New abstracts added to Literature (see link on left) 13th August 2010
ILTS 16th Annual International Congress, Hong Kong
Full program details
ILTS Congress Daily Report: Josh Levitsky reports on the very successful recent meeting in Hong Kong. See also Olaf Guckelberger's reports in Surgery.
Friday June 18
Today I’ll be summarizing some of the key presentations on the Friday of ILTS Hong Kong 2010. An excellent symposia on anesthesia and critical care occurred in the morning. Dr. Aggarwal discussed the 5 key phases of cerebral perfusion abnormalities occurring in fulminant liver failure: coupling, hyperemia, increased ICP, impending herniation, brain death- with an increase in cerebral blood flow until the last stages of ischemic brain injury. The brain is affected by liver failure and the multi-organ failure processes (heart, lung, kidney, metabolic). Dr. Niemann then discussed the fact that more data are needed on the impact of intraoperative hemodynamic alterations on renal function postttransplant. Biomarkers such as NGAL, cystatin-C, KIM1 may be helpful but need further study. Interventions to increase kidney perfusion are needed, such as those that increase perfusion in liver failure (splanchnic vasoconstrictor therapy, colloids). Andre deWolf provided an excellent overview of cardiovascular and hemodynamic alterations in ESLD, focusing on four critical components- vasodilation, vasoconstriction of critical organs (kidney, brain), cardiodepression, autonomic dysfunction. James Findlay then discussed HPS and PPHTN as being associated with vasodilation and vasoobstruction, respectively, and then potential treatments (transplant for both, endothelin antagonists for PPHTN). Dr. Porte rounded out the session with a comprehensive overview of clotting abnormalities in ESLD- which actually are not as ‘abnormal’ as previously thought. For instance, even with low platelets, VWF levels are high that counteract this. Also procoagulant and anticoagulant deficiencies in ESLD balance each other out to allow normal thrombin generation. Lastly he finished the session discussing the importance of low CVP to lower portal pressures intraoperatively and the risk of bleeding, emphasizing a recent RCT showing less intra-op bleeding with low CVP vs. standard approach. More trials are needed to determine if this approach improves other outcomes or survival.
The afternoon abstract session on ALF and ECD had a number of select highlights…Emergency LDLT was presented by Dr. Rao showing excellent survival results (6.4% mortality), with transplants done on average within 5 days after expeditious donor evaluation. Indeterminate ALF was presented by Dr. Coilly showing typical (coagulation, factor V, liver function, Clichy criteria, SOFA score) factors associated with survival. Dr. Hashimoto demonstrated a relatively low rate of biliary/ischemic complications with using TPA injection at the backtable for DCD grafts.. prospective controlled trials are however needed to confirm its efficacy. Rhee et al presented an interesting review on the widely variable DCD policies of hospitals in region 1, with most reporting ambiguous or unclear policies—this aspect did not appear to affect outcomes. Dr. Gao reported on 14 deceased donor grafts infected with Clonorchis sinensis but without abnormal histology, cholangitis, biliary strictures can be used successfully for recipients, after postLT praziquantal therapy and adequate perioperative biliary flushes- no postLT infections in the recipients occurred. The group at Kiel Germany (Braun et al) reported a high (30%) rate of hepatitis E virus IgG positivity in over 70 stable LT recipients.. the significance of this is unclear however. Dr. Kim from Korea then showed successful outcomes of 6 sAg donors being transplanted into 6 sAg+ recipients with standard HBIG and antiviral prophylaxis. None of the donors had fibrosis and all were considered carriers.
The day concluded with the late sessions, of which Recurrent Disease was a highlight. Dr. Petridis presented on the different timings of portal hypertension developing postLT, noting early development associated with fibrosis but no cirrhosis, cholestasis, and a number showing nodular regenerative hyperplasia suggesting aberrant/abnormal microvascular circulation. Late portal HTN (>3 months) was most typically seen in cirrhotic, cholestatic patients. Outcomes for both (graft/pt survival) were much worse than the non-portal HTN patients. An interesting study by Bertuzzo showed that the neutrophil-to-lymphocyte ratio at transplant was highly associated with postLT HCC recurrence, alongside and correlating with microvascular invasion, and higher with sirolimus therapy. A highlight of this session was an abstract by Deruytter on aspects and outcomes of patients returning to ETOH use after transplant. The groups were divided into no ETOH, slips, and harmful drinkers (>2-3/day). Risk factors for harmful drinking were time of sobriety preLT, #relapses, and family history. However, long term patient and graft survival (5 yr) were no different among the groups, even though up to 30% either had slips or harmful drinking. Finally Kashyap presented on piecemeal necrosis on explants of HCV patients being highly associated with the development of recurrence later, suggesting the need to closely monitor and treat these patients earlier as they are higher risk for recurrence
Final day is tomorrow..
Thursday June 17
Thursday began with Vanguard case sessions – here’s a report on Session#2. Interesting case presentation by Andrew Cameron on an alcoholic patient with Tylenol overdose, who underwent temporary portocaval shunt and hepatectomy (as he was medically unstable for transplant), followed by transplant a few days later.The discussion by Dr. Belghiti focused on this two stage procedure that is generally associated with poor outcomes, as well as when fulminant patients are too sick for transplant: multiorgan failure, uncontrollable acidosis, high pressor requirement. The second case presented by Albert Chan involved a child developing small for size syndrome, even though the GRWR was 1.2% which would normally be appropriate for adults (but perhaps not for children). The Clavien criteria for small for size in GRWR < 0.8% were discussed and the management utilizing splenic artery ligation or hemiportocaval shunt was reviewed by Dr. John Roberts. Dr. Roberts stressed the importance of measuring the portosystemic gradient and that older donors (such as this case) may be more susceptible even with larger sized grafts.
The Plenary Session I had a number of interesting oral presentations. The first two involved 1) prediction of 5 year survival for OLT in HCC patients utilizing the ‘metroticket’, suggesting multinodular patients benefit the most (Vitale et al), and 2) factors associated with very low HCC recurrence (Milan criteria, AFP<400, lack of cholangiocarcinoma component or poor differentiation), suggesting biopsy might be helpful (Irtan et al). A highlight of the session was Dr. Cheung’s presentation on the high sensitivity, specificity, PPV and NPV of dual tracer (FDG, C-Acetate) PET scan for diagnosis of HCC, better than conventional CT or single tracer FDG PET. Next the French experience (Boleslawski et al) regarding OLT for cholangiocarcinoma in the last >20 years was presented, demonstrating poor outcomes (24% 10 year survival, median survival 26 months due to recurrence). The patients receiving neoadjuvant therapy fared better, although no significant predictors were identified. Kymberly Watt then presented SRTR data on factors associated with death in HCV vs. non-HCV transplanted patients. The use of any sirolimus therapy at discharge and even up to a year posttransplant was associated with an increased risk of death only in the HCV+ population, although graft loss was not significant. The reasons for this are unclear and need to be further evaluated in other prospective studies. The next abstract (Teperman et al) demonstrated excellent interim safety and viral efficacy results with the use of Truvada and discontinuation of HBIG 6-9 months after transplant. Another highlight was a presentation (De Simone) on the use of CAGE to identify posttransplant patients with problem alcohol drinking, finding that 23% of liver transplant recipients (whether alcohol was the etiology of cirrhosis or not) reported ≥1 CAGE response and in 50% abnormal liver histology related to alcohol. This CAGE questionnaire can be readily applied to all patients to screen for recidivism or new drinking. Finally D’Amico reported an interesting randomized study of giving N-acetylcysteine at the time of donor harvest, demonstrating reduced signs of ischemia/reperfusion injury and graft loss at 3 months.
Dr. Richard Freeman gave the State of the Art Lecture I and poignantly used Confucius’ principles of impartiality, humanity, rightness, and timeliness in discussing liver allocation. He pointed out failures of the MELD system to not account for patients with poor quality of life or have diseases with a high chance of progression/drop-out on the list. The challenge, according to Dr. Freeman, is determining who has the best chance of success, a balance of timing vs. need.
Two of the abstract sessions in the afternoon had notable highlights. For the Immunosuppression session, a number of key abstracts were presented: 1) Efficacy of everolimus in de novo LT recipients, demonstrating improved GFR vs. CNI therapy and a low rate of rejection with conversion (Saliba et al); 2) 2 abstracts (Stenard et al) on Tregs- Tr1 CD49b cells lower in HCV+ recipients responding to IFN therapy, suppressive Tregs higher with conversion from CNI to rapamycin. This CD49b assay could be used to identify patients unlikely or likely to respond to antiviral therapy, perhaps similar to IL28b; 3) Measurement of an immunosuppressive test (HCV-specific) prior to transplant to determine if FK inhibits HCV responses (Perella). This group is doing a prospective study to see if use of this pretransplant in vitro assay helps guide immunosuppressive therapy selection after transplant- i.e. avoiding FK in patients with strong suppression of HCV responses pretransplant; 4) Immuknow assay at transplant may predict subsequent risk of infection if low, but not rejection if high (Yu). This is similar to other prior reports, but this is utilizing the Immuknow at transplant rather than later during rejection or infection, as a predictive assay. Prospective studies are underway per the author; 5) Better compliance with once-daily Advagraf after switch from standard Prograf, with no safety concerns during the switch (Toti).
The Hepatitis C concurrent session presented a number of clinically applicable abstracts: 1) Italian (Rigamonti) report of use of transient elastography to predict recurrent HCV early after the transplant. The authors advocate early elastography to avoid the delay in HCV recurrence diagnosis and treatment, but also mention that non-HCV recurrence graft dysfunction (inflammation, rejection) can alter this test and confound the results; 2) A large Spanish (Berenguer) study of predictive factors of SVR in treatment of recurrent HCV in 128 IFN-treated recipients, with a focus on the impact of baseline disease (fibrosis) severity. SVR was completely dependent on 3 factors: genotype (non-1), young age, and Fibrosis 1 or less- suggesting that early treatment before advanced fibrosis is more successful at viral eradication (SVR in F0-1 54%, F2-4 33% and 18% in F4); 3) Interesting report (Prakoso) on ductular reaction and hepatic progenitor cells in recurrent HCV- this correlates with fibrosis at early stage, but ductular reaction persists and the progenitor cells diminish with more advanced disease, suggesting abnormal regeneration and response to injury; 4) French (Duclos-Vallee) report on FCH being high (19%) and with high mortality (82%) in HIV/HCV vs. HCV alone recipients. In fact approximately ¾ of coinfected patients had F2 or greater at 2 years from transplant; 5) 2 abstracts (Jain, Takada) demonstrating equivalent HCV recurrence rates and outcomes in living donor vs. deceased donor- similar to other more recent studies; 6) REFINE study (Tryphonopoulos) showing that steroids + CNI increase graft HCV replication but do not appear to worsen outcomes (i.e. recurrence, graft loss, survival) at 12 months vs. a steroid-free CNI (IL-2R + MPA) group.
Excellent data and sessions today… expect more tomorrow…
Wednesday June 16
Welcome ILTS website visitors! Today I’ll be summarizing some of the key issues discussed on the first day of ILTS Hong Kong 2010. As usual with the first day of the meeting, the Satellite Symposium “The Art of Surgery and Medicine in Liver Transplantation: Today & Tomorrow” took place and was highly informative. I’ll be reviewing the middle sessions on Medicine, and my surgical colleague Olaf Guckelberger will report separately on the first and last Surgery sessions.
Session II focused on pretransplant considerations and management. The first talk was given by Christian Toso on successful downstaging as a criteria for liver transplantation. He noted that most downsizing studies had excellent 5 year survivals after transplant (80-90%) but cautioned that these were carefully selected patients who had HCCs reduced into and then maintained in Milan criteria. He then discussed his paper demonstrating that total tumor volume <115 and AFP<400 after downstaging therapy was highly associated with long term recurrence-free survival, while the opposite situation (either TTV >115 or AFP>400 after downstaging) were associated with recurrence. Thus, both biological (AFP) and morphological (total combined size) downstaging (i.e. “not just downsizing”) are important before considering transplant. Dr. Michael Ramsey then gave a provocative talk on portopulmonary hypertension and pointed out that no matter what the pulmonary pressures or vascular resistance are, the most important factor is the right ventricular function of the candidate. If this is well maintained, patients typically do well with liver transplant, although some with pulmonary hypertension can still develop intraoperative/postoperative worsening, resulting in congestive hepatopathy and high morbidity/mortality. He reviewed the multidimensional approach to these patients, including vasodilator (prostacyclin, phosphodiesterase inhibitors, endothelin antagonists, NO) and antiproliferative agents on the horizon (imatinib, IL-6 antagonists). Michael Charlton from Mayo then provided a comprehensive review of indications for simultaneous liver-kidney transplantation, pointing out 3 classes of patients identified as candidates by the ILTS Consensus Conference (2009): 1) ESRD on dialysis 2) GFR<30 and proteinuria >3 g/day 3) Acute kidney injury on dialysis for >6 weeks. He also noted that many have discussed prioritizing liver transplant recipients who require dialysis for more than 6 weeks after transplant (no kidney) high on the kidney transplant waiting list, although no formal policies are in place. Session II then ended with Dr. Anil Dhawan from the UK who discussed the importance of early Kasai for biliary atresia, and to consider transplantation in children who continue to be jaundiced for 3-6 months after Kasai (indicating failure of the procedure).
Session III was devoted to posttransplant management and began with a debate between Dr. Didier Samuel (pro-HBIG) and Dr. Jack Lake (anti-HBIG). Dr. Samuel pointed out that sAg and HBV DNA recurrence both need to be prevented, and can only be done with combination HBIG and antiviral therapy, respectively. However, he and Dr. Lake both agreed that low risk patients (undetectable HBV DNA at transplant, fulminant hepatic failure) could have HBIG stopped in place of antiviral therapy associated with minimal resistance (combination lamivudine + adefovir, tenofovir). Next Dr. Patrizia Burra from Padova discussed retransplantation for recurrent HCV, a growing problem. Main factors were identified in contributing to recurrence and poor retransplant outcomes: immunosuppression (with most studies not showing a difference between tacrolimus and cyclosporine), donor age and steatosis, recipient age and degree of liver failure (high MELD, bilirubin >10), lack of response to posttransplant antiviral therapy, and early recurrence (<1 year). Dr. John O’Grady and Dr. Norman Kneteman then reviewed extensive literature on the impact of immunosuppression on HCC recurrence, pointing out several factors: high dose CNI therapy (particularly cyclosporine) as contributing to recurrence, similar to high AFP or vascular invasion, and using IL-2R antagonists and particularly sirolimus, with antiproliferative effects, as reducing recurrence. Finally, Dr. Geoffrey McCaughan provided an elaborate mechanistic and clinical review of animal and liver transplant tolerance. He focused on how donor hepatocytes and CTLs engulf recipient lymphocytes (so called “suicidal emperipolesis”) in the early pathway toward tolerance. For human studies, he pointed out recent data from Barcelona on gene signatures (NK cells, δγ T cells) and PBL Tregs seen in tolerant recipients, all of which are undergoing prospective investigation in a European multicenter trial.
More to come tomorrow…..
To view New York 2009 lectures, click on Lectures (see link on left) but to view the abstracts and posters, click on the links below:
- All abstracts as published in Liver Transplantation Annual Meeting Supplement;
- Poster pdfs subset of above, with extended text, tables and graphs.
Hepatology Section Editor: Ed Gane;
Editorial Assistant: Caroline McAleese;
Associate Editors: Michael Heneghan, Josh Levitsky, Dider Samuel, Simone Strasser.
The ILTS physician web administrator for the specialty sections is Dr John Klinck. To contact him with constructive comments and ideas on these sections use john.klinck@addenbrookes.nhs.uk.
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