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Pediatric MASLD (previously referred to as NAFLD) incidence has continued to rise along with the obesity pandemic. Pediatric MASLD increases the risk of liver fibrosis and cirrhosis in adulthood. Early detection and intervention can prevent and reduce complications. Liver biopsy remains the gold standard for diagnosis, although imaging modalities are increasingly being used. We performed a retrospective study of 202 children seen in a pediatric gastroenterology clinic with a complaint of abdominal pain, elevated liver enzymes or MASLD, or a combination of the three to evaluate screening methods for MASLD. A total of 134 of the 202 patients included in the study underwent laboratory testing and abdominal ultrasound. Ultrasound images were reviewed with attention to liver size and echotexture by a fellowship-trained pediatric radiologist for liver size and echotexture. Overall, 76.2% of the initial radiology reports correctly identified hepatomegaly based on age and 75.4% of the initial radiology reports correctly described hepatic echogenicity that was consistent with increased hepatic fat deposition. Use of screening ultrasound in concert with other clinical evaluations can be helpful to identify children at risk of MASLD. Utilizing ranges for liver span according to age can help to diagnose hepatomegaly, and understanding how to identify hepatic echogenicity is important for identifying possible hepatic steatosis.

Introduction: Many hepatologic pathologies mimic autoimmune hepatitis (AIH). Researchers developed the International Autoimmune Hepatitis Group (IAIHG) scoring system to compensate for the lack of specific diagnostic tests for AIH. The scoring system was not designed with pediatric patients in mind, so there are limits to its pediatric use. Additionally, there is limited information on the value of a liver biopsy in conjunction with its use., Methods: In this retrospective study, we evaluated the effect of liver biopsy scores on the IAIHG scoring system in patients that were 0-18 years old with suspected AIH. We also analyzed demographic data and laboratory values associated with a final AIH diagnosis., Results: We found that interface hepatitis and predominant plasma cells found during the biopsy were significantly associated with a final AIH diagnosis. We also found that abnormal laboratory values were associated with an AIH diagnosis. We found that IAIHG scores calculated post-liver biopsy showed a greater area under the receiver operating characteristic curve (AUROC) of 0.95, which was compared to 0.88 for the scores calculated before a liver biopsy. Including biopsy metrics lowered the optimized cutoff score and test specificity., Conclusion: Incorporating liver histopathological features improved the performance of the IAIHG scoring system. Further studies to identify other potential elements in liver histology may improve the performance metrics of the IAIHG test in the pediatric population.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well as developmental delays, a spectrum of behavioral and psychiatric concerns, endocrinopathies, orthopedic issues, and less commonly, seizures, sleep apnea, and narcolepsy with or without cataplexy. This study used data in the Global PWS Registry (N = 893) to explore the onset and severity over time of the neuropsychiatric features reported in individuals with PWS and explored its associations with sleep disorders, seizures, and psychiatric symptoms. Results demonstrate that seizures are more common in the deletion subtype and that narcolepsy and cataplexy are more common in individuals who have sleep-related seizures. Finally, this work shows that anxiety and compulsive behaviors are persistent features of PWS that may arise early in childhood, and that anxiety is associated with higher frequency of other comorbid psychiatric diagnoses. In conclusion, this study is one of the largest to date characterizing sleep disorders and neuropsychiatric characteristics of individuals with PWS and reports on the novel association between sleep disorders and seizures. This study is also one of the first to offer details on the nature of the progression of these features in individuals with PWS., (© 2022 Wiley Periodicals LLC.)

Background: Hydrothorax in the presence of ascites is a serious condition, but it is not well studied, particularly in pediatrics. We aim to identify risk factors for having hydrothorax, compare morbidity and mortality, and report the prevalence of hepatic hydrothorax and non-hepatic hydrothorax in pediatric patients with diagnosis of ascites and hydrothorax., Methods: This is a retrospective study of pediatric patients under 22 years of age with both ascites and hydrothorax. Hydrothorax was categorized into hepatic and non-hepatic hydrothorax. Demographic data and clinical data including ascites grade, ascites etiology, treatments, length of stay, and death were collected and analyzed using logistic regression., Results: We identified 120 patients with ascites and hydrothorax, 63 (53%) being female. The median age was 13 years (IQR: 4-18). Patients 6 years of age or older (OR=1.90; 95% CI=1.16-3.17; p = 0.012), patients with higher grades of ascites (OR=1.77; 95% CI=1.27-2.47; p < 0.001), those treated with furosemide (OR=2.27; 95% CI=1.37-3.76; p = 0.001), and those with hepatorenal syndrome (OR=4.22; 95% CI=1.19-15.63; p = 0.025) had increased risk of hydrothorax. The underlying etiology of ascites was not associated with mortality, but it was associated with length of stay (p = 0.013), with veno-occlusive disease being the largest contributor. Hepatic versus non-hepatic hydrothorax was also not found to be associated with mortality, but length of stay was significantly greater in former (23 days; IQR=13-38) compared to the latter group (14 days; IQR=8-26) (p = 0.009)., Conclusions: With pediatric ascites, there are  certain risk factors that are associated with having hydrothorax, and ascites etiology may be associated with morbidity., Competing Interests: Declaration of competing interest The co-authors declare no financial or personal conflicts of interests. Title of Manuscript: Hepatic and Non-Hepatic Hydrothorax in Pediatric Ascites Authors: Paul Wasuwanich; Joshua M. So; Ann O. Scheimann; Harisa Spahic; Wikrom Karnsakul The authors declare no conflicts of interest. This study was internally funded by the authors., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Based on systematic review and meta-analysis, the risk for developing cancers in patients with cystic fibrosis (CF) is known to be significantly greater than in the general population, including site-specific cancers of the esophagus, small bowel, colon, liver, biliary tract, and pancreas. An even higher risk has been found in patients who have severe CF transmembrane conductance regulator ( CFTR ) genotypes or who have undergone organ transplantation and are immunosuppressed. The risk continues to rise as life expectancies steadily climb due to advancements in medical care and treatment for CF. The colorectal cancer risk is at such a high level that CF has now been declared a hereditary colon cancer syndrome by the Cystic Fibrosis Foundation. The CFTR gene has been strongly-associated with the development of gastrointestinal (GI) cancers and mortality in the CF population. Even CF carriers have shown an increased rate of GI cancers compared to the general population. Several limitations exist with the reported guidelines for screening of GI and hepatopancreatobiliary cancers in the CF population, which are largely universal and are still emerging. There is a need for more precise screening based on specific risk factors, including CFTR mutation, medical co-morbidities (such as gastroesophageal reflux disease, distal intestinal obstruction syndrome, and diabetes mellitus), familial risks for each cancer, gender, age, and other factors. In this review, we propose changes to the guidelines for GI screening of patients with CF. With the development of CFTR modulators, additional studies are necessary to elucidate if there is an effect on cancer risk., Competing Interests: Conflict-of-interest statement: The co-authors declare no financial or personal conflicts of interests., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Ascites is a pathologic buildup of fluid in the peritoneal cavity. Knowledge is lacking in clinical outcome in pediatric patients with ascites. We aim to identify and assess clinical variables, associated with morbidity and mortality in pediatric patients who are hospitalized with ascites., Methods: A retrospective cohort study was performed on patients ages 0 to 21 hospitalized at Johns Hopkins Hospital between 1983 and 2010 with an ICD-9 discharge diagnosis of ascites (789.5, 789.51, 789.59). A total of 518 pediatric patients were studied, all with a diagnosis of ascites during hospitalization. Study outcomes included hospital length of stay (LOS) as a proxy for morbidity and death at hospital discharge for mortality. Variables analyzed included demographic data, ascites etiology and grade, comorbidities, and laboratory markers. Variables were analyzed by log-linear regression and competing risk model., Results: Among the 3 age groups (0-5, 6-12, and 13-21), the 0 to 5 age group experienced significantly increased LOS (P < 0.001) and mortality (P = 0.027). Ascites etiology of veno-occlusive disease (VOD) and the presence of hydrothorax or thrombocytopenia was also significantly associated with increased LOS. Ascites with the etiology of congestive hepatopathy and the presence of grade 3 ascites, hepatic encephalopathy, hepatorenal syndrome, hydrothorax, hyponatremia, and thrombocytopenia were associated with increased mortality. Additionally, black pediatric patients have an increased risk of mortality (P = 0.027). Other factors including sex, leukopenia, portal vein thrombosis, and splenomegaly were not associated with LOS or mortality., Conclusions: Morbidity and mortality in pediatric patients hospitalized with ascites are associated with specific demographic and clinical factors. Further studies are required to apply this knowledge to predict the clinical outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Abdominal paracentesis is performed as a diagnostic test in children with ascites. Serum albumin to ascitic fluid albumin gradient (SAAG) is frequently used in adults to distinguish types of portal hypertension. We aim to investigate the utilization of SAAG and other biomarkers in determining the etiology of significant ascites in children., Methods: In this retrospective study, children aged 0-21 years with significant ascites were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes and medical records during the period 1983-2010. Medical records of children who had abdominal paracentesis were examined in detail., Results: 207 children had significant ascites and of those children, 20 (9.6%) had abdominal paracentesis. Our data showed that high albumin gradient (SAAG ≥ 1.1 g/dL) differentiates causes of ascites secondary to portal hypertension (cirrhosis, hepatic vein outflow obstruction, or congestive hepatopathy) from other causes. In addition, ascitic fluid total protein (AFTP) may help in differential diagnosis of ascites. Children with high SAAG manifest clinical features of portal hypertension including esophageal varices or variceal hemorrhage., Conclusion: Among patients with initially unclear causes of ascites, SAAG and AFTP can provide guidance for appropriate investigations., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Hepatitis E is considered rare in the United States (US) despite its widespread occurrence in Asian and African countries. The objective of this study was to describe the characteristics of hepatitis E-related pregnancies and acute-on-chronic liver failure and analyse trends for hepatitis E diagnosis among hospitalized patients in the US. We examined data from the 2010-2017 National Inpatient Sample from Healthcare Cost and Utilization Project to determine mortality, morbidity, pregnancy diagnoses, chronic liver disease diagnoses, and other conditions during hospitalization. Data were extracted for hospitalizations with hepatitis E as defined by ICD-9 codes 070.43 and 070.53 and ICD-10 code B17.2. Of 208,462,242 hospitalizations from 2010-2015, we identified 960 hepatitis E hospitalizations. The hospitalization rate of hepatitis E was 3.7 per 10 million in 2010 and 6.4 per 10 million in 2015 (β = 0.60, p = 0.011). From 2015 to 2017, the hospitalization appeared to increase with slope (β) of 0.50. Among those hospitalizations, 34 (4%) died and 85 (9%) had acute-on-chronic liver failure. Ninety-five (10%) had a diagnosis of pregnancy, there were no reports of maternal or foetus/neonate deaths, but there was a high proportion of adverse events for both during hospitalization. Having a chronic liver disease was associated with hepatic coma diagnosis (OR = 10.94, p = 0.002). Although the hospitalization rate of hepatitis E in the US is low, it appears to be increasing over time. Further studies are necessary in order to conclude a causal association of hepatitis E with adverse events and mortalities in pregnancy and chronic liver disease in the US., (© 2020 John Wiley & Sons Ltd.)

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth., Methods: We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8-17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis., Results: At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH and/or in fibrosis was associated with adolescent age, and higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein cholesterol at baseline (<0.05), and over follow-up time, with increasing level of alanine aminotransferase, hemoglobin A1C (P<.05), gamma-glutamyl transferase and development of type 2 diabetes (P<.01). Increasing level of gamma-glutamyl transferase was also associated with reduced odds of any improvement (P = .003)., Conclusions: One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Disaccharides such as lactose and sucrose are sugars commonly found in human diet. They are broken down by mucosal disaccharidases in the duodenum. Previous small studies found no associations between gastrointestinal (GI) symptoms and combined low disaccharidase activity. We aim to explore the associations of low activity of disaccharidase and combinations of low activity of different disaccharidases with general GI symptom presentations in a large cohort of pediatric patients., Methods: We examined a cohort (0-21 yrs.) who have undergone esophagogastroduodenoscopy and received disaccharidase activity assay from duodenal biopsy in the time period 2010 to 2012. Disaccharidase assays tested for activity of lactase, sucrase, maltase, and palatinase. GI symptoms were grouped into four categories, abdominal pain, diarrhea, weight loss, and gastroesophageal reflux., Results: Of the 347 subjects, we found an association between low lactase activity and abdominal pain (OR = 1.78; 95% CI = 1.07-2.97; p < 0.05). Subjects with a lactase/sucrase ratio < 0.2 were found to be associated with abdominal pain (OR = 2.25; 95% CI = 1.25-4.04; p < 0.05), Subjects with low pandisaccharidase may be correlated with abdominal pain and have a unique frequency of GI symptoms due to low frequency of diarrhea and weight loss, but they were not statistically significant., Conclusions: Low activities of certain disaccharidase combinations may be associated with GI symptoms in subjects; a prospective study may be needed to investigate further.

Sleep quality and sleep disorders affect symptom manifestation and the pathogenesis of digestive diseases. Sleep is largely regulated by the light-dark cycle and associated circadian rhythms. These occurrences are closely regulated through several mechanisms with direct effects on the gastrointestinal tract. Misalignment of the circadian system is a common cause of sleep complaints, which play an important role in the presentation of many gastrointestinal disorders. This Review will focus on sleep disorders and how these alterations in sleep play an important role in many commonly encountered digestive diseases, such as gastro-oesophageal reflux disease, irritable bowel syndrome, inflammatory bowel disease, and non-alcoholic fatty liver disease. Therapeutic interventions focusing on resolving sleep disorders could optimise treatment and improve quality of life in these patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Prader-Willi syndrome (PWS) is a rare genetic disorder associated with varying degrees of hyperphagia, obesity, intellectual disability, and anxiety across the affected individuals' lifetimes. This study quantified caregiver priorities for potential treatment endpoints to identify unmet needs in PWS., Methods: The authors partnered with the International Consortium to Advance Clinical Trials for PWS (PWS-CTC) and a diverse stakeholder advisory board to develop a best-worst scaling instrument. Seven relevant endpoints were assessed using a balanced incomplete block design. Caregivers were asked to determine the most and least important of a sub-set of four endpoints in each task. Caregivers were recruited nationally though patient registries, email lists, and social media. Best-worst score was calculated to determine caregiver priorities; ranging from 0 (least important) to 10 (most important). A novel kernel-smoothing approach was used to analyze caregiver endpoint priority variations with relation to age of the PWS individual., Results: In total, 457 caregivers participated in the study. Respondents were mostly parents (97%), females (83%), and Caucasian (87%) who cared for a PWS individual ranging from 4-54 years. Caregivers value treatments addressing hyperphagia (score = 7.08, SE = 0.17) and anxiety (score = 6.35, SE = 0.16) as most important. Key variations in priorities were observed across age, including treatments targeting anxiety, temper outbursts, and intellectual functions., Conclusions: This study demonstrates that caregivers prioritize hyperphagia and, using a novel method, demonstrates that this is independent of the age of the person with PWS. This is even the case for parents of young children who have yet to experience hyperphagia, indicating that these results are not subject to a hypothetical bias.

Prader-Willi syndrome (PWS) is a genetic syndrome in which individuals have multisystem medical challenges. Gastroenterological difficulties in the syndrome include decreased vomiting, constipation, delayed gastric emptying, delayed colonic transit, dysphagia, increased choking, and increased risk of gastric dilation and rupture. In addition, self-injurious behavior such as rectal picking may be present and severe enough to lead to rectal ulceration and bleeding. Many patients have extensive gastroenterological workup and treatment before their ultimate diagnosis of severe rectal picking. We describe 4 new cases of rectal picking in individuals with PWS leading to rectal bleeding and ulceration as well as a review of the literature of prior cases of severe rectal picking in PWS and potential treatment options. It is important to recognize these cases early in order to prevent unnecessary treatments and implement appropriate behavioral interventions.

Aims: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib., Materials and Methods: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151., Results: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo., Conclusions: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity., (© 2017 John Wiley & Sons Ltd.)

Objectives: The aim of our study was to describe the changing prevalence, demographic features, etiologies, and treatment of ascites in children hospitalized during a 27-year period at the Johns Hopkins Hospital (Baltimore, MD)., Methods: We retrospectively reviewed discharges from 1983 to 2010 to select patients whose records included a diagnosis of ascites. We assessed the etiologies and degrees of ascites (ascites grade 1 detectable only by radiologic tests; ascites grades 2 and 3 recognized by moderate and marked abdominal distension by physical examinations)., Results: We classified 518 children into 9 etiology groups: intrahepatic disease (IH) (105), hepatic vein outflow obstruction (HVOO) (45), congestive heart disease (CH) (33), nephrotic syndrome (NS) (36), pancreatitis (26), inflammatory and infectious diseases (77), malignancy (49), idiopathic (71), and miscellaneous (76). IH and CH were predominant in the younger age group (0-5 years) versus HVOO, pancreatitis, and malignancy in the older age group (13-21 years) (P < 0.001). The prevalence of ascites increased over time from 1983 to 2006 and declined thereafter. Ascites grade 1 was more common than ascites grades 2 and 3 in all the groups (P = 0.048). IH and NS were more likely to have ascites grade 2 and 3 (P = 0.02). Although spironolactone was more frequently used in the IH group versus other etiologies, furosemide was used more frequently in NS and CH versus other etiologies (P < 0.001)., Conclusions: The increased prevalence of ascites during the initial study period could reflect improved detection radiologic detection. The proportion of severe ascites and the various medical treatments differed among the etiologic groups.

This article describes the outcomes of a pediatric weight management program for a population primarily composed of minority ethnic groups and those from a lower socioeconomic status group. As these groups are disproportionally affected by pediatric obesity and overweight complicated by higher rates of attrition and poorer response to intervention, it is important that adequate and effective treatment exists for patients in these groups. Further research is needed to analyze the outcomes and attrition in these high-risk populations., Competing Interests: Authors disclose no potential conflicts of interest.

Objective: We aim to identify the spectrum of etiologies of steatosis in pediatric liver biopsies., Methods: Information was collected from 155 children with steatosis on liver biopsy, including anthropometrics, laboratory, and radiologic data. Biopsies were reviewed by a liver pathologist., Results: The 4 major diagnoses associated with hepatic steatosis were nonalcoholic fatty liver disease (37%), metabolic disease (9%), oncologic disease (8%) and viral hepatitis (7%). Patients with nonalcoholic fatty liver disease were older (P = .0001) and more likely to have a body mass index z score >2 (P < .0001). Patients with a metabolic diagnosis were younger (P = .0002). Radiologic imaging of the liver yielded normal results in 44 of 108 of children (30%); 7 of these had >66% macrovesicular fatty change on biopsy, and 3 had severe fibrosis/cirrhosis., Conclusions: The range of causes of steatosis in pediatric liver biopsies is broad. Not all patients, even with advanced liver disease, had abnormalities with liver imaging, emphasizing the role for liver biopsy in certain cases., (© The Author(s) 2015.)

Objective: Acute pancreatitis is one of the leading causes of rising pediatric hospitalizations in North America. The aim of this study was to assess the role of nutritional status and racial influences on the severity of acute pancreatitis in children., Methods: The institutional review board approved this retrospective chart review of children with the diagnosis of acute pancreatitis between the ages of 0 and 18 years hospitalized at the Johns Hopkins Hospital between 1998 and 2008. Parameters studied included biochemical markers associated with pancreatitis, review of severity of illness reflected through the length of stay, and pediatric intensive care unit admission., Results: The length of in-patient hospitalization was longer for children with imaging findings of pseudocyst or pancreatic necrosis (23.1 ± 26.4 days vs 4.4 ± 10.6 days; P = 0.0074) and malnourished children versus normal weight and obese children (16.5 days for malnourished vs 10.6 days for normal weight vs 10.7 days for obese; P = 0.04). There was also a significant difference in the need for pediatric intensive care unit admission across ethnic groups (18% African American vs 7% white) (P = 0.04)., Conclusions: Ethnicity and nutritional status may influence the severity and duration of hospitalization among children with pancreatitis.

Objectives: In adults, vitamin D deficiency is common in patients with nonalcoholic fatty liver disease (NAFLD) and has been associated with the severity of histology. There are known differences between adult and pediatric NAFLD, with little data regarding the relation between vitamin D and pediatric NAFLD. The aim of the present study was to examine the relation between vitamin D levels and NAFLD in children., Methods: Clinical and histological data were used from children ages 2 to 18 years with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network studies. 25(OH) vitamin D levels were measured from serum. Data examined included demographics, anthropometrics, laboratory markers, and liver histology. Data were analyzed using 3 categories of vitamin D level: deficient (≤ 20 ng/mL), insufficient (21-29 ng/mL), and sufficient (≥ 30 ng/mL)., Results: A total of 102 children were studied. There was a high prevalence (80/102, 78%) of vitamin D deficiency or insufficiency; however, there were no significant associations between vitamin D level and the histological characteristics or severity of NAFLD. Significantly higher levels of triglycerides were found in those with vitamin D deficiency (P = 0.004), but there was no association with other features of the metabolic syndrome., Conclusions: There is a high prevalence of vitamin D deficiency and insufficiency in children with biopsy-proven NAFLD; however, no association was found between vitamin D deficiency and the severity of disease on biopsies. This differs from adult NAFLD studies in which vitamin D deficiency correlates with histological severity, suggesting differences in the risk factors for or consequences of pediatric NAFLD.

Objective: To investigate the histological spectrum of nonalcoholic fatty liver disease (NAFLD) in children with normal, mildly elevated (26-50 U/L boys, 23-44 U/L girls), or elevated (>50 U/L in boys, >44 U/L in girls) serum alanine aminotransferase (ALT) levels., Study Design: The Nonalcoholic Steatohepatitis Clinical Research Network enrolls children aged 5-18 years with NAFLD. We analyzed baseline clinical and histological data from 91 children with suspected NAFLD and normal or mildly elevated ALT and liver biopsy analysis within 180 days of ALT measurement, and compared them with data from 392 children with elevated ALT., Results: Seventeen of the 91 children with suspected NAFLD (19%) had a normal ALT level, and 74 (81%) had a mildly elevated ALT level. Overall, 45% of the biopsy specimens analyzed had steatosis ≥33%, 22% had grade ≥2 lobular inflammation, 81% had portal inflammation, 29% had ballooned hepatocytes, 35% had "suspicious/borderline" steatohepatitis, 8% had definite nonalcoholic steatohepatitis, 34% had an NAFLD activity score ≥4, and 46% had fibrosis (38% mild/moderate and 8% bridging/cirrhosis). Marked steatosis (50% vs 24%) and fibrosis (54% vs 12%) were significantly more common in the patients with mildly elevated ALT compared with those with normal ALT, with no difference in ballooning, inflammation, or NAFLD activity score ≥4 between the 2 groups. Fibrosis stage 3/4 was seen in none of the children with normal ALT, in 9% of those with mildly elevated ALT, and in 15% of those with elevated ALT., Conclusion: Liver biopsy specimens from children with NAFLD with normal or mildly elevated ALT levels show significant histological abnormalities, including advanced fibrosis in children with mildly elevated ALT. Thus, measurement of ALT may underestimate liver injury in NAFLD. The use of appropriate ALT cutoff levels can help identify children at risk for more severe disease., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Mesalamine or 5-aminosalicylic acid (5-ASA) has proven efficacy in treating patients with ulcerative colitis (UC). Although mesalamine is considered safe, it has been associated with acute interstitial nephritis and renal failure., Methods: Herein we present a case of a child with UC who developed acute renal failure on mesalamine therapy., Results: A 15-year-old African-American girl with well-controlled UC presented to the Johns Hopkins Hospital with a four-day history of high fever, malaise, generalized body aches, and productive non-bloody cough. Over the next three days, she developed acute renal failure with fluid retention, and elevated serum creatinine and blood urea nitrogen. A kidney biopsy showed drug induced acute interstitial nephritis and focal segmental glomerulosclerosis with viral inclusion bodies likely secondary to cytomegalovirus., Conclusion: When treating UC patients with a history of underlying renal disease, it is advised to carefully monitor renal function while on mesalamine therapy.

Pediatric obesity is rapidly emerging as a serious chronic disease affecting an increasing number of children worldwide. In this report, we review current aspects of pediatric obesity and obesity related management as it relates to the primary care provider who is often the first line of prevention in pediatric obesity.

Background & Aims: Physiological changes that occur during puberty might affect pathologic features of nonalcoholic fatty liver disease (NAFLD). We investigated associations between pubertal development and clinical and histopathologic features of NAFLD., Methods: We studied 186 children (age <18 years, 143 boys) with biopsy-proven NAFLD. The population was divided into 3 groups on the basis of Tanner stage (prepuberty, puberty, and postpuberty). Clinical characteristics and histologic features were compared among groups. Multivariable regression models were used to adjust for potential confounders., Results: After adjusting for other factors, hyperuricemia and low levels of high-density-lipoprotein cholesterol were more prevalent among children who entered puberty with lower levels of quantitative insulin sensitivity check index (P < .05). The degree of steatosis, numbers of Mallory-Denk bodies, and diagnostic categories of NAFLD differed among groups (P < .05). There were potential sex differences in associations between stages of puberty and lobular inflammation, hepatocyte ballooning, and borderline steatohepatitis of zone 3; these were therefore not included in multivariable analyses of the overall population. After adjustment for different sets of confounders, patients at or beyond puberty were less likely to have high-grade steatosis, severe portal inflammation, borderline steatohepatitis (zone 1), or a high stage of fibrosis than patients who had not entered puberty (P < .05). On the contrary, the prevalence of Mallory-Denk body was greater among postpuberty subjects (P = .06)., Conclusions: Steatosis, portal inflammation, and fibrosis are less severe during or after puberty than before puberty among subjects with NAFLD. Postpubescent individuals have a lower prevalence of borderline steatohepatitis of zone 1 but are more likely to have Mallory-Denk bodies. These findings indicate that puberty affects the pathologic features of NAFLD., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Childhood obesity represents a significant challenge for paediatric healthcare delivery. As obesity rates increase, obese children and adolescents are at significant risk for the development of a myriad of medical and surgical problems as well as mental health problems. Moreover, children with mental health problems are increasingly presenting to their psychiatrists with obesity. Treatment of paediatric obesity requires a multidisciplinary approach with incorporation of the family into the treatment plan although still typically only offering suboptimal results. Paediatric providers from all disciplines should focus efforts primarily on obesity prevention and encouragement of healthy lifestyles, while incorporating treatment for obesity when such efforts fail. The goals of this article are to provide an overview of the epidemiology, pathophysiology, genetics, clinical features and treatment strategies for paediatric obesity.

Background: There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency., Objective: We sought to determine whether subjects with biopsy-proven NAFLD and evidence of an inadequate intake of choline had more severe histologic features., Design: We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN-developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9-13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicine's definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI., Results: Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women., Conclusion: Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT00063635.

The prevalence of obesity and obesity related comorbidities including diabetes and nonalcoholic fatty liver disease (NAFLD) has been rising globally. Nonalcoholic fatty liver disease is emerging as a common liver disease among adults which can lead to the eventual development of complications including cirrhosis and hepatocellular carcinoma. With the rise of obesity in children, the development of detection methods for the presence of NAFLD is becoming imperative. Although the gold standard for diagnosis is liver biopsy, practical issues limit pediatric use and warrant development of noninvasive or minimally invasive screening tools for the detection and staging of NAFLD. A variety of diagnostic methods have been studied including use aminotransferases, imaging studies and serologic markers which have some population-based limitations. Additional factors such as gender and ethnicity may also play a role in the screening of NAFLD in pediatric population studies.

Context: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established., Objective: To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin., Design, Setting, and Patients: Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks., Main Outcome Measures: The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures., Results: Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features., Conclusion: Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD., Trial Registration: clinicaltrials.gov Identifier: NCT00063635.

Background: Nonalcoholic fatty liver disease (NAFLD) in children can lead to steatohepatitis, cirrhosis, and end-stage liver disease. The cause of NAFLD is unknown, but it is commonly associated with obesity, insulin resistance, and dyslipidemia., Objectives: TONIC is conducted to test whether treatment with metformin, an insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvements in biochemical and histological features of nondiabetic children with biopsy-proven NAFLD., Design: TONIC is a randomized, multicenter, double-masked, placebo-controlled trial of 96 weeks of treatment with metformin or vitamin E. The primary outcome measure chosen for the trial is improvement in serum alanine aminotransferase (ALT) levels with treatment as compared to placebo. An improvement in ALT is defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or less) during the last 48 weeks of treatment. Histological improvement is defined by changes in liver histology between a baseline and end-of-treatment liver biopsy in regards to (1) steatohepatitis, (2) NAFLD Activity Score, consisting of scores for steatosis, lobular inflammation, and hepatocellular injury (ballooning), and (3) fibrosis score., Methods: Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States. Participants were randomized to receive either metformin (500 mg b.i.d.), vitamin E (400 IU b.i.d.), or placebo for 96 weeks. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB). (ClinicalTrials.gov number, NCT00063635.)., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Background: In conjunction with the rising prevalence of obesity during the past several decades, the clinical profile of the obese child has changed. Hypothesis. Environmental influences and eating practices have had an impact on the presence of medical morbidities among obese children., Design: Retrospective chart review of data collected from 90 children entering into a pediatric weight management program was performed. Fisher's exact tests and Wilcoxon rank sum tests were used to compare outcomes between subpopulations., Results: There was greater elevation in systolic blood pressure among children who ate in front of the television (P = .03) and a greater degree of fast-food consumption among children with more than 3 medical morbidities (P = .02). Breast-feeding did not have a protective effect on the degree of obesity (P = .02)., Conclusion: Aggressive assessment for symptoms should be an important part of evaluating the overweight child. Environmental influences and social feeding practices can counteract the protective effects of breast-feeding in infancy.

Fatal peripheral cholangiocarcinoma developed in 2 girls with progressive familial intrahepatic cholestasis, ABCB11 mutations, and absent bile salt export pump (BSEP) expression. BSEP deficiency may cause cholangiocarcinoma through bile-composition shifts or bile-acid damage within cells capable of hepatocytic/cholangiocytic differentiation. This observation suggests the need for hepatobiliary-malignancy surveillance and early consideration for liver transplantation.

Prader-Willi syndrome (PWS) is the most common known syndromic cause of life-threatening obesity, yet few studies have examined the causes of death in PWS. The objective of this study was to examine the contribution of choking leading to mortality in PWS. In 1999, a brief survey was made available from the Prader-Willi Syndrome Association (USA) bereavement program, which documented demographic data and causes of death. Families were subsequently offered the opportunity to fill out a detailed questionnaire and additional forms to release medical records. Demographic information was available on 178 deceased individuals with PWS, and cause of death available on 152 individuals. Fifty-four families completed questionnaires. Of the deceased individuals with completed questionnaires, 34% reported a history of choking. Choking was listed by familial report as the cause of death in 12 (7.9%) of 152 subjects with an average age of 24 years (range 3-52 years; median 22.5 years) at death from choking. Only two of these individuals were less than 8 years of age. The data suggest that risks associated with choking are different in the PWS population compared with others. Potential causes of increased choking in PWS include poor oral/motor coordination, poor gag reflex, hypotonia, hyperphagia, decreased mastication, and voracious feeding habits. We recommend implementation of preventive measures and education for families and group home care providers for all individuals with PWS including the Heimlich maneuver, supervised meals, better food preparation, and diet modification to avoid high-risk choking items., ((c) 2006 Wiley-Liss, Inc.)

Background: Although famotidine pharmacokinetics are similar in adults and children older than 1 year of age, they differ in neonates owing to developmental immaturity in renal function. Little is currently known about the pharmacokinetics of famotidine in infants aged between 1 month and 1 year, a period when renal function is maturing., Objective: To characterise the pharmacokinetics of famotidine in infants., Design: This was a two-part multicentre study with both single dose (Part I, open-label) and multiple dose (Part II, randomised) arms., Patients: Thirty-six infants (20 females and 16 males) who required treatment with famotidine and who had an indwelling arterial or venous catheter for reasons unrelated to the study., Methods: Infants in Part I were administered a single dose of famotidine 0.5 mg/kg; the dose was intravenous or oral according to the judgement of the attending physician. Infants receiving 0.5 mg/kg intravenously were divided into two groups by age, and pharmacokinetic parameters in infants 0-3 months and >3 to 12 months of age were compared. Infants in Part II were randomised to one of the following treatments: 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 and subsequent days, or 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 followed by doses of either 0.5 mg/kg/dose intravenously or 1 mg/kg/dose orally on subsequent days. From day 2 onwards, age-adjusted dose administration regimens (once daily in infants <3 months of age and every 12 hours in infants >3 months of age) were used; the total number of famotidine doses ranged from 3 to 11 and the total number of days of dose administration ranged from two to eight., Results: In infants <3 months of age, plasma and renal clearance of famotidine were decreased compared with infants >3 months of age. Pharmacokinetic parameters for the older infants (i.e. those >3 months) were similar to those previously reported for children and adults. Approximate dose-proportionality, no accumulation on multiple dosing and an estimated bioavailability similar to adult values were also observed., Conclusion: A short course of famotidine therapy in infants appears generally well tolerated, and the characteristics of famotidine pharmacokinetics during the first year of life are explained to a great degree by the development of renal function, the primary route of elimination for this drug.

Insulin inhibits insulin-like growth factor binding protein-1 (IGFBP-1) transcription by preventing FKHR protein family members from binding a specific insulin response element in the IGFBP-1 promoter. In most cells, three serine/threonine moieties in FKHR family members are phosphorylated after insulin treatment or protein kinase B/Akt (PKB) transfection, and each of the three phosphorylated PKB sites contributes to insulin- or PKB-mediated inhibition of both the action and the nuclear localization of FKHR family members. In hepatocytes, however, the middle PKB site (PKB2) of FKHR was required for insulin to phosphorylate FKHR and was the only PKB site that participated in insulin inhibition of FKHR action, indicating that insulin utilizes a unique pathway to regulate FKHR action in hepatocytes. In studies presented here, plasmids expressing native or mutant FKHR forms, either with or without N-terminal fusion to green fluorescent protein (GFP), were transiently transfected into HEP G2 cells. All FKHR forms stimulated IGFBP-1 promoter activity, and mutating any of the three FKHR PKB sites impaired the ability of insulin both to inhibit FKHR-stimulated IGFBP-1 promoter activity and to induce FKHR accumulation in cytoplasm. Thus, in hepatocytes as in other cell lines, all three FKHR PKB sites participate in insulin-mediated inhibition of FKHR action and in insulin-mediated accumulation of FKHR in cytoplasm.

The practice of upper gastrointestinal endoscopy in children continues to evolve. Therapeutic endoscopic procedures are now routinely performed in children. Patient preparation, sedation, and instrumentation have improved, allowing therapeutic endoscopy to be performed for a wide variety of conditions. This article focuses on the role of endoscopy in the diagnosis and care of caustic ingestion, balloon dilation of esophageal strictures, and new developments in the treatment of achalasia in children.

Background: Percutaneous liver biopsy is a valued tool of pediatric hepatology. Recent advances in technology have incorporated spring-loaded biopsy needles and ultrasonography in percutaneous liver biopsy., Methods: To determine the frequency of complications after liver biopsy and whether variables such as needle selections (Jamshidi, Monopty, or ASAP) and ultrasound guidance could predict complications, medical records were retrospectively reviewed of all patients who underwent percutaneous liver biopsy during a 7-year period. Available data were collected from 123 patients who had undergone a total of 249 percutaneous liver biopsies. All patients with evidence of mild clotting abnormalities (8.83%) received platelets, cryoprecipitate, or fresh-frozen plasma., Results: There was a 6.83% incidence of overall complications, and a 2.4% incidence of major complications. The mortality rate was 0.4%. Ultrasound localization did not diminish the risk of bleeding during biopsy. There was no significant difference in the change of hematocrit between the aspiration (Jamshidi) and spring-loaded (Monopty) needles. However, in patients less than 5 years of age, the change of hematocrit was significantly higher (P < 0.05) with the 15- or 18-gauge ASAP needle (Microvasive, Quincy, MA, U.S.A.) than with either the Jamshidi (Allegience Healthcare, Columbia, MD, U.S.A.) or Monopty (Bard Technologies, Covington, GA, U.S.A.) needles., Conclusion: Percutaneous liver biopsy is safe, using either aspiration or spring-loaded needles. Ultrasound guidance may not be helpful except in patients who underwent segmental liver transplantation.