Characterization of the Gut Microbiota and Mycobiota in Italian Pediatric Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, cholestatic liver disease of unknown etiopathogenesis, often associated with inflammatory bowel diseases. Recent evidence ascribes, together with immunologic and environmental components, a significant role to the intestinal microbiota or its molecules in the PSC pathogenesis. METHODS: By metagenomic sequencing of 16S rRNA and ITS2 loci, we describe the fecal microbiota and mycobiota of 26 pediatric patients affected by PSC and concomitant ulcerative colitis (PSC-UC), 27 patients without PSC but with UC (UC), and 26 healthy subjects (CTRLs). RESULTS: Compared with CTRL, the bacterial and fungal gut dysbiosis was evident for both PSC-UC and UC groups; in particular, Streptococcus, Saccharomyces, Sporobolomyces, Tilletiopsis, and Debaryomyces appeared increased in PSC-UC, whereas Klebsiella, Haemophilus, Enterococcus Collinsella, Piptoporus, Candida, and Hyphodontia in UC. In both patient groups, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma and Malassezia were decreased. Co-occurrence analysis evidenced the lowest number of nodes and edges for fungi networks compared with bacteria. Finally, we identified a specific patient profile, based on liver function tests, bacterial and fungal signatures, that is able to distinguish PSC-UC from UC patients. CONCLUSIONS: We describe the gut microbiota and mycobiota dysbiosis associated to PSC-UC disease. Our results evidenced a gut imbalance, with the reduction of gut commensal microorganisms with stated anti-inflammatory properties (ie, Akkermansia, Bacteroides, Parabacteroides, Oscillospira, Meyerozyma, and Malassezia) and the increase of pathobionts (ie, Streptococcus, Saccharomyces, and Debaryomyces) that could be involved in PSC progression. Altogether, these events may concur in the pathophysiology of PSC in the framework of UC.

In this study, we report the gut microbiota and mycobiota dysbiosis in pediatric patients affected by primary sclerosing cholangitis (PSC) associated with ulcerative colitis (UC), with an increase in pro-inflammatory pathobionts and a reduction in anti-inflammatory commensals.

Juvenile Autoimmune Hepatitis: Recent Advances in Diagnosis, Management and Long-Term Outcome.

Juvenile autoimmune hepatitis (JAIH) is severe immune-mediated necro-inflammatory disease of the liver with spontaneous progression to cirrhosis and liver failure if left untreated. The diagnosis is based on the combination of clinical, laboratory and histological findings. Prothrombin ratio is a useful prognostic factor to identify patients who will most likely require a liver transplant by adolescence or early adulthood. JAIH treatment consists of immune suppression and should be started promptly at diagnosis to halt inflammatory liver damage and ultimately prevent fibrosis and progression to end-stage liver disease. The risk of relapse is high especially in the setting of poor treatment compliance. Recent evidence however suggests that treatment discontinuation is possible after a prolonged period of normal aminotransferase activity without the need for liver biopsy prior to withdrawal.

The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review.

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.

Cold Ischemia Time and Graft Fibrosis Are Associated with Autoantibodies after Pediatric Liver Transplantation: A Retrospective Cohort Study of the European Reference Network TransplantChild.

The reported prevalence of autoantibodies (AAB) (ANA, SMA, LKM, SLA) after pediatric liver transplantation (pLTX) varies considerably from 26-75%, but their clinical impact on outcome is uncertain. We aimed to study the prevalence of AAB after pLTX, their association with donor-, transplant-, and recipient-characteristics, and their relation to outcome. In our multicenter retrospective study, we aimed to clarify conflicting results from earlier studies. Six ERN TransplantChild centers reported data on 242 patients, of whom 61% were AAB positive. Prevalence varied across these centers. Independent of the interval between pLTX and AAB analysis, a one-hour increase in CIT resulted in an odds ratio (OR) of 1.37 (95% CI 1.11-1.69) for SMA positivity and an OR of 1.42 (95%CI 1.18-1.72) for ANA positivity. Steroid-free immunosuppression (IS) versus steroid-including IS (OR 5.28; 95% CI 1.45-19.28) was a risk factor for SMA positivity. Liver enzymes were not associated with ANA or SMA positivity. We did not observe an association of rejection activity index with ANA or SMA. However, the liver fibrosis score in follow-up biopsies was associated with ANA titer and donor age. In conclusion, this first multicenter study on AAB after pLTX showed high AAB prevalence and varied widely between centers. Longer CIT and prednisolone-free-IS were associated with AAB positivity, whereas AAB were not indicative of rejection, but instead were associated with graft fibrosis. The detection of AAB may be a marker of liver fibrosis and may be taken into consideration when indications for liver biopsy and immunosuppressive regimes, or reduction of immunosuppression in long-term follow-up, are being discussed. Prospective immunological profiling of pLTX patients, including AAB, is important to further improve our understanding of transplant immunology and silent graft fibrosis.

Sarcopenia in children with chronic liver disease: Prevalence and impact on liver transplant outcomes.

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.

Does the Treatment After Kasai Procedure Influence Biliary Atresia Outcome and Native Liver Survival?

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 Gesù 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.

To Wean or Not to Wean: The Role of Autologous Reconstructive Surgery in the Natural History of Pediatric Short Bowel Syndrome on Behalf of Italian Society for Gastroenterology, Hepatology and Nutrition (SIGENP).

Pediatric Short Bowel Syndrome (SBS) can require prolonged parenteral nutrition (PN). Over the years, SBS management has been implemented by autologous gastrointestinal reconstructive surgery (AGIR). The primary objective of the present review was to assess the effect of AGIR on weaning off PN. We also evaluated how AGIR impacts survival, the need for transplantation (Tx) and the development of liver disease (LD). We conducted a systematic literature search to identify studies published from January 1999 to the present and 947 patients were identified. PN alone was weakly associated with higher probability of weaning from PN (OR = 1.1, p = 0.03) and of surviving (OR = 1.05, p = 0.01). Adjusting for age, the probability of weaning off PN but of not surviving remained significantly associated with PN alone (OR = 1.08, p = 0.03). Finally, adjusting for age and primary diagnosis (gastroschisis), any association was lost. The prevalence of TX and LD did not differ by groups. In conclusion, in view of the low benefit in terms of intestinal adaptation and of the not negligible rate of complications (20%), a careful selection of candidates for AGIR should be required. Bowel dilation associated with failure of advancing EN and poor growth, should be criteria to refer for AGIR.

The contribution of plasma oxysterols in the challenging diagnostic work-up of infantile cholestasis.

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-3ß,5α,6ß-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.

Fat soluble vitamins deficiency in pediatric chronic liver disease: The impact of liver transplantation.

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.

WITHDRAWN: Fat soluble vitamins deficiency in pediatric chronic liver disease: The impact of liver transplantation.

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.

Eosinophilic esophagitis in children: current knowledge to open new horizons.

Eosinophilic Esophagitis (EoE) is a chronic immune/antigen-mediated condition which is also driven by genetic and environmental factors. It has been deeply investigated over the last years and its incidence is widely increasing in childhood. Although atopic diseases are closely linked with EoE, it does not recognize a classical IgE-mediate immune pathogenesis but it is rather a T helper type 2 inflammatory process. Familial clustering supports genetic predisposition in EoE and recent advances in understanding the genetic basis for EoE may eventually translate into targeted management of the disease. EoE diagnosis is based on clinical symptoms, micro, and macroscopic findings along with exclusion of gastroesophageal reflux disease (GERD) evidence. Management of the disease encompasses both dietary and pharmacological solutions that need to be specifically targeted on patients' history, clinical symptoms, and diagnostic evaluations. New therapies, currently not available in children, may represent the basis for future therapeutic options in the next years.

Fighting Fatty Liver Diseases with Nutritional Interventions, Probiotics, Symbiotics, and Fecal Microbiota Transplantation (FMT).

Pediatric obesity is rising worldwide leading the worrying phenomenon of nonalcoholic fatty liver disease (NAFLD) to shift into one of the most frequent causes of chronic liver illness in childhood. Occurrence of NAFLD depends on several factors such as the geographical area and the diagnostic modalities used; overall it ranges between 3% and 10% of pediatric population, increasing up to 70% in patients with metabolic comorbidities (Manco M, Bottazzo G, DeVito R et al, J Am Coll Nutr 27:667-676, 2008).Recent findings have related the intestinal microbiota to a plethora of pathological conditions, including type 2 diabetes (T2D), obesity, and nonalcoholic steatohepatitis (NASH). One of the emerging areas of the study is the link between liver diseases and gut microbiome, which has added new information to the understanding of the so-called gut-liver axis.In order to address the role of gut microbiome in NAFLD onset and progression, it is necessary to "decipher" operational codes for microbiome investigation within the context of advanced laboratory medicine to capture microbiome features and, hence, to address the function of the intestinal microbiome within the gut microbiota-liver axis.Results of these investigations have allowed the beginning of implementing the usage of probiotics and symbiotics in the medical approach of obesity and NAFLD in adults and children. Several randomized clinical trials (RCTs) have been already published on fecal microbiota transplantation (FMT), T2D, NASH, and inflammatory bowel disease (IBD).This review proposes to describe the current state of knowledge on the ways fatty liver diseases can be addressed with nutritional interventions, probiotics, symbiotics, and FMT.

Unmet needs in pediatric NAFLD research: what do we need to prioritize for the future?

INTRODUCTION: Pediatric nonalcoholic fatty liver disease (NAFLD) is common disorder that has complex pathophysiology and unquantified clinical significance. Though there have been major advances in the field, there is much yet to be understood. Areas covered: PubMed/MEDLINE and Embase were searched for articles related to pediatric NAFLD and nonalcoholic steatohepatitis (NASH) between January 1998 and January 2018. The areas considered to be 'unmet needs' were the relationship between the intestinal microbiome and perinatal events, clinical event risk stratification, and mechanisms underlying portal inflammation. Expert commentary: In utero and ex utero factors have been associated with NAFLD and also with the intestinal microbiome, but it is not yet known how intestinal dysbiosis can be reversed and whether intervention in high-risk neonates could alter their propensity for the metabolic syndrome. Children with NAFLD are at increased risk of cardiovascular, diabetic, and hepatic diseases, but it is unclear how best to stratify children into appropriate risk groups for targeted interventions. Finally, the immune processes underlying pediatric NASH are thought to differ to those in adult NASH, yet the events surrounding activation of periportal lymphocytes are poorly understood. Deepening our understanding of these topics may lead to novel therapeutic targets.

Paediatric departments need to improve residents' training in adolescent medicine and health: a position paper of the European Academy of Paediatrics.

In many European countries, paediatric junior staff has no formal training in adolescent medicine and is ill-equipped to deal with issues and health problems such as substance use, unprotected sex, eating disorders and transition to adult care. This position paper of the European Academy of Paediatrics proposes a set of competency-based training goals and objectives as well as pedagogic approaches that are expected to improve the capacity of paediatricians to meet the needs of this important segment of the paediatric population. The content has been developed from available publications and training programmes and mostly covers the generic aspects of adolescent healthcare, such as how to communicate effectively, how to review and address lifestyles, how to perform a respectful and relevant physical examination, how to address common problems of adolescents and how to support adolescents in coping with a chronic condition. CONCLUSION: The European Academy of Paediatrics urges national bodies, paediatric associations and paediatric teaching departments to adopt these training objectives and put them into practice, so that paediatricians will be better prepared in the future to meet the challenge of delivering appropriate and effective healthcare to adolescents.

Autoimmune liver diseases and inflammatory bowel diseases in children: current issues and future perspectives.

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.

Mixed Botryoid and Spindle Cell Bladder Rhabdomyosarcoma: An Outstanding Pediatric Case.

We report a case of a 3-year-old North African child, initially assessed for nonspecific urinary symptoms such as haematuria and burning urination. The ultrasound evaluation showed a vegetating mass occupying the lumen with weak vascular signs at the Colour-Doppler evaluation. An explorative cystoscopy was performed and it revealed a nonbleeding lesion, white in colour, pedunculated, projecting into the lumen, and associated with a brown satellite formation. Histological examination showed a mixed Botryoid and Spindle Cell Rhabdomyosarcoma. This mixed histology has not been described before and no statistical data are reported in literature so far. Despite the Embryonal Rhabdomyosarcoma variant being the most common, the association characterized by two histological Rhabdomyosarcoma subtypes such as Botryoid and Spindle Cell is rarely observed and it is important to get an accurate histological diagnosis in order to immediately start the correct treatment protocol.

Mode of delivery and atopic phenotypes: Old questions new insights? A retrospective study.

BACKGROUND: To date studies on the relation between mode of delivery and atopic diseases in are controversial. OBJECTIVE: The aim of the study was to determine a possible relationship between mode of delivery and risk of atopic phenotypes and, to assess the critical role of some pre-and post-natal parameters as a link between mode of delivery and risk of atopy. METHODS: 1516 children were assessed by skin prick tests, serum total and specific IgE levels. Parental reports on demographic and clinical data were also recorded. RESULTS: Of the 1516 children enrolled for the study, clinical and laboratory informations were obtained from 917 children. 460 children of them were born via CD and 457 via VD. Mode of delivery did not modify the prevalence of immune sensitization and/or allergic diseases. However, CD was associated with increased risk of atopy (p<0.001). Moreover, some parameters such as familiar history of atopy (p<0.001), habits smoking (p<0.05), exclusive artificial feeding (p<0.001); and breast-feeding time (<3months) (p<0.001) were associated with a major risk of atopy in CD group. Additionally, although our study confirmed that breast-feeding is associated to lower serum total IgE levels than artificial-feeding (p<0.001), it seems that the protective role of breast-feeding is negatively influenced from CD. Also in artificial-feeding subjects CD is related to a significant higher levels of IgE than VD (p<0.001). CONCLUSIONS: Our findings suggest that CD influences only the risk of atopy but no prevalence of immune sensitization and allergic diseases.

Role of prebiotics and probiotics in pediatric diseases.

The increasing knowledge about the composition and activities of the microflora has shown the close link between the bacteria and the health of the human organism. For this reason it has focused attention on the possibility of modulating the gut flora. The use of probiotics and prebiotics has increased enormously in recent years, more for real beneficial effects demonstrated in patients than for their safety profiles. However, it is recorded an indiscriminate use also in conditions in which there are no scientific evidence to support. Their use in case of immunocompromised patients or with severe and debilitating chronic diseases should be very prudent, because of the risk of complications including sepsis. The use of a probiotic cannot ignore the knowledge of the genus and species of the strain and in pediatric patients has been demonstrated their role for treating acute viral gastroenteritis and preventing antibiotic-associated diarrhea in healthy children. Moreover probiotics are considered as an option for recurrent and relapsing antibiotic sensitive pouchitis and in select patients with mild ulcerative colitis. Further studies are needed to evaluate clinical conditions that may require their use and to define the optimal doses and intake durations.

Mode of delivery and risk for development of atopic diseases in children.

Atopic diseases are a major public health problem worldwide, and several factors are thought to contribute to this rapid increase. The observed association between mode of delivery and risk of atopy in childhood has had a great deal of interest during the past few decades. In fact, even during delivery, exposure to antigens can index immune system in newborn, which induces the release of biologically active molecules, which are polarizing immune responses toward the T-helper 2 atopic profile. However, to date, studies on the relationship between mode of delivery and atopy have produced conflicting findings. The aim of this review was to summarize what is known about the relationship between mode of delivery and risk of atopic diseases in children. A literature search of electronic databases was undertaken for the major studies published from 1994 to today. The databases searched were PubMed, EMBASE, Medline, and Cochrane Library. The following key words were used: mode of delivery, cesarean section, vaginal delivery, atopy, and atopic diseases.