Diagnosis and Treatment of Pouch Disorders in Children: A Systematic Review.

BACKGROUND: Restorative proctocolectomy and IPAA have become the surgical procedure of choice in pediatric patients with medically refractory colitis or familial adenomatous polyposis. OBJECTIVE: This systematic review aims to assess the diagnosis and treatment of pouch disorders in pediatric patients who undergo IPAA. DATA SOURCES: A literature search was performed using MEDLINE, Google Scholar, and Embase for all publications describing outcomes of pediatric IPAA. STUDY SELECTION: Studies between January 1, 2000, and September 7, 2022, published in English were included. Studies were excluded on the basis of title, abstract, and full-length review. INTERVENTIONS: IPAA. MAIN OUTCOME MEASURES: Pouch disorders described include anastomotic leaks, pouch strictures, pouch failure, pouchitis, cuffitis, and de novo Crohn's disease of the pouch. RESULTS: Thirty-three studies were included in this review, all of which were retrospective in nature. The outcomes of 2643 pediatric patients were included in the 33 studies. LIMITATIONS: Management is largely informed by clinical practices in adult patients with scant data on treatment efficacy in children. CONCLUSIONS: The reported incidence of disorders of the pouch in children varies widely and is likely attributable to differences in definitions and follow-up periods across studies. Pouchitis was the most frequently described outcome. The overall rate of pouch failure in children is relatively low, with de novo Crohn's disease of the pouch being the most significant risk factor. Multicenter prospective studies are needed in the pediatric population to accurately identify risk factors, standardize the assessment of pouch complications, and determine effective treatment strategies. See video from the symposium .

Emulsifiers and Intestinal Health: An Introduction.

ABSTRACT: Food additives in general, and emulsifiers in particular, are considered to be important dietary components with a potential to harm the intestine, in part by promoting intestinal inflammation. There is inadequate objective information about the specific nature and the magnitude of the problem.The Food and Drug Administration (FDA) has recognized approximately 450 items added to our foods as being generally regarded as safe and has placed them on a generally regarded as safe (GRAS) list. Additionally, it has also approved approximately 3000 "food additives." There is a general lack of transparency as to how either of these selections were and continue to be made. Once items are officially designated by the FDA as "food additives" or placed on the GRAS list, there is no regulatory mechanism for the ongoing monitoring of their safety.The most widely used emulsifier is "lecithin," which is biochemically identified as phosphatidylcholine (PC). Regulatory guidelines allow manufacturers to use the label "lecithin" to be applied to emulsifiers that contain PC plus other phospholipids in a variety of unspecified concentrations. The PC used in experiments cited in the literature, is unlikely to be the same thing as the "lecithin" in our diets.The objective of this introduction to emulsifiers is to raise awareness of the current state of food additives in the USA and to encourage thoughtful approaches to the study of all additives found in our diets. The overriding goal should be to assure the safety of what we eat. As examples we discuss eight widely distributed food additives; four "natural" emulsifiers that are classified as GRAS as well as an additional emulsifier-associated food additive that is also on the GRAS list, and three synthetic emulsifying agents that are FDA approved as "food additives."

Harmonizing Nutritional Therapies for Pediatric Inflammatory Bowel Disease.

Uses of nutritional therapies for inflammatory bowel disease (IBD) are of tremendous interest to the lay and professional communities. This interest currently outweighs the scientific basis for deciding on a particular therapy for any given patient. Some nutritional therapies have credible reports, in peer-review journals, validating their use for some patients. The broad pediatric gastroenterology community in the United States has, however, been unable or unwilling to agree on the details necessary to disseminate the most effective therapies with adequate reliability and validity to implement these interventions successfully. The well-established importance of the appropriate use of nutritional interventions for the treatment of undernutrition and maintenance of optimal nutrition is not an issue. A consensus and widely applicable solution for nutrition as therapy for IBD is, however, not imminent. In the interim, we aim to help the science-based reader to evaluate manuscripts appearing in our journals and to use this information to make rational, informed therapeutic decisions. We outline the current limited evidence base and make recommendations to advance the field of nutritional therapy in IBD.

Omes of Inflammatory Bowel Disease: A Primer for Clinicians.

Recent advances in high-throughput laboratory technologies and bioinformatics tools are redefining how we view inflammatory bowel disease (IBD). Instead of 2 diseases, we now see a diverse set of molecular subtypes. Large-scale investigation of the genome, exome, transcriptome, proteome, metabolome, microbiome, and epigenome are providing transformative insights into the pathophysiology of IBD, with the promise of accurately predicting prognosis and targeting therapy. Understanding these tools and their application is crucial to navigating the molecular era of IBD. This review aims to help the IBD clinician understand, appreciate, and eventually incorporate this coming paradigm shift to improve the care of children with IBD.

Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea.

Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in human DGAT1 result in severe congenital diarrhea and protein-losing enteropathy. Additionally, pharmacologic inhibition of DGAT1 led to dose-related diarrhea in human clinical trials. Here we identify a previously unknown DGAT1 mutation in identical twins of South Asian descent. These male patients developed watery diarrhea shortly after birth, with protein-losing enteropathy and failure to thrive. Exome sequencing revealed a homozygous recessive mutation in DGAT1, c.314T>C, p.L105P. We show here that the p.L105P DGAT1 enzyme produced from the mutant allele is less abundant, resulting in partial loss of TG synthesis activity and decreased formation of lipid droplets in patient-derived primary dermal fibroblasts. Thus, in contrast with complete loss-of-function alleles of DGAT1, the p.L105P missense allele partially reduces TG synthesis activity and causes a less severe clinical phenotype. Our findings add to the growing recognition of DGAT1 deficiency as a cause of congenital diarrhea with protein-losing enteropathy and indicate that DGAT1 mutations result in a spectrum of diseases.

Communicating the benefits and risks of inflammatory bowel disease therapy to patients and families.

PURPOSE OF REVIEW: Treatment options for inflammatory bowel disease (IBD) have rapidly expanded as the treatment paradigm has shifted from controlling symptoms to reducing lifetime inflammatory burden. Families are confronted with the actual and perceived risks of this ever-expanding array of choices. We aim to review the shared decision-making process in pediatric IBD to ensure an optimal therapeutic plan for the child and their family. RECENT FINDINGS: Mucosal healing is a critical treatment target in pediatric IBD but it may not coincide with clinical symptoms. Evidence-based therapies carry important risks, some of which may be less severe than previously suspected, and a family's understanding of these risks plays a crucial role in how they make health decisions. To form an effective shared therapeutic plan, the physician must incorporate an understanding of the values of both the child and family along with their lived experience of illness. SUMMARY: To limit harm and promote health in pediatric IBD, the physician must communicate collaboratively with the child and their family to form mutually understood goals of care - both subjective experiential and objective biological - and appreciate actual and perceived risks of treatment options to effectively educate families and navigate toward the best treatment choices. VIDEO ABSTRACT.

Phenotypic Heterogeneity of Neutropenia and Gastrointestinal Illness Associated with G6PC3 Founder Mutation.

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1G>A). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.

Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination.

BACKGROUND: L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS: Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS: The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.

Gastrojejunal tube placement through an established gastrostomy via an endoscopic transgastric approach in a pediatric population.

BACKGROUND AND AIMS: Gastrojejunal feeding tubes (GJTs) are typically converted from gastrostomy feeding tubes by interventional radiology in many pediatric centers to provide both postpyloric feeding and gastric decompression. Endoscopic transgastric GJT placement via an established gastric stoma can be performed without sedation and with minimal fluoroscopy but is relatively new in pediatrics with limited description. This study analyzed the success rate, adverse events, and technical issues associated with endoscopic GJT placement via a transgastric approach in pediatric patients at a large children's hospital. METHODS: We retrospectively reviewed endoscopic GJT placements in pediatric patients performed over a 16-month period at the Children's Hospital of New York-Presbyterian, Columbia University Medical Center. Indication for GJT placement, patient demographic characteristics and medical history, use of sedation, fluoroscopy time, and procedural and postprocedural adverse events were assessed. RESULTS: A total of 47 GJT placements were performed, all successful, in a patient cohort with a mean age of 8 years. The mean fluoroscopy time was 10 seconds, and sedation was used in 30% of placements. In 8 patients who had undergone GJT placement by endoscopy and interventional radiology, the fluoroscopy time was significantly reduced by using the endoscopic method (10 seconds vs 299 seconds, P = .001). CONCLUSIONS: Endoscopic transgastric GJT placement via an established gastrostomy with fluoroscopic confirmation can be safely performed by pediatric gastroenterologists without sedation and with minimal radiation exposure.

Advances in Endoscopy for Pediatric Inflammatory Bowel Disease.

Endoscopic characterization of pediatric inflammatory bowel disease (IBD) has developed in accordance with advances in treatment and improved understanding of disease progression and complications. Reliable and consistent endoscopic reporting practices and tools continue to evolve. The roles of endoscopic ultrasonography, capsule endoscopy, and deep enteroscopy in the care of children and adolescents with IBD are beginning to be clarified. Opportunities for therapeutic intervention with endoscopy in pediatric IBD, including endoscopic balloon dilation and electroincision therapy, require further study. This review discusses the current utility of endoscopic assessment in Pediatric Inflammatory Bowel Disease, as well as emerging and evolving techniques to improve patient care.

De Novo Crohn's Disease in the Pediatric Pouch.

Children who undergo ileal pouch anal anastomosis (IPAA) surgery for refractory ulcerative colitis (UC) may ultimately develop a Crohn's disease (CD) phenotype. This de novo CD is open to broad interpretation and misattribution, and its manifestation in children is poorly understood. The surgically altered environment of the ileal pouch is at risk of a spectrum of ileal pouch disorders, which have limited description in children. In this issue of Inflammatory Bowel Diseases, a multicenter, retrospective study of children with UC who underwent IPAA and developed de novo CD highlights the challenges and opportunities of ileal pouch characterization in children.

In this issue of Inflammatory Bowel Diseases, a multicenter, retrospective study provides insight into the poorly understood circumstances in which children who have undergone ileal pouch anal anastomosis surgery for refractory ulcerative colitis develop a Crohn's disease phenotype.

Diagnosis and Classification of Fistula from Inflammatory Bowel Disease and Inflammatory Bowel Disease-Related Surgery.

Fistula in inflammatory bowel disease (IBD) is a well-known yet poorly understood phenotype. Pathophysiology is largely based on the activation of the epithelial-mesenchymal transition (EMT); however, interactions with the microbiome, genetics, mechanical stress and the presence of stricturing disease, and surgical complications play a role. Perianal penetrating disease represents a more severe phenotype in IBD. Pouch-associated fistula can arise as a result of an anastomotic leak, surgical complications, or Crohn's disease (CD) of the pouch. Classification is site-dependent, includes a range of severity, and informs management. It is important to determine associated symptoms and recognize the complex interplay of underlying etiologies to form the basis of appropriate care.

Quantification of Mucosal Activity from Colonoscopy Reports via the Simplified Endoscopic Mucosal Assessment for Crohn's Disease.

BACKGROUND: Endoscopic mucosal healing is the gold standard for evaluating Crohn's disease (CD) treatment efficacy. Standard endoscopic indices are not routinely used in clinical practice, limiting the quality of retrospective research. A method for retrospectively quantifying mucosal activity from documentation is needed. We evaluated the simplified endoscopic mucosal assessment for CD (SEMA-CD) to determine if it can accurately quantify mucosal severity recorded in colonoscopy reports. METHODS: Pediatric patients with CD underwent colonoscopy that was video recorded and evaluated via Simple Endoscopic Score for CD (SES-CD) and SEMA-CD by central readers. Corresponding colonoscopy reports were de-identified. Central readers blinded to clinical history and video scoring were randomly assigned colonoscopy reports with and without images. The SEMA-CD was scored for each report. Correlation with video SES-CD and SEMA-CD were assessed with Spearman rho, inter-rater, and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopy reports were read a total of 347 times. The simplified endoscopic mucosal assessment for CD without images correlated with both SES-CD and SEMA-CD from videos (rho = 0.82, P < .0001 for each). The addition of images provided similar correlation. Inter-rater and intrarater reliability were 0.93 and 0.92, respectively. CONCLUSIONS: The SEMA-CD applied to retrospective evaluation of colonoscopy reports accurately and reproducibly correlates with SES-CD and SEMA-CD of colonoscopy videos. The SEMA-CD for evaluating colonoscopy reports will enable quantifying mucosal healing in retrospective research. Having objective outcome data will enable higher-quality research to be conducted across multicenter collaboratives and in clinical registries. External validation is needed.

Treatment of pouchitis, Crohn's disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium.

Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of inflammatory bowel disease in patients with pouches are similar to those in patients without pouches.

Telemedicine Expansion in Pediatric Gastroenterology in Response to COVID-19: Early Results of an International Physician Survey.

The COVID-19 pandemic triggered an unprecedented expansion of telemedicine, leading to development of new workflows. We conducted a survey of telemedicine practice among pediatric gastroenterology practitioners on March 26, 2020. Responses were coded and analyzed. The survey garnered 33 responses. Most centers were 3 weeks into the implementation. The most commonly used telemedicine software was Zoom followed by FaceTime, telephone, and Epic software. Provider education was through online meetings, webinars, and tip sheets. Patient education was by nonclinical staff at the time of visit scheduling or tip sheets. A major barrier was the need for patients to enroll in an electronic portal. Two thirds of practices offered telemedicine to both new and return patients. Most sites billed based on time. This represents a record of the very early response of the pediatric gastroenterology community to the COVID-19 telemedicine expansion and can inform follow-up studies.

Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing.

The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF. Thirteen had isolated and 32 had nonisolated EA/TEF; none had a family history of EA/TEF. We identified de novo variants in protein-coding regions, including 19 missense variants predicted to be deleterious (D-mis) and 3 likely gene-disrupting (LGD) variants. Consistent with previous studies of structural birth defects, there is a trend of increased burden of de novo D-mis in cases (1.57-fold increase over the background mutation rate), and the burden is greater in constrained genes (2.55-fold, p = 0.003). There is a frameshift de novo variant in EFTUD2, a known EA/TEF risk gene involved in mRNA splicing. Strikingly, 15 out of 19 de novo D-mis variants are located in genes that are putative target genes of EFTUD2 or SOX2 (another known EA/TEF gene), much greater than expected by chance (3.34-fold, p value = 7.20e-5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identified APC2, AMER3, PCDH1, GTF3C1, POLR2B, RAB3GAP2, and ITSN1 as plausible candidate genes in the etiology of EA/TEF. We conclude that further genomic analysis to identify de novo variants will likely identify previously undescribed genetic causes of EA/TEF.

Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn's Disease: The SEMA-CD.

OBJECTIVES: Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn's disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn's disease (SEMA-CD). METHODS: We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn's disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn's disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD. CONCLUSION: The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed.