Bile Duct Strictures

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:

• In the US: 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.

• Internationally: 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.

Treatment
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
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.

Drug Name	Piperacillin and tazobactam sodium (Zosyn) -- Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.
Adult Dose	3/0.375 g (piperacillin 3 g and tazobactam 0.375 g) IV q6h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe pneumonia; bacteremia; pericarditis; emphysema; meningitis and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage
Interactions	Tetracyclines may decrease effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Perform CBC count prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; exercise caution in patients diagnosed with hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy, and adjust dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions

Drug Name	Imipenem and cilastatin (Primaxin) -- For treatment of multiple-organism infections in which other agents do not have broad-spectrum coverage or are contraindicated due to potential toxicity.
Adult Dose	1 g IV/IM q6-8h
Pediatric Dose	<12> >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in renal insufficiency

Drug Name	Metronidazole (Flagyl, Protostat) -- Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).
Adult Dose	500 mg IV q6-8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiram reaction may occur with orally ingested ethanol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy

Drug Name	Gentamicin (Garamycin, Gentacidin) -- Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be given IV/IM.
Adult Dose	Loading dose: 1-2.5 mg/kg IV Maintenance dose: 1-1.5 mg/kg IV q8h Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV/IM q6-8h Monitor each regimen by drawing at least a trough level on the third or fourth dose (0.5 h before dosing); may draw a peak level 0.5 h after 30-min infusion
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	D - Unsafe in pregnancy
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Penicillin G (Pfizerpen) -- Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
Adult Dose	2.4 million U IM (single dose) in 2 injection sites
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid can increase effects; coadministration of tetracyclines can decrease effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in impaired renal function