Current state of living donor liver transplantation

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The discrepancy between the number of patients waiting for a liver and the available number of deceased donors has led to the use of living donors to increase the donor pool. Segmental grafts and living donor liver transplantation (LDLT) was first pioneered in children in the late 1980s due to a lack of appropriately sized donors and the high mortality rate among children awaiting liver transplantation.1, 2 As experience with liver resection techniques grew and success with pediatric live donor transplantation became apparent, LDLT was ultimately introduced for adults in the early 1990s, with the first successful adult LDLT being performed in Japan. LDLT has now become an important part of the armamentarium of busy liver transplantation centers.

Adult‐to‐adult LDLT has been particularly well embraced by Asian countries due to the lack of infrastructure and/or cultural barriers to the use of deceased donors in these areas. Given the comparatively greater availability of deceased donors in Western countries, LDLT comprises a much lower percentage of transplantations compared with Asian countries and probably has the greatest impact in recipients who are currently disadvantaged by the current Model for End‐Stage Liver Disease (MELD)‐based system of liver allocation and in regions where access to deceased donor organs at lower MELD scores is not possible. In the United States, LDLT constituted approximately 2% to 9% of adult liver transplantations over the last decade, with a larger percentage of children receiving LDLTs (Fig. 1A,B).

Figure 1.

Total number of (A) adult and (B) pediatric liver transplants in the United States (2011 Scientific Registry of Transplant Recipients annual report, available at http://srtr.transplant.hrsa.gov/annual_reports/2011/). Adapted with permission from the Health Resources and Services Administration, US Department of Health and Human Services. Copyright 2011, US Department of Health and Human Services.

Some obvious advantages of LDLT over deceased donor liver transplantation (DDLT) include the ability to provide transplantation before the recipient becomes too ill, knowledge of donor history, avoidance of the physiologic derangement induced by brain death in the donor, and reduced cold ischemic time. These advantages are balanced by the risk to the donor, the additional technical complexity of receiving a partial graft with smaller vessels and bile ducts, and the need for careful medical and surgical judgment in choosing the appropriate donor and recipient.

Recipient Outcomes

Current multicenter outcomes of adult LDLT in the United States are available from the Adult‐to‐Adult Living Donor Liver Transplantation (A2ALL) Cohort Study. This consortium has reported detailed retrospective and long‐term prospective data on both donor and recipient outcomes of adult LDLT in the United States among nine experienced transplantation centers and has provided definitive evidence for the use and safety of LDLT in the United States. An initial learning curve is present in almost all programs initiating an LDLT program,3 but current patient and graft survival outcomes among adult LDLT recipients are comparable or better than those among adult DDLT recipients, and the national outcomes mirror A2ALL outcomes.4 A2ALL has demonstrated the survival benefit of LDLT, primarily by minimizing wait list death, and has shown that LDLT provides survival benefit for patients at most MELD scores.5, 6, 7 Specifically, overall mortality is significantly diminished among patients who undergo LDLT compared with patients who are waiting for DDLT (Fig. 2), due to expeditious transplantation and avoidance of death while on the wait list. Organ Procurement and Transplantation Network (OPTN) data for adults demonstrate comparable 5‐year patient survival among DDLT recipients (Fig. 3A) and LDLT recipients (Fig. 3B) for MELD scores ≤20, and the European Liver Transplant Registry reports comprehensive 1‐year and 5‐year graft survival rates of 80% and 69%, respectively.8

Figure 2.

Mortality rates following initial potential donor evaluation for transplant candidates without hepatocellular carcinoma according to MELD score at evaluation and LDLT versus no LDLT. The data shown are for patients who met the following criteria: age 50 years, no hepatocellular carcinoma, hepatitis C virus infection, no other cholestatic disease, and MELD score of 10 (for MELD <15 group) or 20 (for MELD 15+ group) at enrollment. Adapted with permission from Hepatology.7 Copyright 2011, Wiley.

Figure 3.

Graft survival among adult liver transplant recipients transplanted in the United States in (A) 2006 (deceased donors) and (B) 2003–2006 (living donors) (2011 Scientific Registry of Transplant Recipients annual report, available at http://srtr.transplant.hrsa.gov/annual_reports/2011/). Adapted with permission from the Health Resources and Services Administration, US Department of Health and Human Services. Copyright 2011, US Department of Health and Human Services.

All things being equal, diagnosis is not a significant predictor of outcome when compared with DDLT. The presence of hepatocellular carcinoma resulted in decreased long‐term survival, but this was thought to be due to a greater extent of tumor burden.9 DDLT is a better option for critically ill recipients who have a very high MELD score; however, LDLT has been performed successfully in candidates with higher MELD scores in certain high‐volume centers in North America with comparable short‐ and long‐term outcomes compared with DDLT.10 Other data have emerged from A2ALL that show no significant difference in the incidence or severity of acute cellular rejection between LDLT and DDLT recipients, and no difference in progression of hepatitis C virus.11, 12

Early data from the OPTN demonstrated a higher early graft failure rate and higher retransplantation rate (Table 1).13 However, as center experience increased, complications dropped dramatically, and outcomes improved. More recent data show a decrease in surgical complications associated with increased experience (Table 1).14 Without question, biliary complications are more frequent in recipients of LDLT versus DDLT on account of the tenuous nature of the bile duct blood supply, small size, and frequent necessity for multiple duct anastomoses. The frequency of biliary complications is reported to be approximately 25% to 35%, often requiring endoscopic or surgical treatment.15, 16

Table 1.

Complication Rates Among Recipients of LDLT Versus DDLT

Complication	Rate (%)
	LDLT	DDLT
Retransplantation13	12	6.5
Complications leading to retransplantation or death14	15.9	9.3
Biliary leak14	27	10
Bile duct bacterial infection14	8	3
Vascular14
Hepatic artery thrombosis	6.5	2.3
Portal vein thrombosis	2.9	0

A unique complication of LDLT that contributes significantly to the complexity of patient selection and recipient morbidity and mortality is the development of small‐for‐size syndrome (SFSS). Although there is no agreed‐upon definition of SFSS, this syndrome is generally ascribed to patients who develop prolonged cholestasis, coagulopathy, and ascites within the first week in the absence of technical or immunologic reasons for graft dysfunction, with a reported incidence of 3% to 19%.17 Preoperative calculation of recipient parenchymal requirements in order to avoid graft dysfunction is important, and avoidance of a graft weight/recipient weight ratio of <0.8% is the most common parameter used. Recently, investigators have found that neither graft weight/recipient weight ratio nor standard liver volume can reliably predict the development or outcome of SFSS,18, 19 because these calculations do not account for other factors that may contribute to the pathogenesis of SFSS (eg, portal hyperperfusion of the allograft, poor outflow, liver disease severity, or metabolic demand of the recipient).

Although most adult LDLTs worldwide are performed using right grafts, increasing donor safety concerns have led to a corresponding increase in the utilization of smaller left lobe allografts in recent years.20 These grafts decrease morbidity in the donor but provide a significantly smaller graft for the recipient, so inflow modification of the graft may need to be performed to attenuate the degree of portal hyperperfusion. Techniques that are widely described include splenic artery ligation, splenectomy, and portomesenteric shunting.21

There is significant concern that the smaller graft mass provided by LDLT may be inadequate in patients who have a high physiologic demand, including status 1 patients and patients who have high MELD scores. However, MELD score alone does not reliably identify recipients who are too ill for LDLT; rather, it is a multifactorial process that involves metabolic stress, parenchymal quality, magnitude of portal hypertension, vascular inflow and outflow, and avoidance of complications.10

Abbreviations.

A2ALL

Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study

LDLT

living donor liver transplantation

MELD

Model for End‐Stage Liver Disease

OPTN

Organ Procurement and Transplantation Network

SFSS

small‐for‐size syndrome

Donor Outcomes

The limited expansion of living donor programs in the West can be attributed primarily to access to deceased donors and valid concerns regarding donor safety. Although most complications are minor in this healthy population, any adverse event in an altruistic donor who did not otherwise require an operation is cause for concern. Significant donor morbidity, including death, has been observed, even among the most experienced centers.22, 23 Furthermore, although protocols are devised to minimize complications, it is impossible to make the risk negligible for an operation of such magnitude. Counseling a potential donor with respect to the risks involved in donor hepatectomy is ethically mandated before proceeding with LDLT, but until recently there have been few registry data to allow an estimation of true risk, and the ability to provide truly informed consent continues to be a challenge and deserves further study.

Data regarding donor outcomes, morbidity, and complications in Western centers have been published by single centers as well as the A2ALL consortium.24, 25 Current available data suggest that overall donor mortality after liver donation in the United States and Europe is on the order of 0.2%. Reporting of donor death is mandated by the United Network for Organ Sharing and the OPTN in the United States, and compiled data suggest that mortality is higher among donors of the right hepatic lobe versus the left hepatic lobe; however, this finding has not been reported consistently among the limited number of Western centers that have evaluated this issue retrospectively. In studies that have included donors of either the right or left hepatic lobe, the overall complication rate has been approximately 21%. However, in studies including only right hepatic lobe donors, complications rates are higher and have ranged between 38% and 47%. The most recent publication from the A2ALL consortium reports an overall donor complication rate of 40%, ranging from mostly minor complications to a few life‐threatening complications.24 Approximately 50% of donor complications were minor, defined as grade 1 by the Clavien system, and Clavien grade 3 or 4 complications were very rare (1.1%). Of all donor complications reported by the A2ALL consortium, infections, pleural effusion, biliary leak, and incisional hernia were the most common (Table 2). Most laboratory abnormalities that occur in donors after lobectomy resolve quickly, and 20% of donors have persistently lower platelet counts 2 to 3 years after donation, although the clinical significance of this finding is unknown.26 In addition, there is documented trauma in an estimated 1.2% of donors due to unforeseen problems arising in the recipient, leading to abandonment of the donor hepatectomy.27 Liver failure requiring rescue transplantation is extremely rare; only five cases have been reported in the literature, four of which involved right lobe donors.27

Table 2.

Donor Complications Reported by the A2ALL Cohort Study24 (n = 740)

Complication	Frequency (%)	Clavien Grade (%)
		1	2	3	4
Biliary leak	8.1	3.3	4.7
Biliary stricture	0.6	0.1	0.5
Incisional hernia	6.6	1.3	5	0.1
Unplanned re‐exploration	2.7	0.1	2.6
Bowel obstruction	1.6	0.4	1.1	0.1
Deep venous thrombosis	0.8	0	0.8
Pulmonary embolism	0.9	0.2	0.7
Liver failure	0
HAT/PVT	0.5	0.2	0.2
Infection	13.2	3.3	9.7		0.1
Psychological difficulties	5.6	3.1	2.3		0.3

Abbreviations: HAT, hepatic artery thrombosis; PVT, portal vein thrombosis.

Summary

In conclusion, living donor liver transplantation has successfully allowed the transplantation of many patients with excellent recipient outcomes over the last decade. Children, in particular, benefit greatly from LDLT, and outcomes among adult recipients continue to improve such that they now exceed those of DDLT. Favorable outcome with LDLT depends on the following critical factors: (1) appropriate recipient selection, (2) careful and meticulous donor evaluation and selection, (3) adequate parenchymal functional mass for both donor and recipient, and (4) optimizing vascular inflow and outflow. It must be recognized that LDLT is performed only in a select group of recipients, and not all patients are appropriate candidates. The benefit of LDLT must always be balanced against any potential harm to the donor, and efforts to minimize donor risk must be ongoing. Future studies will need to focus on selection of the best recipients, optimal timing to obtain the maximum survival benefit, and continued assessment of potential long‐term consequences in the donor.