Advances in adult living donor liver transplantation: A review based on reports from the 10th anniversary of the adult-to-adult living donor liver transplantation meeting in Tokyo
In 1993, the Shinshu Group performed the first successful adult-to-adult living donor liver transplantation (LDLT). During the first 10 years of LDLT, many technical innovations have been reported. The major limitation of LDLT for adult recipients is the size of the graft. To overcome the problem, several graft types were designed, including left liver graft with caudate lobe, right liver, modified right liver, and right lateral sector and dual grafts. The necessity and criteria of reconstruction of middle hepatic vein is still on debate in right liver graft without trunk of middle hepatic vein. Biliary reconstruction remains a significant source of morbidity in LDLT. Donor safety must always be the primary consideration in LDLT and the selection criteria and management of the living donor must continue to be refined. On February 21, 2004, the 10th anniversary of the adult-to-adult LDLT meeting was held in Tokyo to review the accumulated experience and the presented information is summarized. (Liver Transpl 2004;10:715–720.)
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Living donor liver transplantation (LDLT) was first introduced among the pediatric population in 1989,1 and the first successful case in the total occurred in 1990.2 On November 2, 1993, the Shinshu Group performed the first successful adult-to-adult LDLT.3 The patient, who was a 53-year-old woman with primary biliary cirrhosis, received a left liver graft from her son. The number of LDLT procedures for adult patients has increased rapidly since then. By June 2002, there were 433 adult LDLT cases recorded in the European Liver Transplantation Registry4 with 3-year graft and patient survival rates of 65% and 68%, respectively.
According to the United Network for Organ Sharing,5 731 adult LDLT cases had been performed in the United States by October 2001. The 3-year graft survival was 47% between 1998 and 1999 (n =156), but it improved significantly to 61% between July 1999 and June 2000 (n = 285). According to the Japanese Liver Transplantation Society,6 1063 adult LDLT procedures were performed in Japan by the end of 2002. All of the donors were related to the patients; most of them were within the third degree of consanguinity. During the same period, only 10 adult patients underwent liver transplantation using grafts from deceased donors. Death of one living donor was reported from Japan. The donor was a woman in her 40s with complicated mild hypertension and fatty liver preoperatively. Right liver resection was performed, and estimated remnant liver volume was 29% of the total. Postoperatively the donor progressed to liver failure and received a whole liver from a familial amyloid polyneuropathy patient 5 months after her donation. However, she expired 8 months after the donation. The 5-year survival rates were 83% in children and 69% in adults. The lesser outcome in adults compared to that in children (P < .0001) indicates that problems remain in adult LDLT.
During the first 10 years of LDLT, many technical innovations have been reported. Now appears to be a good time to review the accumulated experience. On February 21, 2004, the 10th anniversary of the adult-to-adult LDLT meeting was held in Tokyo. The presented information is summarized below.
Selection and evaluation of a living liver donor for adult recipients is a complex process that involves optimizing graft size in relation to the safety of donors and recipients, technical details of liver procurement, and ethical problems of using nonrelated live donors. As in most countries, including the United States and Japan, no legal restrictions exist in for living donation, local ethics committees confirm whether the candidates are appropriate potential donors. Voluntarism is the primary selection criterion and medical evaluation can only be started after confirmation of the voluntary nature of the donation.
Volumetric study using computed tomography scans is mandatory. For patients with advanced liver disease, a graft volume of greater than 40% of the recipient standard liver volume is necessary,7 while for the living donor the remnant liver mass must be more than 30% of the whole liver.8 The term “standard liver volume”9 has become a key concept in LDLT. Estimated liver volume on computed tomography in healthy volunteers is proportional to body surface area and is calculated using the following formula:
Donor safety must always be the primary consideration in LDLT. At least 3 cases of donor death have been reported in the United States10 and 1 in Japan. Therefore, the selection criteria and management of the living donor must continue to be refined. Cherqui et al. reported on laparoscopic left lateral segmentectomy in a living donor for pediatric liver transplantation.11 This laparoscopic technique was used in 8 donors, and early graft function was satisfactory in all cases. Unfortunately, 2 patients were complicated with hepatic arterial thrombosis, and 1 of them died. The application of laparoscopic donor hepatectomy for adult liver transplantation requires further technical advances but should be possible in the near future.
Small-for-Size Graft Problem
The major limitation of LDLT for adult recipients is the size of the graft that can be procured from a living donor, because a small-for-size graft might not meet the metabolic demands of an adult recipient.
Left Liver Graft
In the initial adult LDLT procedures, only a left liver graft was used. In 1998, the Shinshu group reported satisfactory results using a left liver graft in 13 patients.12 The donor was selected if, based on computed tomography volume examination, the calculated size of the liver graft was larger than 30% of the recipient's standard liver volume. By January, 2004, the group had performed 95 adult LDLTs using left liver grafts. The 5-year graft and patient survival rates were 81% and 82%, respectively. Graft survival did not appear to be related to the graft volume / patient standard liver volume ratio. One-year graft survival was 83%, 83%, and 100% in patients who received grafts with graft volume / patient standard liver volume ratios ranging from 30% to 39%, 40% to 49%, and more than 50%, respectively. Their data indicate that left liver graft provides satisfactory results for appropriately selected recipients.
Miyagawa et al13 reported on LDLT using the left liver grafts including the left-side caudate lobe (the Spiegel lobe and the left side of the paracaval portion of the caudate lobe). Takayama et al.14 designed a similar procedure with direct anastomosis to the vena cava of the hepatic vein from the caudate lobe. The caudate lobe corresponds to only 3% to 4% of the whole liver volume. In conjunction with a left liver graft, however, the caudate lobe increases the graft weight by 8% to 12%.
Fifty-six percent of the patients in the University of Tokyo program received a left liver or left liver with caudate lobe graft with patient and graft 5-year-survival rates of 82% and 84%, respectively.15 The strategy for selection of left or right liver graft, is influenced by the patient's preoperative condition,16 as patients with advanced liver disease require a larger liver mass. The model for end-stage liver disease score17 could become a satisfactory criterion for differentiating between high- and low-risk patients and therefore to determine the type of graft to use.
Extended Right Liver Graft
Use of right liver grafts has had a large impact on the results of adult LDLT. The Hong Kong group was the first to transplant a right liver graft including reconstruction of the middle hepatic vein (MHV) in 1996,18 terming it an extended right liver graft. The outcome of the initial 8 donors and recipients were not without complications. One recipient died, and the recipients as well as the donors experienced high morbidity. The next 92 patients subsequently received extended right liver grafts with the following innovations: elimination of veno-venous bypass from the routine protocol, preservation of segment IV venous drainage in the donor, venoplasty of MHV and right hepatic vein into a single orifice for better venous return and easy vein reconstruction in recipients,19 and preservation of blood supply to the right hepatic ducts. Over time, the mortality rate of the recipients decreased from 16% in the initial 50 cases to 0% in 50 more recent patients.
Right Liver Graft
In 1998, the University of Colorado group20 introduced the right liver graft without reconstruction of the MHV trunk in adult LDLT. From January 1997 until July 2003, the group performed 80 adult LDLTs. In the first 10 cases, in which the MHV branches of the graft were not preserved, 3 grafts were lost. Based on the group's preliminary experience, the resection line of the graft in the donor was moved to the left to preserve the MHV branches and their connections with the right hepatic vein (RHV).21 The new transsection line was set between the right border of the MHV and the left margin of the gallbladder bed. In the subsequent 70 cases, no graft loss due to venous congestion was experienced.
Right Lateral Sector Graft
The small graft problem related to the left liver graft has been overcome by the use of a right liver graft. Right hepatectomy, however, imposes an increased surgical risk on the donor, due to the reduced residual liver volume. Fan and associates8 concluded that safe donation was possible only when the estimated residual liver volume was over 30%. A recent report indicated that in 25% of the potential donors the right liver had an estimated volume of more than 70% of the whole.22 Thus, based on these volumetric considerations, right hepatectomy is not possible for some potential donors.
The University of Tokyo group was the first to design the right lateral sector graft, consisting of segments VI and VII.23 The indication for harvesting this type of graft includes a right liver of over 70% of the estimated total donor liver volume, while the estimated volume of the 2 right lateral sectors is greater than that of the left liver. In addition, this graft needs to be larger than 40% of the recipient's standard liver volume. Between January, 2000, and April, 2001, 6 of 32 adult-to-adult LDLTs with a right lateral sector graft24 were performed at our institution. The postoperative course was uneventful in all donors. All recipients survived the operation. Three patients experienced bile leakage from the dissection plane of the graft. By January, 2004, 16 adult patients had received right lateral sector grafts, and 15 patients were still alive, with normal graft function.
From a technical point of view, careful attention must be paid to transecting the bile duct of the right lateral sector. When the right lateral duct enters the common bile duct separately (caudal right lateral duct), the duct is divided at its origin. Otherwise, after the right portal branch is dissected first and pulled cranially, the right lateral duct is dissected as far as possible from surrounding connective tissues.
Lee et al. were the first to devise dual grafts from two living donors.25 Most commonly, both donors donate the left liver or left lateral segments, although various combinations of graft types can be used.26 The first left liver graft is orthotopically implanted at the original left position. The second left liver graft is rotated 180 degrees and positioned heterotopically in the right upper quadrant fossa. Modifications in the surgical technique are needed for implantation of the second graft. Because the bile duct is now located behind the portal vein and the hepatic artery, bile duct reconstruction is necessary before reconstruction of the vessels. An interposition vein graft might be necessary for the reconstruction of the hepatic or portal vein, because the second left liver graft is too small to bridge the distance between the hepatic and portal veins. By the end of 2003, this technique was used in 93 patients with satisfactory results. Also, the Kyoto group has implanted dual grafts in 1 adult patient.27 However, the procedure has limited appeal due to the high requirements of economic and medical resources: 3 operating rooms and 3 surgical teams are required simultaneously. Therefore, liver transplantation using dual grafts is clearly technically demanding and not widely performed around the world.
MHV Reconstruction in Right Liver Graft
A right liver graft without the MHV trunk can cause severe congestion of the right paramedian sector. However, a strategy to prevent such congestion or the necessity to reconstruct the MHV has not been discussed in detail.
In the meeting, Igal Kam et al. reported that only 2 of 70 patients who received a right liver graft without the MHV trunk required reconstruction of the MHV tributaries. Their research stated that, in general, the MHV can be ligated during the procurement of right liver graft, as connecting the MHV to the vena cava is unnecessary. They emphasized that reconstruction of the MHV is mainly indicated when right hepatic vein of the graft is small. This policy might50 affect the selection of the potential recipients of the right hemiliver graft. Whole liver grafts from deceased donors can be used for poor-risk patients, while hemiliver grafts from living donors can be used for good-risk patients who can tolerate lesser parenchymal liver mass.
In contrast, Lee et al. aggressively reconstructed the MHV tributaries in right liver grafts without the MHV trunk and named this type of graft a modified right liver graft.28 As it is difficult to predict the degree of right paramedian sector congestion, they recommended routine reconstruction of MHV tributary veins. Ghobrial et al.29 also recommended reconstruction of the MHV tributary veins when RHV in graft was less than 1.5 cm in diameter. From July, 1997, to February, 1998, 2 of 5 right lobe grafts without MHV drainage reconstruction were complicated with severe congestion of the paramedian sector. Since then, 42 adult recipients, who received right liver grafts with fairly sized MHV tributaries, underwent reconstruction of these veins.30 All MHV tributaries with a size of >5 mm were preserved during donor hepatectomy and were reconstructed with the autogenous interposition vein grafts of the recipient during bench surgery.
It remains unclear whether all modified right liver grafts require MHV drainage. Sano et al.31 proposed clear criteria for MHV reconstruction. During the donor operation, hepatic venous congestion in the right paramedian sector was investigated after transsection of the liver parenchyma. First, liver surface discoloration in the right paramedian sector was observed after 5 minutes of simultaneous clamping of MHV tributaries and the right hepatic artery. Next, intra-operative Doppler ultrasonography was performed after declamping only the hepatic artery. If the portal flow of the paramedian sector was found to be hepatofugal, the area was considered congested. If the congestive area was significant, as determined by the clamping test and ultrasonography, bench reconstruction of MHV tributaries was performed. Using these criteria, we performed MHV reconstruction in 18 of 30 grafts, resulting in an uneventful functional recovery of all grafts.32 The necessity of short hepatic vein reconstruction can be determined using the same criteria.
Biliary reconstruction remains a significant source of morbidity in liver transplantation, with a complication rate of 6% to 47%. Complications include anastomotic leakage and stenosis, problems related with T or stent tubes, and rarely, nonanastomotic strictures or intrahepatic bilomas. These complications can lead to cholangitis, sepsis, and eventually retransplantation and death. Therefore, due to the diminished functional reserve of the hemiliver graft, it might lead to serious complications in adult LDLT.
Initially, the type of biliary anastomosis commonly used in LDLT was the hepaticojejunostomy. Kiuchi and colleagues33 were the first to report preliminary results of duct-to-duct biliary reconstruction in adult LDLT. Now duct-to-duct biliary reconstruction is enthusiastically performed in a growing number of programs.34–39 The reports advocate the advantages of duct-to-duct biliary reconstruction over hepaticojejunostomy, such as an aseptic surgical field and shorter duration for reconstruction. The physiologic bilioenteric circulation and bowel continuity can also be preserved, preventing delayed peristalsis. Duct-to-duct reconstruction allows easy endoscopic access to the biliary tree for diagnostic and therapeutic instrumentation and management. For the management of biliary stenosis, the duct-to-duct anastomosis is usually converted to the hepaticojejunostomy. However, the Kyoto group40 recently reported that 13 of 14 patients were successfully treated with an internal stent. The endoscopic approach appears to be a therapeutic alternative to reoperation. However, the follow-up period in these patients is still short. Long-term postoperative observation is necessary to confirm the safety and feasibility of this procedure.
Viral Hepatitis and Hepatocellular Carcinoma
Hepatitis B Virus
The results of liver transplantation in patients with hepatitis B (HBV) have improved significantly as a result of the rapid evolution in strategies for postoperative prophylaxis. Hepatitis B immunoglobulin, which is costly, was the first effective prophylactic agent. Lamivudine monotherapy prevents emergence of viral mutants. Now, combination therapy with hepatitis B immunoglobulin and lamivudine has become a widely adopted approach. Other nucleotide analogs, such as adefovir, are promising alternative agents.
The HBV prophylactic regimen at Queen Mary Hospital in Hong Kong consists of lamivudine monotherapy,41, 42 while adefovir is reserved for breakthrough reinfection after transplantation. Lo et al. performed 180 liver transplants for HBV-positive patients (120 LDLT and 60 grafts from deceased donors). The 5-year cumulative mutant-free survival was 86%. In contrast, the Tokyo University group43 presented satisfactory results of LDLT for HBV (n = 20) using hepatitis B immunoglobulin monotherapy. The use of lamivudine was limited to the perioperative period to avoid generating mutants.
One recent report of active production of HBV-antibodies after liver transplantation suggests the possibility of adoptive transfer of immunity against HBV through a liver graft from an immune donor.44 Active immunization with standard hepatitis B vaccines was recently reported, with conflicting results.45
Hepatitis C Virus
Early experience suggested rapid and severe recurrence of hepatitis C (HCV) following adult LDLT. Ghobrial et al.46 reported that the time interval to HCV recurrence (n = 11) was significantly shorter in LDLT patients than in patients who received grafts from deceased donors (n = 510). The University of Colorado group47 reported that serum alanine aminotransferase and total bilirubin levels increased more rapidly after the operation in LDLT patients (n = 24) than in cadaveric graft recipients (n = 41). In addition, LDLT patients had greater serum aspartate aminotransferase levels at 1, 3, and 6 months, compared with a matched group of cadaveric controls.48
Gaglio et al.49 reported that the overall incidence of severe sequelae of hepatitis C recurrence—either cholestatic hepatitis, grade III-IV inflammation, and/or hepatitis C–induced graft failure requiring retransplantation—were not different between cadaveric grafts (n = 45) and those grafts from living liver donors (n = 23). However, the morbidity of cholestatic hepatitis C was more severe in LDLT patients (0% vs. 17%, respectively; P = .001). These preliminary reports indicate that more intensive antiviral therapy might be necessary for recipients of living donor grafts. All of these reports, however, have some limitations, which include small numbers of patients, lack of standard virologic evaluation, and short-term follow-up. The results must be confirmed in larger, multicenter studies.
LDLT is an established therapeutic option for patients with hepatocellular carcinoma. From 1990 to the end of 2002, LDLT for hepatocellar carcinoma was performed in 225 cases in Japan.
Prof. Furukawa from the Hokkaido University reported in the Tokyo meeting that 160 patients were alive, with a recurrence rate of 5%, while 65 patients were dead, with a recurrence rate of 32%. Multivariate analysis revealed that alpha-fetoprotein levels, tumor size, and invasion of hepatic and portal veins are significant predictors for outcome. When the subjects were categorized into two groups (patients meeting the Milan criteria, and those beyond), difference both in patient and recurrence-free survival reached significance (76% vs. 52%, respectively; P = .001; and 76% vs. 50%,respectively; P = .001).
During the 10-year period, many technical innovations have been developed for LDLT, contributing to a better patient outcome. LDLT was originally devised and performed in countries where organs from deceased donors are extremely scarce. The contributions made by Asian countries with regard to the design of several graft types, including left liver graft with caudate lobe, right liver, modified right liver, and right lateral sector grafts, are noteworthy. A recent review by Grewal,50 however, has failed to acknowledge the significant Asian contribution to LDLT.
In LDLT, the physical and psychological sacrifice by the donor is significant and is associated with high expectations regarding a good outcome for themselves and the recipient. We should not be satisfied with the present outcome and need to strive to achieve 0% donor mortality.15 Firm criteria for graft selection and further technical advances will be helpful in reaching this goal.