M. Bravi

Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience.

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%. Liver Transpl 12:573–577, 2006.

Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.

Romano F, Stroppa P, Bravi M, Casotti V, Lucianetti A, Guizzetti M, Sonzogni A, Colledan M, D’Antiga L. Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.
Pediatr Transplantation 2011: 15: 573–579.

Fulminant hepatic failure of autoimmune aetiology in children.

Objective: Autoimmune hepatitis (AIH) is considered an underdiagnosed cause of fulminant hepatic failure (FHF). Autoimmune FHF (AI-FHF) is believed to lead invariably to liver transplantation (LTX) or death. We aimed to describe the autoimmune features of children diagnosed as having AI-FHF and indeterminate FHF (ID-FHF), and describe the outcome of patients with AI-FHF treated with immunosuppressive drugs. Methods: In this case–control study, the files of patients with AI-FHF and ID-FHF were reviewed and compared. AIH was diagnosed based on positive autoantibodies, raised immunoglobulin G, and histology when available. FHF was defined by raised transaminases, international normalised ratio ≥ 2.0, presence of encephalopathy, and no previously recognised liver disease. Results: A total of 46 children with FHF were managed in the last 15 years: 10/46 (22%) had AI-FHF, 20/46 (43%) ID-FHF, and 16 had other diagnosis. The mean follow-up time was 4.6 years. AI-FHF and ID-FHF differed for the presence of autoantibodies (10/10, 6/10 liver/kidney microsome [LKM]-type, vs 3/20, none LKM, P < 0.0001), immunoglobulin G level (1845 vs 880 mg/dL, P < 0.001), median age at diagnosis (6.4 vs 1.8 years, P = 0.017), and alanine aminotransferase level (1020 vs 2386 IU/L, P = 0.029). Liver histology did not allow to differentiate the 2 conditions. Among the patients with AI-FHF, 4/9 who received steroids recovered; 5/9 required LTX and 1 died awaiting treatment. Conclusions: AIH is a much more common cause of FHF than previously suggested, and a complete autoantibody testing including LKM-type is essential in this setting. Autoantibodies are uncommon in ID-FHF, and histology cannot distinguish it from AI-FHF. A cautious steroid trial may avoid LTX in some of the patients with AI-FHF.

Cyclosporin in steroid-resistant autoimmune hepatitis and HCV-related liver diseases

Cyclosporin has been used for many years in transplantation, and in this field its role is widely documented. However, other fields of application merit to be investigated, including the role of cyclosporin in treating autoimmune hepatitis and its possible role as an antiviral agent in hepatitis C virus (HCV) infections in both immunocompetent patients and in recipients of orthotopic liver transplants. Cyclosporin A has given promising results in small studies, and experience in transplantation and other immunological disorders indicates that its side-effects can be adequately managed. Cyclosporin certainly deserves further clinical investigation for first-line therapy in autoimmune hepatitis. Cyclosporin A suppresses the HCV genome dose-dependently in vitro at clinically relevant concentrations (150-250 ng/mL). The maximum effect is similar to that obtained with IFN alpha, and the effects of these two agents are certainly additive, and possibly synergistic. The inhibitory action of cyclosporin A appears to be independent upon its immunosuppressive action. Analysis of indirect endpoints in clinical trials on cyclosporin A for immunosuppression in transplant recipients indicates that cyclosporin A treatment can delay recurrence of HCV. Small, open label studies suggest that the observed anti-HCV activity of cyclosporin A can be translated into a real clinical benefit; nevertheless, these findings need to be confirmed in randomized, controlled clinical trials.

Intestinal Transplantation in Children: The First Successful Italian Series

The preliminary experience of the first Italian program of pediatric intestinal transplantation is presented herein. A multidisciplinary group with broad experience in pediatric solid organ transplantation started the program. Nine children with complications of chronic intestinal failure were listed for transplantation. One child died on the waiting list; one received an isolated liver transplantation; three isolated intestinal; three multivisceral; and one, a combined liver/intestine transplantation. There was no in-hospital mortality, and all children were weaned from parenteral nutrition. The recipient of the multivisceral graft died after 14 months for unknown causes. All other recipients are alive after a median follow-up of 13 months. Patient and graft actuarial survivals for recipients of intestinal grafts were 100% at 1 year and 75% at 2 years.

93 AUTOIMMUNE ACUTE LIVER FAILURE IN CHILDREN: CLINICAL CLUES AND A NEW DIAGNOSTIC SCORE

93 AUTOIMMUNE ACUTE LIVER FAILURE IN CHILDREN: CLINICAL CLUES AND A NEW DIAGNOSTIC SCORE A. Di Giorgio, M. Bravi, E. Bonanomi, G. Alessio, A. Sonzogni, M. Colledan, L. D’Antiga. Paediatric Liver, GI and Transplantation, Paediatric Intensive Care, Laboratory Medicine, Transplant Pathology, General Surgery and Transplantation, Ospedali Riuniti Bergamo, Bergamo, Italy E-mail: ldantiga@ospedaliriuniti.bergamo.it

PP57 MORTALITY AND MORBIDITY OF PAEDIATRIC LIVER TRANSPLANTATION PERFORMED AT EARLY AGES

cerevisiae (ASCA) and anti-neutrophil cytoplasmic (ANCA) antibodies were not increased. Abdominal ultrasound was normal. Computerized bowel tomography showed an abnormal terminal ileum and cecum with thickened bowel wall. These findings were confirmed by a duoble-contrast barium enema. The esophagogastroduodenoscopy was normal. Colonoscopy and videocapsule endoscopy showed intestinal multiple mucosal ulcerations, which were compatible with Crohn’s disease. The histopathology of the colon and terminal ileum showed inflammation extending through the muscolaris propria, with a predominance of plasma cells, lymphocytes, and eosinophils, but a paucity of neutrophils and no granuloma (probably caused by the impaired neutrophil extravasation). On the basis of clinical history, endoscopy, and extraintestinal manifestations (arthritis, ulcerative stomatitis), a Crohn’s disease was diagnosed and a course of prednisone (2 mg/kg/day) and mesalamine (70 mg/kg/day) was started and ibuprofen was discontinued. One month later the patient experienced a recurrence with abdominal pain, diarrhea, arthritis and worsening anemia. Thus prednisone and mesalamine were reducted and terapy with Infliximab was started. After the first infusion, her bowel and extraintestinal manifestations completely cleared up. After 6 months of treatment the child is still in clinical remission and no complications have appeared. To the best of our knowledge, gastrointestinal problems in LAD-1 consists of a few case reports including Hirschsprung disease, necrotizing enterocoitis, and chronic enterocolitis. The only previous report of IBD-like illness in LAD-1 was in a severely affected patient with a complitely resolution after bone marrow transplantation. In conclusion, disorders of leukocyte adhesion should be included in the differential disgnosis of pediatric Crohn’s disease, particularly in the presence of recurrent infections. Therapy with Infliximab appears to be effective in these patients.