Role of π-Radical Localization on Thermally Stable Cross-Links Between Polycyclic Aromatic Hydrocarbons.

The thermal stability of cross-links between polycyclic aromatic hydrocarbons (PAHs) is critical for understanding the formation of soot pollutants, graphite, and carbon blacks. Recently, a variety of different π-radicals have been directly imaged and suggested to enable thermally stable bonding; however, a systematic study of reactivity has been lacking. In this work, we use density functional theory to study the reactivity of PAH π-radicals. The Mulliken spin densities are initially used to categorize the different classes of localization, and the bond energy is computed to determine the degree of localization required for thermal stability. The results showed that the bond energies of PAHs are strongly correlated with the calculated spin densities, but bond energies do not exist with the bond lengths due to significant rearrangement and steric effects during bond formation. A threshold for π-radical localization is suggested that will be stable in combustion and pyrolysis environments of ρMα ≥ 0.5. Finally, the formation of multicenter bonds between localized and delocalized π-radicals was investigated using the nudge elastic band (NEB) scan, and it was found that only delocalized π-radicals provided local energy minima. These results show that the localization of π-radicals is critical for the formation of thermally stable single-center bonds between aromatic radicals.

Segmental Arterial Mediolysis Presenting as a Pancreatic Mass in a Pediatric Patient: A Case Report.

We describe a case of segmental arterial mediolysis (SAM) in a 2-year-old male who presented with symptoms of acute pancreatitis. SAM is a vascular entity of unknown etiology that involves medium-sized arteries in which the integrity of the vessel wall is compromised, resulting in increased susceptibility to ischemia, hemorrhage, and dissection. The clinical presentation is variable and can range from abdominal pain to more ominous findings of abdominal hemorrhage or organ infarction. This entity should be considered in the correct clinical setting and after other vasculopathies have been excluded. We aim to bring awareness to pediatric providers given this is a rare entity with variable presentation, which could be potentially life threatening.

Accuracy of noninvasive fibrosis scores in predicting advanced fibrosis in pediatric patients after liver transplantation.

BACKGROUND: Liver biopsy is the gold standard to stage fibrosis in liver disease. Several scoring systems have been studied to predict advanced fibrosis in liver disease. Those scores have not been validated in pediatric liver transplant patients. AIM: Evaluate the performance of three fibrosis scores (FSc) in assessing the presence of advanced fibrosis (AF) in children after orthotopic liver transplantation (OLT). METHODS: Patients < 20 years of age who underwent liver biopsy post-OLT with laboratory values within 1 month of the biopsy were included. Fibrosis was determined by an experienced pathologist (F0-4). We defined AF as F3-4. The following FSc were calculated: AST/ALT ratio, APRI, and FIB-4 index. Receiver operating characteristic curve analysis was done to assess the FSc performance in predicting AF. RESULTS: A total of 232 biopsies were analyzed, of those 42 (18.1%) showed AF (F3-4). FIB-4 was significantly higher in patients with AF compared to those without AF [median value of 1.1 [0.7, 3.0] and 0.6 [0.2, 1.4], respectively (p = .02)]; however, FIB-4 had satisfactory accuracy to diagnose AF with significant overlap and AUC of 0.68 (CI 0.56-0.81). Cutoff points of 0.2 and 3.03 were used to rule in and rule out AF, respectively. AST/ALT and APRI were not significantly different between patients with and without AF. CONCLUSION: Even though FIB-4 had satisfactory accuracy in detecting AF in pediatric transplant patients, noninvasive hepatic FSc developed in adults still performed poorly. Our results highlight the need to develop a reliable pediatric FSc.

Measurement of Quality-of-Life Outcomes in Pediatric and Young Adult Patients Treated for Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic, immune-mediated esophageal condition that may lead to impairment of quality of life in pediatric and young adult patients. We performed a prospective, cross-sectional study on 40 patients between the ages of 2-21 years with an established diagnosis of eosinophilic esophagitis. The study evaluated physical, emotional, social, and school functioning in patients undergoing treatment with proton pump inhibitors, dietary elimination, or swallowed corticosteroids. There were no statistically significant differences in total or domain-specific quality of life scores between proton pump inhibitors, dietary elimination, and swallowed corticosteroid therapy. Overall, total and domain-specific quality of life were well-preserved in patients with eosinophilic esophagitis, with the highest scores reported in social functioning. There were also no statistically significant associations between clinical, endoscopic, and histologic features and quality-of-life measures.

Eosinophilic esophagitis: A review of the pediatric population and consideration of upcoming therapies.

Eosinophilic esophagitis (EoE) is a disease entity that has become increasingly recognized in the pediatric population over the last decade and was first recognized as early as 1990. EoE is a clinicopathologic diagnosis with signs and symptoms varying between age groups. The clinical presentation of EoE is variable ranging from milder nonspecific symptoms, such as abdominal pain, vomiting, and dyspepsia, to more severe presentations such as failure to thrive, dysphagia and even food impaction and is dependent on age of diagnosis 2. There is growing body of evidence with regards to the pathophysiology, diagnostic modalities, and treatment options for EoE in the past decade. In this review article, we aim to discuss the disease burden, pathophysiology, diagnostic strategies, and currently available treatment options for EoE based on existing literature.

Performance Characteristics, Intra- and Inter-operator Agreement of Transient Elastography in Pediatric Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Transient elastography (TE) is a valuable tool in assessment of hepatic steatosis and fibrosis using liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), respectively. Although widely used in adults, little is known about performance characteristics and reproducibility of TE (using Fibroscan device) in evaluation of pediatric nonalcoholic fatty liver disease (NAFLD). METHODS: We prospectively recruited children with NAFLD. Three consecutive Fibroscan examinations were performed during the same visit-twice by a single expert operator and once by a different novice operator. Intra and inter-operator agreement was calculated using concordance correlation coefficient (CCC). Failure was defined as inability to obtain 10 valid measurements and examination was considered unreliable if LSM interquartile range/median was greater 30%. RESULTS: Fifty-one children (34 boys; median age 15 years) were recruited. Failure rates for expert and novice operator were 10% (5/51) and 12% (6/51) while unreliable readings were obtained in 2% (1/46) and 4% (2/45) of patients, respectively. Patients with failed/unreliable measurements were significantly more obese (median BMI 46.2 vs 33.1 kg/m2, P = 0.002) compared with those with reliable measurements. The intra-operator agreement was almost perfect for LSM and substantial for CAP values (CCC = 0.85 and 0.73, respectively). Inter-operator agreement was substantial for LSM and moderate for CAP values (CCC = 0.76 and 0.58, respectively). The inter-operator agreement in LSM did not vary significantly over time but showed an inverse correlation with BMI and CAP. CONCLUSION: Our study demonstrated that use of TE in assessment of hepatic fibrosis and steatosis in children with NAFLD is highly reliable with low failure rate and highly reproducible with high intra- and inter-operator reproducibility.

Assessment of Gastric Emptying Times Between Pediatrics and Adults With Cyclic Vomiting Syndrome.

BACKGROUND & AIMS: Cyclic vomiting syndrome (CVS) is characterized by episodes of nausea and vomiting separated by symptom-free intervals. Rome IV guidelines have now distinguished CVS from other disorders such as cannabinoid hyperemesis. The pathogenesis of CVS, however, is poorly understood. Limited data exist on gastric emptying (GE) in patients with CVS. Therefore, the authors aim to measure the GE profile in pediatrics and adults with CVS. MATERIALS AND METHODS: Patients with the diagnosis of CVS (per NASPGHAN and Rome IV) between December 1998 and March 2017 who underwent gastric emptying study (GES) and without documented cannabis use were included. Clinical features including demographics, medication use, and comorbidities were also recorded. Frequency of rapid, normal, and delayed emptying was reported, and multinomial univariate logistic regression was used to identify factors associated with each type of emptying. KEY RESULTS: Sixty-seven subjects were included (50.7% female individuals, pediatrics n=15, adults n=52). At 2-hour retention, 40% of pediatric patients met criteria for rapid, 33.3% for normal, and 26.7% for delayed GE. In adults, 50% met criteria for rapid, 46.2% for normal, and 3.8% for delayed GE. For every 5-year increase in age, odds of rapid emptying on GES increased. CONCLUSIONS: (1) GE is predominantly rapid at 2 hours in pediatrics and adults with CVS. (2) Rapid GE seems to increase with age. (3) Current guidelines do not recommend GE in the initial management, however, further studies may play a role to help differentiate CVS from other functional gastric disorders.

Pediatric cholestatic liver disease: Successful transition of care.

With recent medical advances, more patients with childhood-onset liver disease and more pediatric liver transplant recipients are surviving into adulthood, generating distinctive challenges to adult primary care providers. Young adults with pediatric liver disease are a unique cohort of patients with different evaluation and monitoring strategies, treatment, complications, and comorbidities. This creates a critical need for successful transition of these patients into adult care, with incorporation of a formal transitional model and multidisciplinary team.

Comparison between non-alcoholic fatty liver disease screening guidelines in children and adolescents.

BACKGROUND & AIM: There is currently no agreement on the screening strategy for non-alcoholic fatty liver disease (NAFLD) in children at risk. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) recommends screening for NAFLD using alanine aminotransferase (ALT) in obese/overweight children, while the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends using both ALT and abdominal ultrasound. The aim of this study was to assess the prevalence of suspected NAFLD in obese children based on the 2 screening strategies. METHOD: Consecutive overweight/obese children seen at a weight-management program were included. Each child underwent a liver ultrasound and had ALT level measured at first visit. Two screening strategies were compared: the NASPGHAN strategy using ALT ≫2x the gender specific cut-off and the ESPGHAN strategy using elevated ALT ≫45 IU/L and/or fatty liver on ultrasound. Univariate and multivariate analyses were performed to assess predictors of low ALT in individuals with evidence of suspected NAFLD on ultrasound. RESULTS: Overweight/obese children were included. NAFLD was suspected as follows: 26% based on the NASPGHAN strategy, and 58% based on the ESPGHAN strategy. Fatty liver was present on ultrasound in 53% of our cohort. ALT was ≫2x the gender specific cut-off in only 26% of children with fatty liver on ultrasound. Univariate and multivariate analyses indicated that children with fatty infiltration on ultrasound and low ALT were less likely to have metabolic syndrome, insulin resistance, or hypertriglyceridemia. CONCLUSION: By relying on ALT values alone to screen for NAFLD, suspected NAFLD might be missed in many children who are at risk. Children with fatty infiltration on ultrasound and low ALT may be less likely to have metabolic syndrome, insulin resistance or hypertriglyceridemia. LAY SUMMARY: Using the combination of elevated alanine aminotransferase and fatty infiltration on ultrasound increases the detection rate of suspected non-alcoholic fatty liver disease in at-risk children. Notably, a significant percentage of children with fatty infiltration on ultrasound have low alanine aminotransferase (≪52/44). Children with fatty infiltration on ultrasound and low alanine aminotransferase may be less likely to have features of the metabolic syndrome.

The Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with prevalence increasing in parallel with the rising incidence in obesity. Believed to be a "multiple-hit" disease, several factors contribute to NAFLD initiation and progression. Of these, the gut microbiome is gaining interest as a significant factor in NAFLD prevalence. In this paper, we provide an in-depth review of the progression of NAFLD, discussing the mechanistic modes of hepatocyte injury and the potential role for manipulation of the gut microbiome as a therapeutic strategy in the prevention and treatment of NAFLD.

Nonalcoholic Fatty Liver Disease in Children: Not a Small Matter.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased substantially in the past two decades and NAFLD has now become the most common cause of chronic liver disease in children and adolescents. NAFLD is a broad clinicopathologic spectrum ranging from simple steatosis to varying degrees of necroinflammation called nonalcoholic steatohepatitis (NASH), leading to fibrosis and subsequently to cirrhosis. Despite the increasing prevalence and progressive nature of NAFLD even among children, therapy for NAFLD in both adults and children are limited. Weight loss remains the only consistently effective therapy for NAFLD. Pharmacologic options are even more limited in children than in adults with NAFLD. Vitamin E has been shown to be effective in improving histology in children with NASH. Few pharmacologic options such as metformin, probiotics, omega-3 fatty acids, and cysteamine bitartrate have been studied in children, with limited beneficial effects. However, these studies are limited by small sample size and heterogeneity of outcome assessment after treatment. Recent studies show promising results with bariatric surgery with regards to weight loss and improvement in liver histology in adolescents with NAFLD. In this review article, we discuss epidemiology, pathophysiology, and extrahepatic comorbidities of pediatric NAFLD and review existing therapeutic options for children with NAFLD. We also review novel therapeutic strategies studied in adults that could potentially be studied in children in the future.

The search for noninvasive methods to identify liver fibrosis in children with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the obesity epidemic. Recent studies have clearly shown that the stage of fibrosis in adults with NAFLD is the most important histological feature in long-term outcomes and the development of liver-related complications. Despite the paucity of data regarding the natural history of pediatric NAFLD, its progression to cirrhosis and end-stage liver disease requiring liver transplantation is well documented. Given the high prevalence of NAFLD in children and adults, there is an urgent need to find safe and cost-effective alternatives to biopsy to determine the stage of liver fibrosis. In this review, we provide a concise overview of different noninvasive methods for diagnosing and staging liver fibrosis in children with NAFLD.

Prevalence of Suspected Nonalcoholic Fatty Liver Disease in Lean Adolescents in the United States.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) can develop in lean subjects referred to as lean NAFLD. We aim to evaluate the prevalence and risk factors of NAFLD in lean adolescents in the United States (US). METHODS: Cross sectional data from 1482 lean subjects (body mass index <85th percentile) ages between 12 and 18 years, who were enrolled in the National Health and Examination Survey during the 2005 to 2014 cycles were included. We defined suspected NAFLD as alanine aminotransferase >25.8 U/L for boys and >22.1 U/L for girls; hypertriglyceridemia as triglycerides ≥150 mg/dL; low HDL as HDL <40 mg/dL and insulin resistance (IR) as homeostatic model assessment of IR ≥3. RESULTS: The mean weighted prevalence of suspected NAFLD among lean adolescents during 2005 to 2014 cycles was 8% (95% CI 6.2-9.9). Lean subjects with suspected NAFLD were significantly older compared with lean non-NAFLD subjects (15.5 vs 15 years, P value <0.05). Low HDL (15.5% vs 6.8%; P value 0.016) and hypertriglyceridemia (10% vs 3.9%; P value 0.028) were also found to be more common among lean NAFLD subjects compared with their non-NAFLD counterparts. Presence of IR increased the risk of having suspected NAFLD by 4-fold among lean adolescents. Non-Hispanic black lean adolescents were less likely to have suspected NAFLD compared with non-Hispanic white lean adolescents. CONCLUSIONS: The estimated prevalence of suspected NAFLD among lean adolescents in the US was found to be 8% with evidence of metabolic derangements such as low HDL, hypertriglyceridemia, and IR.

Accuracy of Noninvasive Fibrosis Scores in Predicting the Presence of Fibrosis in Patients after Liver Transplantation.

OBJECTIVES: Several scoring systems have been developed to noninvasively predict the presence of advanced fibrosis in patients with chronic liver disease. Hepatitis C virus and nonalcoholic fatty liver disease are the 2 most common indications for orthotopic liver transplant and are associated with disease recurrence that can lead to fibrosis progression. Here, we evaluated the performance of commonly used fibrosis scores in assessing the presence of advanced fibrosis in patients after orthotopic liver transplant. MATERIALS AND METHODS: Our study consisted of consecutive patients with hepatitis C virus or nonalcoholic fatty liver disease who underwent a liver biopsy after transplant and had laboratory measurements within 1 week of biopsy. Graft fibrosis was determined by an experienced pathologist (stage F0-F4). Advanced fibrosis was defined as stage F3-F4. The following fibrosis scores were calculated for each patient: aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index, and fibrosis-4 index. RESULTS: We analyzed 93 patients with median age of 59 years (25th and 75th percentile of 53 and 64 y) and median body mass index of 31.8 kg/m² (25th and 75th percentile of 27 and 37.6 kg/m²). Of total patients, 41 (44%) were diabetic. Median time to liver biopsy posttransplant was 27.7 months (25th and 75 percentile of 10.8 and 59.9 mo). We found that 54 patients (58%) had no fibrosis, 15 (16.1%) had F1, 8 (8.6%) had F2, 7 (7.5%) had F3, and 9 (9.7%) had F4. Overall, advanced fibrosis (F3-F4) was present in 16 patients. Aspartate aminotransferase/alanine amino-transferase ratio, aspartate aminotransferase/platelet ratio index, and fibrosis-4 index were not significantly different between patients with and without advanced fibrosis (all P > .05). The calculated fibrosis scores had poor diagnostic accuracy for presence of advanced fibrosis posttransplant. CONCLUSIONS: Commonly used liver fibrosis scores are not accurate in predicting the presence of advanced fibrosis in patients after liver transplant.

Nonalcoholic Fatty Liver Disease in Children: Hepatic and Extrahepatic Complications.

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the most common form of chronic liver disease in children and adolescents. The histologic spectrum of NAFLD is broad ranging, from the relatively benign form of simple steatosis to the aggressive form of nonalcoholic steatohepatitis, eventually leading to fibrosis and cirrhosis. NAFLD has also been recognized as an independent risk factor for extrahepatic complications, such as cardiovascular disease, type 2 diabetes mellitus, sleep disorders, and osteoporosis. In this review, we discuss both the hepatic and extrahepatic complications of NAFLD in children.

A 9-Day-Old With Weight Loss and Diarrhea.

A 9-day-old infant girl presented with diarrhea and weight loss of 19% since birth. She was born via spontaneous vaginal delivery at 39 weeks' gestation to a mother positive for group B Streptococcus who received adequate intrapartum prophylaxis. The infant was formula-fed every 2 to 3 hours with no reported issues with feeding or swallowing. The infant had nonmucoid watery stools ∼5 to 15 times per day. Her family history was significant for hypertrophic cardiomyopathy in several of her family members. Her initial vital signs and physical examination were normal. Laboratory data on hospital admission showed a normal complete blood cell count, but her chemistry analysis revealed significant hypernatremia, hyperkalemia, metabolic acidosis, and acute kidney injury. Her hypernatremia was resistant to fluid management. In this article, we discuss the infant's hospital course, our clinical thought process, and how we arrived at our final diagnosis.

Prevalence of Nonalcoholic Steatohepatitis-Associated Cirrhosis in the United States: An Analysis of National Health and Nutrition Examination Survey Data.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of manifestations ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and eventually cirrhosis. The prevalence of NAFLD has been shown to be increasing over time; however, the prevalence of NASH cirrhosis and advanced fibrosis over time has not been well studied. Estimate the changes in prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis among adults in the United States. METHODS: National Health and Nutrition Examination Survey (NHANES) data obtained during the periods from 1999-2002 and 2009-2012 were analyzed to estimate the prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis in subjects aged ≥18 years at the time of enrollment. We excluded patients with viral hepatitis, excessive alcohol consumption, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >500 and patients who were pregnant. Cirrhosis was defined by AST to platelet ratio index (APRI) >2 and abnormal liver function tests. NASH cirrhosis was defined as cirrhosis that presented with at least one of the following: obesity, diabetes, insulin resistance (HOMA-IR≥3), and metabolic syndrome. Advanced fibrosis was defined by using well-established cutoff values for APRI, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS). Population weighted prevalence was calculated separately for two groups to account for complex sampling method of NHANES. RESULTS: A total of 7034 NHANES participants from 1999-2002 and 2009-2012 group were included with mean age of 46.2±0.59 and 47.3±0.51 years, respectively, at the time of screening. The prevalence of NASH cirrhosis was significantly higher in 2009-2012 group (0.178% with an estimated 417,524 American adults with NASH-associated cirrhosis) compared to 1999-2002 group (0.072%); P value<0.05. The prevalence of NAFLD with advanced fibrosis also increased from 0.84 to 1.75% during the same time period (P value<0.001) corresponding to 4,104,871 American adults. During these time periods, there were also significant increases in obesity (29.8 vs. 36.6%), diabetes (8.3 vs. 11.9%), and insulin resistance (34.7 vs. 42.1%); P value <0.005 for all of them. CONCLUSIONS: There has been a 2.5-fold and 2-fold increases in the prevalence of NASH cirrhosis and NAFLD-associated advanced fibrosis, respectively, in 2009-2012 compared to 1999-2002. Extrapolation of NHANES data suggests that in 2010, 417,524 in the US had NASH cirrhosis, and 4,104,871 had NAFLD-associated advanced fibrosis. This represents a major disease burden and suggests the need for widespread programs to identify and treat those affected, and public health efforts aimed at controlling the burden of NAFLD and its complications.