With the spread of orthotopic liver transplantation

Transcription

1 Original Article / Transplantation Liver retransplantation for ischemic-type biliary lesions after orthotopic liver transplantation: a clinical report of 66 cases Zhi-Jun Zhu, Wei Rao, Ji-San Sun, Jin-Zhen Cai, Yong-Lin Deng, Hong Zheng, Ya-Min Zhang, Wen-Tao Jiang, Jian-Jun Zhang, Wei Gao and Zhong-Yang Shen Tianjin, China BACKGROUND: Ischemic-type biliary lesions (ITBLs) play an extremely important role in influencing the long-term survival and quality of life of recipients after orthotopic liver transplantation (OLT). Some patients can be cured by interventional therapies, however others lose their grafts at last and receive liver retransplantation (re-olt). The aim of this study was to analyze the data of 66 patients who had received re-olt at our center because of ITBL and to discuss the treatment of ITBL after OLT. METHODS: We retrospectively analyzed 66 re-olt cases due to ITBL from September 2001 to February 2007 at our center. The Kaplan-Meier method and the Cox-Mantel test were used to identify factors associated with mortality for univariate analysis and multivariate analysis, respectively. RESULTS: Fifty-five of 66 ITBL cases underwent interventional therapies before re-olt. The actuarial survival at 1 month and 1 year for these patients was 83% and 74%, respectively. Prognostic factors for mortality in univariate analysis were model of end-stage liver disease score (MELD) >16.5 (χ 2 =5.856, P=0.016), cold ischemia time >8 hours (χ 2 =6.539, P=0.011), infections (χ 2 =5.550, P=0.018) and complications (χ 2 =12.168, P=0.002) after re-olt. In the multivariate analysis (Cox regression), the risk factors independently associated with mortality were MELD score >16.5 (RR: 3.140; P=0.035), cold ischemia time >8.2 hours (RR: 0.192; P=0.016) and complications (RR: 3.896, P=0.003). Author Affiliations: Department of Organ Transplantation, Transplant Center, Tianjin First Central Hospital, Tianjin , China (Zhu ZJ, Rao W, Sun JS, Cai JZ, Deng YL, Zheng H, Zhang YM, Jiang WT, Zhang JJ, Gao W and Shen ZY) Corresponding Author: Zhi-Jun Zhu, MD, Department of Organ Transplantation, Transplant Center, Tianjin First Central Hospital, Tianjin , China (Tel: ; Fax: ; Zhu-zhijun@medmail.com.cn) 2008, Hepatobiliary Pancreat Dis Int. All rights reserved. CONCLUSIONS: The incidence of ITBL in China is higher than in other countries. Based on our experience, MELD score, cold ischemia time and complications after re-olt are risk factors independently associated with mortality in retransplanted ITBL patients. (Hepatobiliary Pancreat Dis Int 2008; 7: ) KEY WORDS: ischemic-type biliary lesions; liver transplantation; retansplantation; risk factor Introduction With the spread of orthotopic liver transplantation (OLT) and the development of surgical techniques in China, the incidence of vascular complications, rejection and infections after OLT is decreasing, which in turn gives more and more recipients a longer life-span. However, complications of the biliary tract, which occur in 5.8% to 24.5% of adult liver transplant recipients, are one of the most important reasons for morbidity, graft loss, [1, 2] and mortality after OLT. Furthermore, ischemic-type biliary lesions (ITBLs) as a special type of complications, show nonanastomotic strictures and dilations involving only the biliary tree of the graft, and may be associated with the formation of sludge or stones. They often start at the bile duct bifurcation and progress to the intrahepatic bile ducts. Since ITBLs are still difficult to deal with they have been regarded as "the Achilles' heel of the [3, 4] procedure". Methods Patients were selected conditionally from 136 patients Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,

2 Hepatobiliary & Pancreatic Diseases International who had undergone liver retransplantation (re-olt) at our center from September 2001 to February 2007, excluding those who were indicated for re-olt because of tumor recurrence, vessel complications, relapse of primary disease, and primary graft nonfunction, those who had had OLT more than twice or combined liver-kidney transplantation, those who were younger than 16 years, and those who were missed with data. Finally, 66 patients were enrolled in this study. They were 61 men and 5 women, aged from 16 to 62 years, median 45.0 years. The recipient and operative variables were collated with univariate analysis (Kaplan-Meier method) and multivariate analysis (Cox-Mantel test) to identify factors effecting mortality. The following factors were investigated: general condition of recipients; clinical data of the first operation (date, place and procedure); history of interventional therapy before re-olt; clinical data of re-olt (date, procedure, reconstruction of vessels and the bile duct, operative time, quantity of bleeding and transfused blood, Child stage, model of end-stage liver disease score (MELD)); complications after re-olt; and survival time. All patients were scheduled for regular follow-up until October Continuous variables were assessed as medians to establish cut-off points, and qualitative variables were dichotomized. A P value of less than 0.05 was considered statistically significant. Results Of the 66 patients, 36 received OLT at our center whereas 30 at other centers. Fifty-nine recipients underwent a transplantation of the whole liver and 7 underwent a transplantation of partial liver. The time interval between the first and second OLT was less than 1 year in 39 patients (59.1%), between 1 and 2 years in 15 (22.7%), and over 2 years in 12 (18.2%). The mean time between the two operations was 564 days, and the median was 319 days (range 43 days-10 years). Fiftyfive patients (83.3%) received interventional therapy for different biliary complications before re-olt, including choledochoscopy therapy through T tube (23), endoscopic retrograde cholangiopancreatography (ERCP), endoscopic nasobiliary drainage (ENBD) or stent-support (31), and percutaneous transhepatic cholangial drainage (PTCD) (13). At the time of retransplantation, the mean prothrombin time (PT) was 18 seconds, and the median was 14.9 seconds (range seconds). The mean concentration of bilirubin was 17.4 mg/dl, and the median was 15.6 mg/dl (range ). The mean concentration of ALT was IU/L, and the median was 78.3 IU/L (range IU/L). The mean concentration of ALB was 35.9 g/l, and the median was 35.7 g/l (range g/l). The mean concentration of serum creatinine was 1.1 mg/dl, and the median was 0.89 mg/dl (range mg/dl). The mean MELD score was 18.5, and the median was 16.5 (range ). Fifty-four (81.82%) of the 66 patients received classic OLT, 12 (18.18%) received piggy-back transplantation, and 2 (3.03%) received OLT with veno-veno bypass. The mean time of cold ischemia was 8.2 hours, and the median was 8 hours (range 3-13 hours). The mean time of warm ischemia was 4.3 minutes, and the median was 5 minutes (range 2-15 minutes). The mean anhepatic time was 72.1 minutes, and the median was 60 minutes (range minutes). In 74.2% of the patients it was less than 70 minutes and in 90.9% of the patients it was less than 100 minutes. The mean intra-operative transfusion of red blood cells was 1830 ml, and the median was 1000 ml (range ml). In 51.5% of the patients it was less than 4000 ml and in 89.4% of the patients it was less than 8000 ml. The mean operative time was 11.7 hours, and the median was 11.2 hours (range hours), and in 84.8% of the patients it was less than 15 hours. The mean ventilation time was 14.5 hour, and the median was 10 hours (range hours). The mean time in ICU was 4.5 days, and the median was 3.5 days (range 1-24 days). The median time of follow-up was 25 months (range 9-60 months). The survival rate at 1-month and 1-year for the retransplanted patients was 83% and 74%, respectively, and the median survival was 494 days (Fig. 1). Thirteen patients (68.4%) died of infection and multiple organ dysfunction, 4 (21.1%) vessel complications, and 2 (10.5%) tumor recurrence. Prognostic factors for mortality shown by Cum survival (%) % 74% 70% 63% Survival time (month) Fig. 1. Survival rate of the 66 ITBL patients (Kaplan-Meier method). 472 Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,2008

3 Liver retransplantation for ischemic-type biliary lesions after OLT Table 1. Results of recipient variables after univariate analysis Age >45 years Gender Blood type Interval between OLT and re-olt (cut-off 319 days) Median PT (cut-off 14.9 seconds) Median ALT (cut-off 78.3 IU/L) Median TBIL (cut-off 15.6 mg/dl) Median ALB (cut-off 35.7 g/l) Median Cr (cut-off 0.89 mg/dl) Child stage MELD score (cut-off 16.5) * Cum survival (%) Complications Multi-complication group Non-complication group Single complication group Multi-complication group-censored Non-complication group-censored Single complication group-censored Survival time (d) Fig. 2. Survival rate of the 66 ITBL patients, based on complications (Kaplan-Meier method, χ 2 =12.168, P=0.002). Table 2. Results of surgical variables after univariate analysis Median cold ischemia time (cut-off 8 hours) * Median warm ischemia time (cut-off 5 minutes) Operation time (cut-off 11.2 hours) Anhepatic time (cut-off 60 minutes) Transfusion red blood cells (cut-off 1000 ml) Table 3. Results of post-operation variables after univariate analysis Ventilator time (cut-off 10 hours) Days in ICU (cut-off 3.5 days) Infections * Complications * Table 4. Results in multivariate analysis (Cox-Mantel test) β SE Wald P Exp (β) 95.0% CI for Exp (β) MELD score * Cold ischemia * time Infections Complications * univariate analysis (the Kaplan-Meier method) included MELD score >16.5, cold ischemia time >8 hours, infections and complications after re-olt (Tables 1-3). Multivariate analysis (Cox-Mantel test), showed that the risk factors independently associated with mortality included MELD score >16.5 (RR: 3.140; P=0.035), cold ischemia time >8.2 hours (RR: 0.192; P=0.016) and complications (RR: 3.896, P=0.003) (Table 4 and Fig. 2). Discussion ITBL is the most common type of biliary complications after OLT in China. It is characterized by nonanastomotic strictures and dilations involving the biliary tree of the graft, and may be associated with the formation of sludge or stones. Starting at the bifurcation of the bile duct and progressing to the intrahepatic bile ducts, ITBL is caused by failure of the microcirculation around the bile duct. Its incidence varies from 2% to 19% of all OLT recipients in other countries, [5] but fluctuates from 5.5% to 27.4% in [6, 7] China. Usually, sludge or stones in the bile tract are formed at first, then the bile tract is strictured, and destroyed with functional loss of the graft. ITBL occurs in the intra-hepatic or extra-hepatic bile ducts, or both. It has several clinical features, like pruritus, high ALP or GGT, even obstructive jaundice or cholangitis, and local or diffuse stricture on the bile tract image. [8, 9] These lesions are associated with hepatic artery thrombosis, prolonged preservation time, ABO-incompatible organs, and immunological injuries, including injuries, to vascular endothelial cells (chronic rejection) and the bile duct (primary sclerosing cholangitis). [10-16] Currently, conservative therapy has become the first choice for ITBL after OLT. ITBL in some cases can be relieved by interventional therapies, such as choledochoscopy through a T-tube, ERCP, ENBD, stenting, or PTCD. The reported effective rates of Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,

4 Hepatobiliary & Pancreatic Diseases International these therapies vary from 40% to 65%. [5, 7, 17-19] Jiang et al [20] reported 40 patients with ITBL who received interventional therapy at the Tianjin First Central Hospital. Twenty-nine of them recovered well, with an effective rate of 72.5%. In our 66 patients, 55 (83.3%) received interventional therapy more than once before re-olt, and the remaining 11 received re-olt but interventional therapy. Repeated interventional therapy worsens the permanent residence of bacteria and infection, and causes biloma, bile leakage, internal fistula between the biliary and intestinal tracts, and even alimentary tract hemorrhage and fistula. Failure of repeated interventional therapy aggravates inflammation in the hepatic hilum, and causes multiple abscesses in the liver under the diaphragm or around the inferior vena cava stoma. These make re-olt more difficult, and increase the volume of bleeding and risk of alimentary tract fistula or infection after re-olt. Although interventional therapy is the first choice for ITBL, repeated interventional therapies should be avoided and re-olt be performed as soon as possible or directly in those patients who do not recover well through non-operative therapy, or those patients complicated by thrombosis of the hepatic artery, viral infection, or chronic rejection. [21] In our study, MELD score was one of the risk factors which influenced the prognosis of ITBL recipients. Dense adhesion around the first porta hepatis is a problem in re-olt for ITBL patients, because biliary stricture is formed from 3 to 6 months after the first operation, and the interval between OLT and re-olt varies from 1 to 2 years. And the congealed tissue around the porta hepatis, local infection, and internal fistula between the biliary and intestinal tracts result in longer operative time, more bleeding and more blood transfusion, because of repeated interventional therapies. In such circumstances, proper anastomotic method including dissociation of the inferior vena cava is required. If the inferior vena cava is disconnected adequately, standard OLT or piggyback operation can be performed. The original vena caval cuff is kept, but a fresh one should be firmly incorporated with at least part of the original. After the portal vein is dissociated, it is necessary to determine whether there is stricture around the portal vein. If it is too difficult to dissociate the congealed tissue, or the blood flow is not sufficient, vessel bypass is suggested, such as removal of anastomotic cuff of the intrinsic hepatic artery, and bypass of the spleen artery, celiac axis or abdominal aorta. It is important to evaluate the condition of the bile tract (length and blood supply), and the risk of reflux and infection for its reconstruction. The bile duct of the original graft and the anastomotic site should not be reused in re-olt. Roux-en-Y choledochojejunostomy is suggested when the bile tract loses its function, under a high tensile force or there is a high risk of reflux and infection. A T-tube is usually placed during re-olt. [22] In our study, the 1-month survival rate was 83%, while the 1-year survival rate was 74% (Fig. 1). Pares et al [23] reported that the 1-year survival rate of re- OLT was 31.25% from 1984 to 1992, rising to 54.55% from 1993 to 1995 and rising further to 62.5% from 1996 to In a study [24] the 1-, 5- and 10-year survival rates of 299 re-olt patients were 62%, 47% and 45%, respectively, whereas the 1-, 5- and 10-year survival rates of first OLT were 83%, 74% and 68%, respectively. The 1-year survival rate in our patients corresponded with the above results, but the 5- and 10-year survival rates await further follow-up. Accordingly, we suggest that re-olt is an effective choice for the ITBL patients who do not benefit from interventional therapy or when such therapy fails. The death of re-olt patients were due to infection and multiple organ dysfunction (68.42%), similar to those mentioned by Markmann's team (60.7% of the patients died of serious infections). Furthermore, in this study, MELD score, cold ischemia time and complications after re-olt were risk factors independently associated with mortality in these ITBL patients (Tables 1-4). And the survival curve showed significant differences among no-complication, onecomplication and multi-complication groups (P=0.002, Fig. 2). Hence, we suggest that performing re-olt at a suitable time, shortening the cold ischemia time, and preventing complications will increase the success rate of re-olt. Our experience in re-olt indicates the importance of 1) making the right decision at the most suitable time, which is dependent on the clinical features, biochemical indicators, nutritional status, image features and typing of the bile tract, and results of interventional therapy; 2) evaluating sufficiently before re-olt, and shortening the cold ischemia time; 3) decreasing the risk of infection (The dose of immunosuppressants is reduced before re-olt, and adjusted according to the function of the liver and kidney. Effective measures should be taken to avoid bacterial, fungal and viral infection); and 4) giving nutritional support (Retaining the jejunum nutrient canal in for patients receiving choledochojejunostomy, is helpful to recover and prevent infection or multiple organ dysfunction). 474 Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,2008

5 Liver retransplantation for ischemic-type biliary lesions after OLT Funding: This study was supported by a grant from the China Medical Board in New York (No ). Ethical approval: Not needed. Contributors: ZZJ proposed the study and wrote the first draft. RW analyzed the data. All authors contributed to the design and interpretation of the study. ZZJ is the guarantor. Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. References 1 Park JS, Kim MH, Lee SK, Seo DW, Lee SS, Han J, et al. Efficacy of endoscopic and percutaneous treatments for biliary complications after cadaveric and living donor liver transplantation. Gastrointest Endosc 2003;57: Rerknimitr R, Sherman S, Fogel EL, Kalayci C, Lumeng L, Chalasani N, et al. Biliary tract complications after orthotopic liver transplantation with choledochocholedo chostomy anastomosis: endoscopic findings and results of therapy. Gastrointest Endosc 2002;55: Wilson BJ, Marsh JW, Makowka L, Stieber AC, Koneru B, Todo S, et al. Biliary tract complications in orthotopic adult liver transplantation. Am J Surg 1989;158: Zhu Y, Jiang CP, Fung JJ, Jain A. Retransplantation the only means to save recipient's life after failure of liver transplantation: a report of 774 cases. Chin J Hepatobiliary Surg 2002;8: Abou-Rebyeh H, Veltzke-Schlieker W, Radke C, Steinmüller T, Wiedenmann B, Hintze RE. Complete bile duct sequestration after liver transplantation, caused by ischemic-type biliary lesions. Endoscopy 2003;35: Zheng SS, Xu X, Liang TB, Xia WL, Wang WL, Wu J, et al. Management of biliary complications following orthotopic liver transplantation. Chin J Gen Surg 2005;8: Chen ZY, Li XW, Dong JH. Ischemic type of biliary lesions after liver transplantation. J Hepatobiliary Surg 2005;13: Zhu ZJ, Zhang HM, Deng YL, Zheng H, Jiang WT, Zhang YM, et al. Identification of risk factors associated with nonanastomotic biliary stricture after liver transplantation. Chin J Hepatobiliary Surg 2004;8: Fisher A, Miller CH. Ischemic-type biliary strictures in liver allografts: the Achilles heel revisited? Hepatology 1995;21: Li S, Stratta RJ, Langnas AN, Wood RP, Marujo W, Shaw BW Jr. Diffuse biliary tract injury after orthotopic liver transplantation. Am J Surg 1992;164: Sanchez-Urdazpal L, Gores GJ, Ward EM, Maus TP, Buckel EG, Steers JL, et al. Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation. Hepatology 1993;17: Ludwig J, Batts KP, MacCarty RL. Ischemic cholangitis in hepatic allografts. Mayo Clin Proc 1992;67: Nakamura N, Nishida S, Neff GR, Vaidya A, Levi DM, Kato T, et al. Intrahepatic biliary strictures without hepatic artery thrombosis after liver transplantation: an analysis of 1113 liver transplantations at a single center. Transplantation 2005;79: Campbell WL, Sheng R, Zajko AB, Abu-Elmagd K, Demetris AJ. Intrahepatic biliary strictures after liver transplantation. Radiology 1994;191: Guichelaar MM, Benson JT, Malinchoc M, Krom RA, Wiesner RH, Charlton MR. Risk factors for and clinical course of non-anastomotic biliary strictures after liver transplantation. Am J Transplant 2003;3: Schlitt HJ, Meier PN, Nashan B, Oldhafer KJ, Boeker K, Flemming P, et al. Reconstructive surgery for ischemictype lesions at the bile duct bifurcation after liver transplantation. Ann Surg 1999;229: Jagannath S, Kalloo AN. Biliary complications after liver transplantation. Curr Treat Options Gastroenterol 2002;5: Moser MA, Wall WJ. Management of biliary problems after liver transplantation. Liver Transpl 2001;7:S Patkowski W, Nyckowski P, Zieniewicz K, Pawlak J, Michalowicz B, Kotulski M, et al. Biliary tract complications following liver transplantation. Transplant Proc 2003;35: Jiang WT, Zhu ZJ, Deng YL, Zheng H, Pan C, Cai JZ, et al. Choledochoscopic treatment of biliary obstruction after orthotopic liver transplantation: a report of 40 cases. J Dig Surg 2006;5: Krawczyk M, Nyckowski P, Zieniewicz K, Pawlak J, Michalowicz B, Malkowski P, et al. Biliary complications following liver transplantation. Transplant Proc 2000; 32: Shen ZY, Zhu ZJ, Deng YL, Zheng H, Pan C, Zhang YM, et al. Liver retransplantation: report of 80 cases and review of literature. Hepatobiliary Pancreat Dis Int 2006;5: Pares D, Figueras J, Rafecas A, Fabregat J, Torras J, Ramos E, et al. Liver retransplantation in adults: clinical course and results of 13 years' experience. Gastroenterol Hepatol 1999;22: Markmann JF, Markowitz JS, Yersiz H, Morrisey M, Farmer DG, Farmer DA, et al. Long-term survival after retransplantation of the liver. Ann Surg 1997;226: Received December 10, 2007 Accepted after May 4, 2008 Hepatobiliary Pancreat Dis Int,Vol 7,No 5 October 15,