Liver transplantation has long been established as the only option for patients with endstage liver disease suffering from complications of their disease. For most such patients the primary question is not if but when, and it is a question made even more crucial given the increasing shortage of available liver allografts. The desperate shortage of deceased donor liver allografts has forced the allocation system to rank patients in order of urgency, knowing that not all patients will make it to the front of the line. In addition, this shortage has led to the genesis of living donor liver transplantation where the question of when to transplant becomes even more critical due to the consideration of risk for the potential living donor.
In the current issue of HEPATOLOGY, Berg et al.,1 on behalf of the A2ALL multicenter consortium, attempt to provide some guidance on the issue of when by examining which patients could demonstrate a survival benefit from living donor liver transplantation (LDLT). In their analysis of A2ALL registry data, the authors compare outcomes for patients listed for liver transplantation who had a potential donor evaluated for them. Those who underwent an LDLT were compared with those who underwent a deceased donor liver transplant (DDLT) or remained on the wait list. These analyses were performed for patients with Model for Endstage Liver Disease (MELD) <15 or ≥15, for patients with and without hepatocellular carcinoma (HCC).
With a median follow-up of 4.5 years, the authors report a clear survival benefit of LDLT in both low and high MELD patients without HCC when compared to DDLT or remaining on the wait list. For patients with HCC, a survival benefit of LDLT could only be demonstrated for those with MELD of ≥15 when compared to DDLT. For patients with HCC and MELD <15, LDLT and DDLT had similar survival outcomes, which is not surprising given they had similar waiting times at 2.5 months and 3 months, respectively, likely due to the allocation policy for patients with HCC.
The finding of a clear survival benefit for non-HCC patients with a MELD <15 who underwent LDLT is somewhat unexpected. A previous report by Merion et al.2 demonstrated no survival benefit for deceased donor transplant recipients with a MELD <15 compared to waiting on the list for up to 2 years. This seminal report resulted in a major allocation policy change for patients with MELD <15, and led many in the liver transplant community to conclude that there would be no benefit to transplant for patients with a MELD <15. Importantly, a subsequent report did a show survival benefit down to MELD of 12 when using donors with a low donor risk index (DRI).3 Thus, further analysis of LDLT outcomes across the spectrum of low MELD patients such as between 12-15 and 8-11 may provide additional granularity to the current findings.
Because the authors included only patients for whom an available living donor was evaluated, this may reduce potential bias that may come from a subtle (and immeasurable) survival benefit for patients with enough social support and/or healthy family members that they have a potential living donor compared to those wait-listed candidates who have no potential donors. They also controlled for the presence of HCC, hepatitis C virus (HCV), MELD, age, and presence of cholestatic liver disease. Additionally, the authors analyzed the quality of the deceased donor organs in DDLT candidates to ensure that recipients of DDLT in the A2ALL cohort were not getting highly inferior deceased donor organs, which could account for the benefit of LDLT. They compared the DRI of patients receiving deceased donor transplants for both those in the A2ALL study as well as those patients at the participating centers who were not in the study and found it was similar.
Notably, the stage of HCC was not controlled and the percentage of patients with more advanced T3 lesions was nearly double in the LDLT group compared to the DDLT group. Again, this may relate to allocation policy, as patients with T3 lesions are not given priority for deceased donation. It is also important to note that the non-LDLT group did contain significantly more patients with HCV, fewer with cholestatic liver disease, and more racial diversity. Although these factors were adjusted for in the model, the power to detect differences is impacted as the numbers decrease. In addition, although this was a multicenter study the results of individual centers were not reported. A center effect has been reported to have a major impact on outcomes with liver transplantation.4 Although it is likely all centers within A2ALL are highly experienced at both living donor and deceased donor transplant, it is not known whether these results could be applied to all centers. In addition, there are marked geographic differences in MELD threshold for access to deceased donor transplant, as well as in the quality of deceased donor allografts.5, 6 These differences would likely augment or mitigate the survival benefit of living donor transplant, depending on the donor service area and region of the transplant center. Finally, and most essentially, this was not a randomized trial of all patients wait-listed for liver transplantation, but rather of a selected group of patients deemed appropriate candidates for LDLT by their transplant centers.
Thus, centers must still consider what is best for each and every individual patient on their wait list based on factors that may impact outcome at their center. If there is a very short anticipated wait time to DDLT based on factors such as HCC MELD exception or favorable blood type, then a survival benefit to LDLT compared to DDLT likely will not be present. For individual patients, other factors that impact the decision to proceed to LDLT beyond the potential for a survival benefit, such as uncontrolled encephalopathy, refractory ascites, and intractable pruritus must also be carefully considered. In the future, information regarding validated quality of life outcomes following LDLT versus prolonged time on the wait list and/or DDLT would provide exceptionally helpful additional guidance to assist in discussion with patients and families regarding timing and donor options for liver transplantation.