Living donor liver transplantation and hepatitis C

LDLT, living donor liver transplantation; HCV, hepatitis C; DD, deceased-donor; MELD, Model for End-Stage Liver Disease. Outcomes for living donor liver transplantation (LDLT) recipients infected with hepatitis C (HCV) are some of the most important and controversial issues in liver transplantation: important because HCV is the most common indication for liver transplantation, and controversial because the current data is insufficient to determine whether LDLT recipients have the same outcome or a worse outcome than deceased-donor (DD) transplant recipients. Some reports have indicated that LDLT recipients have earlier and more severe recurrence of HCV following transplantation1-3; other data have failed to show a difference.4 The important study by Russo et al. in this issue of Liver Transplantation helps provide another piece of the picture.5 These investigators reviewed the data in the Scientific Registry of Transplantation Recipients to compare the patient and graft survival in LDLT versus DD patients infected with HCV. Their findings are particularly important because the data set is the largest reported to date for posttransplantation outcomes for HCV-infected LDLT recipients; the data set includes most or all LDLT cases performed in the United States since 1999. Furthermore, the investigators have performed a careful analysis that provides important insights into the topic. In their paper, Russo et al.5 demonstrate that HCV patients who have undergone transplantation with a live donor have similar patient and graft survival rates compared to HCV patients receiving a DD graft. For patients and physicians, this information could provide assurance that LDLT is as efficacious as transplantation with a DD. However, these data should be interpreted with caution because of the important clinical distinction between LDLT and DD recipients. At the time of transplantation, LDLT recipients are far less sick than their DD counterparts. LDLT recipients are younger, thinner, less likely to be hospitalized in the intensive care unit, and they have a lower Model for End-Stage Liver Disease (MELD) score.5, 6 These factors are important to consider regarding posttransplantation outcomes for two reasons. First, the sicker the patient at the time of transplantation, the worse the posttransplantation outcome. That is, without assessing the illness severity at the time of transplantation, direct comparisons of posttransplantation outcomes between LDLT and DD recipients are problematic. Although patient and graft survival for LDLT and DD patients may be similar, the relative outcome for LDLT recipients is actually worse because they are significantly less sick at transplantation than DD patients. This was demonstrated in a recent presentation by Shaked, who reported that the relative risk of patient and graft survival for LDLT recipients was 88% and 123% higher, respectively, compared to DD recipients (P ≤ .001).7 These data take into the account the severity of illness at the time of transplantation. In fact, a closer look at Russo's data supports the same conclusion. Although univariate analysis suggests that LDLT and DD have similar survival rates, after adjusting for illness severity (age, bilirubin, creatinine, diabetes, and presence of life support), Russo et al. in fact demonstrate that LDLT is associated with a 44% increased risk of graft failure compared to DD5 Second, compared to DD patients, LDLT recipients do not receive as great a benefit from transplantation since the urgency of transplantation may be less than for DD patients. According toRusso et al.,5 the technical success of the LDLT operation is similar to DD: approximately 88% survival 1 year after surgery. For the typical DD patient with a MELD score of 24, 88% survival is a favorable outcome. Without transplantation, such a patient would die within a few months. However, for the LDLT recipient, who is typically less ill and has an average MELD of 14, the benefit of transplantation may be less clear. An 88% 1-year survival for this patient could be lower than the expected 1-year survival without transplantation. Therefore, survival statistics must be interpreted relative to the expected outcome without transplantation. For LDLT patients, the benefit is less than for DD patients who are far sicker at time of transplantation. What does all of this mean in terms of comparison of outcomes for LDLT and DD recipients? If DD recipients are significantly sicker at the time of transplantation, can we ever perform meaningful outcome comparisons with LDLT patients? The answer is yes, but we need to change our point of reference. As noted above, using the time of surgery as the point of reference for measuring the efficacy of LDLT is inadequate. The outcomes relative to LDLT must be measured while the patient is listed for transplantation. In doing this, we recognize that selection of LDLT as a treatment option fundamentally changes the risk-benefit equation for a given patient. The potential benefit of expedited transplantation with a live donor eliminates one of the greatest risks of DD transplantation: death on the waiting list. On the other hand, expedited transplantation with a live donor places the patient at immediate risk of posttransplantation problems, which are fatal in approximately 12% of patients within 1 year. For the DD patient, waiting time before transplantation is longer compared to the LDLT recipient. During this time, the patient may develop problems related to end-stage liver disease, which can lead to death on the waiting list. In addition, the DD recipient is usually sicker at the time of surgery; this can jeopardize the success of the procedure. To determine whether LDLT is better or worse for a given patient than DD, we must measure outcomes following the selection of LDLT as a treatment option while the patient is still listed for transplantation. Thereafter, the rate of complications and mortality for LDLT recipients compared to DD patients will determine whether the choice of LDLT is better or worse than DD transplantation. Currently, there is no data to determine which alternative will lead to the best outcome for a particular patient. To answer this question will clearly require a long-term prospective trial. The most likely source of this information is the National Institutes of Health LDLT Cohort Study, which will begin enrollment in 2004. However, meaningful data regarding patient and graft survival will not be available for several more years. In the meantime, how should we select appropriate candidates for LDLT, and how should the results by Russo et al.5 impact the selection of HCV-infected patients for LDLT? One could interpret the data to support LDLT as a treatment option for any patient with HCV, since patient and graft survival are the same as DD transplantation. However, as discussed above, we believe that the illness severity must be carefully considered in each patient. The patients who stand the most to gain from an expedited transplantation with a live donor are those at risk for dying while on the transplant list. From a practical standpoint, the MELD score provides some help in identifying these patients. In general, the 90-day mortality begins to increase precipitously for patients with a MELD score greater than or equal to 18. In almost all cases, these patients should be considered sick enough to potentially benefit from LDLT. However, since the MELD score is a statistical formula that may not accurately predict mortality risk for all patients, there may be selected patients with a MELD score less than 18 who may benefit from live donation. In fact, a substantial number of appropriate LDLT recipients may be patients who are at risk for dying despite a low MELD score. These patients have virtually no chance for cadaveric transplantation, and live donation may be their only viable treatment option under the current MELD allocation scheme. In short, the MELD score along with clinical judgment should be used to select patients at risk for dying on the transplant list. These patients should be offered live donation as a treatment option to prevent one of the most important risks of DD transplantation: death on the waiting list. In summary, the current data are inadequate to determine whether outcomes for HCV-infected patients are better or worse following LDLT compared to DD. The study by Russo et al.5 demonstrates that, after LDLT, patient and graft survival are similar compared to DD transplantation. However, multivariate analysis suggests that LDLT may be associated with worse survival compared to DD liver transplantation. A full measure of the impact of LDLT will require a prospective analysis that evaluates outcomes at the time that LDLT is selected as a treatment option for a given patient.