Perspectives in LiverTransplantationJanuary 24–25, 2008Johann Wolfgang Goethe-University FrankfurtGermany

AbstractsPoster Abstracts

Falk Workshop

Abstracts of Invited Lectures Poster Abstracts Falk Workshop PERSPECTIVES IN LIVER TRANSPLANTATION

Frankfurt (Germany) January 24–25, 2008 Scientific Organization: W.O. Bechstein, Frankfurt (Germany)

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CONTENTS Page Session I Liver transplantation for viral hepatitis

Chair: J. Bruix, Barcelona E. Roeb, Giessen Preventing hepatitis B recurrence after liver transplantation (no abstract) D. Samuel, Villejuif Treatment of hepatitis B recurrence after liver transplantation M. Schuchmann, Mainz 9 – 10 Risk factors for hepatitis C recurrence after liver transplantation M. Berenguer, Valencia 11 Treatment of hepatitis C recurrence after liver transplantation W.P. Hofmann, S. Zeuzem, Frankfurt 12

Session II Liver transplantation in malignant disease

Chair: H.E. Blum, Freiburg C. Mönch, Frankfurt Liver transplantation for hilar cholangiocarcinoma H. Lang, Mainz 15 The future of liver transplantation for HCC J. Bruix, Barcelona 16 Liver transplantation for uncommon tumors: A good indication? J. Lerut, G. Orlando, V. Karam, Brussels 17 Liver transplantation for pediatric tumors D. Bröring, Kiel 18

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Session III Acute liver failure

Chair: A.W. Lohse, Hamburg C. Sarrazin, Frankfurt Changing epidemiology of acute liver failure G. Gerken, Essen 21 Extracorporal liver support in acute liver failure M.P. Manns, K. Rifai, Hannover 22 Liver transplantation for acute liver failure J. Pratschke, P. Neuhaus, Berlin 23

Session IV Liver transplantation in metabolic disease

Chair: G. Ramadori, Göttingen C.W. Strey, Frankfurt Liver transplantation for familiar amyloid polyneuropathy A.-P. Barreiros, G. Otto, Mainz 27 Hepatocyte transplantation A. Dhawan, London 28 – 29 Pediatric liver transplantation in metabolic liver disease M. Burdelski, Kiel 30 – 31 Adult liver transplantation for metabolic disease H.H.J. Schmidt, Münster 32

List of Speakers, Moderators and Scientific Organizers 33 – 35

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Poster Abstracts 1. Accessibility of microRNAs by real-time PCR is equal in formalin-fixed paraffin-

embedded and snap-frozen tissue H. Varnholt, M. Tscheuschler, A. Manav, U. Drebber, F. Schulze, I. Wedemeyer, P. Schirmacher, H.-P. Dienes, M. Odenthal (Köln, Heidelberg, D)

2. Acute mesenteric ischemia (AMI)

P. Hasanpour Haghighi (Shiraz, IR) 3. Intrasplenic or subperitoneal transplantation of hepatocytes increases survival

after surgically induced hepatic failure in an allogenic rat model? G. Gäbelein, A.K. Nüssler, N.C. Nüssler, P. Neuhaus, M. Glanemann (Berlin, München, D)

4. Living liver donation a non-calculatable risk for the donor? Or just a lack of

standardized reporting of negative events in LDLT? C. Wilms, N. Heits, D.C. Bröring (Kiel, D)

5. Resection of leiomyosarcoma of the inferior vena cava (IVC) with renal

infiltration and pulmonary metastases. Is a radical concept justified? A case report S. Minouchehr, M.-B. Pitton, G. Otto (Mainz, D)

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Session I Liver transplantation for viral hepatitis

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Treatment of hepatitis B recurrence after liver transplantation Marcus Schuchmann Innere Medizin, Klinikum der Universität, Mainz, Germany Preventing the need for therapy Naturally, the best treatment of hepatitis B after liver transplantation is prevention of reinfection. The inability to do so, an almost inevitable occurring reinfection of the graft and poor overall outcome made HBV associated cirrhosis initially nearly to a contradiction for liver transplantation. It was Samuel et al. who described in their seminal paper in 1993 that prophylaxis with hepatitis B immunoglobulins (HBIg) made it possible to transplant these patients with reasonable good outcome – particularly of benefit was this approach for patients with HBV/HDV coinfection and patients with low viral load at transplantation. However, despite further elaborated regimens of prophylactic treatment, including the use of HBIg in combination with antiviral drugs, recurrence happens: Lok reviewed 12 studies of prophylactic combination therapy with HBIG and lamivudine and reported that post-transplant HBV recurrence was observed in 7/168 patients (between 0 and 10% in the reviewed studies) during a mean follow up of 13–22 months. Viral breakthrough and non-compliance seem to be major contributing factors in this setting, which predominantly is seen in patients who undergo transplantation with detectable viral load. In addition to recurrence, the use of anti-Hbc organs potentially leads to de-novo HBV infection after LTx: Feo et al. demonstrated a de-novo infection rate as high as 43% for HBV-negative patients without prophylactic treatment against HBV infection. Thus demonstrating the need for prophylactic treatment in this group of recipients of anti-HBc positive organs. Treatment of active HBV infection after liver transplantation Since results of treatment of HBV infection with interferon-alpha were dismal – combination of HBIg with nucleos(t)id analogues are part of current treatment strategies. However, HBIg is expensive, has to be given parenterally and mutations that permit HBV to escape the antiviral effect of HBIg can develop. Among antivirals, the nucleoside analogue lamivudine, which inhibits the viral polymerase, kept to be the mainstay of antiviral therapy. However, long-term use of lamivudine is compromised by the frequent emergence of lamivudine-resistant HBV mutants. In a prospective study, Perillo et al. demonstrated, that 32% of transplanted patients had reappearance of serum HBV DNA and YMDD mutations detected after a median of 74 weeks of lamivudine therapy. In 2002, adefovir opened the avenue for treatment of patients with lamivudine resistant viral strains. Entecavir and telbivudine can now be added to the armamentarium with tenofovir as an additional powerful option at the horizon in 2008. In a recently published study, Schiff et al., showed that upon treatment with adefovir of patients in a posttransplant setting, serum HBV DNA levels became undetectable in 40% and 65% at weeks 48 and 96, respectively. Surprisingly, application of HBIg did not further decrease the rate of reinfection in this study. Entecavir is approved for the treatment of wild-type and lamivudine-resistant HBV. However, its activity against lamivudine-resistant HBV is lower compared to wild-type HBV. Despite the use of a higher dose, entecavir 1 mg daily, 60% of patients with lamivudine refractory HBV still had detectable HBV DNA after 96 weeks of treatment. Recent data showed also a higher risk for developing entecavir-

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resistant mutants in the presence of lamivudine resistant mutant. To clear safety and efficacy of entecavir in the post transplant setting more data are needed. Tenofovir was shown to effectively suppress HBV replication in lamivudine-resistant HBV-infection in the non-transplant setting – and preliminary data suggest that this holds true for transplanted patients. In summary, with the availability of newer treatments with lower risk of resistance, lamivudine is no longer an appropriate first-line HBV therapy, particularly for LTx patients with high viral load who require long durations of therapy. Adefovir is associated with a lower rate of drug resistance than lamivudine but it is not an ideal first-line therapy for LTx patients because its antiviral activity is weaker and it has potential for nephrotoxicity. Entecavir, the most potent of the approved nucleos(t)ide analogues for HBV, with a low rate of drug resistance in nucleoside-naive patients seems to be suited as a first-line therapy. However, data in support of its use in LTx patients are lacking as well as for the recently approved telbivudine. Therefore, controlled trials have to be set up, especially to re-evaluate the need of (long-term) HBIg treatment in a time of effective antiviral substances. Along with the guidelines for the treatment in the non-transplant setting, combination therapy may have the greatest benefit in LTx patients with emerged resistant HBV mutants.

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Risk factors for hepatitis C recurrence after liver trans-plantation Marina Berenguer Department of Hepatogastroenterology, Hospital La Fe, Valencia Associated Professor, University of Medicine, Valencia, Spain Recurrent hepatitis C occurs invariably following liver transplantation for HCV-cirrhosis. The severity of disease recurrence though varies substantially between patients; indeed, there are some patients who continue to have minimal changes in their 10th to 15th year liver biopsy while others progress to allograft failure within one year from transplantation. Factors that have been implicated in the natural history of recurrent HCV include those related to the infecting virus (viral load pretransplantation, HCV genotype), the host (race, gender, age…), the immunosuppression (type and intensity), the donor (age, gender, steatosis..) or the surgery (LDLT, ischaemic time, preservation injury..). For instance, there are several studies that have shown a detrimental effect of using old donors in HCV-recipients, with a faster fibrosis progression and a reduced survival observed in those receiving organs from donors older than 40–50 years of age. A strong immunosuppression, mostly in the setting of anti-rejection therapy with boluses of steroids, has also been described in association with aggressive recurrence and impaired survival. In contrast, data on the association between specific immunosuppressive agents (calcineurin inhibitors, mycophenoylate, sirolums..) and hepatitis C recurrence are controversial. The development of post-transplantation diabetes, HIV coinfection, CMV infection, biliary complications or a prolonged ischaemia during the surgery are additional potential factors associated with aggressive recurrence. Most of the data on these factors though come from retrospective studies where positive or negative associations have been described. Determining whether a modification of these factors results in an improvement in outcome is still lacking for most variables. Interestingly, in two recent studies, the modification of immunosuppression (avoidance of steroid boluses, avoidance of triple/quadruple therapy at full doses, gentle reduction of steroids, complete and successful discontinuation of immunosuppression) resulted in a significant histologic benefit. Address for correspondence: Marina Berenguer Hospital La Fe Servicio de Medicina Digestivo Avda Campanar nº 21 E-46009 Valencia, Spain E-mail: mbhaym@teleline.es

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Treatment of hepatitis C recurrence after liver transplantation Wolf Peter Hofmann, Stefan Zeuzem Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Germany Reinfection with the Hepatitis C Virus (HCV) is universal after liver transplantation (LT) for HCV-related end-stage liver disease and leads to chronic hepatitis C in at least 50% of grafts after 1 year and up to 100% after 5 years. At steady-state, HCV viral load is generally ten times higher after LT than before. The progression of chronic hepatitis C is accelerated after LT and decompensated liver disease develops in approximately 40% of the patients. After LT, the tolerability of interferon and ribavirin combination therapy is suboptimal most frequently due to drug-induced bone-marrow suppression and renal insufficiency which is associated with high discontinuation rates. Furthermore, interferon treatment is associated with increased risk of graft rejection. Generally, two interferon-based antiviral strategies after LT have been studied in recent years: early postoperative antiviral therapy before histologically proven liver injury, and the directed antiviral therapy after HCV-induced liver injury occurs. In patients with early postoperative anti-HCV treatment, sustained virologic response rates of 8–20% can be achieved with a discontinuation rate of 12–50%. Treatment of established recurrent HCV infection leads to sustained virologic response rates of 7–26% and is associated with a discontinuation rate of 30–50%. Appropriate patient selection and timing of antiviral treatment are needed to improve outcomes. In the future, new strategies e.g. with specifically targeted antiviral therapy in hepatitis C (STAT-C) are awaited in the transplant population after they have been proven effective and safe in non-cirrhotic patients with chronic hepatitis C. Address for correspondence: Prof. Dr. Stefan Zeuzem Zentrum der Inneren Medizin Medizinische Klinik 1 Klinikum der Johann Wolfgang Goethe-Universität Theodor-Stern-Kai 7 D-60590 Frankfurt am Main Telephone: +49-69-6301-6899 Telefax: +49-69-6301-6448 E-mail: zeuzem@em.uni-frankfurt.de

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Session II Liver transplantation in malignant disease

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Liver transplantation for hilar cholangiocarcinoma Hauke Lang, MA, M.D., FACS Klinik und Poliklinik für Allgemein- und Abdominalchirurgie, Johannes Gutenberg-Universität Mainz, Germany Hilar resection in combination with partial hepatectomy and caudate lobectomy is currently regarded as the treatment of choice for hilar cholangiocarcinoma. Overall 5-year-survival rates range from 9–28%, reaching up to 24–43% in R0-resections. Five-year survival rates in the very limited experience with LTx in hilar cholangiocarcinoma are not dramatically worse than those after resection. However, hilar cholangiocarcinoma is currently not an accepted indication for LTx because of the good results of LTx for benign diseases and the dramatic organ shortage. From an oncologic point of view, a 5-year-survival rate of over 30% for a highly aggressive and otherwise irresectable gastrointestinal tumor is a more than acceptable result. Therefore, and considering the fact that LTx may represent the only possibility for cure, the general exclusion of patients with hilar cholangiocarcinomas from liver transplantation does not seem to be justified. With regard to the present dramatic organ shortage, the use of marginal donor livers otherwise not accepted for patients with end-stage liver disease could provide an alternative. While aggressive surgical approaches such as LTx in combination with Whipple operations or upper abdominal exenterations have failed to improve the results of LTx for hilar cholangiocarcinoma, recent advances in multimodal tumor therapy seem to be most promising in combination with LTx. This is particularly true in selected patients, i.e. those with lymph node negative T1 or T2 tumors. Prospective studies are required to elucidate the influence of a better patient selection and the role of multimodal treatment on the outcome of LTx in hilar cholangiocarcinoma. If the encouraging data achieved with neoadjuvant therapy prior to LTx is confirmed, then not only the general reluctance to proceed with LTx in cases of hilar cholangiocarcinoma will be questioned, but also a discussion about the application of LDLTx could arise.

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The future of liver transplantation for HCC Jordi Bruix, M.D. Hospital Clinico y Provincia, Universidad de Barcelona, BCLC Group, Liver Unit, Barcelona, Spain Transplantation for patients with hepatocellular carcinoma (HCC) has evolved from being a non-allowed indication to one of the major portion of several programs. The experience in the pioneering years of the procedure showed that transplantation of patients with advanced tumor stage was a futile effort, as recurrence and cancer related death at short term was the rule. However, refinement in diagnostic capacity and proper recognition of HCC at an early stage evidenced that transplantation is an optimal therapy for patients with HCC. Since this cancer arises in the setting of chronic liver disease, it could theoretically cure both the tumor and the underlying cirrhotic liver. The seminal paper by Mazzaferro et al in 1995 established the optimal criteria for selecting candidates (single HCC ≤ 5 cm or 3 nodules up to 3 cm each), and thereafter several centers have validated the proposal. Current and future effort have to focus in different fronts. These include the potential to slightly expand the selection criteria (a risky decision as the main problem is the shortage of donors), how to manage and give priority to patients enlisted and facing a long waiting time, strategies to diminish the risk of recurrence in those patients with parameters indicating a higher likelihood of such event and, finally, prevention and treatment of graft reinfection that ultimately damages the new organ and shortens survival. All these challenges require a joint effort by teams devoted to basic and clinical research. Failure to establish such collaborative groups involving state of the art expertise will prevent the advancement in our knowledge and delay the further expansion of the already established benefits of liver transplantation for HCC patients.

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Liver transplantation for uncommon tumors: A good indication? Jan P. Lerut, Giuseppe Orlando, Vincent Karam and the ELTR-registry* Abdominal Transplant Unit, Department of Abdominal and Transplantation Surgery (Prof. J.F. Gigot) University Hospitals St. Luc, B – Brussels, Belgium * The European Liver Transplant Registry is a service of the European Liver and Intestinal Transplant Association (ELITA). E-mail: lerut@chir.ucl.ac.be Due to their scarcity, indications of liver transplantation for vascular tumors are many times either unknown or incorrect. The review of the literature and of European Liver Transplant Registry data has permitted to clarify this matter. LT is very exceptionally indicated in case of giant haemangioma; most indications relate to the presence of a clinically relevant Kasabach-Merritt syndrome. LT is absolutely contra-indicated in case of haemangiosarcoma due to the very rapid and aggressive disease recurrence. Hepatic epithelioid haemangioendothelioma in contrary may represent an excellent indication for LT allowing long-time (disease free) survival even in the presence of extrahepatic disease localisation at moment of transplantation. Haemangiopericytoma may in some exceptional cases such as the development of paraneoplastic syndrome, benefit of LT in terms of improved quality of life. Severe non-cirrhotic portal hypertension caused by nodular regenerative hyperplasia can be cured by liver transplantation. LT is not indicated in case of hepatic schwannoma, lymphoma and non endocrine hepatic metastasis. LT may appear as an option for certain well selected metastasised endocrine tumors if conventional surgery is not feasible and if quality of life clearly improves post transplantation and if the estimated perioperative risk is low. The role of living donor liver transplantation in these settings must be evaluated with care.

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Liver transplantation for pediatric tumors Dieter Bröring Klinik für Allgemeine und Thorxchirurgie, UKSH Campus Kiel, Germany The role of liver transplantation in pediatric hepatic malignancies, especially for hepatoblastoma has been described controversially in several studies. Hepatocellular carcinoma in children as a very rare and mostly advanced disease at the time of diagnosis was always treated with a similar approach. Factors that remained unclear were the prognostic value of vascular invasion, metastatic disease, relapse after primary resection, the optimal timing of neoadjuvant and adjuvant chemotherapy, the technique of liver transplantation and the role of immunosuppression. Furthermore the treatment of other liver malignancies remained unclear. In order to address the value of primary liver transplantation for unresectable hepatoblastoma and hepatocellular carcinoma the SIOPEL 1 (Societé Internationale d’Oncologie Pédiatrique-Child Liver Tumor Strategy group) was performed. The PRETEXT (Pretreatment extent of disease) staging system was developed and was shown to have prognostic relevance: Results of SIOPEL I and II showed a 85% disease free survival at 10 years for primary transplants but only 40% 10-year survival for rescue transplants for hepatoblastoma. The UNOS database also reported favourable outcome for liver transplantation in children with unresectable hepatoblastoma. In contrast to the European studies the American approach involves primary surgical resection and postsurgical staging for resectable tumors. According to the SIOPEL I and II studies indications for LTX for hepatoblastoma are multifocal PRETEXT stage IVB even after clearance of one lobe post standard chemotherapy, a large unifocal PRETEX stage IVB tumor unless chemotherapy allows trisegmentectomy, large unifocal central PTRETEXT stage II involving central veins or hilar structures. The only absolute contraindication is extrahepatic viable tumor mass. Rescue LTX for hepatoblastoma recurrence has very poor results. For hepatocellular carcinoma or hemangioendothelioma liver transplantation has very poor results in children and therefore the development of new chemotherapeutic agents seems to be a rather promising perspective.

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Session III Acute liver failure

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Changing epidemiology of acute liver failure Guido Gerken Universitätsklinikum Essen, Germany Background: Acute liver failure (ALF) is a rare clinical condition with a high rate of mortality. Epidemiologic data is scarce. We know that drug toxicity, with acetaminophen as the major cause, has become the predominant present etiology in the USA and United Kingdom, yet there is only a very limited body of data available on the more recent situation in Germany, especially with respect to the clinical and laboratory features associated with the short-term outcomes of ALF. Aims: (1) To assess the causes of ALF in a monocenter study enrolling patients from a metropolitan area in northwestern Germany; (2) To evaluate clinical and laboratory parameters in association with the patients’ outcome. Methods: A retrospective four-year study (01/2002–12/2005) employed 105 patients fulfilling established criteria for ALF. Detailed clinical and laboratory data were collected during hospitalization, including four weeks after study admission. Results: Sixty-three percent of patients were female and all patients had a median of 42 ± 16 years of age. Drug toxicity accounted for 51% of all cases and, thus, was the most common cause of ALF; combined viral hepatitides A and B were implicated in 22% of the cases; 12% were due to autoimmune hepatitis; and 16% were of unknown origin. Overall patient survival at four weeks was 83%. Fifteen (14%) patients underwent liver transplantation, and 72 patients recovered under best supportive therapy. An increased BMI is significantly (p < 0.5) associated with a poor outcome. Interestingly, high rates of cholestatic enzymes were significantly (p < 0.5) associated with a positive outcome. Conclusion: This study reveals for the first time epidemiologic information showing that, like in the United States and United Kingdom, drug toxicity – in particular due to acetaminophen – has replaced viral hepatitis as the most frequent cause of ALF in a densely populated urban area in Germany. The apparent cause and BMI were associated with higher mortality rates. In contrast, high cholestatic enzymes appeared to be positively correlated to survival rates; this observation may support recent data from animal studies on liver regeneration.

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Extracorporeal liver support in acute liver failure Michael P. Manns, Kinan Rifai Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany Patients with acute liver failure still have a high mortality if liver transplantation is not available in time. Therefore, extracorporeal liver support devices have already been evaluated for a long time. In contrast to bioartificial systems, artificial systems (“liver dialysis”) only support liver detoxification by removing toxic substances. New devices such as MARS (Gambro, Lund, Sweden) and Prometheus (Fresenius Medical Care, Bad Homburg, Germany), often referred to as “albumin dialysis”, have been developed to combine the removal of albumin-bound and of water-soluble substances. Both systems use a different technical approach: In MARS, toxins diffuse along a concentration gradient through an albumin-impermeable membrane into a secondary circuit that is prefilled with an albumin solution. The albumin is continuously “recycled” inside the secondary circuit by different adsorber and low flux dialysis. In contrast, Prometheus® includes an albumin-permeable filter allowing separation of the albumin fraction into the secondary circuit where the albumin-bound toxins are directly removed by two adsorbers. Thereafter, high flux dialysis is performed inside the primary circuit. For these extracorporeal systems, an improvement of hepatic encephalopathy and biochemical markers such as bilirubin is consistently reported. In-vivo comparisons of both systems showed significantly higher extraction capacities for protein-bound and water-soluble substances under Prometheus® than under MARS treatment. Possible pathophysiological mechanisms could be a reduction of portal pressure, the attenuation of intracranial pressure or a removal of vasoactive cytokines. However, only few randomised controlled trials with low patient numbers and conflictive results regarding patient survival exist. Especially regarding use in patients with acute liver failure, only few data exist, most of them uncontrolled trials. One of them reported an improvement of hemodynamic parameters under MARS in comparison to controls. As large randomised controlled multicentre trials are currently on the way, better evidence will be available soon to better define the clinical role of extracorporeal liver support devices in patients with liver failure. Address for correspondence: Prof. Dr. Michael P. Manns Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Carl Neuberg Strasse 1 D-30625 Hannover, Germany Telephone: + 49-511-532-3305 Telefax: +49-511-532-4896 E-mail: manns.michael@mh-hannover.de

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Liver transplantation for acute liver failure Johann Pratschke and Peter Neuhaus Allgemein- und Viszeralchirurgie, Charité Universitätsmedizin, Campus Virchow-Klinikum (CVK), Berlin, Germany Liver failure, whether fulminate or acute-on-chronic, remains a life-threatening syndrome. Under conservative management, acute hepatic failure has a poor prognosis with mortality rates between 60% and 80%. Urgent liver transplantation (LTx) has evolved since 1963 from an experimental procedure to the standard treatment in the life-threatening syndrome of acute liver failure (ALF) in individuals who, according to clinical and laboratory criteria, have a less than 20% chance of survival. In Europe, ALF patients comprise approximately 11% of those transplanted, with 1-year survival rates of between 50 and 75%. Introduction of LTx as a therapeutic option reduced mortality to 20–40%. However, LTx is a costly procedure and has several limitations: ALF is a potentially reversible clinical condition. Early performance of liver transplantation eliminates the chance of spontaneous liver regeneration. Due to the growing disparity between the need for transplantation and the availability of donor organs, only 10% of patients with ALF actually receive an organ. Following transplantation, patients require lifelong immunosuppression and are subject to inevitable infectious complications and a higher rate of malignancy. Some patients are not considered suitable for transplantation for social or medical reasons, such as an active drug abuse or a morbid psychological profile, and the presence of multi-organ failure might contraindicate LTx. With the growing disparity between the numbers of suitable donor organs and patients waiting for transplantation, efforts have been made to optimize the allocation of organs (e. g. split liver transplantation, living donation liver transplantation, recruitment of marginal organs) and to develop extracorporeal methods to support or replace the failing organ.

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Session IV Liver transplantation in metabolic disease

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Liver transplantation for familiar amyloid polyneuropathy A.-P. Barreiros1, G. Otto21Medical Department I and 2Department of Transplantation Surgery, Johannes Gutenberg- University Mainz, Germany Introduction: Orthotopic liver transplantation (OLT) is the only curative option for patients with hereditary amyloidosis. The major problems in these young patients are subsequent diseases like cardiac problems (arrhythmias), intestinal problems and central nervous system complications at transplantation. This leads to a higher perioperative risk and complications like neuropathia may remain for several years. Simultaneously, the amyloidosis liver may be transplantated to other patients in need for an organ but not suffering from amyloidosis (domino-transplantation). Results: 19 patients with hereditary amyloidosis (7 females, 12 males, 49 ± 13 years) underwent a liver transplantation between 05/1998 and 01/2007 at our center. Diagnosed mutations included Val30Met (7 patients) and 10 other mutations in the remaining 12 patients. Symptoms of the disease persisted between 12 and 57 months. 7 patients received a pacemaker prior to OLT for prophylaxis of arrhythmias. Overall, 7 patients died after OLT, 4 of them within the first year after transplantation. 4 patients underwent a combinated liver and heart transplantation because of simultaneous cardiac amyloidosis. Of these, 1 patient did not survive. The causes of death were in cardiac complications (4 patients), infections (2 patients) and malnutrition (1 patient). 1-year survival was 66.7%, 5-year survival 57.3% (Kaplan Meier). Women tended to have a better outcome than men. Prophylactic pace makers, organ rejections or type of mutation had no influence on the survial of the patients. Explanted livers of 17 patients with hereditary amyloidosis were transplanted into other patients as domino-transplantations. The remaining 2 livers of the tranplanted amyloidosis patients could not be transplanted due to steatosis. Most of the domino-transplant recipients suffered from hepatocellular carcinoma (HCC, n = 16), one patient had an alcoholic liver cirrhosis. Of these, 2 recipients of domino organs died after OLT due to arrhythmia after 4 years and due to a recurrance of HCV (fulminant cholestatic hepatitis) 1 year after OLT. Conclusions: Survival after OLT in patients with heriditary amyloidosis is limited. No differences were observed between OLT and a simultanious liver and heart transplantation. The major cause for limited survival were severe subsequent complications of advanced amyloidosis in these patients. Therefore, early transplantation of patients is critical to a beneficial outcome. Domino-transplantation of amyloidotic livers were safe and may be valuable therapeutic alternatives especially for patients with limited therapeutic options and urgent need of an organ, like patients with HCC.

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Hepatocyte transplantation Anil Dhawan, M.D., FRCPCH Director, King’s Cell Isolation Unit, King’s College Hospital, London, United Kingdom Liver transplantation is the accepted method of treatment for end stage liver disease. The improvements in patient and graft survival have mainly resulted from the developments in immunosuppressive drug therapy. Advances in surgical techniques, now allow the use of auxiliary liver transplantation in the management of patients with acute liver failure and certain liver based metabolic defects such as Crigler-Najjar syndrome, urea cycle defects, and familial hypercholesterolaemia. The success of auxiliary transplantation in humans has supported the observation in animal experiments that relatively small amounts of liver tissue can correct the underlying metabolic defect. This has led to the interest in using human hepatocytes for cell transplantation in the management of various liver-based metabolic conditions and acute liver failure. There are a number of potential advantages of hepatocyte transplantation if the technique can prove successful. It avoids the risks and undertaking of major surgery and as the native liver is still in place can help bridge a patient to whole organ transplant or allow liver regeneration in the case of acute liver failure. There is the possibility of better utilisation of donor organs which remain in short supply, particularly if methods can be developed to isolate good quality hepatocytes from marginal donor livers, currently rejected for clinical transplantation. Hepatocyte transplantation has been used as a new treatment for acute liver failure and metabolic liver diseases such as Crigler-Najjar syndrome type I, glycogen storage disease type 1a, and urea cycle defects for long-term correction of the underlying metabolic deficiency. Considerable progress has been made in bringing hepatocyte transplantation to the bedside. However, there are a number of areas for improvement and development. In terms of the livers currently available to isolate hepatocytes, fatty livers are those most commonly rejected for clinical transplantation and represent an important potential source for hepatocytes. Thus improvement of the outcome of isolation and purification of cells from fatty livers is key part of future research plans. There is no doubt that stem cells offer the potential to overcome the current limitations of both supply of hepatocytes and the extent of repopulation of the liver after transplantation. Human foetal hepatocytes, presumably with greater numbers of stem cells, were administered intraperitoneally to patients with fulminant hepatic failure in 1994. Sources of stem cells for therapy could be foetal hepatocytes, cord blood, embryonic, and bone marrow. This is the focus of research world-wide on stem cell biology and there is no doubt that there are many hurdles to cross before any clinical application. If these are overcome then stem cells could differentiate into all types of liver cells, be easier to cryopreserve and thaw with good function, have proliferative capacity in vitro and in vivo, may be less immunogenic and could be used for in vitro gene therapy. Autotransplantation of stem cells would avoid the need of immuno

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suppression and its attendant problems and this could be combined with specific gene replacement e. g. ornithine transcarbamylase, bilirubin glucuronyltransferase In summary the experience gained so far in the handling of hepatocytes and hepatocyte transplantation gives a good basis for the application of the stem cell technologies now being developed.

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Pediatric liver transplantation in metabolic liver disease M. Burdelski University Hospital Schleswig – Holstein, Campus Kiel, Department of Pediatrics, Kiel, Germany Indications for transplantation in metabolic disorders have to be reconsidered, since long-term survival in the natural course of these metabolic disorders is no longer superior to results of LTX. In disorders like cystic fibrosis, some variants of mitochondrial depletion syndrome and organic acidurias with only partial cure LTX may be considered. Indications for LTX in hepatic metabolic disorders are: Chronic and acute liver failure, failure of a second organ and evenpoor quality of life. Preemptive transplantation is justified in patients at risk for failure of a second organ or development of a hepatocellular carcinoma. Transplantation technique includes all technical variants: full-, reduced-size, split- and even living related transplantation and auxiliary partial orthotopic transplantation (APOLT). The role of hepatocyte transplantation in metabolic disorders needs further evaluation. Results of transplantation reflect the severity of the multiorgan diseased patient before transplantation. Worst results are seen in Wilson’s disease and hyperoxaluria type 1. Statistically, survival is not different in metabolic disorders compared to non-metabolic ones. Disease related complications are cerebral death in mitochondriopathy, disease recurrence in the transplanted organ in Niemann-Pick type C, cerebral convulsions in Crigler-Najjar syndrome (CN) and urea cycle defects (UCD), progress of renal failure in hyperoxaluria due to bone released oxalate. The role of antibody formation against the transporter protein in PFIC2 is actually under discussion. Quality of life after transplantation is a major issue. There is no longer a need of 10–14 hours phototherapy in CN-syndrome, no complex and time consuming bad tasting diet in urea cycle defects or tyrosinemia. These benefits should be balanced against the risk of transplantation and transplantation related disease. The timing of transplantation is difficult, since changing modalities in organ allocation have to be taken into consideration. Early presentation in an experienced transplant center therefore is mandatory. References: 1. Burdelski M. Liver transplantation in metabolic diseases: current status. Pediatr

Transplat. 2002; 6: 361 2. Broering DC, Kim JS et al. One-hundred –thirty-two consecutive pediatric liver

transplants without hospital mortality: lessons learned and outlook for the future. Ann Surg 2004; 240: 1002–1012

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3. Morioka D, Kasahara M et al.Living donor liver transplantation for pediatric patients with inheritable metabolic disorders. Am J Transplant. 2005; 5: 2754–2763

4. Kasahara M, Takada Y et al. Auxiliary partial orthotopic living donor liver

transplantation : Kyoto University experience. A, J Transplant. 2005; 5: 558–565 5. Richter A, Grabhorn E et al. Hepatoblastoma in a child with progressive familial

intrahepatic cholestasis. Pediatr Transplant, 2005; 9: 805–808 6. Dhawan A, Mitry RR et al. Hepatocyte transplantation for metabolic disorders,

experience at King´s College Hospital and review of the literature. Acta Gastroenterol Belg. 2005; 68: 457–460

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Adult liver transplantation for metabolic disease H.H.J. Schmidt Infektion, Klinikum der Universität, Münster, Germany The spectrum of metabolic diseases, which necessitates liver transplantation depends on age to some extent. Currently Wilson disease represents the most common metabolic etiology in adult liver transplant recipients. Hereditary hemochromatosis is genetically the most prevalent metabolic liver disease, but disease penetrance is less frequent and liver transplantation is required only in a minor cohort. Potential reasons may include early diagnosis initiating effective treatment, delayed diagnosis due to late onset of symptoms, contraindications for liver transplantation due to multiorgan failure or advanced stage of hepatocellular carcinoma, and failure of identification of disease. In addition, hereditary hemochromatosis has been very recently identified to represent a much more genetically and clinically heterogenous disease than believed before. Genetic testing in the setting of liver transplantation is required, since treatment options and patients´ perspectives may depend on the underlying mutation. In addition, this knowledge enables a simple and rapid screening of relatives from the index patient to detect presymptomatic carriers. It is noteworthy, that metabolic diseases requiring liver transplantation may appear even at very advanced ages. Posttransplant follow-up in patients with Wilson disease, hereditary hemochromatosis, hereditary amyloidosis, cystic liver disease, and familial hypercholesterolemia will be presented and criteria for transplant indication will be discussed. Address for correspondence: Hartmut H.-J. Schmidt Transplantationshepatologie Universitätsklinikum Münster Domagkstr. 3A D-48149 Münster, Germany E-mail: hepar@ukmuenster.de

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List of Speakers, Moderators and Scientific Organizers Dr. A.-P. Barreiros Innere Medizin I Klinikum der Universität Langenbeckstr. 1 D-55131 Mainz Germany barreiro@uni-mainz.de Prof. Dr. W.O. Bechstein Allgemein- und Gefäßchirurgie Klinikum der Johann Wolfgang Goethe-Universität Frankfurt Theodor-Stern-Kai 7 D-60596 Frankfurt Germany wolf.bechstein@kgu.de Dr. M. Berenguer Hospital La Fe Servicio de Medicina Digestivo Avda Campanar 21 E-46009 Valencia Spain mbhaym@teleline.es Prof. Dr. Dr. h.c. mult. H.E. Blum Innere Medizin II Universitätsklinikum Freiburg Hugstetter Str. 55 D-79106 Freiburg Germany hubert.blum@uniklinik-freiburg.de Prof. Dr. D. Bröring Transplantationschirurgie Universitätsklinikum Schleswig-Holstein, Campus Kiel Arnold-Heller-Str. 7 D-24105 Kiel Germany dieter.broering @uksh-kiel.de

Prof. Dr. J. Bruix Hospital Clinico y Provincial Universidad de Barcelona BCLC Group Liver Unit Villarroel 170 E-08036 Barcelona Spain bruix@medicina.ub.es Prof. Dr. M. Burdelski Kinder- und Jugendmedizin Universitätsklinikum Schleswig-Holstein, Campus Kiel Schwanenweg 20 D-24105 Kiel Germany martin.burdelski@uk-sh.de Dr. A. Dhawan King's College Hospital Paediatric Liver Service Denmark Hill London SE5 9RS Great Britain anil.dhawan@kcl.ac.uk Prof. Dr. G. Gerken Gastroenterologie/Hepatologie Universitätsklinikum Essen Hufelandstr. 55 D-45147 Essen Germany g.gerken@uni-essen.de Prof. Dr. H. Lang Klinik für Allgemein- und Abdominalchirurgie Johannes Gutenberg-Universität Mainz Langenbeckstr. 1 D-55131 Mainz Germany lang@ach.klinik.uni-mainz.de

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Prof. Dr. J. Lerut Clinique St. Luc Département de Chirurgie Avenue Hippocrate 10 B-1200 Bruxelles Belgium lerut@chir.ucl.ac.be Prof. Dr. A.W. Lohse Innere Medizin I Universitätsklinikum Eppendorf Martinistr. 52 D-20251 Hamburg Germany alohse@uke.uni-hamburg.de Prof. Dr. M.P. Manns Abteilung für Gastroenterologie, Hepatologie und Endokrinologie Medizinische Hochschule Hannover Carl-Neuberg-Str. 1 D-30625 Hannover Germany manns.michael@mh-hannover.de Dr. C. Mönch Allgemein- und Gefäßchirurgie Klinikum der Johann Wolfgang Goethe-Universität Frankfurt Theodor-Stern-Kai 7 D-60596 Frankfurt Germany christian.moench@kgu.de Prof. Dr. P. Neuhaus Allgemein- und Viszeralchirurgie Charité Universitätsmedizin Campus Virchow-Klinikum (CVK) Augustenburger Platz 1 D-13353 Berlin Germany peter.neuhaus@charite.de Dr. J. Pratschke Allgemein- und Viszeralchirurgie Charité Universitätsmedizin Campus Virchow-Klinikum (CVK) Augustenburger Platz 1 D-13353 Berlin Germany johann.pratschke@charite.de

Prof. Dr. Dr. h.c. G. Ramadori Gastroenterologie Universitätskliniken Göttingen Robert-Koch-Str. 40 D-37075 Göttingen Germany gramado@med.uni-goettingen.de Prof. Dr. E. Roeb Gastroenterologie Universitätsklinikum Giessen und Marburg Paul-Meimberg-Str. 5 D-35392 Gießen Germany elke.roeb@innere.med.uni-giessen.de Prof. Dr. D. Samuel Hôpital Paul Brousse Centre Hépato-Bilaire UPRES 3541 12-14, ave. P. V. Couturier F-94804 Villejuif France eva.cochet@pbr.ap-hop-paris.fr Prof. Dr. C. Sarrazin Innere Medizin I Klinikum der Johann Wolfgang Goethe-Universität Frankfurt Theodor-Stern-Kai 7 D-60596 Frankfurt Germany sarrazin@em.uni-frankfurt.de Prof. Dr. H.H.J. Schmidt Infektion Klinikum der Universität Domagkstr. 3a D-48149 Münster Germany hepar@ukmuenster.de PD Dr. M. Schuchmann Innere Medizin I Klinikum der Universität Langenbeckstr. 1 D-55131 Mainz Germany schuchm@mail.uni-mainz.de

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Dr. C. Strey Allgemein- und Gefäßchirurgie Klinikum der Johann Wolfgang Goethe-Universität Frankfurt Theodor-Stern-Kai 7 D-60596 Frankfurt Germany christoph.strey@kgu.de Prof. Dr. S. Zeuzem Innere Medizin I Klinikum der Johann Wolfgang Goethe-Universität Frankfurt Theodor-Stern-Kai 7 D-60596 Frankfurt Germany zeuzem@em.uni-frankfurt.de