Split Liver Transplantation

Given the high wait-list mortality rate among pediatric patients with end-stage liver disease and improved understanding of segmental liver anatomy, various techniques were developed to provide reduced-size allografts with complete arterial, portal, biliary, and venous drainage. Although split-liver transplantation was initially used for deceased-donor grafts in the pediatric population, the lessons learned from split-liver transplantation have been successfully applied to live-donor liver transplantation to benefit both pediatric and adult recipients. ^[6]

In 1984, Bismuth and Houssin reported successful transplantation of a reduced-size liver in which only a portion of the donor organ was used and the remaining liver discarded. ^[7]  In reduced-size liver transplantation, the liver allograft can be tailored to the recipient's size by using various functional lobes or segments. The graft most commonly used in pediatric patients includes the left lateral segments (segments 2 and 3) and the left lobe (segments 2-4). The right lobe (segments 4-8) is rarely used in pediatric patients because it does not offer notable size advantages over whole livers. Although this technique was successful in increasing the number of pediatric transplants, it did not increase the total number of organs available for transplantation.

In 1990, Strong et al reported the first successful living-related liver transplantation for a pediatric recipient, utilizing the left lateral segment from a mother to her son. ^[8]  Broelsch and colleagues (1991) subsequently reported outcomes in 20 children receiving left lateral segments from adult living donors. Patient survival was 85%. ^[9]

Since these initial experiences, live-donor transplantation has been expanded to adult recipients and is currently the subject of a large multicenter trial by the National Institutes of Health (NIH), the Adult To Adult Living Donor Liver Donor Liver Transplantation Cohort Study (A2ALL). Advantages of living-donor liver transplantation include the following:

• Selection of an ideal donor
• Ability to schedule the case electively
• Maximal time to prepare the recipient
• Relatively short cold ischemia time

Although living-donor transplantation increases the number of livers available for pediatric and adult recipients, donor safety remains a major concern. Several donor deaths were highly publicized. Although the exact risks remain uncertain, serious donor morbidity and mortality are possible. Ethical issues, such as those regarding donor coercion and informed consent, raise concerns about application of this technique in both urgent and elective settings.

Split-liver transplantation takes advantage of the knowledge gained in reduced-liver transplantation to increase the organ supply by using the right lobe or trisegmental graft that remains after the left lateral segment or left lobe is removed for a pediatric recipient. In 1988, Pichlmayr et al described the technical approach to split-liver transplantation, including preservation of arterial, biliary, venous drainage for both grafts. ^[10]  Broelsch reported the first large series in 1990, ^[11]  although the results were initially poor, hampering widespread acceptance of this technique. ^{[12, 13, 2]}

Early series had higher-than-expected rates of primary nonfunction and biliary complications that substantially reduced recipient survival. Ethical questions were also raised about the potential of disadvantaging adult recipients to provide grafts for pediatric patients.

In the past two decades, refinements in surgical techniques and improved organ preservation have improved patient survival rates. Particularly in the case of right trisegment–left lateral segment splits, adult recipients can expect results that approach those of patients who receive standard deceased-donor transplants. ^{[14, 15, 16, 17, 18, 19, 20]}

The success of split-liver transplantation in children has led some authors to argue that live-donor transplantation is no longer necessary in the pediatric population. ^[21]  Overall, the transplantation community has endorsed the expanded use of split-liver transplantation as a technique to increase the organ supply and to reduce wait-list mortality rates. ^{[22, 23]}

The goal of split-liver transplantation is to produce two grafts with preserved vascular supply (ie, portal vein, hepatic artery), venous drainage, and bile duct. Anatomic variations (replaced arteries, biliary anomalies) are not considered to be a contraindication to liver splitting as long as both right- and left-sided allografts have a complete set of vessels and biliary drainage. In most cases, the vena cava and the common bile duct are maintained with the right-sided allograft, and the left hepatic vein and left bile duct are divided for the left allograft.

For left-lobe grafts, the middle and left hepatic veins are preserved. In these cases, the surgeon transplanting the right-lobe graft should recognize and either preserve or reconstruct the large veins in segment 5, which frequently drain into the middle hepatic vein. The main portal vein and the main arterial supply can be maintained with either side, depending on the anatomy and the designated primary recipient of the allograft.

For more information about the relevant anatomy, see Liver Anatomy.

The etiology of end-stage liver disease is the subject of several other Medscape articles. However, several specific comments are relevant to patients undergoing split-liver transplantation.

For pediatric patients, biliary atresia remains the most common indication for liver transplantation, followed by fulminant hepatic failure, metabolic diseases, and various other causes, including cholestatic diseases and malignancy (hepatoblastoma). Given the preponderance of childhood transplantation for biliary atresia, a considerable number of children undergoing transplantation are younger than 2 years and, therefore, excellent candidates for a left lateral segment graft from a split liver. Older children require larger grafts, including left-lobe grafts, which have increased rates of graft loss and complications, although the increase may reflect differences in recipients' characteristics and their underlying illnesses. ^[24]

The etiologies of liver disease in adult recipients of split-liver transplants do not notably differ from those receiving whole-organ grafts. Initial concerns regarding the potential for increased recurrence of hepatitis C in regenerating allografts have not been validated in the literature. ^[25] Split-liver transplantation has now been applied in all patient groups, including status 1 patients and patients requiring retransplantation. ^[19]

In the young pediatric population, split-liver transplantation or reduced-liver transplantation has become an increasingly frequent procedure. In a 2005 review of 755 patients undergoing transplantation for biliary atresia, only 44% received whole-organ grafts. Deceased-donor variants (reduced or split) represented 31% of grafts, whereas live donors provided the remaining 24%. ^[26]

More recently, a European center reported that only 21% of patients with biliary atresia who received a liver transplant received a whole organ, while 21% received a reduced-size liver, 11% received a split liver, and 47% received a liver graft from a live donor. ^[27]

In the adult population, split-liver transplantation remains infrequent. Among patients receiving a transplant from a deceased donor allograft in 2002-2005, split-liver transplantation was performed in only 2.9% of the total population. However, this percentage does appear to be increasing over time.

Split-liver transplantation has traditionally been restricted to organs from ideal deceased donors. Although the exact definition of ideal donors remains controversial, the Organ Procurement and Transplantation Network (OPTN) identifies a liver as one with the potential to be split if the donor meets all the following criteria ^[28] :

• Age younger than 40 years
• Use of no more than a single vasopressor
• Transaminases no greater than three times the normal level
• Body mass index (BMI) 28 kg/m ² or less

However, while those criteria are met by more than 10% of all deceased donors, and more than 20% of donors younger than 35 years, less than 1.5% of all donor livers have been split since the OPTN adopted those criteria in 2007. ^[28]

The following characteristics are used to exclude donors from consideration, according to the OPTN Pediatric Subcommittee:

• Age younger than 10 years or older than 40 years
• History of cancer or insulin-dependent diabetes mellitus
• Infection with HIV, hepatitis B virus, or hepatitis C virus
• Use of both dopamine and dobutamine
• Serum bilirubin value of more than 3 mg/dL
• Serum alanine aminotransferase (ALT) or serum aspartate aminotransferase (AST) level greater than 150 U/L
• Cardiac arrest after neurologic event leading to brain death
• Serum sodium level of more than 170 mEq/L

In addition, a suitable pediatric recipient must be available for the left lateral segment or left lobe.

For live-donor transplants, donor characteristics that are contraindications include hemodynamic instability, hospitalization for longer than 5 days, liver function results exceeding three times the mean. Anatomically aberrant hepatic arterial anatomy is not a contraindication to splitting, as long as the arterial supply to each of the segmental grafts is not compromised.

Initial results after split-liver transplantation were disappointing. ^{[12, 13, 2]}  Overall patient survival and graft survival were reduced, and surgical complications were increased in patients who underwent split-liver transplantation. However, because of technical refinements and appropriate selection of recipients, results of ex vivo and in situ split-liver transplantation both are nearly equivalent to those expected with whole organs. ^{[29, 19, 30, 31, 32]}

In a series reported by Washburn et al (2005), survival in adult patients and graft survival after right trisegmental splits were equivalent to survival after whole-organ transplantation (87.1% and 85.5%, respectively, at 1 year). ^[19] In a large single-center series (> 3000 liver transplants), Busuttil and colleagues (2005) demonstrated comparable outcomes between whole-liver transplants and other types of grafts. ^[29]  However, the experience in large centers may not be completely generalizable to other settings.

In their 2006 analysis of the risk of graft failure, based on a review of the entire database of the Organ Procurement and Transplantation Network (OPTN), Feng et al reported a significant increase in the risk of graft failure associated with split grafts. ^[33]  In addition, Merion et al (2001) reported that the need for retransplantation was higher in recipients of split-liver grafts than in recipients of whole-liver grafts. ^[34]

A 2014 review by Schrem et al of ex situ split liver transplantation in adults noted continuous improvement in survival over 24 years of experience. The observed 10-year survival rate was 40.6%. ^[35]

Centers performing in situ splitting techniques have also reported successful results with low rates of biliary and bleeding complications. In the series that Rogiers et al reported (1995), 6-month patient survival and graft survival rates after in situ split-liver transplantation were 92.8% and 85.7%, respectively, without any biliary complications. ^[36]  Goss and colleagues (1997) reported a 92% patient survival rate and an 86% graft survival rate, with a 3% rate of biliary complications in 28 patients. ^[17]

Pediatric recipients

Results in pediatric patients remain a subject of contention. Single-center series have demonstrated excellent results with deceased-donor left lateral segment grafts. Lee et al (2005) reported 82% graft survival at 1 and 3 years. Overall patient survival was 90%. ^[37]  Large, multi-institutional series, including reports for the Studies of Pediatric Liver Transplantation (SPLIT) research group, continue to show that deceased donor split livers are associated with an increased risk of graft failure. ^[26]  Using the SPLIT registry, Englesbe et al completed a survey of current practices and offer a six-step approach for a model to improve transplantation initiatives. ^[38]

In a single-center study by Doyle et al (2013), results of split-liver transplants were equivalent to those of whole-organ transplantation. In the 30 pediatric recipients of split liver grafts,  1-, 5-, and 10-year overall rates were 96.7%, 80.0%, and 80.0%, respectively, while 1-, 5-, and 10-year graft survival rates were 93.3%, 76.8, and 76.8%, respectively. ^[39]

A multicenter analysis of the Society of Pediatric Liver Transplantation (SPLIT) registry database (2023) found no significant differences in patient and graft survival based on graft types. Patient survival at 3 years was 96% for whole-liver recipients (n=1029), 96% for living-donor split liver recipients (n=335), and 93% for deceased-donor split liver recipients (n=475). ^[40]

Finally, Roberts et al (2004) analyzed data from UNOS and a scientific registry of transplant recipients and determined that living-donor livers were associated with improved graft and patient survival in children younger than 2 years. The association was reversed in the older pediatric and adolescent population. ^[41]

A systematic review and meta-analysis by Garzali et al (2023) that included 4836 pediatric and adult patients reported better graft survival and overall survival with living-donor transplantation versus deceased-donor split liver grafts. With living-donor transplantation, the hazard ratio for graft survival at 3 years was 1.28 (95% confidence interval: 1.01-1.63; P = 0.04). ^[42]

Two-adult recipients

Outcomes after a liver is split for two adult recipients have been reported. The left lateral segment can be transplanted into a small adult. As an alternative, to overcome small-for-size graft problems, the liver can be split through the midplane, resulting in a full left lobe and a right lobe. Sommacale et al (2000) reported using the midplane and retaining the middle hepatic vein with the left-sided graft, ^[43]  while Gundlach et al (2000) reported longitudinally splitting the inferior vena cava for venous reconstruction. ^[44]  In both reports, the midplane was used for bipartitioning of the liver, resulting a full left lobe liver; the outcomes were successful.

In 2001, Azoulay et al reported ex vivo splitting of the liver through segment 4 for two adults; results were comparable to those of whole-organ grafts in 34 patients. ^[45]  Axelrod et al (2005) reported the results of split-liver transplantations in adolescents and found reduced survival among patients receiving a left-lobe graft. ^[24]

A 2014 retrospective review by Hashimoto et al of 25 lobar grafts (10 left lobes and 15 right lobes) for adult-sized recipients determined that the 5-year graft survival for hemilivers was comparable to whole livers (80.0% vs. 81.5%, P = 0.43). In 92% of donors, the livers were split in situ. Hemiliver recipients did experience biliary complications more frequently (32.0% vs. 10.7%, P = 0.01). ^[46]

Waiting time reduction

The effect of liver splitting on waiting times for transplantation has the potential to be substantial. In Brousse's experience, the number of transplantable grafts was increased by 28%. ^[14]  Investigators from the Hamburg group, King's College, and UCLA have reported improved use and transplant efficiency. ^{[36, 17, 18]}

Maximal use of split-liver transplantation would provide enough grafts to treat most patients on the pediatric waiting list. Merion and colleagues (2004) demonstrated that splitting all available livers for whom there was an appropriate pediatric recipient would help 59 additional recipients for every 100 livers split, even after they accounted for the slightly increased need for retransplantation. In this analysis, splitting of 100 livers was associated with a net increment of 11 life-years compared with continued time on the waiting list. ^[34]