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Zhu–Tokita–Takenouchi–Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Haploinsufficiency in SON may affect multiple genes, including those involved in the development and metabolism of multiple organs. Considering the broad spectrum of SON functions, it is to be expected that pathogenic variants in this gene can cause a wide spectrum of clinical symptoms. We present an additional ZTTK syndrome case due to a de novo heterozygous variant in the SON gene (c.5751_5754delAGTT). The clinical manifestations of our patient were similar to those present in previously reported cases; however, the diagnosis of ZTTK syndrome was delayed for a long time and was carried out during the diagnostic work-up of significant chronic liver disease (CLD). CLD has not yet been reported in any series; therefore, our report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement. Correspondingly, we recommend screening patients with SON variants specifically for liver involvement from the first years of life. Once the CLD has been diagnosed, an appropriate follow-up is mandatory, especially considering the role of SON as an emerging player in cancer development. Further studies are needed to investigate the role of SON haploinsufficiency as a downregulator of essential genes, thus potentially impairing the normal development and/or functions of multiple organs.

Objectives Early diagnosis of biliary atresia is essential to improve long-term outcomes. Newborn screening with an infant stool color card allows early recognition of biliary atresia patients. Our aim was to develop and validate a mobile phone application (PopòApp) able to identify acholic stools. Methods An intuitive app was developed for iOS and Android smartphones. A learning machine process was used to generate an algorithm for stools color recognition based on the seven colors of the infant stool color card, which were considered as the gold standard. Consecutive images of stools were taken by the PopòApp, directly into the diapers of children aged ≤6 months. The PopòApp classified the photographs as “normal”, “acholic” or “uncertain”. To validate the PopòApp, four doctors independently classified all images, and only those for which all doctors agreed were included. The sensitivity, specificity, positive/negative predictive values, and accuracy of the PopòApp were evaluated. Results Of 165 images collected, 160 were included in the study. All acholic stools were recognized by the PopòApp. The PopòApp sensitivity was 100% (95% CI:93.9%–100%) with no false negatives, regardless of the brand of phone. The specificity was 99.0% (95% CI:94.6%–99.9%). The accurancy of the PopòApp was 99.4% (95% CI:96.6%–99.9%), with a positive predictive value of 98.4% (95% CI:89.8%–99.8%). Conclusion The current study proved, in a large cohort, that the PopòApp is an accurate and easy tool for recognition of acholic stools. The mobile App may represent an effective strategy for the early referral of children with acholic stools, and potentially could improve the outcomes of biliary atresia.

Background Infantile cholestasis (IC) is defined as an impairment of bile production or flow occurring in the first months of life. The diagnostic approach in IC is challenging since the differential diagnosis is broad. Methods We retrospectively evaluated 91 cholestatic infants referred to our department from 2014 to 2019. Patients with cholestasis underwent a complete IC diagnostic work-up including quantification of plasma oxysterols 7-ketocholesterol (7-KC) and cholestan-3β,5α,6β-triol (C-Triol). Results Oxysterols concentrations were mildly elevated in IC compared to control population. 7-KC and C-Triol plasma levels presented a linear relationship between them and with Spleen-Z score. Patients with NP-C showed the highest concentrations of both oxysterols compared with other etiologies of IC. Excluding NP-C patients, oxysterols concentrations were similar among all other etiological groups with no correlations found between them and the levels of cholesterol and bilirubin. ROC analysis identified AUCs of 1.0 for both oxysterols in predicting NP-C. Conclusion Infants with IC should undergo a stepwise evaluation in which detailed clinical and deep analytical assessments are the main crossroads. Plasma oxysterols, a simple, reliable, and convenient diagnostic test should be included in the first steps of the diagnostic process in IC.

Objectives Biliary atresia (BA) is a rare and progressive idiopathic disease affecting the biliary tract that can lead to end-stage liver disease. The main treatment is Kasai portoenterostomy (KP). The use of adjuvant therapy (AT; prophylactic antibiotics and steroids) after KP aims to prevent cholangitis and reduce the need for liver transplantation (LT), but there is a lack of evidence on their effectiveness. We investigated the impact of significant changes in the post-KP protocol on the overall outcomes of BA. Methods We enrolled 43 consecutive infants undergoing KP at Bambino Gesu Children's Hospital between July 2012 and October 2018. We compared AT (AT group; n=25) against no treatment (AT-free group; n = 18). Results No significant differences in anthropometric and laboratory parameters were shown between the 2 groups at baseline and every study evaluation (1, 3, and 6 months). The incidences of clinical complications of liver disease were similar. Six months post-KP, the achievement of serum total bilirubin ≤1.5 mg/dL and satisfactory Pediatric End-Stage Liver Disease scores were not significantly different between the 2 groups. Cholangitis was observed in 30% of patients in the first 6 months postoperatively: 33% and 28% in the AT-free and AT groups, respectively (P = 0.18). Survival to LT listing at 12 months and without LT at 24 months were not significantly different between the 2 groups (P > 0.05). Conclusions AT after KP confirmed conflicting results; therefore, multicentered, prospective, randomized control studies are needed to better understand its utility after KP, especially in the multidrug resistance spread era.

Children affected with chronic liver disease are at risk for fat-soluble vitamins (FSV) deficiency, in this scenario the role of liver transplant has been only partially explored.This study aimed to evaluate the prevalence of FSV deficiency in a cohort of paediatric patients awaiting liver transplant, analyze relationships between plasma vitamin concentrations and risk of acute rejections and liver fibrosis and assess the impact of the transplant on vitamin status.166 children candidates for liver transplant were retrospectively evaluated. Vitamin concentrations were measured before and 12 months after transplantation.Before transplant vitamin A, vitamin E and vitamin D deficiency was found in 66.6%, 40.6% and 36.3% of patients, respectively. 12 months after surgery, the prevalence of deficiency decreased to 29,5% and 2,6% for vitamin A and E while remained the same for vitamin D (36.3%). No association was found between vitamin status and the risk of acute rejections or the severity of liver fibrosis.Liver transplant was effective to improve vitamin A and E, but it did not affect vitamin D. A consensus is needed to define optimal nutritional management of these patients in order to prevent deficiencies.

In patients with Anorexia Nervosa (AN) malnutrition can lead to life-long nutritional treatments. The refeeding process can combine natural feeding (NF) with specific nutritional strategies, including oral nutritional supplements (ONS) and nasogastric feeding (NGF). Aims of the present study were to assess the efficacy of hospital protocol and identify the most effective inpatient nutritional strategies for weight restoration.All patients hospitalized from April 2015 to April 2020 were enrolled. According to hospital protocol, NF was proposed to all patients; ONS were combined with NF if caloric intake was70% of the requirements and NGF was added if caloric intake did not reach 30% in the first week from admission.Overall, 186 patients [M = 20; median age 14 (interquartile range 1316)] were included. Nutritional issues were the main indication to admission (56.6%). A significant effect of combination treatment, with a shorter duration of hospitalization when using ONS with NGF in addition to NF was found (ß: -20.28 [95% confidence interval -34.92:-5.65], P 0.001). Only one patient showed a significant but limited increase of liver enzymes.We provide a safe and effective standardized protocol to treat the malnutrition of teenagers with AN in an inpatient setting. Malnutrition was the most important cause of admission, and more than half of the patients admitted were severely malnourished. The combination of NF, ONS, and NGF was the most effective strategy to achieve the weight restoration; however, this result should be validated on larger series of patients treated with NGF and NF.

Allograft fibrosis (AF) after pediatric liver transplantation (pLT) is frequent, but its dynamics are unclear. Our aim was to assess the evolution and risk factors of AF after pLT. A retrospective single-center analysis of pLT patients with a follow-up of ≥5 years who underwent protocol liver biopsies at 6 months, 1 year, 2 years, 5 years, and 10 years was performed. Fibrosis was assessed using the METAVIR and Ishak systems and the liver allograft fibrosis score (LAFs). Of 219 pLTs performed from 2008 to 2018, 80 (36.5%) pLTs were included, and 320 biopsies were reviewed. At 6 months after pLT, fibrosis was found in 54 (67.5%) patients by the METAVIR/Ishak systems and in 59 (73.8%) by the LAFs (P = 0.65). By 5 years, AF was detected in 67 (83.8%), 69 (86.3%), and 72 (90%) specimens using the METAVIR, Ishak, and LAFs systems, respectively (P = 0.54); mild (METAVIR, 51 [63.8%]; Ishak, 60 [75%]; LAFs, 65 [81.2%]) and moderate (METAVIR, 16 [20%]; Ishak, 9 [11.9%]; LAFs, 7 [8.8%]) stages were detected, but severe fibrosis was not found (P = 0.09). In the LAFs, fibrosis involved the portal (85%), sinusoidal (15%), and centrolobular (12%) areas. Of 18 patients with 10-year protocol biopsies, AF was present in 16 (90%), including 1 (5.5%) with severe fibrosis. In all systems, 36.3% of patients showed fibrosis progression from 2 years to 5 years after LT, but they remained stable at the 10-year biopsies without clinical implications. In multivariate analysis, only donor age40 years was a risk factor for moderate AF at 5 years after LT (odds ratio, 8.3; 95% confidence interval, 1.6-42.1, P = 0.01). Cold ischemia time (CIT)8 hours was associated with portal (P 0.001)/sinusoidal fibrosis (P = 0.04), donor age40 years was associated with sinusoidal (P = 0.01)/centrilobular (P = 0.04) fibrosis, and low tacrolimus trough level within 1 year after LT was associated with centrilobular fibrosis (P = 0.02). AF has a high incidence after pLT, occurring early after transplantation. In most cases, AF is mild or moderate and remains stable in the long run without clinical implications. Donor selection, short CIT, and immunosuppression adherence are crucial to reducing the risk of advanced AF.

Von Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary haemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall. Hydrodynamic forces are responsible for extensive conformational transitions in the VWF multimers that change their structure from a globular form to a stretched linear conformation. This feature makes this protein particularly prone to be investigated by mechanochemistry, the branch of the biophysical chemistry devoted to investigating the effects of shear forces on protein conformation. This review describes the structural elements of the VWF molecule involved in the biochemical response to shear forces. The stretched VWF conformation favors the interaction with the platelet GpIb and at the same time with ADAMTS-13, the zinc-protease that cleaves VWF in the A2 domain, limiting its prothrombotic capacity. The shear-induced conformational transitions favor also a process of self-aggregation, responsible for the formation of a spider-web like network, particularly efficient in the trapping process of flowing platelets. The investigation of the biophysical effects of shear forces on VWF conformation contributes to unraveling the molecular mechanisms of many types of thrombotic and haemorrhagic syndromes.

We describe the establishment of a seronegative occult hepatitis B virus (HBV) infection (OBI) in a successfully vaccinated infant who underwent liver transplantation from an donor positive for antibody to hepatitis B core antigen (anti-HBc). The use of highly sensitive droplet digital polymerase chain reaction assays revealed a not negligible and transcriptionally active intrahepatic HBV reservoir (circular covalently closed DNA, relaxed circular DNA, and pregenomic RNA: 5.6, 2.4, and 1.1 copies/1000 cells, respectively), capable to sustain ongoing viral production and initial liver damage. Next-generation sequencing revealed a peculiar enrichment of hepatitis B surface antigen vaccine-escape mutations that could have played a crucial role in OBI transmission. This clinical case highlights the pathobiological complexity and the diagnostic challenges underlying OBI.

Background Recombinant (rec-) coagulation factor VIII concentrates available for hemophilia A (HA) treatment differ in cell line production and structure, which could affect their pharmacodynamics and immunogenicity. Clinical trials showed that previously untreated patients with severe HA present higher rates of inhibitor development if treated with rec-FVIII products and that differences do exist as to inhibitor's formation among different rec-FVIII products. This finding could arise from several causes, such as absence of von Willebrand factor, different glycosylation profiles, or processes of molecular aggregation of the recombinant FVIII molecules. Objectives/Methods In this study, using size exclusion high-performance liquid chromatography (SE-HPLC), dynamic light scattering (DLS) spectroscopy, and functional biochemical assays, we investigated the purity grade, FX activating ability, and aggregation status of three recombinant marketed products (Advate [Baxalta], Refacto AF [Pfizer], and Kogenate [Bayer]). Results The overall analysis of the results obtained with SE-HPLC and DLS spectroscopy showed that the three recombinant FVIII concentrates contain low but significant amounts of molecular aggregates. This phenomenon was less evident for the Advate product. Molecular aggregation negatively affects the in vitro pharmacodynamics of the concentrates with higher aggregates' content. Conclusions This study shows that the three pharmaceutical formulations of recombinant FVIII contain variable amounts of molecular aggregates after their reconstitution at therapeutic concentrations. This phenomenon negatively affects the in vitro potency of the products with higher aggregates' content and might be invoked as a contributing cause of their increased risk to induce the formation of FVIII inhibitors.

Background Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT. Methods A retrospective single-center study including all BA children listed for LT in 2008–2016. Clinical, endoscopical, and biochemical data were analyzed. Results Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1–37.9 years] vs 11.2 years [range, 5.1–43 years]; P = .03 vs 10.7 years [range, 6.9–39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0–17.7 months] vs 2.2 months [0–17.9 months], respectively; P = .89). After 45.5 months (range, 13.7–105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16). Conclusions Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation.

Direct oral anticoagulants (DOAC) and vitamin K antagonist drugs (VKA) are recommended for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism. Undoubtedly, DOAC have contributed to improve quality of life of these patients, but unfortunately, available 'real world' data show a very high variable compliance to DOAC.to evaluate predictors that adversely affect therapeutic adherence in patients naivethis study was conducted on an outpatient population in oral anticoagulant therapy in a period between January 2019 and February 2020. Patients naiveto DOAC and treated for at least 6 months were enrolled. Non-Italian-speaking patients, cognitive or psychiatric disorders, refusal to participate or non-consent to the interview were exclusion criteria. A socio-demographic scale and the 8-item Morisky scale (MMAS-8) questionnaire assessed therapeutic adherence.One hundred two DOAC-naïve patients were selected from a population of 407 patients on the first visit at our centre. The population was homogeneously represented for gender (males 48%). The mean age was 79.5 years. Atrial fibrillation (65.7%) resulted the main reason for DOAC prescription and a polypharmacy was detected in 47.1% of the patients. Moreover, an optimal adherence to DOAC therapy was assessed in less than 30% of patients.Polypharmacy, patient's isolation, such as a low education level were statistically associated with a low therapeutic adherence. Therapeutic adherence remains an unsolved problem for anticoagulated patient. To identify patients at higher risk of poor compliance and therapeutic failure and establish targeted care pathways is a priority.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver pathology, ranging from simple hepatic steatosis to more advanced forms of liver damage, up to cirrhosis. It has been described an important increase in the prevalence of NAFLD, likely related to the dramatic rise in the incidence of obesity during the past three decades. Despite an increase in public awareness, overweight/obesity and related conditions, such as NAFLD, remain underdiagnosed and underestimated.

We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G>A and (2) c.6532G>T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D′D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient’s daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C>T mutation in exon 25 of the VWF gene causing the p.P1127S substitution, inherited from her mother. The in vitro expression of the heterozygous in cis VWF mutant rVWFWT/rVWF924Q-2178S confirmed and recapitulated the ex vivo VWF findings. Molecular modeling showed that these in cis mutations stabilize a partially stretched and open conformation of the VWF monomer. Transmission electron microscopy and atomic force microscopy showed in the heterozygous recombinant form rVWFWT/rVWF924Q-2178S a stretched conformation, forming strings even under static conditions. Thus, the heterozygous in cis mutations 924Q/2178S promote conformational transitions in the VWF molecule, causing a type 2B–like VWD phenotype, despite the absence of typical mutations in the A1 domain of VWF.

Background Children affected with chronic liver disease are at risk for fat-soluble vitamins (FSV) deficiency, in this scenario the role of liver transplant has been only partially explored. Aims This study aimed to evaluate the prevalence of FSV deficiency in a cohort of paediatric patients awaiting liver transplant, analyze relationships between plasma vitamin concentrations and risk of acute rejections and liver fibrosis and assess the impact of the transplant on vitamin status. Methods 166 children candidates for liver transplant were retrospectively evaluated. Vitamin concentrations were measured before and 12 months after transplantation. Results Before transplant vitamin A, vitamin E and vitamin D deficiency was found in 66.6%, 40.6% and 36.3% of patients, respectively. 12 months after surgery, the prevalence of deficiency decreased to 29,5% and 2,6% for vitamin A and E while remained the same for vitamin D (36.3%). No association was found between vitamin status and the risk of acute rejections or the severity of liver fibrosis. Conclusion Liver transplant was effective to improve vitamin A and E, but it did not affect vitamin D. A consensus is needed to define optimal nutritional management of these patients in order to prevent deficiencies.

Exhaustion of vascular accesses is a major complication in patients undergoing hemodialysis, especially in pediatric setting. We report the case of a boy treated for loss of hemodialysis access after a combined liver-kidney transplantation and transient renal dysfunction. An interventional dilatation of calcific superior vena cava allowed to insert a stable central venous line for dialysis until full graft recovery. Careful management of central lines allows to spare the main vessels and reduces the need for unusual accesses.

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.

Inflammatory bowel diseases (IBDs) represent a group of intestinal disorders with a chronic and relapsing inflammation of the gut, and with a potential risk of systemic involvement of other organs and systems. Over the pediatric age, an incidence higher than 20% of developing extraintestinal manifestation during follow-up has been reported. The liver and the biliary system are frequently involved, and primary sclerosing cholangitis (PSC) is the most predominant entity with an incidence rate of 6.4-7.8% in children. PSC recognizes a multifactorial pathogenesis, and so far a not fully known mechanism for this association. The peculiar phenotype and the distinct clinical course of patients with IBD and PSC-associated make this 'linkage' an attractive study model to better understand mechanisms underlying these diseases. Approaching to these patients is complex and multidisciplinary, and a unique therapeutic strategy has not been standardized yet. New medications are being studied; however, further studies are needed to fully understand the pathogenesis and to improve the care of these patients. The aim of this paper is to review the recent literature regarding hepatobiliary involvement in IBD patients, with particular attention to PSC, and to provide the latest information for a correct diagnosis and appropriate management.

We report the case of a 14-year-old boy affected by ulcerative colitis (UC) and acute thrombocytopenic purpura (ITP) with simultaneous onset. UC diagnosis was based on symptoms, endoscopy and histology findings. ITP diagnosis was based on the normal bone marrow megakaryocyte count, the presence of platelet associated IgG and the absence of splenomegaly. Medical treatments including high doses of steroids, intravenous immunoglobulins were ineffective on ITP course, while UC course was mild for several months after the onset. When colonic inflammation became untractable not responsive at steroids and immunosuppressive agents, colectomy resolved both pathologies.

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

BACKGROUND Outcome of liver disease in children is mainly determined by severity and progression of liver fibrosis. Liver biopsy is the accepted standard for evaluating fibrosis but is limited by the need for sedation in children, sampling error, and risks including bleeding. The aim of the present study was to compare tools for noninvasive assessment of liver fibrosis in a paediatric cohort. METHODS Children undergoing liver biopsy for chronic liver disease were recruited and underwent transient elastography (TE). Liver biopsies were scored by a hepatohistopathologist from F0 (no fibrosis) to F4 (cirrhosis). TE was compared with biopsy score. RESULTS During the study period, 104 children (62 boys) were enrolled (median age 13.6 years). Diagnosis was autoimmune liver disease in 27; nonalcoholic fatty liver disease in 37; posttransplant in 16; hepatitis B/C in 8; Wilson disease in 5; and the remainder, miscellaneous. TE was successful in all but 7 patients and was a good discriminator of significant fibrosis (≥ F2) (P < 0.001), severe fibrosis (≥ F3) (P < 0.001), and cirrhosis (F4) (P = 0.003). The area under the receiver operating characteristic curve for the prediction of ≥ F2, ≥ F3, and F4 using TE was 0.78, 0.79, and 0.96, respectively. TE performed best in children with autoimmune liver disease and in those posttransplant. CONCLUSIONS The present study demonstrates that TE is a reliable tool in distinguishing different stages of liver fibrosis in paediatric patients. Thus, TE may serve as a useful adjunct to liver biopsy for diagnostic purposes providing a reliable method of noninvasively monitoring liver disease progression in children.

Dear Editor, We read with interest the paper from Papadia et al. [1] that suggests the potential role of the serum citrulline (CIT) level as biomarker of malabsorption. Intestinal CIT originates from the intestinal villi located in the proximal small bowel, which justifies its potential usefulness in the diseases associated with villous atrophy such as celiac disease (CD) [1]. Currently, the serological screening for suspected pediatric CD is based on the two major serological markers represented by the anti-transglutaminase type 2 (tTG) and by the anti-endomysial antibodies (EMA) [2]. Recently a third antibody against deamidated forms of gliadin peptides (DGP) has been identified that seems to be more sensitive in young children [2]. However, all these auto-antibodies may be undetectable in some clinical conditions [2]. In these cases, the diagnosis of CD may be supported by a screening tool not based on the evaluation of antibodies, but seemingly predictive of intestinal atrophy. From this perspective, the use of the CIT level might be helpful. We would like to report our experience with the CIT level in subjects highly suspected for CD. In 2011, we planned a prospective study to evaluate whether the serum CIT level might be included in a practical diagnostic work up of subjects with suggestive symptoms for CD. The setting of our study was the Hepatology, Gastroenterology and Nutrition Unit of ‘‘Bambino Gesu’’ Children’s Hospital in Rome. Between June 2011 and March 2012, all patients referred for suspected CD were enrolled. In all suspected CD subjects, a blood sample for IgA, tTG of IgA class, EMA, serum CIT and creatinine was taken. The biological sampling of CIT was made during stable clinical conditions and in a post-absorptive state and determined by RF-HPLC. In patients with IgA deficiency (total IgA B 5 mg %), we assessed the tTG of IgG class [3]. A biopsy was performed in all suspected CD, with suggestive symptoms isolated or associated with positive tTG/EMA. In agreement with the recommendations of the North American Society for Pediatric Gastroenterology Hepatology and Nutrition [3], type 3 specimens according to Marsh-Oberhuber classification [4] were considered characteristics of CD. The Marsh 1 and 2 lesions were considered nonspecific, but in line with the CD diagnosis in presence of positive tTG/EMA [3]. In patients with Marsh 3 lesions and negative tTG/EMA, HLA-DQ was assessed, and the symptoms were evaluated after starting a glutenfree diet (GFD). The patients with positive HLA-DQ2 and DQ8 and disappearance of the symptoms on a GFD were considered as CD cases. During the same period we enrolled all consecutive CD patients on a GFD. The inclusion criteria were the following

The prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The outcome of these patients is particularly bleak when the disease is complicated by portal vein tumor thrombosis (PVTT), since the increased portal pressure often causes serious gastrointestinal bleedings. Before the introduction of sorafenib (SOR), a tyrosine kinase inhibitor, no effective treatment was available for patients with advanced disease. SOR is now considered the standard treatment even for patients with tumor thrombosis, although the well-known interference between tyrosine kinase inhibitors and the coagulation pathway calls for caution against their use in this setting. Here, we report the case of a 74-year-old male patient with advanced HCC and PVTT treated with sunitinib (SUN), another multikinase inhibitor. During the third cycle, our patient experienced a life-threatening hematemesis with hemorrhagic shock that required intensive care treatment and SUN discontinuation. However, he completely recovered, and the PET/CT scan performed 1 year after the adverse effect demonstrated no evidence of the tumor together with portal vein recanalization. The short course of SUN causing both tumor response and gastrointestinal bleeding warrants further studies on the effectiveness of SUN in this setting as well as on the duration of treatment with multikinase inhibitors in patients with tumor thrombosis.

Patients on long-term parenteral nutrition (PN) are at significantly increased risk for the development of metabolic bone disease (MBD); this condition is characterized by incomplete mineralization of osteoid with consequent disturbances ranging from osteopenia to severe bone disease with fractures. The aim of the study was: (1) to evaluate the prevalence of MBD, (2) to identify the PN- or intestinal failure (IF)-related factors and (3) to assess annual changes of bone mineral status. Since September 2005 all patients affected by IF and treated with PN started a BMD evaluation program using dual-energy X-ray absorptiometry (DXA). Twenty-four IF patients were included [15 with short bowel syndrome (SBS), 5 with severe protracted diarrhea and 4 with chronic intestinal pseudostruction]. The bone mineral density (BMD) Z-score was significantly lower in patients than in the control group. In our series SBS patients showed a BMD Z-score significantly higher in comparison with the medical causes of IF. No significant correlations were found between bone mineral status and PN duration and nutrient intake. Nine IF patients were submitted to a second DXA evaluation after 1 year from the baseline. All bone mineral variables were significantly increased at the second DXA evaluation. The high prevalence of MBD in IF patients undergoing long-term treatment with PN requires that these patients undergo careful and periodic monitoring of their bone mineral status; patients with congenital gut dysfunctions, such as epithelium defects and motility anomalies, are at major risk of developing this complication, probably due to the association with extra-intestinal causes of bone loss.

Gastric bypass has been reported to be associated with markedly suppressed plasma ghrelin levels, suggesting that it is one of the possible weight-reducing factors related to this procedure. The aim of this study was the evaluation of plasma ghrelin levels in patients who had undergone laparoscopic Roux-en-Y gastric bypass (LRYGBP) and laparoscopic adjustable silicone gastric banding (LASGB). Normoweight, obese subjects and patients who had undergone total gastrectomy were used as controls. In this cross-sectional study, we selected 10 subjects who underwent LASGB, 11 subjects with LRYGBP, 10 obese subjects, eight patients with total gastrectomy, and eight normoweight subjects. Plasma ghrelin, insulin, and glucose profiles were determined before and after breakfast and lunch. Obese subjects showed a ghrelin plasma level significantly lower than normoweight subjects (407.3 +/- 21.6 vs. 813 +/- 72.4 pg/ml, P < 0.01). Patients with LRYGBP showed baseline ghrelin levels lower than LASGB (213.5 +/- 73.9 vs. 314.2 +/- 84.3 pg/ml, P = 0.04). Both groups of patients who underwent bariatric surgical procedures also had ghrelin lower than normoweight and obese subjects (P < 0.01 and P < 0.05, respectively). Patients with total gastrectomy showed plasmatic ghrelin levels extremely lower than those in all other groups (32.6 +/- 18.7 pg/ml, P < 0.001 for all). The ghrelin profile in both groups of subjects who underwent LRYGBP and LASGB did not show any meal-related changes as observed in obese and normoweight control groups. Significant difference in plasma ghrelin levels between LRYGBP and LASGB was found, suggesting that both procedures could induce weight loss by different mechanisms in which ghrelin could be involved.

OBJECTIVE To investigate whether skeletal muscle uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) gene expression is altered in massive obesity and whether it correlates with in vivo insulin sensitivity and with metabolic and hormonal status. DESIGN Quantification of UCP2 and UCP3 gene expression in skeletal muscle of obese and lean subjects displaying different degrees of insulin sensitivity. PATIENTS Fourteen obese and 10 age- and sex-matched healthy control subjects with a mean body mass index (BMI) of 43.6 +/- 1.4 and 22.8 +/- 1.8 (+/- SEM), respectively. MEASUREMENTS Insulin sensitivity by glucose clamp, body composition by bio-impedance, fasting plasma glucose, insulin, leptin and free fatty acids (FFA). Skeletal muscle UCP2 and UCP3 mRNA levels by quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS No significant differences in UCP2 or UCP3 mRNA levels were found between obese and control subjects. No significant correlation was observed, in both groups, between UCP2 or UCP3 mRNA levels and both anthropometrical and metabolic parameters. In contrast, a highly significant correlation was observed between skeletal muscle UCP3, but not UCP2, mRNA levels and plasma FFA in the obese, but not in the lean, group. Furthermore, exposure of human myocytes to FFA for 24 h strongly induced both UCP3 and peroxisome proliferator-activated receptor-gamma (PPARgamma) but not UCP2 gene expression. CONCLUSIONS FFA levels correlate strongly with skeletal muscle UCP3 mRNA levels in obese, but not in lean, subjects; in addition, in human myocytes, high FFA concentrations promote UCP3 expression. Our studies therefore provide evidence that supports a role for increased plasma FFA concentrations in the regulation of human skeletal muscle UCP3 gene expression.

Background: Necrotizing colitis (NC) represents a severe, although rare, complication in patients with anorexia nervosa. Objective: We report the only case of NC with good prognosis in a severely malnourished AN patient. Method: Available patient records, imaging, and biochemical data were evaluated. Discussion: This case represents an unusual gastrointestinal complication and underlines the important clinical role that Parentera Nutrition (PN) has for some selected very malnourished AN patients. The severe starvation may compromise the normal function of gastrointestinal tract and it can also lead to an incomplete tolerance of enteral refeeding thus making PN required to reach the nutritional rehabilitation. © 2010 by Wiley Periodicals, Inc. (Int J Eat Disord 2011; 44:91–93)

The clinical presentation of celiac disease in children is very variable and differs with age. The prevalence of atypical presentations of celiac disease has increased over the past 2 decades. Several studies in adults and children with celiac disease indicate that obesity/overweight at disease onset is not unusual. In addition, there is a trend towards the development of overweight/obesity in celiac patients who strictly comply with a gluten-free diet. However, the pathogenesis and clinical implications of the coexistence of classic malabsorption (e.g., celiac disease) and overweight/obesity remain unclear. This review investigated the causes and main clinical factors associated with overweight/obesity at the diagnosis of celiac disease and clarified whether gluten withdrawal affects the current trends of the nutritional status of celiac disease patients.

Background/Objectives: The practice of home enteral nutrition (HEN) represents a relevant aspect of the clinical management of both malnourished children and well-nourished children unable to be fed using an oral diet. The aim of this study was to estimate in an Italian paediatric population over a 14-year period (1996-2009), the clinical relevance and results over time of HEN activity. Subjects/methods: HEN-computerized database and medical/dietetic charts were evaluated for patients aged at start of HEN 1 month. Results: During the study period, we recorded 757 HEN programs. HEN began at a median age of 2 years for a median duration of 8.1 months. The complication rate was 14.8%. In the second period of the survey (2003-2009), the main changes concerned the underlying diseases requiring HEN, choice of formula feeding and access route. In 2009, the estimated overall prevalence of HEN was 3.47 and the incidence 2.45 per 100 000 inhabitants from 0 to 18 years of age. Conclusions: The epidemiological data of this study demonstrate that HEN concerns a growing number of Italian children and families. Some aspects of HEN clinical management should be modified to reach the recommended standards. © 2013 Macmillan Publishers Limited.

Background In 2007, sorafenib was the first drug able to improve overall survival in patients with advanced hepatocellular carcinoma. Aim In 2005 we designed a phase II study to assess safety and efficacy of sunitinib. Methods This is a single arm, open-label, single-centre phase II trial. Eligibility criteria were advanced hepatocellular carcinoma; no prior chemotherapy, performance status 0–1; and Child ≤ B8. The treatment schedule was 50 mg each day orally, 4 weeks on, 2 weeks off. Results Between 10/2007 and 10/2010, 34 patients were enrolled. A significant worsening of liver functional reserve after sunitinib was observed. Grade 3/4 adverse effects occurred in 80% of patients and included fatigue (47%), nausea (15%), liver failure (15%), encephalopathy (12%) and upper gastrointestinal bleeding (12%). Six patients (18%) died within 60 days of enrolment. A partial response was observed in 4 patients (12%). Median time to tumour progression was 2.8 months and median overall survival was 5.8 months. Conclusion A dose of 50 mg/d induces a high rate of severe adverse events. Toxicity remains a key concern also at the dose of 37.5 mg/d. However, sunitinib is able to induce a prolonged response in some patients. Positron Emission Tomography/Computed Tomography scans may select good responders.

The main objective of the study was to prospectively assess if the prevalence of celiac disease (CD) in patients with anorexia nervosa (AN) is higher than that reported in the general population to require a regular screening program. The study was conducted at the Neuropsychiatry Unit of “Bambino Gesu” Children’s Hospital in Rome from January 2005 to December 2010. All patients with diagnosis of AN according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria were screened for CD. One hundred and seventy-seven patients (33 males and 144 females) were enrolled. Only one patient was found to be affected with CD as confirmed by intestinal biopsy. The overall prevalence of CD in AN patients was 0.6 % which is similar to that observed in the general population. In conclusion, AN patients do not seem to require a regular screening program for CD. The screening for CD may be useful in selected AN patients in which the symptoms are only partially responding to psychiatric interventions.

CNI have improved the outcome of LT. However, their inherent potential to nephrotoxic and sometimes-inadequate immunosuppressive effect has lead to the usage of newer drugs like SRL. Aim of this study was to review children who received SRL. Thirty-seven (20 women) children post-LT, median age 10.4 yr (0.8-17.4) with a minimum follow-up of six months comprised the study group. Indications for SRL were biopsy-proven resistant acute allograft rejection (n = 12), early CR (n = 12), and CNI-induced nephropathy with MMF intolerance (n = 11). In two patients, the indication was the recurrence of BSEP disease in the allograft. In patients with acute rejection, AST normalized in 10/12 patients. In patients with CR, AST normalized in 6/12 patients. Those with renal impairment showed improvement in their creatinine levels from a mean baseline of 99-56.7 μm (p = 0.03) and their mean cystatin C was 1.02 after SRL. Side effects leading to discontinuation of SRL were seen in three patients. SRL was effective in rescuing patients with acute and chronic allograft rejection and improving renal function in CNI-induced nephropathy group.

Thyroid autoimmunity (TA) is often associated with coeliac disease (CD).To evaluate, in children and adolescents with CD on a gluten-free diet (GFD): (1) the prevalence of TA; (2) the impact of TA on growth and the need for L-thyroxine (L-T4) treatment, during a longitudinal survey.Between January and December 2005, 545 patients with CD, prospectively followed up until December 2007, and 622 controls were screened for TA. Antithyroperoxidase and antithyroglobulin antibodies were assayed and, if positive, serum free tri-iodothyronine, free thyroxine and thyroid-stimulating hormone (TSH) assays and thyroid ultrasound were performed. L-T4 was started if TSH was5.5 mU/ml at two successive measurements.There was no significant difference in TA prevalence between patients with CD on a GFD (10%) and controls (8.2%). Duration of GFD differed significantly in coeliac patients with TA in comparison with those without TA (7.9±0.9 and 10.2±0.3 years, p0.001), but no significant difference was found for weight and height gain (1.8±1.0 vs 3.7±1.5 and 2.1±1.2 kg/year vs 4.0±1.1 cm/year, respectively). At the end of the follow-up an increase of 7% in the prevalence of patients with CD with TA requiring L-T4 was found.TA seems no more common in paediatric and adolescent patients with CD on a GFD than in controls; its clinical evolution does not seem to impact on growth. Therefore, a long-term regular screening programme for thyroid disease may not be necessary for all patients with CD on a GFD, but only for those who are suspected of having thyroid diseases.

Background Some reports highlight the potential application of fecal calprotectin as a direct biomarker of intestinal inflammation and, therefore, as support in choosing candidates for endoscopy. The value of 100 μg/g was recently assumed as the best cutoff for this assay. The purpose of this study was to assess the diagnostic precision of the fecal calprotectin assay, compared to histology, as a stool-screening biomarker for inflammatory bowel disease (IBD) among a group of prospectively identified patients referred for recurrent abdominal pain and altered bowel habits. Methods Between 1999 and 2007 we prospectively evaluated the calprotectin assay in a cohort of patients with recurrent abdominal pain and altered bowel habits associated or not with other symptoms suggestive of IBD. All patients suspected of IBD, according to Rome and Porto criteria, provided stool specimens for the calprotectin assay and subsequently underwent endoscopic procedures. Results Compared to histology, the cutoff of 100 μg/g reached a sensitivity and specificity of 100% and 68%, respectively, and a likelihood ratio (LR) of 3.1. The cutoff value of 160 μg/g, however, in our series produced the best joint estimate of sensitivity and specificity: 100% and 80%, respectively, with an LR of 5. Conclusions In pediatric patients with recurrent abdominal pain and changes in stool habits, a positive calprotectin assay is closely associated with IBD; its systematic employment, therefore, seems to improve the process of endoscopy referral. This test, simple and inexpensive, could be included in the first noninvasive phase of an IBD diagnostic work-up.

Parenteral nutrition (PN) is the primary treatment for intestinal failure, which is considered irreversible in patients who remain partially or fully dependent on PN. Causes of irreversible intestinal failure are short bowel syndrome (SBS), motility disorders (MD), and severe protracted diarrhea (SPD). The aim of this study was to report the clinical outcome in these patients in relation to the underlying disease.From January 1, 1989 to December 31, 2006, 218 intestinal failure patients were observed in our center, but only 96 (48 SBS, 39 SPD, and 9 MD) were included because they required at least 50% of their total calories as PN for not less than 3 months. In these patients, survival and complication rates were evaluated.The survival rate was significantly higher in SBS patients than in the other groups (P0.01). SBS patients showed a higher rate of major complications, although only intestinal failure-associated liver disease was significantly higher (P0.001). In our series, MD was the main cause of irreversible intestinal failure.The potential for bowel adaptation is higher in surgical than in medical causes of intestinal failure and does not seem to be influenced by complications of intestinal failure. SBS, although worsened by the major number of complications, was not the main category contributing to intestinal failure.

Background: Inflammatory bowel diseases (IBD) are characterized by periods of remission with recurrent episodes of symptom exacerbation because of acute intestinal inflammation, which is correctly evaluated by endoscopy with biopsy sampling. However, many surrogate markers of intestinal inflammation, including fecal calprotectin (FC), are detected as potential predictors of mucosal inflammation in IBD patients. The aim of our study was to retrospectively assess the clinical efficacy of the calprotectin assay in determining histological relapses of pediatric IBD patients. Methods: We retrospectively reviewed the histological examinations, clinical records, and FC values of patients who had undergone colonoscopy at our hospital over an 8-year period, from December 31, 1998, to December 31, 2006. Only patients with a first histological examination showing a quiescent IBD who submitted to a second histological examination during the next 3 years were selected. Results: Seventy-three IBD patients, all with a first biopsy showing a quiescent IBD, were studied; at the second histological examination, 32 presented with relapse and 41 presented with remission. Relapsed patients showed significantly increased FC levels compared with nonrelapsed patients. A FC value of 275 μg/g achieved sensitivity and negative predictive value of 97% and specificity and positive predictive value of 85% in predicting histological relapse. Conclusions: FC seems to be a direct measure of intestinal inflammation and therefore a good marker of the risk of histological relapse in pediatric IBD patients. The application of this test in clinical practice may enable the avoidance of invasive tests as well as targeting treatment. (Inflamm Bowel Dis 2008)

Purpose Anorexia nervosa (AN) is a common chronic disorder characterized by severe malnutrition and psychological disturbances. Parenteral nutrition (PN) is not usually used in nutritional rehabilitation of AN. The aim of our study was to retrospectively evaluate the indications, clinical efficacy, and safety of PN as assessed by short- and long-term outcomes in AN inpatient girls. Methods During the last 10 years a total of 198 inpatients were included in our study: 104 (53%) received oral and parenteral refeeding (group A) and 94 (47%) oral refeeding alone (group B). For each nutritional treatment, clinical efficacy was evaluated by short- and long-term outcomes, and safety was assessed by complication rate. Results Short-term outcome assessment indicated weekly weight gain and maximum caloric intake to be higher in PN-treated patients. Long-term outcome evaluation showed rehospitalization and recovery rate to be similar in the two groups, but failure of first nutritional rehabilitation requiring PN significantly greater in group B (17.5%) than in group A (3%) ( p = .01). The number of complications was significantly higher in group A than in group B ( p = .004), although all complications resolved. Conclusion Among all nutritional rehabilitation strategies, PN offers an alternative and safe way to successfully treat AN patients. Presence of clinical complications and reduced compliance with individual, group, and family therapy seem to be the main indications for PN, as it promptly improves nutritional status. At pediatric and adolescent ages, psychological disturbances can also contraindicate the use of enteral nutrition, and therefore represent an additional indication for PN.