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Clinical from an ChinaH e p at o b i l i a r y & P a nc r e a ti c Di s e a se s I n te r n a ti o na l , V o l 1，N o 4 (N o ve m b e r ), 2002，487-491487T ransplantationexperience in liver transplantation organ transplantation center in Shu-Sen Zheng, Ting-Bo Liang, Wei-Lin Wang, Dong-Sheng Huang, Yan Shen ， Min Zhang, Xiao Xu and Ling-Jun MouObjective ： To sum up the experience in liver transplantation in a period of ten years at a single center. Methods ： We retrospectively reviewed the clinical records of 120 patients receiving liver transplantation from April 1993 to October 2002. The patients ，clinical characteristics, surgical techniques, complications and survival were compared in the phases of 1993-1997 (phase I), 1999 (phase H), and 2000- 2002 (phase m).Results ： Malignant liver diseases were m^jor indications for liver transplantation in phase I (100 %) and n (53. 3%), but decreased markedly in percentage in phase m (34.0%). When compared with recipients in phase I and n, the survival of recipients with benign liver diseases in phase m was significantly improved with the 3-month, 6-month and 1-year survival rates of 85.7%,84.5% and 83.1%, respectively. For patients with malignant liver diseases ，the 3-month, 6-month and 1-year survival rates were 87.4%, 81.1% and 46.0%, respectively. The reinfection rate of hepatitis B virus was 24% 12 months after transplantation. With technical refinements, the incidence of postransplantation vascular complications has significantly decreased from 29.4% in phase I and n to 4.9% in phase m. Biliary complications remained one of the m^jor obstacles to longterm survival. No veno-venous bypass was applied in phase m, providing a promising outcome.Conclusion ： Strict selection of potential recipients, technical refinement, appropriate management of vascular and biliary complications,andprophylaxisofrecurrences of hepatitis B and malignant liver diseases are important to obtain long-term survival of patients receiving liver488 Shu-Sen Zheng, Ting-Bo Liang, Wei-Lin Wang et altransplantation in China.(HBPD Int 2002；1：487-491) Key words： liver transplantation； complications；veno-venous bypass； hepatitis B recurrenceIntroductionith the improvement of perioperative management and technical refinement, orthotopic liver transplantation ( OLT), which was started in the late 1970s and nearly abandoned in the 1980s, faces its second upsurge in China since the 1990s. From April 1993 to October 2002， 120 patients with various end-stage liver diseases underwent liver transplantation at our center. To summarize our experience in liver transplantation, we retrospectively analyzed the clinical data in a period of ten years.MethodsThree phases of the liver transplant program at our center can be defined： phase I, April 1993 - 1997 ；phase II，February 1999-December 1999；and phase III，January 2000-0ctober 2002 (Table 1).In the 120 patients, 6 received combined liv- er-kidney transplantation, and 2 living-related liver transplantation ( LRLT ).[1_ 3] Patients in phaseFrom die Department of Surgery, First Affiliated Hospital, Zhgiang University School of Medicine，Hangzhou 310003, China (Zheng SS, Hang TB, Wang WL, Huang DS, Shen Y, Zhang M, Xiao Xu and Mou LJ) Correspondence: Shu-Sen Zheng, MD, PhD( Tel: 86- 571-87236570；Fax：86-571-87072577Email：zhengss @mail. hz.2/. cn)WClinical experience in liver transplantation from an organ transplantation center in China 489BD: benign disease ； MD: malignant disease ； MS: maximum survival ( until October 1，2002) ； PMD: percentage of malignant disease in each phase.I and II were all subjected to veno-venous bypass (V-V bypass), whereas those in phase III were not. Triple regimen of cyclosporin ( CsA), aza- thioprin ( Aza ) /mycomphenolate mofetil ( MMF) and steroid were used as the first line immunosuppressantsafterlivertransplantation ，followed by a dual regimen of immunosuppressive therapy consisting of tacrolimus (FK506) and steroid. Lami- vudine was used routinely for prophylaxis of HBV reinfection for recipients with hepatitis B. Systemic intravenous chemotherapy was given routinely in patients with malignant liver tumor. Comprehensive therapy including local hepatectomy, transhepaticartery chemotherapy and embolism (TACE), and percutaneous alcohol injection (PEI) was prescribed selectively for recurrent cases. Radiotherapy was given immediately after occurrence of bone metastasis. One patient with early portal vein thrombosis received emergencythrombectomyandretransplantation thereafter. Biliary tractballoon dilation and/or stent placement wereapplied in patients with vascular and/ or biliary complications such as stricture or stenosis. ResultsTwo recipients with malignant tumors in phase I died of intracranial infection and primary graft dysfunction on day 43 and 21 respectively after transplantation. Of the 15 patients in phase II, 7 suffered from benign hepatic diseases and 8 malignant diseases with survival rates of 57.1% , 100% (3-month)； 57.1%，62.5% (6-month)； 42. 9%，25.0% (1-year), respectively. The major fetal complications included massive hemorrhage after operation, dysfunction ofliver graft, failure of acute rejection treatment, vascular complications ,and disorder of the nervous system. Tumor recurrence was another fatal fector for the recipients with malignant lesions, usually occurring 6 months after transplantation. The common sites of recurrence and metastasis were the lung, liver graft, bone and retroperitonium.490 Shu-Sen Zheng, Ting-Bo Liang, Wei-Lin Wang et alPatients with tumor invasion to the portal vein, giant hepatic carcinoma (diameter >10 cm), high level of preoperative AFP or hepatectomy history appeared to have a higher recurrence rate and earlier recurrence. But patients with Klatskin tumor showed satisfactory results. The two recipients with cholangiocarcinoma survived 29 and 20 months respectively with a good quality of life. In the 103 patients of phase III, the percentage of benign liver disease for OLT increased to 66.0%(68/63), but that of malignant liver disease for OLT decreased to 34.0% (35/103 ). The operative mortality and technique-related complications de-creased gradually. The 3 -month, 1-year survival rates of patients with benign liver diseases were 85.7%, and 83.1%, whereas 87.4% and 46.0% for malignancy. The major complications in this period were biliary tract stricture, bile mud forma- tion or recurrence of primary diseases ( e. g. rein-fection of HBV). The recurrence of HBV-related hepatitis or reinfection of HBV was usually noted within 6-12 months after operation. Serum HB- sAg positive conversion was found following HBV duplication in the graft by immunostaining test. Finally the patients could be defined as HBV carriers or have HBV-related hepatitis. The recurrence rate of hepatitis B was 3. 8% , and the serum positive rate was 11% (the 6-, 12-month positive rates were 12% and 24% ). Of the 3 patients with recurrent hepatitis B in YMDD mutation ,one died of feilure of hepatic function, one had the recurrence of HCC, and one recoveredClinical experience in liver transplantation from an organ transplantation center in China 491after persistent administration of lamivudine. HBV DNA was serologically negative and liver function was normal in the recovered. The incidence was 12.5%for biliary complications including bile leakage, stricture, and sludge of the intrahepatic biliary tract. The overall incidence was 9. 2% for vascular complications including stricture of the hepatic artery/portal vein, thrombosis, and stenosis of the inferior vena cava from distortion. However ,the percentage of the vascular complications in phase III was only 4. 9%. The treatment modality for the biliary or vascular complications was radiological intervention, though some patients received re-operationJ4"6] Refering to OLT in other countries, we successfully performed OLT without V-V bypass for 75 patients in phase III. A significant difference was observed in operation time, bleeding volume, blood transfusion volume during operation, and ICU stay time between patients with V-V bypass and those without V-V bypass (Table 2 ). But it was not found in creatine, BUN, and failure of renal function after OLT.DiscussionSince liver transplantation was first performed in 1963 in the USA, it has been accepted by the Nation Institutes of Health. It is estimated that over 80 000 patients received liver transplantation in a- bout 150 transplantation centers around the world with the maximum survival being more than 30 years. In China, liver transplantation was started in 1977 and has been developing rapidly in recent years. The majority of the few patients undergoing liver transplantation in the early period in China died shortly after operation because of technical problems, lack of effective immunosuppressants, and poor perioperative management. Fortunately, frequent international academic communication in the last two decades hasTable 2. Comparison of characteristics of recipients with and without V-V bypassWith Without P Operative 8.6±2.15.6±1.4<0.0 Anhepatic 82 ±1553 ±10<0.0 Intraoperative 6800 3750 ± <0.0 (ml)Blood 7200 4200 <0.0 ICU stay 15.7±1.36.3 ±0.8<0.0 Bowel 3.3 ±0.23.2±0.2>0.0 (d)492 Shu-Sen Zheng, Ting-Bo Liang, Wei-Lin Wang et alnarrowed the gap between China and Western countries in liver transplantation. Since the early 1990s, a total of 120 liver transplants have been performed at our center.In phase I (the initial period), the longest survival of the two patients was only 43 days. Both were died of early complications, which was obviously related to inadequate experience in postoperative management [7] and unskilled techniques. Contrast to phase I, the incidence of lethal complications decreased sharply in phase II and III. Poor general conditions of recipients such as preoperative hepatic encephalopathy, during upper digestive tract hemorrhage, severe jaundice ,ascites, and malnutrition before operation and uncontrollable intracranial hemorrhage， thrombosis or central pontine myelinolysis after operation were all major causes of death in phase I. In addition, systemic fungi infection was another cause of failure, which was closely related to graft function. More importantly, tumor recur-rence was a vital factor leading to the death of recipients with malignant liver disease in late stage after OLT. Most hepatocellular carcinoma recipients were found tumor recurrence in 6-12 months, and died in 1 - 2 years after operation, except three patients with Klatskin tumor survived over 2 years. Patients with large tumors, portal vein/hepatic vein invasion, and high AFP level before operation were associated with high possibility of recurrence and distant metastasis. Thus HCC patients especially those with large tumors (>5 cm) were only considered as relative potential candidates for transplantation. The percentage of malignant diseases obviously decreased from 100% in phase I，53.3% in phase II to 34% in phase III. This is due to the modification of inclu-sion criteria of recipient-candidates in phase III. Strict inclusion criteria could avoid liver transplantation for patients with advanced HCC in our hospital. Patients with small HCC are still candidates for liver transplantation, especially those with severe liver cirrhosis and liver lobe resection is rather dangerous. Experience of other centers revealed that OLT for small HCC is as good as for benign liver diseases. Moreover, the life quality of patients with advanced malignant liver diseases is not poor shortly after operation, though the long-term result is not exciting. Most of these patients may not only have a satisfectory free-tumor survival in short-term, but also recover more quicklyClinical experience in liver transplantation from an organ transplantation center in China 493than those with severe benign liver diseases after operation because the former usually have better general conditions, as was proved by the 3 - 6 month survival rate of our patients with malignant tumors in phase II and III.HBV reinfection is a main factor influencing the long-term survival of patients with benign liver disease after transplantation in Asia, especially in China. About 85% of our recipients were HBV- related liver cirrhosis patients with HBsAg and/or HBV DNA positive before OLT. Postoperative prescription of immunosuppressants especially corticosteroid induced the duplication and reactivation of HBV. Serum HBV markers including HBsAg ，HBeAg and HBV DNA turned to be negative soon after the operation, and antibodies of HBsAb and HBcAb appeared simultaneously ignoring of previous HBV states. Studies^5-* showed that the rate of HBV recurrence could reach 100% if no prophylatic treatment was given. The reinfection rate (12% in 6 months, and 24% in 12 months in our group) remains high in spite of the use of new analogue of nucleosides such as lamivudine and famiciclovir in recent years. We found that HBV reinfection is characterized first in hepatic tissue by immunostaining, then conversion of serum positive markers and finally the patient pres-enting as a HBV carrier or a fellow of HBV hepa- titis.「8_10] The longer lamivudine is used, the higher rate of HBV YMDD mutation is. Theoretically, the strain of HBV YMDD mutation is resistant to lamivudine therapy, and whether the drug should be used continuously is questioned. Most centers insist on the continuous use of lamivudine while adding HBIG simultaneously. The long-term use of lamivudine would improve the pathological changes of liver tissue although HBV mutation exists. Fortunately, a new analogue of nucleosides named as adefovir used clinically in other contries is potent to inhibit duplication of HBV mutation strain. Combined use of HBIG and adefovir may effectively control the recurrence of YMDD varia- ted hepatitis」11] We prefer to prescribe a larger dose of lamivudine (150 mg/d), while tapering or stopping the use of corticosteroid. Famiciclovir therapy is added sometimes.V-V bypass is necessary in anhepatic phase for maintenance of patients’ central venous pressure and arterial blood pressure.494 Shu-Sen Zheng, Ting-Bo Liang, Wei-Lin Wang et alRenal function recovered soon after operation with V-V bypass. Although V-V bypass technique has been widely used in OLT in most Chinese centers, more and more their counterparts abroad performed OLT without V-V bypass in recent years.[12’13] In phase IE, we have abandoned V-V bypass in anhepatic stage because of its disadvantages of disturbance of coagulation state, large volume blood transfusion needed, and high-cost. OLT without V-V bypass is valuable because of its short time of opera-tion and ICU stay, and decreased bleeding and exogenic blood transfusion during operation. It seems to lower the incidence of renal dysfunction or shorten the recovery time of gastrointestinal function. Nevertheless, this does not mean that all recipients are suitable for the operation without V-V bypass. To those with acute or chronic hepatic failure, hepatic tumor, and metabolic hepatic disease without dysfunction of the heart, lung and kidney, V-V bypass is not advisable because of their good resistance to anhepatic stage insult. But for those patients with renal dysfunction, poor cardiac function, or pulmonary artery hypertension, V-V bypass is still recommended to maintain a stable physiologic state during operation. V-V by-pass is not indispensable if fine techniques of operation and anesthesia ensured, and it is believed that 2 hours portal vein clampping is safe.Although liver transplantation has undergone a tremendous progress in biliary reconstruction and vascular anastomosis, the incidence of biliary and vascular complications remains high. Biliary complications occur several months after OLT and their causes are obscure. The incidence of vascular complications in our group obviously decreased from 29.4% in phase I to 4.9% in phase III because of the improvement of surgical techniques with magnification of loop. Contrarily, the inci-dence of biliary complication was kept at a high level of 12. 6%, though it was lower than that reported by other centers. Measures taken to improve graft harvesting technique, methods for biliary anastomosis, T-tube drainage and prophylaxis and prompt treatment of postoperative CMV infection are important to further decrease the inci-dence of biliary and vascular complications after OLT.In summary, liver transplantation has been developing rapidly in recent years inClinical experience in liver transplantation from an organ transplantation center in China 495China. The profiles of recipients change in different periods. End-stage benign liver disease is the main cause for OLT now. Though the result has been improved gradually and the 1-year survival rate of 83.1% is satisfectory for patients with benign disease ,problems such as HBV reinfection, vascular and biliary complications need to be resolved.Competing interestNo 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.References1Zheng SS, Pan SL, Huang ZY. Orlhotopic liver transplantation ：1 case report. Chin J Oi^an Trans-plant 1995;16:6-8.2Zheng SS, Liang TB, Chen JH, et al. Two cases of combined liver-kidney transplantation. Chin Med J 2000；113：1104-1107.3Zheng SS, Huang DS, Wang WL, et al. Living related liver transplantation for an infant with biliary atresia. HBPD Int 2002；1：172-175.4Zheng SS, Liang TB, Huang DS. Human orthotopic liver transplantation ： 13 cases report. Chin J Organ Transplant 2000；21 ：272-274.5Zheng SS, Liang TB, Huang DS. Clinical experience of human orthotopic liver transplantation (33 cases report). Chin J Pract Surg 2001 ；21 ：48- 50.6Zheng SS, Wu J, Liang TB. Clinical experience of management of complications of orthotopic liver transplantation :26 cases report. Chin J Gen Surg 2001 ；16:711-713.7Zheng SS, Huang DS, Liang TB. Management of post liver transplantation complications ( 2 cases report). Chin J Hepatobiliary Surg 1999;5:157-158.8Zheng SS, Wu J, Liang TB. Management of HBV reinfection after liver transplantation. Chin J Organ Transplant 2000；21 ：366-368.9Fonatana RJ, Hann HWL, Wri^it. A multicenter study of496 Shu-Sen Zheng, Ting-Bo Liang, Wei-Lin Wang et al lamivudine treatment in 33 patientswith hepatitis B after liver transplantation. Liver Transplanta-tion 2001 ；7 ：504-510.10Mutimer D. Lamivudine forhepatitis B after liver transplantation. LiverTransplantation 2001 ;7:511 - 512.11Perrillo R, Schiff E, Yoshida E.Adefovir dipivoxil for the treatmentof lamivudine-resistant hepatitis Bmutants. Hepatology 2000；32 ：129-134.12Reddy KS, Johnston TD, PatnamLA. Piggyback technique andselective use of veno-venous bypassin adult orthotopic liver transplantation. Clin Transplant2000；14：370-374.13Ross G, Langer M, Maggi U.Veno-venous bypass versus nobypass in orthotopic livertransplantation ：hemodynamic,metabolic and renal data.Transplant Proc 1998；30：1871-1873.Recewed June 24 , 2002Accepted after revision July16，2002。