REVIEW URRENT C OPINION
Living donor liver transplantation Gi-Won Song and Sung-Gyu Lee
Purpose of review Living donor liver transplantation (LDLT) continues to evolve, generating interesting issues on the applicability and safety of new techniques. Recent findings Specific selection criteria and standardized surgical techniques with high ethical and medical standards are needed to minimize donor risk. In this aspect, minimally invasive donor hepatectomy has caused controversies. The reproducibility and safety of pure laparoscopic major hepatectomy in LDLT remains uncertain. Therefore, a stepwise approach is needed to avoid unnecessary donor risk. To expand the living donor pool, dual graft and ABO-incompatible LDLT have emerged as well tolerated and effective methods. The extended selection criteria for hepatocellular carcinoma in LDLT appear acceptable to balance donor risk and recipient outcome. However, these criteria should be validated based on the risk–benefit ratio. Despite technical advances, technical challenges persist such as Budd–Chiari syndrome and portal vein thrombosis. To address these issues, several innovative surgical techniques have been proposed and have shown promising results. Summary LDLT is associated with donor safety concerns, technical complexity, and small-for-size issues. Nonetheless, accumulated experience and technical know-how from large-volume Asian LDLT centers have led to progress in LDLT. Further technical refinement and investigation to overcome the disadvantages of partial grafts will broaden the applicability of LDLT. Keywords current innovation, liver transplantation, living donor, outcome
INTRODUCTION
DONOR SAFETY ISSUES
In countries with a scarcity of deceased donor liver graft, the availability of deceased donor liver transplantation (DDLT) is always a short of recipient’s demand, hence living donor liver transplantation (LDLT) has a crucial role in the relief of donor shortage [1]. Unfortunately, LDLT is a more complicated procedure than DDLT, mainly because of its technical complexity and different physiological requirements resulting from regeneration of a partial graft. Moreover, donor safety continues to be a major hurdle in LDLT. Despite these issues, current recipient and donor outcomes have become acceptable with the establishment of standardized surgical techniques as well as a better understanding of the anatomical variations, and hemodynamic properties of partial graft regeneration. Furthermore, despite established guidelines to address various technical and ethical issues, LDLT continues to evolve based on new data, especially in adult LDLT (ALDLT). In this review, we discuss the current innovations in ALDLT, focusing on technical advances and emerging issues that may expand its application.
LDLT is with a low but definite donor risk, which has been extensively reported in the literature [2,3]. Furthermore, since the adoption of right lobe graft for ALDLT by a Hong Kong group [4], there have been concerns about donor death or moribund morbidity following major hepatectomy (Hx) in living donors. Interestingly, living donor deaths have generated far more media coverage and public attention than other medical complications, the consequences of which have affected LDLT programs worldwide. According to a recent worldwide survey on living donor risk by Cheah et al. [5 ], the overall donor mortality and morbidity rates were &&
Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Correspondence to Sung-Gyu Lee, MD, PhD, FACS, 88 Olympic-Ro, 43-Gil, Songpa-Gu, Seoul 138-736, Korea. Tel: +82 2 3010 3485; fax: +82 2 474 9027; e-mail: [email protected] Curr Opin Organ Transplant 2014, 19:217–222 DOI:10.1097/MOT.0000000000000088
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KEY POINTS LDLT has replaced deceased donor liver transplantation despite technical complexity in Asian countries with the scarcity of deceased donor organ. To minimize the risk in living donor, all LDLT programs must establish institutional protocols and standardized guidelines based on the highest ethical and medical standards. For the expansion of donor pool without the additional donor risk, dual graft and ABO-incompatible LDLT are effective and well tolerated methods. The extended criteria of LDLT for HCC require further investigations and validations. LDLT is still evolving. Continuous technical advances and challenges are enabling us to overcome the technical obstacles in LDLT.
0.2 and 24%, respectively, with the majority of deaths involving right lobe donors. Interestingly, technical experience has no impact on the incidence of living donor morbidity or mortality, indicating that donor Hx carries significant risk even with experienced surgeons. Therefore, all LDLT surgeons attempt to accurately evaluate each case and operate on the living donor with extreme caution. In addition, all LDLT programs must establish institutional protocols and standardized guidelines based on the highest ethical and medical standards to minimize living donor risk. Each LDLT center has developed its own evaluation criteria and selection protocol for living donor candidates, however differences exist between centers in the components considered. There is a consensus that remnant liver volume (RLV), degree of steatosis, and donor age are the most important determining factors for donor safety. The right lobe is regarded as the most suitable graft type in terms of recipient outcome. However, right Hx is not always well tolerated and, compared with left-Hx, is associated with a potentially higher risk depending on the RLV. Kubota et al., using computed tomography volumetry, showed that individuals with normal liver function can tolerate resection of up to 60% of their non-tumorous liver [6]. Furthermore, in a clinical study of living donors, a Hong Kong group showed that 27% of total liver volume (TLV) is the lowest limit of RLV that guarantees survival of a nonfatty liver [7]. Therefore, most LDLT programs accept 30% TLV to allow a safety margin for minimal RLV. In addition, steatosis is associated with a high risk of post-Hx morbidity and mortality of living 218
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donor in LDLT. Steatosis affects hepatocyte function and impairs regeneration after major Hx. Several studies have reported that hepatic steatosis itself is a risk factor and has an important impact on outcome and even mortality [8 ]. However, there are no universal guidelines for the acceptable range of steatosis in LDLT. In general, donor candidates with hepatic steatosis of more than 30% are rejected for right lobe donation because of donor safety. By contrast, candidates with high BMI and liver fat can donate their right lobe after weight loss [9]. Since the first pediatric LDLT in Korea in December 1994, we have performed over 3000 cases of LDLT. Since 2010, we have performed more than 300 LDLT cases each year. In an analysis of graft type in 3372 grafts from December 1994 to December 2012, 85% were right lobe. In our program, we have had no cases of donor mortality, although we have experienced six cases with serious complications, including bleeding from the right hepatic artery stump and hilar plate, and pulmonary thromboembolism. In the early stage of our LDLT program, the morbidity rate of right lobe donors was 10.7%. Through meticulous and innovative surgical techniques, as well as increased experience-based knowhow, donor complications are generally avoided or overcome. In addition, careful selection of right lobe graft donors according to specific guidelines probably contributes to a reduction in donor complications. In our institution, the selection criteria for right lobe grafts are similar to those of other LDLT centers. However, procurement of right lobe grafts is allowed from candidates aged more than 35 years only if the RLV is estimated to be greater than 35% of the TLV. Since 2002, the perioperative annual major donor morbidity rate (Claviens classification grades II and III) declined from 6.7 to 1.3% [10]. &
MINIMALLY INVASIVE DONOR HEPATECTOMY Laparoscopic (LAP) approaches in hepatobiliary surgery, mainly used for non-malignant disease, have proven to be feasible and effective to reduce the invasiveness of surgery and maximize early recovery of the patient. Cherqui et al. [11] described LAP left lateral sectionectomy (LLS) for pediatric LDLT. The safety and reproducibility of LAP donor LLS has been shown in several studies [12,13]. Over the past decade, however, there have been remarkable improvements in surgical techniques and instruments for LAP procedures. Hence, we adopted a hybrid technique for right lobe donor Hx, utilizing LAP mobilization of the liver, followed by completion of parenchymal transection through a small Volume 19 Number 3 June 2014
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Living donor liver transplantation Song and Lee
upper midline or right subcostal incision [14]. Furthermore, several experienced centers for LAP Hx recently reported their successful experiences with pure LAP major Hx (left or right hemi-Hx) in living donor [15,16 ]. In kidney transplantation, the benefit of LAP nephrectomy in living donor was shown in a recent meta-analysis [17,18]. Although several reports of successful cases have provided supporting evidence for LAP donor major Hx, the reproducibility and risk–benefit balance remains under question. Despite technical advances, there are certain safety issues with pure LAP Hx [19,20 ], such as concerns of graft injury during mobilization or procurement. Furthermore, immediate damage control for accidental injuries to large vessels during the procedure, which can occasionally occur in open surgery, can be limited by poor visualization or difficulty in the handling of instruments. Although a few cases of gas embolism have been reported, the impact of pneumoperitoneum and long operation time on donors receiving LAP major Hx requires further investigation. From a technical perspective, the transection of the bile duct as well as maintenance of the right plane of transection may be important issues that require further development, especially in donors with vascular or biliary anatomical variations. It is obvious that there will be a learning curve before LAP can be used as a standard technique. Therefore, although LAP liver surgery appears promising, the complexity of the procedure may limit its applicability [21]. &
&
EXPANSION OF LIVE LIVER DONOR POOL As the deceased donor pool is a limited public resource, donor selection criteria for DDLT have been widened to accept marginal donors in an attempt to balance supply and demand. However, donor selection criteria for LDLT need to be stricter to avoid unnecessary donor risk. Liver volume discrepancy between right lobe and left lobe in donors is a major reason for donor rejection in LDLT. Leelaudomlipi et al. [22] reported that 25% of donor candidates had a greater than 70% volume ratio of right lobe to TLV. In such candidates, the right lobe cannot be allowed because of donor safety and the left lobe is too small to meet the metabolic demand of an adult recipient. To overcome these issues, several technical innovations in grafting have been introduced, but their impact on living donor pool expansion has proven minimal [23–25]. To cope with this issue, Lee et al. introduced dual graft LDLT, which provides sufficient graft volume without additional donor risk [26]. If right lobe donation is not possible and the left liver is too small, left liver grafts are procured from two living donor and are
then implanted into one recipient. In such cases, two left lobe grafts are usually implanted, although various other combinations have also been used. Despite the promising potential of this technique, expansion of the living donor pool using dual graft LDLT is limited because of the technical complexity and higher demands of manpower and facilities. Nonetheless, the indications for and survival outcomes of dual graft LDLT are similar to those of single right lobe LDLT [27]. Therefore, several centers have adopted this procedure and reported successful experiences [28–30]. ABO-incompatible (ABOi) LDLT is another efficacious alternative to overcome the current issues in organ availability. However, the initial outcome of ABOi liver transplantation has been very disappointing. Despite these findings, ABOi LDLT is an inevitable alternative because of the lack of deceased donors in Asian countries [31]. Local infusion therapy involving the direct infusion of anti-inflammatory agents into the graft via a catheter placed in the hepatic artery or portal vein has improved the survival rates of ABOi LDLT, even in adult patients, with an increase in 3-year survival rate from 27 to 56% [32,33]. Furthermore, since Usuda et al. [34] first reported the use of rituximab in ABOi LDLT in 2005, the paradigm of ABOi LDLT in adult patients has dramatically changed. Egawa et al. [35] reported that the 3-year survival rate of ABOi adult LDLT increased to as much as 70% after the introduction of rituximab. According to the latest Japanese multicenter study, the incidence of antibody-mediated rejection dropped from 23.5 to 6.3% with the use of rituximab [36 ]. In our institution, we used a paired donor exchange program to overcome the ABOblood group barrier, but the rate of successful matching was lower than expected. Between July 2003 and June 2009, 16 donor exchanges were performed among 1351 cases of ALDLT at our institution [37]. Several factors, such as the resources and manpower needed to perform two simultaneous LDLT operations, balancing recipient outcome and donor safety, and cultural background issues of the donors (taking into account any consanguinity) limited the application of the donor exchange program. Therefore, we initiated an adult ABOi LDLT program in November 2008, which has shown successful outcomes [38]. Over 4 years, 1207 cases of ALDLT including 161 (13.1%) cases of ABOi have been performed. The annual number of adult ABOi LDLT cases is increasing and has made up over 20% of the total annual number of ALDLT cases in our institution since 2012. The 3-year graft and patient survival rates were 90.9 and 96.3%, respectively (unpublished data). Therefore, we can confidently claim on the basis of our recent success rates that ABOi living
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donor transplant is an effective means to expand the living donor pool.
LIVING DONOR LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA: FEASIBILITY OF EXPANDED INCLUSION CRITERIA The Milan criteria or University of California at San Francisco criteria have served as the gold standard for validation of other selection criteria of liver transplantation for hepatocellular carcinoma (HCC) [39,40]. However, these criteria are based on DDLT and focus on maximizing efficacy using limited social resources. For this reason, these guidelines have been criticized for being overly strict and limiting the use of liver transplantation for patients with HCC. Furthermore, liver grafts for LDLT are not considered as a public resource, but rather as a private gift. Therefore, most Asian LDLT centers have challenged these criteria, citing comparable long-term survival outcomes using more expanded selection criteria for HCC [41–45]. However, whether these new criteria can replace the Milan criteria remains under debate. To enable the expanded criteria to reasonably predict the risk of recurrence, it is necessary to validate the criteria through well designed multicenter studies in large patient cohorts. Although LDLT surgeons are in increasing need of expanded criteria for HCC in clinical practice, a cautious selection approach based on qualified risk–benefit analyses should be used. The development of new effective adjuvant treatments to be used before or after liver transplantation may allow further expansion of the selection criteria without incurring an increase in recurrence rate.
TECHNICAL CHALLENGES IN LIVING DONOR LIVER TRANSPLANTATION RECIPIENTS In most Asian countries, the high demand for LDLT is a powerful driver for the development of numerous technical innovations to overcome anatomical barriers in partial graft liver transplantation. Despite recent advances, technical challenges persist because of anatomical conditions, such as Budd–Chiari syndrome (BCS) or extensive portal vein thrombosis (PVT). Liver transplantation for BCS is indicated for patients with decompensated liver cirrhosis due to hepatic venous obstruction leading to liver congestion and progressive liver fibrosis. In contrast with DDLT, additional surgical techniques are needed to create a new orifice for implantation of the partial graft in LDLT. Yamada et al. [46] introduced an 220
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innovative surgical technique using cavoplasty with various vein grafts. Another option to allow venous outflow in LDLT for BCS is the replacement of the diseased retrohepatic inferior vena cava (IVC) with a cryopreserved IVC or autologous vein graft [47,48]. However, the availability of homografts is a limitation to those procedures. Moon et al. [49] described a technique that involves replacing the diseased retrohepatic vena cava with a large-caliber synthetic graft, which is placed between the right atrium and the infra-hepatic IVC without the need for a cardiopulmonary bypass. LDLT for patients with PVT is technically demanding and is usually complicated by extensive collaterals around the obliterated portal vein as well as significant intraoperative blood loss. Therefore, for such cases, it is important to generate a precise surgical plan based on sufficient information on the portal vein and portosystemic collaterals. The Kyoto group suggested a well organized operative strategy including thrombectomy and venoplasty for PVT according to the location and extent of PVT [50]. However, thrombectomy for longstanding PVT is associated with a significant risk of uncontrollable bleeding. To avoid accidentally tearing the portal vein during thrombectomy, the use of a hybrid technique combing thrombectomy and portal vein stent insertion by intraoperative portography, especially in stenosis of intra-pancreatic portal vein, may be appropriate [51]. In cases of extensive PVT, extra-anatomical portal vein anastomosis is a feasible alternative. Co-existing large porto-systemic collaterals can be used for portal vein inflow [52,53,54 ]. A jumping graft from the SMV or any available splanchnic vein is an alternative method for complete occlusion of the main portal vein. In cases of thrombosis of the entire splanchnic venous system without any sizable posto-systemic collateral, porto-caval hemitransposition can be applied in DDLT, however the feasibility of this approach needs validation because LDLT requires adequate portal flow for the regeneration of a partial graft. &
BILIARY COMPLICATION IN LIVING DONOR LIVER TRANSPLANTATION Despite technical advances in LDLT, the high incidence of biliary complication remains the most intractable problem associated with LDLT. Biliary complication might reflect the anatomical and physiological limitations associated with ALDLT, such as multiple or small-sized graft duct openings, arterial hypoperfusion of the liver graft secondary to portal hypertension, edematous bowel loops, and poor blood supply to bile duct [55,56]. A previous study that included a large number of ALDLT at a Volume 19 Number 3 June 2014
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single institute showed a considerably higher frequency of biliary complications, with 1, 3, and 5-year biliary complication rates of 12.9, 18.2, and 20.2%, respectively [57]. There have been numerous studies that aimed to elucidate the risk factor for biliary complication in LDLT. However, it is very difficult to verify the real impact of technical factors in biliary complications of LDLT because there are many perturbed variables in the surgical field. Technical factors such as biliary drainage tube (use or not), suture material (absorbable or nonabsorbable), suture method (interrupted or continuous), among others might be of less importance to account for biliary complications. To minimize the risk of biliary complication in LDLT, therefore, the maintenance of fundamental principles of surgical anastomosis such as minimal tension, regular intervals between suture bites, accurate approximation of mucosa, and avoidance of injury or trauma to bile duct epithelium is of supreme importance. From that prospective, Lin et al. [58] reported the excellent results of routine microsurgical biliary anastomosis in LDLT. In addition, the preservation of blood supply to anastomosis is also important to prevent late biliary stricture [59]. Unnecessary excessive dissection around donor hepatic duct should be avoided. During recipient hepatectomy, connective tissue around the native common duct was preserved to maintain the ascending axial vascular circulation for successful duct-to-duct anastomosis.
CONCLUSION With the establishment of reasonable selection criteria and continuous technical refinement, LDLT has replaced DDLT in most Asian countries. The expansion of LDLT in Asia has been mainly driven by technical advances that overcome technical and anatomical obstacles and promote donor availability. Although technical and safety issues persist, minimally invasive donor Hx may play a role in LDLT after the clarification of the limit and advantages. Based on acceptable survival outcomes, LDLT can be expanded to the treatment of HCC, especially for HCC cases that do not meet the Milan criteria. A future understanding of hemodynamic and immunological characteristics of partial graft liver transplantation is required to further expand the applicability of LDLT. Acknowledgements None. Conflicts of interest The authors of this study declare no conflicts of interest.
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Liver transplantation 27. Lee SG, Hwang S, Kim KH, et al. Toward 300 liver transplants a year. Surg Today 2009; 39:367–373. 28. Lu CH, Chen TY, Huang TL, et al. Regeneration and outcome of dual grafts in living donor liver transplantation. Clin Transplant 2012; 26:E143–E148. 29. Dayangac M, Taner CB, Akin B, et al. Dual left lobe living donor liver transplantation using donors unacceptable for right lobe donation: a case report. Transplant Proc 2010; 42:4560–4563. 30. Soejima Y, Taketomi A, Ikegami T, et al. Living donor liver transplantation using dual grafts from two donors: a feasible option to overcome small-for-size graft problems? Am J Transplant 2008; 8:887–892. 31. Raut V, Uemoto S. Management of ABO-incompatible living-donor liver transplantation: past and present trends. Surg Today 2011; 41:317–322. 32. Tanabe M, Shimazu M, Wakabayashi G, et al. Intraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation. Transplantation 2002; 73:1959–1961. 33. Nakamura Y, Matsuno N, Iwamoto H, et al. Successful case of adult ABOincompatible liver transplantation: beneficial effects of intrahepatic artery infusion therapy: a case report. Transplant Proc 2004; 36:2269–2273. 34. Usuda M, Fujimori K, Koyamada N, et al. Successful use of anti-CD20 monoclonal antibody (rituximab) for ABO-incompatible living-related liver transplantation. Transplantation 2005; 79:12–16. 35. Egawa H, Teramukai S, Haga H, et al. Present status of ABO-incompatible living donor liver transplantation in Japan. Hepatology 2008; 47:143–152. 36. Egawa H, Teramukai S, Haga H, et al. Impact of rituximab desensitization on & blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study. Am J Transplant 2014; 14:102–114. This multicenter study analyzed the impact of rituximab on the survival outcome of ABO-incompatible LDLT. 37. Hwang S, Lee SG, Moon DB, et al. Exchange living donor liver transplantation to overcome ABO incompatibility in adult patients. Liver Transpl 2010; 16:482–490. 38. Song GW, Lee SG, Hwang S, et al. Successful experiences of ABOincompatible adult living donor liver transplantation in a single institute: no immunological failure in 10 consecutive cases. Transplant Proc 2013; 45:272–275. 39. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334:693–699. 40. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33:1394–1403. 41. Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008; 14:935–945. 42. Ito T, Takada Y, Ueda M, et al. Expansion of selection criteria for patients with hepatocellular carcinoma in living donor liver transplantation. Liver Transpl 2007; 13:1637–1644. 43. Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis 2007; 25:310–312.
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44. Zheng SS, Xu X, Wu J, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experiences. Transplantation 2008; 85:1726–1732. 45. Ng KK, Lo CM, Chan SC, et al. Liver transplantation for hepatocellular carcinoma: the Hong Kong experience. J Hepatobiliary Pancreat Sci 2010; 17:548–554. 46. Yamada T, Tanaka K, Ogura Y, et al. Surgical techniques and long-term outcomes of living donor liver transplantation for Budd-Chiari syndrome. Am J Transplant 2006; 6:2463–2469. 47. Yan L, Li B, Zeng Y, Wen T, et al. Living donor liver transplantation for Budd– Chiari syndrome using cryopreserved vena cava graft in retrohepatic vena cava reconstruction. Liver Transpl 2006; 12:1017–1019. 48. Shimada M, Marubashi S, Dono K, et al. Utilization of autologous vein graft for replacement of the inferior vena cava in living-donor liver transplantation for obliterative hepatocavopathy. Transpl Int 2007; 20:804–807. 49. Moon DB, Lee SG, Hwang S, et al. More than 300 consecutive living donor liver transplants a year at a single center. Transplant Pro 2013; 45:1942– 1947. 50. Egawa H, Tanaka K, Kasahara M, et al. Single center experience of 39 patients with preoperative portal vein thrombosis among 404 adult living donor liver transplantations. Liver Transpl 2006; 12:1512–1518. 51. Kim YJ, Ko GY, Yoon HK, et al. Intraoperative stent placement in the portal vein during or after liver transplantation. Liver Transpl 2007; 13:1145– 1152. 52. Kato T, Levi DM, DeFaria W, et al. Liver transplantation with renoportal anastomosis after distal splenorenal shunt. Arch Surg 2000; 135:1401– 1404. 53. Moon DB, Lee SG, Ahn CS, et al. Side-to-end renoportal anastomosis using an externally stented polytetrafluoroethylene vascular graft for a patient with a phlebosclerotic portal vein and a large spontaneous splenorenal shunt. J Am Coll Surg 2011; 212:e7–e11. 54. Moon DB, Lee SG, Ahn CS, et al. Restoration of portal flow using pericho& ledochal varix in adult living donor liver transplantation for total portosplenomesenteric thrombosis patients. Liver Transpl . [Epub ahead of print] This article gave us very interesting and useful ideas for the restoration of portal flow in the patient with total in press portosplenomesenteric thrombosis and large pericholedochal varix. 55. Chan SC, Fan ST. Biliary complications in liver transplantation. Hepatol Int 2008; 2:399–404. 56. Wang SF, Huang ZY, Chen XP. Biliary complications after living donor liver transplantation. Liver Transpl 2011; 17:1127–1136. 57. Hwang S, Lee SG, Sung KB, et al. Long-term incidence, risk factors, and management of biliary complications after adult living donor liver transplantation. Liver Transpl 2006; 12:831–838. 58. Lin TS, Concejero AM, Che CL, et al. Routine microsurgical biliary reconstruction decreases early anastomotic complications in living donor liver transplantation. Liver Transpl 2009; 15:1766–1775. 59. Liu CL, Lo CM, Chan SC, et al. Safety of duct-to-duct biliary reconstruction in right-lobe live-donor liver transplantation without biliary drainage. Transplantation 2004; 77:726–732.
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Living donor liver transplantation Gi-Won Song and Sung-Gyu Lee
Purpose of review Living donor liver transplantation (LDLT) continues to evolve, generating interesting issues on the applicability and safety of new techniques. Recent findings Specific selection criteria and standardized surgical techniques with high ethical and medical standards are needed to minimize donor risk. In this aspect, minimally invasive donor hepatectomy has caused controversies. The reproducibility and safety of pure laparoscopic major hepatectomy in LDLT remains uncertain. Therefore, a stepwise approach is needed to avoid unnecessary donor risk. To expand the living donor pool, dual graft and ABO-incompatible LDLT have emerged as well tolerated and effective methods. The extended selection criteria for hepatocellular carcinoma in LDLT appear acceptable to balance donor risk and recipient outcome. However, these criteria should be validated based on the risk–benefit ratio. Despite technical advances, technical challenges persist such as Budd–Chiari syndrome and portal vein thrombosis. To address these issues, several innovative surgical techniques have been proposed and have shown promising results. Summary LDLT is associated with donor safety concerns, technical complexity, and small-for-size issues. Nonetheless, accumulated experience and technical know-how from large-volume Asian LDLT centers have led to progress in LDLT. Further technical refinement and investigation to overcome the disadvantages of partial grafts will broaden the applicability of LDLT. Keywords current innovation, liver transplantation, living donor, outcome
INTRODUCTION
DONOR SAFETY ISSUES
In countries with a scarcity of deceased donor liver graft, the availability of deceased donor liver transplantation (DDLT) is always a short of recipient’s demand, hence living donor liver transplantation (LDLT) has a crucial role in the relief of donor shortage [1]. Unfortunately, LDLT is a more complicated procedure than DDLT, mainly because of its technical complexity and different physiological requirements resulting from regeneration of a partial graft. Moreover, donor safety continues to be a major hurdle in LDLT. Despite these issues, current recipient and donor outcomes have become acceptable with the establishment of standardized surgical techniques as well as a better understanding of the anatomical variations, and hemodynamic properties of partial graft regeneration. Furthermore, despite established guidelines to address various technical and ethical issues, LDLT continues to evolve based on new data, especially in adult LDLT (ALDLT). In this review, we discuss the current innovations in ALDLT, focusing on technical advances and emerging issues that may expand its application.
LDLT is with a low but definite donor risk, which has been extensively reported in the literature [2,3]. Furthermore, since the adoption of right lobe graft for ALDLT by a Hong Kong group [4], there have been concerns about donor death or moribund morbidity following major hepatectomy (Hx) in living donors. Interestingly, living donor deaths have generated far more media coverage and public attention than other medical complications, the consequences of which have affected LDLT programs worldwide. According to a recent worldwide survey on living donor risk by Cheah et al. [5 ], the overall donor mortality and morbidity rates were &&
Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Correspondence to Sung-Gyu Lee, MD, PhD, FACS, 88 Olympic-Ro, 43-Gil, Songpa-Gu, Seoul 138-736, Korea. Tel: +82 2 3010 3485; fax: +82 2 474 9027; e-mail: [email protected] Curr Opin Organ Transplant 2014, 19:217–222 DOI:10.1097/MOT.0000000000000088
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KEY POINTS LDLT has replaced deceased donor liver transplantation despite technical complexity in Asian countries with the scarcity of deceased donor organ. To minimize the risk in living donor, all LDLT programs must establish institutional protocols and standardized guidelines based on the highest ethical and medical standards. For the expansion of donor pool without the additional donor risk, dual graft and ABO-incompatible LDLT are effective and well tolerated methods. The extended criteria of LDLT for HCC require further investigations and validations. LDLT is still evolving. Continuous technical advances and challenges are enabling us to overcome the technical obstacles in LDLT.
0.2 and 24%, respectively, with the majority of deaths involving right lobe donors. Interestingly, technical experience has no impact on the incidence of living donor morbidity or mortality, indicating that donor Hx carries significant risk even with experienced surgeons. Therefore, all LDLT surgeons attempt to accurately evaluate each case and operate on the living donor with extreme caution. In addition, all LDLT programs must establish institutional protocols and standardized guidelines based on the highest ethical and medical standards to minimize living donor risk. Each LDLT center has developed its own evaluation criteria and selection protocol for living donor candidates, however differences exist between centers in the components considered. There is a consensus that remnant liver volume (RLV), degree of steatosis, and donor age are the most important determining factors for donor safety. The right lobe is regarded as the most suitable graft type in terms of recipient outcome. However, right Hx is not always well tolerated and, compared with left-Hx, is associated with a potentially higher risk depending on the RLV. Kubota et al., using computed tomography volumetry, showed that individuals with normal liver function can tolerate resection of up to 60% of their non-tumorous liver [6]. Furthermore, in a clinical study of living donors, a Hong Kong group showed that 27% of total liver volume (TLV) is the lowest limit of RLV that guarantees survival of a nonfatty liver [7]. Therefore, most LDLT programs accept 30% TLV to allow a safety margin for minimal RLV. In addition, steatosis is associated with a high risk of post-Hx morbidity and mortality of living 218
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donor in LDLT. Steatosis affects hepatocyte function and impairs regeneration after major Hx. Several studies have reported that hepatic steatosis itself is a risk factor and has an important impact on outcome and even mortality [8 ]. However, there are no universal guidelines for the acceptable range of steatosis in LDLT. In general, donor candidates with hepatic steatosis of more than 30% are rejected for right lobe donation because of donor safety. By contrast, candidates with high BMI and liver fat can donate their right lobe after weight loss [9]. Since the first pediatric LDLT in Korea in December 1994, we have performed over 3000 cases of LDLT. Since 2010, we have performed more than 300 LDLT cases each year. In an analysis of graft type in 3372 grafts from December 1994 to December 2012, 85% were right lobe. In our program, we have had no cases of donor mortality, although we have experienced six cases with serious complications, including bleeding from the right hepatic artery stump and hilar plate, and pulmonary thromboembolism. In the early stage of our LDLT program, the morbidity rate of right lobe donors was 10.7%. Through meticulous and innovative surgical techniques, as well as increased experience-based knowhow, donor complications are generally avoided or overcome. In addition, careful selection of right lobe graft donors according to specific guidelines probably contributes to a reduction in donor complications. In our institution, the selection criteria for right lobe grafts are similar to those of other LDLT centers. However, procurement of right lobe grafts is allowed from candidates aged more than 35 years only if the RLV is estimated to be greater than 35% of the TLV. Since 2002, the perioperative annual major donor morbidity rate (Claviens classification grades II and III) declined from 6.7 to 1.3% [10]. &
MINIMALLY INVASIVE DONOR HEPATECTOMY Laparoscopic (LAP) approaches in hepatobiliary surgery, mainly used for non-malignant disease, have proven to be feasible and effective to reduce the invasiveness of surgery and maximize early recovery of the patient. Cherqui et al. [11] described LAP left lateral sectionectomy (LLS) for pediatric LDLT. The safety and reproducibility of LAP donor LLS has been shown in several studies [12,13]. Over the past decade, however, there have been remarkable improvements in surgical techniques and instruments for LAP procedures. Hence, we adopted a hybrid technique for right lobe donor Hx, utilizing LAP mobilization of the liver, followed by completion of parenchymal transection through a small Volume 19 Number 3 June 2014
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Living donor liver transplantation Song and Lee
upper midline or right subcostal incision [14]. Furthermore, several experienced centers for LAP Hx recently reported their successful experiences with pure LAP major Hx (left or right hemi-Hx) in living donor [15,16 ]. In kidney transplantation, the benefit of LAP nephrectomy in living donor was shown in a recent meta-analysis [17,18]. Although several reports of successful cases have provided supporting evidence for LAP donor major Hx, the reproducibility and risk–benefit balance remains under question. Despite technical advances, there are certain safety issues with pure LAP Hx [19,20 ], such as concerns of graft injury during mobilization or procurement. Furthermore, immediate damage control for accidental injuries to large vessels during the procedure, which can occasionally occur in open surgery, can be limited by poor visualization or difficulty in the handling of instruments. Although a few cases of gas embolism have been reported, the impact of pneumoperitoneum and long operation time on donors receiving LAP major Hx requires further investigation. From a technical perspective, the transection of the bile duct as well as maintenance of the right plane of transection may be important issues that require further development, especially in donors with vascular or biliary anatomical variations. It is obvious that there will be a learning curve before LAP can be used as a standard technique. Therefore, although LAP liver surgery appears promising, the complexity of the procedure may limit its applicability [21]. &
&
EXPANSION OF LIVE LIVER DONOR POOL As the deceased donor pool is a limited public resource, donor selection criteria for DDLT have been widened to accept marginal donors in an attempt to balance supply and demand. However, donor selection criteria for LDLT need to be stricter to avoid unnecessary donor risk. Liver volume discrepancy between right lobe and left lobe in donors is a major reason for donor rejection in LDLT. Leelaudomlipi et al. [22] reported that 25% of donor candidates had a greater than 70% volume ratio of right lobe to TLV. In such candidates, the right lobe cannot be allowed because of donor safety and the left lobe is too small to meet the metabolic demand of an adult recipient. To overcome these issues, several technical innovations in grafting have been introduced, but their impact on living donor pool expansion has proven minimal [23–25]. To cope with this issue, Lee et al. introduced dual graft LDLT, which provides sufficient graft volume without additional donor risk [26]. If right lobe donation is not possible and the left liver is too small, left liver grafts are procured from two living donor and are
then implanted into one recipient. In such cases, two left lobe grafts are usually implanted, although various other combinations have also been used. Despite the promising potential of this technique, expansion of the living donor pool using dual graft LDLT is limited because of the technical complexity and higher demands of manpower and facilities. Nonetheless, the indications for and survival outcomes of dual graft LDLT are similar to those of single right lobe LDLT [27]. Therefore, several centers have adopted this procedure and reported successful experiences [28–30]. ABO-incompatible (ABOi) LDLT is another efficacious alternative to overcome the current issues in organ availability. However, the initial outcome of ABOi liver transplantation has been very disappointing. Despite these findings, ABOi LDLT is an inevitable alternative because of the lack of deceased donors in Asian countries [31]. Local infusion therapy involving the direct infusion of anti-inflammatory agents into the graft via a catheter placed in the hepatic artery or portal vein has improved the survival rates of ABOi LDLT, even in adult patients, with an increase in 3-year survival rate from 27 to 56% [32,33]. Furthermore, since Usuda et al. [34] first reported the use of rituximab in ABOi LDLT in 2005, the paradigm of ABOi LDLT in adult patients has dramatically changed. Egawa et al. [35] reported that the 3-year survival rate of ABOi adult LDLT increased to as much as 70% after the introduction of rituximab. According to the latest Japanese multicenter study, the incidence of antibody-mediated rejection dropped from 23.5 to 6.3% with the use of rituximab [36 ]. In our institution, we used a paired donor exchange program to overcome the ABOblood group barrier, but the rate of successful matching was lower than expected. Between July 2003 and June 2009, 16 donor exchanges were performed among 1351 cases of ALDLT at our institution [37]. Several factors, such as the resources and manpower needed to perform two simultaneous LDLT operations, balancing recipient outcome and donor safety, and cultural background issues of the donors (taking into account any consanguinity) limited the application of the donor exchange program. Therefore, we initiated an adult ABOi LDLT program in November 2008, which has shown successful outcomes [38]. Over 4 years, 1207 cases of ALDLT including 161 (13.1%) cases of ABOi have been performed. The annual number of adult ABOi LDLT cases is increasing and has made up over 20% of the total annual number of ALDLT cases in our institution since 2012. The 3-year graft and patient survival rates were 90.9 and 96.3%, respectively (unpublished data). Therefore, we can confidently claim on the basis of our recent success rates that ABOi living
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donor transplant is an effective means to expand the living donor pool.
LIVING DONOR LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA: FEASIBILITY OF EXPANDED INCLUSION CRITERIA The Milan criteria or University of California at San Francisco criteria have served as the gold standard for validation of other selection criteria of liver transplantation for hepatocellular carcinoma (HCC) [39,40]. However, these criteria are based on DDLT and focus on maximizing efficacy using limited social resources. For this reason, these guidelines have been criticized for being overly strict and limiting the use of liver transplantation for patients with HCC. Furthermore, liver grafts for LDLT are not considered as a public resource, but rather as a private gift. Therefore, most Asian LDLT centers have challenged these criteria, citing comparable long-term survival outcomes using more expanded selection criteria for HCC [41–45]. However, whether these new criteria can replace the Milan criteria remains under debate. To enable the expanded criteria to reasonably predict the risk of recurrence, it is necessary to validate the criteria through well designed multicenter studies in large patient cohorts. Although LDLT surgeons are in increasing need of expanded criteria for HCC in clinical practice, a cautious selection approach based on qualified risk–benefit analyses should be used. The development of new effective adjuvant treatments to be used before or after liver transplantation may allow further expansion of the selection criteria without incurring an increase in recurrence rate.
TECHNICAL CHALLENGES IN LIVING DONOR LIVER TRANSPLANTATION RECIPIENTS In most Asian countries, the high demand for LDLT is a powerful driver for the development of numerous technical innovations to overcome anatomical barriers in partial graft liver transplantation. Despite recent advances, technical challenges persist because of anatomical conditions, such as Budd–Chiari syndrome (BCS) or extensive portal vein thrombosis (PVT). Liver transplantation for BCS is indicated for patients with decompensated liver cirrhosis due to hepatic venous obstruction leading to liver congestion and progressive liver fibrosis. In contrast with DDLT, additional surgical techniques are needed to create a new orifice for implantation of the partial graft in LDLT. Yamada et al. [46] introduced an 220
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innovative surgical technique using cavoplasty with various vein grafts. Another option to allow venous outflow in LDLT for BCS is the replacement of the diseased retrohepatic inferior vena cava (IVC) with a cryopreserved IVC or autologous vein graft [47,48]. However, the availability of homografts is a limitation to those procedures. Moon et al. [49] described a technique that involves replacing the diseased retrohepatic vena cava with a large-caliber synthetic graft, which is placed between the right atrium and the infra-hepatic IVC without the need for a cardiopulmonary bypass. LDLT for patients with PVT is technically demanding and is usually complicated by extensive collaterals around the obliterated portal vein as well as significant intraoperative blood loss. Therefore, for such cases, it is important to generate a precise surgical plan based on sufficient information on the portal vein and portosystemic collaterals. The Kyoto group suggested a well organized operative strategy including thrombectomy and venoplasty for PVT according to the location and extent of PVT [50]. However, thrombectomy for longstanding PVT is associated with a significant risk of uncontrollable bleeding. To avoid accidentally tearing the portal vein during thrombectomy, the use of a hybrid technique combing thrombectomy and portal vein stent insertion by intraoperative portography, especially in stenosis of intra-pancreatic portal vein, may be appropriate [51]. In cases of extensive PVT, extra-anatomical portal vein anastomosis is a feasible alternative. Co-existing large porto-systemic collaterals can be used for portal vein inflow [52,53,54 ]. A jumping graft from the SMV or any available splanchnic vein is an alternative method for complete occlusion of the main portal vein. In cases of thrombosis of the entire splanchnic venous system without any sizable posto-systemic collateral, porto-caval hemitransposition can be applied in DDLT, however the feasibility of this approach needs validation because LDLT requires adequate portal flow for the regeneration of a partial graft. &
BILIARY COMPLICATION IN LIVING DONOR LIVER TRANSPLANTATION Despite technical advances in LDLT, the high incidence of biliary complication remains the most intractable problem associated with LDLT. Biliary complication might reflect the anatomical and physiological limitations associated with ALDLT, such as multiple or small-sized graft duct openings, arterial hypoperfusion of the liver graft secondary to portal hypertension, edematous bowel loops, and poor blood supply to bile duct [55,56]. A previous study that included a large number of ALDLT at a Volume 19 Number 3 June 2014
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single institute showed a considerably higher frequency of biliary complications, with 1, 3, and 5-year biliary complication rates of 12.9, 18.2, and 20.2%, respectively [57]. There have been numerous studies that aimed to elucidate the risk factor for biliary complication in LDLT. However, it is very difficult to verify the real impact of technical factors in biliary complications of LDLT because there are many perturbed variables in the surgical field. Technical factors such as biliary drainage tube (use or not), suture material (absorbable or nonabsorbable), suture method (interrupted or continuous), among others might be of less importance to account for biliary complications. To minimize the risk of biliary complication in LDLT, therefore, the maintenance of fundamental principles of surgical anastomosis such as minimal tension, regular intervals between suture bites, accurate approximation of mucosa, and avoidance of injury or trauma to bile duct epithelium is of supreme importance. From that prospective, Lin et al. [58] reported the excellent results of routine microsurgical biliary anastomosis in LDLT. In addition, the preservation of blood supply to anastomosis is also important to prevent late biliary stricture [59]. Unnecessary excessive dissection around donor hepatic duct should be avoided. During recipient hepatectomy, connective tissue around the native common duct was preserved to maintain the ascending axial vascular circulation for successful duct-to-duct anastomosis.
CONCLUSION With the establishment of reasonable selection criteria and continuous technical refinement, LDLT has replaced DDLT in most Asian countries. The expansion of LDLT in Asia has been mainly driven by technical advances that overcome technical and anatomical obstacles and promote donor availability. Although technical and safety issues persist, minimally invasive donor Hx may play a role in LDLT after the clarification of the limit and advantages. Based on acceptable survival outcomes, LDLT can be expanded to the treatment of HCC, especially for HCC cases that do not meet the Milan criteria. A future understanding of hemodynamic and immunological characteristics of partial graft liver transplantation is required to further expand the applicability of LDLT. Acknowledgements None. Conflicts of interest The authors of this study declare no conflicts of interest.
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