An Open Label, Randomized, Multicenter Study of Elafibranor in Children With Nonalcoholic Steatohepatitis.

OBJECTIVES: Nonalcoholic fatty liver disease is the most common chronic liver disease in children. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). The aims were to (1) describe pharmacokinetics (PK), safety, and tolerability of oral elafibranor at 2 doses (80 and 120 mg) in children 8-17 years and (2) assess changes in aminotransferases. METHODS: Children with NASH were randomized to open-label elafibranor 80 mg or 120 mg daily for 12 weeks. The intent-to-treat analysis included all participants who received at least 1 dose. Standard descriptive statistics and PK analyses were performed. RESULTS: Ten males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to 80 mg (n = 5) or 120 mg (n = 5). Baseline mean alanine aminotransferase (ALT) was 82 U/L (SD 13) and 87 U/L (SD 20) for 80 mg and 120 mg groups, respectively. Elafibranor was rapidly absorbed and well tolerated. Elafibranor plasma exposure increased between the 80 mg and 120 mg dose with a 1.9- and 1.3-fold increase in median Cmax and AUC 0-24 , respectively. End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of -37.4% (SD 23.8%) at 12 weeks. CONCLUSIONS: Once daily dosing of elafibranor was well tolerated in children with NASH. There was a 37.4% relative reduction from mean baseline ALT in the 120 mg group. Decreasing ALT may be associated with improvement in liver histology, thus could be considered a surrogate for histology in early phase trials. These results may support further exploration of elafibranor in children with NASH.

Peroral Endoscopic Myotomy (POEM) in Children: A State of the Art Review.

Esophageal achalasia is a relatively rare disease in children that has been treated with balloon dilatation, botulinum toxin injection, and Heller myotomy. Peroral endoscopic myotomy (POEM) is another treatment that has been successfully employed to treat adults with achalasia for over a decade and has been increasingly used in children. This State of the Art Review from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Endoscopy Committee reviews the current literature in pediatric POEM including the technique, success rate, complications as well as training guidelines. Though there is limited data, POEM in children has shown encouraging success rates and with further study may become the mainstay of pediatric achalasia treatment.

Postpyloric Feeding Access in Infants and Children: A State of the Art Review.

Achieving postpyloric feeding access is a clinical challenge faced by the pediatric gastroenterologist in everyday practice. Currently, there is limited literature published on the topic. This article provides a practical summary of the literature on the different methods utilized to achieve postpyloric feeding access including bedside, fluoroscopic, endoscopic and surgical options. Indications and complications of these methods are discussed as well as a general approach to infants and children that require intestinal feeding.

Risk Factors for Suboptimal Bowel Preparation for Colonoscopy in Pediatric Patients.

BACKGROUND/AIMS: Suboptimal bowel cleansing is common in children and can impact diagnostic and therapeutic outcomes. We aimed to identify risk factors for suboptimal bowel preparation for colonoscopy in pediatric patients. METHODS: This was a retrospective study of all patients ages 0 to 21 years who underwent colonoscopy at a children's hospital from 2015 to 2019 in the United States. Demographics and clinical information were obtained from the electronic health record. The primary outcome was suboptimal bowel preparation measured by the endoscopist on a dichotomized Aronchik Scale. Univariate and multivariate regression modeling were used to determine independent predictors of suboptimal preparation. RESULTS: Nine hundred and eight patients (mean age 12.17 years [±5.14], boys 465 (51.2%), were included in the analysis. Suboptimal preparation was noted in 242 (26.7%). On univariate analysis, suboptimal preparation was more common in those of younger age (38.6%), Medicaid (32.1%), Spanish as primary language (35.7%), and failure to thrive (FTT) (45.9%). Suboptimal preparations were less common in patients with inflammatory bowel disease (IBD) (11.6%). After adjustment for other covariates, IBD and FTT maintained their statistical associations, IBD (odds ratio [OR] 0.27 95% confidence interval [CI] 0.095-0.75, P =  0.01), FTT (OR 1.98 95% CI 1.28-3.06, P =  <0.01). CONCLUSIONS: To our knowledge, this is the first investigation of pediatric patients to identify independent risk factors for suboptimal bowel preparation. We confirm Medicaid status and English as a second language as risk factors as well as highlight distinct associations from those reported in the adult literature including FTT and younger age. IBD was associated with optimal cleansing. Future research to understand the mechanisms of inferred risk or potential protection is required.

Upper Gastrointestinal Endoscopy in Adolescents With Severe Obesity Before Vertical Sleeve Gastrectomy.

OBJECTIVES: Esophagogastroduodenoscopy (EGD) is often performed to evaluate for mucosal and anatomical abnormalities before vertical sleeve gastrectomy (SG). Little is known, however, about how prebariatric EGD in adolescents influences clinical management or outcome. Our aim was to assess if an abnormal prebariatric EGD resulted in interventions or modification of bariatric surgery. METHODS: We performed a retrospective cohort study of adolescents undergoing evaluation for bariatric surgery. We obtained demographic and anthropometric data in addition to EGD findings, biopsy pathology, gastrointestinal symptoms, and surgical outcomes. An EGD was considered abnormal if either abnormal gross findings or abnormal pathology was reported. Patients were followed until a 6-week postop visit. RESULTS: Of 134 patients presenting for evaluation, 94 (70%) underwent preoperative EGD. Fifty-one (54%) had a normal EGD and 43 (46%) had EGD abnormalities including 7 with an anatomical abnormality and 36 with mild mucosal abnormalities. Among patients with EGD abnormalities, 22% received medical intervention including proton pump inhibitor (PPI) administration (n = 10) and Helicobacter pylori eradication (n = 11). GI symptoms were the only predictor of EGD abnormalities (odds ratio [OR] 4.9: 95% confidence interval [CI] 1.6-15.0; P < 0.001). No factors predicted likelihood of a post-EGD intervention. An abnormal EGD did not correlate with any postoperative complications. CONCLUSIONS: In this cohort of adolescents undergoing evaluation for SG, 46% had an abnormal EGD, of which 22% received a medical intervention. Symptoms were the only predictor of EGD abnormalities. Abnormal EGD findings were not associated with modification of the surgery or any adverse outcome.

Pediatric Nonalcoholic Fatty Liver Disease in New York City: An Autopsy Study.

OBJECTIVE: To assess the prevalence and severity of nonalcoholic liver disease (NAFLD) in children in a diverse population sample in New York City. STUDY DESIGN: Liver specimens were examined from children 2-19 years old who died of unexpected causes within 48 hours of medical presentation and underwent autopsy in New York City from 2005 to 2010. Records were reviewed for age, sex, weight, height, and race. Two hepatopathologists evaluated each liver specimen to determine pathologic diagnosis. RESULTS: The final study cohort (n = 582) was 50% black, 33% Hispanic, 12% white, 3% Asian, and 2% other; 36% had a body mass index >85%. There were 26 cases of NAFLD (4.5%) of which 10 had nonalcoholic steatohepatitis (1.7%). There were no cases with severe fibrosis or cirrhosis. One percent (3/290) of black children had NAFLD and none had nonalcoholic steatohepatitis. White and Hispanic children had the highest percentages of NAFLD at 8.3% and 7.9%, respectively. In multiple logistic regression models, we observed that body mass index z-score (P < .001) was associated with NAFLD, and that white (P = .003) and Hispanic (P = .005) children had higher odds of having NAFLD compared with black children. CONCLUSIONS: This review of liver tissue demonstrates a lower prevalence and severity of NAFLD in black children compared with the general obese pediatric population. Hispanic children did not have a significantly increased rate of NAFLD compared with white children, most likely related to the large proportion of Caribbean Hispanic children in New York City.

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.

Predictors of low weight and tube feedings in children with congenital diaphragmatic hernia at 1 year of age.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) survivors often have gastrointestinal disorders, and limited outcome data exist. This study reviewed risk factors for low weight and use of feeding tubes after CDH repair at 1 year of age. The hypothesis was that patients who required extracorporeal membrane oxygenation (ECMO) or with significant pulmonary arterial hypertension (PAH) would have lower weight percentiles and more often require tube feedings. METHODS: A retrospective chart review of 89 infants with CDH diagnosed in the neonatal period was conducted. Statistical analysis was performed using χ test, Fisher exact test, and logistic regression. RESULTS: Seventy-two patients (81%) survived to 1 year of age. Of these patients, 35% were <5th percentile for weight and 18% were receiving tube feedings. Both ECMO and PAH were associated with an increased risk for requiring tube feedings at 1 year of age, with respective odds ratios of 6.00 (P = 0.01) and 15.75 (P = 0.02); however, neither ECMO nor PAH was associated with low weight at 1 year of age. No statistical correlation was found between an abnormal pH probe and tube feedings at 1 year of age. CONCLUSIONS: Patients with CDH are at increased risk for having a weight <5th percentile at 1 year of age. A history of ECMO and PAH are independently associated with an increased requirement for tube feedings at 1 year of age. Close nutritional monitoring and counseling should be considered in all of the patients with CDH, particularly those with a history of ECMO or PAH.

Metastatic cutaneous involvement of granulomatous colitis in Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disorder characterized by oculocutaneous albinism, a hemorrhagic diathesis due to platelet dysfunction, and lysosomal ceroid accumulation that can cause a Crohn's-like granulomatous colitis and pulmonary fibrosis. We report peristomal and vulvar cutaneous involvement of the granulomatous colitis in HPS.

Advances in Pediatric Diagnostic Endoscopy: A State-of-the-Art Review.

Pediatric endoscopy has revolutionized the way we diagnose and treat gastrointestinal disorders in children. Technological advances in computer processing and imaging continue to affect endoscopic equipment and advance diagnostic tools for pediatric endoscopy. Although commonly used by adult gastroenterologists, modalities, such as endomicroscopy, image-enhanced endoscopy, and impedance planimetry, are not routinely used in pediatric gastroenterology. This state-of-the-art review describes advances in diagnostic modalities, including image-enhanced endoscopy, confocal laser endomicroscopy, optical coherence tomography, endo functional luminal imaging probes, wireless motility/pH capsule, wireless colon capsule endoscopy, endoscopic ultrasound, and discusses the basic principles of each technology, including adult indications and pediatric applications, safety cost, and training data.

Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition.

BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. METHODS: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl(4) administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2-deficient mice following BDL or CCl(4) administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. RESULTS: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl(4) administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) beta-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-beta signaling in human HSCs. In vivo, pan-JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl(4). JNK1-deficient mice had decreased fibrosis after BDL or CCl(4), whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl(4). Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. CONCLUSIONS: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches.

Nonalcoholic fatty liver disease in children.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease in children from the developed world. The purpose of this review is to provide both a focused overview of pediatric NAFLD as well as a summary of the most recent advancements in the field. RECENT FINDINGS: Pediatric NAFLD is an underdiagnosed condition which can result in significant liver injury including cirrhosis. Although liver biopsy remains the standard for diagnosis and monitoring disease activity, several noninvasive biomarkers and imaging techniques hold significant promise. Dietary constituents, the intestinal bacterial flora, and sex hormones have been implicated as modulators of disease activity. NAFLD predisposition runs strongly in families and an allele in the PNPLA3 gene has shown a strong association with liver steatosis and hepatic inflammation. Treatment for pediatric NAFLD remains diet and exercise, but vitamin E may be a helpful adjunct. SUMMARY: Pediatric NAFLD shares many features with its adult counterpart but is a distinct entity which requires independent investigation. Our understanding of NAFLD in terms of epidemiology and risk factors has improved considerably but significantly more investigation is required to unravel its pathophysiology and identify novel therapeutic targets.

Primary gastrojejunostomy tube placement using laparoscopy with endoscopic assistance: A novel technique.

BACKGROUND: Gastrojejunostomy (GJ) tubes are commonly used to provide postpyloric enteral nutrition in pediatric patients who cannot tolerate gastric feeds. Most techniques depend on a preexisting gastrostomy tube (GT) site to convert to a gastrojejunostomy. Several minimally invasive techniques have been described; however, their risk profile varies widely. DESCRIPTION OF THE OPERATIVE TECHNIQUE: We present a technique for primary laparoscopic GJ tube placement that minimizes the risk of hollow viscus injury and the use of fluoroscopy through endoscopic assistance. RESULTS: Eleven GJ tubes were placed using this technique in patients ranging from 5 months to 17 years of age and weighing 6.3 to 46.0 kg. Endoscopy through the gastrostomy site allowed direct visualization of wire and tube placement. There were no intraoperative or postoperative complications within 30 days of operation. Use of fluoroscopy was limited with minimal total radiation exposure. CONCLUSION: The described technique of laparoscopic primary gastrojejunostomy tube placement with endoscopic assistance was associated with a low complication rate and minimal use of fluoroscopy. LEVEL OF EVIDENCE: IV.

Toll-like receptor 4 and hepatic fibrogenesis.

Inflammation is strongly associated with chronic hepatic injury and the ensuing wound-healing process. Recent evidence from mouse models and human studies implicates Toll-like receptors (TLRs) as important regulators of the inflammatory response and a functional link between inflammation and fibrosis in the chronically injured liver. Here, we review mechanisms by which TLR4 and TLR4 ligands from the intestinal microbiota contribute to hepatic injury, inflammation, hepatic stellate cell activation, and fibrosis.

Effect of TSH on Non-Alcoholic Fatty Liver Disease (NAFLD) independent of obesity in children of predominantly Hispanic/Latino ancestry by causal mediation analysis.

BACKGROUND: Nonalcoholic Fatty Liver Disease (NAFLD) is a common co-morbidity of obesity. Elevated TSH levels (eTSH), also associated with obesity, may contribute to the dysmetabolic state that predisposes to NAFLD. OBJECTIVE: To assess the relationship between TSH levels and NAFLD in children with biopsy-proven NAFLD compared to controls. DESIGN AND METHODS: In this retrospective study of children with biopsy-proven NAFLD and age-matched controls, the association of eTSH with NAFLD was investigated and the role of TSH as a mediator between obesity and NAFLD was assessed. RESULTS: Sixty-six cases and 4067 controls (69.7 vs 59% Hispanic/Latino ancestry, p = 0.1) of the same age range seen in the same time duration at an urban Children's Hospital were studied. Children with NAFLD were more likely to be male (74.6 vs 39.4%, p < 0.001), have higher modified BMI-z scores (median 2.4 (IQR 1.7) vs 1.9 (IQR 1.7), p < 0.001), and abnormal metabolic parameters (TSH, ALT, HDL-C, non-HDL-C, and TG). Multivariate analyses controlling for age, sex and severity of obesity showed significant association between the 4th quartile of TSH and NAFLD. Causal mediation analysis demonstrates that TSH mediates 33.8% of the effect of modified BMI-z score on NAFLD. This comprises of 16.0% (OR = 1.1, p = 0.002) caused by the indirect effect of TSH and its interaction with modified BMI-z, and 17.7% (OR = 1.1, p = 0.05) as an autonomous effect of TSH on NAFLD. Overall, 33.8% of the effect can be eliminated by removing the mediator, TSH (p = 0.001). CONCLUSIONS: The association of eTSH and biopsy-proven NAFLD is demonstrated in children of Hispanic/Latino ancestry. Further, a causal mediation analysis implicates an effect of TSH on NAFLD, independent of obesity.

Clinical and prognostic significance of urinary trypsin inhibitor in patients with hepatocellular carcinoma after hepatectomy.

BACKGROUND: Urinary trypsin inhibitor (UTI), produced in the liver, has been considered to suppress inflammation. The production of UTI may decrease after a hepatectomy and thereby increase the incidence of postoperative inflammation. This study investigated whether the changes in the UTI level affected the postoperative course in patients undergoing a hepatectomy for hepatocellular carcinoma (HCC). The prognostic significance of UTI was also analyzed. METHODS: The perioperative plasma UTI was measured in 25 HCC patients who underwent hepatic resection, and the correlation between the kinetics of UTI and clinicopathological factors was investigated. The expression of UTI in the resected specimens was examined by immunohistochemistry in 65 patients. Expression of UTI in the cancer cells were then correlated to both the liver pathology and the clinical outcomes in the corresponding patients. RESULTS: The plasma UTI level greatly decreased on the first postoperative day. This decrease significantly correlated with the resected tumor volume (r (s) = -.530, P = .006), but it had no influence on inflammatory complications. Immunohistochemistry revealed UTI expression in both noncancerous and cancerous lesions. An overexpression of UTI in HCC tissue was found to be an independent prognostic factor for early recurrence (P = .006). CONCLUSIONS: Although UTI plasma levels were noted to decrease after the removal of an HCC tumor, this decrease did not lead to an increase in inflammatory complications. However, overexpression of UTI in cancer was found to be a risk factor for tumor recurrence after resection, suggesting that UTI expression may be a useful prognostic marker.

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis.

UNLABELLED: Alpha-1 antitrypsin (alpha1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous alpha1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The alpha1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic alpha1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P = 0.0003) and hydroxyproline (P = 0.007) than wild-type mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P = 0.02, P = 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. CONCLUSION: PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in alpha1-AT deficiency, and the alpha1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.