M. Candusso

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.

Long-term outcome of home parenteral nutrition in patients with ultra-short bowel syndrome.

Objective: The patients with ultra-short bowel syndrome (U-SBS) have been considered potential candidates for a preemptive/rehabilitative intestinal transplantation owing to the high risk of death from the underlying disease. We hypothesized that children with U-SBS, in the absence of intestinal failure-associated liver disease (IFALD), could also have a good rate of survival on home parenteral nutrition (HPN). Methods: A prospective database from the “Bambino Gesù” Artificial Nutrition and Intestinal Failure Program was used to evaluate outcomes and morbidities of consecutive patients with ⩽10 cm of small bowel enrolled since 2000. Results: Eleven patients were identified with a median bowel length of 7.5 (3–9) cm. Eight patients developed IFALD, which reversed in 7 of them; the IFALD progressively worsened in 1 patient until death. One patient underwent isolated intestinal transplantation and 1 patient is no longer receiving parenteral nutrition (PN) and both are fully enterally fed. The other patients remained at least partially dependent on HPN. The number of days of inpatient care decreased in all of the patients except for the 1 who had repeated episodes of central line infections. Conclusions: The survival of patients with U-SBS receiving HPN was good. Although IFALD was frequent, it had been manageable in most of the patients, but in a single complex case, it led to death. The multidisciplinary management warranted to these patients to approach the school age, to grow, and to maintain the oral intake. Patients with U-SBS are rare, and to better understand their long-term survival, further studies, including more large patient populations, are required.

Meso-Rex bypass as an alternative technique for portal vein reconstruction at or after liver transplantation in children: Review and perspectives

de Ville de Goyet J, Lo Zupone C, Grimaldi C, D’Ambrosio G, Candusso M, Torre G, Monti L. Meso‐Rex bypass as an alternative technique for portal vein reconstruction at or after liver transplantation in children: Review and perspectives.

Fulminant autoimmune hepatitis in a girl with 22q13 deletion syndrome: a previously unreported association.

We report a 7-year-old girl with 22q13 deletion syndrome, 46,XX,Ish del(22)(q13.3)(ARSA-; D22S1726), who developed a fulminant autoimmune hepatitis requiring orthotopic liver transplantation. Recently, it has been suggested that the Shank3 gene product, whose deficiency is responsible for the features observed in this syndrome, could play a role in immunological response. Despite an increased incidence of respiratory infections, autoimmune diseases have thus far not been reported in patients with this syndrome. This is the first case of fulminant autoimmune hepatitis associated with the 22q13 deletion syndrome. The possible relationships between immune system dysfunctions peculiar of this syndrome and autoimmune hepatitis are discussed.

Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature

BackgroundUnlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has never been reported in early childhood, while type 2 autoimmune hepatitis (AIH) is eminently a paediatric disease.Case presentationWe describe a case of type 2 AIH with serological positivity for PBC-specific anti-mitochondrial antibodies (AMA) in a 3-year old girl. We found this observation intriguing as AMA and indeed an overlap with PBC are virtually absent in Type 2 AIH, a pediatric form of AIH which is distinct precisely because it is characterized by pathognomonic anti-liver kidney microsomal type 1 (LKM-1) showing a remarkable antigen-specificity directed against cytochrome P4502D6. We also review the literature in relation to AMA positivity in paediatric age and adolescence. In our case, the presence of AIH-2-specific anti-LKM-1 and PBC-specific AMA was confirmed by indirect immunofluorescence (IIF), and immunoblotting and ELISA based on recombinant mitochondrial antigens. The clinical, laboratory and histological features of the child are given in detail. Interestingly the mother was AMA positive without other features of PBC. The child was successfully treated with immunosuppression and five years after the original diagnosis is on a low dose of prednisolone and azathioprine, with no signs of relapse. Anti-LKM-1 antibodies are still present in low titres. AMA were detectable for the first 4 years after the diagnosis and disappeared later.ConclusionThis is the first case report in the literature of AIH type 2 with an unexpected PBC-specific AMA positivity in a young child. Response to immunosuppressive treatment was satisfactory and similar to that described in AIH. A review of published reports on AMA positivity in paediatric age shows that the antibody may arise in the context of immunodeficiency and is variably associated with liver damage.

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.

Steatosis and fibrosis in paediatric liver transplant: insidious graft's enemies--a call for clinical studies and research.

Within two decades, liver transplant has become a safe procedure for children with end-stage liver disease of any cause. A combination of both medical and surgical advances, including patient selection, improved peri-operative care, and availability of new immunosuppressive agents, has significantly improved overall survival after transplantation that currently exceeds, in experienced centres, 90% and 85% rates at one and five yr, respectively (1, 2). Long-term outcome is still compromised by delayed and chronic graft damage and by the late adverse effects of immunosuppressive agents, as for example renal dysfunction or increased risk to develop cancer (3). During the last decade, the focus has mostly been on the immunological monitoring and immune system modulation, with prevention of early rejection and induction of operational tolerance being the centre of all interests. It may be time to diversify our interests and target other enemies of the liver graft, and possibly some more insidious ones that have been left with little attention because acting silently and progressively at a time when the attention of clinicians drops because the patient seems out of the known risks. It is clear that the prevalence of a variety of late onset problems is increased in those transplanted patients who are likely to survive for a prolonged time after transplantation, which is particularly the case in children who have a longer life expectancy with respect to adults. Among these possible late post-transplant complications are the development of steatosis and fibrosis, typically observed in patients with recurrent hepatitis C infection (4, 5) and reported with an increasingly higher incidence in paediatric series in absence of viral background (6). In the latter groups, it is hypothesized that the aetiology is multifactorial and that liver-transplanted children cumulate several risk factors (independently of viral or recurrent disease) that might predispose them to develop progressive liver steatosis and/or fibrosis (NAFLD: nonalcoholic fatty liver disease/NASH: non-alcoholic steatohepatitis): hypertension, obesity, hyperlipidemia, and diabetes mellitus (7, 8). The effect of the metabolic dysfunction/syndrome that predisposes the patients to develop steatosis and fibrosis (9) may be aggravated in post-transplant patients by several factors present as rapid changes in nutritional status (weight increase) or long-term exposure to drug toxicity (immunosuppressive therapy). In particular, cyclosporine has been associated with a high incidence of hypertension and hyperlipidemia (10) as is tacrolimus with a variety of different toxic effects, including diabetes mellitus (11). However, even if, overall, external factors clearly have a major role in the pathogenesis of liver graft steatosis/fibrosis, it can also be hypothesized that genetic profile of the recipient plays a contributive role, directly or indirectly. Genetic polymorphism is considered as an important acting agent in individual metabolic profile variations and it has been considered as important physiopathological factor either in pharmacobiology and sensitivity to drug toxicity or in individual risk of developing fatty liver, steatohepatitis, and fibrosis (12). Last but not least, in allograft transplantation, the graft characteristics itself may contribute to the pathogenesis of steatosis and fibrosis, as the donor s own personal history and genetic predispositions may influence the graft response to the new and different environment provided within the recipient (13). There is currently little or nothing in literature about this exciting area Pediatr Transplantation 2010: 14: 441–444 2010 John Wiley & Sons A/S.

Pediatric Short Bowel Syndrome: Predicting Four-Year Outcome after Massive Neonatal Resection

Objectives The aim of this study was to ascertain predictors of survival, liver disease (LD), and enteral autonomy 48 months after resection in neonatal short bowel syndrome (SBS) patients with residual small bowel length (SBL) ≤40 cm. Patients and Methods Medical records of all SBS patients followed up between 1996 and 2016 were retrospectively reviewed. Survival rate, prevalence of LD, and of enteral autonomy were evaluated. Results Forty‐seven patients were included, and 43 were still alive at the end of the study period, with cumulative 48‐month survival of 91.5%. Twenty‐one (45%) patients developed LD, all within the first 6 months. On the final follow‐up visit, three (6%) patients were still jaundiced and progressed toward end‐stage LD. LD prevalence was higher in patients with recurrent bloodstream infections (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.5‐19.3). Of the 43 surviving patients, 22 (51%) had enteral autonomy 48 months after resection. The probability of weaning off parenteral nutrition (PN) was strongly correlated with the remaining SBL. Conclusion Survival of patients who have undergone neonatal massive small bowel resection has improved in recent years. Multidisciplinary strategies can improve the course of LD, but not the probability of weaning off PN, which seems to be strongly dependent on the anatomical profile of residual bowel. Therefore, the primary surgical approach should be as conservative as possible to gain even small amounts of intestinal length, which may be crucial in promoting intestinal adaptation.

Liver Transplantation and Gut Microbiota Profiling in a Child Colonized by a Multi-Drug Resistant Klebsiella pneumoniae: A New Approach to Move from Antibiotic to “Eubiotic” Control of Microbial Resistance

The increase of microorganisms multi-drug resistant (MDR) to antibiotics (ATBs) is becoming a global emergency, especially in frail subjects. In chronic liver disease (LD) with indications for liver transplantation (LT), MDR colonization can significantly affect the LT outcome. However, no clear guidelines for microbial management are available. A novel approach toward MDR-colonized patients undergoing LT was developed at our Center refraining from ATBs use during the transplant waiting list, and use of an intensive perioperative prophylaxis cycle. This study aimed to couple clinical evaluation with monitoring of gut microbiota in a pediatric LD patient colonized with MDR Klebsiella pneumoniae (KP) who underwent LT. No peri-transplant complications were reported, and a decontamination from the MDR bacteria occurred during follow-up. Significant changes in gut microbiota, especially during ATB treatment, were reported by microbiota profiling. Patterns of Klebsiella predominance and microbiota diversity revealed opposite temporal trends, with Klebsiella ecological microbiota niches linked to ATB-driven selection. Our infection control program appeared to control complications following LT in an MDR-KP-colonized patient. The perioperative ATB regimen, acting as LT prophylaxis, triggered MDR-KP overgrowth and gut dysbiosis, but buffered infectious processes. Mechanisms modulating the gut ecosystem should be taken into account in MDR colonization clinical management.

Gastroenterology: Biliary Atresia, Choledochal Cyst, Cystic Fibrosis

Hepatobiliary imaging evaluates the function of the liver showing whether there are any blockages in the gallbladder or biliary duct system.