Complete Bile Duct Sequestration after Liver Transplantation, Caused by Ischemic-Type Biliary Lesions

• Introduction
• Case Report
• Discussion
• References

Ischemic-type biliary lesions (ITBLs) are the most frequent cause of nonanastomotic biliary strictures in liver grafts, affecting about 2-19 % of patients after liver transplantation. ITBL is characterized by bile duct destruction, subsequent stricture formation, and sequestration. We report here the case of a patient affected by extremely severe ITBL, with sequestration and disintegration of the entire bile duct system, in which it was possible to extract the complete biliary tree endoscopically in a single piece. Histological examination revealed that all cells of the bile duct wall had been destroyed within 3 months after liver transplantation and replaced by connective tissue. Subsequently, biliary stricture formation occurred at the hepatic hilum, as well as the adjacent large bile ducts. It may be hypothesized that cellular rejection of small bile ducts leads to the vanishing bile duct syndrome, whereas cellular rejection of large bile ducts results in ITBL. The strictures were repeatedly dilated by endoscopic means, allowing successful control of stricture formation, as well as maintenance of liver function. At the time of writing, the grafted organ and the patient had survived for more than 3 years in good health. This is the first detailed report on a sequestration of the entire bile duct system caused by ITBL, successfully treated for several years by endoscopic means.

Introduction

Ischemic-type biliary lesions (ITBLs) occur as a severe biliary complication after liver transplantation [1]. This disease is also known by synonymous terms, such as ischemic-type biliary complications, ischemic-type biliary strictures, ischemic-type lesions, and ischemic cholangitis [2] [3].

The reported incidence of ITBL varies from 2.5 % to 19 % [1] [2]. In general, ITBL becomes manifest 3 - 6 months after orthotopic liver transplantation (OLT), leading to bile duct destruction and subsequently to inflammatory biliary stricture formation [1]. Most patients with ITBL show destroyed intrahepatic, as well as extrahepatic bile ducts, while a few patients develop only extrahepatic or intrahepatic lesions. The etiology is still unknown. Some authors have hypothesized that immunological effects might cause spasms in hepatic arteries, resulting in hypoxemia and necrosis of the bile duct system [4]. Other suggested risk factors have included cold ischemic time [3] and ABO incompatibility [5]. It has been claimed that early retransplantation is required in cases of ITBL [6]. Alternative treatment options, such as liver resection and endoscopic dilation therapy, have been used in some 60 - 72 % of ITBL patients [1] [7]. This report describes an unusual case of ITBL in a woman who had undergone liver transplantation, leading to the sequestration of the entire bile duct system.

Case Report

A 50-year-old woman was suffering from deteriorating alcoholic cirrhosis of the liver, complicated by portal hypertension and intractable ascites. In addition, the patient was affected by mild arterial hypertension, controlled by treatment with diuretics. The physical examination and history did not reveal any other remarkable findings. After 1 year of alcohol abstinence, she underwent orthotopic liver transplantation. The donor liver was compatible with regard to the ABO and rhesus blood group system. After explantation, the donor liver was stored in University of Wisconsin solution and implanted after a cold ischemic period of 6.9 h. Bile duct anastomosis was carried out as a side-to-side choledochocholedochostomy. Hepatic artery and portal vein anastomosis was carried out in the standard end-to-end microsurgical fashion. To prevent anastomotic biliary stricture, a T-tube was inserted into the recipient common bile duct (CBD) 1 cm downstream from the anastomosis, in order to splint the biliary anastomosis.

The first postoperative week was unremarkable. Initially, elevated liver enzymes due to common reperfusion injury declined within a few days to near-normal levels. Liver synthesis was completely restored, and liver graft function was normal. One week after liver transplantation, a sudden increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred, whereas γ-glutamyltransferase (GGT), alkaline phosphatase and bilirubin did not significantly change (Figure [1]).

Histological examination of a liver biopsy disclosed acute cellular rejection. A 3-day course of immunosuppression with methylprednisone 500 mg daily was curative, as indicated by ALT and AST declining into the normal range, as well as histological regression of the cellular rejection. The patient soon recovered, and was released from hospital 1 month after OLT. Therapeutic immunosuppression was ensured with tacrolimus, mycophenolate, and prednisolone.

The T-drain was extracted 6 weeks after OLT, at which time retrograde cholangiography through the T-drain confirmed a normal bile duct morphology (Figure [2]). Three months postoperatively a sudden increase in GGT, alkaline phosphatase, and bilirubin appeared, heralding the onset of a post-transplant biliary complication (Figure [1]). Ultrasonography and CT images revealed dilation of the intrahepatic and extrahepatic bile ducts. Endoscopic retrograde cholangiography (ERC) demonstrated major biliary destruction in the liver transplant, with bile duct dilation and a large longitudinal filling defect in the common bile duct and both main hepatic ducts, whereas the biliary anastomosis appeared normal (Figure [3]). The ERC findings showed the pathognomonic morphology of ITBL, with sequestration of the entire graft bile duct system. After sphincterotomy, it was possible to remove the complete tree-shaped bile duct sequester by basket extraction. Histological examination of the extracted sequester revealed that the normal bile duct epithelium had been completely replaced by connective tissue within 3 months after transplantation (Figure [4]). Previously, 4 weeks after OLT, a liver biopsy had already revealed lymphocytic inflammation of the large bile ducts, leading to complete replacement of biliary cells by connective tissue (Figure [5]). After ERC-guided sequester extraction, normal bile flow was completely restored, as indicated by a marked decline in the cholestatic blood values and as evident in ERC images (Figure [6]).

During a 3-year follow-up period, biliary stricture formation occurred at the hepatic hilum, which was successfully controlled by balloon dilation (MaxForce balloon catheters, 6 mm diameter, Boston Scientific Corporation, Watertown, Massachusetts, USA) scheduled every 6 months. So far, endoscopic therapy has kept the patient in good physical condition for more than 3 years, thus avoiding the need for early retransplantation.

Discussion

Biliary complications account for significant morbidity in orthotopic liver transplantation (OLT), with a reported incidence ranging from 6 % to 47 % [8]. Biliary strictures usually occur at the bile duct anastomosis, with a reported incidence of 5 - 30 % [9]. By contrast, nonanastomotic strictures predominantly affect large bile ducts of the liver graft. ITBL, with a reported incidence of 2-19 %, is the most frequent nonanastomotic bile duct stricture in liver grafts [1] [2].

Other diseases mimicking ITBL had to be considered in the present case. Hepatic artery obstruction was excluded by angiography. Recurrence of primary sclerosing cholangitis (PSC) has been reported in about 20 % of liver grafted PSC patients [10]. Cholangiocarcinoma may develop in liver grafts in patients transplanted due to PSC or cholangiocarcinoma. Bile duct strictures secondary to localized lymphoproliferative disorder of the liver are quite rare, but have been reported in 12 cases [11]. In the present patient, recurrence of PSC, the onset of cholangiocarcinoma, and lymphoproliferative hepatic disorder were definitely ruled out in view of the clinical course, as well as histological examination of liver biopsies.

One week after OLT, the patient developed early acute cellular rejection, which was successfully treated with immunosuppressive therapy. This quite common post-transplant complication usually occurs within the first 3 weeks after transplantation, with an incidence of 40 - 70 % [10]. In contrast to other solid organ transplants, such as the heart and kidney, early acute cellular rejection episodes do not affect late function of liver allografts in humans [12].

Histological features of the extracted bile duct sequester suggested that soon after liver transplantation, all tissue layers of the bile duct wall became involved in a process of complete cell destruction and complete replacement by connective tissue, followed by sequestration. Histological follow-up examinations of liver biopsies revealed lymphocytic invasion of the biliary epithelium and subsequent degenerative changes and necrosis of bile duct cells accompanied by proliferation of segmental bile ducts, and finally replacement of biliary cells by connective tissue. Hence, the putative pathogenetic mechanism for ITBL could be a direct lymphocytic effect on bile duct epithelial cells. Lymphocyte cultures generated from hepatic allografts with rejection cholangitis have shown cytotoxic activity directed against donor major histocompatibility complex (MHC) antigens [13]. As class I MHC antigens are normally expressed on bile ducts during rejection episodes, direct lymphocytotoxic attack aimed at MHC antigens or other biliary antigens appears to be an important immunological mechanism [10]. Ductopenic rejection - leading to the so-called vanishing bile duct syndrome, which is found in about 9 % of patients after OLT - is diagnosed if interlobular and septal bile ducts are absent from more than 50 % of portal tracts [13]. Since the present patient did not experience bile duct loss, a vanishing bile duct syndrome, as well as the onset of primary biliary cirrhosis (PBC), which also can be associated with ductopenia, were excluded. The large and small bile ducts have a different embryonic development, resulting in different molecular patterns and subcellular architecture [14]. Different antigens are therefore presented on large and small bile ducts, resulting in different immunological features. ITBL-induced damage predominantly occurs in the large bile ducts of liver grafts, as was also observed in this case. It may be hypothesized that cellular rejection of small bile ducts leads to the vanishing bile duct syndrome, whereas cellular rejection of large bile ducts results in ITBL. Further studies will be needed to determine the precise molecular mechanisms involved in ITBL.

Endoscopic therapy is able to offer effective and safe treatment for anastomotic and nonanastomotic biliary strictures - postponing, if not avoiding, the need for another surgical intervention [15]. The case presented here is a remarkable example of a very severe biliary complication of OLT, leading to complete bile duct sequestration and biliary stricture formation. At the time of writing, ITBL strictures in this patient had been successfully controlled by repeated dilation therapy. The patient has survived for more than 3 years in good health and physical condition, without the need for retransplantation. This case demonstrates that even severe ITBL can be adequately treated by endoscopic therapy.

References

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• 14 Tan C E, Vijayan V. New clues for the developing human biliary system at the porta hepatis.  J Hepatobiliary Pancreat Surg. 2001;  8 295-302
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H. Abou-Rebyeh, M. D.

Dept. of Hepatology, Gastroenterology, Endocrinology and Metabolism ·

University Hospital Charité, Campus Virchow-Klinikum · Humboldt University · Augustenburger Platz 1 · 13353 Berlin · Germany

Fax: +49 30 450 553 917

Email: Hassan.Abou-Rebyeh@charite.de

References

• 1 Hintze R E, Abou-Rebyeh H, Adler A. et al . Endoscopic therapy of ischemic-type biliary lesions (ITBL) in patients after orthotopic liver transplantation.  Z Gastroenterol. 1999;  37 13-20
  PubMedSearch in Google Scholar
• 2 Sanchez Urdazpal L, Gores G J, Ward E M. et al . Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation.  Hepatology. 1993;  17 605-609
  PubMedSearch in Google Scholar
• 3 Fisher A, Miller C H. Ischemic-type biliary strictures in liver allografts: the Achilles heel revisited?.  Hepatology. 1995;  21 589-591
  CrossrefPubMedSearch in Google Scholar
• 4 Nakamura K, Murase N, Becich M J. et al . Liver allograft rejection in sensitized recipients: observations in a clinically relevant small animal model.  Am J Pathol. 1993;  142 1383-1391
  PubMedSearch in Google Scholar
• 5 Sanchez Urdazpal L, Batts K P, Gores G J. et al . Increased bile duct complications in liver transplantation across the ABO barrier.  Ann Surg. 1993;  218 152-158
  PubMedSearch in Google Scholar
• 6 Schlitt H J, Meier P N, Nashan B. et al . Reconstructive surgery for ischemic-type lesions at the bile duct bifurcation after liver transplantation.  Ann Surg. 1999;  229 137-145
  CrossrefPubMedSearch in Google Scholar
• 7 Sebagh M, Farges O, Kalil A. et al . Sclerosing cholangitis following human orthotopic liver transplantation.  Am J Surg Pathol. 1995;  19 81-90
  CrossrefPubMedSearch in Google Scholar
• 8 Johnson M W, Thompson P, Meehan A. et al . Internal biliary stenting in orthotopic liver transplantation.  Liver Transpl. 2000;  6 356-361
  CrossrefPubMedSearch in Google Scholar
• 9 Davidson B R, Rai R, Kurzawinski T R. et al . Prospective randomized trial of end-to-end versus side-to-side biliary reconstruction after orthotopic liver transplantation.  Br J Surg. 1999;  86 447-452
  CrossrefPubMedSearch in Google Scholar
• 10 Wiesner R H. Advances in diagnosis, prevention, and management of hepatic allograft rejection.  Clin Chem. 1994;  40 2174-2185
  PubMedSearch in Google Scholar
• 11 Baron P W, Heneghan M A, Suhocki P V. et al . Biliary stricture secondary to donor B-cell lymphoma after orthotopic liver transplantation.  Liver Transpl. 2001;  7 62-67
  CrossrefPubMedSearch in Google Scholar
• 12 Seiler C A, Renner E L, Czerniak A. et al . Early acute cellular rejection: no effect on late hepatic allograft function in man.  Transpl Int. 1999;  12 195-201
  CrossrefPubMedSearch in Google Scholar
• 13 Wiesner R H, Ludwig J, van Hoek B, Krom R AF. Current concepts in cell-mediated hepatic allograft rejection leading to ductopenia and liver failure.  Hepatology. 1991;  14 721-728
  CrossrefPubMedSearch in Google Scholar
• 14 Tan C E, Vijayan V. New clues for the developing human biliary system at the porta hepatis.  J Hepatobiliary Pancreat Surg. 2001;  8 295-302
  CrossrefPubMedSearch in Google Scholar
• 15 Mahajani R V, Cotler S J, Uzer M F. Efficacy of endoscopic management of anastomotic biliary strictures after hepatic transplantation.  Endoscopy. 2000;  32 943-949
  Thieme ConnectPubMedSearch in Google Scholar

H. Abou-Rebyeh, M. D.

Dept. of Hepatology, Gastroenterology, Endocrinology and Metabolism ·

University Hospital Charité, Campus Virchow-Klinikum · Humboldt University · Augustenburger Platz 1 · 13353 Berlin · Germany

Fax: +49 30 450 553 917

Email: Hassan.Abou-Rebyeh@charite.de