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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%.

Glycogen storage disease type II (GSDII) is an autosomal recessive disorder due to the deficiency of the lysosomal enzyme acid alpha glucosidase. Four novel mutations (C670T, G989A, G2188T, and Delta 23 nt 828-850) were identified in five Italian patients with the infantile form of the disease. The C670T mutation was present in two unrelated patients in heterozygosity; the effect on enzyme activity was assessed by in vitro expression. COS-1 cells expressing the C670T allele had a twofold higher activity than the negative control cells. The G989A and G2188T point mutations lead to the introduction of premature stop signals that results in truncated forms of alpha glucosidase. The in vitro expression of G2188T allele demonstrated no increment in activity compared to negative control. The frame shifting deletion of nucleotides 828-850 was identified in one patient in heterozygosity. The shift in the reading frame introduces a stop codon 135 nucleotides downstream the deletion junction that results in a truncated protein without catalytic activity. Nested PCR screening showed that the mutation was carried by the mother and was absent in the other members of the family. The four novel severe mutations herein described concerned only infantile onset GSDII patients; the loss of enzyme activity is correlated with the severity of the disease.

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).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.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.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.

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.

The benefits of early treatment of nutritional and respiratory problems in the CF infant and of genetic counselling for the parents are widely recognized. However, clinical diagnosis of CF is often delayed despite early onset of symptoms and the usefulness of neonatal population screening as a preventive measure is still under debate. This study analyses the clinical history of CF patients diagnosed exclusively on the basis of positive neonatal screening tests with the aim of identifying the earliest markers of the disease. We studied 103 CF infants born in north-east Italy, diagnosed following neonatal screening: assay of immunoreactive trypsin (IRT) from a heel-prick blood sample followed by a measurement of meconium lactase in cases with raised IRT. Diagnosis was confirmed by sweat test at an average age of 39 days. Eighty-one patients (79%) had symptoms strongly suggestive of CF at diagnosis, and signs and/or symptoms of pancreatic insufficiency were present in 16 of the remaining 22 cases. The most frequent symptom was growth failure (69% of infants) and of these, 44% weighed the same as at birth or less. Pancreatic insufficiency was confirmed by the low level of faecal chymotrypsin found in 85% of cases. IRT was elevated in all cases. CF had not been suspected in any symptomatic infant, although most of the infants had been monitored by a paediatrician. In conclusion, most infants with CF diagnosed by neonatal screening are already symptomatic in the first six weeks of life and the most frequent symptom is failure to thrive; pancreatic insufficiency was already present in most cases. In areas without CF neonatal screening programs, the disease should be excluded by differential diagnosis in all cases with growth failure notwithstanding adequate caloric intake in the first months of life. The high sensitivity, low cost and simple execution of IRT and fecal chymotrypsin tests make them an ideal first step in suspect cases before proceeding to the sweat test, often performed late because of limited availability.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal disorders. PFIC type 2 is due to mutation in ABCB11, the gene encoding the bile salt export pump (BSEP) protein. The aim of the study was to describe a child with a de novo mutation in a compound heterozygous for ABCB11 gene. We report a 1.7-year-old girl who presented with pruritus, jaundice and liver dysfunction of PFIC type 2. Immunohistochemistry and molecular analysis are described. Liver biopsy showed micronodular cirrhosis and immunohistochemical staining for BSEP, the protein encoded by ABCB11, displayed a patchy and faint reactivity. Molecular analysis revealed two novel mutations of ABCB11. We give details that one mutation is transmitted by the mother while the second one appears a de novo mutation as mutations or a potential mosaicism were ruled out in the natural father. We further speculate that the ABCB11 mutations do not prevent BSEP glycoprotein to be expressed at the canalicular pole of hepatocytes, but interfere with its ability to export bile salts. As in most instances, mutational analysis is performed following the histochemical demonstration of an undetectable BSEP on liver biopsy specimen. This case stresses that clinical PFIC with an attenuated rather than absent BSEP immunostaining can still be due to ABCB11 mutations presumably encoding a functionally deficient protein.

The prognosis of children suffering from chronic intestinal failure has been dramatically improved by parenteral nutrition (PN) which allows normal growth and development in the absence of a sufficient enteral supply of nutrients. A small percentage of patients may become permanently dependent on PN and in these cases, home parenteral nutrition (HPN) is crucial for allowing growth within a normal family environment. 14 However, new problems (such as venous access availability, metabolic complications, and psychological adaptation), are emerging in the management of life-long PN dependent patients which also pose possible difficulties for HPN. In this paper, we report our experience with HPN paediatric patients and have focused on long-term patients.

The management of de novo hepatitis B (HBV) infection in children after liver transplantation is not well defined. Because this infection may induce severe liver disease in the graft liver, an efficient antiviral therapy is desirable. Here, we describe the favorable viral outcome observed in a liver transplanted girl with de novo HBV infection following combination therapy with lamivudine and tenofovir.

Background & aims: Indications and timing for referral for intestinal transplantation (ITx) were investigated through a review of the literature on home parenteral nutrition (HPN) for benign intestinal failure and a benchmarking to the results of a prospective European survey which evaluated the appropriateness of the current indications for ITx. Methods: Manuscripts reporting outcomes of adults and children on HPN were retrieved through a PubMed search. Data from the European survey were compared with those on HPN reported in the literature, and with those on ITx reported by the USA registry and by the Pittsburgh center. Results: HPN is a safe treatment with a high probability of survival. The risk of death during HPN is increased by the absence of a specialist team, and appears greater during the early period of treatment. Survival probability is decreased in patients with: age >40 or

AIM: To explore the prevalence of local and genetic thrombophilic disorders as risk factors for portal vein thrombosis (PVT) in our series, the largest ever published in pediatric literature. METHODS: We conducted a case-control study enrolling 31 children with PVT and 26 age-matched controls. All were screened for thrombophilia, including genetic disorders, protein C, protein S and homocysteine deficiencies. All coagulation parameters were studied at least 3 mo after the diagnosis of portal vein obstruction. RESULTS: In our study we showed that most pediatric patients with PVT have local prothrombotic risk factors, which are probably the most important factors leading to PVT. However, there is a clear association between the presence of prothrombotic disorders and PVT, suggesting that these increase the risk of thrombosis in patients with local factors such as perinatal umbilical vein catheterization or sepsis. CONCLUSION: Patients with PVT should be screened for inherited prothrombotic disorders regardless of a history of an obvious local risk factor.

A balance study of Ca and P has been performed in 12 Very Low Birth Wt babies receiving prolonged Total Parenteral Nutrition. The mean intake of both minerals was 54.4 mg/kg/day (range 40-70). In order to avoid the formation and precipitation of CaP crystals in the solution, fructose-1,6-diphosphate was used as a source of P. 30 balance studies were performed between the seven and 63 day of life: they were always positive with a mean retention of 47.4 mg/kg/day of Ca and 48.1 mg/kg/day of P. For both minerals, 88% of the amount infused was retained: the correlation between intake and retention was linear and statistically significative (Ca:r = 0.9, p0.0001; P:r = 0.68, p0.0001). The post-natal and post-conceptional ages of the babies had no influence on Ca and P balance. The blood levels of Ca and P were poorly correlated to both intake and excretion, and were not as indicative of the mineral balance as the retention rates calculated on the basis of the 24 h urinary excretion of the minerals. A very useful test for clinical monitoring of Ca and P balance proved to be the Ca/creatinine and P/creatinine ratios measured on simple urine samples, which were strongly correlated to 24 h excretion. All infants developed radiological signs of mild osteopenia, but there was no case of acute metabolic derangement or rickets. Our data demonstrated that even in sick VLBW infants on TPN it is possible to achieve good retention rates of Ca and P, which are not different from those observed in well VLBW babies fed a 'standard' premature formula.

T. Capriati 1,∗, G. Torre1, F. Fusaro3, C. Grimaldi4, M. Candusso1, D. Elia2, J. De Ville De Goyet4, M. Rollo5, F. Chiusolo6, P.M.S. Schingo7, A. Diamanti1 1 Hepatology, Gastroenterology and Nutrition Unit Nutrition Unit, Bambino Gesu Children’s Hospital, Rome, Italy 2 Artificial Nutrition Unit, Bambino Gesu Children’s Hospital, Rome, Italy 3 Department of Medical and Surgical Neonatology, Bambino Gesu Children’s Hospital, IRCCS Rome, Rome, Italy 4 Hepatobiliary Surgery Unit, Department of Surgery, Bambino Gesu Children’s Hospital, Roma, Italy 5 Department of Surgery and Transplantation Center, Interventional Radiology Unit, Bambino Gesu Children’s Hospital, Rome, Italy 6 Pediatric Intensive Care Unit, Department D.E.A.-A.R.C.O. Bambino Gesu Children’s Hospital, Rome, Italy 7 Department of Radiology, Bambino Gesu Children’s Hospital, Rome, Italy

To assess the evidence supporting early antibiotic treatment in asymptomatic cystic fibrosis (CF) patients colonised by Pseudomonas aeruginosa (PA). We carried out a computerised (Medline, Embase) and hand search of journals for suitable publications. All English-language clinical studies regarding the efficacy of early antibiotic treatment on PA colonisation in asymptomatic patients were considered. Each eligible publications fitting these criteria were assessed for the following outcome measures: frequency of positive PA cultures; serum level of precipitating antibodies; lung function; survival; number of hospitalisations; adverse effects and resistance to antibiotics. Of the 11 studies eventually considered, 3 were randomised—2 versus placebo— and 8 were cohort studies—2 of which had historical controls. Overall, 309 patients (population range 7–91 patients) were recruited. There was a high variability between the individual studies for age, outcome measures, duration of follow-up (1 to 44 months) and treatment (three studies used only aerosol tobramycin, one colistin, four aerosol colistin plus oral ciprofloxacin, one used intravenous treatment and two miscellaneous therapy). An overall evaluation indicated that early antibiotic treatment can reduce the number of positive cultures and the anti-PA antibody titre. In one study, FEV1 was better in the treated group (oral ciprofloxacin and nebulised colistin) than in historical controls, while in one placebo-controlled trial, no effect on lung function was shown after 1 year of tobramycin inhalation. Collateral effects and bacterial resistance were not increased. The short follow-up did not allow definite conclusions with regard to the long-term progression of respiratory insufficiency or survival. Evidence was found that antibiotic treatment can reduce the rate of positive cultures and of anti-PA antibody titres in asymptomatic CF patients with newly isolated PA. Different therapeutic options have not been directly compared: a multi-centre comparative study needs to be carried out.

In this review the current status of home parenteral nutrition is analysed, with respect to the predictability of weaning from nutritional support and the risk of developing major complications associated with the technique, the loss of vascular access and liver disease. These two complications were evaluated because they represent the more important indication for intestinal transplantation, the availability of which has changed the perspectives of patients and of physicians. Analysis of outcomes from the largest series allows the identification of patients who could be weaned from parenteral nutrition. Important prognostic factors in patients affected by short bowel syndrome are the length and type of the remnant and the time to tolerate enteral feeding. The main complications of therapy are sepsis, thrombosis, nutrient imbalances and liver disease. Sepsis and thrombosis could lead to line replacement and the loss of vascular access. Sepsis no longer represents a major cause of death, but it is a frequent complication. In some patients, it is difficult to assess the risk factors for sepsis, which is possibly related to a poorer outcome. The care of gut failure appears to be the best preventative measure for the occurrence of cholestatic liver disease, but further studies are needed to define the eventual role of lipid emulsion and of specific nutrient deficiency. The quality of life still remains to be studied: because home parenteral nutrition in children has a longer duration, its analysis is mandatory.

Several proinflammatory cytokines are involved in the pathogenesis of inflammatory bowel diseases. A significant role has been given to tumor necrosis factor alpha (TNF-alpha) as a guide proinflammatory cytokine. Thalidomide selectively reduces TNF-alpha production by inflammatory cells. The aim of the study was to assess the efficacy of thalidomide to induce and maintain remission in refractory Crohn disease.The decision to administer thalidomide was made on the basis of patient intolerance or resistance to conventional medical treatment or as the last medical resort before surgical intervention. Only 5 of 96 patients with inflammatory bowel disease satisfied these criteria. All five patients had Crohn disease (male: mean age, 17 years). Thalidomide was administered at night at a dose of 1.5-2 mg/kg/day. The Pediatric Crohn Disease Activity Index, modified Harvey-Bradshaw scores, and steroids reduction were used to assess clinical response.Disease activity decreased consistently in four patients with a reduction of mean Pediatric Crohn Disease Activity Index from 36,9 to 2,5 and the mean Harvey-Bradshaw from 8.5 to 0.75 after 3 months of treatment. Steroid treatment (mean dose, 35 mg/day before treatment) was tapered and then discontinued, in four patients, within 1-3 months. Four patients are in remission after 19-24 months of treatment. The fifth patient discontinued thalidomide after 1 week because of distal paresthesia.Thalidomide seems to be an effective and safe treatment in patients with refractory Crohn disease. This is the first report of long-term use of thalidomide in refractory Crohn disease in pediatric patients.

Parenteral nutrition (PN) represents a main therapy in intestinal failure of childhood, but complications related to the catheter, the artificial nutrition and the disease might influence prognosis of patients.1,2 We analyzed the occurence of line-related complications in our cases treated by long-term PN, to define risk factors and to plan for preventive measures.

To assess the type, severity, and regional lung distribution of cystic fibrosis (CF) lesions as shown using high-resolution CT (HRCT), comparing these findings with chest radiographs and pulmonary function tests (PFTs), we obtained HRCTs in 36 patients with CF (mean age 13), who were clinically stable. We assessed four lung regions (upper and lower, right and left) and assigned each a semiquantitative score for (a) bronchial abnormalities, (b) parenchymal abnormalities, and (c) overinflation, based on the severity and profusion of the corresponding lesions. A similar regional assessment of chest radiographs was also done using the Chrispin-Norman method. PFT results were correlated with the radiological data. On HRCT, bronchial lesions were present in 89% of the patients and in 78% of the regions; bronchiectasis was the predominant abnormality in our population, visible in 100% of the abnormal regions. Less frequent were bronchial wall thickening (48%) and mucous plugs (29%). Parenchymal abnormalities were recognizable in 58% of the patients and 31% of the regions; alveolar consolidation was more frequent (80%) than were destructive changes (36%). Overinflation was found in 81% of the patients and 85% of the regions. We found the severity and profusion of bronchial lesions and parenchymal destructive changes to be unevenly distributed among the different regions, the upper lungs being more heavily involved than the lower, particularly on the right. Alveolar consolidation and overinflation were more uniform in distribution. HRCT patient scores correlated significantly with radiographic scores (r = 0.861) and with PFTs, especially with forced expiratory volume for 1 s (FEV1; r = 0.658). HRCT can be useful in the clinical management of patients with CF, depicting the type and distribution of bronchial and parenchymal lesions, particularly when chest radiographic results are unclear. In the planning and postural drainage, special attention should be given to the apical and posterior parts of the lungs, especially on the right; these are the areas most frequently and most severely involved by the disease.

year of life, while there are no data concerning high-protein formulas during the subsequent 12 months (Koletzko 2009). The randomized clinical trial CHOP (Socha 2011) shows that the intake of milk with high protein content in the 1st year of life, stimulates the GHIGF-1 axis and, therefore, a weight gain. Subsequent monitoring up to 24 months, however, shows an obesogenic effect limited to this type of feeding given during the first 6 months of life. Conclusions: Toddlers milks have compositions which are substantially equivalent. After 12 months of age and up to 3 years a toddler milk is preferable to standard cow’s milk, as it presents qualitative and quantitative characteristics (vitamins, minerals, dietary fiber, w3/w6 ratios) potentially advantageous for bone growth, decreased risk of iron deficiency and prevention of cardiovascular disease. Their protein content, at times variable, does not seem to have clear obesogenic implications. Hitherto, obesogenic implications have been demonstrated only for type 1 and type 2 higher-protein formulas fed during the first six (-twelve) months of life and not later for toddlers milks.

Background: Primary neoplasms of the liver are rare in children, comprising only 1.1% of malignancies in younger than 20 years of age. Hepatoblastoma comprises over two-thirds of the malignant tumors of the liver in children and hepatocellular carcinoma (HCC) accounts for most of the remaining cases. In pediatric population, HCC is a very rare tumour and is traditionally linked to liver chirrosis and to ongoing process of liver necrosis/regeneration (viral hepatitis or metabolic disease) but could also be observed in a non-chirrotic liver. In contrast to the age-incidence relationship for hepatoblastoma, the incidence of HCC increased with each successive 5-year age group. We report our single center experience with 3 patients with HCC in non-chirrotic liver and their therapeutic management. Methods: The medical records of 3 male children, with median age of 9 years (range, 8–10) who presented, with primary hepatocellular carcinoma on non –chirrotic liver, at our centre were reviewed. Ultrasonography, computed tomographic (CT) scan, and needle biopsy were the initial methods used to diagnose malignant tumors. The following data were analyzed: age at diagnosis, treatment modalities, histopathologic findings, surgical details, operative complications, and treatment results. Data related to surgery included the extent of the hepatic resection, macroscopic margins, and operative complications. When the tumor was considered unresectable by the postchemotherapy CT scan, transplantation was considered. Before that could occur, the patient underwent extensive scanning to assess for distant metastases. Treatment results were evaluated by the occurrence of local or distant recurrence and duration of survival. Results: In all patients clinical symptoms were history of fever, abdominal pain, and hepatosplenomegaly. Their serum α-fetoprotein level at presentation was markedly raised, with median value of 41142 ng/mL (range 1266070768). Hepatic biopsy was performed under sonographic guidance, and the diagnosis of HCC was made. In 1 case the extent of disease, limited to the liver, lead to tumour resection with hepatectomy, nevertheless 2 years later he underwent to repeated resection for primary liver tumor recurrence. Actually he is in well clinical condition, his serum α-fetoprotein is in the normal range and the radiological assessment show the absence of distant metastases. In 2 cases chemotherapy treatment was started according to the protocols of SIOPEL V, but the tumor did not respond to allow a resection. This fact, along with the absence of distant metastases on whole-body CT, suggested liver transplantation as a possible therapeutic option. The patients underwent surgical resection en bloc of the native liver and received a whole liver transplant. Immunosuppression with Tacrolimus was started first days after surgery. The serum α-fetoprotein level after transplantation fell down reaching normal values in 1 month for both patients (median value 9.5 ng/mL, range 9-10 ng/mL). Our 2 patients received tacrolimus as primary component of their post-OLT immunosuppression, adding SRL at least 1 month after transplantation to reduce the risk of delayed wound healing or incisional hernia due to the property of mTor inhibitor. Both transplanted patients recieved 1 year neoadiuvant therapy post OLTx. Contrast-enhanced CT of the transplanted liver was performed once a year: no lesion was seen in the liver parenchyma and the absence of liver metastasis was confirmed. In their 2 years follow-up survival and event free survival were comparable even better between this group and all patients who underwent OLTx for all the other indications. Discussion: Non-resectable forms of intrahepatic recurrence may, in the absence of extrahepatic spread, benefit from liver transplantation. This attitude may broaden the curative possibilities. Recurrence of hepatocellular carcinoma after liver transplantation is common (30% in adults), and the prognosis is not favorable. We try to avoid possible recurrence drawing a specific immunosuppression regimen. Experience with sirolimus (SRL)-based immunosuppression following OLT is rapidly accumulating. In different models, mTOR inhibitors (mTORIs) were effective in reducing cell growth and tumor vascularity. In combination with calcineurin inhibitors, SRL may reduce the incidence of acute rejection and lower overall required drug levels. Different studies indicate that sirolimus might be a promising drug for this treatment, but further clinical studies elucidating the biological effects are advocated to reach further improvement in the management of advanced disease. Repeat resection for primary liver tumor recurrence is feasible in patients with recurrence limited to the liver and good liver function. A survival at 5 years of 59% similar to that after the first hepatectomy, suggests a benefit from a hepatectomy for recurrent HCC.