Biliary complications after liver transplantation

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 32–37

© 2012, Indraprastha Medical Corporation Ltd

Biliary complications after liver transplantation

Ajay Kumar*, Manav Wadhawan*, Sunil Taneja*, Rajiv Shandil**Consultant, Department of Gastroenterology and Hepatology and Liver Transplantation, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.

ABSTRACT

Liver transplantation (LT) has become the established means of treating patients with end-stage liver disease. However, biliary complications remain a significant cause of postoperative morbidity and possibly mortality. Biliary strictures and leaks are the most common complications following liver transplantation. The incidence of biliary tract complications after orthotopic LT (OLT) varies from 11% to 34%. The reported incidence of biliary complications is 5–15% after deceased donor liver transplantation (DDLT) and 20–34% after right lobe living-related liver transplant (LRLT). There are several predisposing risk factors for development of biliary complications post transplant with a higher risk in LRLT compared to DDLT. Bile duct strictures occur in 4–13% of patients after DDLT and account for approximately 40% of all biliary complications where as the incidence of biliary leaks after LT ranges between 2% and 25%. Biliary strictures after liver transplantation have been classified as anastomotic strictures (AS) and non-anastomotic strictures (NAS). Most bile leaks and strictures can be resolved nonoperatively with early endoscopic intervention. Endoscopic retrograde cholangiopancreatography (ERCP) is the first line treatment at our center for both bile leaks as well strictures. However, in spite of excellent results surgery is required in small proportion of patients.

Keywords: Biliary complications, biliary leaks, biliary strictures, ERCP, liver transplantation

Correspondence: Dr. Ajay Kumar, E-mail: [email protected]: 10.1016/S0976-0016(12)60117-3

INTRODUCTION

Liver transplantation (LT) has become the established means of treating patients with end-stage liver disease.1 Despite remarkable improvement in the surgical technique, postop-erative care, immunosuppression, and organ preservation resulting in improved survival rates for transplant recipients, biliary tract complications still remain the Achilles heel of LT.2 Biliary reconstruction is often considered the least tech-nically demanding anastomosis in orthotopic LT (OLT).3 However, biliary complications remain a significant cause of postoperative morbidity and possibly mortality.

Biliary complications have a major impact on the qual-ity of life for a liver allograft recipient, as they entail fre-quent readmission, reoperation, hospital stays, and escalating costs which add to the emotional trauma that patients suffer. Biliary strictures and leaks are the most common complica-tions following LT. The conventional management of these conditions in the past was mainly surgical; however, with the rapid progress in the field of endoscopy and radiology, the majority of these complications are now amenable to endoscopic interventions, while the role of surgery is now mainly confined to treatment failures as a backup option.

INCIDENCE OF BILIARY COMPLICATIONS

The incidence of biliary tract complications after OLT varies from 11% to 34%. The reported incidence of biliary com-plications is 5–15% after deceased donor liver transplanta-tion (DDLT)4–10 and 20–34% after right lobe living-related liver transplantation (LRLT).11–15 Unpublished data from our center of 338 consecutive LRLT patients have shown overall incidence of biliary complications at 19% (65/338). Biliary complications fall into three main categories: leaks, strictures, and a miscellaneous group that includes biliary sludge, stones, casts, and sphincter of Oddi dysfunction.

TYPES OF BILIARY ANASTOMOSIS

Biliary reconstruction during LT today is generally per-formed by end-to-end, sometimes side-to-side choledocho-choledochostomy (CC) or Roux-Y choledocho-jejunostomy (CRY). The method of choice in patients with healthy native bile ducts of suitable caliber is the CC while CRY is preferred in cases of pre-existing biliary tract disease or previous biliary

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Biliary complications after liver transplantation Review Article 33


tract surgery. Some surgeons prefer to keep a stent or insert a T-tube. The practice followed at our center has been to do hepaticojejunostomy in left lobe liver transplant recipients which is done primarily in pediatric population and CC anastomosis in right lobe liver transplant recipients. Our surgical team does not prefer using any stent or T-tube during biliary reconstruction.

PREDISPOSING FACTORS FOR BILIARY

COMPLICATIONS

There are several predisposing risk factors for development of biliary complications post transplant. The solitary blood supply of the bile ducts is from the hepatic artery and any thrombosis of the artery (HAT) can lead to complex hilar strictures. Complications may result from devascularization of the bile duct at the hilar dissection, failure to recognize anomalies of the biliary tree, technically challenging biliary reconstruction (small-sized ducts, multiple ducts), and biliary leaks from the cut surface in a partial liver transplant. The donated organ itself can be a risk if it is a donation after car-diac death, if the donor was of an older age, or if there was prolonged cold and warm ischemia time.16 Pre-LT diagno-sis of cytomegalovirus infection is also associated with an increased risk of biliary complications (Table 1).12,13,17–19

There is a higher risk of biliary complications in LRLT compared with DDLT. Overall, biliary complications occur more frequently in right liver graft recipients than with left liver grafts. In right liver graft recipients with single biliary reconstruction, duct-to-duct anastomosis involving a small-sized duct (<4 mm in diameter) is more of a risk for biliary complications than when a hepaticojejunostomy is used with these duct sizes (Table 2).20

BILE LEAKS

Early complications are composed primarily of bile leaks and anastomotic strictures (ASs). The incidence of biliary leaks

after LT ranges between 2% and 25%.5,7,21–25 A recent review has reported an incidence of biliary leakage at 9.5% among LRLT recipients26 which is similar to experience from our center of 8.8%. Bile leaks can occur from the anastomosis (Figure 1), the cystic duct remnant, the T-tube tract, or from the cut surface of the liver (Figure 2). They can be classified as early or late depending on if they occur before or after 1 month from the LT. Early bile leaks usually occur at the anastomotic site and are often related to technical issues,

Table 1 Risk factors associated with biliary leaks.

Donor Recipient Technical issues

Age >50 yr Anatomic biliary diversity Experience of transplant centerThree or more bile ducts Hepatitis C Anatomic biliary diversityMultiple reconstructions MELD >35 Complicated surgical procedure Pre-LT CMV Prolonged cold and warm ischemia time

CMV: cytomegalovirus; LT: liver transplantation; MELD: model for end-stage liver disease.

Table 2 Biliary complications after liver transplantation.

Early complications Late complications

Bile leaks Late stricturesAnastomotic site AnastomoticCystic duct Non-anastomoticAccessory bile ducts Filling defects‘T’-tube tract CholedocholithiasisIncidental intrahepatic injury SludgeCut surface of the liver Biliary cast syndromeMigrated T-tube Cholangitis

Early stricturesMismatched bile duct diametersTechnical errors

Figure 1 Anastomotic leak.

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not to the type of biliary reconstruction. Factors that predis-pose grafts to early bile leaks include lack of perfusion from the hepatic artery and other technical reasons. Late bile duct leaks usually are related to the removal of the T-tube, resulting from delay in T-tube tract maturation as a result of immunosuppression. A relatively higher propor-tion of patients with late bile leaks later present with biliary strictures than do those with early leaks.

Clinical symptoms of a bile leak include fever, abdomi-nal pain, and peritoneal irritation. Bile in the abdominal drains is highly suspicious for a leak, but absence of bile in the drains does not preclude the diagnosis. Blood tests may demonstrate an elevation of the white blood cell count, bilirubin, and alkaline phosphatase; unfortunately, no labo-ratory test is pathognomonic. Ultrasound may demonstrate a fluid collection, but often cholangiography is required for diagnosis. This is simple to perform if an external biliary stent is in place. In the absence of an external stent, options include magnetic resonance cholangiography (MRC), endo-scopic retrograde cholangiography (ERC), or percutaneous transhepatic cholangiography (PTC).

Bile leakage from any source may be serious, but leaks from the anastomosis are the most hazardous. Most bile leaks can be resolved nonoperatively with early endoscopic intervention. Leaks from the anastomosis can also be suc-cessfully managed without surgery if they are small and localized. Endoscopic or percutaneous stenting can resolve minor leaks in the absence of significant right upper quad-rant or systemic sepsis. However, if the anastomosis is seri-ously disrupted or biliary extravasation is major, reoperation with revision is the safest approach.27 Endoscopic retrograde cholangiopancreatography (ERCP) is the first line treatment at our center for both bile leaks and strictures. The technical success rate for stenting of bile leaks achieved at our center

was 82% (14/17). The time to complete resolution of bile leaks was 5–45 days in our series (unpublished data).

Bilomas occur because of bile duct rupture and extrava-sation of bile into the hepatic parenchyma or the abdominal cavity. Most post-LT bilomas occur in the perihepatic area. Large bilomas not communicating with the bile ducts should be treated with percutaneous drainage and antibiot-ics. After drainage of biloma, ERCP, and stenting is done if the leak is persisting. Surgery is indicated only when the bile leak cannot be controlled effectively with endoscopic stenting.

BILIARY STRICTURES

Biliary strictures after LT have been classified as AS and non-anastomotic strictures (NAS)28,29 (Figure 3). The two types of strictures cannot be compared as they have inher-ent differences in their pathology, time to presentation, treat-ment, and response to treatment. Bile duct strictures occur in 4–13% of patients after DDLT and account for approxi-mately 40% of all biliary complications after LT.16,30,31 Much higher stricture rates are reported in LRLT setting (10–25%). In our experience, 10/17 patients who underwent ERCP for bile leaks formed strictures. The overall stricture rate in our study was 13.3% (45/338). Strictures that occur early after LT are mostly attributable to technical problems, whereas late strictures are mainly attributable to vascular insufficiency and problems with healing and fibrosis.32,33 Up to 80% of biliary strictures are anastomotic, occurring either at the CC or at the CRY sites. By definition, they are single and short in length, making them suitable for endoscopic intervention. The ASs are secondary to imperfect healing that produces

Figure 2 Cut surface leak. Figure 3 Anastomotic stricture.

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excessive scarring in an otherwise satisfactory anastomosis or one in which the blood supply to cut ends of the duct was not perfect.

Non-anastomotic strictures (ischemic strictures) result mainly from hepatic artery thrombosis, increased cold ische-mia time, or ABO blood-type incompatibility. True ischemic strictures occur >0.5 cm proximal to the anastomosis and often involve the hilum and multiple separate obstructions at the level of the sectoral or segmental branch ducts. Non-anastomotic strictures are usually multiple, longer in length, and located in the intrahepatic ducts and/or in the donor duct proximal to the site of anastomosis. Non-anastomotic strictures are generally more difficult to treat than AS and include multiple episodes of cholangitis and hospitalizations (Table 3).

Patients with biliary stricture usually present with cholestasis (increased bilirubin, alkaline phosphatase, and gammaglutamyl transferase) or cholangitis, or both. Leuko-cytosis, fever, and right upper quadrant pain may often be absent in the case of cholangitis. Ultrasound can be mislead-ing in making the diagnosis in LRLT setting, since ductal dilatation may not be seen; however, it is still a crucial test in order to exclude potential hepatic arterial flow complications (which is a potential cause of bile duct stricture). Cholangi-ography (T-tube cholangiography, ERC, MRC, or PTC, depending on the type of bile duct [BD] reconstruction per-formed) is always necessary for diagnosis of BD stricture.

The conventional method of endoscopic treatment consists of identification of the mouth of the stricture fol-lowed by cannulation by the guide wire, balloon dilatation of the stricture, and subsequent placement of plastic stents. The stents are generally replaced by larger stents every 3 months34–36 to prevent the complication of clogging, cholan-gitis, or stone formation. In last few years, there have been multiple reports of use of removable fully covered self-expanding metal stents (SEMS) in DDLT-SEMS has been used where there is a single biliary anastomosis and there is a long segment of bile duct available before its division with good results. However, in live donor liver transplant (LDLT), as there is very short interval between the common stump and branches, fully covered SEMS is unlikely to work. Intrahepatic strictures are more difficult to treat and require more frequent ERCP, and success rates are only about 25%

with prolonged follow-up. The outcomes of NAS are not as favorable as AS. The role of an intervention radiologist in managing complex ASs is evolving over the last several decades. Strictures where endoscopic access cannot be obtained have been resolved by using rendezvous technique using percutaneous biliary drainage. Surgical revision may ultimately be required in a few patients with strictures that are refractory to endoscopic or percutaneous treatment and some may even require a retransplantation.

OTHER CAUSES OF BILIARY OBSTRUCTION

Biliary filling defects occur in approximately 5% of patients after LT.37 These filling defects can be caused by stones, sludge, debris, blood clots, casts, or migrated stents; as many as 70% of such defects are caused by stones. Calculi may be dealt with by endoscopic or percutaneous methods, but an associated stricture has to be dealt with effectively to prevent recurrent stones and sludge. Casts of inspissated bile and necrotic debris usually indicate severe and diffuse biliary injury. Endoscopic extraction may be tried, but even repeated interventions may not result in complete and permanent clearance of the biliary tree.38 Biliary revision is usually required.

SPHINCTER OF ODDI DYSFUNCTION

Dysfunction of the sphincter of Oddi after LT that produces dilatation of both the recipient and donor ducts has been described. Sphincter of Oddi dysfunction has been described in 2–7% of patients who undergo LT.23,39 It is hypothesized that dyskinesia of the sphincter of Oddi could result from denervation and devascularization at the time of hepatec-tomy.45 A functional abnormality of the sphincter or fixed ampullary stenosis may respond to endoscopic sphincterotomy, but results have been conflicting.

CONCLUSION

Biliary complications are common after LT, though more after LDLT. Biliary complications still remain a significant source of patient morbidity and mortality in LT. The incidence is higher in multiple duct anastomosis. Biliary strictures are more common than leaks and most leaks subsequently form strictures. The ERCP has become the first line treatment for

Table 3 Differences between types of strictures.

Type Anastomotic Non-anastomotic

Time (mo) 5–8 3–6Number Single Single or multipleResponse to endotherapy Good (80%) Variable (40%)

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biliary complications. Interventional radiology support does help in minority of patients obviating the need for surgery. However, in spite of excellent results surgery is required in small proportion of patients.

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Biliary complications after liver transplantation

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