Sarcopenia is increasingly recognized in pediatric chronic diseases, yet its prevalence and determinants in children with intoxication-type inborn errors of metabolism (IEM) have never been investigated. This study aimed to evaluate sarcopenia in this population and to investigate associated metabolic alterations. We conducted a retrospective single-center study including 45 pediatric patients (0-18 years) with maple syrup urine disease (MSUD, 11 pts.), organic acidurias (OA, 22 pts.), or urea cycle defects (UCD, 12 pts.) considered for liver transplantation. Sarcopenia was defined as total psoas muscle area z-score ≤ -2 on CT scan. Anthropometric, dietary, and laboratory parameters were analyzed. Forty percent of patients exhibited sarcopenia, most frequently among OA (54.5%) and UCD (33.3%), and only occasionally in MSUD (18.2%). Sarcopenic children showed lower weight, height, and were more likely to require enteral nutritional support. Plasma levels of essential amino acids, particularly branched-chain amino acids (leucine, isoleucine, valine), histidine, and glutamine, were significantly reduced in sarcopenic patients. Leucine emerged as an independent predictor of sarcopenia (p = 0.016). FGF21 levels were elevated in sarcopenic OA and UCD patients, whereas MSUD patients with higher branched-chain amino acids levels showed lower FGF21, suggesting a role beyond mitochondrial stress signaling. Sarcopenia is common in pediatric patients with severe intoxication-type IEM and is closely linked to essential amino acid deficiencies and altered FGF21 signaling. These monogenic diseases provide unique pathophysiological models for better understanding of sarcopenia. Our findings highlight the need for targeted nutritional and metabolic strategies to preserve muscle mass in these vulnerable patients.

Cholestatic diseases in children represent a heterogeneous group of disorders that, with few exceptions, have no cure. For decades, off-label drugs and/or drugs with little evidence of efficacy have been used to treat pruritus or as supportive therapy. In recent years, a family of molecules known as bile acid transporter inhibitors (IBATis) has been developed, with two of these being approved for treating pruritus in progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (ALGS). Blocking the ileal reabsorption of bile acids (BAs) lowers serum levels. This contributes to reducing cholestatic pruritus. Such a mechanism of action may also have a potential benefit in other cholestatic diseases and even in the consequences of chronic cholestasis. This is a narrative review of the literature, including the most recent communications, to summarize data on the efficacy and safety of IBATis in the treatment of pruritus in PFIC and ALGS in children, including a description of the latest results from their use in a real-world setting. Reports on off-label use and experiences in adults are also discussed. This review aims to help physicians understand the potential and limitations of these new drugs in the treatment of cholestatic pruritus.

Background: Pan-enteric capsule endoscopy (PCE) provides useful information for the management of Crohn's disease (CD), especially in children. No study has evaluated the ability of PCE to characterize CD phenotypes and outcomes in children and adults. Methods: In a prospective multicenter observational study, we recruited patients with CD >6 years from 4 centers in Italy. Patients underwent clinical, biomarker assessment and PCE. Lesions were graded using the PCE system. For each segment, the most common lesion (MCL), the most severe lesion (MSL), and the extent of involvement were defined. Disease severity, extent, and clinical outcomes were compared between children and adults. A logistic regression analysis was used to identify predictive factors for negative outcomes in both age groups. Results: One hundred ninety-four consecutive patients (adults/children: 144/50) were evaluated for a total of 249 procedures. Children were more likely to have extensive disease, particularly in the colon. Higher MCL scores were independently associated with treatment escalation (odds ratio [OR], 4.09; 95% CI, 1.80-9.25; P = .001), while >30% disease extent was more indicative of clinical and endoscopic relapse (OR, 2.98; 1.26-7.08; P = .013). Disease extent was the only factor associated with endoscopic recurrence in children (OR, 4.50; 95% CI, 1.47-13.77; P = .008), while severe lesions in adults provided a better predictor of treatment escalation (OR, 4.31; 95% CI, 1.52-12.1; P = .006). Postexamination, PCE contributed to a change of therapy in 196/249 (79%) of the procedures. Conclusions: PCE allowed the characterization of CD phenotypes in children and adults by assessing disease severity and extent, which are of different importance in predicting clinical outcomes in these age groups.

Liver transplantation (LTx) is increasingly used in Urea Cycle Defects (UCDs) to prevent recurrent hyperammonemia and related neurological irreversible injury. Among UCDs, argininosuccinate lyase deficiency (ASLD) has a more complex phenotype than other UCDs, with long-term neurocognitive deficits. Therefore, the role of LTx in ASLD is still debated. The impact of LTx on nine patients with early-onset ASLD was assessed through pre- and post-LTx clinical, neuropsychological, MRI and biochemical evaluations. After LTx, no episodes of metabolic decompensations were reported. Neuropsychological evaluations documented significant improvement in cognitive/developmental functioning especially in patients transplanted in early childhood. Improvements were also highlighted in daily living skills and emotional-behavioral problems, with a reduction in attention disturbances and somatic complaints. Movement disorders resolved after LTx in patient transplanted in early childhood. Any patients developed epilepsy with stability of EEG alterations after LTx. A positive effect of LTx on other disease-related outcomes such as growth, diet, medications, hospitalizations, and long-term ASLD-related complications was highlighted. The primary biomarker argininosuccinic acid dramatically reduced in plasma after transplantation with a decreasing trend in CSF at long-term follow-up. Moreover, health-related quality of life improved after LTx, especially when assessed through MetabQoL, a tool designed for intoxication diseases such as ASLD. In conclusion, our study showed a global beneficial impact of LTx in early-onset ASLD patients to avoid episodes of hyperammonemia, and improve neurocognitive outcome, adaptive and behavioral deficits when performed in early childhood with a dramatic benefit in terms of quality of life.

Non-alcoholic fatty liver disease (NAFLD) is now identified as a hepatic sign of metabolic syndrome and is the most frequent cause of chronic liver disease in all ages. It is assumed that a genetic predisposition associated with epigenetic factors participates in the evolution of this condition. Visceral obesity and insulin resistance (IR) have always been considered the most important causative factors of Metabolic Syndrome (MetS) and NAFLD, but currently, the interaction between genetic heritage and environmental factors is increasingly considered fundamental in the genesis of metabolic disorders associated with NAFLD. In fact, in patients with NAFLD, insulin resistance, arterial hypertension, abdominal obesity, dyslipidemia and reduced intestinal permeability have often been found, as well as a higher prevalence of coronary artery disease, obstructive sleep apnea, polycystic ovary syndrome and osteopenia, which define a MetS framework. Early diagnosis is needed to prevent disease progression through primarily lifestyle interventions. Unfortunately, at present, there are no molecules recommended for pediatric patients. However, several new drugs are in clinical trials. For this reason, targeted studies on the interaction between genetics and environmental factors involved in the development of NAFLD and MetS and on the pathogenetic mechanisms that determine the evolution in non-alcoholic steatohepatitis (NASH), should be implemented. Therefore, it is desirable that future studies may be useful in identifying patients at risk of developing NAFLD and MetS early.

The treatment of hepatitis C virus (HCV) infection with the new directacting antivirals (DAAs) has dramatically modified the natural history of the HCV-related disease, eradicating the virus in over 90% of treated patients, with negligible collateral effects. The high costs of treatment, however, represent a factor that limits patients’ access to therapy and burdens the countries’ healthcare systems. In Italy the estimated cost of treatment for a naïve patient (8/12 weeks) amounts to approximately €5,500 (VAT excluded). HCV liver disease especially affects adults, in Italy the average prevalence of hepatitis C ranges between 2.4% and 3.3% in the general population. The prevalence of hepatitis C in children is significantly lower (0.15%) and the liver disease is rarely progressive in the paediatric age; however, there are not tools capable of interrupting the main route of infection, namely the vertical transmission from the infected mother. The effectiveness and great manageability of these new direct antivirals have also allowed their use in paediatrics starting from three years of age.

BACKGROUND:The role of histological inflammation at diagnosis as a possible prognostic factor for disease course has not been investigated. AIMS:To assess whether histologic findings at diagnosis could predict clinical outcomes and evaluate the association between clinical, biochemical, endoscopic, and histological findings. METHODS:Prospective single-center study including pediatric UC patients with a minimum follow-up of 12 months. The association between histological activity (Nancy Index, Robarts Histopathology Index, and Geboes Score) and 12-month clinical outcomes was evaluated. Secondarily, we assessed the correlation between histological scores and endoscopic and inflammatory markers at the diagnosis. Inter-observer agreement for histologic and endoscopic scores was also evaluated. RESULTS:Forty-nine UC patients were included. No association was found between 1-year clinical relapse and the three histological indices at diagnosis (p > 0.05). Good concordance was found among the three histological scores (p < 0.001), and between all histological and endoscopic indices (p < 0.05). No correlation was found between histologic scores and serum inflammatory markers. Inter-observer agreement was good for eMayo, Nancy and Robarts score (k = 0.71, k = 0.74 and k = 0.68, respectively) and moderate for Geboes (k = 0.46). CONCLUSIONS:Histological findings at diagnosis cannot be used as a predictor of the disease course. The three histological scores used in routine clinical practice show an overall good correlation and reliability.

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:Anemia is one of the most common extraintestinal manifestations of pediatric inflammatory bowel disease (IBD). We aimed to evaluate the prevalence of anemia in children newly diagnosed with IBD and assess the efficacy and safety of oral iron therapy over a 12-month follow-up period. Methods:This single-center, retrospective, observational cohort study included all children newly diagnosed with IBD at the Pediatric Gastroenterology Unit of Sapienza University of Rome from May 2015 to May 2019 presenting with anemia. At baseline, demographic, clinical, laboratory data (hemoglobin, mean corpuscular volume, serum iron, ferritin, transferrin levels, erythrocyte sedimentation rate, and C-reactive protein), and treatment received, were recorded. Clinical and laboratory data, as well as anemia therapy and adverse events (AEs), were collected every 3 months during the 1-year follow-up. Results:Eighty-nine out of 140 patients newly diagnosed with IBD presented with anemia (64%); 13 were excluded due to incomplete follow-up, thus 76 were included [median age 12.7 (interquartile range 9.8-15), 25 (33%) Crohn disease, 51 (67%) ulcerative colitis]. All patients received sucrosomial iron (SI) alone or in combination with intravenous ferric carboxymaltose. Treatment with SI was effective in 67 (88%) patients at the end of follow-up [37 (48%) within 3 months], regardless of anemia severity at baseline. No serious AEs related to SI treatment were reported. Conclusions:We confirmed a high prevalence of anemia at the time of the diagnosis of pediatric IBD. Our data suggest that SI is safe and effective, leading to anemia resolution in approximately half of the patients within 3 months.

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a multifaceted disease that includes a wide spectrum of liver damage. The presence and the degree of fibrosis are considered important factors for the prognosis of NAFLD and in predicting the risk of developing cirrhosis. Our aim was to evaluate the usefulness of four fibrosis scores (aspartate aminotransferase/Platelet Index [APRI], FIB-4, NAFLD Fibrosis Score [NFS], and Hepamet) in predicting different degrees of fibrosis among children with biopsy-proven NAFLD.MethodsAbout 286 adolescents [mean age 14.3 years ± 2.5; 154 (53.6%) males], referred between January 2014 and December 2019, with biopsy-proven NAFLD were enrolled.ResultsAbout 173 (60.4%) patients presented fibrosis at histological analysis. In particular: 140 (49.3%) patients had F = 1, 31 (10.8%), had F = 2 and 2 (0.66%) had F = 3. APRI (AUROC 0.619, 95% CI 0.556–0.679) and Hepamet (AUROC 0.778, 95% CI 0.722–0.828) scores had significant (p < 0.001) accuracy to distinguish subjects with fibrosis; while NFS and FIB-4 had not. APRI had a positive predictive value (PPV) of 62.77% (95% CI 57.96–67.35) and an negative predictive value (NPV) of 52.01% (95% CI 46.54–57.43); Hepamet a PPV of 63.24% (95% CI 59.95–66.41) and an NPV of 61.29% (52.9–69.01).ConclusionsOur study showed that Hepamet and APRI perform better than NFS and FIB-4 for identifying fibrosis in patients with NAFLD, but do not have PPVs so high to be considered diagnostic. Therefore, they cannot be employed, in children, for a certain diagnosis of fibrosis or its progression and cannot replace liver biopsy as the gold diagnostic standard. It is, therefore, necessary to continue to research and develop new markers of exclusive fibrosis.

Sarcopenia is a clinical condition characterized by a reduction in muscle mass, which typically affects adult patients; however, it has recently been recognized in pediatric literature. Few studies in children with chronic liver disease (CLD) undergoing liver transplantation (LT) have investigated the role of sarcopenia, with controversial results. The aim of our study was to assess the prevalence and impact of sarcopenia among children with CLD who are candidates for LT. We conducted a retrospective, single-center study at Bambino Gesù Children's Hospital (Rome, Italy) from July 2016 to July 2021, evaluating all children (0–16 years old) with CLD listed for LT with an abdomen computed tomography imaging available before LT. The total psoas muscle surface area (t-PMSA) was defined as the sum of left and right psoas muscle surface area measured at L4–L5 on axial images. The t-PMSA z-score was calculated according to reference data, and sarcopenia was defined as a t-PMSA z-score of ≤−2 (1–16 years) or a psoas muscle index [PMI; PMI = t-PMSA/(100 × BSA)] of <50th percentile of the population examined (<1 year). Clinical, laboratory, and LT outcome data were collected from all the patients with CLD. 27 out 48 (56%) of the patients aged 1–16 years were sarcopenic. No differences were noted in anthropometrics, nutritional support, liver function tests, model for ESLD (MELD), or pediatric ESLD (PELD) scores between patients with and without sarcopenia. The former showed a higher prevalence of respiratory complications (66.7% vs. 42.1%) and need for inotropes (40.7% vs. 10.8%) after LT. Among patients aged 0–1 years (n: 36), those with reduced muscle mass (50%) had a longer hospitalization time (44 vs. 24 days) and higher incidences of multi-organ failure syndrome (38.9% vs. 0%) and intensive care unit-related infections (61.1% vs. 27.8%) compared to those with greater muscle mass. t-PMSA and PMI were statistically significant predictors of LT outcomes. Sarcopenia is a reliable index of frailty in children with CLD, as its presence is associated with the risk of a more challenging LT. Future studies will have to investigate the functional aspects of sarcopenia and conceive preventive measures of muscle wasting in CLD patients.

Background and study aims Two scores have been implemented to standardize capsule endoscopic (CE) findings in patients with Crohn’s disease (CD): Lewis score (LS) and Capsule Endoscopy Crohnʼs Disease Activity Index (CECDAI). Both have limitations and are not well validated in the pediatric population. The aim of our study was to assess a new score (capsule endoscopy – Crohn’s disease index, CE-CD) in pediatric patients with CD and to compare it to preexisting scores. Patients and methods This was a double-center, retrospective study involving pediatric subjects with CD who underwent CE. Correlation analyses between CE-CD, endoscopy scores and noninvasive markers of disease activities were performed. The ability of different CE scores to predict clinical and endoscopic outcomes was evaluated with regression and survival analyses. Results A total of 312 subjects were analyzed. The CE-CD score showed a moderate (Pearson’s r = 0.581, P < 0.001) and strong (r = 0.909, P < 0.001) association with LS and CECDAI, respectively. CE-CD was a statistically significant predictor of hospitalization (hazard ratio [HR]1.061), treatment escalation (HR 1.062), steroid therapy (HR 1.082), clinical (HR 1.064) and endoscopic (HR 1.060) relapse over the twenty-four months (P < 0.001). Subjects with mucosal inflammation according to CE-CD (CE-CD ≥ 9) had worse outcomes compared to patients without inflammation (CE-CD < 9) (Log rang test < 0.001). Conclusions The CE-CD score is a simple, reliable, reproducible, and predictive score for evaluation of small bowel inflammation in pediatric patients with CD. Prospective validation is needed to confirm the applicability of this new index in clinical practice.

Objective: To identify risk and protective factors for mental health symptoms associated with lifestyle changes caused by home confinement in pediatric subjects and in children and adolescents with a neuropsychiatric disorder. Study design: This was a prospective, cross-sectional study conducted from May 10 to May 31, 2020. Two online anonymous surveys were developed: population-based and clinical-based (children with neuropsychiatric disorders). Outcomes included emotional and behavioral symptoms, as assessed by psychometric scales (BPSC, PPSC, PSC, CES-DC and SCARED, respectively), and lifestyle changes during home confinement (i.e., physical activity, screen time, home schooling, reading). Results: The sample included 9,688 pediatric subjects, and 289 children and adolescents with a neuropsychiatric disorder. The presence of siblings was a protective factor in all ages. In pre- and school children: male sex, a diagnosis of autism, residency in highly affected areas, high parental educational level or job loss, and screen time (>2 h/day) were risk factors. Physical activity, home-schooling, reading, talking with other people were protective factors. Residency in highly affected areas, a diagnosis of mood disorder, parental job loss, and screen time, were associated with a worsening of the depressive symptoms, whereas physical activity, talking with other people, playing with parents were protective activities. Screen time was also a risk factor for anxiety symptoms, while physical activity, reading and talking with other people were protective factors. Conclusions: This study identified risk and protective factors for mental health symptoms associated with lifestyle changes caused by COVID-19 home confinement to promote mental well-being in pediatrics during pandemic times.

Eosinophilic esophagitis (EoE) is an immune-mediated condition characterized by symptoms of esophageal dysfunction and an eosinophilic inflammation of the esophagus.1 Swallowed topical steroids represent one of the possible strategies for inducing and maintaining remission in EoE.2 To date, a validated maintenance strategy has yet to be defined, especially in children. The available evidence suggests decreasing the dose after a successful induction therapy.3 No study has reported the efficacy of a continuous progressive dose reduction; thus, it is unknown if all patients need to use the same dosages and for how long.4,5.

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-3 beta,5 alpha,6 beta-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.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.dld.2019.10.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.