Meeting report of the 16th Annual International Congress of the International Liver Transplantation Society.

As the society coupled to Liver Transplantation, the International Liver Transplantation Society (ILTS) considers it important to recap and distribute the highlights of its annual meeting to the recipients of the journal. Thus, this report summarizes key symposia and oral abstracts delivered recently at the 16th ILTS Congress in Hong Kong. It is separated into clinical and surgical sections, and there are subheadings focusing on hot topics in the field of liver transplantation (LT). For each abstract, the full reference is reported in a supplemental issue of Liver Transplantation.1 AFP, alpha-fetoprotein; CNI, calcineurin inhibitor; GFR, glomerular filtration rate; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IL, interleukin; ILTS, International Liver Transplantation Society; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; mTOR, mammalian target of rapamycin; SRL, sirolimus; SVR, sustained virological response; TPA, tissue plasminogen activator; Tr1, T regulatory type 1. Two symposia at the meeting focused on viral hepatitis after LT. The posttransplant session of the opening symposium, which was entitled “The Art of Surgery & Medicine in Liver Transplantation: Today & Tomorrow,” began with a debate between Didier Samuel and John Lake on the pros and cons of hepatitis B immune globulin (HBIG) therapy for the prevention of hepatitis B virus (HBV) recurrence. Both agreed that for low-risk patients (undetectable HBV DNA at transplant and fulminant hepatic failure), HBIG can be stopped at some point after transplantation and replaced by antiviral therapy with a high barrier to resistance. However, the optimal length of HBIG therapy and the specific antiviral regimen are yet to be defined in this population. Patrizia Burra then discussed the main factors leading to hepatitis C virus (HCV) recurrence [high-dose immunosuppression, donor age and steatosis, recipient age, and Model for End-Stage Liver Disease (MELD) score at transplant] and poor retransplant outcomes (lack of a response to posttransplant antiviral therapy and significant recurrence within 1 year). The avoidance of bolus corticosteroids or lymphodepletional therapy and the consideration of LT in younger donors and recipients are more likely to lead to favorable graft and patient outcomes. A second symposium on viral hepatitis began with a presentation by Michael Charlton, who shared data on the association of the donor and recipient interleukin-28b (IL-28b) CC genotype with less fibrosis and a greater response to HCV therapy, consistent with recent pretransplant data.2 This may have future implications for donor selection and decision making when posttransplant antiviral therapy is being considered. James Trotter then reviewed the interaction between posttransplant immunosuppressive therapy and viral hepatitis recurrence, pointing out that convincing data supporting the use of a specific calcineurin inhibitor (CNI) or other immunosuppressive regimen for HCV+ recipients are lacking. Marina Berenguer discussed a number of key points specific to posttransplant antiviral therapy: (1) the achievement of sustained virological response (SVR) is associated with excellent long-term outcomes, (2) treatment at advanced fibrosis stages is less effective in achieving SVR, and (3) early elevations in the hepatic venous pressure gradient (≥6 mm Hg) and FibroScan value (>8 kPa) may predict later development of advanced disease and signify the need for earlier treatment. Thus, early histological and radiological assessments of HCV recurrence may be required to determine the optimal time after transplantation for commencing HCV therapy. Edward Gane then reviewed recent data on the potential for HBIG dose reduction, withdrawal, and even complete avoidance in the setting of highly effective antiviral therapy with low resistance, concurring with previous discussions of the opening symposium. Finally, James Fung discussed the efficacy of pretransplant HBV therapy in patients with decompensated cirrhosis; this may reduce the need for transplantation if biochemical and virological responses occur. This is congruent with other studies demonstrating clinical improvement after antiviral therapy in wait-listed, decompensated patients positive HBV+.3-5 A number of informative abstracts on viral hepatitis were presented. T regulatory type 1 (Tr1) CD49b+ regulatory cells were found to be significantly lower in HCV+ recipients responding to interferon therapy versus those lacking a response (abstract O-17). This assay might have future applications in determining which patients are likely (a low Tr1 CD49b percentage) or unlikely (a high Tr1 CD49b percentage) to respond to antiviral therapy, perhaps similar to IL-28b typing. With the caveat that non-HCV graft dysfunction such as rejection can elevate elastography values, transient elastography was shown to predict early recurrent HCV after transplantation (abstract O-60). Therefore, although this is promising, the low specificity of elastography in the posttransplant setting may limit clinical applications. Next, a large Spanish study demonstrated significantly higher SVR rates when recurrent HCV was treated early (F0-F1: 54% SVR rate) versus late (F2-F4: 18%-33% SVR rate; abstract O-61). These findings support earlier treatment initiation and challenge a more standard, conservative approach of waiting to initiate antiviral therapy until the fibrosis stage is F2 or higher. An interesting French study reported that fibrosing cholestatic hepatitis occurred in a larger percentage (19%) of human immunodeficiency virus (HIV)/HCV-coinfected recipients versus HCV-monoinfected recipients (abstract O-65), and the mortality rate (82%) was higher as well. This was true even in the absence of bolus immunosuppressive therapy, and it was poorly responsive to antiviral therapy. This highlights the negative impact of HIV, even when it is adequately controlled, on HCV recurrence. Finally, Michael Charlton presented data from a large antiviral therapy study showing no clinical benefit of initiating preemptive interferon therapy (before any histological recurrence) soon after transplantation versus waiting for recurrence (abstract O-162). This study and other negative studies have provided strong evidence for not using the preemptive treatment approach for HCV+ recipients.6-8 The theme of many of the presentations was related to factors associated with posttransplant HCC recurrence. In the opening satellite symposium, Christian Toso presented data on HCC downstaging and demonstrated that a total tumor volume ≤ 115 cm3 and an alpha-fetoprotein (AFP) level ≤ 400 ng/mL after downstaging therapy are highly associated with long-term recurrence-free survival. However, a total tumor volume > 115 cm3 or an AFP level > 400 ng/mL after downstaging is highly associated with recurrence after orthotopic LT. In comparison with more standard, traditional criteria (ie, downgrading to the Milan stage), these criteria may more definitively help to determine which downstaged patients are acceptable candidates for transplantation. The plenary sessions had a number of select abstracts focusing on HCC recurrence: A predictive model of 5-year survival benefits of orthotopic LT in HCC patients was reported (abstract O-1). Using the Metroticket, it suggests that multinodular patients without vascular invasion benefit the most. This study highlights the need for biomarkers for the prediction of vascular invasion on explant. A report demonstrated that HCCs with a cholangiocarcinoma component or poor differentiation are more likely to recur after transplantation (abstract O-2). This suggests that performing pretransplant lesion biopsy may be helpful in decision making for transplantation instead of later identifying such negative features on explant histology. The neutrophil-to-lymphocyte ratio at the time of transplant appears to be highly associated with microvascular invasion and posttransplant HCC recurrence (abstract O-134). This simple assay needs to be tested in further predictive models, evaluated before and after locoregional therapy prior to transplantation, and compared to more traditional assays (e.g. AFP). A number of presentations focused on the antiproliferative (antitumor and antifibrotic) effects and overall impact of mammalian target of rapamycin (mTOR) inhibitor therapies. During the opening symposium, John O'Grady and Norman Kneteman reviewed data on the impact of immunosuppression on HCC recurrence and pointed out possible higher risk [CNIs (particularly cyclosporine)] and lower risk [sirolimus (SRL)] immunosuppressive therapies. Although recent data have demonstrated the potential impact of mTOR therapy on HCC recurrence and associated patient/graft survival,9-11 prospective randomized studies currently being performed are needed to confirm these findings and provide more convincing evidence for using these agents in these specific populations. For the antiproliferative effects of mTOR therapy, the Baylor group presented 16 patients who had HCV fibrosis regression (−0.19) when they were converted from a CNI to SRL a year after transplantation and compared them to a nonrandomized CNI-maintained group in which fibrosis progressed by 0.54 (P = 0.04; abstract O-164). These alleged antifibrotic effects of mTOR therapy need to be confirmed in adequately powered randomized studies and correlated with other virological and immunological endpoints. In distinct contrast, a report at this meeting demonstrated significantly worse outcomes in HCV+ recipients treated with SRL (abstract O-5). An exact reason for this finding, such as more aggressive HCV recurrence, rejection, or infectious complications due to SRL, could not be determined because of the limitations of Scientific Registry of Transplant Recipients data. Finally, conversion from a CNI to a new mTOR inhibitor now approved for kidney transplant recipients, everolimus, was associated with a low rate of rejection and significantly improved kidney function versus continued CNI therapy in LT recipients (abstract O-15). In summary, although mTOR inhibitor therapy is controversial and does not have a well-defined indication after LT, the potentially beneficial antitumor and antifibrotic effects need to be explored further and investigated in such subpopulations of recipients. During the opening symposium, Michael Ramsey discussed portopulmonary hypertension and stressed the importance of right ventricular function to peri/postoperative survival. Preoperative and intraoperative echocardiographic monitoring of cardiac function may provide the most useful information for risk-stratifying and managing patients undergoing LT. He then reviewed multifaceted treatments for portopulmonary hypertension, including established (prostacyclin) and novel vasodilator therapy (phosphodiesterase inhibitors, endothelin antagonists, nitric oxide) and antiproliferative agents (imatinib and IL-6 antagonists). Regardless of therapy, however, patients with severe portopulmonary hypertension and/or impaired right ventricular function are still deemed to be inappropriate LT candidates because of their high perioperative mortality. Michael Charlton then enumerated the acceptable indications for simultaneous liver-kidney transplantation from the ILTS consensus conference12: (1) end-stage renal disease with dialysis, (2) a glomerular filtration rate (GFR) < 30 mL/minute/1.73 m2 and proteinuria > 3 g/day, and (3) acute kidney injury with dialysis for longer than 6 weeks. These were established to provide guidance to centers concerning the appropriate allocation of kidney allografts to patients on the LT waiting list. A special symposium exclusively dealing with anesthesia and critical care aspects of liver failure and transplantation was held during the meeting. Shushma Aggarwal discussed the 5 key progressive phases of cerebral perfusion abnormalities in fulminant liver failure: the coupling of cerebral metabolism/neuronal activity and blood flow, hyperemia, increased intracranial pressure, impending herniation, and brain death. Claus Niemann discussed the significant and often unrecognized impact of intraoperative hemodynamic alterations on posttransplant renal function and stressed the need for kidney injury biomarkers (neutrophil gelatinase-associated lipocalin, cystatin C, and kidney injury molecule–1) that can predict impending renal injury. Supporting this concept, one of the abstracts presented demonstrated that serum cystatin C concentrations correlate well with the measured GFR (a level > 1.04 mg/L matches a GFR < 80 mL/minute/1.73 m2) (abstract O-9). Andre deWolf then provided a comprehensive overview of cardiovascular and hemodynamic alterations in decompensated cirrhosis and focused on 4 components: splanchnic vasodilation, vasoconstriction of critical organs (kidneys and brain), high-output cardiac failure, and autonomic dysfunction. He emphasized that impairment of contractility leading to a normal or reduced ejection fraction in LT recipients, who are expected to have high ejection fractions from splanchnic vasodilation, carries an appreciable perioperative risk for cardiopulmonary and hemodynamic complications. Robert Porte finished the session with an overview of clotting abnormalities in cirrhosis, which he stressed are actually not as abnormal or deranged as commonly believed. For instance, even with a low number of platelets and procoagulant deficiencies, von Willebrand factor levels are high, and levels of natural anticoagulants (proteins C and S and antithrombin III) are low; this provides a balance toward normal thrombin generation. Thus, bleeding risks, particularly with interventional procedures, are likely overestimated, often resulting in unnecessary platelet and plasma transfusions. As such, more accurate functional assessments of clot formation in place of standard laboratory tests are needed in this patient population. During the satellite symposium, Ronald Busuttil reviewed data on the outcomes of survivors of LT beyond 20 years. Remarkably, the survival rate exceeds 50% from that time period, and quality-of-life measures demonstrate superior results in comparison with other patients with chronic conditions. Although these data come from a select population, they provide encouraging results for more recent transplant patients with respect to the potential for long-term success. Two select abstracts specifically dealt with the topic of alcohol recidivism after transplantation. The first reported on the utility of the CAGE questionnaire for identifying problematic alcohol use after transplantation. It found that 23% of all recipients reported ≥1 CAGE responses, and approximately 50% of these had abnormal liver histology attributed to alcohol (abstract O-7). This is not surprising as it is known that a significant number of recipients will consume variable amounts of alcohol after transplantation,13 although this abstract challenges the perception that alcohol-related hepatotoxicity and histological injury are rare in this population. In addition, the CAGE questionnaire appears to be a simple, valid screening tool for identifying problem drinking in the posttransplant setting. Another abstract reported on risk factors and outcomes of patients returning to alcohol consumption after transplantation (abstract O-135). Typical pretransplant risk factors (length of sobriety, number of relapses, and family history) were present, but interestingly, there was no difference in 5-year patient and graft survival for these patients versus those not using alcohol. Thus, even with histological injury, alcohol recidivism may not affect early outcomes and instead have negative impacts on survival, often due to cardiovascular disease and malignancy, only much later (>10 years) after transplantation.14 The ILTS meeting had a strong focus on topics and research related to worldwide LDLT. In the surgical sessions of the opening symposium, Dieter Broering and Hasan Yersiz reported results of the right and left lobe splitting procedure for 2 adult recipients and discussed the controversy regarding reconstruction of the middle hepatic vein and the high number of biliary complications. The following recipient criteria for this procedure were proposed: graft-to-recipient weight ratio > 1%, MELD score < 30, cold ischemia time < 10 hours, and recipient age < 60 years. These criteria may delineate the more favorable settings in which the use of this uncommon procedure could be expanded. Yashuhiko Sugawara and Kimberly Olthoff presented the respective East and West LDLT experiences for recipients with high MELD scores (>30). Although long-term results are comparable in patients with high versus low MELD scores, the short-term outcomes (early graft and patient survival) are clearly inferior and should be weighed against the risk to the donor. Michael Abecassis and Chung Mau Lo then debated the technique of minimally invasive living donor hepatectomy using hand-assisted laparoscopy, and they discussed the risks and benefits (cosmetic issues, operating time, costs) of this procedure. This procedure needs to be performed in centers with a large amount of experience with LDLT and this technique. Charles Miller then made the case for left lobe adult living donation using inflow modification (splenic artery embolization and partial portosystemic shunting) to achieve a transhepatic pressure gradient ≤10 mm Hg and a portal flow of 1.5 to 2.5 cc/g/minute. Although the experience of left lobe donation in adults is limited, this procedure may provide expansion of the donor pool while maintaining reasonable recipient outcomes and reducing donor risks. Regarding right lobe grafts, Koichi Tanaka discussed paying close attention to the venous outflow of the graft and the preoperative determination of the middle hepatic vein dominancy to avoid small-for-size syndrome. Chao-Long Chen advocated the use of nonabsorbable sutures to optimize biliary reconstruction in microsurgical duct-to-duct anastomoses. The final debate was related to the use of temporary portocaval shunting versus the application of venovenous bypass. Nigel Heaton supported the practice of portocaval shunting because there are trends toward shorter operative times, reduced requirements for blood products, and stabilization of arterial pressures during the anhepatic phase. Peter Neuhaus, however, supported caval replacement to prevent venous outflow congestion, which depends on circulatory parameters during cross-clamping. A final meeting symposium focused on donor safety. Elizabeth Pomfret presented an update on donor morbidity and mortality based on a survey mailed to several transplant centers. The overall complication rate was reported to be 38%, which was similar to previous data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study.15 The survey reported 26 significant events (21 patients died, 4 required LT, and 1 entered a vegetative state). See-Ching Chan discussed several factors affecting donor quality of life postoperatively, such as preexisting donor psychiatric conditions or risky recipient behavior after transplantation (e.g., substance abuse or noncompliance). Measures to minimize these situations on the donor and recipient sides are mandatory for optimizing outcomes for all individuals. Gary Levy closed the session with a discussion of ethical controversies in donation. He stressed that anonymous donation may help to address the disadvantages experienced by lower MELD score recipients without a suitable donor. He further contended that although many incentives are already in place in Canada (eg, lifelong health insurance for living donors and burial cost coverage for deceased donors), regulated regional and/or national reimbursement policies should be considered and developed for living donors. A number of abstracts focused on LDLT outcomes in different regions of the world. Sung Gyu Lee reported that 300 LDLTs are being performed yearly at the Asan Medical Center in Seoul, Korea (abstract O-158). Significant improvements in outcomes have occurred since the program's inception, likely due to enhanced anterior sector drainage, selection of patients, and surgical expertise. The European LDLT registry compared outcomes of donation in the 1990s versus 2000s (abstract O-159). Donor mortality decreased from 0.7% to 0.1% and Clavien 1-2 complication rates were reduced, but 4 donors requiring transplantation more recently were a concern. Balachandran Palat presented LDLT experiences from Delhi and provided evidence supporting the use of lower graft-to-recipient weight ratios (0.6-0.8; abstract O-160). In his center, recipients experienced excellent outcomes when their MELD scores were not high and there was a balance of portal inflow (30% had splenic artery ligation) and venous outflow. Another abstract addressed the impact of donor age on graft regeneration in LDLT, demonstrating worse early recipient graft function and survival with older donors (abstract O-47). This supports the practice of having age limitations for living donors to optimize both donor and recipient outcomes. Finally, quality-of-life data from donors showed that their mental and physical health scores were above the general population averages (abstract O-86). However, for reasons unknown, donors with lower regenerated liver volumes displayed reduced physical SF-36 scores. A number of notable non-LDLT surgical abstracts were presented. The issue of preserving graft function in donation after cardiac death grafts was addressed by a group that performed TPA graft infusion at the back table before implantation (abstract O-105). This was associated with a relatively low rate of biliary/ischemic complications. Although this is promising, prospective controlled trials are needed to confirm these findings to implement this strategy. Another abstract reported the successful use of 14 deceased donor grafts infected with Clonorchis sinensis, which is highly prevalent in healthy individuals in endemic regions (abstract O-109). Successful transplantation was related to the absence of donor liver fibrosis or biliary strictures, the use of perioperative biliary flushes, and to post-LT treatment with praziquantel. Finally, a number of abstracts demonstrated excellent results of radiological interventions in the treatment of early surgical complications: portal vein stenosis (abstract O-122) and hepatic artery stenosis/thrombosis (abstracts O-124, O-143, and O-146) and biliary strictures after LDLT (abstracts O-129 and O-141). Many of the cases avoided the need for reoperation and had excellent long-term biliary and vascular patency rates; this supports the growing role of interventional radiology in posttransplant management. The 16th annual ILTS meeting was both informative and productive with a focus on worldwide experiences in living donation, viral hepatitis, immunosuppression, and HCC. The next ILTS meeting, which will be held in Valencia, Spain in June 2011, should continue to expand knowledge and improve clinical care in these and other areas.