Bile Duct Stricture

Etiology

Bile duct strictures can be congenital or acquired.[2][3] Acquired strictures are further classified as either benign or malignant.[4] A wide range of benign acquired conditions cause bile duct strictures, contributing to 30% of biliary strictures, including iatrogenic strictures, which comprise the majority of benign biliary strictures.[5] Misidentification of the bile duct as the cystic duct during laparoscopic cholecystectomy leads to bile duct injury, which may be partial or complete. The long-term sequelae of these injuries lead to the formation of benign biliary strictures.[6] 

The incidence of injury may be decreased by obtaining an intraoperative cholangiogram, especially in cases of gangrenous cholecystitis or empyema of the gallbladder.[7][8] The Critical View of Safety, a technique helping surgeons to identify the cystic duct and artery, is utilized to minimize bile duct injuries and associated morbidity from bile leaks and strictures.[9] Understanding the anatomy of the blood supply to the bile duct is paramount to its repair.[10] Pancreatic ductal adenocarcinoma and cholangiocarcinoma are the most common causes of malignant strictures.

Benign causes include:

• Iatrogenic
  • Cholecystectomy [11]
  • Pancreaticoduodenectomy: Incidence of 4%, especially when there are small-caliber thin-walled ducts [1]
  • Liver transplantation [12] 
  • Due to radiation therapy
  • Secondary sclerosing cholangitis due to 5-fluorouracil or bevacizumab chemotherapy (these usually affect the intrahepatic ducts)[13]
• Chronic pancreatitis
• Primary sclerosing cholangitis
• Acute cholangitis
• Blunt and penetrating abdominal trauma
• Autoimmune diseases: Sarcoidosis, immunoglobulin G4 pancreatitis, or eosinophilic cholangitis
• Mirizzi syndrome
• Ischemic cholangiopathy
• Ischemic due to vasculitis
• Systemic mastocytosis
• Langerhans cell histiocytosis
• Infectious:
  • Oriental cholangiohepatitis (due to Ascaris lumbricoides and Clonorchis sinensis infections)
  • Acquired immunodeficiency syndrome cholangiopathy
  • Mycobacterium tuberculosis (rare)[14]
• Portal cholangiography (obstruction due to compression of the biliary tree by a portal vein thrombus and portosystemic collateral vessels)
• Biliary inflammatory pseudotumors [3]

Malignant causes (more common than benign biliary strictures):

• Pancreatic head cancer
• Cholangiocarcinoma
• Ampullary carcinoma
• Gallbladder carcinoma
• Hepatocellular carcinoma
• Lymphoma
• Metastasis to regional solid organs and lymph nodes [15]

Epidemiology

Globally, the incidence of biliary strictures is increasing primarily because of iatrogenic bile duct injuries resulting from the widespread practice of laparoscopic cholecystectomy. The estimated rate of biliary injuries is about 0.7% after laparoscopic cholecystectomy. Most of these injuries are minor injuries or bile leaks. Biliary strictures are rare in the pediatric age group.[16] There is no published difference in the incidence or prevalence of biliary strictures in males compared to females. However, some risk factors, like chronic pancreatitis, are more common in males who more often drink alcohol and smoke.

Pathophysiology

Biliary strictures are characterized by narrowing of a bile duct segment associated with proximal ductal dilatation, except in primary or secondary sclerosing cholangitis, where sclerosis prevents the ducts from dilating. Obstruction of bile flow leads to elevation of serum bilirubin levels with clinical and laboratory features of obstructive jaundice. Stasis of bile is a significant risk factor for ascending cholangitis.[17] Magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography shows that benign strictures have tapered margins with smooth and symmetric borders. On the other hand, malignant strictures have shouldering of the margins with irregular and asymmetric borders.[12] Malignant strictures typically involve a longer duct segment than benign strictures. Malignant strictures appear to enhance contrast-enhanced cross-sectional imaging.[17]

Histopathology

Generally, histopathological findings in biliary strictures depend on the etiological agent or mechanism. For example, in the case of primary sclerosing cholangitis, histopathology reveals intrahepatic or extrahepatic bile duct inflammation and fibroobliteration.[4] In assessing biliary strictures, histological appraisal with aspiration cytology or tissue biopsy is required to rule out malignancy.[17]

History and Physical

The clinical presentation depends on the location and cause of the stricture.[12] Biliary strictures can be asymptomatic with an unremarkable physical examination. Nevertheless, some patients with biliary strictures present with features of biliary obstruction, including jaundice, pruritus, pale stools, and dark urine.[18] Constitutional symptoms, such as weight loss, fever, nausea, vomiting, and malaise, may also be present. Patients may present with an acute abdomen secondary to cholangitis or a hepatic abscess as complications of the bile duct stricture.[19] A history of fever and leukocytosis suggests an infectious cause or as a result of a stricture. A history of weight loss, abdominal or back pain, and worsening performance status is more suggestive of a malignant etiology.[20] A previous history of hepatobiliary surgery, autoimmune disease, pancreatitis, cholelithiasis, or chemotherapy should be elicited as it can be pivotal in determining the underlying diagnosis.[12]

Physical examination may show specific clinical features, such as a Murphy sign, suggesting biliary stone disease. A Courvoisier sign (a palpable and enlarged but nontender gallbladder) or a palpable abdominal mass elsewhere in the right upper quadrant of the abdomen may point toward pancreatic or biliary malignancy. A Courvoisier sign, however, is not specifically a sign of malignancy, and it may be elicited due to an obstructing distal common bile duct stone or pancreatitis.

Evaluation

The evaluation of biliary strictures is performed using a multi-pronged approach.[21] Contributory laboratory findings are mainly drawn from a liver function test, a coagulation profile, and a complete blood count. Liver function tests typically reveal elevated levels of conjugated bilirubin, alkaline phosphatase, and gamma-glutamyl transferase. Transaminases may or may not be significantly elevated. The prothrombin time and International Normalized Ratio can be prolonged if there is biliary obstruction due to vitamin K malabsorption. Immunological studies may be obtained to assess specific autoimmune etiologies of biliary strictures. Apt diagnosis and further management are based on the correlation of laboratory data and imaging findings with epidemiologic and clinical data.

Deranged liver function tests and coagulation profiles may help to determine the algorithm of subsequent imaging and minimally invasive studies.[20][22] Likewise, when present, certain immunological markers help in accurate diagnosis and management. For example, immunoglobulin (Ig)G4-associated sclerosing cholangitis presents as hilar or distal common bile duct strictures associated with IgG4-related autoimmune pancreatitis. Both of these disease entities are responsive to steroid therapy.[5][12] Antinuclear antibodies and rheumatoid arthritis factors may help support this diagnosis.

Assay of serum carbohydrate antigen or cancer antigen (CA) 19-9 is often elevated in patients with suspected pancreatic ductal adenocarcinoma or cholangiocarcinoma, so it can help with diagnosis and follow-up in some patients with these diagnoses. Of note, the elevation of this marker is not specific to biliary malignancy, can be abnormal in cirrhosis, cholangitis, pancreatitis, gallstones, other malignancies, and hyperbilirubinemia due to any cause of biliary obstruction. For this reason, this marker is best drawn when other diagnostic studies strongly suggest biliary cancer or when monitoring the response to treatment after cancer has been diagnosed. The CA 19-9 level is more likely to be abnormal with larger tumors.

Endoscopic ultrasound-guided fine needle aspiration cytology is highly sensitive and specific in diagnosing malignant biliary strictures, particularly when associated with a mass. Still, it is ineffective in ruling out malignancy.[5] Endoscopic ultrasound-guided fine needle aspiration or tissue sampling at endoscopic retrograde cholangiopancreatography (ERCP) doesn't carry the risk of spreading malignant cells, which is a concern with a percutaneous needle biopsy. Ductal dilatation is a major feature of imaging for biliary strictures.[1] Imaging of suspected biliary strictures can begin with a transabdominal ultrasound, which detects biliary dilatation and is highly sensitive for detecting biliary obstruction and the level of obstruction. However, it has a low yield for the detection of strictures. Malignant biliary strictures typically cause more severe ductal dilation than benign strictures.[5][12]

Computed tomography (CT) scan has higher sensitivity than trans-abdominal ultrasound for biliary malignancy, and its utility can be improved with the use of a multidetector CT scan and CT-pancreatic protocol in providing more information on tumor vascular encroachment and biliary tree obstruction. CT can also detect complications from biliary obstruction, such as cholangitis and abscesses.[1] Magnetic resonance cholangiopancreatography (MRCP) can provide a high-quality cholangiogram, thus establishing the location and extent of biliary strictures. This provides a cross-sectional and 3-dimensional reconstruction of the biliary tree.[4] MRCP helps guide endoscopic therapy, especially if ERCP is contraindicated. MRCP does not use radiation, thus making it a superior option over a multi-detector CT scan. However, its sensitivity and specificity (which can be improved by diffusion-weighted imaging) are comparable to those of ERCP.[1][4]

ERCP can determine the etiology, provide tissue samples for cytology and histology, and facilitate therapeutic interventions, including dilatation and stenting of obstructing biliary (and pancreatic) strictures. However, because of the relatively high risk of post-ERCP pancreatitis, MRCP has replaced ERCP when only a diagnostic study is needed. ERCP is limited to therapeutic interventions. Emerging technologies useful in assessing the etiology of biliary strictures include confocal laser endomicroscopy[23], fluorescent in-situ hybridization (FISH),[24] direct peroral cholangioscopy,[25] and intraductal ultrasound.[4][15][26]2

Treatment / Management

Medical management of biliary strictures is restricted mainly to addressing complications from biliary obstruction, reducing the serum bilirubin to improve absorption of fat, and, in some cases, treating the underlying cause. Therefore, analgesics, empiric antibiotics, hemodynamic support with intravenous fluids with or without vasopressors, and inotropes are instituted where applicable.[27] These efforts are often supportive and in preparation for definitive therapy.[28] Other forms of medical treatment could be aimed at the prevention of further complications like excessive bleeding due to a coagulopathy, as well as deep vein thrombosis and sepsis in the early postoperative period.

The goal of the interventions includes reestablishing ductal patency and avoiding additional procedures.[12][18] There are varying options for operative or interventional management. These options can be accomplished endoscopically, surgically, or percutaneously. The stricture's etiology, location, and the patient's hemodynamic stability and nutritional status could determine the timing and type of intervention required.[28] The Bismuth classification can further guide the most appropriate approach since it offers a guide to determining the level at which healthy biliary tissue is available for repair and anastomosis.[12] Likewise, the Strasberg classification system, which incorporates the presence of a bile leak and lateral injuries into consideration, can also be useful in some cases in choosing the best intervention.[18] Additionally, preoperative determination of malignancy is pivotal to treatment planning. In general, endoscopic treatment is the first line of treatment for biliary strictures,[29] but interventional radiology and surgery are required in some cases. Common interventions for biliary strictures include the options shown below, but managing other specific causes of biliary strictures is outside the scope of this article. 

Hydrostatic Balloon Dilatation

• The preferred approach for the management of benign biliary stricture [12]
• Sphincterotomy and hydrostatic balloon dilatation are done for both malignant and benign strictures, including those resulting from primary sclerosing cholangitis [4]
• Commonly performed endoscopically at ERCP, usually to facilitate the placement of one or more stents
• Alternatively, percutaneous transhepatic biliary drainage tracts can be used for access during dilatation [30]
(B3)

 Stenting

• Usually performed endoscopically, but can be done percutaneously
• Used in the management of both malignant and benign biliary strictures
• Used to reduce hyperbilirubinemia or to drain infected bile in patients with cholangitis before definitive surgery [22] 
• Useful for palliation of inoperable malignant strictures
• Plastic, uncovered self-expandable metal stent (SEMS), or retrievable covered SEMS can be used alone or in combination, depending on the clinical indication [18]
• A percutaneous transhepatic biliary drainage catheter may be placed to palliate hyperbilirubinemia in patients with cancer who either have inoperable disease or until completion of neoadjuvant therapy. 

 Surgery

• Resection and anastomosis have a role in some diagnoses depending on the underlying etiology of the stricture and whether the desired outcome is palliative or curative.[28] Surgical resection for this indication is associated with significant morbidity and high cost.[5]
• Bypass: Hepaticojejunostomy and choledochoduodenostomy are performed in some instances.[28]
• Mirizzi syndrome is managed by exploratory surgery with cholecystectomy and clearance of the impacted stone from the cystic duct or gallbladder neck.

Other Techniques

• Another technique is intraductal radiofrequency ablation for palliation of extrahepatic cholangiocarcinoma, a simpler and less risky alternative to intraluminal brachytherapy or photodynamic therapy.[31]
• Placement of biodegradable stents may be options.[17] 
• Percutaneous large-bore catheterization with progressive dilatation up to 20 French is another technique.[32]
• Magnetic compression anastomosis: Magnets are placed on either side of a benign biliary stricture, on the distal side by ERCP, and on the proximal side by percutaneous transhepatic cholangiography. The magnetic attraction causes tissue compression, ischemic necrosis, and eventual recanalization.[33] The risk of re-stenosis is reduced by maintenance of the lumen with a stent or percutaneous internal drain for 6 months after initial recanalization.[34]

Differential Diagnosis

In diagnosing and managing biliary strictures, the most valuable and critical distinction that should be made is between benign and malignant etiology. This differentiation presents a major diagnostic and therapeutic challenge. Therefore, elaborate history taking, physical examination, and diagnostic workup should be completed.[15] Other techniques like fluorescence in situ hybridization, Kras/p53 mutation analysis, intraductal biopsies, and confocal laser endomicroscopy may be considered to improve the diagnostic yield.[5] A diagnosis of choledocholithiasis should also be considered in cases of suspected biliary strictures.

Prognosis

The mortality in patients with biliary structures depends on the underlying etiology. Biliary strictures due to chronic pancreatitis, trauma, or operative injury have a good prognosis. In contrast, those resulting from malignancy, treatment of malignancy (ie, strictures due to radiation therapy and chemotherapy), primary sclerosing cholangitis, and patients with human immunodeficiency virus cholangiopathy usually have a less favorable prognosis.

Complications

The consequences of chronic biliary obstruction can complicate biliary strictures.[29] These complications include:

• Recurrent episodes of cholangitis
• Gram-negative septicemia
• Biliary stone formation
• Hepatic abscesses
• Secondary biliary cirrhosis
• End-stage liver disease
• Cholangiocarcinoma

Other complications could result from interventional procedures, and these may include:

• Pancreatitis
• Cholangitis
• Bleeding
• Biliary perforation
• Additionally, there are reports of distal migration of biliary stents leading to duodenal perforation.[35] Tumor ingrowth can also complicate stents, rendering them non-functional.[29] Covered SEMS are more prone to migration, while uncovered SEMS have a greater risk of tumor ingrowth.