AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Bile duct stricture is an uncommon but challenging clinical condition requiring a coordinated multidisciplinary approach involving gastroenterologists, radiologists, and surgical specialists. Unfortunately, most benign bile duct strictures are iatrogenic, resulting from operative trauma. Bile duct strictures may be asymptomatic but, if ignored, can cause life-threatening complications, such as ascending cholangitis, liver abscess, and secondary biliary cirrhosis. However, not all strictures are benign. Pancreatic cancer is the most common cause of malignant biliary strictures. Most of these patients die of complications of tumor invasion and metastasis rather than from the biliary stricture, per se. Nonetheless, both benign and malignant strictures can be associated with distressing symptoms and excessive morbidity.

Pathophysiology

Strictures of the bile duct can be benign or malignant. Benign strictures develop when the bile ducts are injured in some way. The injury may be a single acute event, such as damage to the bile ducts during surgery or trauma to the abdomen; a recurring condition, such as pancreatitis or bile duct stones; or a chronic disease, such as primary sclerosing cholangitis (PSC). After the injury, an inflammatory response ensues, which is followed by collagen deposition, fibrosis, and narrowing of the bile duct lumen.

Depending on the nature of the insult, bile duct strictures can be single or multiple. Atrophy of the hepatic segment or lobe drained by the involved bile ducts, associated with hypertrophy of the unaffected segments, can occur, especially with chronic high-grade strictures. These changes can eventually progress to secondary biliary cirrhosis and portal hypertension. Malignant strictures usually are the result of either a primary bile duct cancer (ie, causing a narrowing of the bile duct lumen and obstructing the flow of bile) or extrinsic compression of the bile ducts by a neoplasm in an adjacent organ, such as the gallbladder, pancreas, or liver.

Frequency

United States

Although quite uncommon, the exact prevalence of bile duct strictures is unknown. One major category of bile duct strictures is postoperative bile duct stricture, which usually occurs as a result of a technical mishap during cholecystectomy, causing bile duct injury. Data from many large series of patients in the United States have revealed that the incidence rate of major bile duct injury is 0.2-0.3% after open cholecystectomy and 0.4-0.6% after a laparoscopic cholecystectomy.

International

Data from Europe have shown a similar rate of occurrence of postoperative bile duct strictures.

Mortality/Morbidity

• Bile duct strictures, independent of etiology, can cause significant morbidity from recurrent obstructive jaundice, right upper quadrant abdominal pain, biliary stones, and recurrent episodes of ascending cholangitis.
• The major determinant of mortality in patients with bile duct strictures is the underlying disease condition. Patients with biliary strictures due to operative injury, radiation, trauma, or chronic pancreatitis generally have a good prognosis. Conversely, patients with bile duct strictures due to PSC and malignancy have a less favorable outcome.

Sex

• Data on the overall sex ratio of bile duct strictures are lacking. Some conditions causing bile duct strictures, such as PSC and chronic pancreatitis, are more common in men. The incidence of postcholecystectomy strictures is comparable in men and women.

CLINICAL

Section 3 of 11  

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History

• In the absence of symptoms of the primary disease, most patients with biliary strictures remain asymptomatic until the lumen of the bile duct is sufficiently narrowed to cause resistance to the flow of bile. Occasionally, patients may have intermittent episodes of right upper quadrant pain (biliary colic), with or without laboratory features of biliary obstruction. Patients most often present with features of obstructive jaundice. On occasion, a patient may present dramatically with sepsis and hypotension due to ascending cholangitis.
• The clinical manifestations of obstructive jaundice may develop rapidly or slowly depending on the underlying cause. Patients may report right upper abdominal discomfort, pruritus, yellow discoloration of skin, and steatorrhea. With chronic cholestasis, xanthomas appear around the eyes, chest, back, and on extensor surfaces. Weight loss and deficiency of calcium and fat-soluble vitamins can occur. Patients also may report anorexia, nausea, vomiting, and cachexia. Insidious weight loss may suggest malignant obstruction.
• Cholangitis occurs in the presence of partial or complete obstruction of the common bile duct (CBD), with increased intraluminal pressures, bacterial infection of the bile with multiplication of the organisms within the duct, and seeding of the bloodstream with bacteria or endotoxin. Cholangitis can rapidly become a life-threatening condition. Clinical presentation varies, with the Charcot triad of fever and chills, jaundice, and right upper quadrant abdominal pain occurring in most patients. A smaller proportion of those with cholangitis also may have altered mental status and hypotension (ie, Reynold pentad). In the absence of prior instrumentation, cholangitis is uncommon with malignant strictures.
• The etiology of bile duct strictures is sometimes obvious at the time of presentation. In unclear cases, clues from the patient's history may help in making an accurate diagnosis. Most of the benign biliary strictures following injury during cholecystectomy go unrecognized at the time of surgery (as many as 75% of cases). Presentation after more than 5 years may occur in 30% of cases; therefore, a history of recent or past cholecystectomy should be sought in all cases. Information about the postoperative period, especially excessive drainage from surgical wounds and drains and episodes of fever, jaundice, and abdominal distention, are important in patients presenting shortly after surgery.
• A detailed history with emphasis on symptoms suggestive of pancreatitis, recurrent episodes of cholangitis, cholestatic disorders (eg, primary sclerosing cholangitis), hepatobiliary surgery, trauma or radiation to the upper abdomen, alcohol abuse, intravenous drug use, or HIV infection should be obtained. This history provides valuable clues regarding the underlying disease and may prove useful in guiding management.

Physical

• Asymptomatic patients may have unremarkable examination findings. Most patients with tight strictures have clinically apparent jaundice. Excoriations of the skin may be seen in patients with pruritus.
• Patients presenting with cholangitis also may have fever and right upper quadrant tenderness in addition to jaundice (ie, Charcot triad), hypotension, and altered mental status (ie, Reynold pentad).
• The presence of palmar erythema, Dupuytren contracture, gynecomastia, spider angiomas, ascites, and splenomegaly may suggest underlying cirrhosis and portal hypertension. A palpable nontender gallbladder and jaundice usually are observed in patients with malignant obstruction. The presence of these symptoms is called the Courvoisier sign. An enlarged nodular liver or large right upper quadrant mass may indicate a malignancy involving the liver or gallbladder, respectively. The presence of a friction rub or bruit also may suggest malignancy.
• Patients with a major surgical injury to the bile duct and those with recurrent strictures and interventions may have evidence of a bile leak in the form of biliary fistula, biliary peritonitis, or a biloma. These complications usually become evident early in the postoperative period but sometimes appear weeks to months later.
• Attention should be given to the nutritional status of the patient. Features of fat-soluble vitamin deficiency may be present and should be sought.

Causes

Bile duct strictures can be benign or malignant, described as follows:

• Benign bile duct strictures
• • Postoperative injury after cholecystectomy: Approximately 80% of benign strictures occur following injury during a cholecystectomy. Injury to bile ducts can occur during either laparoscopic or open cholecystectomy. Most strictures after a laparoscopic procedure are short and occur more commonly in the common hepatic duct, distal to the confluence of the right and left hepatic ducts. After open cholecystectomy, strictures are more common in the CBD. This phenomenon is likely due to the ease with which this area may be accessed by the laparoscope. Most iatrogenic injuries go unrecognized at the time of operation.
  • The causes usually are surgical inexperience, failure to recognize abnormal biliary anatomy and congenital anomalies, acute inflammation, misplacement of clips, excessive use of cautery, and excessive dissection around the major bile ducts resulting in ischemic injury. However, a significant proportion of strictures occur during operations described as simple and uneventful. Bile duct strictures also can occur as unexpected complications after other surgeries, such as gastrectomy, pancreatic surgery, or hepatic and portal vein surgery.
  • Pancreatitis: Jaundice due to obstruction of the intrapancreatic segment of the CBD occurs in patients with chronic pancreatitis and accounts for approximately 10% of the benign strictures. Acute pancreatitis, pseudocyst, and pancreatic abscess also are uncommonly associated with the development of biliary strictures
  • Primary sclerosing cholangitis: PSC is a disease causing strictures, beading, and irregularities of the intrahepatic and extrahepatic bile ducts. Approximately 70% of PSC cases are associated with inflammatory bowel disease. The extent and distribution of bile duct involvement is variable.
  • HIV cholangiopathy: Patients with HIV cholangiopathy usually have advanced AIDS with CD4 lymphocyte counts less than 100/mm³ and poor long-term survival prognoses. Cryptosporidium and cytomegalovirus may be responsible for more than 90% cases. Other causes of HIV cholangiopathy, occurring in fewer than 10% of patients, include microsporidia Mycobacterium avium-intracellulare, Cyclospora, Isospora, and Cryptococcus. Most patients present with severe right upper quadrant pain, nausea, vomiting, and fever.
  • Orthotopic liver transplantation: Biliary strictures usually occur 2-6 months after orthotopic liver transplantation (OLT). Anastomotic strictures are more common, with choledochocholedochostomy site stricture being more common than choledochojejunostomy site stricture. Hepatic artery ischemia after OLT also can present as an anastomotic stricture, a hilar stricture, or diffuse stricturing of the biliary tree. Other causes of strictures after OLT are ABO incompatibility, ischemia-reperfusion injury, and chronic allograft rejection.
  • Mirizzi syndrome: This is observed in 1% of patients with cholecystectomies. Pressure on the common hepatic duct due to a gallstone impacted in the Hartmann pouch or cystic duct results in jaundice and cholangitis. Repeated episodes of inflammation can lead to formation of a stricture (type I) or pressure necrosis leading to the formation of a cholecysto-choledochal fistula (type II).
  • Radiation: Bile duct stricture can occur as a late complication of radiation therapy in the upper abdomen for cancer or lymphoma, sometimes presenting many years after treatment.
  • Blunt abdominal trauma: This can lead to bile duct strictures, which usually have a delayed presentation.
  • Polyarteritis nodosa and systemic lupus erythematosus: These are autoimmune diseases involving small- to medium-sized arteries. They can present (rarely) as extrahepatic biliary obstruction secondary to biliary strictures.
  • Tuberculosis and histoplasmosis: These conditions have rarely been reported to cause bile duct strictures in individuals who are immunocompetent.
  • Chemotherapeutic drugs: Hepatic artery infusion of 5-fluorodeoxyuridine or other chemotherapeutic drugs may cause biliary stricture.
  • Sphincter of Oddi dysfunction or papillary stenosis: Patients usually present with biliary colic after cholecystectomy. The anomaly is in the smooth muscle surrounding the terminal portion of the CBD, with abnormal basal sphincter pressure of more than 40 mm Hg.
  • Choledochal cyst: Choledochal cysts are uncommon anomalies of the biliary system manifested by cystic dilatation of the extrahepatic biliary tree, intrahepatic biliary tree, or both. This condition is found most frequently in Asian persons and in females. Associated hepatobiliary complications include recurrent cholangitis, biliary stricture, cholelithiasis, choledocholithiasis, and recurrent acute pancreatitis.
  • Recurrent pyogenic cholangitis: This condition (previously known as Oriental cholangiohepatitis) and hepatolithiasis are prevalent in Southeast Asia and present a difficult management problem. Recurrent pyogenic cholangitis is characterized by recurrent attacks of suppurative cholangitis with strictures and dilatation of bile ducts and numerous pigment stones in the intrahepatic and extrahepatic bile ducts. It is thought to be precipitated by an infestation of liver flukes and round worms. In the United States, this disease is observed mostly in Asian immigrants.
  • Inflammatory strictures: In addition to pancreatitis, choledocholithiasis can also cause chronic inflammation and fibrosis, leading to strictures of the CBD and sphincter of Oddi.
  • Endoscope-related strictures: Postendoscopic sphincterotomy stricture is possible.
  • Idiopathic: A few cases of idiopathic benign biliary strictures have been reported.
  • Miscellaneous: Strictures have been described in association with duodenal diverticulum, Crohn disease, hepatic artery aneurysm, cystic fibrosis with liver involvement, eosinophilic cholecystitis, and cholangitis.
• Malignant causes of biliary strictures
• • Pancreatic cancer: In the United States, adenocarcinoma of the pancreas is the most common cause of malignant biliary obstruction. Pancreatic cancer accounts for nearly 32,000 cases of cancer each year and has become the fifth leading cause of cancer mortality. Pancreatic cancer usually presents in the sixth and subsequent decades of life.
  • Mucinous cystadenocarcinoma: This pancreatic tumor may invade the bile duct and cause obstruction, which characteristically results in extrusion of mucin from the lumen.
  • Ampullary carcinoma: Adenocarcinoma of the ampulla of Vater usually arises from a benign adenoma. It is less common than pancreatic cancer, but symptoms of obstructive jaundice or pancreatitis are observed relatively early in its course.
  • Gallbladder carcinoma: Extension of the cancer beyond the gallbladder can cause long biliary strictures and obstruction and is a poor prognostic sign. In the United States, gallbladder cancer is the fifth most common gastrointestinal malignancy, with 6000 new cases each year. Gallbladder cancer occurs at a higher frequency in Native Americans and in people from Asia, Africa, and Latin America.
  • Cholangiocarcinoma: This cancer arises from the biliary epithelium and usually is seen in association with choledochal cysts, PSC, chronic ulcerative colitis, and infestation by liver flukes. Obstructive jaundice is the major clinical manifestation of cholangiocarcinoma. Cholangiocarcinoma is more common in the upper portions of the biliary tree (hilar or Klatskin tumor) than in the lower portions of the biliary tree (distal bile duct cancer) but also can be diffuse in 10% of cases.
  • Hepatocellular cancer: This is the most common primary liver malignancy. Hepatocellular cancer is more common in the Far East than in the United States and usually is associated with cirrhosis resulting from hepatitis B or hepatitis C. The condition can present (rarely) with features of invasion of the extrahepatic biliary system as the predominant clinical manifestation.
  • Lymphoma and metastatic cancers to the liver and nodes in the porta hepatis: These cancers can sometimes be the cause of malignant biliary strictures. Colorectal carcinoma, adenocarcinoma of the lung, pancreatic carcinoma, and renal cell carcinoma are the common tumors metastasizing to the liver. Metastatic porta lymphadenopathy may cause high-grade obstruction of the common hepatic duct.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Drug-induced cholestasis
Primary sclerosing cholangitis
Primary biliary cirrhosis
Autoimmune cholangiopathy
Cholestasis associated with parenteral nutrition
Cholestasis associated with sepsis
Postoperative jaundice

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Patients with partial obstruction have elevated serum alkaline phosphatase and gamma-glutamyl transpeptidase. The serum of patients with clinically apparent jaundice shows increases in total and conjugated bilirubin. Alkaline phosphatase levels are increased to more than 3-times normal. Elevated alkaline phosphatase levels are accompanied by increases in gamma-glutamyl transpeptidase and 5' nucleotidase, usually disproportionate to serum transaminase levels. Serum aminotransferase levels usually are less than 300 IU/mL.
• The prothrombin time and International Normalized Ratio may be prolonged and usually can be normalized with parenteral administration of vitamin K. Total cholesterol and lipoprotein levels may be elevated in patients with chronic cholestatic disorders.
• In malignant biliary strictures with complete obstruction, the level of total serum bilirubin is generally much higher than that observed in benign strictures, and a bilirubin level of more than 20 mg/dL is highly suggestive of malignant obstruction. Again, in malignant strictures causing only partial obstruction (eg, Klatskin tumor), a rise in the alkaline phosphatase level may not be accompanied by a rise in the bilirubin level.
• Other laboratory abnormalities sometimes observed are anemia, elevated amylase and lipase levels, and an elevated erythrocyte sedimentation rate and lactic dehydrogenase level.
• Several tumor markers may be helpful in the diagnosis of malignant strictures. A serum carbohydrate antigen 19-9 value of greater than 100 U/mL is 55-65% sensitive for cholangiocarcinoma and gallbladder cancer. Elevated carcinoembryonic antigen levels may be present in 50-70% of cases of pancreatic cancer, and alpha-fetoprotein levels are elevated in as many as 60% cases of hepatocellular carcinoma.

Imaging Studies

• In patients presenting acutely with features of cholangitis, the initial radiological study should be an urgent right upper quadrant ultrasound (US). If the US examination findings show dilated bile ducts but do not provide clues to the site or cause of the obstruction, magnetic resonance cholangiopancreatography (MRCP) or abdominal CT scan should be performed next. In some patients, endoscopic retrograde cholangiopancreatography (ERCP) may be needed for definitive diagnosis and has the advantage of being therapeutic.
• Ultrasound
• • US generally is considered the imaging modality of choice for the initial screening of biliary disorders. US can help differentiate between intrinsic liver diseases and extrahepatic obstruction. Furthermore, US is more sensitive for detecting stones in the gallbladder.
  • Sonography can accurately detect dilatation of intrahepatic and extrahepatic bile ducts, thus providing indirect evidence for the presence of bile duct strictures. However, sonography is less accurate for determining the etiology and level of obstruction and cause of obstruction.
  • Cholangiocarcinoma and PSC may cause biliary obstruction without ductal dilatation, and some benign strictures with partial obstruction may not be associated with biliary dilatation.
  • The sensitivity of US also depends on the degree of obstruction and has been found to be 94% with a serum bilirubin level of more than 10 mg/dL but only 47% with bilirubin levels of less than 10 mg/dL.
• CT scanning
• • Spiral CT and multidetector CT scanning are highly sensitive for the diagnosis of biliary obstruction, particularly when they are performed with oral and intravenous contrast agents.
  • Similar to US, CT scanning also helps detect intrahepatic or extrahepatic bile duct dilatation; however, the main value of CT scanning is its ability to detect the site of obstruction with greater accuracy than US and to help predict the cause of obstruction, especially malignant obstruction. CT scanning is rather insensitive for detecting stones in the CBD.
  • CT cholangiography scanning is another technique that rivals ERCP in delineating biliary tract abnormalities but has not achieved widespread use because of some adverse reactions to the contrast material.
  • CT scanning also is superior to US in visualizing the distal CBD area because gas artifacts may obscure this region when examined by the latter.
  • Other important areas that can be seen better on CT scans are the porta hepatis, pancreas, and liver parenchyma.
• MRI
• • Since its introduction, MRCP has rapidly become an important tool for visualizing the biliary system.
  • MRCP takes advantage of the fact that bile has a high signal intensity on T2-weighted images, whereas the surrounding structures do not enhance and can be suppressed during image analysis.
  • MRCP is as sensitive as US for helping detect cholelithiasis and is superior to sonography for helping diagnose CBD stones, malignant biliary obstruction, and benign pancreatic disease.
  • The presence of biliary dilation can be accurately detected by MRCP in 97-100% of patients. The level of obstruction is correct in almost 87% cases.
  • In one study, sensitivity and specificity for the detection of any abnormality was 89% and 92%, respectively, and, for the detection of malignancy, 81% and 100%, respectively. These results were equivalent to the figures for ERCP (91% and 92% for any abnormality, 93% and 94% for malignant diseases). High-quality MRCP exams require a high level of patient cooperation.
  • Bile duct calculi also appear as low signal intensity. CBD strictures and stones can be differentiated as a cause of obstruction in most cases.
  • MRCP also is very useful in helping identify cholangiocarcinoma, which characteristically appears as enhancement in delayed images.
  • More importantly, MRCP provides valuable staging information because of its ability to help visualize the hepatic parenchyma and surrounding vascular structures in the same examination.
  • Benign strictures due to sclerosing cholangitis are multifocal and alternate with slight dilatation or normal-caliber bile ducts, producing a beaded appearance.
  • Dilatation of both the pancreatic and bile ducts viewable using MRCP is highly suggestive of a pancreatic head malignancy. Side-branch ectasia is the most prominent and specific feature of chronic pancreatitis. Thus, MRCP provides a viable alternative to ERCP and allows imaging of the biliary tree when ERCP is unsuccessful, although, unlike ERCP, it is not therapeutic.
• Hepatic iminodiacetic acid scan
• • A hepatic iminodiacetic acid (HIDA) scan is a radionuclide scanning technique commonly used for the diagnosis of acute cholecystitis and biliary leaks. HIDA scanning can help determine the clearance of bile across strictures and surgical anastomosis, thus providing a functional assessment of incomplete strictures and surgical anastomosis.
  • HIDA scanning also is useful for distinguishing cholangitis from cholecystitis. HIDA scan findings suggest complete biliary obstruction if the small intestine is not visualized in 60 minutes.
  • However, HIDA scans are insensitive for helping detect biliary dilatation or the site and cause of bile duct obstruction.

Other Tests

• Cytology
• • Cytologic sampling is best performed by brushing the biliary stricture during ERCP or percutaneous transhepatic cholangiography (PTC). Under optimal conditions and using a variety of techniques, cytology sampling can provide a cytologic diagnosis in 75% of cholangiocarcinomas and 50% of pancreatic carcinomas. The results in practice are more disappointing.
  • Cytologic brushing of bile duct strictures is usually performed with wire guidance across the stricture. A plastic brush collects the cytologic specimen from the lining of the bile duct during an ERCP. There is little morbidity associated with brushing of the bile duct.
  • Histologic sampling of a bile duct stricture is performed with an unguided biopsy forceps. This technique is particularly effective for exophytic lesions.

Procedures

• Endoscopic retrograde cholangiopancreatography (ERCP)
• • ERCP has been used for the examination of the pancreaticobiliary region for more than 30 years and is still the criterion standard.
  • The endoscope used for ERCP is a side-viewing duodenoscope that has the capacity to control the direction of catheters as they exit the instrument channel of the scope. The endoscopist localizes the ampulla of Vater, which is on the medial wall of the second portion of duodenum; and the entrance to the bile and pancreatic ducts contained within the ampulla of Vater is then cannulated with specialized catheters.
  • This is followed by injection of contrast media into the bile and pancreatic ducts under continuous fluoroscopic monitoring, with visualization of the anatomy of the intrahepatic and extrahepatic bile ducts and the pancreatic duct.
  • ERCP is a valuable technique in biliary disease because other diagnostic maneuvers (eg, sphincter of Oddi manometry) and therapeutic interventions (eg, stone extraction, biliary drainage, stent placement) can be carried out at the same time as the primary diagnosis. The success rate of ERCP is often 90-95%, with a complication rate of approximately 3-5%. The success rate of ERCP is decreased in the presence of a Billroth II, Whipple, or roux-en-Y anatomy.
  • ERCP can help detect intrahepatic and extrahepatic biliary dilatation, stones, and the site of bile duct stricture with the highest sensitivity and specificity (both approximately 90-100%). ERCP findings also are valuable for helping differentiate malignant from benign biliary obstruction. Infectious causes of biliary obstruction can be diagnosed using collected bile samples or brushings.
  • Usually, performing ERCP is highly diagnostic for PSC. ERCP findings show areas of irregular stricturing and dilatation (ie, beading) of the intrahepatic and extrahepatic biliary tree. However, the risk of cholangitis is greater in patients with PSC. Care should be taken to avoid poor biliary drainage after ERCP in patients with PSC.
  • ERCP also is the criterion standard for the diagnosis of AIDS-related cholangitis and is essential for differentiating PSC from AIDS-related cholangitis.
  • Nevertheless, ERCP is associated with significant complications, including pancreatitis, bleeding, perforation, infection, and cardiopulmonary depression from conscious sedation.
• Endoscopic ultrasound
• • Endoscopic ultrasound (EUS) involves the use of echoendoscopes, which have an US transducer mounted at the end of a side-viewing or oblique-viewing endoscope.
  • The linear-array EUS system also has color Doppler capability, enabling the endosonographer to be able to differentiate between vascular and fluid-filled structures. The extrahepatic bile duct is readily imaged from the duodenum.
  • The instrument also has a small biopsy channel for fine-needle aspiration (FNA) and fine-needle injection.
  • The pancreas, CBD, and the gallbladder are in close proximity to the distal stomach and the duodenum and can be viewed. EUS can help detect choledocholithiasis, especially small stones, with a sensitivity of more than 95%.
  • EUS and EUS-guided FNA is a sensitive technique for the diagnosis and staging of cholangiocarcinoma and gallbladder, ampullary, and pancreatic cancer because it also can help detect involvement of regional lymph nodes and vascular invasion by the tumor (an advantage over ERCP in this regard).
  • EUS also is superior to CT scanning for tumor, node, and metastases (TNM) staging of luminal and pancreaticobiliary malignancies. Porta hepatis lymph nodes are particularly well seen with EUS, in contrast to the relative inability of CT scanning to evaluate the porta region.
• Percutaneous transhepatic cholangiography
• • Since the 1960s, PTC has been used for the diagnosis and treatment of biliary tract disorders.
  • The technique consists of introducing a 22- or 23-gauge needle through the skin in the right ninth or tenth intercostal space in the midaxillary line and advancing into the liver parenchyma under fluoroscopic guidance. Contrast material is injected while the needle is slowly withdrawn, until the bile ducts are opacified.
  • Indications for PTC in biliary strictures are the presence of biliary-enteric anastomosis (eg, Roux-en-Y anastomosis with hepaticojejunostomy, choledochojejunostomy, Billroth II gastrectomy), the presence of complex hilar strictures, or when ERCP fails. Both the right and left ductal systems can be accessed using this technique.
  • The success rate of PTC approaches 100% when ducts are dilated. This technique is used for complex intrahepatic strictures or when ERCP is not possible.
  • Therapeutic intervention, such as biliary drainage, also can be performed at the same time. However, stones cannot be removed with this technique.
  • Complications, including sepsis, bile leak, intraperitoneal hemorrhage, hemobilia, hepatic and perihepatic abscess, pneumothorax, and skin infection and granuloma at the catheter entry site, can occur in as many as 10% of cases.
  • PTC is contraindicated in patients with bleeding diatheses and significant ascites. Patients should be warned prior to the procedure about the possibility of external drainage.
• Fistulography
• • In postsurgery patients with an external biliary fistula or T tube, contrast medium can be injected into the biliary system through the tube or the fistula.
  • This outlines the intrahepatic and extrahepatic bile ducts and delineates the site of stricture and the anatomy of the fistula.
  • This study can precipitate cholangitis; therefore, patients should receive antibiotic prophylaxis.

Histologic Findings

Surgically resected segments of the biliary tree will show the etiology of the bile duct stricture. In benign lesions the involved segment of the bile duct is surrounded by a collar of fibrosis causing a narrowing of the lumen. This is accompanied by a variable amount of inflammatory cellular infiltrate comprising a mixture of neutrophils, lymphocytes, plasma cells, and eosinophils. The mucosa of the strictured segment usually is atrophic, with areas of squamous metaplasia.

In cholangiocarcinoma, there will be evidence of adenocarcinoma in the cross-sectional histology of the bile duct. In contrast, in autoimmune disease, the hallmark finding is dense lymphocytic infiltration.

Staging

Staging systems have been developed for strictures due to operative trauma, cholangiocarcinoma, and HIV disease. The choice of operative repair of a bile duct stricture depends on the location of the stricture. Strictures involving the CBD and low common hepatic duct are easier to repair compared to strictures that are more proximal.

• In 1982, Bismuth proposed an anatomic classification of bile duct strictures, based on location, into the following 5 types:
• • Type 1: This is a low common hepatic duct stricture. At least 2 cm of the hepatic duct is intact.
  • Type 2: This is a mid common hepatic duct stricture. The hepatic duct stump is smaller than 2 cm.
  • Type 3: This is a hilar stricture. The common hepatic duct is not involved, but the confluence of right and left hepatic ducts is intact.
  • Type 4: In this type, the hilar confluence is destroyed. The right and left hepatic ducts are separated.
  • Type 5: The aberrant right sectorial duct is involved, alone or with the CBD.
• The modified Bismuth and Corlett classification of hilar cholangiocarcinoma is the most widely adopted anatomical classification of this tumor. The following 4 types are recognized:
• • Type 1: The confluence of the hepatic ducts is not involved, but the tumor generally is within 2 cm of the hilum.
  • Type 2: The obstruction is limited to the confluence of the right and left hepatic ducts.
  • Type 3a: The confluence is involved, with extension of the tumor into the right hepatic duct.
  • Type 3b: The confluence is involved, with extension of the tumor into the left hepatic duct.
  • Type 4: The tumor extends into the right and left hepatic ducts.
• Using ERCP, 4 distinct patterns of HIV cholangiopathy have been described, as follows:
• • Papillary stenosis: This occurs in approximately 15-25% of patients. A smooth distal tapering of the CBD associated with proximal dilation to wider than 8 mm is present. Contrast is retained beyond 30 minutes.
  • Sclerosing cholangitis: This pattern is observed in 20% of patients and is characterized by focal strictures and dilations involving intrahepatic and extrahepatic bile ducts. The caliber of extrahepatic ducts is normal.
  • Combined papillary stenosis and sclerosing cholangitis: This is the most common pattern of HIV cholangiopathy and is observed in more than 50% of cases.
  • Long strictures of extrahepatic bile ducts: This pattern is observed in approximately 15% of patients. The strictures are 1-2 cm long and do not have features suggesting another cause, such as prior biliary surgery or pancreatitis.

TREATMENT

Section 6 of 11  

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Medical Care

Medical treatment consists of managing complications of bile duct strictures until definitive therapy can be instituted. Most patients presenting with cholangitis respond to antibiotics and supportive management. Patients who are elderly and frail and those presenting with hypotension or altered mental status are best treated in an intensive care unit.

• The common organisms causing cholangitis are Escherichia coli and Klebsiella, Enterococcus, Proteus, Bacteroides, and Clostridium species. Empiric antibiotic therapy should be effective against these organisms.
• A combination of a penicillin, aminoglycoside (gentamicin), and metronidazole traditionally has been the preferred regimen. Newer penicillins, such as piperacillin/tazobactam or imipenem/cilastatin, also have excellent activity against anaerobes, enterococci, and gram-negative cocci.
• Approximately 70-80% of patients respond to medical therapy and do not need urgent intervention. Patients not responding to empiric antibiotic therapy within 24 hours or those with hypotension requiring vasopressors, disseminated intravascular coagulation, or multiorgan system failure should be considered for immediate biliary decompression, which can be performed surgically, percutaneously, or endoscopically. Endoscopic or percutaneous decompression often is associated with lower morbidity and should be considered first.

Surgical Care

Patients with cholangitis whose conditions fail to improve with conservative treatment usually require urgent decompression of the obstructed biliary system. Treatment options for bile duct strictures include (1) endoscopic or percutaneous balloon dilatation and insertion of an endoprosthesis or (2) surgery.

• Decompression of the biliary system
• • Decompression usually is performed endoscopically, with placement of a nasobiliary tube or stent after sphincterotomy.
  • Alternatives to ERCP are percutaneous transhepatic biliary drainage and surgical decompression. However, operative biliary decompression is associated with much higher morbidity and mortality compared to endoscopic therapy.
• Endoscopic management
• • Benign biliary strictures (eg, postcholecystectomy, after liver transplantation) can be treated effectively with endoscopic therapy, which achieves a symptomatic and biochemical response in most cases.
  • Recent studies show that the long-term success rate of endoscopic stenting is comparable to that of surgery, with similar recurrence rates. Therefore, surgery should probably be reserved for those patients with complete ductal obstruction or those in whom endoscopic therapy has failed.
  • Endoscopic therapy generally involves a sphincterotomy, which is performed at the first endoscopic session simultaneously with the placement of one or two 10F-12F stents across the area of obstruction. Dilatation of the stricture may be necessary if the stricture is too tight.
  • The insertion of a second stent may be possible only during a second endoscopy session. Thereafter, elective replacement of the stents seems desirable to prevent cholangitis by stent occlusion because polyethylene stents generally clog in 3-4 months.
• Sphincterotomy and endoscopic balloon dilation
  • The combination of sphincterotomy and endoscopic balloon dilation alone is not a reliable method of treating benign strictures.
  • Dilation followed by short- to intermediate-term stent placement appears to provide a more durable result.
• Endoscopic biliary stenting
  • This procedure is an alternative to surgery for the initial treatment of jaundice and cholangitis in patients with biliary strictures due to chronic pancreatitis.
  • The morbidity and mortality rates associated with biliary stent insertion are low. Endoscopic therapy appears to be effective in this situation; however, the efficacy of this treatment in the long-term management of biliary strictures from pancreatitis is limited by frequent stent blockages and migration and should be considered an alternative to surgery only in high-risk surgical candidates.
  • The role of metallic stents in this situation needs further evaluation. Opinions vary considerably regarding the clinical significance of biliary strictures secondary to pancreatitis in asymptomatic patients and the appropriate treatment of these lesions. The low incidence of cholangitis and secondary biliary cirrhosis in association with asymptomatic biliary strictures may justify a less aggressive approach.
• Endoscopic therapy for PSC
  • Endoscopic therapy of PSC is palliative. The main goal is to improve pruritus and relieve jaundice before transplantation.
  • The treatment involves balloon dilatation of strictures, stone removal, and placement of plastic stents.
  • Endoscopic stent therapy is a safe and effective treatment modality for an acute exacerbation of disease caused by dominant extrahepatic bile duct strictures in patients with PSC. Stent therapy is generally not effective for multiple intrahepatic ductal strictures.
  • In carefully selected patients with PSC who do not have cirrhosis, resection and long-term stenting remain good options. Patients with cirrhosis should undergo liver transplantation.
  • The role of endoscopy in the treatment of secondary biliary stricture associated with conditions such as HIV infection remains undefined. These patients have advanced AIDS; however, AIDS-related cholangitis per se rarely causes death. ERCP and sphincterotomy may help relieve an individual patient's pain and improve quality of life.
• Endoscopic therapy for malignant strictures
  • The treatment of malignant bile duct strictures requires consideration of a number of factors, the most important being the extremely low survival and cure rates associated with this disease. Most patients die from this disease within 6-12 months.
  • The primary objective in unresectable disease is to provide palliation of the jaundice. Given the morbidity and mortality associated with an operative procedure, nonoperative techniques of palliation are preferred.
  • Self-expanding metal stents provide effective palliation of malignant biliary strictures and should be considered as an alternative to open surgery
  • Metallic stents, although more expensive and not removable once placed, remain patent longer than polyethylene stents; usually a single session of metal stenting can palliate biliary obstruction and, therefore, may be a better choice for malignant strictures.
  • With tumors affecting the bifurcation of the hepatic ducts (Klatskin tumor), stents can be placed into both the right and left intrahepatic ducts to provide decompression. However, stent placement is technically more difficult in patients with proximal tumors.
  • Metal stents may become occluded as a result of tumor ingrowth through the open mesh design. A covered self-expanding metal has recently been introduced in an effort to reduce the frequency of tumor ingrowth.
• Percutaneous transhepatic cholangioplasty and biliary stenting
  • Similar to endoscopy, the percutaneous balloon dilatation of benign (especially after OLT) and malignant biliary strictures and the insertion of plastic or metallic stents also are well tolerated by patients. The stents provide good drainage.
  • This procedure is executed in a few stages as the tract through the liver is dilated gradually to pass the optimal size stent. The stent may be completely internalized, with one lumen in the duodenum and the other proximal to the stricture, or may be an internal-external stent, with one lumen outside and one distal to the stricture.
  • Percutaneous therapy is associated with a 5-10% rate of major complications.
• Operative treatment
  • Surgical management of benign bile duct strictures is necessary for patients with a low surgical risk in whom endoscopic therapy has failed. Surgical management consists of restoration of biliary enteric continuity, which usually is achieved with a defunctionalized Roux-en-Y jejunal loop by means of hepaticojejunostomy, choledochojejunostomy, or intrahepatic cholangiojejunostomy.
  • Biliary-enteric anastomosis is a safe, effective, and lasting therapy for biliary strictures. However, before definitive operative therapy for bile duct strictures is performed, patients must be stabilized and, if possible, biliary drainage should be achieved either endoscopically or percutaneously.
  • Patients with long-standing biliary stricture due to pancreatitis may require pancreaticoduodenectomy. However, surgical drainage has been associated with considerable morbidity and mortality.
  • In patients with PSC without cirrhosis, resection of the extrahepatic bile ducts and long-term transhepatic stenting are alternatives to nonoperative dilation with or without stenting and may be associated with a better outcome.
  • Surgical therapy of malignant bile duct strictures consists of either attempting a curative resection of the tumor or performing a palliative operation. Unfortunately, the surgical cure rate of pancreatic, bile duct, and gallbladder carcinoma causing malignant strictures is dismal. Careful staging of the tumor should be performed in order to select patients who are likely to have surgically resectable disease.
  • Surgical intervention is recommended for those patients who are otherwise healthy, whose disease appears to be localized, or in whom duodenal or gastric outlet obstruction is present.
  • Palliative surgery is directed towards relieving jaundice by creating a biliary-enteric anastomosis, and if a gastric or duodenal outlet obstruction is present or a likely possibility, a gastrojejunostomy should be created at the same time. Although palliative surgery is effective in achieving its goal of circumventing the obstruction, no survival advantage has been described when compared with nonoperative techniques. Thus, for most patients, palliative surgery is not necessary.

Consultations

• Gastroenterologist
• Surgeon
• Infectious disease specialist
• Interventional radiologist
• Oncologist

Diet

• No special diet is required.

Activity

• No restriction on physical activity is required.

MEDICATION

Section 7 of 11  

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• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to eradicate the infection, prevent complications, and reduce morbidity.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

FOLLOW-UP

Section 8 of 11  

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Patients who develop obstructive jaundice complicated by fever, infection, or duodenal obstruction are often admitted for urgent treatment of obstruction and/or infection.
• Patients presenting with ascending cholangitis may need to be admitted to the intensive care unit, especially if they have altered mental status and hypotension. These patients should be started on broad-spectrum antibiotics with good gram-negative and anaerobic coverage.
• In addition, urgent drainage and decompression of the biliary tree may be required when an appropriate response to antibiotic therapy is not achieved.
• Patients with strictures amenable to endoscopic therapy can be treated in an inpatient or outpatient setting. Those requiring surgery generally have a longer hospital stay, especially in the postoperative period.

Further Outpatient Care

• Patients with percutaneous drains should have their catheters flushed with 5-10 mL of saline once or twice every day to prevent catheter blockage.
• Patients should be monitored closely for recurrence of cholangitis and obstructive jaundice, which can occur if the biliary drainage catheters or stents are occluded or if they migrate.
• Those treated with biliary stenting with plastic stents or balloon dilatation of biliary strictures need periodic follow-up with a gastroenterologist or interventional radiologist for stent changes and periodic stricture dilatation.
• Patients with external biliary drains also should seek follow-up with an interventional radiologist for catheter exchanges every 2-3 months for internalization of drains.
• Those with a malignant obstruction treated with metallic endoprosthesis should be monitored with periodic liver function testing. Progressively abnormal liver function tests suggest stent dysfunction.

Transfer

• Management of bile duct strictures is a complex problem requiring a multidisciplinary approach. The patient should be in a specialized center where expertise in diagnostic and therapeutic ERCP and biliary interventional radiology is available. Surgical therapy also should be performed in centers with staff experienced in performing hepatobiliary and pancreatic surgery.

Complications

• Complications include development of stones in the gallbladder and bile ducts proximal to the stricture, pyogenic liver abscess due to recurrent episodes of ascending cholangitis, secondary biliary cirrhosis, and weight loss and malnutrition from steatorrhea with fat-soluble vitamin deficiency.

Prognosis

• The prognosis for patients with benign strictures is good. Patients who develop symptoms of biliary obstruction do well after surgical or endoscopic therapy.
• Conversely, patients with HIV cholangiopathy or malignant biliary obstruction usually present at a late stage with widespread disease and generally have a dismal prognosis.

Patient Education

• Patients with biliary stents should be educated regarding how to recognize the symptoms of biliary obstruction and cholangitis that indicate blocked stents. Those with external drains should be taught how to flush their catheters until the catheters are internalized.
• Patients with alcoholic chronic pancreatitis may benefit from counseling and alcohol abuse rehabilitation.
• For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article Cirrhosis.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Patients presenting with acute ascending cholangitis should undergo urgent biliary drainage when an appropriate response to antibiotic therapy is not achieved or when the initial presentation is severe.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  ERCP image of a cholangiocarcinoma at the bifurcation of the right and left hepatic ducts (Klatskin tumor).
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Media file 2:  ERCP cholangiogram demonstrating a long bile duct stricture representing external compression by gallbladder cancer.
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Media file 3:  Transhepatic cholangiogram with an external drainage catheter in place.
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Media file 4:  ERCP image of a cholangiogram in a patient with cholangiocarcinoma which has been treated with a metal stent.
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Media file 5:  ERCP cholangiogram of a solitary benign stricture of the distal bile duct. Resection demonstrated sclerosing cholangitis.
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Media file 6:  ERCP cholangiogram demonstrating an isolated mid-hepatic duct stricture as a result of pancreatic cancer.
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Media file 7:  ERCP cholangiogram demonstrating diffuse stricturing of the intrahepatic ducts consistent with primary sclerosing cholangitis.
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Media file 8:  Bile duct strictures.
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Media file 9:  Bile duct strictures.
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Media file 10:  Bile duct strictures.
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Media file 11:  Bile duct strictures.
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Media file 12:  Ultrasound and CT scan findings show dilated intrahepatic and extrahepatic bile ducts.
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Media file 13:  Benign bile duct strictures.
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Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg. Jan 1992;215(1):31-8. [Medline].
• Bjornsson E, Lindqvist-Ottosson J, Asztely M. Dominant strictures in patients with primary sclerosing cholangitis. Am J Gastroenterol. Mar 2004;99(3):502-8.
• Brugge WR. Endoscopic techniques to diagnose and manage biliary tumors. J Clin Oncol. Jul 10 2005;23(20):4561-5.
• Bueno JT, Gerdes H, Kurtz RC. Endoscopic management of occluded biliary Wallstents: a cancer center experience. Gastrointest Endosc. Dec 2003;58(6):879-84.
• Cello JP. Human immunodeficiency virus-associated biliary tract disease. Semin Liver Dis. May 1992;12(2):213-8. [Medline].
• Cherqui D, Palazzo L, Piedbois P. Common bile duct stricture as a late complication of upper abdominal radiotherapy. J Hepatol. Jun 1994;20(6):693-7. [Medline].
• Colonna JO, Shaked A, Gomes AS. Biliary strictures complicating liver transplantation. Incidence, pathogenesis, management, and outcome. Ann Surg. Sep 1992;216(3):344-50; discussion 350-2. [Medline].
• Deviere J, Cremer M, Baize M. Management of common bile duct stricture caused by chronic pancreatitis with metal mesh self expandable stents. Gut. Jan 1994;35(1):122-6. [Medline].
• Fan ST, Ng IO, Choi TK. Tuberculosis of the bile duct: a rare cause of biliary stricture. Am J Gastroenterol. Apr 1989;84(4):413-4. [Medline].
• Frattaroli FM, Reggio D, Guadalaxara A. Benign biliary strictures: a review of 21 years of experience. J Am Coll Surg. Nov 1996;183(5):506-13. [Medline].
• Gibbons JC, Williams SJ. Progress in the endoscopic management of benign biliary strictures. J Gastroenterol Hepatol. Feb 1998;13(2):116-24. [Medline].
• Hanau LH, Steigbigel NH. Acute (ascending) cholangitis. Infect Dis Clin North Am. Sep 2000;14(3):521-46. [Medline].
• Hastier P, Buckley JM, Peten EP. Long term treatment of biliary stricture due to chronic pancreatitis with a metallic stent. Am J Gastroenterol. Jul 1999;94(7):1947-8. [Medline].
• Ishizuka D, Shirai Y, Hatakeyama K. Ischemic biliary stricture due to lymph node dissection in the hepatoduodenal ligament. Hepatogastroenterology. Nov-Dec 1998;45(24):2048-50. [Medline].
• Itani KM, Taylor TV. The challenge of therapy for pancreatitis-related common bile duct stricture. Am J Surg. Dec 1995;170(6):543-6. [Medline].
• Kadir S, White RI. Biliary stricture dilatation: multicenter review of clinical management in 73 patients. Radiology. Jan 1987;162(1 Pt 1):286. [Medline].
• Kamisawa T, Tu Y, Egawa N. Involvement of pancreatic and bile ducts in autoimmune pancreatitis. World J Gastroenterol. Jan 28 2006;12(4):612-4.
• Kim KH, Sung CK, Park BG. Clinical significance of intrahepatic biliary stricture in efficacy of hepatic resection for intrahepatic stones. J Hepatobiliary Pancreat Surg. 1998;5(3):303-8. [Medline].
• Klein AS, Savader S, Burdick JF. Reduction of morbidity and mortality from biliary complications after liver transplantation. Hepatology. Nov 1991;14(5):818-23. [Medline].
• Lipsett PA, Pitt HA, Colombani PM. Choledochal cyst disease. A changing pattern of presentation. Ann Surg. Nov 1994;220(5):644-52. [Medline].
• Lombard M, Farrant M, Karani J. Improving biliary-enteric drainage in primary sclerosing cholangitis: experience with endoscopic methods. Gut. Nov 1991;32(11):1364-8. [Medline].
• Magistrelli P, Masetti R, Coppola R. Changing attitudes in the palliation of proximal malignant biliary obstruction. J Surg Oncol Suppl. 1993;3:151-3. [Medline].
• Maier M, Kohler B, Benz C. [Percutaneous transhepatic cholangioscopy (PTCS)--an important supplement in diagnosis and therapy of biliary tract diseases (indications, technique and results)]. Z Gastroenterol. Aug 1995;33(8):435-9. [Medline].
• Mansfield JC, Griffin SM, Wadehra V. A prospective evaluation of cytology from biliary strictures. Gut. May 1997;40(5):671-7. [Medline].
• McDonald ML, Farnell MB, Nagorney DM. Benign biliary strictures: repair and outcome with a contemporary approach. Surgery. Oct 1995;118(4):582-90; discussion 590-1. [Medline].
• Mendler MH, Bouillet P, Sautereau D. Value of MR cholangiography in the diagnosis of obstructive diseases of the biliary tree: a study of 58 cases. Am J Gastroenterol. Dec 1998;93(12):2482-90. [Medline].
• Moore AV, Illescas FF, Mills SR. Percutaneous dilation of benign biliary strictures. Radiology. Jun 1987;163(3):625-8. [Medline].
• Morrison MC, Lee MJ, Saini S. Percutaneous balloon dilatation of benign biliary strictures. Radiol Clin North Am. Nov 1990;28(6):1191-201. [Medline].
• Mosca S, Militerno G, Guardascione MA. Late biliary tract complications after orthotopic liver transplantation: diagnostic and therapeutic role of endoscopic retrograde cholangiopancreatography. J Gastroenterol Hepatol. Jun 2000;15(6):654-60. [Medline].
• Nakakubo Y, Kondo S, Katoh H. Biliary stricture as a possible late complication of radiation therapy. Hepatogastroenterology. Nov 2000;47(36):1531-2. [Medline].