography


EUS


Endoscopic ultrasound


FISH


Fluorescence in situ hybridization


FNA


Fine needle aspiration


IBD


Inflammatory bowel disease


IDUS


Intraductal ultrasound


IPAA


Ileal pouch-anal anastomosis


MRCP


Magnetic resonance cholangiopancreatography


pCLE


Probe-based confocal laser endomicroscopy


POC


Peroral cholangioscopy


PSC


Primary sclerosing cholangitis


PTC


Percutaneous transhepatic cholangiography


SOC


Single operator cholangioscopy


UC


Ulcerative colitis




Introduction


Inflammatory bowel disease (IBD) can be associated with a variety of extraintestinal manifestations (EIMs), which affect the eyes, skin, liver, and joints. Such EIMs are seen in about 25%–40% of patients with IBD and can occur in patients with both Crohn’s disease and ulcerative colitis (UC). EIMs commonly involve liver, biliary tract, and pancreas ( Table 20.1 ), and primary sclerosing cholangitis (PSC) is the most important hepatopancreatobiliary manifestation of IBD. Of the various conditions listed in Table 20.1 , endoscopic intervention plays a particularly vital role in the diagnosis and treatment of PSC and cholangiocarcinoma (CC).



Table 20.1

List of Hepatopancreatobiliary Diseases in IBD







































Biliary Tract/Gall Bladder Diseases


  • 1.

    Classical primary sclerosing cholangitis (PSC)



  • 2.

    Small duct type PSC



  • 3.

    PSC/autoimmune hepatitis overlap



  • 4.

    Cholangiocarcinoma

Hepatic Diseases


  • 1.

    Hepatic steatosis



  • 2.

    Drug-induced hepatitis



  • 3.

    Liver cirrhosis



  • 4.

    Granulomatous hepatitis



  • 5.

    Hepatic amyloidosis



  • 6.

    Liver abscess



  • 7.

    Primary biliary cirrhosis.

Pancreatic Diseases


  • 1.

    Gall stone pancreatitis



  • 2.

    Drug-induced pancreatitis



  • 3.

    Idiopathic acute and chronic pancreatitis



  • 4.

    Autoimmune pancreatitis.





Diagnosis of Primary Sclerosing Cholangitis


In the right setting, PSC can be reliably diagnosed with endoscopic imaging or CT or MRI imaging. Tissue diagnosis may be needed in small-duct PSC.


Definition


PSC is an autoimmune disease, which affects intrahepatic and extrahepatic biliary tree. It is characterized by progressive inflammation and fibrosis of biliary tract resulting in multifocal strictures and chronic cholestatic liver disease, which eventually progress to portal hypertension, cirrhosis, and hepatic decompensation.


Primary Sclerosing Cholangitis and Inflammatory Bowel Disease


PSC is very closely related to IBD, and about 60%–80% of patients with PSC have IBD. Among IBD, UC is more prevalent in PSC and is present in about 48%–86% patients of PSC. Conversely PSC is estimated to be present in about 2.4%–7.5% of patients with UC. UC patients with PSC demonstrate characteristic endoscopic and clinical features, as compared to UC without PSC. These include rectal sparring, pancolitis, back wash ileitis, mild clinical symptoms, higher risk of colorectal cancer, and increased risk of pouchitis after colectomy and ileal pouch-anal anastomosis (IPAA).


Diagnostic Criteria for Primary Sclerosing Cholangitis


Following are the essential diagnostic criteria of PSC: (1) cholestatic pattern of liver enzyme elevation (elevated alkaline phosphatase is the most common biochemical abnormality in PSC) ; (2) cholangiography (e.g., magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP], percutaneous transhepatic cholangiography [PTC]) showing multifocal strictures and segmental dilatations in bile ducts ( Fig. 20.1 ); (3) exclusion of secondary causes of sclerosing cholangitis ; and (4) in patients with cholestatic liver injury and characteristic findings on cholangiography, a liver biopsy is typically not required. Liver biopsy is reserved for patients with suspected small-duct PSC or an overlap syndrome with autoimmune hepatitis is suspected.




Figure 20.1


Cholangiogram showing a high-grade stricture measuring 3.5 cm in length involving the distal bile duct up to the cystic duct take off with moderate proximal biliary dilation. Severe intrahepatic primary sclerosing cholangitis changes are noted.


Endoscopic Retrograde Cholangiopancreatography and Magnetic Resonance Cholangiopancreatography for Primary Sclerosing Cholangitis Diagnosis


ERCP is the standard of reference for PSC diagnosis and was originally considered as the gold standard for diagnosis of PSC. ERCP has certain advantages and disadvantages to MRCP in the evaluation of patients with PSC. Advantages include increased sensitivity to peripheral intrahepatic duct abnormalities and capabilities for interventions like dilatation of a stricture, stone removal, stent placement, and biopsy. ERCP also has a useful role in excluding large duct PSC where views with MRCP may not be optimal. However being an invasive procedure, it is often associated with serious side-effects like pancreatitis, bacterial cholangitis, perforations, and hospitalization in approximately 10% of patients undergoing the procedure.


MRCP is a noninvasive technique for cholangiography. It offers several advantages over ERCP in terms of it being cheaper, noninvasive, no ionizing radiation exposure, requires no anesthesia, and better demonstration of ducts proximal to an obstruction. A metaanalysis showed that MRCP has a high sensitivity (86%) and a very high specificity (94%) for detection for PSC. Given these factors MRCP has become the diagnostic imaging modality of choice when PSC is suspected. Hence MRCP should be performed a first step toward a diagnosis up of PSC, followed by ERCP, if required, for any nondiagnostic MRCP or interventions.




Endoscopic Treatment of Primary Sclerosing Cholangitis


PSC is characterized by the formation of biliary strictures. Dominant biliary stricture in PSC is defined as: (1) stenosis ≤1.5 mm in diameter in the common bile duct; or (2) stenosis ≤1 mm in the right or left hepatic duct. These strictures can lead to extrahepatic biliary obstruction resulting in jaundice, pruritus, abdominal pain, cholangitis, and progressive hepatic dysfunction, necessitating intervention. Primary aim of the intervention is to relieve the biliary obstruction and reestablish the biliary flow. Endoscopic approach with ERCP is the most preferred method. Several endoscopic modalities including sphincterotomy, catheter or balloon dilatation, and stent placement can be used alone or in combination ( Figs. 20.2 and 20.3 ).




Figure 20.2


Balloon dilatation of the distal biliary stricture.



Figure 20.3


10 F × 10 cm plastic stent insertion in the bile duct.


Endoscopic Retrograde Cholangiopancreatography With Stenting


Initial studies used in situ stent placement for 2–3 months, for treatment of PSC-associated dominant stricture, but were associated with high incidence of cholangitis with stent occlusion (50%). This led to studies with temporary stent placement (average 9–11 days), which showed significant improvement in cholestatic symptoms and sustained benefits for several years. However they were associated with complications including pancreatitis, biliary tract perforation, and hydrops of the gallbladder in 7%–15% of the cases.


Endoscopic Retrograde Cholangiopancreatography With Balloon Dilatation and Stenting


Subsequent studies showed that stenting with dilatation offered no additional benefit as compared to dilatation alone and that stenting is associated with more complications.


Endoscopic Retrograde Cholangiopancreatography With Balloon Dilatation


In a prospective study of 106 PSC patients taking ursodeoxycholic acid, 52 patients developed dominant biliary strictures over a period of 13 years. They were managed endoscopically with repeated balloon dilatations and required a mean of 4.5 dilatations per patient over 5 years. The authors preferred dilatation of the dominant stricture over stenting due to following two reasons: (1) frequent and rapid occlusion of stents by inflammatory material draining out of the biliary tree in PSC; and (2) in patients with dominant stricture of the common hepatic duct and another stenosis of one of the hepatic ducts, placement of one stent into a hepatic duct very often worsens the drainage of the other unstented hepatic duct. Very importantly it was also noted that, after relatively frequent dilatations in the first year, the need for further endoscopic measures decreased to 0 to 2 dilatations per year after 3 years and thereafter. The risk for complications of endoscopic procedures is relatively low, including pancreatitis (5.2%) and bacterial cholangitis (3.3%). Stents were only used as temporary measure in patients with evidence of bacterial cholangitis in 5 patients (10%) and were removed within 1–2 weeks after their insertion.


Hence currently, endoscopic balloon dilation alone is the preferred method managing for dominant strictures in PSC. It is an effective method and can be performed periodically. Biliary stents cause more complications and are reserved for cases of unsatisfactory stricture dilatation or cholangitis. This is in accordance with guidelines from the American Association of Study for Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL).


Percutaneous transhepatic interventions including dilatation and/or stenting, produced improvements similar to those brought about by endoscopic therapy, however given the increased morbidity it is reserved for patients with failed endoscopic management.




Diagnosis of Cholangiocarcinoma and Indeterminate Strictures


One of the main adverse consequences of PSC is the development of CC. Some of the patients may develop indeterminate biliary strictures.


Evaluation of Cholangiocarcinoma


CC is the second commonest primary liver tumor after hepatocellular carcinoma, with an incidence of 1–2 cases/100,000 person/year. It is commonly diagnosed in elderly individuals (age > 65 years), but patients with PSC and choledochal cysts often develop CC at a much earlier age. PSC is in fact the most common predisposing factor for CC, with a lifetime risk of 5%–35%. CC originates from cholangiocytes lining the biliary tree. Based on the location, it is classified as intrahepatic (20%), perihilar (50%–60%), and distal extrahepatic tumors (20%). Perihilar tumors are a subtype of extrahepatic CC and further subdivided into type I-IV, based on the extent of perihilar disease (Bismuth-Corlette Classification System). Clinical features also vary depending on the location of the tumor. Extrahepatic tumors commonly present with obstructive features like painless jaundice and pruritus, whereas intrahepatic tumors present with systemic signs like weight loss or malaise with jaundice being a late presentation.


On cross-sectional imaging, the tumor can present as intrahepatic mass, a hilar or distal bile duct stricture/obstruction, with or without a discernible mass. Distinction between benign and malignant biliary strictures is challenging. CC is rare but is associated with poor overall survival (5-year survival rates of <5%) as the majority of the cases are diagnosed at an advanced stage. Hence it is very important to establish the diagnosis at an earlier stage, to offer an opportunity for cure with surgical resection or liver transplantation.


Evaluation of Indeterminate Biliary Stricture


ERCP plays an important role in the evaluation of a biliary stricture, as it enables the provider to obtain cytology/tissue specimens. Cytology specimens are obtained by biliary brushing and biopsy specimens by endobiliary forceps. Although these modalities are highly specific, they are limited by very modest sensitivities when used individually (biliary brush cytology: 45%; Intraductal biopsy: 48%) or even in combination (59%). Low sensitivities are linked to inexperienced endoscopist, sampling errors, intense desmoplastic reaction in the tumor, and difficulty in cytology interpretation. Repeated brushings has shown a higher sensitivity for cytology detection, but it does not improve with a longer brush length or initial stricture dilatation. As a result, there is a growing need for more sensitive but equally specific tests for early diagnosis of CC and detection of malignancy in indeterminate biliary strictures. This has led to the development of several new techniques which offer enhanced cytology assessment and endoscopic options for a more accurate diagnosis.


Advanced Cytological Analysis of Biliary Brushing Specimen


Fluorescence in situ hybridization (FISH) is performed on biliary brushings obtained by ERCP, as an adjunctive test to routine cytology. It uses fluorescence-based polynucleotide probe to detect chromosomal aneuploidy (increase or decrease in chromosome number). The FISH assay includes a 4-probe mixture targeting chromosomes 3,7,17, and a locus-specific probe to 9p21. FISH polysomy, that is, when five or more cells show gains of two or more of the four probes, is considered as a positive result and indicates chromosomal instability. FISH may detect polysomic cells in biliary brushings before other pathological or imaging techniques identify the underlying tumor. Patients with multifocal polysomy (multiple segments of biliary tree) or serial polysomy FISH results are at higher risk for developing CC as compared to those with isolated polysomy.


FISH is more sensitive than cytology and nearly as specific as cytology for the detection of malignant biliary strictures in biliary brushing specimens. A recent metaanalysis evaluated 690 PSC patients for CC with FISH assay, where the pooled sensitivity and specificity of polysomy for CC was 51% and 93% respectively, providing only slight improvement in diagnostic sensitivity over routine brush cytology.


Digital image analysis (DIA) is used as an adjunctive test to routine cytology, and it determines the DNA content of individual cells. A digital image of the nucleus and other cellular constituents is produced by computer analysis. This allows quantification of DNA content, chromatin distribution, and nuclear morphology, which may help distinguish benign and malignant strictures of the biliary tract. In a prospective study comparing, DIA and routine cytology for detecting malignancy in biliary strictures, DIA was associated with higher sensitivity (39% vs. 18%) but significantly lower specificity (77% vs. 98%), limiting its wide spread use.


Flow cytometry is used to identify aneuploid cell populations in tumors and can help establish a diagnosis of malignancy. A study combined ERCP-derived brush cytology, flow cytometric analysis along with serum analysis of CA19-9, and CEA, yielding a diagnostic sensitivity of 88% but a relatively low specificity of 80%. Another study comparing flow cytometry to routine cytological analysis showed similar sensitivity (42%) but significantly lower specificity (77% vs. 92%). As a result, flow cytometry is infrequently used in clinical practice.


Recent advances in technology have rendered peroral cholangioscopy (POC), a useful diagnostic technique in the evaluation of an indeterminate biliary stricture. The permits direct visualization of the biliary tract and obtain image-guided biopsies of the lesion in question, with improved sensitivity and a high specificity. POC can be performed by one of the following methods: (1) mother–daughter (dual operator) cholangioscopy; (2) direct cholangioscopy (DC) with a slim gastroscope; and (3) single-operator catheter-based cholangioscopy (SOC).


One of the important drawbacks of the dual operator cholangioscopy is the requirement of two experienced operators, and it has fallen out of favor after the advent of the SOC and direct cholangioscopy. Advantage of the DC with slim gastroscope is a bigger working channel, superior image quality and capability of using narrow band imaging. However it can only be used in patients with dilated bile ducts. Also, the range of access for DC is limited to the main bile duct. Therefore, its use is limited to pathologies located proximal to bifurcation of the bile ducts. SpyGlass DS is the newest SOC system. A prospective single center study of peroral cholangioscopy by using SpyGlass system reported an overall accuracy of 89% in differentiating benign from malignant biliary stenosis. According to a systemic review, a sensitivity of 76.5% and 66.2% were noted with SpyBite biopsy and SpyGlass cholangioscopy respectively for the diagnosis of malignant biliary strictures. A recent metaanalysis included all three types of POC aforementioned for the evaluation of indeterminate biliary strictures and reported an accuracy of 89% for making a visual diagnosis, 79% for histological diagnosis, and 7% overall adverse event rate. Hence peroral cholangioscopy is an important tool for an advanced endoscopist when conventional evaluation of a biliary stricture with imaging and ERCP is nondiagnostic.


Intraductal Ultrasound


Intraductal ultrasound (IDUS) is a useful adjunct to ERCP for the evaluation of choledocholithiasis, tumor staging, and evaluation of indeterminate biliary strictures. IDUS employs the uses of a slim, high-frequency ultrasound probe entering directly inside the biliary tract to obtain detailed visualization of the biliary tree. It is performed in conjunction with ERCP and only adds additional 5–10 min to the overall ERCP duration. Technically IDUS is not a difficult test to perform, sphincterotomy is not required for cannulation with the newer, smaller IDUS catheters, and complications directly related to IDUS are rare. Biliary strictures noted at IDUS are classified as malignant if is asymmetric or a hypoechoic infiltrating lesion is identified. Hyperechoic and symmetric lesions are considered as benign. In a retrospective study comparing ERCP and IDUS for the evaluation of indeterminate stricture, a correct diagnosis was identified in 67% of the patients by ERCP as compared to 90% by IDUS. A study comparing endoscopic ultrasound (EUS) and IDUS showed that the latter to be significantly more accurate than former for differentiating between benign and malignant strictures. IDUS also performs better in the assessment of proximal biliary lesions, where accuracy of EUS is suboptimal.


EUS With Fine Needle Aspiration


Role of endoscopic ultrasound with fine needle aspiration (EUS-FNA) for the evaluation of indeterminate biliary stricture is still evolving. Multiple studies have reported the sensitivity of EUS-FNA of biliary strictures to be ranging from 47% to 87%. In a recent review of six studies, mean sensitivity of EUS-FNA was 59% for the diagnosis of malignancy in a biliary stricture. In patients with prior negative ERCP-guided sampling, the sensitivity of EUS-FNA has been reported to be 77% and 89% in two series, suggesting ability of EUS-FNA to diagnose malignancy when ERCP-guided tissue sampling is negative. EUS-FNA also plays a central role in determining nodal staging of CC.


EUS may also visualize a mass not captured by other imaging modalities like ERCP or MRCP. In a recent study, a mass was visualized in 94% of patients with EUS as compared to only 30% and 42% with CT and MRI scan respectively. Despite these advantages of EUS-FNA, there are significant concerns for potential needle tract seeding resulting in peritoneal metastasis. As a result, EUS-FNA of the primary tumor is strongly discouraged for concerns about potential tumor spread, impact on transplant candidacy, and patient outcomes. In a study of 81 patients, the sensitivity of EUS-FNA for diagnosis of CC was significantly higher for distal (81%) than proximal (59%) lesions. Hence EUS-FNA can be considered as a useful adjunct to ERCP for the evaluation of distal biliary tract strictures and for the nodal staging of CC.


Probe-Based Confocal Laser Endomicroscopy


pCLE uses an intravenously injected contrast agent, fluorescein, and imaging by a CLE probe passing through the working channel of an endoscope. pCLE detects neovascularization and abnormal vessels in biliary strictures. In a recent study, the sensitivity and specificity of pCLE was 100% and 61% respectively for the evaluation of strictures in PSC patients. Another study assessed indeterminate biliary strictures in 102 patients, where the sensitivity for detecting malignancy was 98%; however, specificity was relatively low at 69%. Currently pCLE is not widely available and lacks prospective data, as a result further studies are required before it can be routinely employed for evaluation of indeterminate biliary strictures.

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Dec 30, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on Endoscopic Management of Hepatobiliary Complications of Inflammatory Bowel Disease
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