Living-related liver transplantation.

Abstract

At the beginning of the 21st century, living-related liver transplantation (LRLT) has emerged as a routine procedure in pediatric liver transplantation, together with transplantation of a full-size, a reduced, or a split cadaveric liver. Living-related liver transplantation allows an optimal selection of donors with normal livers, a minimal preservation injury, and an electively scheduled operation before clinical deterioration of the recipient. More than 1,500 LRLTs have been performed in children throughout the world, and the technique is increasingly developing in adult patients as well. However, LRLT requires invasive surgery in a healthy subject, the donor. The donor's safety must remain the most important issue in the whole procedure. Ethical considerations are a priority when establishing a program of LRLT. HISTORY The first LRLTs were reported from Brazil in 1989 (1) and from Australia 1 year later (2). The technique was then developed extensively in Japan, where procurement of cadaveric organs was impossible until recently (1998) for cultural and legal reasons. Nowadays, the largest LRLT programs are the Japanese ones (more than 500 at Kyoto University (3). To alleviate the lack of small organs for very young recipients, reduced (4) and split (5) cadaveric liver transplantation was introduced from the mid 1980s, first in Europe then in the United States. However the persistent organ shortage and the numerous deaths of infants on the waiting lists were the driving force for the introduction of LRLT in the United States in the early 1990s (6). The technique then spread to Europe. Nowadays, most large pediatric liver transplant programs perform LRLT routinely, together with cadaveric transplantation. Living-related liver transplantation was initially restricted to children with chronic disease in relatively stable condition, to avoid a major psychologic pressure on the potential donor (7). With larger experience, it was extended to emergency cases, such as fulminant hepatic failure. Auxiliary transplantation, initially developed for this indication (8) and in metabolic disorders (9), could also be performed with a living-donor liver (10–13). The graft used in children is in most cases the left liver lobe, its volume being a limitation for older children and adults. It has been overcome by retrieving the right lobe, allowing the introduction of the technique into adult transplant programs (3). ETHICAL CONSIDERATIONS Living-related liver transplantation is, at first glance, contrary to the rule of primum non nocere. The major ethical dilemma is to mutilate a healthy subject to save the life of a child with end-stage liver disease. Living-related renal transplantation has been performed for 25 years. A major difference with kidney transplantation is that patients with end-stage renal disease have access to dialysis, whereas those with end-stage liver disease die unless they undergo transplantation. The pressure on the potential donor is thus far heavier. Nowadays, the risk of donor death during kidney transplantation is evaluated to be approximately 0.03%(14). The prerequisites for LRLT are a very low risk of hepatectomy in a normal liver and the demonstration of similar results with transplantation of a full-size liver or of liver segments (reduced or split liver). Ethical discussion must consider the therapeutic possibilities for the recipient, the risk for the donor, and the liberty of choice for the donor (7,15). Living-related liver transplantation is ethically defensible only if the following conditions are met: Liver transplantation is the only therapeutic option: For metabolic liver diseases, hepatocyte transplantation, or gene therapy may be alternative options in the future. Auxiliary transplantation should be discussed whenever possible. Cadaveric liver transplantation is impossible or problematic for any reason (waiting time, legal considerations, and so forth). Organ shortage and the mortality rate while on the waiting list are the driving force for development of LRLT programs. In countries in which repartition rules favor the children, organ shortage is a lesser problem. Unfortunately, the system of organ allocation in the Eurotransplant area has become less favorable to children since 1998, when the pediatric donor definition was changed from younger than 16 years to less than 40 kg. The net result was a decrease of one third of cadaveric organs allocated to children, and a subsequent increase in percentage of LRLT from 17 to 25% (first half of 1999) (16). The organ shortage is also a major problem for children with rapidly deteriorating liver disease, such as congenital cholestatic disorders, for children with rare blood groups, or for foreigners who cannot benefit from the allocation rules (for example the Japanese child of the first Australian report) (2). There must be reasonable chances that the recipient survives the operation with an acceptable quality of life. The first LRLTs in the United States were restricted to recipients with a higher chance of survival, excluding critically ill patients (7). With the surgical experience in segmental liver transplantation, a survival rate of at least 70 to 80% could be expected. In the extreme situation of fulminant hepatic failure, survival after cadaveric transplantation is around 50%. However, better results can be expected when transplanting a good liver early in the child. When the chances of survival are very low, and although the parents may always be willing to sacrifice for their child, LRLT would be unethical. The mortality risk for the donor is much lower than 1%; the severe morbidity risk (including psychologic) lower than 10%. Twenty years ago, the risk of mortality after major liver resection reached 11%(17). Because of the continuous improvement in hepatic surgery, it is now close to zero in patients with benign diseases, and the morbidity risk approximately 5%(17–19). This means that surgery in the donor should be performed only in centers with demonstrated excellence in hepatobiliary surgery, including all the requirements in anesthesiology and intensive care (16). The potential donor receives all information about the risks and the chances for the recipient, can make his decision without external pressure, is allowed to withdraw consent until the last minute, the reasons of withdrawal remaining confidential. An ethical and legal protocol should be established and approved by the Ethics Committee of the institution, and followed in each case, with no exceptions made to accommodate the recipient's specific needs. In France, the donor must register his consent in law court. The information should be given by a physician external to the transplant team (for example the family doctor), to avoid the bias because of the enthusiasm of the team. Although it is impossible to avoid completely any coercion, it is minimized by introducing LRLT among all other transplant options that have to be available in the center: the parents should be offered the possibility to register their child on the waiting list (16,20). There are no other considerations than medical for the donor. When the donor is a close relative to the patient, mostly a parent, the motivation is clearly altruistic, driven by the need to participate to the care, to take action and “repair” the child's congenital or hereditary defect (7,15). When the donor is distantly or not at all related to the recipient, some centers ensure a systematic evaluation by a psychiatrist (21). Most adult transplant programs, for which this issue is more prevalent, approach it with caution and acknowledge that the ethics of this type of donation require further examination (21,22). In many countries, living donation is strictly restricted by the law to first-or second-degree relatives (23). In conclusion, our experience and that of others (20) is that introducing the concept of LRLT for a child is not per se an absolute coercion because many parents do not show interest in it (23% in UCSF experience (20), 15% in ours). Whitington (24) observed that the expected patient survival after transplantation, taking into account the pretransplantation mortality rate, was 67% in a program not performing LRLT. Based on the experience of his own program, with an 80% survival rate, he concluded that not offering LRLT would be unethical. After complete information, the liberty of choice is left to a responsible adult. THE DONOR Donor Evaluation The potential donor must be older than 18 years of age, without health problems, and ABO-compatible with the recipient. Every medical problem known to increase the perioperative risk should be considered a contraindication. This includes obesity, as the first reported donor death was in an overweight mother (who had continued smoking and taking oral contraceptives despite medical advice) (25). Living-related liver transplantation has been performed across the ABO blood group, mainly in Japan (26). The results are identical to cadaveric transplantation and show a 70% graft and patient survival at 1 year (27,28). The better outcome is observed in the youngest children with low titer of preformed alloantibodies. ABO incompatibility is thus not a contraindication for children younger than 2 years of age in some centers (26,28). The donor evaluation is performed in several phases (25,29,30). First, routine laboratory tests rule out liver or kidney dysfunction, previous viral B or C hepatitides (and of course HIV). Because of the risk of transmission of hepatitis B (31), presence of anti–hepatitis B core antibodies is an absolute contraindication in most transplant programs (20,25), except in Asia because of the prevalence of the virus and the scarcity of alternate cadaveric grafts (32). The choice of the parental donor should be prudent in genetic diseases. Living-related liver transplantation has been performed safely with heterozygous donors in progressive familial intrahepatic cholestasis (33,34) (although a case of possible recurrence of the disease has been reported (35)), α 1 -antitrypsine deficiency (10,33,34), and Wilson disease (36). In ornithine transcarbamylase deficiency, the gene is located on the X chromosome, and a carrier mother should preferably not be a donor (13), although it has been performed safely (37). In familial hypercholesterolemia, both parents are hypercholesterolemic and probably not suitable for donation (38). In Alagille syndrome, the transmission is autosomic dominant with variable penetrance; the procedure had to be aborted intraoperatively in two donors because of the absence of suitable bile ducts for anastomosis despite normal liver tests (39). Physical examination and psychologic assessment are the next steps. A thorough social evaluation must be undertaken. The postoperative hospital stay is approximately 1 week; work incapacity 1 to 2 months. Social and financial considerations may greatly hamper the possibility of donation (20,25). The size of the future graft, from the donor's left lobe, is then evaluated by CT volumetry (40) or magnetic resonance imaging (41). It cannot be estimated only from the donor's weight because of large discrepancies in the size of the left lobe (42). The graft size is important only in the two extreme ages of childhood: the infant and the teenager. If the graft is too large, it may cause surgical, respiratory, or circulatory problems. If the graft is too small, it cannot sustain the metabolic needs, increased by either bleeding or rejection or infection. The minimal graft-to-recipient weight ratio is estimated at 1%(17,21,22,30). The only cases of primary nonfunction in LRLT have been reported with small-for-size grafts (43,44). Some centers report successful transplantation with smaller grafts, as small as 0.47% of the recipient's weight (3,45,46). However, these sporadic cases should not be used as the safety standard for adequate graft volume. Recent experience in adult patients suggests that graft function depends not only on the graft size, but also on the pretransplant disease severity: the more sick the recipient, the more liver needs to be provided (22,47). The problem of a small-for-size graft may be overcome by using it as an auxiliary liver (11). Another way is to retrieve the right instead of the left liver lobe. The first right hepatectomy was performed in a 9-year-old Japanese girl because of vascular inadequacy of the left lobe (48). The technique was extended to adult-to-adult LRLT (21,22,49,50). In this situation, a graft-to-recipient body weight ratio of 0.8% has been evaluated as sufficient to sustain postoperative liver function (3,52). The risk in the donor is not more important in skilled hands (3,21,22,51–53). However, many problems rarely encountered in pediatric transplantation arise: ethical (high proportion of unrelated donors, controversial indications such as cancer), medical (health problems in an older donor), and technical (graft size, venous drainage of the right lobe). The complication rate for the recipients is higher than for recipients of cadaveric grafts, although the survival is comparable (49,51,52). Once more, this very specialized procedure should be performed only in highly experienced centers (54). The vascular distribution of the donor liver is then evaluated by arteriography, computed tomography, or magnetic resonance imaging, depending on the local expertise (41,55). Whatever the technique, it must demonstrate the presence of a good arterial segment for the future graft. Except when the donor has abnormal liver tests, or the suggestion of steatosis on imaging, most centers do not perform a liver biopsy (17). At the end of the evaluation process, a variable percentage of potential donors is accepted for donation, from 90% in Kyoto (29) to 23% in San Francisco (20), 36% in London (56), 66% in Hamburg (25), and 45% (61 of 137) in our own experience in Paris. This discrepancy is explained first by the recruitment of each center (in many large centers the families come from far away for LRLT, whereas psychosocial contraindications are more prevalent in community-based centers) and second, by the availability of an alternate option for transplantation, still problematic in Asia. The majority of contraindications includes blood group mismatch, size discrepancy, inadequate vascular anatomy, or medical problems (obesity, pregnancy, viral hepatitis, genetically transmissible disease, such as Alagille syndrome). Technique of Hepatectomy Before surgery, blood is collected from the donor for autologous transfusion as necessary. The operation usually begins with intraoperative cholangiography to define the biliary anatomy of the donor (3,6,17,21,25). Three types of hepatectomy are possible when using the left lobe. The decision depends on the size of the graft and the donor's anatomy. The hepatectomy is either left lateral (segments 2 and 3), full left (segments 2, 3, and 4), or partial left lateral (segments 2, 3, and part of 4). Most centers use a technique of dissection without vascular exclusion (17,57,58) to minimize the warm ischemic time and to better control bleeding. Care is taken while dissecting the hilar sheath and bile ducts to avoid severing the microvascular supply. After removal, the graft is immediately flushed with preservation solution. Intraoperative return of the donor's blood is used in most cases. Results in the Donor In 1,500 procedures, three donor deaths have been reported after procurement of the left lobe of the liver, and one for the right lobe (21). The first was a result of massive pulmonary embolism (25). Other major complications include nonlethal pulmonary embolism (59), biliary leak (17,25,29,30), infection, ulcers, (25,58), and psychiatric illness (60). Intraoperative bleeding (350–550 mL (3,58)) is minimized by the surgical experience and the intraoperative return of blood. All donors experience a moderate increase in liver enzymes and bilirubin concentrations in the first postoperative days, but no decrease in liver function (25,52,58,61). Regeneration of the resected liver can be demonstrated radiologically as early as the first postoperative weeks (52). No long-term complications have been reported. The liver is known to regenerate (61). Late psychologic assessment of the donor has been performed only in a limited number of cases (16,25,60). One report found a psychologic benefit, even when the child had died after LRLT (25). More studies on this issue are clearly needed. THE RECIPIENT Indications The indications for liver transplantation are mostly congenital cholestatic diseases; in first place, biliary atresia. Before the introduction of reduced-liver techniques and LRLT, early liver failure developed in young children who underwent ineffective Kasai procedure, and the children died in worrisome numbers while on the waiting lists. All other common indications for transplantation are found: cirrhosis, metabolic diseases, and fulminant hepatic failure. In the case of fulminant hepatic failure, coercion for the potential donor is high. However, providing the child with the best liver at the best time may provide optimal chances. The problem is similar in primary liver cancer, in which the waiting time on the list allows metastasis to disseminate. Preparation One of the major advantages of LRLT is to allow optimal preparation of the recipient to surgery (16). For example, in our center, 12 children underwent intensive renutrition: five with combined enteral and parenteral and seven with total parenteral nutrition (62). Recipient Operation It is the same with a living donor graft than with a split cadaveric left lobe (Fig. 1). Vascular anastomoses are performed using magnification or a microsurgical technique (3). Venous grafts have been used previously for the portal vein but may increase the risk of thrombosis. The hepatic vein is enlarged in a triangle to provide a large orifice on the inferior vena cava of the recipient (piggy-back technique), to stabilize the graft and avoid kinking (63). Biliary reconstruction is always cholangiojejunostomy.FIG. 1.: Schematic representation of a living donor graft (left lobe) after implantation in the recipient.Results in the Recipient Survival Patient survival rate is reported in most centers at more than 80%(10,30,33,34,64–66), similar to the results of cadaveric transplantation (67). Young very sick children may benefit more from the technique (68) because the mortality rate on the waiting list is high (24,66) and outcome after cadaveric transplantation may be worse than in older children (24,69,70). Transplantation across the ABO blood group (26) provides good results (see previously). In fulminant liver failure, 73% (8 of 11) (71), 66% (4 of 6) (72), and 90% (13 of 14) (73) survival rates are reported and compare favorably with 68% survival rates after cadaveric transplantation (74). The graft survival rate is also reported to be more than 80% in most centers (10,30,33,34,43,44,64–66). Complications Primary nonfunction: The risk is reduced to nearly zero if the graft is large enough for the recipient. In a large series from San Francisco, it was well shown that a small-for-size graft exposed the recipient to higher morbidity and risk of death (43). In another series, one case of primary nonfunction is reported without further details (65). One of our patients experienced poor primary function, prolonged cholestasis, and low coagulation parameters, with a graft weighing 0.9% of his body mass. The absence of primary nonfunction is explained by the optimal quality of the graft (retrieved from a healthy donor instead of a dying patient) the preparation in situ instead of on a back table, by the short ischemic time, and therefore by the lesser extent of injury on endothelial and bile duct cells (75). Vascular complications: An international survey gave an incidence of 6.4% for arterial and 5.4% for portal thrombosis (30). In the first series, 25% of the grafts were lost because of arterial thrombosis (10), more than after cadaveric (76) transplantation (11%). With the routine use of loupe magnification or intraoperative microscope, these results have greatly improved to a rate as low as 0% in Bruxelles (66), 0.06% in Paris, 0.1% in Baltimore (65), 0.08% in Omaha (17), and 1.7% in the Kyoto series of 250 LRLTs (77). Transplantation across the ABO blood group may increase the risk; however, this is controversial (30). The rate of occurrence of portal thrombosis was higher than that of cadaveric liver in the early experience (78), probably because of the large use of cryopreserved venous segments to enlarge the portal vein. Meticulous reconstruction and increase in surgical experience has greatly reduced this complication to approximately 3 to 5%(17,30,79). Complications on the hepatic vein anastomosis have been extremely rare with use of the piggyback technique (63). Biliary complications: Biliary complications are the Achilles heel of LRLT. In most series, they are observed in 15 to 40% of patients (17,30,33,34,66,80,81). In many cases, they do not affect patient survival but are responsible for a significant and often late morbidity. Most often they are not secondary to arterial thrombosis. In the Japanese series, they are more frequent in patients with intrapulmonary shunting, cytomegalovirus infection, or ABO-incompatible grafts (80), but this is not observed in other series or in ours. Biliary anastomosis is performed at the level of the common bile duct in cadaveric transplantation and of the left hepatic duct in LRLT. The left hepatic duct is smaller and may already be divided in two branches at the level of transsection. The left hepatic duct vascularization comes from small branches of the hepatic artery, which may be severed during graft procurement (82). The severity of biliary complications ranges from bile leaks during the first postoperative days (presumably either biliary radicles from the cut surface or from the biliary anastomosis) to biliary peritonitis or late strictures of the anastomosis and recurrent cholangitis. Leaks may dry up spontaneously. Strictures can be dilated percutaneously, but the procedure has often to be repeated because of restenosis. Surgical reconstruction of the biliary anastomosis is for us the best option (17,33,66,83). Many surgical modifications have been implemented to reduce these complications. Intraoperative cholangiography is performed in the donor to better select the site of section (84). The use of ultrasonic dissectors, the sharp transsection of the duct close to the parenchyma (34), as close as possible to the division between left and right hepatic ducts (17), the intraoperative x-ray guided left bile duct dissection (66), and anastomosis under magnification, with (66) or without plasty to enlarge it, are several improvements in the technique. Biliary complications have also been noted more frequently in some series of split-liver transplantation (84), but not in all (85), probably because of the same difficulty in dissecting a small duct. Rejection: It was suggested that better HLA (human leukocyte antigen) compatibility between donor and recipient would reduce the frequency of rejection. This does not hold true (10,17,33,34,64–66), maybe because the better HLA compatibility is balanced against the better antigen presentation to the immune system (86). One series only shows a lesser use of pulse steroids in LRLT compared with cadaveric transplantation (87). The introduction of tacrolimus in recent years will confound the interpretation of results (66). In most series, the rate of acute rejection is 50 to 70%(10,17,33,34,64–66). One report demonstrates a lower rate of chronic rejection in LRLT (20% versus 8%) (88). However, this very high rate of chronic rejection in cadaveric transplantation is unusual because it is reported at 5 to10% in children (89). Larger series and long-term follow-up will be necessary to clearly demonstrate any immunologic advantage. Infections: The rate of infection is the same as in cadaveric transplantation and is mainly related to the immunosuppression protocol and recipient preoperative status (17,30,90). The rate of occurrence of posttransplant lymphoproliferative disease is not different from cadaveric transplantation and is related to the Epstein–Barr virus status of the recipient, depending on the recipient age at surgery (91). Long-term results Few series report long-term results because the largest cohorts are just reaching the fifth posttransplant year. The Kyoto group describes a very good quality of life and a catch-up growth (although incomplete) of 3 to 6 years after LRLT (92). The results will probably be similar to cadaveric transplantation results after the first posttransplant year. The psychologic consequences of the recipient knowing the liver donor will have to be investigated in comparison with cadaveric transplantation. However, very few studies focus on quality of life and psychologic outcome after transplantation, either cadaveric or living related (93). More studies are needed in this area. Cost Because of the improved outcome in the sickest children, the hospital stay after LRLT may be shorter; therefore, the cost is lower compared with cadaveric transplantation cost (30). This must be proven in large series, taking also into account the cost of time loss for the donor. CONCLUSION Living-related liver transplantation has been developed in response to a shortage of organs for children. It has grown to represent half of the procedures in many large pediatric centers, in which the availability of all modes of transplantation allows most children to undergo surgery in a timely fashion. To ensure the liberty of choice of the families, LRLT should be performed only in centers with an established liver transplant program, in which all the expertise in pediatric hepatology and liver transplantation is available. Donor safety should always be the primary focus in LRLT. The experience of the center for adult liver surgery, anesthesiology, and hepatology must be demonstrated before initiation of any LRLT program. All social, psychologic, and medical aspects have to be thoroughly evaluated. The risk of the routine use is inconscient coercion because LRLT in its scheduled mode may be more convenient for the transplant team, and, to some extent, for the families. The team must constantly struggle to improve in parallel the procurement of cadaveric organs (94,95). Alternative therapies, such as gene therapy and hepatocyte transplantation, in the future may also alleviate the need for liver transplantation in metabolic disorders.