Giuseppe Morino

Intima-media thickness and liver histology in obese children and adolescents with non-alcoholic fatty liver disease

OBJECTIVE To evaluate the relationship between biopsy-proven non-alcoholic fatty liver disease (NAFLD) and carotid artery intima-media thickness (CIMT) in children and adolescents. METHODS A case-control study was performed. Cases were 31 mostly obese children and adolescents, with NAFLD detected at ultrasonography, and confirmed by liver biopsy. Controls were 49 mostly obese children matched for gender, age and BMI without NAFLD at ultrasonography and with normal levels of aminotransferases. Besides standard laboratory measurements, subjects underwent an oral glucose tolerance test to evaluate glucose tolerance and to estimate whole body insulin sensitivity (ISI). RESULTS CIMT was similar in cases and controls on the right side but higher in cases on the left side. Although statistically significant, this difference is unlikely to be clinically relevant because of substantial overlap of CIMT values between cases and controls. Moreover, there was no association between CIMT and the severity of steatosis, ballooning, fibrosis, and the non-alcoholic steato-hepatitis score in cases. At multivariable analysis in the pooled sample (n=80), age and the z-score of BMI but not NAFLD, gender, blood pressure and triglycerides, were associated with CIMT. CONCLUSIONS We found no association between CIMT and NAFLD in children and adolescents. More importantly, there was no association between histological severity and CIMT in children with NAFLD.

Hyaluronic acid predicts hepatic fibrosis in children with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents, and it may progress to liver fibrosis and cirrhosis. Liver biopsy, which is the recognized gold standard for the diagnosis of hepatic fibrosis, is invasive. Thus, there has been increasing interest in the development of noninvasive markers. Hyaluronic acid (HA) has been shown to be a good marker of liver fibrosis in adults. In the current study, we evaluated the association of HA with liver fibrosis in 100 consecutive children with biopsy-proven NAFLD. In all, 65% of the children had liver fibrosis. Using proportional-odds ordinal logistic regression, we found that values of HA ≥ 1200 ng/mL made the absence of fibrosis (F0) unlikely (7%, 95% confidence interval [CI]: 1% to 14%), whereas values of HA ≥ 2100 ng/mL made F2, F3, or F4 fibrosis likely (89%, 95% CI: 75% to 100%). Our study shows that HA is a predictor of fibrosis in children with NAFLD followed at a tertiary care center. Additional studies are needed to test whether HA can be employed to predict liver fibrosis in pediatric populations with similar and lower prevalence of liver fibrosis.

BEYOND THE MORPHOLOGY OF THE GLUCOSE CURVE FOLLOWING AN ORAL GLUCOSE TOLERANCE TEST IN OBESE YOUTH

BACKGROUND To describe the morphology of glucose curve during the oral glucose tolerance test (OGTT) and any association with glucose tolerance, insulin action and secretion in obese youth. STUDY DESIGN Cross-sectional. METHODS OGTT data of 553 patients were analysed. Subjects were divided in groups based on the morphology (i.e. monophasic, biphasic, triphasic and upward monotonous) of glucose curve. Insulin action was estimated by the homeostasis model assessment of insulin resistance, the insulin sensitivity, the muscle insulin sensitivity and the hepatic insulin resistance indexes (HIRI), and the oral glucose insulin sensitivity (OGIS). Insulin secretion was estimated by the insulinogenic index (IGI). Disposition index, including the insulin secretion-sensitivity index-2, and areas under glucose (AUC(G)) and insulin (AUC(I)) curves were computed. RESULTS In patients with normal glucose tolerance (n=522), prevalent morphology of the glucose curve was monophasic (n=285, 54%). Monophasic morphology was associated with the highest concentration of 1 h plasma glucose (P<0.0001) and AUC(G) (P<0.0001); biphasic morphology with better insulin sensitivity as estimated by OGIS (P<0.03) and lower AUC(I) (P<0.0001); triphasic morphology with the highest values of HIRI (P<0.02) and IGI (P<0.007). By combining morphologies of glucose and insulin curves or time of the glucose peak, a deeper characterisation of different phenotypes of glucose metabolism emerged. CONCLUSIONS Morphologies of the glucose curve seem reflecting different metabolic phenotypes of insulin action and secretion, particularly when combined with morphologies of insulin curve or time of glucose peak. Such findings may deserve validation in cohort study, in which glucose metabolism would be estimated by using gold standard techniques.

Prevalence of pathogenetic MC4R mutations in Italian children with early onset obesity, tall stature and familial history of obesity.

BackgroundMelanocortin-4-receptor (MC4R) mutations represent the most frequent genetic cause of non-syndromic early onset obesity. Children carrying MC4R mutations seem to show a particular phenotype characterized by early onset, severe obesity and high stature. To verify whether MC4R mutations are associated with this particular phenotype in the Italian pediatric population, we decided to screen the MC4R gene in a group of obese children selected on the basis of their phenotype.MethodsTo perform this study, a multicentric approach was designed. Particularly, to be enrolled in the study subjects needed to meet the following criteria: Body mass index ≥ 3 deviation scores according to age and sex, familiar history of obesity (at least one parent obese), obesity onset before the 10 years old, height ≥ 2 deviation scores. The coding region of MC4R gene was screened in 240 obese children (mean age 8.3 ± 3.1, mean BMI 30.8 ± 5.4) and in 200 controls (mean age 8.1 ± 2.8; mean BMI 14.2 ± 2.5).ResultsThree mutations have been found in five obese children. The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously. The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients. Functional studies showed that only Q307X impaired protein function.ConclusionThe low prevalence of MC4R mutations (1.6%) in this group of obese children selected according to the obesity degree, the tall stature and the family history of obesity was similar to the prevalence observed in previous screenings performed in obese adults and in not phenotypically selected obese children.

Obalon intragastric balloon in the treatment of paediatric obesity: a pilot study

Lifestyle interventions are often ineffective in the treatment of pediatric obesity. Weight loss devices have been introduced for the temporary nonsurgical treatment of morbid obesity.

Biomarkers of Alzheimer Disease, Insulin Resistance, and Obesity in Childhood

OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid β-protein 42 (Aβ42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI. METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent β-cell function (HOMA-β) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS: Obese adolescents had values of Aβ42 higher than overweight and normal-weight peers (190.2 ± 9.16 vs 125.9 ± 7.38 vs 129.5 ± 7.65 pg/mL; P < .0001) as well as higher levels of PSEN1 (2.34 ± 0.20 vs 1.95 ± 0.20 vs 1.65 ± 0.26 ng/mL; P < .0001). Concentrations of Aβ42 were significantly correlated with BMI (ρ = 0.262; P < .0001), HOMA-IR (ρ = 0.261; P < .0001) and QUICKI (ρ = −0.220; P < .0001). PSEN1 levels were correlated with BMI (ρ = 0.248; P < .0001), HOMA-IR (ρ = 0.242; P < .0001), and QUICKI (ρ = −0.256; P < .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein. CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD.

Insulin sensitivity from preschool to school age in patients with severe obesity.

Background Insulin sensitivity decreases at puberty transition, but little information has been provided on its earlier time-course. Aim of the present study was to describe the time-course of insulin sensitivity in severely obese children at the transition from preschool to school age. Research design and methods Retrospective study of a cohort of 47 severely obese [Body Mass Index (BMI) ≥99° percentile] preschoolers evaluated twice, once between 2 and 6 years of age, and once before age 8. Glucose tolerance, Whole Body Insulin Sensitivity Index (WBISI), Insulinogenic Index (IGI); β-cell demand index (BCDI) and Insulin Secretion-Sensitivity Index 2 (ISSI-2) were longitudinally estimated during the oral glucose tolerance test. Results After a median follow-up of 2.23 (1–4.52) y, obese patients showed significant decrease in WBISI (p<0.0001), and increase in fasting (p = 0.005) and 2 h glucose (2HG, p = 0.001). One child in preschool age and 4 school age children presented with 2HG between 7.8–11.1 mmol/l. Best predictors of WBISI, 2HG and BCDI in the school age were changes in BMI z-score (R2 = 0.309; p = 0.002; β = −0.556), ISSI-2 (R2 = 0.465; p<0.0001; β = −0.682), and BMI z-score (R2 = 0.246; p = 0.008; 0.496), respectively. Conclusions In morbidly obese children, insulin sensitivity seems to decline even before pubertal transition, but changes in total adiposity can only partially explain this variation.

The rehabilitation of children and adolescents with severe or medically complicated obesity: an ISPED expert opinion document

Severe/medically complicated obesity in childhood, and particularly in adolescence, is a real disability that requires an intensive and continuous approach which should follow the procedures and schedule of rehabilitation medicine. Given the lack of a specific document focusing on children and adolescents, the Childhood Obesity Study Group set out to explore the available evidence for the treatment of severe or medically complicated obesity and to set standards tailored to the specific context of the Italian Health Service. Through a series of meetings and electronic communications, the writing committee (selected from members of the Study Group) selected the key issues, explored the literature and produced a draft document which was submitted to the other experts until the final synthesis was approved by the group. In brief, the following issues were involved: (1) definition and epidemiology; (2) identification of common goals designed to regain functional competence and limit the progression of metabolic and psychological complications; (3) a multi-professional team approach; (4) the care setting. This paper is an expert opinion document on the rehabilitation of severe and medically complicated obesity in children and adolescents produced by experts belonging to the Childhood Obesity Study Group of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED).

NutricheQ Questionnaire assesses the risk of dietary imbalances in toddlers from 1 through 3 years of age

Background Although a nutrient-poor diet may affect childrens growth, especially early in life, few tools to assess dietary imbalances in 1- to 3-year-old children have been developed. Objectives To investigate the accuracy and test–retest reliability of the NutricheQ Questionnaire in the identification of toddlers with the risk of inadequate intake of micro- and macronutrients in a sample of Italian toddlers. Design A 3-day weighed food record was performed, and results were compared with outcomes of the NutricheQ Questionnaire in 201 toddlers (training set: 1–3 years old). The accuracy of NutricheQ in the identification of categories of nutritional risk was evaluated using the receiver operating characteristic (ROC) curves. Test–retest of the tool was estimated using the intraclass correlation coefficient (ICC) and the Cronbachs alpha statistic, in a validation set of 50 toddlers. Results The NutricheQ Questionnaire is a valid tool for the identification of toddlers at risk for dietary imbalances. Significant differences in nutrient intake (p<0.005) were found among the three groups of risk identified by the questionnaire: toddlers included in the high-risk group had a lower intake of key nutrients such as iron, vitamin D and other vitamins, and fibre compared to those included in the low-risk group. NutricheQ is also reliable between administrations, as demonstrated by its test–retest reliability. ICC and Cronbachs alpha were 0.73 and 0.83, respectively, for Section 1 of NutricheQ, and 0.55 and 0.70 for Section 2. Conclusions The NutricheQ Questionnaire is a reliable and consistent tool for the assessment of possible dietary risk factors in Italian toddlers. It consistently identifies toddlers with a high probability of having poor iron and vitamin D intake, and other dietary imbalances.

Diagnosis, treatment and prevention of pediatric obesity: consensus position statement of the Italian Society for Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase.