Liver transplantation in Romania – retrospective analysis of 300 cases

Liver transplantation in Romania – retrospective analysis of 300 cases Introduction: Liver transplantation (LT) is considered the treatment of choice for the patients with end-stage liver diseases, acute liver failure, metabolic diseases and liver cancer. The introduction of this therapeutic method can be considered one of the most important achievements of modern Romanian surgery. Material and methods: Three hundred cases of LTs were performed in 286 patients in Fundeni Clinical Institute between April 2000 and September 2011. There were 172 men and 114 women, both adults (252) and children (34). In the adult group the main etiology was represented by viral liver cirrhosis, whereas the glycogenosis and biliary atresia were the main indications for children. The surgical technique consisted in 225 whole graft LTs, 62 living donor LTs, 8 split LTs, 4 reduced LTs and one domino LT. Results: The immediate postoperative patients' survival was 91.6% (262 patients). The patient and graft survival at one and five years were 80.7% and 78.7%, 71.7% and 65.8% respectively. The early complications occurred in 193 patients (67.5%). The late complications were recorded in 95 patients (33.2%). The intraoperative and early postoperative mortality rate was 8.4% (24 patients). Conclusions: The Romanian liver transplantation program from Fundeni Clinical Institute includes all types of current surgical techniques and the results are comparable with those from other international centers. Key words: liver transplantation, indications, surgical techniques Address for correspondence: Irinel Popescu, MD, FACS, FEBS, Professor of Surgery, "Dan Setlacec" Center for General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, 258, 022328, Bucharest, Romania, e-mail: irinel.popescu220@gmail.com Introduction Liver transplantation (LT) is considered the treatment of choice for the end-stage liver diseases, acute liver failure, metabolic diseases and liver cancer. The operation is a formidable "tour de force" which became possible due to the progress recorded in the surgical, anesthesiology and intensive care fields as well as immunology and immunosuppressive regimens. The first LT performed in Fundeni Clinical Institute was carried out in June 21, 199, but the patient died because of multiple system organ failure in the immediate postoperative period (1). The first successful LT was performed in April 2000. In the same year the first living-related transplantation was also successfully performed (3). This paper is the retrospective analysis of 300 cases of LT performed between April 2000 and September 2011 in Fundeni Clinical Institute. The experience with liver transplantation, at various stages of our program, was also presented before (2-6). Material and method Three hundred cases of LT were carried out in 286 patients (14 retransplantations). All the patients were on the waiting list from our institute and were transplanted according to the severity of the liver disease ­ MELD score and emergency degree established by local ethical committee. There were transplanted 172 men and 114 women, both adults (252) and children (34). The main indications are listed in Table 1. It is worth mentioning rare causes requiring LT such as: recurring hepatoblastoma, primary liver lymphoma, hereditary fructosemia, homozygous familial hypercholesterolemia, cholangiocarcinoma and polycystic liver disease. Some of these cases had remarkable features: Table 1 ­ Major indications for LT LT indication Number of patients HBV ± HDV LC 96 HCV LC 54 Hepatocellular carcinoma and LC 45 (1 - fibrolamellar) HBV+HCV LC 5 Biliary cirrhosis (primary and secondary) 18 Wilson disease 16 Alcoholic LC 13 Biliary atresia 6 Glycogenosis 6 Liver fibrosis 3 Ductopenia 2 Miscellaneous 22 LC ­ liver cirrhosis, HCC ­ hepatocellular carcinoma Three yr after transplantation, an autologous CD34 (+) cell transplantation was performed in order to better control the hypercholesterolemia. Seven years after the LT, the donor was in excellent shape socially and professionally after undergoing a kidney transplantation and stenting for coronary artery disease. The recipient, despite an elevated level of serum cholesterol (339 mg/dL), which was partially controlled by medication and diet, showed no signs of ischemic heart disease (verified by a normal coronary angiogram)(9). At ten years post-DLT, the patient is still free of disease, with no recurrence of HCC or complications related to HFHC. Case 2: Polycistic Liver Disease A 39-year old man suffered from isolated polycystic liver disease, clinically highly symptomatic, with massive hepatomegaly, advanced malnutrition, poor quality of life underwent LT. Due to the massive hepatomegaly, and the hepatectomy was difficult. To our knowledge this is the biggest specimen from a PLD patient who was transplanted worldwide (Fig. 1). In a study reported by Pyrenne J et al 16 patients underwent LT for PLD; native liver weights varied from 10 to 20 kg (10). The maximum weight of the liver was 20 kg( ranged from 2.9 kg to 20.0 kg) in a study published by Manns PM on 36 patient that underwent LT or combined liver- kidney transplantation (11). In cases of retranplantations (14 cases) there were two groups: emergency indications such as Case 1: Homozygous Familial Hypercholesterolemia Worldwide, the first DLT for Homozygous Familial Hypercholesterolemia was performed in our center, and reported by Popescu et al. (5,7). A liver from a 25-year-old patient with HFHC was transplanted into a 46-year-old patient with HCC and HBV-related liver cirrhosis in 2001(8). The immediate postoperative course was uneventful. Figure 1 - The liver specimen weighed 23.2 kg hepatic artery thrombosis ­ 7 cases, portal vein thrombosis ­ one case, persistent biliary leak in association with "small-for-size" syndrome ­ 2 cases, primary graft non-function ­ one case, or elective indications ­ 2 cases of recurrence of the initial disease (liver fibrosis, HCV infection) and one case of chronic rejection. The majority of transplants (225) were cadaveric liver transplants; the technique of the operation has been described elsewhere (8). Special types of liver transplantation have been used for the rest of the cases: 62 living donor LTs, 8 split LTs, 4 reduced LTs and one domino LT. A complete procedure involves, basically, 4 stages: 1. procurement of the whole liver (deceased donor or domino donor) or of the segment of the liver (living donor ­ segments 2 and 3, left or right hemiliver); 2. "back-table" procedure ­ preparation of the graft; 3. recipient's total hepatectomy with or without the preservation of inferior vena cava; 4. recipient's grafting with the vascular and biliary anastomosis. Concerning the characteristics of the deceased donors, the were used livers from patients with age ranging from 6 to 66 year-old, mostly blood type A (41.2%) and 0 (32.6%), having as causes of death blunt trauma of the head (55.8%) or stroke (42.9%). It is worth mentioning the use of a liver from a patient with acute methanol poising. The liver graft was normal after transplantation (12). In case of living donor LT there were 62 patients. There was no death among the living donors. The postoperative morbity of living donors was minimal. There were 28 procedures in 27 children (one retransplantation) by using the segments 2 and 3 (23 cases) or the left hemiliver (5 cases); the adult living donor LTs were perfomed by using the right hemiliver (33 cases) or the left hemiliver (one case). The first 6 cases of split LT were carried out between children (segments 2 and 3) and adults (right hemiliver and segment 4); the last couple perfomed in May 2011 was realized between a teenager (17 year-old ­ right hemiliver) and an adult (24 year-old ­ left hemiliver). In the case of domino LT the donor was represented by a patient with homozygous familial hypercholesterolemia (5,7). The immunosuppression was carried out in two phases: induction (during the anhepatic phase) with steroids or monoclonal antibodies, and maintenance by triple association (calcineurin inhibitors, antimetabolite, and steroids). The postoperative course of the patients was related to the patient's underlying disease, the surgical technique and immunosuppressive regimen. The patient and the graft were monitored daily along with the serum concentration of the calcineurin inhibitor. It was initiated the prophylactic therapy against cytomegalovirus (valgancyclovir or gancyclovir) and,in patients with B virus specific treatment with lamivudine and antiHBV immunoglobulin. Results The immediate postoperative survival was 91.6% (262 patients). The one-year and five-year patient and graft survivals were 80.7% and 78.7%, 71.7% and 65.8% according to the Figures 2 and 3. Presently 212 patients are alive and 2 are lost from the follow-up. The longest survivor, who is the first successfully transplanted patient in our program, has more than 11 years survival. The pediatric group comprises 21 patients and the adult group 191 patients. In the adult series, the social reinsertion percentage was almost 100%, while the professional reinsertion was 57% with the maximum between of the age 30- 40 years. Figure 2 - Patient's Survival Figure 3 - Graft survival The early postoperative complications (the first month) occured in 193 patients, being represented by biliary complications (51 patients), vascular complications (30 patients), peritoneal bleeding (30 patients), abdominal (19 patients) or cutaneous (7 patients) infections, "small-for-size" syndrome (8 patients) and primary graft non-function (one case). The biliary complications were mainly leaks ­ 40 patients and stenosis ­ 11 patients, their management being surgical (35 cases with anatomoses remake in 4 cases or conversion to Roux-en-Y hepaticojejunostomy 31cases), interventional (8 cases) or conservative (8 cases). Case 3 A 37-year-old male with whole graft live transplantation for biliary cirrhosis whose postoperative course was complicated by cholestasis; an MRCP showed stenosis of biliary anastomosis (Fig. 4) and the patient underwent surgical conversion to Rouxen-Y hepaticojejunostomy with good postoperative course. Hepatic artery thrombosis (17 cases) was diagnosed by angiography which was also therapeutic in 3 cases. The failure of thrombolysis demanded emergency surgery (7 cases) and retransplantation (7 cases). Because of the severity of this complication, there were recorded 8 deaths. Figure 4 - MRCP showing stricture of the biliary anastomosis Case 4 A 19-year-old male was transplanted with right hemiliver for Wilson disease and developed hepatic artery thrombosis in the 3rd postoperative day (Fig. 5). The angiographic thrombolysis was successfully carried out, but the complication recurred and the patient required an emergency retransplantation with whole graft liver. The outcome was good. There was a case of arterial low flow surgically managed by a new arterial anastomosis and a case of combined stenosis and spasm of hepatic artery managed by intraarterial prostacyclin administration. The stenosis of hepatic artery confirmed by angiography (Fig. 6) in one case required Gore-tex garft interposition with good outcome. Another severe vascular complication was represented by portal vein thrombosis (5 cases) Figure 5 - Complete thrombosis of the hepatic artery ­ celiac axis angiography that required anticoagulant therapy (one case), surgical remake of the anastomosis (2 cases) and retransplantation (one case). A partial thrombosis was managed by anticoagulant therapy. There was also a portal vein stenosis without hemodynamic impact and managed conservatively. A right hepatic vein thrombosis occurred in the setting of emergency retransplantation for primary non-function, with secondary ascites and patient's death because of sepsis. There were 30 cases of peritoneal bleeding requiring emergency surgical hemostasis. The abdominal infectious complications were treated by surgery (10 cases of acute generalized peritonitis and 5 peritoneal abscesses) or CTguided percutanous drainage (4 cases of peritoneal abscess). Extensive skin infections (cellulitis) were recorded in 7 cases with fatal outcome in 5 cases. "Small-for-size" syndrome was encountered in living donor LTs and was managed conservately (3 cases), surgically (3 cases) by splenic artery ligation in all cases and a temporary porto-caval shunt, and retransplantation (2 cases). Early general complications was represented by neurologic ( 55 cases), respiratory (37 cases), renal (29 cases), cardio-vascular disorders (10 cases), metabolic disorders (secondary diabetes mellitus ­ 10 cases) and upper gastro-intestinal bleeding (5 cases). The treatment was specific for each condition. The late complications were recorded in 95 patients (33.2%) ­ biliary ( 24 cases), vascular (7 cases) and also the recurrence of the disease ­ HCV recurrence (34 cases proven by liver biopsy), HBV recurrence ( 2 cases), hepatocellular carcinoma (7 cases), autoimmune hepatitis (one case), liver fibrosis (one case) and alcoholic cirrhosis (one case). The biliary complications, mainly stenosis, were treated by endoscopic stenting (9 cases) or surgery (13 cases). Two cases of recurring cholangitis are under evaluation for percutenous biliary drainage. The vascular complications were represented by hepatic artery stenosis (one case), hepatic artery thrombosis (one case) and portal vein Figure 6 - Stenosis of the hepatic artery ­ before (a) and after (b) Gore-tex graft interposition Figure 7 - Portal vein stenosis ­ angiography stenosis (5 cases). In the cases of portal vein stenosis (Fig. 7), three of them with hemodynamic impact were managed by percutanous dilation and stenting. One of them led to restenosis with ascites and hypersplenism requiring splenectomy. Recurrence of HCV was encountered in 34 patients and required the reduction of the level of immunosuppression and specific treatment with interferon and ribavirin. Recurrence of hepatocellular carcinoma was recorded in 7 patients. All of them were oncologically assessed and treated by chemotherapy (including sorafenib) and radiotherapy and the immunosuppression was switched to sirolimus. There were also "de novo" neoplasia - 6 cases: one case of cervix carcinoma complicated by a lung cancer, two cases of spinocellular carcinoma, lingual cancer and two cases of non-Hodgkin lymphomas. All of them were oncologically assessed and treated accordingly. Discussions 3. metabolic liver disorders; 4. liver malignancies. Initially considered "life-saving" procedure, LT is now indicated in the less severe liver disorders, but with interference with the quality of life (13,14). The main etiology is represented by viral liver cirrhosis (www.eltr.org, www.unos.org), and this was also encountered in this series. The pediatric segment is dominated by metabolic and cholestatic disorders. In case of alcoholic liver cirrhosis, the cornerstone is focused on the neuro-psychiatric assessment for better outcomes, most of the papers showing a mandatory abstinence period of at least 6 months (15,16)}. Concerning the liver malignancy, the main indication is hepatocellular carcinoma. LT has two main objectives ­ treats the neoplasia and the liver cirrhosis (17). Most centers are using Milan criteria (18) and the patients within these criteria are listed for whole graft, whereas those beyond can undergo a living donor LT or receive a marginal graft. Wilson disease represents an elective indication for LT (liver cirrhosis) or emergency need for LT (acute liver failure)(19,20). From the 16 cases of Wilson disease, 4 cases were transplated on an emergency basis. Biliary cirrhosis either primary or secondary (e.g. primary slerosing cholangitis) represented 7.14% of all the adult patients. As expected the pediatric pathology was prominent by glycogenosis and biliary atresia (17.64% each). Donors The shortage of organs and the increasing number of the patients on the waiting list claimed for alternative techniques such as split LT, living donor LT or domino Ltor expansion of the graft pool by accepting marginal donors. The latter tendency is more frequently utilized in case of patients with hepatocellular carcinoma beyond Milan criteria or emergency indication (acute liver failure). From the same category, livers from patients with previous viral infections (HBV, HCV) can be transplated in patients with the same indication (21). Surgical technique Indications for liver transplantation LT is indicated in the follwing liver disorders: 1. end-stage liver diseases; 2. acute liver failure; LT has imposed as the treatment of choice due to the major breakthrough in the field of general surgey ­ procurement and preservation of the graft, improvement of technique and intensive care, as well as immunosuppressive regimens. If initially the recipient's total hepatectomy was performed en-bloc with inferior vena cava (as a consequence there were 2 cava-cavostomies), today this venous segment is preserved. The liver outflow can be reestablished by "piggy-back" (endto-side) or modified techniques such as side-to-side anastomosis (Belghiti) or cavaplasty, the latter being the procedure of choice in this group. The portal anastomosis is done by end-to-end manner with "growth factor" in order to prevent the vascular stenosis. Preoperative portal vein thrombosis in not a contraindication for LT any more. An example for a case of an extenive portal vein thrombosis was the need for a cavo-portal hemitranspositon with good portal flow. In cases of excessive portal hypertension temporary porto-caval shunts have been performed. The arterial anastomosis was carried out at the level of celiac axis, mainly with the donor's common hepatic artery. In case of inadequate flow, the anastomosis were made by graft interposition with the donor's infrarenal aorta. Immunosuppression The progress and the appearance of new immnusuppressive drugs made possible the continuous improvement of graft and patient survival. Classically there is a triple association between the calcineurin inhibitor (tacrolimus or cyclosporin), antimetabolite (mycophenolate) and steroids. Tacrolimus is considered the drug of choice, being associated with a decreased rate of acute rejection, especially the corticoresistant type (22). In case of HCV recurrence there are in vitro studies suggesting the antiviral effect of cyclosporin (23). In the presence of preoperative encephalopathy or renal dysfunction, the induction was made by monoclonal antibodies (daclizumab, basiliximab) which allowed the late introduction of calcineurin inhibitors with favourable result of the patients. The triple immunosuppressive regimen is maintained 3 months posttransplantation when the antimetabolite and steroids are withdrawn, the patient being left on calcineurin inhibitor only. Postoperative course The early postoperative morbidity is variable and estimated between 4.1% (24) to 50% (25) being mainly represented by peritoneal bleeding as well as anastomotic complications (vascular and biliary). The complications of the hepatic artery (either thrombosis or stenosis) with a frequency between 11 and 39%, are associated with biliary pathology (26). The complication can be managed by angiography with or without stenting (27), the failure of the procedure requiring surgical approach. The hepatic artery thrombosis more commonly encountered in case of living donor LT, has many risk factors such as low ratio between the donor's and recipient's age, immunologic factors, coagulation disorders, cytomegalovirus infection (28). The therapy can be done by angiography, surgery with anastomosis remake or retransplantation. Portal vein thrombosis is much rare (1-3%) (29), and induces acute liver failure and portal hypertension. The treatment can be managed by intravenous thrombolysis, interventional radiology or surgery. Outflow syndrome can be present in case of ,,piggyback" technique, either by stenosis or torsion, and produces an acute Budd-Chiari syndrome. In the absence of immediate treatment such as endoluminal prothesis (30), the consequence is the graft loss (31). This sydrome in rare when the caval anastomosis is done using Belghiti method and almost absent in case of cavaplasty. Biliary complications (7-29%) (32) can be leaks or stenosis and the treatment can be endoscopical or surgical. The general complications can be classified according to the system involved in pulmonary, cardio-vascular, renal, neurological, and infectious. The pulmonary complications occur in two thirds of transplanted patients (33,34) as pneumonia, pleural effusion, atelectasis or acute pulmonary edema (35). Although the hepato-pulmonary syndrome is no longer a contraindication for LT, it has a negative impact (36). Cardio-vascular complications include hypertension, myocardial ischemia, arrhythmia, cardiac arrest and, even, sudden death. Renal complications range from a simple dysfunction to an acure renal failure ­ 18% (37), secondary to the side effect of the calcineurin inhibitors. Neurologic complications estimated as 2.8 - 47% of the pateints (38,39) can be simple alteration of mental status to seizures, coma and death. The etiology comprises many factors: calcineurin inhibitors toxicity (40), previous encephalopathy, sodium disturbances. The psychiatric disorders can be translated by cognitive disorders to delusions and hallucinations (41). Some predictive risk factors can be alcoholic or metabolic etiology, necessity of mechanical ventila- tion, MELD > 15, emergency LT (42). In the presence of immunosuppression, the patients present an increased risk or the devepolment of neoplasia (lymphomas, carcinomas, sarcomas) (43) with an incidence between 5-15% (44). A major problem in the field of LT is the recurrence of the disease, especially in case of viral liver cirrhosis. Concerning the recurrence of HBV, this is low due to the prophylaxis with antiviral such as lamivudine and antiHB immunoglobulin (45). The lack of effective prophylaxis against HCV, explains universal rate of recurrence (46) with rapid progression to cirrhosis. A model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT was described by Iacob S et al (47). The antiviral treatment (interferon and ribavirin) has a variable rate of response 25-30% and is associated with serious side effects (pancytopenia, sepsis). Combination of pegylated interferon and ribavirin can be safely and successfully used in liver transplant recipients as reported by Iacob S et al (48). Retransplantation is controversial. Primary slerosing cholangitis can reccur up to 20% of the transplated patients, the diagnosis requiring MRCP and liver biopsy. Alcoholic liver cirrhosis can reaapear in 31% of cases(49) even in the presence of pretransplant abstinence, the differential diagnosis with NASH (non-alcoholic steatohepatitis) associated with obesity, diabetes mellitus or drug toxicity. The selection of the patients is a crucial factor in the development of hepatocellular carcinoma. Among the most important factors are the size of the tumor (>5 cm), the stage (vascular or lymph nodes involvement) and grading (G3). All the studies showed a lower recurrence after LT than after liver resection. Conclusions These 300 cases of LTs represent an important experience in the Eastern Europe and the only one in Romania. The liver transplant program from Fundeni Clinical Institute recorded a continous increase of the number of LT procedure and improvement of results, comparable to those from other international centers. Reference List 1. Popescu I, Radan A, Diculescu M et al. Consideratii privind primul transplant hepatic realizat la Spitalul Clinic Fundeni Bucuresti. Infomedica 1997; 38-47. Popescu I, Tulbure D, Ionescu M et al. Transplantul hepatic consideratii asupra a 8 cazuri operate în anul 2000. Chirugia (Bucur ) 2001;96: 453-467. Popescu I, Malago M, Testa G, Ciurea S, Stanescu C, Socoteanu I. Sequential therapy in a case of extrahepatic biliary atresia associated with ventricular septal defect: liver transplantation followed by surgical closure of the septal defect. Rom J Gastroenterol 2004;13: 125-128. Popescu I, Ionescu M, Tulbure D et al. Transplantul hepatic ortotopic de la donator cadavru la adult. Experienta Centrului de Chirurgie General si Transplant Hepatic Fundeni. Chirurgia (Bucur) 2005;100: 13-26. Popescu I, Habib N, Dima S et al. Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up. Clin Transplant 2009;23: 565-570. Popescu I, Ionescu M, Brasoveanu V et al. [Liver transplantation--indications, surgical technique, results--the analysis of a clinical series of 200 cases]. Chirurgia (Bucur ) 2010;105: 177186. Popescu I, Simionescu M, Tulbure D et al. Homozygous familial hypercholesterolemia: specific indication for domino liver transplantation. Transplantation 2003;76: 1345-1350. Popescu I, Simionescu M, Tulbure D et al. Homozygous familial hypercholesterolemia: Specific indication for domino liver transplantation. Transplantation 2003;76: 1345-1350. Popescu I, Habib N, Dima S et al. Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up. Clinical Transplantation 2009;23: 565-570. Pirenne J, Aerts R, Yoong K et al. Liver transplantation for polycystic liver disease. Liver Transpl 2001;7: 238-245. Kirchner GI, Rifai K, Cantz T et al. Outcome and quality of life in patients with polycystic liver disease after liver or combined liver-kidney transplantation. Liver Transpl 2006;12: 12681277. Zota V, Popescu I, Ciurea S et al. Successful use of the liver of a methanol-poisoned, brain-dead organ donor. Transpl Int 2003;16: 444-446. Busuttil RW, Shaked A, Missis MJ et al. One thousand liver transplants: the lessons learned. Ann Surg 1994;219: 490499. Lake JR. Changing indications for liver transplantation. Gastroenterol Clin North Am 1993;22: 213-229. Berlakovich GA, Langer F, Freundorfer E et al. General compliance after liver transplantation for alcoholic cirrhosis. Transpl Int 2000;13: 129-135. Anantharaju A, Van Thiel DH. Liver transplantation for alcoholic liver disease. Alcohol Res Health 2003;27: 257-268. Bismuth H. [Multimodal therapy concepts in hepatocellular carcinoma]. Zentralbl Chir 2000;125: 647-649. Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients Mortality rate in LT According to the Europen Liver Transplantation Registry, one-year and five-year mortality rate was 14% and 23% respectively (50). Survival in LT The overall immediate postoperative survival reaches 90% and 78% at one year (51,52). The fiveyear and ten-year survival can be estimated as 65.7% (25) ­ 70% (53), and 58.3%, respectively (25). There is usually a major improvement in the quality of life of the patient, with excellent familial and social reinsertion. with cirrhosis. N Engl J Med 1996;334: 693-699. 19. Roberts EA, Schilsky ML. A practice guideline on Wilson disease. Hepatology 2003;37: 1475-1492. 20. Marinescu TS, Gheorghe L. Boala Wilson. In: Popescu I, ed. Chirurgia ficatului. Bucuresti: Editura Universitara "Carol Davila", 2004: 897-906. 21. Manzarbeitia C, Reich DJ, Ortiz JA, Rothstein KD, Araya VR, Munoz SJ. Safe use of livers from donors with positive hepatitis B core antibody. Liver Transpl 2002;8: 556-561. 22. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. The U.S. Multicenter FK506 Liver Study Group. N Engl J Med 1994;331: 1110-1115. 23. Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003;38: 12821288. 24. Navarro F, Le Moine MC, Fabre JM et al. Specific vascular complications of orthotopic liver transplantation with preservation of the retrohepatic vena cava: review of 1361 cases. Transplantation 1999;68: 646-650. 25. Lerut J, Laterre PF, Roggen F et al. Adult liver transplantation: UCL experience. Acta Gastroenterol Belg 1999;62: 306-318. 26. Carles J, Dubuisson V, Bernard P, Lebail B, Grenier N, Saric J. [Arterial and biliary complications of hepatic transplantation]. Chirurgie 1994;120: 202-207. 27. Denys AL, Qanadli SD, Durand F et al. Feasibility and effectiveness of using coronary stents in the treatment of hepatic artery stenoses after orthotopic liver transplantation: preliminary report. Am J Roentgenol 2002;178: 1175-1179. 28. Pastacaldi S, Teixeira R, Montalto P, Rolles K, Burroughs AK. Hepatic artery thrombosis after orthotopic liver transplantation: A review of nonsurgical causes. Liver Transpl 2001;7: 75-81. 29. Lerut J, Tzakis AG, Bron K et al. Complications of venous reconstruction in human orthotopic liver transplantation. Ann Surg 1987;205: 404-414. 30. Bilbao JI, Herrero JI, Martinez-Cuesta A et al. Ascites due to anastomotic stenosis after liver transplantation using the piggyback technique: treatment with endovascular prosthesis. Cardiovasc Intervent Radiol 2000;23: 149-151. 31. Stieber AC, Gordon RD, Bassi N. A simple solution to a technical complication in "piggyback" liver transplantation. Transplantation 1997;64: 654-655. 32. Popescu I, Sheiner P, Mor E et al. Biliary complications in 400 cases of liver transplantation. The Mount Sinai Journal of Medicine 1994;61: 57-62. 33. Stieber A, Popescu I. Transplantul hepatic cu grefa de la cadavru. In: Popescu I, ed. Chirurgia ficatului. Bucuresti: Editura Universitara "Carol Davila", 2004: 1047-1086. 34. Duran FG, Piqueras B, Romero M et al. Pulmonary complications following orthotopic liver transplant. Transpl Int 1998;11 Suppl 1: S255-S259. 35. Golfieri R, Giampalma E, Morselli Labate AM et al. Pulmonary complications of liver transplantation: radiological appearance and statistical evaluation of risk factors in 300 cases. Eur Radiol 2000;10: 1169-1183. 36. Marinescu TS, Diculescu M. Sindromul hepatopulmonar. In: Popescu I, ed. Chirurgia ficatului. Bucuresti: Editura Universitara "Carol Davila", 2004: 873-880. 37. Gonwa TA, Mai ML, Melton LB et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation 2001;72: 1934-1939. 38. Stein DP, Lederman RJ, Vogt DP, Carey WD, Broughan TA. Neurological complications following liver transplantation. Ann Neurol 1992;31: 644-649. 39. Wszolek ZK, Fulgham JR. Neurologic complications of liver transplantation. In: Maddrey WC, Schiff ER, Sorrell MF, eds. Transplantation of the liver. Philadelphia: Lippincott Williams & Wilkins, 2001: 297-317. 40. Jain A, Brody D, Hamad I, Rishi N, Kanal E, Fung J. Conversion to neoral for neurotoxicity after primary adult liver transplantation under tacrolimus. Transplantation 2000;69: 172-176. 41. Strouse TB. Neuropsychiatric outcomes in liver transplantation. In: Busutill RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia: W.B. Saunders Company, 1996: 659-664. 42. Kanwal F, Chen D, Ting L et al. A model to predict the development of mental status changes of unclear cause after liver transplantation. Liver Transpl 2003;9: 1312-1319. 43. Penn I. Posttransplantation de novo malignancies. In: Busutill RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia: W.B. Saunders Company, 1996: 731-738. 44. Rubio E, Moreno JM, Turrion VS, Jimenez M, Lucena JL, Cuervas-Mons V. De novo malignancies and liver transplantation. Transplant Proc 2003;35: 1896-1897. 45. Angus PW, McCaughan GW, Gane EJ, Crawford DH, Harley H. Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transpl 2000;6: 429-433. 46. Vivarelli M, Burra P, La BG et al. Influence of steroids on HCV recurrence after liver transplantation: A prospective study. J Hepatol 2007;47: 793-798. 47. Iacob S, Cicinnati VR, Hilgard P et al. Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation. Transplantation 2007;84: 56-63. 48. Iacob S, Gheorghe L, Hrehoret D, Becheanu G, Herlea V, Popescu I. Pegylated interferon alpha-2a and ribavirin combination therapy in HCV liver transplant recipients. Experience of 7 cases. J Gastrointestin Liver Dis 2008;17: 165-172. 49. Pageaux GP, Bismuth M, Perney P et al. Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter? J Hepatol 2003;38: 629-634. 50. Adam R, Cailliez V, Majno P et al. Normalised intrinsic mortality risk in liver transplantation: European Liver Transplant Registry study. Lancet 2000;356: 621-627. 51. Detre KM, Belle SH, Beringer KC, Bost JE, Daily OP. Overall national results of liver transplantation between 1987 and 1991. In: Busutill RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia, London, Toronto: W.B. Saunders Comp., 1996: 824-834. 52. Keeffe EB. Liver Transplantation: Current Status and Novel Approaches to Liver Replacement. Gastroenterology 2001;120: 749-762. 53. Sheiner PA, Magliocca JF, Bodian CA et al. Long-term medical complications in patients surviving > or = 5 years after liver transplant. Transplantation 2000;69: 781-789. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Fundeni Hospital de Gruyter

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Abstract

Introduction: Liver transplantation (LT) is considered the treatment of choice for the patients with end-stage liver diseases, acute liver failure, metabolic diseases and liver cancer. The introduction of this therapeutic method can be considered one of the most important achievements of modern Romanian surgery. Material and methods: Three hundred cases of LTs were performed in 286 patients in Fundeni Clinical Institute between April 2000 and September 2011. There were 172 men and 114 women, both adults (252) and children (34). In the adult group the main etiology was represented by viral liver cirrhosis, whereas the glycogenosis and biliary atresia were the main indications for children. The surgical technique consisted in 225 whole graft LTs, 62 living donor LTs, 8 split LTs, 4 reduced LTs and one domino LT. Results: The immediate postoperative patients' survival was 91.6% (262 patients). The patient and graft survival at one and five years were 80.7% and 78.7%, 71.7% and 65.8% respectively. The early complications occurred in 193 patients (67.5%). The late complications were recorded in 95 patients (33.2%). The intraoperative and early postoperative mortality rate was 8.4% (24 patients). Conclusions: The Romanian liver transplantation program from Fundeni Clinical Institute includes all types of current surgical techniques and the results are comparable with those from other international centers. Key words: liver transplantation, indications, surgical techniques Address for correspondence: Irinel Popescu, MD, FACS, FEBS, Professor of Surgery, "Dan Setlacec" Center for General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni, 258, 022328, Bucharest, Romania, e-mail: irinel.popescu220@gmail.com Introduction Liver transplantation (LT) is considered the treatment of choice for the end-stage liver diseases, acute liver failure, metabolic diseases and liver cancer. The operation is a formidable "tour de force" which became possible due to the progress recorded in the surgical, anesthesiology and intensive care fields as well as immunology and immunosuppressive regimens. The first LT performed in Fundeni Clinical Institute was carried out in June 21, 199, but the patient died because of multiple system organ failure in the immediate postoperative period (1). The first successful LT was performed in April 2000. In the same year the first living-related transplantation was also successfully performed (3). This paper is the retrospective analysis of 300 cases of LT performed between April 2000 and September 2011 in Fundeni Clinical Institute. The experience with liver transplantation, at various stages of our program, was also presented before (2-6). Material and method Three hundred cases of LT were carried out in 286 patients (14 retransplantations). All the patients were on the waiting list from our institute and were transplanted according to the severity of the liver disease ­ MELD score and emergency degree established by local ethical committee. There were transplanted 172 men and 114 women, both adults (252) and children (34). The main indications are listed in Table 1. It is worth mentioning rare causes requiring LT such as: recurring hepatoblastoma, primary liver lymphoma, hereditary fructosemia, homozygous familial hypercholesterolemia, cholangiocarcinoma and polycystic liver disease. Some of these cases had remarkable features: Table 1 ­ Major indications for LT LT indication Number of patients HBV ± HDV LC 96 HCV LC 54 Hepatocellular carcinoma and LC 45 (1 - fibrolamellar) HBV+HCV LC 5 Biliary cirrhosis (primary and secondary) 18 Wilson disease 16 Alcoholic LC 13 Biliary atresia 6 Glycogenosis 6 Liver fibrosis 3 Ductopenia 2 Miscellaneous 22 LC ­ liver cirrhosis, HCC ­ hepatocellular carcinoma Three yr after transplantation, an autologous CD34 (+) cell transplantation was performed in order to better control the hypercholesterolemia. Seven years after the LT, the donor was in excellent shape socially and professionally after undergoing a kidney transplantation and stenting for coronary artery disease. The recipient, despite an elevated level of serum cholesterol (339 mg/dL), which was partially controlled by medication and diet, showed no signs of ischemic heart disease (verified by a normal coronary angiogram)(9). At ten years post-DLT, the patient is still free of disease, with no recurrence of HCC or complications related to HFHC. Case 2: Polycistic Liver Disease A 39-year old man suffered from isolated polycystic liver disease, clinically highly symptomatic, with massive hepatomegaly, advanced malnutrition, poor quality of life underwent LT. Due to the massive hepatomegaly, and the hepatectomy was difficult. To our knowledge this is the biggest specimen from a PLD patient who was transplanted worldwide (Fig. 1). In a study reported by Pyrenne J et al 16 patients underwent LT for PLD; native liver weights varied from 10 to 20 kg (10). The maximum weight of the liver was 20 kg( ranged from 2.9 kg to 20.0 kg) in a study published by Manns PM on 36 patient that underwent LT or combined liver- kidney transplantation (11). In cases of retranplantations (14 cases) there were two groups: emergency indications such as Case 1: Homozygous Familial Hypercholesterolemia Worldwide, the first DLT for Homozygous Familial Hypercholesterolemia was performed in our center, and reported by Popescu et al. (5,7). A liver from a 25-year-old patient with HFHC was transplanted into a 46-year-old patient with HCC and HBV-related liver cirrhosis in 2001(8). The immediate postoperative course was uneventful. Figure 1 - The liver specimen weighed 23.2 kg hepatic artery thrombosis ­ 7 cases, portal vein thrombosis ­ one case, persistent biliary leak in association with "small-for-size" syndrome ­ 2 cases, primary graft non-function ­ one case, or elective indications ­ 2 cases of recurrence of the initial disease (liver fibrosis, HCV infection) and one case of chronic rejection. The majority of transplants (225) were cadaveric liver transplants; the technique of the operation has been described elsewhere (8). Special types of liver transplantation have been used for the rest of the cases: 62 living donor LTs, 8 split LTs, 4 reduced LTs and one domino LT. A complete procedure involves, basically, 4 stages: 1. procurement of the whole liver (deceased donor or domino donor) or of the segment of the liver (living donor ­ segments 2 and 3, left or right hemiliver); 2. "back-table" procedure ­ preparation of the graft; 3. recipient's total hepatectomy with or without the preservation of inferior vena cava; 4. recipient's grafting with the vascular and biliary anastomosis. Concerning the characteristics of the deceased donors, the were used livers from patients with age ranging from 6 to 66 year-old, mostly blood type A (41.2%) and 0 (32.6%), having as causes of death blunt trauma of the head (55.8%) or stroke (42.9%). It is worth mentioning the use of a liver from a patient with acute methanol poising. The liver graft was normal after transplantation (12). In case of living donor LT there were 62 patients. There was no death among the living donors. The postoperative morbity of living donors was minimal. There were 28 procedures in 27 children (one retransplantation) by using the segments 2 and 3 (23 cases) or the left hemiliver (5 cases); the adult living donor LTs were perfomed by using the right hemiliver (33 cases) or the left hemiliver (one case). The first 6 cases of split LT were carried out between children (segments 2 and 3) and adults (right hemiliver and segment 4); the last couple perfomed in May 2011 was realized between a teenager (17 year-old ­ right hemiliver) and an adult (24 year-old ­ left hemiliver). In the case of domino LT the donor was represented by a patient with homozygous familial hypercholesterolemia (5,7). The immunosuppression was carried out in two phases: induction (during the anhepatic phase) with steroids or monoclonal antibodies, and maintenance by triple association (calcineurin inhibitors, antimetabolite, and steroids). The postoperative course of the patients was related to the patient's underlying disease, the surgical technique and immunosuppressive regimen. The patient and the graft were monitored daily along with the serum concentration of the calcineurin inhibitor. It was initiated the prophylactic therapy against cytomegalovirus (valgancyclovir or gancyclovir) and,in patients with B virus specific treatment with lamivudine and antiHBV immunoglobulin. Results The immediate postoperative survival was 91.6% (262 patients). The one-year and five-year patient and graft survivals were 80.7% and 78.7%, 71.7% and 65.8% according to the Figures 2 and 3. Presently 212 patients are alive and 2 are lost from the follow-up. The longest survivor, who is the first successfully transplanted patient in our program, has more than 11 years survival. The pediatric group comprises 21 patients and the adult group 191 patients. In the adult series, the social reinsertion percentage was almost 100%, while the professional reinsertion was 57% with the maximum between of the age 30- 40 years. Figure 2 - Patient's Survival Figure 3 - Graft survival The early postoperative complications (the first month) occured in 193 patients, being represented by biliary complications (51 patients), vascular complications (30 patients), peritoneal bleeding (30 patients), abdominal (19 patients) or cutaneous (7 patients) infections, "small-for-size" syndrome (8 patients) and primary graft non-function (one case). The biliary complications were mainly leaks ­ 40 patients and stenosis ­ 11 patients, their management being surgical (35 cases with anatomoses remake in 4 cases or conversion to Roux-en-Y hepaticojejunostomy 31cases), interventional (8 cases) or conservative (8 cases). Case 3 A 37-year-old male with whole graft live transplantation for biliary cirrhosis whose postoperative course was complicated by cholestasis; an MRCP showed stenosis of biliary anastomosis (Fig. 4) and the patient underwent surgical conversion to Rouxen-Y hepaticojejunostomy with good postoperative course. Hepatic artery thrombosis (17 cases) was diagnosed by angiography which was also therapeutic in 3 cases. The failure of thrombolysis demanded emergency surgery (7 cases) and retransplantation (7 cases). Because of the severity of this complication, there were recorded 8 deaths. Figure 4 - MRCP showing stricture of the biliary anastomosis Case 4 A 19-year-old male was transplanted with right hemiliver for Wilson disease and developed hepatic artery thrombosis in the 3rd postoperative day (Fig. 5). The angiographic thrombolysis was successfully carried out, but the complication recurred and the patient required an emergency retransplantation with whole graft liver. The outcome was good. There was a case of arterial low flow surgically managed by a new arterial anastomosis and a case of combined stenosis and spasm of hepatic artery managed by intraarterial prostacyclin administration. The stenosis of hepatic artery confirmed by angiography (Fig. 6) in one case required Gore-tex garft interposition with good outcome. Another severe vascular complication was represented by portal vein thrombosis (5 cases) Figure 5 - Complete thrombosis of the hepatic artery ­ celiac axis angiography that required anticoagulant therapy (one case), surgical remake of the anastomosis (2 cases) and retransplantation (one case). A partial thrombosis was managed by anticoagulant therapy. There was also a portal vein stenosis without hemodynamic impact and managed conservatively. A right hepatic vein thrombosis occurred in the setting of emergency retransplantation for primary non-function, with secondary ascites and patient's death because of sepsis. There were 30 cases of peritoneal bleeding requiring emergency surgical hemostasis. The abdominal infectious complications were treated by surgery (10 cases of acute generalized peritonitis and 5 peritoneal abscesses) or CTguided percutanous drainage (4 cases of peritoneal abscess). Extensive skin infections (cellulitis) were recorded in 7 cases with fatal outcome in 5 cases. "Small-for-size" syndrome was encountered in living donor LTs and was managed conservately (3 cases), surgically (3 cases) by splenic artery ligation in all cases and a temporary porto-caval shunt, and retransplantation (2 cases). Early general complications was represented by neurologic ( 55 cases), respiratory (37 cases), renal (29 cases), cardio-vascular disorders (10 cases), metabolic disorders (secondary diabetes mellitus ­ 10 cases) and upper gastro-intestinal bleeding (5 cases). The treatment was specific for each condition. The late complications were recorded in 95 patients (33.2%) ­ biliary ( 24 cases), vascular (7 cases) and also the recurrence of the disease ­ HCV recurrence (34 cases proven by liver biopsy), HBV recurrence ( 2 cases), hepatocellular carcinoma (7 cases), autoimmune hepatitis (one case), liver fibrosis (one case) and alcoholic cirrhosis (one case). The biliary complications, mainly stenosis, were treated by endoscopic stenting (9 cases) or surgery (13 cases). Two cases of recurring cholangitis are under evaluation for percutenous biliary drainage. The vascular complications were represented by hepatic artery stenosis (one case), hepatic artery thrombosis (one case) and portal vein Figure 6 - Stenosis of the hepatic artery ­ before (a) and after (b) Gore-tex graft interposition Figure 7 - Portal vein stenosis ­ angiography stenosis (5 cases). In the cases of portal vein stenosis (Fig. 7), three of them with hemodynamic impact were managed by percutanous dilation and stenting. One of them led to restenosis with ascites and hypersplenism requiring splenectomy. Recurrence of HCV was encountered in 34 patients and required the reduction of the level of immunosuppression and specific treatment with interferon and ribavirin. Recurrence of hepatocellular carcinoma was recorded in 7 patients. All of them were oncologically assessed and treated by chemotherapy (including sorafenib) and radiotherapy and the immunosuppression was switched to sirolimus. There were also "de novo" neoplasia - 6 cases: one case of cervix carcinoma complicated by a lung cancer, two cases of spinocellular carcinoma, lingual cancer and two cases of non-Hodgkin lymphomas. All of them were oncologically assessed and treated accordingly. Discussions 3. metabolic liver disorders; 4. liver malignancies. Initially considered "life-saving" procedure, LT is now indicated in the less severe liver disorders, but with interference with the quality of life (13,14). The main etiology is represented by viral liver cirrhosis (www.eltr.org, www.unos.org), and this was also encountered in this series. The pediatric segment is dominated by metabolic and cholestatic disorders. In case of alcoholic liver cirrhosis, the cornerstone is focused on the neuro-psychiatric assessment for better outcomes, most of the papers showing a mandatory abstinence period of at least 6 months (15,16)}. Concerning the liver malignancy, the main indication is hepatocellular carcinoma. LT has two main objectives ­ treats the neoplasia and the liver cirrhosis (17). Most centers are using Milan criteria (18) and the patients within these criteria are listed for whole graft, whereas those beyond can undergo a living donor LT or receive a marginal graft. Wilson disease represents an elective indication for LT (liver cirrhosis) or emergency need for LT (acute liver failure)(19,20). From the 16 cases of Wilson disease, 4 cases were transplated on an emergency basis. Biliary cirrhosis either primary or secondary (e.g. primary slerosing cholangitis) represented 7.14% of all the adult patients. As expected the pediatric pathology was prominent by glycogenosis and biliary atresia (17.64% each). Donors The shortage of organs and the increasing number of the patients on the waiting list claimed for alternative techniques such as split LT, living donor LT or domino Ltor expansion of the graft pool by accepting marginal donors. The latter tendency is more frequently utilized in case of patients with hepatocellular carcinoma beyond Milan criteria or emergency indication (acute liver failure). From the same category, livers from patients with previous viral infections (HBV, HCV) can be transplated in patients with the same indication (21). Surgical technique Indications for liver transplantation LT is indicated in the follwing liver disorders: 1. end-stage liver diseases; 2. acute liver failure; LT has imposed as the treatment of choice due to the major breakthrough in the field of general surgey ­ procurement and preservation of the graft, improvement of technique and intensive care, as well as immunosuppressive regimens. If initially the recipient's total hepatectomy was performed en-bloc with inferior vena cava (as a consequence there were 2 cava-cavostomies), today this venous segment is preserved. The liver outflow can be reestablished by "piggy-back" (endto-side) or modified techniques such as side-to-side anastomosis (Belghiti) or cavaplasty, the latter being the procedure of choice in this group. The portal anastomosis is done by end-to-end manner with "growth factor" in order to prevent the vascular stenosis. Preoperative portal vein thrombosis in not a contraindication for LT any more. An example for a case of an extenive portal vein thrombosis was the need for a cavo-portal hemitranspositon with good portal flow. In cases of excessive portal hypertension temporary porto-caval shunts have been performed. The arterial anastomosis was carried out at the level of celiac axis, mainly with the donor's common hepatic artery. In case of inadequate flow, the anastomosis were made by graft interposition with the donor's infrarenal aorta. Immunosuppression The progress and the appearance of new immnusuppressive drugs made possible the continuous improvement of graft and patient survival. Classically there is a triple association between the calcineurin inhibitor (tacrolimus or cyclosporin), antimetabolite (mycophenolate) and steroids. Tacrolimus is considered the drug of choice, being associated with a decreased rate of acute rejection, especially the corticoresistant type (22). In case of HCV recurrence there are in vitro studies suggesting the antiviral effect of cyclosporin (23). In the presence of preoperative encephalopathy or renal dysfunction, the induction was made by monoclonal antibodies (daclizumab, basiliximab) which allowed the late introduction of calcineurin inhibitors with favourable result of the patients. The triple immunosuppressive regimen is maintained 3 months posttransplantation when the antimetabolite and steroids are withdrawn, the patient being left on calcineurin inhibitor only. Postoperative course The early postoperative morbidity is variable and estimated between 4.1% (24) to 50% (25) being mainly represented by peritoneal bleeding as well as anastomotic complications (vascular and biliary). The complications of the hepatic artery (either thrombosis or stenosis) with a frequency between 11 and 39%, are associated with biliary pathology (26). The complication can be managed by angiography with or without stenting (27), the failure of the procedure requiring surgical approach. The hepatic artery thrombosis more commonly encountered in case of living donor LT, has many risk factors such as low ratio between the donor's and recipient's age, immunologic factors, coagulation disorders, cytomegalovirus infection (28). The therapy can be done by angiography, surgery with anastomosis remake or retransplantation. Portal vein thrombosis is much rare (1-3%) (29), and induces acute liver failure and portal hypertension. The treatment can be managed by intravenous thrombolysis, interventional radiology or surgery. Outflow syndrome can be present in case of ,,piggyback" technique, either by stenosis or torsion, and produces an acute Budd-Chiari syndrome. In the absence of immediate treatment such as endoluminal prothesis (30), the consequence is the graft loss (31). This sydrome in rare when the caval anastomosis is done using Belghiti method and almost absent in case of cavaplasty. Biliary complications (7-29%) (32) can be leaks or stenosis and the treatment can be endoscopical or surgical. The general complications can be classified according to the system involved in pulmonary, cardio-vascular, renal, neurological, and infectious. The pulmonary complications occur in two thirds of transplanted patients (33,34) as pneumonia, pleural effusion, atelectasis or acute pulmonary edema (35). Although the hepato-pulmonary syndrome is no longer a contraindication for LT, it has a negative impact (36). Cardio-vascular complications include hypertension, myocardial ischemia, arrhythmia, cardiac arrest and, even, sudden death. Renal complications range from a simple dysfunction to an acure renal failure ­ 18% (37), secondary to the side effect of the calcineurin inhibitors. Neurologic complications estimated as 2.8 - 47% of the pateints (38,39) can be simple alteration of mental status to seizures, coma and death. The etiology comprises many factors: calcineurin inhibitors toxicity (40), previous encephalopathy, sodium disturbances. The psychiatric disorders can be translated by cognitive disorders to delusions and hallucinations (41). Some predictive risk factors can be alcoholic or metabolic etiology, necessity of mechanical ventila- tion, MELD > 15, emergency LT (42). In the presence of immunosuppression, the patients present an increased risk or the devepolment of neoplasia (lymphomas, carcinomas, sarcomas) (43) with an incidence between 5-15% (44). A major problem in the field of LT is the recurrence of the disease, especially in case of viral liver cirrhosis. Concerning the recurrence of HBV, this is low due to the prophylaxis with antiviral such as lamivudine and antiHB immunoglobulin (45). The lack of effective prophylaxis against HCV, explains universal rate of recurrence (46) with rapid progression to cirrhosis. A model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT was described by Iacob S et al (47). The antiviral treatment (interferon and ribavirin) has a variable rate of response 25-30% and is associated with serious side effects (pancytopenia, sepsis). Combination of pegylated interferon and ribavirin can be safely and successfully used in liver transplant recipients as reported by Iacob S et al (48). Retransplantation is controversial. Primary slerosing cholangitis can reccur up to 20% of the transplated patients, the diagnosis requiring MRCP and liver biopsy. Alcoholic liver cirrhosis can reaapear in 31% of cases(49) even in the presence of pretransplant abstinence, the differential diagnosis with NASH (non-alcoholic steatohepatitis) associated with obesity, diabetes mellitus or drug toxicity. The selection of the patients is a crucial factor in the development of hepatocellular carcinoma. Among the most important factors are the size of the tumor (>5 cm), the stage (vascular or lymph nodes involvement) and grading (G3). All the studies showed a lower recurrence after LT than after liver resection. Conclusions These 300 cases of LTs represent an important experience in the Eastern Europe and the only one in Romania. The liver transplant program from Fundeni Clinical Institute recorded a continous increase of the number of LT procedure and improvement of results, comparable to those from other international centers. Reference List 1. Popescu I, Radan A, Diculescu M et al. Consideratii privind primul transplant hepatic realizat la Spitalul Clinic Fundeni Bucuresti. Infomedica 1997; 38-47. Popescu I, Tulbure D, Ionescu M et al. Transplantul hepatic consideratii asupra a 8 cazuri operate în anul 2000. Chirugia (Bucur ) 2001;96: 453-467. Popescu I, Malago M, Testa G, Ciurea S, Stanescu C, Socoteanu I. Sequential therapy in a case of extrahepatic biliary atresia associated with ventricular septal defect: liver transplantation followed by surgical closure of the septal defect. Rom J Gastroenterol 2004;13: 125-128. Popescu I, Ionescu M, Tulbure D et al. Transplantul hepatic ortotopic de la donator cadavru la adult. Experienta Centrului de Chirurgie General si Transplant Hepatic Fundeni. Chirurgia (Bucur) 2005;100: 13-26. Popescu I, Habib N, Dima S et al. Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up. Clin Transplant 2009;23: 565-570. Popescu I, Ionescu M, Brasoveanu V et al. [Liver transplantation--indications, surgical technique, results--the analysis of a clinical series of 200 cases]. Chirurgia (Bucur ) 2010;105: 177186. Popescu I, Simionescu M, Tulbure D et al. 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Duran FG, Piqueras B, Romero M et al. Pulmonary complications following orthotopic liver transplant. Transpl Int 1998;11 Suppl 1: S255-S259. 35. Golfieri R, Giampalma E, Morselli Labate AM et al. Pulmonary complications of liver transplantation: radiological appearance and statistical evaluation of risk factors in 300 cases. Eur Radiol 2000;10: 1169-1183. 36. Marinescu TS, Diculescu M. Sindromul hepatopulmonar. In: Popescu I, ed. Chirurgia ficatului. Bucuresti: Editura Universitara "Carol Davila", 2004: 873-880. 37. Gonwa TA, Mai ML, Melton LB et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation 2001;72: 1934-1939. 38. Stein DP, Lederman RJ, Vogt DP, Carey WD, Broughan TA. Neurological complications following liver transplantation. Ann Neurol 1992;31: 644-649. 39. Wszolek ZK, Fulgham JR. Neurologic complications of liver transplantation. In: Maddrey WC, Schiff ER, Sorrell MF, eds. Transplantation of the liver. Philadelphia: Lippincott Williams & Wilkins, 2001: 297-317. 40. Jain A, Brody D, Hamad I, Rishi N, Kanal E, Fung J. Conversion to neoral for neurotoxicity after primary adult liver transplantation under tacrolimus. Transplantation 2000;69: 172-176. 41. Strouse TB. Neuropsychiatric outcomes in liver transplantation. In: Busutill RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia: W.B. Saunders Company, 1996: 659-664. 42. Kanwal F, Chen D, Ting L et al. A model to predict the development of mental status changes of unclear cause after liver transplantation. Liver Transpl 2003;9: 1312-1319. 43. Penn I. Posttransplantation de novo malignancies. In: Busutill RW, Klintmalm GB, eds. Transplantation of the liver. Philadelphia: W.B. Saunders Company, 1996: 731-738. 44. Rubio E, Moreno JM, Turrion VS, Jimenez M, Lucena JL, Cuervas-Mons V. De novo malignancies and liver transplantation. 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Annals of Fundeni Hospitalde Gruyter

Published: Dec 1, 2011

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