41.1 Introduction

Benign biliary disorders may occur in various traumatic and nontraumatic conditions. In daily practice, the most common situation of benign biliary disorders is benign biliary strictures. Benign biliary strictures account for significant morbidity and mortality and are difficult to treat. These originate from a variety of etiologies, most commonly postoperative injury (e.g., postcholecystectomy), orthotopic liver transplantation (OLT), chronic pancreatitis, and chronic cholangiopathies (e.g., primary sclerosing cholangitis [PSC]).

Accurate diagnosis and management of benign biliary disorders are based on correlating imaging findings with epidemiologic, clinical, and laboratory data.

41.2 Postoperative Biliary Stricture

Benign biliary strictures are rarely encountered in the general population and require coordinated care between medical, surgical, pathologic, and radiologic specialties for appropriate evaluation and management. Benign biliary stricture can be the result of a wide array of nonneoplastic causes. In Western countries, iatrogenic stricture is the most common benign biliary stricture and accounts for up to 80% of all benign strictures. The incidence of iatrogenic injuries of the bile ducts has increased two- to threefold (0.3–0.7%) after the advent of laparoscopic cholecystectomy. ¹ , ² This is mostly due to misidentification of anatomical structures during laparoscopic surgery, acute inflammation, or fibrous adhesions in the gallbladder fossa, excessive use of electrocautery, inaccurate placement of clips, sutures, and ligations. ¹ , ³ Postcholecystectomy strictures often involves the common hepatic duct or the common bile duct (CBD). The clinical and biochemical manifestations may be evident early in the postoperative period, and may be associated with jaundice and cholangitis, or with peritonitis caused by a bile leak. Delayed presentation is commonly related to ischemic injury or reanastomosis of the CBD, with the time to presentation dependent on the individual rate of fibrosis. ³

The main classification used to evaluate biliary duct strictures is the Bismuth classification (▶Fig. 41.1) that is based on stricture location. ⁴

Several biliary complications may develop following OLT, including the formation of strictures, bile leaks, and biliary filling defects. Benign biliary strictures are the most common complication of OLT. Patients who undergo liver transplantation are at highest risk of developing biliary strictures with a rate of about 20 to 30%. Biliary strictures can occur during` the early (< 30 days) or late (> 30 days) posttransplantation time and may be anastomotic or nonanastomotic. (▶Fig. 41.2). Early strictures may be the result of CBD size mismatch between the donor and the recipient. These may also be caused by surgical technique and are often anastomotic. Hepaticojejunostomy is more likely to result in early stricture development than duct-to-duct anastomosis. Late strictures are usually associated with ischemic damage and result in a higher rate of retransplantation or surgical revision. ³ Anastomotic strictures develop secondary to fibrosis and are caused by focal stenosis at the junction of the recipient’s CBD with donor’s common hepatic duct. About 80% of post-OLT bile duct strictures are anastomotic. Nonanastomotic strictures result from biliary ischemia induced by hepatic artery thrombosis or stenosis and prolonged donor organ ischemic time. Typically, they start at the hilum and may progress to the intrahepatic ducts. Nonanastomotic strictures after OLT respond less favorably to endoscopic therapy than anastomotic strictures, with up to 25 to 50% of patients expiring or undergoing retransplantation.

Clinically, benign biliary strictures may present with pain, jaundice, cholangitis, pruritus, or only with alteration of liver function tests (bilirubin, alkaline phosphatase, and gamma-glutamyl transferase). In patients with OLT, the clinical presentation of biliary strictures may occur during the early posttransplantation time or even several years after surgery. Ultrasound is the initial imaging modality of choice for the detection of biliary dilation. Ultrasound is also useful and accurate to detect the level of obstruction. Computed tomography (CT) scan is indicated to show bile duct dilation and the underlying cause of biliary obstruction, and potential complications (i.e., cholangitic abscess). ⁵ In addition, CT scan may help in differentiating benign from malignant biliary strictures. Magnetic resonance cholangiopancreatography (MRCP) can accurately delineate the biliary anatomy, site and length of the stenosis, being therefore very useful before endoscopic retrograde cholangiopancreatography (ERCP) for planning therapy. Unlike ERCP, MRCP offers the advantage of noninvasive imaging without the risk of any procedure-related complications, allows evaluation of the biliary system beyond a tight stricture. In patients with a nonanastomotic stricture following OLT, the evaluation for hepatic artery thrombosis or stenosis by Doppler ultrasound and/or angiography by CT scan or magnetic resonance imaging (MRI) should be considered. Flow-limiting hepatic artery disease is a known cause of nonanastomotic stricture and may require endovascular stenting, thrombolysis, or surgery. ³ Endoscopic ultrasound (EUS) has been shown to improve the accuracy of ERCP in differentiating benign from malignant strictures, including also the feasibility of EUS-guided fine-needle aspiration (FNA). The combination of endoscopic ultrasound with ERCP results in higher accuracy for diagnosis (up to 85%) compared with EUS-guided FNA or ERCP-guided biopsy alone (70 and 67%, respectively). ⁶ , ⁷ Several diagnostic tools for assessment of biliary strictures and for intraluminal tissue characterization have been developed in the last few years. These are mainly indicated in case of uncertainty and when a differential diagnosis between malignant and benign stricture is required. These include intraductal ultrasound, peroral videocholangioscopy, confocal laser endomicroscopy, and optical coherence tomography. The majority of these techniques are still under evaluation in clinical trials. ¹ , ³

Minimally invasive procedures such as endoscopic or percutaneous transhepatic biliary dilation and stenting are considered treatments of choice for iatrogenic strictures. ⁸ Nevertheless, considering the access route, endoscopy is preferred to the percutaneous approach due to a reduced morbidity, better efficacy, and increased comfort for the patient. ERCP has emerged as the therapeutic intervention of choice for managing biliary strictures. Postoperative biliary strictures benefit from an “aggressive” endoscopic approach, with the insertion of an increasing number of plastic stents at 3-monthly stent exchange intervals until there is complete morphologic disappearance of the stricture, independent of the duration of treatment. ¹ , ⁹ , ¹⁰ Placing multiple side-by-side, large-bore plastic stents has been shown to improve long-term outcomes of benign biliary strictures compared with placing one or two stents alone (with a 3-monthly exchanges for a period of 1 year). Anastomotic strictures following liver transplantation can also benefit from this aggressive approach. This strategy results in very high efficacy (80–90%) for postoperative strictures. ³ , ¹¹ , ¹² Patients who are candidates to the endoscopic treatment, a complete sphincterotomy is necessary stent placement, to allow stent insertion. Despite the high success rate of multiple plastic stent therapy, multiple treatment sessions are required. Because placement of a single, fully covered, self-expandable metallic stent (cSEMS) results in radial dilation of a stricture equivalent to that of at least three side-by-side plastic stents, preliminary studies including small clinical trials were designed to support the hypothesis that deployment of cSEMS would be beneficial in patients with benign strictures. Results of these studies have generally been contradictory, with high long-term morbidity rates. Moreover, these have been limited by retrospective and nonrandomized design, small sample sizes, and inclusion of patients with partially treated strictures. ¹³ , ¹⁴ , ¹⁵ Recently in a well-designed trial, ¹⁶ patients were randomized to receive multiple plastic stents or a single cSEMS, stratified by stricture etiology and with endoscopic reassessment for resolution every 3 months (plastic stents) or every 6 months (cSEMS). Patients were followed up for 12 months after stricture resolution to assess for recurrence. Among patients with benign biliary strictures and a bile duct diameter 6 mm or more in whom the covered metallic stent would not overlap the cystic duct, cSEMS were not inferior to multiple plastic stents after 12 months in achieving stricture resolution. In specific settings, therefore, metallic stents should be considered an appropriate option in patients with benign biliary stricture. In case of endoscopic/percutaneous treatment failure, surgery represents a valid treatment alternative.

41.3 Chronic Pancreatitis and Biliary Strictures

Chronic pancreatitis (CP) may result in obstruction of the intrapancreatic part of the CBD and accounts for up to 10% of benign biliary strictures. A stricture of the intrapancreatic bile duct develops in approximately 3 to 46% of patients with CP ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ and can seriously compromise the clinical course of disease. Biliary strictures usually complicate a long-lasting disease, as a result of severe fibrosis of the pancreatic head parenchyma, which compresses and narrows the distal CBD. Parenchymal fibrosis in CP is a slow, irreversible process, and these strictures usually occur late in the natural history of the disease. However, CP-related bile duct strictures may also be seen in patients with a recently diagnosed disease and can be the result of an acute pancreatic inflammation, being the final consequence of the edema of the pancreatic head that compresses the intrapancreatic bile duct. These strictures may resolve spontaneously or, in more severe cases, be persistent and require biliary drainage. Biliary strictures in patients with CP can also be the result of an extrinsic compression from a pancreatic pseudocyst, retention cyst, or a walled-off pancreatic necrosis. These strictures usually disappear after the drainage of the pancreatic fluid collection. It is of paramount importance to reasonably rule out malignancy before embarking on the endoscopic treatment of presumed CP-related biliary strictures, as such a treatment usually lasts for 1 year and the course of pancreatic cancer is rapid. Patients with CP have a higher risk of pancreatic cancer compared to reference population. CT scan and/or EUS should be periodically performed in patients with CP, to early identify suspected nodules and masses.

Biliary strictures have a broad spectrum of presentation, varying from mildly elevated levels in liver function tests to severe jaundice in case of complete biliary obstruction. The incidental finding of a CP-related biliary stricture accounts for up to 17% of cases. ¹⁷ Abdominal pain is usually considered the predominant symptom in most patients, but is mainly caused by a bout of acute pancreatitis rather than by a biliary stricture per se. Jaundice may be present in 30 to 50% of patients at diagnosis. ⁵ , ¹⁷ Alteration of liver function test results and biochemical markers of cholestasis, including alkaline phosphatase and gamma-glutamyl transferase, may be persistent for some weeks after the normalization of bilirubin levels. A small proportion of patients with a biliary stricture secondary to CP may develop secondary biliary cirrhosis. The combination of a dilated CBD at abdominal ultrasound and elevation of levels of biochemical markers of cholestasis usually allows to make a diagnosis of a biliary stricture. CT-scan is usually required to exclude neoplasms, evaluate the severity of chronic pancreatitis, to identify stones and calcifications, and to plan the necessary treatment. MRCP may be helpful to differentiate a benign from a malignant biliary stricture. However, cholangiographic features are unreliable because of a wide variability of the radiologic appearance of the stricture. Cytologic and histologic confirmation is often indicated to rule out the presence of malignancy. Brush cytology and endobiliary biopsies can be obtained during ERCP, but the sensitivity of the sampling is low. EUS-guided FNA is the option of choice to obtain cytologic and histologic sampling from biliary duct thickening and/or pancreatic masses because of its safety profile and diagnostic accuracy. ¹⁷ , ²²

Patients with CP-related bile duct strictures are recommended to receive treatment in cases of symptoms (i.e., cholangitis, jaundice), secondary biliary cirrhosis, bile duct stones, progression of biliary stricture, or when anicteric cholestasis (a serum alkaline phosphatase level greater than twice the upper limit) persists for more than 1 month. The management of CP-related biliary strictures should be carefully evaluated and tailored on the patient conditions and needs. CP-related biliary strictures are more difficult to be dilated than other benign biliary strictures. The presence of parenchymal calcifications and stones increases the fibrosis and tightness of the strictures, which are often permanent with only partial and not sustained benefits after simple dilation. Furthermore the risk of incidental pancreatic cancer should be taken into the account. The possibility of surgical management of CP-related biliary strictures should be conscientiously considered, especially in young patients in good health conditions and with a long life expectancy. In such patients surgical drainage is still considered the gold standard. However, comorbidities and local consequences of repeated attacks of pancreatitis, or patient’s preferences may contraindicate surgery. ERCP and stent placement may be the therapeutic intervention of choice for managing biliary strictures secondary to CP only in selected patients. If the stricture does not disappear after a 1-year treatment, the patients should undergo surgical hepaticojejunostomy. When a CBD stricture caused by chronic pancreatitis has been treated endoscopically using a single biliary plastic stent, the long-term success has been disappointing. ²³ Stenting with multiple plastic stents has led to success in 60 to 92 % of cases. ²⁴ , ²⁵ Every biliary stricture that persists and is associated with alteration of biochemical markers of cholestasis is indicated for drainage by either surgery or endoscopy. ¹⁷ Biliary drainage is also indicated when frequent relapses of biliary obstruction occur in order to reduce the risk of secondary biliary cirrhosis and cholangitis. In asymptomatic patients or in patients with a slight increase of biochemical markers of cholestasis, a conservative management is indicated with close monitoring of liver functions tests. Endoscopic bile duct stricture dilation with stent placement is one of the therapeutic option. Usually, biliary strictures disappear in about one-third of patients who undergo single plastic stenting for 3 to 6 months. An aggressive approach with multiple simultaneous side-by-side stents to obtain calibration of the biliary tract appears to be superior to single stent placement, providing the long-term benefit. Self-expandable metal stents in patients with CP-related biliary strictures show good outcomes at midterm follow-up, and might be proposed for patients unfit for surgery as a more effective treatment to plastic stenting. ¹⁴ , ²⁶ , ²⁷ , ²⁸ The role of fully covered, removable, self-expandable metal stent in patients with CP-related strictures, who are unfit for surgery, is particularly interesting. These patients may need a prolonged stenting period: differently from patients with malignancies these patients have a longlife expectancy, and plastic stents do not usually offer sustained benefits in case of tight and fibrotic strictures. Fully covered SEMS, with their large diameter, can improve dilation of the stricture, facilitate bile drainage for a long time, and reduce the number of hospitalization due to stent exchange and cholangitis. Fully covered SEMS can be very easily removed and exchanged, and their placement do not require very special skills ²⁶ (▶Fig. 41.3). Unfortunately, some complications caused by long-term stenting with SEMS have been observed and include SEMS migration, embedding into the CBD and consequent difficulties at SEMS removal, and hyperplastic overgrowth above the proximal end of the SEMS that may result in creation of de novo strictures.