Fulminant hepatic failure in children: Mortality and the role of orthotopic liver transplantation

Abstracts / Digestive and Liver Disease 39 (2007) A49–A87 PP 33 ANTIMITOCHONDRIAL ANTIBODIES: TWO PAEDIATRIC CASE REPORT G. Torre a , V. Casotti a , M. Candusso a , M.L. Melzi a , P. Stroppa a , M. Bravi a , L. Cavalleri a , M. Bosisio a , M.G. Alessio b , A. Sonzogni c , P. Invernizzi d a

Pediatric Liver Transplantation Centre, Ospedali Riuniti, Bergamo, Italy Biochemistry Laboratory Ospedali Riuniti, Bergamo, Italy c Clinical Pathology, Ospedali Riuniti, Bergamo, Italy d Division of internal medicine and liver unit, S. Paolo Hospital, School of Medicine, Milan, Italy b

Antimitochondrial antibodies (AMA) are the classic serologic marker in primary biliary cirrhosis (PBC). Unlike other autoimmune liver diseases, PBC has not been reported in childhood. We report here two cases of AMA detection in paediatric patients. Case 1: A 4-year-old girl developed acute cholestatic disease (bilirubin 24 mg/dl; liver enzymes × 100) with rapid progression to acute liver failure. Her laboratory tests showed a hypergammaglobulinaemia (>2 g/l) and the positivity of both AMA and liver–kidney microsomial (LKM)-type 1 antibodies, as determined by conventional indirect immunofluorescence on rodent-triple tissues and confirmed by two different liver-blot and immunoblot and a dot-blot. The presence of LKM 1 autoantibody leads to diagnosis of AIH type 2. She was treated by steroid and i.v. cyclosporine. Liver biopsy was not performed at admission, because of coagulation disorder. Two days after starting the therapy, she improved with a rapid recovery of neurological damage and progressive decrease in bilirubin level and liver enzymes. One month after, her liver function tests were within normal range. Liver biopsy showed both inflammatory lobular/interface and intrahepatic biliary tree lesions with ductular proliferation and biliary metaplasia as demonstrated by specific staining techniques (citokeratine) similar to adult PBC. Case 2: A 4-year-old child was investigated in our centre for persistent temperature. We determined occasionally the positivity of AMA autoantibodies on HEP 2 in occasion of ANA investigation. Liver index were completely normal. AMA positivity was determined also by conventional indirect immunofluorescence on rodent-triple tissues and confirmed by two different liver-blot and immunoblot and a dot-blot. These are first two reports of AMA detection under age 10. In first child typical lesions of adult PBC were associated with cholestatic AIH type 2. In the second girl at moment there is no biochemical evidence of liver involvement (further investigations are in progress). doi:10.1016/j.dld.2007.07.096 PP 34 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 , L. Cavalleri a,b,c , M. Bosisio a,b,c , F. Bruni a,b,c , G. Torre a,b,c a

Pediatric Liver Transplantation Centre, Italy Biochemistry Laboratory, 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 hep-

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atic fibrosis (4), methylmalonic acidaemia (2), tyrosinaemia (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, cranio ectodermal dysplasia. Retransplant was required in 8 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 pts (19.4%), vascular complications in 3 pts. 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.2007.07.097 PP 35 FULMINANT HEPATIC FAILURE IN CHILDREN: MORTALITY AND THE ROLE OF ORTHOTOPIC LIVER TRANSPLANTATION F. Bruni, M. Bravi, M. Candusso, L. Cavalleri, M. Bosisio, M.L. Melzi, P. Stroppa, D. Pinelli, M. Colledan, Giuliano Torre Paediatric Liver Transplantation Centre, Ospedali Riuniti, Bergamo, Italy To evaluate the role of orthotopic liver transplantation (OLTx) in fulminant hepatic failure (FHF), defined by coagulopathy (INR > 2) with or without encephalopathy in a patient with no identified chronic liver disease. Retrospective analysis of all children with FHF referred to our centre from October 1997 to August 2006. FHF was diagnosed in 41 patients (23 male, 18 female; mean age 41 months; range 1 day–163 months): metabolic disorder in 10, toxic hepatitis in 7, autoimmune hepatitis in 6, multi-systemic disease in 4 patients; in 14 patients there was a cryptogenic hepatic failure. In 56% of cases, waiting list for OLTx was activated; in the others, there was no indication for it because of underlying disease (multi-systemic disorder) or improvement after appropriate medical therapy. The overall mortality rate was 20%. OLTx was performed in 19 out of 23 listed children; 4 were not transplanted for spontaneous recovery (2), for parents’ refusal (1), for death on waiting list (1). Indications for OLTx in the 19 patients were: cryptogenic hepatic failure (nine), metabolic diseases (five cases: three neonatal hemocromatosis, two Wilson’s disease), autoimmune hepatitis (four) and mushroom poisoning (one). Survival rate was 74% (14/19) in OLTx for FHF and 87% in OLTx with elective indication; the difference between FHF OLTx and elective OLTx cases is not significant (Fischer test). Primary non-function, re-transplantation for chronic reject, multi-organ failure and neurological complications were the cause of death. At a mean of 36.5 months follow-up time, in the transplanted children, we reported four biliary complications: two chronic rejections, one neurological delay as major long-term complications. According to intention-to-treat analysis, the survival rate was 74% (17/23) among listed children and 89% (16/18) among children not assessed for OLTx (2 children died for the underlying disease (respiratory-chain disorder)). The difference in mortality rate in the two groups was not statistically significant (Fischer test). Children with FHF should be referred to a specialized transplantation centre to receive all needed treatments. In our experience, mortality in FHF patients is low, as compared with other series, even in transplanted cases.

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Abstracts / Digestive and Liver Disease 39 (2007) A49–A87

The lack of significant difference in survival rate with elective cases means that OLTx is a safe therapeutic option even in the most severe cases. doi:10.1016/j.dld.2007.07.098 PP 36 PAEDIATRIC LIVER TRANSPLANTATION IN BERGAMO M. Candusso, M.L. Melzi, P. Stroppa, M. Bravi, L. Cavalleri, 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 patients); 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 patients); secondary cirrhosis in 4% (11 patients); sclerosant cholangitis in 2% (5 patients); hepatic congenital fibrosis in 2% (5 patients); autoimmune hepatitis in 1% (4 patients) and graft-versus-host-disease in 1 patient. Immunusuppression 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; 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 case), congenital hepatic fibrosis (two cases), familiar uraemic-haemolytic syndrome (two cases), methylmlonic acidaemia (one case) and for chronic renal insufficiency associated to biliary cirrhosis (two cases). Thirty-eight patients required re-transplant. Thirty-five patients needed 2 and 3 patients 3 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%. 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 months follow-up is 83.3%. doi:10.1016/j.dld.2007.07.099 PP 37 LIVER STEATOSIS IN PAEDIATRIC PATIENTS WITH CHRONIC HEPATITIS B: VIRAL AND HOST FACTORS A. Giannattasio a , F. Cirillo a , D. Liccardo a , V. Terlizzi a , G. Ranucci a , S. Rinaldi a , R. Vecchione b , R. Iorio a a b

Department of Pediatrics, University Federico II, Naples, Italy Department of Phatology, University Federico II, Naples, Italy

Background and aim. Hepatic steatosis is a common histological feature of chronic hepatitis C virus infection. The significance of liver steatosis in chronic hepatitis B (CHB) has not been clearly studied. Aim of the present study was to evaluate the prevalence of steatosis at liver biopsy in paediatric patients with CHB and to investigate factors associated to presence of steatosis. Patients and methods. The study included 56 (38 males; median age at liver biopsy 8 years, range 2.2–17.3) consecutive otherwise healthy children with CHB who underwent liver biopsy for diagnostic purposes at our Pediatric Liver Unit during a 14-year period. In all patients demographic data, clinical features, anthropometric and laboratory data (liver functional tests, fasting glucose, cholesterol and triglycerides) were evaluated at the time of

liver biopsy. As for liver histology, activity of necroinflammation and fibrosis staging were evaluated according to Ishak scoring system. Hepatic steatosis was graded semi-quantitatively by determining the percentage of affected hepatocytes (Brunt classification). Results. Fifty-four patients had no steatosis at liver biopsy. Steatosis of grade 1 (<33% of hepatocytes affected) was present in only 2 (3.6%) children (both males). The two groups were comparable for median age, sex, route of HBV infection. Mean relative BMI was significantly higher in the 2 patients with steatosis (132 ± 9) compared with the group without steatosis (109 ± 15) (P = 0.04). Among 54 patients without steatosis, 6 (11.1%) were overweight and 6 (11.1%) were obese. One of patients with steatosis was overweight and the other one was obese. Relative BMI did not statistically differ between the two patients with steatosis (126.4 ± 1.2) and 12 overweight/obese children without steatosis (125.7 ± 12.3). As for biochemical and virological parameters, no significant difference between patients with and without steatosis were found with regard to ALT, GGT, serum HBV DNA level. Further, cholesterol, triglycerides, fasting glucose serum levels were comparable between the two groups. Conclusions. Differently from chronic hepatitis C, histological evidence of steatosis is detectable only in a small percentage of paediatric patients with CHB. Although in CHB steatosis seems to be related to obesity rather than to viral factors, our data needed to be confirmed with larger scale studies. doi:10.1016/j.dld.2007.07.100 PP 38 IS THE EXCHANGE TRANSFUSION A POSSIBLE SPECIFIC TREATMENT FOR NEONATAL HAEMOCHROMATOSIS? E. Nicastro a , G. Timpani b , F. Foti b , A. Nicol`o b , M. Tufano a , A. Vicinanza a , R. Iorio a a b

Department of Pediatrics, University “Federico II”, Naples, Italy Neonatal Intensive Care Unit, Ospedali Riuniti, Reggio Calabria, Italy

Background. Neonatal haemochromatosis (NH) is a rare congenital disorder that affects the fetus in the late gestation, clinically defined as severe neonatal liver disease associated with extrahepatic siderosis. It is widely accepted that NH is the result of an alloimmune disorder that causes liver injury in the fetus: an alloantibody-mediated liver injury would lead to iron mishandling with resulting siderosis. Poor results have been observed with a treatment with antioxidants and an iron chelator. Although the effectiveness of the exchange transfusion (EXT) in the treatment of neonatal alloimmune diseases is well-known, the effectiveness of this approach in NH has never been evaluated. We report a second born of two siblings with NH successfully treated with EXT. Case report. The patient was a male born at 33 weeks of gestation by caesarean section. The familial anamnesis revealed a first sister died at 18 days for severe coagulopathy and acute renal failure. Apgar scores were 8 at 1 and 9 at 10 . He appeared to have mild generalized oedema and placental hydrops. Laboratory tests showed severe coagulopathy, hypoalbuminaemia and low platelet count. Aminotransferases and D-dimers were normal. The patient did not respond to the treatment with fresh frozen plasma, albumin, activated C protein and antithrombin III. Before achieving a definite diagnosis, the extremely severe coagulopathy and the unfavourable outcome of the elder sister led us to treat the child with an EXT as an intensive supportive care, with rapid clinical and laboratory improvement. Diagnosis of NH was based on elevated ferritin concentration of 2.219.25 ng/ml (N < 800 ng/ml); low transferrin concentration of 101 mg/dl (N 190–320 mg/dl); transferrin saturation 101% (N < 33%); serum AFP was 188,306.25; liver siderosis documented at MRI scanning. Placental biopsy revealed stainable iron in the specimens from either the patient and his elder sister, confirming the diagnosis of NH. Further supportive therapy consisted of continuative substitutive therapy, followed by a second EXT on the fifth day of life. The clear improvement of the patient at the moment of the diagnosis of NH, the lack of conclusive evidence about the efficacy of treatment with chelator/antioxidant cocktail and the risk of side effects associated to the iron-chelating therapy led us to treat the patient with n-acetylcysteine, vitamin E and selenium until a com-