Paediatric liver transplantation in Bergamo

Abstracts / Digestive and Liver Disease 39 (2007) A29–A47 USAGE OF DONOR STEATOTIC LIVERS AFTER A SHORT-TERM INTENSIVE DIETARY TREATMENT IN LIVING DONOR LIVER TRANSPLANTATION IN ADULTS L. Randisi a,b , R. Volpes a,b , S. Gruttadauria a,b , M. Castellese a,b , M. Rubino a,b , M. Minervini a,b , G. Vizzini a,b , B. Gridelli a,b a

Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione, Palermo, Italy b Thomas Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Introduction and aim. An adult-to-adult living donor liver transplant (LDLT) programme has been developed in our centre since 2003, as alternative for recipients who otherwise would have limited or delayed access to a cadaveric organ. Around 20% of our total liver transplant activity currently comes from living donors. The safety of donors must always have priority when considering LDLT, and therefore an accurate and comprehensive step-by-step work-up protocol for donor evaluation has been designed in our centre in order to ensure donor safety and, additionally, to confirm that donor is capable of providing a suitable graft for the recipient. The usefulness of steatotic livers depends on the percentage of fat, being livers with steatosis >30% decrease graft and patient survival (with an additional unpredictable risk for liver donor regeneration). Body mass index (BMI) >30 may reliably predict higher degree of steatosis in most donors. In order to enlarge the pool of living donors livers, but also to improve post-transplant outcomes, we did an attempt to lower the percent of steatosis, rather than to turn down such fat donors, by applying a short-term treatment of diet and exercise in all living-donor candidates with hepatic steatosis. Materials and methods. Fourteen potential LDLT donors (age 27–59, M/F 10/4) with a BMI >30, and/or steatosis at imaging (US, CT or MRI) or at histology, were treated with diet and exercise starting immediately after the initial work-up, and then re-evaluated within 3 months. After nutritional assessment (nutritional and dietary anamnesis, lifestyle evaluation and REE calculation) the dietician arranged a personal diet, moderately hypocaloric (carbohydrates 55–57%, proteins 17–19%, and lipids 24–27%) and encouraged the donor to perform physical activity. Acceptable monthly weight loss was considered about 2–4 kg, with a final gained BMI <30 kg/m2 . Our follow-up protocol included a monthly dietician consult. Results. 7/14 donors did not complete the 3-month dietician follow-up for donor unrelated reasons. In all 7/14 donors who successfully completed the 3-month treatment (BMI <30), a protocol liver biopsy was performed. In all seven treated donors hepatic steatosis <30% was found, and therefore they were considered eligible for donation. After LDLT, none of such donors experienced life-threatening complications or died. Liver function of both resected donors and transplanted graft showed a good outcome, with no differences between them and other LDLT without hepatic steatosis. No differences were found also in term of hospital LOS, liver functional parameter normalization after resection, and liver regeneration. No long-term clinical impairment of treated donors has been observed, and after donation all of them returned to previous activity. Conclusion. In an experienced LDLT programme, donor livers with <30% steatosis are usable and anticipated to have good function. A shortterm dietician intensive regimen for fat donors seems to be effective in lowering hepatic steatosis by reaching such acceptable histological cut-off. This approach may provide a way for persons with steatosis to be successful liver donors and may be therefore useful to increase the organ pool without affecting the donor and recipient safety. doi:10.1016/j.dld.2007.07.043

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PERIPHERAL BLOOD MONONUCLEAR CELLS GZB POSITIVE INCREASE AFTER THE FIRST WEEK FROM LIVER TX IN PATIENTS EXPERIENCING HCV RECURRENCE WITHIN 6 MONTHS A. Perrella, G. Arenga, O. Cuomo Department of Laparascopic, Hepatic Surgery and Liver Transplant Unit, AORN, A. Cardarelli Hospital, Naples, Italy Background. It has been demonstrated that the Granzyme B (GZB) ELISPOT assay might be used as an alternative marker for the cytotoxic T-lymphocyte (CTL) precursor frequency in the evaluation of CD8+ T cells. Furthermore it has been demonstrated that GZB plays a role during HCV infection as marker of CD8+ activation to clear the virus. We aimed to verify whether GZB could be used as marker to early predict HCV recurrence after liver transplantation. Material and methods. We enrolled 26 patients (pts) undergoing LTx for end stage liver disease HCV related. On this subset of subjects we assayed the GZB spot forming colonies (SFCs) on PBMCs by means of ELISpot assay stimulated with tethanic toxoid (TT), before (T0) and 1 week after liver TX (T1). Furthermore, we also performed a GZB ELISpot assay when HCV clinical recurrence was diagnosed (positive high HCV-RNA viral load and histological evidence; in mean at the 4th month). All patients underwent the same immunosuppressive treatment schedule (calcineurin inhibitors + steroids + mycophenolate) and were divided in two groups on the basis of HCV recurrence (group A 16 pts with HCV recurrence; group B 10 pts no HCV recurrence) statistical analysis (U Mann whitney Test) has been managed once the two groups were settled. Results. A T0 we had 132 ± 42 GZB SFCs in group A and 118 ± 36 GZB SFCs in group B without any statistical significant difference. At T1 we had 270 ± 89 SFCs in group A and 120 ± 58 SFCs in group B, with statistical significant increase in group A respect group B (Mann–Whitney U-test, p < .0001). Moreover, at the onset of HCV clinical recurrence, GZB SFCs were 256 ± 68 in group A, without any statistical significant difference respect to T1. Conclusion. Granzyme B, markers of CTL activation during viral infection, has been found increased 1 week after OLTx in those patients who experience a HCV recurrence and to remain triggered at the onset of HCV clinical recurrence. These results would suggest GZB ELISpot assay as an useful tool to assess the early HCV recurrence and to candidate those patients to a pre-emptive interferon plus ribavirin treatment. doi:10.1016/j.dld.2007.07.044 PAEDIATRIC LIVER TRANSPLANTATION IN BERGAMO M. Candusso, M.L. Melzi, P. Stroppa, M. Bravi, M. Bosisio, F. Bruni, G. Torre, V. Corno, M. Guizzetti, A. Lucianetti, D. Pinelli, M. Zambelli, M. Colledan Pediatric Liver Transplantation Centre, Ospedali Riuniti, Bergamo, Italy We retrospectively studied 312 patients, undergone 350 OLTx from October 1997 till April 2007, at a median age of 3.5 years (range 29 days–17.3 years). Extrahepatic biliary atresia (EHBA) was present in 56% of cases (177 patients); Alagille’s syndrome in 8% (26 patients); primitive cirrhosis in 6% (18 cases); hepatic tumours in 4% (12 patients); metabolic diseases in 7% (22 patients); acute liver failure in 5% (17 patients); Byler’s disease in 4% (14); secondary cirrhosis in 4% (11 cases); sclerosant cholangitis in 2% (5); hepatic congenital fibrosis in 2% (5); autoimmune hepatitis in 1% (4) and graft-versus-host disease in 1 patient. Immunosuppression therapy (IS) has been based on steroid and cyclosporine till 2000, and later on steroid for 4 months and tacrolimus (TAC). The median waiting time was 55 days (range 1–367 days). At transplant, the median weight was 14.3 kg (range 2–82 kg). The overall survival rate at 5 years is 86.2%; EHBA survival rate is 92%. The mean follow-up is 50.4 months. Split liver was performed in 75% of cases;

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Abstracts / Digestive and Liver Disease 39 (2007) A29–A47

whole liver in 20.8%; reduced liver in 4.2% of total cases. Kidney–liver transplants were needed in eight patients: for ossalosys oxaluria (one), congenital hepatic fibrosis (two), familiar uremic–haemolytic syndrome (two), methylmlonic acidaemia (one) and for chronic renal insufficiency associated to biliary cirrhosis (two). Thirty-eight patients required re-transplant. Thirty-five patients needed two and three patients needed three grafts, with an overall survival rate of 60.5%. Biliary complications were reported in 34.3% of cases; vascular complications (stenosis or thrombosis of hepatic vessels) in 20.8%. Acute rejection was diagnosed in 33% of children, every case recovered after steroid bolus. Chronic rejection in 24.4% (7% early chronic rejection, 6.2% late chronic rejection, 2.8% vanishing bile duct syndrome, 3.8% de novo autoimmune hepatitis). PTLD was diagnosed in 13.7% of total cases; monomorphic form occurred in 17.9% of PTLD cases, after 24 months on average from OLTX; polymorphic PTLD was diagnosed in one case; in the majority of patients, only early lesions were reported. In each case of monoclonal PTLD, IS was stopped. Complete remission was reached in 97% of cases, survival rate at 41 follow-up months is 83.3% doi:10.1016/j.dld.2007.07.045 LIVER TRANSPLANTATION IN CHILDREN WITH METABOLIC AND GENETIC DISORDERS: EXPERIENCE OF ONE CENTRE P. Stroppa a,b,c , M. Candusso a,b,c , M.L. Melzi a,b,c , M. Bravi a,b,c , M. Bosisio a,b,c , F. Bruni a,b,c , G. Torre a,b,c a

Pediatric Liver Transplantation Centre, Bergamo, Italy Biochemistry Laboratory, Bergamo, Italy c Clinical Pathology, Ospedali Riuniti, Bergamo, Italy b

Metabolic and genetic diseases are a heterogeneous group of disorders, often with liver involvement. Transplant could be a feasible therapy both for irreversible, acute or chronic, liver failure and for enzyme replacement. In our centre metabolic diseases are the second largest indication for orthotopic liver transplantation (OLTx) in children after extrahepatic biliary atresia (EHBA). We retrospectively reviewed the 350 OLTX performed in 312 children between October 1997 and April 2007; out of these, 67 children (40 M, 27 F) with metabolic/genetic disease (21.5%) underwent 75 OLTX for: Alagille’s syndrome (26 cases), Byler disease (14), Crigljer Najjar 1 (4), glicogenosis IV (3), familiar haemolytic uremic syndrome (SEU) (2), neonatal haemochromatosis (2), Wilson’s disease (2), congenital hepatic fibrosis (4), methylmalonic acidaemia (2), tyrosinemia (2) and 1 case for each propionic acidaemia, ornithine transcarbamylase deficiency (OTC), cystic fibrosis, oxalosyis oxaluria, citrullinemia and cranio ectodermic dysplasia. At OLTX the median age was 2.63 years (range 29 days–16.7 years); the median weight 11 kg (range 2.3–55 kg); the median waiting time 37 days (range 1–367 days). Split liver technique was performed in 45 cases, whole liver in 19 and reduced liver in 3, all from cadaveric donors. Indication for combined kidney and liver transplantation included oxaluria (1), familiar SEU (2), congenital hepatic fibrosis (2), methylmalonic acidaemia, cranioectodermal dysplasia. Re-transplant was required in eight cases (13.4%), for chronic rejection in the OTC patient, acute rejection in 1 case (SEU), PNF in 3 Alagille’s syndrome, in 2 Byler diseases and in one haemochromatosis. The overall survival rate (OSR) is 87% at 1 year (OSR of EHBA is 92%). The main complications were acute (11 cases, 16.4%) and chronic (10 cases, 14.9%) rejection, de novo autoimmune hepatitis (4), and PTLD (1). Biliary complications were reported in 13 patients (19.4%), vascular complications in 3 patients. Neurological complication in one case of SEU. OLTx represents an effective therapy for replacing failing liver, and corrects underlying defects. Clinical phenotype of all our patients was corrected and metabolic decompensation did not occur after OLTX. Transplantation should be considered as a promising treatment currently available to improve quality of life. Mortality rates of this group of patient are mostly comparable to that of the other group of transplanted children. doi:10.1016/j.dld.2007.07.046

HCC PROGRESSION BEFORE LIVER TRANSPLANTATION: DROPOUT OR SALVAGE LIVER TRANSPLANTATION? A. Vitale a , E. Gringeri b , M. Valmasoni b , F. D’Amico b , M. Polacco b , P. Burra c , D. Dupuis a , A. Brolese b , G. Zanus b , D.F. D’Amico a , U. Cillo a a

Istituto Oncologico Veneto, IRCCS, Unit`a di Chirurgia Oncologica, Padua, Italy b Dipartimento di Chirurgia Generale e Trapianti d’Organo, Unit` a di Chirurgia Epatobiliare e Trapianto Epatico, Padua, Italy c Dipartimento di Scienze Chirurgiche e Gastroenterologiche, Divisione di Gastroenterologia, Padua, Italy Background and aims. Tumour progression before liver transplantation (LT) is the main cause of dropout from the waiting list of patients with hepatocellular carcinoma (HCC). This prospective study was designed to evaluate the effectiveness of a policy prioritizing HCC patients with a progressive disease although pre LT adjuvant therapy. Methods. Study period: 2000–2006. Exclusion criteria for LT: macroscopic vascular invasion, metastases, and poorly differentiated disease at percutaneous biopsy. A specific multimodal adjuvant algorithm was used to treat HCC before LT. Among HCC patients of the same blood group, response to adjuvant therapy (complete, partial, or progressive/stable disease) was the main priority criterion: patients with a controlled disease progression (complete re-staging and biopsy of the tumour) without aggressive features were maintained in the waiting list and prioritized. Adult patients with benign chronic liver disease enlisted for primary LT in the same period at our Institution represented the control group. Results. The overall risk of drop out/death for the HCC group (128 patients) during the waiting list was not significantly different with respect to the control group (420 patients): 12% versus 15%, respectively. Although 29 HCC patients with a progressive/stable disease (8 within and 21 outside the Milan criteria) were maintained in the waiting list, the intention-to-treat survival curve of the HCC group overlapped with that of the benign group (5-year survivals were 73% and 71%, respectively). Progressive disease did not prove to be a significant predictor of dropout Probability or survival rates using Cox analysis. Only 3 HCC recurrences developed in the 85 HCC-transplanted patients (47 within and 38 outside the Milan criteria at pathologic exam) after a median follow-up of 21 months. Conclusion. The results of this study strongly support a policy using salvage liver transplantation for selected HCC patients with a progressive disease. doi:10.1016/j.dld.2007.07.047 PROGNOSTIC FACTORS AFFECTING 1-YEAR HEPATOCELLULAR CARCINOMA (HCC) PROGRESSION IN LIVER TRANSPLANTATION CANDIDATES M.G. Luc`a a , S. Vezzoli b,c , E. Armellini a , M. De Giorgio a,b , R. Bezzo b , G. Gaffuri a , R. Nani a , M. Colledan a , S. Fagiuoli a , M. Strazzabosco d,b

a

Ospedali Riuniti di Bergamo, Italy CeLiver, Ospedali Riuniti, Bergamo, Italy c Universita’ di Milano-Bicocca, Italy d Yale University, United States b

Introduction. HCC is heterogeneous cancer with different risk factors, biological features and response to therapy. Liver transplantation allows achievement of best overall survival. A modified HCC patients MELD score is used for transplant waiting lists and treatments of patients while in waiting list are commonly used to down stage HCC. A subset of patients shows HCC progression despite treatments conditioning drop out from waiting list and no differences are found in comparison to patients without progression in MELD score. The ability to identify these patients would be important in decision making and organ allocation.