Correction: Sakulsaengprapha et al. Applicability of International Autoimmune Hepatitis Group (IAIHG) Scoring System for Autoimmune Hepatitis in Pediatrics. Biology 2023, 12, 479.

There was a spelling mistake in the original publication [...].

Applicability of International Autoimmune Hepatitis Group (IAIGH) Scoring System for Autoimmune Hepatitis in Pediatrics.

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.

Critical review of bariatric surgical outcomes in patients with Prader-Willi syndrome and other hyperphagic disorders.

OBJECTIVE: The aim of this study was to review bariatric procedure outcomes among patients with Prader-Willi syndrome (PWS), melanocortin 4 receptor (MC4R) mutations, Bardet-Biedl syndrome, and hypothalamic obesity. METHODS: Systematic published literature review used the following search terms: "Prader-Willi syndrome," "Bardet-Biedl syndrome," "hyperphagia," "bariatric surgery," "MC4R"/"melanocortin 4 receptor", "hypothalamic obesity," and "bariatric procedure." Information collected included demographics, genetics, anthropometry, procedure type, outcomes, and complications, with inclusion of case series and clinical reports given the rarity of the disorders. For PWS, postoperative weight-change percentage and BMI up to 14 years following surgery were analyzed using general linear mixed models, with descriptive outcomes for other conditions. RESULTS: A total of 54 publications were identified, with variable follow-up periods for 202 patients (114 with PWS, 43 with MC4R mutations, 7 with Bardet-Biedl syndrome, and 38 with hypothalamic obesity) among bariatric procedures. Weight loss of patients with PWS was greatest within 1 year of surgery, with weight-change percentage not significantly different from 0 at 5 years. Long-term results in other conditions were variable and featured suboptimal weight loss and increased reoperation risk. CONCLUSIONS: Bariatric procedures among hyperphagic individuals, including those with PWS, report variable results and outcomes. Benefits of bariatric surgery may be less durable in hyperphagic disorders in comparison with other patients with severe obesity.

Hepatic and non-hepatic hydrothorax in pediatric ascites.

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.

Neuropsychiatric features of Prader-Willi syndrome.

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.

Screening strategy for gastrointestinal and hepatopancreatobiliary cancers in cystic fibrosis.

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.

Clinical Predictors of Morbidity and Mortality in Hospitalized Pediatric Patients With Ascites.

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.

Clinical usage of serum albumin to ascitic fluid albumin gradient and ascitic fluid total protein in pediatric ascites.

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.

Hepatitis E-Associated Hospitalizations in the United States: 2010-2015 and 2015-2017.

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 (ß = 0.60, p = 0.011). From 2015 to 2017, the hospitalization appeared to increase with slope (ß) 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.

A retrospective study on the association of gastrointestinal symptoms in children with low lactase activity and low activity of other disaccharidases.

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.

Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice.

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.

The effect of sleep on gastrointestinal functioning in common digestive diseases.

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.

Caregiver priorities for endpoints to evaluate treatments for Prader-Willi syndrome: a best-worst scaling.

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.

Rectal Picking Masquerading as Inflammatory Bowel Disease in Prader-Willi Syndrome.

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.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

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.

Ascites in Children: A Single-Center Experience of 27 Years.

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.

Pediatric Weight Management Program Outcomes in a Largely Minority, Low Socioeconomic Status Population.

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.

Relation between vitamin D status and nonalcoholic fatty liver disease in children.

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.