The International Liver Transplantation Society (ILTS) held its 18th annual congress in San Francisco, CA. The meeting included several thematic symposia focusing on hepatitis C virus (HCV) management, advances in hepatocellular carcinoma (HCC) treatment, new developments in biomarkers, patient and graft optimization, living donor transplantation, and long-term outcomes of pediatric transplantation. A combination of oral presentations, poster presentations, and interactive sessions covered a wide range of topics. This report focuses on research abstracts on several key topics such as viral hepatitis, acute liver failure, perioperative management, liver cancer, living donor liver transplantation (LDLT), expansion of the donor pool, and organ allocation, and they are presented in the context of the published literature.
From May 16–19, 2012, the International Liver Transplantation Society held its annual congress in San Francisco, CA. More than 1300 registrants attended the meeting, which included a premeeting conference entitled Balancing Risk in Liver Transplantation, focused topic sessions, and a variety of oral and poster presentations. This report is not all-inclusive and focuses on specific research abstracts on key topics in liver transplantation. As always, the new data herein are presented in the context of the published literature to further enhance knowledge in the field. Liver Transpl 19:27–35, 2013. © 2012 AASLD.
Numerous presentations focused on factors associated with the development of hepatitis C virus recurrence (HCV-R) and minimization of fibrosis progression. Gehrau et al.1 presented data on the use of biopsy microRNA to predict more aggressive HCV-R after orthotopic liver transplantation (LT), and this research was similar to their work on other genomic molecular markers.2, 3 Nadig et al.4 showed compelling data demonstrating a reduced incidence of HCV-R with the complete avoidance of induction and steroid therapy. In a previous study,5 steroid avoidance was not shown to be more beneficial, although that study included interleukin-2 receptor inhibitor therapies in the steroid-free arm. Andreani et al.6 from King's College showed no differences in fibrosis related to HCV-R and mortality between standard criteria donors, extended criteria donors, and donation after cardiac death (DCD) donors. These data add to the controversy and debate concerning the use of nonstandard donors for recipients with HCV.7-9 Finally, the putative antifibrotic effects of the molecular target of rapamycin (mTOR) inhibitor everolimus (EVL) versus calcineurin inhibitor (CNI) therapy were analyzed in 3 prospective studies.10-12 One showed no significant difference in HCV-related fibrosis, whereas the others showed either reduced fibrosis or less fibrosis progression in the EVL groups. A major caveat is that not all patients underwent biopsy after randomization. Thus, although the antifibrotic effects of mTOR inhibitors may be encouraging,13, 14 the evidence is not definitive and needs further confirmation.
A number of abstracts focused on the treatment of HCV-R in the LT population. Flemming et al.15 reported a novel study looking at whether achieving stable histology at the end of antiviral therapy without a sustained virological response (SVR) affects patient survival. Nearly 50% of the patients who did not achieve SVR on pegylated interferon/ribavirin therapy had stable/improved fibrosis and achieved better survival after treatment in comparison with patients with worsening fibrosis. This argues for continuing to treat patients even if a virological response is not achieved, although there are no data for more prolonged or maintenance therapy known to be ineffective before LT.16 Aguilera et al.17 reported higher patient and graft survival for patients with stage 2 or lower fibrosis who achieved SVR with antiviral therapy in comparison with patients with more advanced fibrosis or no SVR. This supports recent data showing better outcomes when antiviral therapy is initiated before the development of advanced fibrosis.18, 19 However, therapy very early after LT has been associated with a higher incidence of cytomegalovirus and mortality without an SVR benefit.20 Early preemptive therapy might also be more successful (SVR rate = 46%) in stable LDLT recipients who routinely undergo splenectomy, although this is not the standard of care at most centers.21 Thus, clinicians should perhaps wait until 6 months after LT to initiate therapy in patients with HCV-R, but not until advanced fibrosis is detected.
Three abstracts reported preliminary results for the use of protease inhibitors (telaprevir and boceprevir) in conjunction with pegylated interferon and ribavirin in LT recipients with HCV-R.22-24 No published data are yet available, and there are known significant drug interactions with CNI therapy.25, 26 The numbers of treated patients were 12,22 14,23 and 25,24 and full SVR data are not yet available for all patients. Overall, an early virological response was seen in more than 50% of the patients who tolerated therapy. However, a number of serious side effects and adverse events (severe anemia, rashes, anal pain, and progressive liver disease) requiring discontinuation occurred during triple therapy, and a few patients with advanced liver disease who were treated expired. The message appears to be that noncholestatic patients with less advanced liver disease may be considered for triple therapy after LT, although further prospective studies and SVR data are greatly needed.
As for hepatitis B virus (HBV), one study compared entecavir to lamivudine prophylaxis without hepatitis B immunoglobulin (HBIG) after LT.27 HBV DNA suppression over time was equal in the 2 groups, although 17% of the lamivudine patients eventually developed resistance and virological rebound. This supports the use of antiviral therapy with low resistance, perhaps without HBIG, for HBV prophylaxis.28-30 Two Italian papers31, 32 showed the efficacy of weekly subcutaneous HBIG as a replacement for intravenous or intramuscular HBIG late after transplantation, and their findings were similar to those of other reports.33, 34 This resulted in high surface antibody titers and no recurrence, although all patients were on antiviral therapy. The advantages of this approach are self-administration and lower costs, although it remains to be seen if less frequent dosing will be as effective.
ACUTE/CHRONIC LIVER FAILURE AND PERIOPERATIVE MANAGEMENT
Teperman35 reported on a multicenter randomized controlled study testing an extracorporeal liver assist device for either alcoholic hepatitis or acute-on-chronic liver failure. An extracorporeal liver assist device uses C3a human liver cells immortalized from a hepatoblastoma line and plasma ultrafiltration. Although there was no difference in survival, there was a trend toward improvement in patients with alcoholic hepatitis, who may have more liver regenerative capacity and generally do not have transplantation as an option. Further studies using an extracorporeal liver assist device for alcoholic hepatitis (in contrast to failed approaches to acute liver failure) are currently being planned.33, 34, 36-38 Basu et al.39 presented the results of a small trial of transdermal rivastigmine, a cholinergic agent used to treat dementia, for the treatment of hepatic encephalopathy. All patients received rivastigmine or placebo in addition to lactulose. The study showed a positive effect, but the exact contribution of lactulose versus rivastigmine could not be discerned because of the small number of patients. Salvalaggio et al.40 discussed the relationship between the Model for End-Stage Liver Disease (MELD) score, postoperative complications, and resource utilization. Not surprisingly, patients with high MELD scores had more infectious and renal complications and required significantly more resources in the postoperative phase, although the re-admission rates were similar. Finally, for intraoperative outcomes, Yassen et al.41 showed that using the right ventricular end diastolic volume via a pulmonary artery catheter as a measure for fluid resuscitation was similar to using the central venous pressure, and patients often received unnecessary fluids with the former measure. Thus, central venous pressure measurements appear to be adequate and avoid the complications associated with pulmonary artery catheters.
IMMUNOSUPPRESSION, REJECTION, AND TOLERANCE
A number of presentations on EVL therapy in LT recipients highlighted the sessions on immunosuppression. De Simone et al.42 reported a large study that randomized patients 1 month after LT to standard tacrolimus (TAC) therapy, EVL and reduced TAC, or EVL and reduced TAC followed by TAC withdrawal. The last group was stopped because of more acute rejection, so only the EVL and reduced TAC group and the standard TAC group were continued. Although proteinuria was higher with EVL (nephrotic in only 1 case), this group had an 8 to 10 mL/minute higher glomerular filtration rate than the standard TAC group at 1 year. The efficacy failure was comparable, and the EVL and reduced TAC group actually had fewer rejections. Fischer et al.43 reported no differences in wound healing, incisional hernias, or hepatic artery thrombosis with EVL therapy in the same cohort. Higher rejection rates with CNI discontinuation in favor of EVL were not seen in a separate study,44 although less improvement in the glomerular filtration rate and no differences in endpoints were found. Notably and similarly to sirolimus (SRL) therapy,36 a higher percentage of patients had to discontinue EVL versus CNI therapy because of side effects. Although the data are encouraging, it is unclear whether EVL will be approved for use in LT recipients.
As reflected in the recently published literature,37, 38, 45-47 there was a high level of interest in donor-specific antibodies (DSAs) affecting LT outcomes. Kaneku et al.48 reported on 912 patients and found that 38% had DSAs before LT. Higher rejection rates were seen for DSA-positive patients (45% versus 36%; mainly class II), and less rejection occurred after induction therapy. This association was also seen after LDLT in a separate study.49 This combination of circulating DSAs and diffuse portal complement component 4d deposition is often seen in rejection and more refractory rejection cases.38, 47 This may translate to outcomes as O'Leary et al.50 showed associations between de novo class II DSAs with high mean fluorescent intensity and patient/graft survival. These associations, however, are retrospective and have not been confirmed in other studies,45 and this highlights the need for prospective assessments.
The meeting also had a number of presentations on LT tolerance and long-term graft outcomes. The Immune Tolerance Network group51 reported an interim analysis of a study into which 275 LT recipients had been enrolled; to date, 89 had been randomized to immunosuppression withdrawal 1 year after LT. Although only a few patients are off immunosuppression therapy, many tolerated a 50% to 75% reduction in immunosuppression therapy. Rejection episodes during withdrawal were mild and rarely required steroid boluses. Thus, early after LT, drug minimization can be achieved in many patients and may reduce the long-term impact of immunosuppression. Of concern, however, is the fact that these minimization/withdrawal approaches can stimulate a low-grade alloimmune or fibrotic response: a report on 20-year protocol biopsy samples showed that nearly all had histological abnormalities.52 Uchida et al.53 reported their histological results for immunosuppression weaning in pediatric recipients, and they focused on those who required immunosuppression re-initiation. Follow-up biopsy samples from this cohort showed that 55% had improved but 21% had worsened fibrosis despite immunosuppression reinstitution. This could have been related to either recurrence of the original disease or chronic inflammation.54-56 Whether protocol biopsy should be performed to guide immunosuppression changes and whether outcomes are affected by this strategy are not well defined in clinical practice.
Abstracts on the management of HCC before LT focused on the roles of resectional surgery and early detection. Del Gaudio et al.57 argued that liver resection for patients with small HCCs and a MELD score <11 can help in selecting appropriate patients for LT and may be a bridge to LT. In these patients, salvage LT offered at the time of recurrence or liver decompensation appears to be a safe and effective approach. This is in keeping with recent publications suggesting no detrimental effects of previous liver resection on the outcomes of a subsequent transplant.58, 59 Goldberg et al.60 discussed the issue of wait-list mortality in patients with or without HCC. The authors suggested that MELD upgrades for HCC could be detrimental to non-HCC patients by leading to higher dropout rates.61, 62
The early detection of HCC is currently being explored by various groups.63-68 In line with this, Gehrau et al.69 presented a multigenic test as a surveillance tool for the development of HCC in HCV-positive patients. Sixty-nine patients with HCC (n = 24) or without HCC (n = 45) had nontumor cirrhotic tissue signatures tested. Seventeen genes were identified as having a high diagnostic performance and were used to correctly classify 81% of the samples, including those with incidental HCC. A proteomic analysis is now being investigated by this group.
Postoperative surveillance for HCC recurrence is an important clinical topic, and the role of microRNA expression as a biomarker of recurrence is of significant interest.70 Ng et al.71 reported data on specific plasma microRNA profiles immediately after transplantation. Their study showed that mir-1246 and mir-151-5p were significant predictors of disease-free survival, and high plasma levels correlated with tumor recurrence after transplantation. This supports the need to study these markers prospectively for use in posttransplant surveillance.
A meta-analysis analyzed 8 studies involving the use of SRL for LT recipients with HCC (6 were retrospective, and 2 were prospective; 4 compared SRL to CNIs).72 The long-term overall and recurrence-free survival rates were improved for SRL-treated patients. The patients benefiting the most were those with microvascular invasion and outside the Milan criteria according to explant findings. Further randomized studies are needed to conclude that SRL or other mTOR inhibitor therapy is beneficial in this setting.
The role of LT for secondary malignancies and particularly colorectal metastases is highly controversial.73, 74 However, 2 presentations from Norway75, 76 suggested promising results. Patients in good health with nonresectable colorectal metastases who had undergone previous surgery for primary colorectal cancer and received at least 6 weeks of chemotherapy underwent LT. These patients achieved a 5-year survival rate of 60%, and even though many had disease recurrences, 33% of the patients had no evidence of this after a median follow-up of 27 months. The metastasis diameter, more recent primary tumor surgery, an elevated carcinoembryonic antigen level before LT, and progressive disease were associated with inferior survival. Thus, selecting patients without these negative predictors may lead to acceptable post-LT outcomes.
EXPANDING THE DONOR POOL
LDLT and Split Donor LT
The assessment of living donor candidates may require liver biopsy to quantify the degree of steatosis seen on imaging. Gallegos-Orozco et al.77 presented a study showing that magnetic resonance elastography assessing liver shear stiffness could be useful in distinguishing abnormal liver histology and particularly in identifying the presence of steatosis. A cutoff of 2.8 kPa was able to identify those with greater than 20% steatosis and was a better discriminator than the body mass index and liver enzymes. Thus, magnetic resonance elastography may supersede the need for biopsy in the process of evaluating acceptable living donor livers.
Song et al.78 reported their 15-year experience with living donation at the Asan Medical Center in Korea. More than 2500 LDLT procedures (the largest series in the world) have been performed with an overall in-hospital mortality rate of 4.8% (3.2% in 2011) and 1- and 5-year survival rates of 90.4% and 78.7%, respectively. The donor morbidity rate has decreased from approximately 10% for right lobe donation during the early stages of the program to approximately 2% (regardless of the graft type) more recently with no donor mortality.
Graft inflow modulation is an important topic in reduced size or living donor transplantation.79-82 In a prospective, randomized, double-blind, placebo-controlled trial, Troisi et al.83 studied the effect of somatostatin on graft inflow modification and ischemia/reperfusion injury. Fifteen patients with a portal vein pressure greater than 15 mm Hg were randomized to receive somatostatin or a placebo. In the 9 patients who received somatostatin, there was a significant reduction in the portal pressure, but there was no difference in ischemia/reperfusion injury as measured by liver enzymes. Cabús et al.84 highlighted the importance of portal inflow in small-for-size syndrome. This study of 45 LDLT recipients suggested that a temporary portocaval shunt should be considered because it allows for flow measurements, which can guide the need for inflow modulation to prevent hyperperfusion. Finally, in a study of 30 living donors, Kakodkar et al.85 proposed that infrared spectroscopy with indocyanine green injection could be useful for identifying small accessory hepatic veins that require reconstruction. The identification and reconstruction of these small vessels should improve the outflow of the living donor graft and reduce hepatic congestion.
Two pediatric reports supported the utilization of left lateral grafts from living and deceased (split) donors. Herden et al.86 showed comparable patient outcomes with a trend toward better graft survival with living donor grafts. Another report87 showed acceptable outcomes in a series of 223 split LT procedures and suggested that the adoption of an intention-to-split policy successfully increased organ utilization and achieved more timely transplantation. The Cleveland group presented a small series of full right and left split LT procedures.88 Patient and graft survival rates were acceptable, but biliary leaks and strictures were present in up to 30% of cases. In keeping with previous reports,89, 90 this highlights the technical difficulties of these split procedures.
Other Extended Criteria Donors
A number of abstracts focused on assessing and improving the quality of the donor liver.91, 92 Dutkowski et al.93 presented an alternative score to the donor risk index. This score (the balance of risk score) detected unfavorable combinations of donor and recipient factors and suggested that livers with greater than 30% macrosteatosis should be used only when the score is low. A translational study by Verhoeven et al.94 showed that microRNA recovered from a preservation solution could be used to assess a donor liver's quality because this is differentially released in donation after brain death grafts versus DCD grafts. Cholangiocyte-abundant miR-296 was lower in perfusate samples of DCD livers, whereas miR-30e correlated with a longer cold ischemia time. Minou et al.95 reported on the use of sevoflurane anesthesia for donors during procurement as a method of preconditioning steatotic grafts. The use of this agent resulted in lower liver enzyme levels and less early allograft dysfunction, even in moderately steatotic grafts. Interestingly, even the discarded grafts of donors who received sevoflurane had less centrizonal necrosis.
The expansion of the donor pool with DCD donors or older donation after brain death donors was supported by 2 single-center studies.96, 97 The first showed no difference in the outcomes of DCD donors who suffered an out-of-hospital cardiac arrest before donation and suggested that these donors could potentially increase the donor pool.96 Taner et al.97 established a link between the incidence of intrahepatic bile duct strictures and the length of time from asystole to cross-clamping in DCD donors.91, 98-100 However, contrary to other published reports,92 the hemodynamic changes in the agonal period during DCD retrieval did not appear to correlate with the development of ischemic cholangiopathy. Giesbrandt et al.101 presented a correlation between the radiological appearance of ischemic cholangiopathy and the clinical outcome following DCD transplantation. Four patterns were identified: hilar strictures, multifocal progressive stenosis, centrifugal progressive stenosis, and rapid progressive peripheral duct necrosis. A subset of patients with cholangiographic abnormalities but no clinical symptoms had outcomes similar to those of patients with clinically significant cholangiopathy. Finally, in a single-center experience,102 the routine use of elderly donors (>75 years of age) was not associated with increases in primary nonfunction, morbidity, or mortality in comparison with patients receiving livers from younger donors.
ABO-incompatible LT has also been developed to increase the donor pool.103-106 Eighty cases of ABO-incompatible LDLT were reported by the Asan Medical Center,107 with rituximab and plasmapheresis used for desensitization. The overall outcomes were comparable to those for ABO-compatible LT, but the development of biliary strictures raises significant concerns.
The prioritization and expanding sharing session featured 7 presentations dealing with worldwide organ sharing issues. The first paper108 suggested that the waiting time has a greater influence than the donor organ quality on the outcome of LT in patients with high MELD scores. Another study109 showed that wider regional sharing of organs to facilitate LT in patients with high MELD scores should be encouraged because it is feasible and allows more expeditious transplantation with similar outcomes. However, the acceptance of donor livers by centers varies widely, and this was confirmed by a study from Argentina.110 The authors identified several factors that could be addressed to improve organ utilization.
The 2012 ILTS meeting in San Francisco, CA was a productive conference with an emphasis on the treatment of viral hepatitis with new protease inhibitors, immunosuppression, liver cancer, and donor allocation. The meeting also highlighted new research directions in genomic testing for the early diagnosis of HCC and the detection of HCC recurrence. The June 2013 ILTS meeting in Sydney, Australia should continue to focus on these novel developments in the field.