Giorgio Attina’, Stefano Mastrangelo, Palma Maurizi, Alberto Romano and Antonio Ruggiero

Pediatric Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Universita’ Cattolica Sacro Cuore, Rome, Italy.

Corresponding Author E-mail: antonio.ruggiero@unicatt.it

DOI : https://dx.doi.org/10.13005/bpj/2833

Abstract

Obesity is a health condition caused by the accumulation of excess body weight in the form of adipose tissue. This condition has negative effects on a person's overall health. Obesity has a multifactorial etiology involving environmental, genetic, hormonal, and epigenetic factors. The percentage of obese people in childhood is constantly increasing. It is therefore important to implement preventive strategies. This is because Obesity is a systemic condition with major consequences on the endocrine-metabolic, psychosocial, musculoskeletal, respiratory, neurological, gastrointestinal, and especially vascular spheres. Obesity is, in fact, an independent cardiovascular risk factor. Appropriate educational therapy aimed at the child/adolescent and their family is essential. Modifying behaviors that contribute to increased food intake and decreased energy expenditure is essential in promoting healthy lifestyles for individuals and their families.

Keywords

Adolescents; Children; Diet; Obesity; Overweight

Download this article as: 

Copy the following to cite this article: Attina G, Mastrangelo S, Maurizi P, Romano A. Ruggiero A. Childhood Obesity and Metabolic Syndrome: A Review . Biomed Pharmacol J 2024;17(1).

Copy the following to cite this URL: Attina G, Mastrangelo S, Maurizi P, Romano A. Ruggiero A. Childhood Obesity and Metabolic Syndrome: A Review . Biomed Pharmacol J 2024;17(1). Available from: https://bit.ly/3V7bPYk

Introduction

Obesity is a chronic condition that is defined by the World Health Organisation (WHO) as excessive body weight caused by the accumulation of fatty tissue, which has a negative impact on health. It has a multifactorial etiology and is accompanied by an increased risk of morbidity and mortality.¹ Although the definition of Obesity refers to excess fat², in clinical practice this is difficult to measure directly. Obesity is therefore assessed by measuring BMI (Body Mass Index), which expresses the ratio between weight (kg) and height (m²). It is the most widely used method clinically, thus representing a good screening tool and an indicator of excess adipose tissue, albeit with some limitations in the clinical setting (BMI may be high in athletes due to the weight of muscle mass and underestimated in those with low muscle mass).^1,3

The World Health Organization (WHO) has categorized different classes of obesity based on BMI. However, this classification is not very useful for children and adolescents, as age and gender-specific BMI reference curves are more applicable in this age group.^4-6 The International Obesity Task Forcehas defined the different clinical weight-related conditions by the following percentile ranges, using age- and gender-specific reference values (Table 1).

Table 1: Percentiles and status.

(5-95)	Status
BMI <5	Underweight
5 ≤ BMI < 85	Normal weight
85 ≤ BMI < 95	Overweight
BMI ≥ 95	Obesity (if above 99, severe)

 

The BMI z-score (SDS=Standard Deviation Score) represents the degree of deviation of an individual’s current BMI value from the mean value of the reference population for a given age and sex.⁷ In addition, BMI changes with age, ethnicity, and lifestyle. To determine age- and sex-specific thresholds for normal weight, overweight, and obesity in childhood, the International Obesity Task Force has gathered BMI data from individuals of both genders, aged 2 to 18 years, from different populations. These values intersect the BMI values of 25 and 30 kg/m2 which, in adults, identify the cut-offs for overweight and Obesity. This aspect is important because, at a developmental age, the cardiometabolic complications of Obesity are generally not clinically evident, so knowing that the subject’s BMI is at or above the line intersecting the BMI value of 25 or 30 kg/m2 indicates that, although the subject is at a developmental age, he or she is on the BMI line that may lead to cardiometabolic complications as an adult.

Other methods^1,3 to assess Obesity aim at measuring body composition: fat mass and its distribution between subcutaneous and visceral fat: fat mass is an indicator for nutritional assessment, since adipose tissue represents the largest energy reserve; lean mass: indicates the amount of water and protein; bone mass: indicates the amount of calcium and mineral deposits.

Methods that can be used to assess Obesity status include: Plicometry: measures the thickness of skin folds. It is a simple but not very accurate method and has its value in patient follow-up, including pediatric patients. Bioimpedance analysis: indirect method of measuring fat mass, taking advantage of the fact that it is a worse conductor than lean mass (which is rich in electrolytes). DEXA (Dual Photon X ray Absorptiometry): evaluates lean, fat and skeletal mass, but is little used in clinical practice. It takes advantage of the different absorption of X-rays. In children, the scan takes about 10 minutes. CT or MRI: allow abdominal quantification of adipose tissue, but cannot be used clinically. Waist circumference: is a measurement, taken with a flexible tape placed circumferentially on a horizontal plane passing through the iliac crest, which gives information about fat distribution, i.e. about android, visceral, central Obesity,⁸ which is in fact related to cardiovascular risk, risk of Diabetes, dyslipidaemia and non-alcoholic steatosis. Percentile curves have been developed for this circumference. The ratio of waist circumference to height is a further estimate of central adiposity. Analyses of data from the NHANES III (National Health and Nutrition Examination Survey) indicate this ratio as one of the best predictors of increased LDL-cholesterol, total cholesterol and triglycerides.⁹ If greater than 0.5, it is indicative of Obesity with elevated cardio-metabolic risk.

Aetiology

Regarding the role of the environment, it is of particular importance that Obesity is a real social disease. Camallero defined ‘Global Epidemic of Obesity’ as a condition influenced by environmental, social, and economic factors that have shaped eating habits and lifestyles, primarily since the 2000s.¹⁰

The term ‘obesogenic environment’ encompasses the various factors contributing to obesity such as urbanization, automation, reliance on cars, sedentary lifestyle due to limited public spaces for physical activity, and unhealthy diets.²

A correlation between time spent watching television and Obesity has been demonstrated.² Such a lifestyle leads to less physical activity, resulting in lower energy expenditure, effects on diet and sleep.  Sleep deprivation/fragmentation has also been associated with Obesity (in 13-year-olds, sleep duration is inversely proportional to BMI z-score;¹¹ in another cohort study, evaluating patients for 15 years, sleep deprivation was found to be associated with the risk of being overweight),¹² alterations in glucose homeostasis and increased insulin resistance;¹³ an unbalanced diet, with high glycemic index foods, sugary drinks, precooked foods, fast food; certain drugs such as psychoactives, antiepileptics and glucocorticoids; microbiome: some studies have also shown this role in humans, not only in animals. A study found a link between antibiotic use in the first six months of life and higher BMI between 10 and 38 months.¹⁴ Another study revealed that prenatal exposure to DDT was associated with obesity in males at 9 years old, but not in females.¹⁵

Meta-analyses in the scientific literature conclude that interventions aimed at Obesity prevention are effective. For example, among them, a Cochrane review16 of 37 studies with 27,946 children found a standardized mean difference in adiposity (measured as BMI or zBMI) of -0.15 kg/m2 in BMI . In addition, the importance of incentivized dietary programs in schools as a cornerstone of prevention and treatment emerges. Hereditary factors play a significant role in the variations seen in adipose tissue, according to several studies. These genetic factors are estimated to be responsible for anywhere between 40 to 85% of the variation observed.²

Obesity is therefore a heritable trait,¹⁷ but the genes that contribute to it present a challenge in their identification. A combined meta-analysis of the GWAS and the Metabochip in almost 340,000 patients showed 97 loci associated with BMI18. It is on this genetic substrate that external factors and the obesogenic environment act. Among the genes, the one most associated with Obesity is the Fat mass and obesity associated protein( FTO) gene that maps onto chromosome 16, a common variant in this gene predisposes to type 2 Diabetes mellitus (DM2) and Obesity in childhood and adulthood.¹⁹ The connection to this association may not be immediately clear, but it seems to be linked to issues involving how adipocytes use and store energy resources, as well as problems with mitochondrial thermogenesis.²⁰ In addition, certain syndromes and defects in individual genes are linked to Obesity. Among the syndromes, Prader-Willi syndrome (chromosome 15, q11-13) is among the most common. It is a hypermethylation syndrome, thus representing an example of epigenetic modification. It is characterized by Hypotonia, eating disorders such as dysphagia and Obesity, and fertility disorders (hypogonadotropic hypogonadism). Bardet-Biedl syndrome is an example of another autosomal recessive syndrome. This syndrome can be attributed to mutations in 15 distinct genes, namely BBS1 to BBS14, as well as SDCCAG8. These genes play a crucial role in the development and functioning of the primary hairpin.²¹ Affected individuals are characterized not only by Obesity, but also by Microorchidism in males, Mental retardation, Renal dystrophies, Polydactyly, Renal malformations especially at the level of the calyces, polyuria and polydipsia.

Monogenic forms of Obesity are rare and are represented by: Melanocortin receptor 4 mutation: evidence from patients with a homozygous mutation suggests that the receptor may mediate the anorectic effects of leptin, whereas patients with heterozygosity may present with severe Obesity. Pro-opiomelanocortin mutation (POMC): MSH, via its receptor 4, mediates the effects of leptin. Patients with such mutations show hyperphagia and Obesity. Leptin gene mutation: obese (ob) mice lacking this gene exhibit hyperphagia, insulin resistance, hyperinsulinaemia, infertility, all of which are reversible with leptin administration. Leptin receptor mutation. Pro-hormone convertase type 1 (PCSK1) deficiency, associated with severe hormonal disorders and early onset of Obesity. Other genes include BDNF (Brain-Derived Neurotrophic Factor) and TrkB (Tropomyosin Receptor Kinase B), whose mutations are associated with hyperphagia, Obesity, impaired short-term memory, hyperactivity and learning difficulties.

Endocrine disorders² can also cause Obesity: excess cortisol (Cushing’s syndrome), hypothyroidism, growth hormone deficiency and pseudo-hypoparathyroidism type 1A (hereditary Albright’s osteodystrophy). Certain hypothalamic lesions² may also be associated with Obesity. In paediatric age, such lesions may occur following surgery, or they may be traumatic, neoplastic or inflammatory in nature. ^22-25 There is a rare cause that includes a rapid onset of Obesity, hypothalamic dysfunction and autonomic dysregulation (ROHHAD: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation), sometimes associated with neuroendocrine tumours (ROHHADNET: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, Autonomic Dysregulation and Neuroendocrine Tumour).

In addition, there is an essential role played by ‘metabolic programming’.^2,26 This concept highlights the significant impact of environmental and nutritional factors on an individual’s predisposition to obesity and metabolic diseases. Specifically, these factors act at the epigenetic level during critical moments in development, leading to permanent effects. Epigenetic changes include methylation, histone modifications, chromatin remodeling and micro-RNA arrangements. These mechanisms could explain the link between external factors, such as nutrition/stress/drugs/hypoxia/hormone levels, and phenotypic changes in gene expression.^27-37

The most important evidence concerns the gestation period. Individuals who are born small for gestational age (SGA), large for gestational age (LGA), or prematurely are more likely to develop insulin resistance and obesity during their developmental years.^38-40

Other studies also show an association between birth weight and Diabetes, cardiovascular disease, insulin resistance and Obesity.^41,42 The mother’s own weight, gestational Diabetes⁴³ and pre-eclampsia^44,45 are factors that correlate with the child’s weight and cardiovascular disease. Early childhood is another critical period that has been the subject of several studies highlighting the connection between weight during this time and the potential risk of developing metabolic syndrome in adulthood.⁴⁶ This relationship is not limited to childhood alone.⁴⁷ In particular, some studies have shown that protein intake in the first two years of life is associated with a higher BMI at school age.⁴⁸

Pathophysiology

With economic, social and lifestyle changes, there has been an imbalance between energy inputs and outputs, with energy inputs increasing. This excess energy, stored in the chemical form of triglycerides in adipose tissue, lays the foundation for Obesity and the accompanying dysmetabolism.¹⁷ The energy balance control system is essential for survival and is designed to conserve and make the best use of the energy required for the organism’s life, but it is not regulated to guard against excess, also for evolutionary reasons.⁴⁹ Energy homeostasis concerns every single cell, but certain components of our organism play a primary role, such as adipose tissue. Adipocytes, which together with vessels, extracellular matrix, macrophages and fibroblasts make up adipose tissue, are very heterogeneous. For example, those in visceral fat are more active than those in subcutaneous fat (this explains the greater negative effects of visceral adiposity). However, the increase in body fat can be either due to an increase in the volume of adipocytes incorporating more triglycerides (hypertrophic Obesity) or to an increase in their number, typical of the pediatric age group (hyperplastic Obesity). The two components often coexist.⁴⁹

Among the functions of adipose tissue is the central role it plays in controlling and storing energy in the form of triglycerides. In this task, the key enzyme is the insulin-sensitive lipoprotein lipase, which breaks down triglycerides when energy is needed, so that fatty acids are available for oxidation in various tissues.⁴⁹ In addition to this storage function, adipose tissue also plays a role at the endocrine level (with production of adipokines), at the metabolic level, in the regulation of blood pressure and coagulation (with production of PAI-1 Plasminogen Activator Inhibitor-1, TF Tissue Factor, angiotensinogen, angiotensin II), in inflammation (by the production of pro-inflammatory cytokines PAF Platelet Activating Factor, Interleukin-6, 8, 10, 18, 1Beta). The adipocyte also produces complement factor D or adipsin.⁵⁰

Among the adipokines produced by adipose tissue, leptin plays an important role. It is a peptide hormone capable of crossing the blood-brain barrier and reaching nerve centers (the arcuate nucleus above all), where it has an inhibitory action on hunger. It also acts at a peripheral level by stimulating energy consumption. It is therefore increased in obese subjects to counterbalance excessive calorie intake, but this compensation is not sufficient or, in any case, not efficient: most obese people are resistant to leptin.⁴⁹ On the contrary, adiponectin exhibits plasma levels that are inversely proportional to the mass of adipose tissue. Its action is mainly at hepatic and muscular level, where, in synergy with insulin stimulation, it optimises the utilisation of energy substrates.⁴⁹ More recently, another adipokine, adrenomedullin (ADM), has been characterised.⁵¹ It is a vasoactive peptide expressed and secreted by a range of tissues, including the adrenal medulla, heart, lung, liver, kidney, pancreatic islets, vessel smooth muscle cells and immune cells. ADM levels are elevated in hypertension, renal failure, shock and Diabetes mellitus. Moreover, it is increased in obese individuals, both in plasma and in adipose tissue. Its transcription is stimulated by insulin, hypoxia and inflammatory stimuli. ADM has a short half-life, so in the above-mentioned study, the level of the central region of proADM (MR-proADM) was assessed: in obese adolescents, the levels were higher than in their healthy counterparts. It was hypothesized that this represents an adaptive mechanism by which the peptide, with its antioxidant and vasodilator effect, antagonises the increased blood pressure and inflammatory state typical of Obesity. Other hormones that regulate hunger/satiety are produced at the gastrointestinal level:⁴⁹ Cholecystokinin: released from the gastrointestinal tract during a meal, stimulates gallbladder motility, pancreatic secretion and intestinal motility and contributes to a central sense of satiety. Ghrelin: peptide of 28 amino acids, produced mainly in the stomach, but also in the intestine, placenta and hypothalamus. Gastric production occurs on an empty stomach, so it contributes to increased hunger. It is immediately reduced at the end of a meal. Pancreatic polypeptide: induces satiety. GLP-1 (Glucagon Like Peptide 1): inhibits appetite with a direct central effect, while peripherally it acts by slowing down gastric emptying. Glucocorticoids, which inhibit lipoprotein lipase, also contribute to this regulation, while adrenalin, GH and sex hormones promote lipolysis. Moreover, sex hormones also play a role in the distribution of body fat: in the male, at puberty, there is a decrease in fat mass and an increase in lean mass, while in the female, there is an increase in fat compared to muscle mass⁴⁹. Thyroid hormones also promote lipolysis because they increase energy consumption through the inefficient utilization of energy substrates.⁴⁹ Cortisol and insulin, on the other hand, promote liposynthesis.⁴⁹

Body weight and fat accumulation are also regulated by the nervous system.⁴⁹ As far as the autonomic nervous system is concerned, the sympathetic system has a lipolytic function and promotes thermogenesis by acting on beta3 receptors in the adipocytes of the brown adipose tissue, while the parasympathetic promotes satiety by slowing down gastro-intestinal emptying. It is the central nervous system, however, that receives various signals from the periphery about nutrient deficit/excess and, based on their integration, modifies the metabolic and cognitive structures. The main center is the hypothalamus, in particular the arcuate nucleus. On this act: Neurotransmitters of the autonomic nervous system; Hormones and metabolites (glucose and fatty acids).

The arcuate nucleus^17,52 is capable of integrating and responding by modifying the energy balance. In fact, it integrates leptin signals by modifying the production and release of peptides, such as neuropeptide Y (NPY), which stimulates appetite, and such as proopiomelanocortin (POMC), which decreases it.

POMC-containing neurons are stimulated by leptin and are connected to the paraventricular nucleus, which is responsible for the cleavage of POMC into the active peptide α-MSH, which binds to melanocortin receptor 4 (MC4R) leading to satiety, increased metabolic rate, and decreased basal insulin levels. NPY-containing neurons, on the other hand, are inhibited by leptin, so a reduction in leptin stimulates the activity of these neurons, causing the feeling of hunger (this contributes, for example, to the feeling of hunger during a period of restrictive dieting in which weight is lost, and body fat is reduced, and thus leptin). Mutations that can involve and alter this leptin signaling system can lead to an obese phenotype, which underlines the importance of this pathway in weight regulation.

Regarding energy expenditure,^49,50 we consider: the thermic effect of exercise (20-30%), so that a sedentary lifestyle is a risk factor for Obesity. The energy cost for metabolism and nutrient storage (10%): a low thermic effect of food is associated with the development of Obesity. A randomized trial set out to determine which level of dietary protein affected body composition, weight gain and energy expenditure. It was seen that a low-protein diet was associated with weight gain in general, but the accumulation of adipose tissue was similar between this type of diet, a high-protein diet and a normal diet.⁵³ Obligatory thermogenesis, i.e. the basal metabolic rate (energy expenditure required for the chemical processes that take place in the body’s cells under basal conditions, i.e. at rest, fasting and at a comfortable temperature). This accounts for 60-70% of energy expenditure and decreases with age. Basal metabolism includes maintaining body temperature, the ionic gradient between cell membranes, gastrointestinal motility, cardiac and respiratory function. If chemical processes are reduced, more energy is dissipated as heat. Thermogenin 1, UCP-1 (uncoupling protein 1), which is located in the mitochondria, reduces the electrochemical gradient and ATP formation, favoring the dissipation of energy in the form of heat. This not only maintains an appropriate body temperature, but also burns excess calories. UCP-1 is found in brown adipose tissue, muscle, viscera and the CNS and thus contributes to basal thermogenesis. Initially, however, it was only identified within brown adipose tissue, which decreases in the individual with advancing age, while it is highest around 13 years (in the pediatric age group, brown adipose tissue, in fact, correlates inversely with Obesity, suggesting its prominent metabolic role).⁵⁴ However, imaging studies (PET-CT) have also identified such adipose tissue in adults, especially in women.⁵⁵ It is essentially located in the supraclavicular and nuchal area. The activation of brown adipose tissue is, therefore, an important component of energy expenditure, also in adults.⁵⁶ There is, however, a non-exercise-related thermogenesis (NEAT: Non-Exercise Activity Thermogenesis), which varies in response to caloric intake (increases with overeating). It has been linked to Obesity and is due to the non-exercise physical activity performed during the day (moving, maintaining posture, and spontaneous muscle contractions). The large variation in fat deposition observed in overfed individuals can be estimated on the basis of the extent of NEAT induction. The molecular basis and regulation, however, are still unclear.⁵⁰ Recent information suggests the role of hypothalamic nuclei and various neuromediators that together form a complex neural network.⁵⁷ It seems that just as physical activity contributes to the prevention of weight gain, an increase in this activity is also a way of controlling it.⁵⁸

However, the energy expenditure of an obese patient is actually similar to that of a normal-weight subject, as weight gain leads to an increase in metabolically active lean mass as well. This expenditure is reduced when weight loss begins, if there is a loss of lean mass, and due to a reduction in sympathetic system activity. There is a tendency to keep this expenditure low at rest, compared to normal-weight subjects, if excess weight starts at a developmental age.^50,59

Clinical manifestations

The term ‘morbid Obesity’² refers to patients with Obesity-related comorbidities. Such comorbidities may also affect pediatric patients, especially those with severe Obesity,⁶⁰ who have a higher risk of early onset of typical adult diseases. They include endocrine-metabolic, psychosocial, respiratory, osteomuscular, neurological, dermatological, gastrointestinal, neoplastic, and cardiovascular disorders:

endocrinological-metabolic:^60-62

Hyper-insulinaemia and insulin resistance are closely correlated with intra-abdominal fat deposits. The molecular link has been well studied, and the various contributing factors include both the fact that insulin itself reduces the expression of its receptor and interference with insulin action by free fatty acids, which are increased in the serum of overweight subjects. Adipokines and hormones produced by adipose tissue also play a role.

Prediabetes, with increased risk of Diabetes mellitus, characterized by:

Impaired fasting blood glucose (between 100 and 125 mg/dL, normal values <100 mg/dL);

Impaired glucose tolerance (blood glucose after OGTT between 140 mg/dL and 199 mg/dL, normal values <140 mg/dL);

Increased glycated haemoglobin (between 5.7% and 6.4%).

DM-2, with increased risk, given the onset at an early age, of complications.

Metabolic syndrome⁴⁸, according to the ATPIII criteria, three of the criteria mentioned below are required, for the International Diabetes Federation (IDF) the first criterion and two of the following, to define this syndrome:

Obesity, assessed as waist circumference with values > 90° percentile,³ according to age- and gender-specific cut-offs (for adults, according to ATPIII, the cut-offs are 88 cm for women, 102 cm for men; whereas according to the IDF, the cut-offs are different according to ethnicity and for Europe, e.g. 80 cm for women, 94 cm for men);

Triglycerides ≥ 150 mg/dL;

HDL < 40 mg/dL;

Increased blood pressure, according to the National High Blood Pressure Education Program Working Group;

Impaired fasting blood glucose (≥ 100 mg/dL).

Actually, for the pediatric group there is no consensus on the definition. However, the IDF specifies that for children between 10 and 16 years of age, the criteria are similar to adults except for waist circumference, as we have specified, while for children over 16, those of adults are fine. For children under 10, on the other hand, one cannot properly speak of metabolic syndrome, but an increase in waist circumference must still be monitored.

Metabolic syndrome is linked to an increased pro-inflammatory and pro-thrombotic state, which increases the risk of cardiovascular disease.

Hyper-androgenism: adolescent girls have an increased risk of PCOS (Poly-Cystic Ovary Syndrome), which includes hirsutism, menstrual irregularities, acanthosis nigricans, acne, seborrhoea.

In males there may be hypogonadism, with reduced circulating levels of testosterone and SHBG (Sex Hormone-Binding Globulin) and a relative increase in oestrogen, with gynaecomastia.

Growth and development: accelerated growth is observed in the obese patient, with a tendency to anticipate pubertal development.

Psychosocial: isolation, discrimination, dysfunctional social and school environments. The issue may also be linked to eating disorders (binge-eating disorder and loss of control in relation to food intake).^60-62

Respiratory: sleep apnoea (severe condition characterized by episodes of respiratory obstruction with awakenings, fragmented sleep and consequent daytime sleepiness, hypoxaemia and hypercapnia) and hypoventilation, with reduced distensibility of the rib cage.^60-62

Musculoskeletal: discomfort of various kinds, such as knee pain, flexible flat feet, valgus knees, increased risk of fractures, but also increased risk of Blount’s disease (characterized by progressive bowing of the legs and torsion of the tibia, caused by growth inhibition of its medial and proximal parts), Slipped Capital Femoral Epiphysis (SCFE) and rheumatoid arthritis (increased pro-inflammatory cytokines, such as IL6, IL1, TNF-alpha).^6,60-64

Neurological: idiopathic intra-cranial hypertension, which can lead to vision disorders.⁶¹

Dermatological: intertrigo, furunculosis, hydrosadenitis suppurativa (characterised by inflammatory nodules and/or deep cysts), acanthosis nigricans, (linked to insulin resistance and manifested by hyperpigmentation and thickening of the skin folds of the neck, elbow, dorsal interphalangeal spaces).^60,61

Gastrointestinal: NAFLD (Non-Alcoholic Fatty Liver Disease), characterized by steatosis up to steato-hepatitis. The cause of this alteration seems to be related to insulin resistance. The presence of NAFLD is associated with elements of the metabolic syndrome, such as dyslipidaemia, hypertension, and Obesity (the prevalence of this disease in paediatric age has increased with the rise in Obesity in this age group, in fact). Most patients are asymptomatic, others have pain in the upper quadrants of the abdomen, fatigue, asthenia and malaise. In addition to liver disease, Obesity is the main cause of cholelithiasis in pediatric age, as there is an increased secretion of cholesterol into the bile in the obese subjects with supersaturation. Signs and symptoms are non-specific and include epigastric and right hypochondrium pain, jaundice, nausea and vomiting.^60,61

Neoplastic: Obesity is associated with increased mortality from cancer (of the oesophagus, colon, rectum, pancreas, liver, prostate; in women, also of the gallbladder, cervix, endometrium, ovary) in adulthood. There is evidence in the literature⁵⁰ of a higher frequency of genomic damage in the lymphocytes of obese adolescents and lower efficiency in the DNA repair system.⁵⁸

Cardiovascular: the subject of this thesis and better described later, it concerns the presence of arterial hypertension, dyslipidaemia, increased levels of AGEs (Advanced Glycation End-Products), changes in cardiac morphology (left ventricular dilatation, cardiac hypertrophy), changes in vessel structure and function, including endothelial dysfunction and microcirculation alterations, early indicators of cardiovascular disease.^60-62

It emerges from this that even in the pediatric population, early recognition of weight gain is important, since Obesity in childhood is predictive of Obesity in adulthood and the risks associated with it. Thus, excess weight, especially if it is part of so-called ‘severe Obesity’, leads to long-term consequences that alter the quality of life throughout childhood, but certainly in adulthood.^2,65-73

This impact justifies the need for urgent and incisive interventions also at the territorial level: the WHO set up the Commission on Ending Childhood Obesity (EChO) to identify the best strategies to tackle the ‘obesogenic environment:^74,75 promote healthy eating (also through marketing strategies); promote physical activity; implement care during pre-conception, pregnancy, prenatal care (in order to reduce the risk of childhood Obesity, preventing too low or too high birth weight, prematurity and other complications); early attention to childhood diet and physical activity, so that children can grow up with healthy habits; implementing programs that promote healthy school environments (e.g. through health education in the school curriculum, eliminating the sale of unhealthy food and drinks, standardizing diets in canteens); management of services, to develop and support the care of the obese child and adolescent.^76-80 All these initiatives are fully in line with the vision offered by the Action Plan on Childhood Obesity 2014-2020, with which the member states, including Italy, wanted to respond to the need to help halt the increase in overweight and Obesity in children and young people (0-18 years) by 2020. The action plan provides a basis on which to work to develop national policies to combat Obesity based on eight priority areas of intervention: support a healthy start in life; promote healthy environments (especially in schools and kindergartens); make the healthy option the easy choice; limit marketing and advertising aimed at children; inform and empower families; encourage physical activity; monitor and evaluate the phenomenon; enhance research.

Patient Assessment and Management

Managing pediatric obesity requires a comprehensive approach that includes preventive strategies, as well as proper management techniques. The important steps include:^7,62,81

1) Conducting an initial assessment, which involves collecting detailed information such as a food diary, physical activity levels (both planned and unplanned), medical history, and family history.

2) Gathering anthropometric data, such as age, height, weight, waist and hip circumference, BMI, and waist circumference to height ratio. These measurements provide important objective data about the child’s physical health.

3) Performing a thorough physical examination to search for signs of potential comorbidities and genetic syndromes. This examination should cover various areas, including the skin (checking for conditions like acanthosis nigricans and hirsutism), abdomen (looking for hepatomegaly), musculoskeletal system (identifying any abnormalities or dysmorphisms), and genito-urinary apparatus (assessing hypogonadism and pubertal status). Additionally, measuring blood pressure is essential, and pediatric hypertension is defined when blood pressure values exceed the 95th percentile for sex, age, and height in three separate assessments.

4) Conducting laboratory tests to evaluate the child’s lipid profile, glycemic profile, liver function, and thyroid function. Further assessments may be necessary based on the child’s history and objective examination, such as measuring sexual and adrenal hormones.

5) Recommending imaging examinations when needed. For instance, an abdominal ultrasound may be performed if there are suspicions of steatosis or vague abdominal pain. Radiography may be useful to examine the skeletal system and identify any associated comorbidities.^82-109

These comprehensive steps provide a detailed and holistic approach to managing pediatric obesity, enabling healthcare professionals to tailor interventions and treatments based on each child’s individual needs. As far as the therapeutic aspects are concerned, educational therapyaimed at the child/adolescent and their family members is fundamental and must be individualized. Modifying behaviors that promote overeating and reducing energy expenditure are crucial. It is essential to guide individuals and their families towards adopting healthy lifestyles.^{60,62,110,111}

For optimal diet, it is not recommended to follow a detailed day-to-day list, but instead, focus on dietary advice that promotes healthy eating habits.^112,113

In fact, the therapeutic objective is the modification of lifestyles that, consequently, will lead to weight control. First, it is important to engage in physical activity, both planned and unplanned, for at least 60 minutes a day.⁶

To maintain a healthy diet, it is crucial to follow these dietary guidelines: regularly consume five well-balanced meals throughout the day, refraining from snacking in between; steer clear of restrictive diets and instead focus on achieving a proper balance of protein, carbohydrates, and fat in your main meals; significantly reduce, or better yet eliminate, the intake of sugary beverages from your diet; make it a habit to include a generous amount of vegetables in every meal; opt for cooking methods like steaming, baking, or grilling instead of frying; and finally, avoid indulging in energy-dense but nutrient-poor foods commonly found in fast-food establishments. By adhering to these guidelines, you can pave the way to a healthier and more fulfilling lifestyle.^6,62

According to the guidelines of the National Heart Lung and Blood Institute, the diet for adults is recommended to be hypocaloric, with a reduction of 500-1000 Kcal/day from the usual diet.In paediatrics, on the other hand, the diet should be normo-caloric (1000 Calories +100 x child’s age), balanced and age-appropriate. To ensure optimal nutrition, it is recommended to consume approximately 1 gram of protein per kilogram of body weight per day. Additionally, carbohydrates should constitute 45-60% of your total calorie intake, with simple sugars accounting for less than 15%. Lipids, on the other hand, should represent 20-35% of total calories, and saturated fats should make up less than 10% of that.⁶

About the timing of intervention, the data in the literature is not unambiguous, but several studies suggest that early treatment is more efficient.^114-116 The choice of treatment approach should be determined by factors such as age, level of excess weight, family history, the presence of other medical conditions, and the support of one’s family.Strategies more typical of adulthood, such as low-calorie diets, drugs and surgery, are reserved for very selected and serious cases. Interventions focused on lifestyle modifications can lead to remarkable improvements in BMI and cardiovascular health in the short to medium term. However, it’s worth noting that these benefits may not always be sustained in the long term.⁶²

Conclusions

Obesity is becoming a global epidemic, and it is crucial to diagnose and prevent it at an early stage. The main risk factors are poor diet and a sedentary lifestyle, but socio-environmental factors may also be associated.  The environmental factors thus include potentially modifiable targets, such as excessive time spent on screens. Over the years, the economic factor has also been added, which over time, becomes an increasingly important risk factor.

 To promote the health and healthy growth of children, collaboration between schools, health professionals and the family is important. By adopting healthy lifestyles, these patients can effectively prevent the development of irreversible vascular complications associated with obesity.

Acknowledgments

The authors thank “Fondazione per l’Oncologia Pediatrica ONLUS” for their dedicated patient care and scientific support.

Conflict of interest

The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Funding support

The authors received no specific funding for this work.

Authors’ contributions

All authors participated in the research design, data analysis, and the writing of the manuscript. All authors approved the final version of the manuscript.

References

1. Kansra AR, Lakkunarajah S, Jay MS. Childhood and Adolescent Obesity: A Review. Front Pediatr. 2021;8:581461.
   CrossRef
2. Park M, Budisavljević S, Alemán-Díaz AY, et al. Child and adolescent health in Europe: Towards meeting the 2030 agenda. J Glob Health. 2023 Jan 20;13:04011. doi: 10.7189/jogh.13.04011..
   CrossRef
3. Alemán-Díaz AY, Backhaus S, Siebers LL, Chukwujama O, Fenski F, Henking CN, Kaminska K, Kuttumuratova A, Weber MW. Child and adolescent health in Europe: monitoring implementation of policies and provision of services. Lancet Child Adolesc Health. 2018;2(12):891-904.
   CrossRef
4. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000; 320(7244): 1240-3.
   CrossRef
5. Cacciari E, Milani S, Balsamo A, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Investigat. 2006; 29(7): 581-93.
   CrossRef
6. Leopold S, Zachariah JP. Pediatric Obesity, Hypertension, Lipids. Curr Treat Options Pediatr. 2020;6(2):62-77.
   CrossRef
7. Bashir A, Doreswamy S, Narra LR, et al. Childhood Obesity as a Predictor of Coronary Artery Disease in Adults: A Literature Review. Cureus. 2020 ;12(11):e11473.
   CrossRef
8. Nittari G, Scuri S, Petrelli F, Pirillo I, di Luca NM, Grappasonni I. Fighting obesity in children from European World Health Organization member states. Epidemiological data, medical-social aspects, and prevention programs. Clin Ter. 2019;170(3):e223-e230.
9. Kahn HS, Imperatore G, Cheng YJ. A population-based comparison of BMI percentiles and waist-to-height ratio for identifying cardiovascular risk in youth. J Pediatr. 2005; 146(4): 482-8.
   CrossRef
10. Caballero B. The global epidemic of obesity: an overview. Epidemiol Rev. 2007; 29: 1-5.
    CrossRef
11. Araujo J, Severo M, Ramos E. Sleep duration and adiposity during adolescence. Pediatrics. 2012; 130(5): e1146-54.
    CrossRef
12. Bonuck K, Chervin RD, Howe LD. Sleep-disordered breathing, sleep duration, and childhood overweight: a longitudinal cohort study. J Pediatr. 2015; 166(3): 632-9.
    CrossRef
13. Koren D, Levitt Katz LE, Brar PC, Gallagher PR, Berkowitz RI, Brooks LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care. 2011; 34(11): 2442-7.
    CrossRef
14. Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and early-life body mass. Intern J Obesity. 2013; 37(1): 16-23.
    CrossRef
15. Warner M, Wesselink A, Harley KG, Bradman A, Kogut K, Eskenazi B. Prenatal exposure to dichlorodiphenyltrichloroethane and obesity at 9 years of age in the CHAMACOS study cohort. Am J Epidemiol. 2014; 179(11): 1312-22.
    CrossRef
16. Waters E, de Silva-Sanigorski A, Hall BJ, et al. Interventions for preventing obesity in children. Cochrane Database System Rev. 2011; (12): CD001871.
    CrossRef
17. Al-Jawaldeh A, Hammerich A, Doggui R, Engesveen K, Lang K, McColl K. Implementation of WHO Recommended Policies and Interventions on Healthy Diet in the Countries of the Eastern Mediterranean Region: From Policy to Action. Nutrients. 2020;12(12):3700.
    CrossRef
18. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015; 518(7538): 197-206.
    CrossRef
19. Frayling TM, Timpson NJ, Weedon MN, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316(5826): 889-94.
    CrossRef
20. Claussnitzer M, Dankel SN, Kim KH, et al. FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. NEJM. 2015; 373(10): 895-907.
    CrossRef
21. Janssen S, Ramaswami G, Davis EE, et al. Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals. Human Gen. 2011; 129(1): 79-90.
    CrossRef
22. Cefalo MG, Maurizi P, Arlotta A, et al. Hepatic veno-occlusive disease: a chemotherapy-related toxicity in children with malignancies. Paediatr Drugs. 2010;12(5):277-84.
    CrossRef
23.  Lindblad A, Samkange-Zeeb F, de Henauw S, et al. Cardiometabolic risk profile among children with migrant parents and role of parental education: the IDEFICS/I.Family cohort. Int J Obes (Lond). 2023 Sep 1. doi: 10.1038/s41366-023-01359-5.
    CrossRef
24. Muskens JB, Ester WA, Klip H, Zinkstok J, van Dongen-Boomsma M, Staal WG. Novel Insights into Somatic Comorbidities in Children and Adolescents Across Psychiatric Diagnoses: An Explorative Study. Child Psychiatry Hum Dev. 2023 Sep 1. doi: 10.1007/s10578-023-01587-w.
    CrossRef
25. Perrone MG, Ruggiero A, Centonze A, Carrieri A, Ferorelli S, Scilimati A. Diffuse Intrinsic Pontine Glioma (DIPG): Breakthrough and Clinical Perspective. Curr Med Chem. 2021;28(17):3287-3317.
    CrossRef
26. Agosti M, Tandoi F, Morlacchi L, Bossi A. Nutritional and metabolic programming during the first thousand days of life. Med Surg Pediatr. 2017; 39(2): 157.
    CrossRef
27. Ruggiero A, Barone G, Liotti L, Chiaretti A, Lazzareschi I, Riccardi R. Safety and efficacy of fentanyl administered by patient controlled analgesia in children with cancer pain. Support Care Cancer. 2007;15(5):569-73.
    CrossRef
28. Peng L, Hu R, Feng Y, Shi W, Zhao L, Jiang L. The relationship betweefamily diet consumption, family environment, parent anxiety and nutrition status in children during the COVID-19 pandemic: a longitudinal study. Front Public Health. 2023 Aug 10;11:1228626. doi: 10.3389/fpubh.2023.1228626.
    CrossRef
29. Matuszak O, Banach W, Pogorzały B, et al. The long-term effect of maternal obesity on the cardiovascular health of the offspring – systematic review. Curr Probl Cardiol. 2023 Aug 29:102062. doi: 10.1016/j.cpcardiol.2023.102062.
    CrossRef
30. Andargie TE, Roznik K, Redekar NR, et al. Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children (MIS-C). J Clin Invest. 2023 Aug 31:e171729. doi: 10.1172/JCI171729.
    CrossRef
31. Zvenyach T, Dietz WH. Quality Measurement Gaps and Future Directions in the Assessment of Obesity. Curr Obes Rep. 2023 Aug 31. doi:10.1007/s13679-023-00525-0.
    CrossRef
32.  Kazeminasab F, Sharafifard F, Miraghajani M, Behzadnejad N, Rosenkranz SK. The effects of exercise training on insulin resistance in children andadolescents with overweight or obesity: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023 Aug 10;14:1178376. doi:10.3389/fendo.2023.1178376.
    CrossRef
33. Ruggiero A, Maurizi P, Larocca LM, Arlotta A, Riccardi R. Childhood CD4+/CD56+ hematodermic neoplasm: case report and review of the literature. Haematologica. 2006;91(12 Suppl):ECR48.
    CrossRef
34. Mier-Mota J, Ponce-González JG, Perez-Bey A, et al. Longitudinal effects of FTO gene polymorphism on body composition, cardiorespiratory fitness, physical activity, inflammatory markers, and cardiovascular risk in children and adolescents. “The UP & DOWN study”. Scand J Med Sci Sports. 2023 Aug 30. doi:10.1111/sms.14469.
    CrossRef
35. Jiang Q, Risica PM, Tovar A, et al. Mediation of the Association between Social Environmental Characteristics of Family Childcare Home and Weight Status in Children by Diet Quality. Res Sq [Preprint]. 2023 Aug 16:rs.3.rs-3147729. doi: 10.21203/rs.3.rs-3147729/v1.
    CrossRef
36. Hager K, Du M, Li Z, et al. Impact of Produce Prescriptions on Diet, Food Security, and Cardiometabolic Health Outcomes: A Multisite Evaluation of 9 Produce Prescription Programs in the United States. Circ Cardiovasc Qual Outcomes. 2023 Aug 29:e009520. doi: 10.1161/CIRCOUTCOMES.122.009520.
    CrossRef
37. Posteraro B, Bruno S, Boccia S, et al. Candida parapsilosis bloodstream infection in pediatric oncology patients: results of an epidemiologic investigation. Infect Control Hosp Epidemiol. 2004;25(8):641-5.
    CrossRef
38. Chiavaroli V, Giannini C, D’Adamo E, de Giorgis T, Chiarelli F, Mohn A. Insulin resistance and oxidative stress in children born small and large for gestational age. Pediatrics. 2009; 124(2): 695-702.
    CrossRef
39. Renom Espineira A, Fernandes-Rosa FL, Bueno AC, et al. Postnatal growth and cardiometabolic profile in young adults born large for gestational age. Clin Endocrinol. 2011; 75(3): 335-41.
    CrossRef
40. Efstathiou SP, Skeva, II, Zorbala E, Georgiou E, Mountokalakis TD. Metabolic syndrome in adolescence: can it be predicted from natal and parental profile? The Prediction of Metabolic Syndrome in Adolescence (PREMA) study. Circulation. 2012; 125(7): 902-10.
    CrossRef
41. Sridhar SB, Darbinian J, Ehrlich SF, et al. Maternal gestational weight gain and offspring risk for childhood overweight or obesity. Am J Obstet Gynecol. 2014; 211(3): 259 e1-8.
    CrossRef
42. Deierlein AL, Siega-Riz AM, Adair LS, Herring AH. Effects of pre-pregnancy body mass index and gestational weight gain on infant anthropometric outcomes. J Pediatr. 2011; 158(2): 221-6.
    CrossRef
43. Lawlor DA, Lichtenstein P, Langstrom N. Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in a prospective cohort of 280,866 men from 248,293 families. Circulation. 2011; 123(3): 258-65.
    CrossRef
44. Washburn L, Nixon P, Russell G, Snively BM, O’Shea TM. Adiposity in adolescent offspring born prematurely to mothers with preeclampsia. J Pediatr. 2013; 162(5): 912-7 e1.
    CrossRef
45. Davis EF, Lazdam M, Lewandowski AJ, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012; 129(6): e1552-61.
    CrossRef
46. Leunissen RW, Kerkhof GF, Stijnen T, Hokken-Koelega A. Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood. JAMA. 2009; 301(21): 2234-42.
    CrossRef
47. Taveras EM, Rifas-Shiman SL, Sherry B, et al. Crossing growth percentiles in infancy and risk of obesity in childhood. Arch Pediatr Adolesc Med. 2011; 165(11): 993-8.
    CrossRef
48. Weber M, Grote V, Closa-Monasterolo R, et al. Lower protein content in infant formula reduces BMI and obesity risk at school age: follow-up of a randomized trial. Am J Clin Nutr. 2014; 99(5): 1041-51.
    CrossRef
49. Vigneri R, Sava L, Scacca L. Note di fisiopatologia dei disordini del peso e del comportamento alimentare. In: Lenzi A, Lombardi G, Martino E, Vigneri R, eds. Endocrinologia Clinica. Torino: Minerva Medica; 2011: 347-52.
50. Alemán-Díaz AY, Backhaus S, Siebers LL, Chukwujama O, Fenski F, Henking CN, et al. Child and adolescent health in Europe: monitoring implementation of policies and provision of services. Lancet Child Adolesc Health. 2018;2:891-904.
    CrossRef
51. Del Ry S, Cabiati M, Bianchi V, Federico G, et al. Mid-regional-pro- adrenomedullin plasma levels are increased in obese adolescents. Eur J Nutr. 2016; 55(3): 1255-60.
    CrossRef
52. Barness LA, Opitz JM, Gilbert-Barness E. Obesity: genetic, molecular, and environmental aspects. Am J Med Genet. (Part A) 2007; 143A(24): 3016-34.
    CrossRef
53. Bray GA, Smith SR, de Jonge L, et al. Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: a randomized controlled trial. JAMA. 2012; 307(1): 47-55.
    CrossRef
54. Drubach LA, Palmer EL, 3rd, Connolly LP, Baker A, Zurakowski D, Cypess AM. Pediatric brown adipose tissue: detection, epidemiology, and differences from adults. J Pediatr. 2011; 159(6): 939-44.
    CrossRef
55. Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. NEJM. 2009; 360(15): 1509-17.
    CrossRef
56. Ouellet V, Labbe SM, Blondin DP, et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012; 122(2): 545-52.
    CrossRef
57. Villablanca PA, Alegria JR, Mookadam F, Holmes DR, Jr., Wright RS, Levine JA. Nonexercise activity thermogenesis in obesity management. Mayo Clinic Proceedings. 2015; 90(4): 509-19.
    CrossRef
58. von Loeffelholz C. The Role of Non-exercise Activity Thermogenesis in Human Obesity. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA); 2000.
59. Taghizadeh S, Farhangi MA. The effectiveness of pediatric obesity prevention policies: a comprehensive systematic review and dose-response meta-analysis of controlled clinical trials. J Transl Med. 2020;18(1):480.
    CrossRef
60. Kelly AS, Barlow SE, Rao G, et al. Severe obesity in children and adolescents: identification, associated health risks, and treatment approaches: a scientific statement from the American Heart Association. Circulation. 2013; 128(15): 1689-712.
    CrossRef
61. Linardon J, Wade TD, de la Piedad Garcia X, Brennan L. The efficacy of cognitive-behavioral therapy for eating disorders: A systematic review and meta-analysis. J Consult Clin Psychol. 2017;85(11):1080-1094.
    CrossRef
62. Liberali R, Del Castanhel F, Kupek E, Assis MAA. Latent Class Analysis of Lifestyle Risk Factors and Association with Overweight and/or Obesity in Children and Adolescents: Systematic Review. Child Obes. 2021;17(1):2-15.
    CrossRef
63. Thompson SV, Hannon BA, An R, Holscher HD. Effects of isolated soluble fiber supplementation on body weight, glycemia, and insulinemia in adults with overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2017;106(6):1514-1528.
    CrossRef
64. Singer G, Granger DN. Inflammatory responses underlying the microvascular dysfunction associated with obesity and insulin resistance. Microcirculation. 2007; 14(4-5): 375-87.
    CrossRef
65. Triarico S, Agresti P, Rinninella E, et al. Oral Microbiota during Childhood and Its Role in Chemotherapy-Induced Oral Mucositis in Children with Cancer. Pathogens. 2022;11(4):448.
    CrossRef
66.  Araújo D, Morgado C, Correia-Pinto J, Antunes H. Predicting insulin resistance in a paediatric population with obesity. J Pediatr Gastroenterol Nutr. 2023 Aug 23. doi: 10.1097/MPG.0000000000003910.
    CrossRef
67. Song Y, Kong Y, Xie X, Wang Y, Wang N. Association between precocious puberty and obesity risk in children: a systematic review and meta-analysis. Front Pediatr. 2023 Aug 11;11:1226933. doi: 10.3389/fped.2023.1226933.
    CrossRef
68. Tomáš S, Terezie Š, Stella S. Masked Hypertension in Healthy Children and Adolescents: Who Should Be Screened? Curr Hypertens Rep. 2023 Aug 28. doi: 10.1007/s11906-023-01260-6.
    CrossRef
69. Palacios-Marin I, Serra D, Jiménez-Chillarón JC, Herrero L, Todorčević M. Childhood obesity: Implications on adipose tissue dynamics and metabolic health. Obes Rev. 2023 Aug 22:e13627. doi: 10.1111/obr.13627.
    CrossRef
70. Kiyak U, Urganci N, Usta M. Assesment of functional gastrointestinal diseases in obese children. Eur J Pediatr. 2023 Aug 22. doi:10.1007/s00431-023-05165-z.
    CrossRef
71. Romano A, Triarico S, Rinninella E, et al. Clinical Impact of Nutritional Status and Sarcopenia in Pediatric Patients with Bone and Soft Tissue Sarcomas: A Pilot Retrospective Study (SarcoPed). Nutrients. 2022;14(2):383.
    CrossRef
72. Yan W, Wu S, Liu Q, Zheng Q, Gu W, Li X. The link between obesity and insulin resistance among children: Effects of key metabolites. J Diabetes. 2023 Aug 25. doi: 10.1111/1753-0407.13460.
    CrossRef
73. Piester TL, Jagtap N, Kalapala R. Review of paediatric obesity and non- alcoholic fatty liver disease-A focus on emerging non-pharmacologic treatment strategies. Pediatr Obes. 2023 Aug 21:e13067. doi: 10.1111/ijpo.13067.
    CrossRef
74. Azzara A, Pirillo C, Giovannini C, Federico G, Scarpato R. Different repair kinetic of DSBs induced by mitomycin C in peripheral lymphocytes of obese and normal weight adolescents. Mutation Res. 2016; 789: 9-14.
    CrossRef
75. Nishtar S, Gluckman P, Armstrong T. Ending childhood obesity: a time for action. Lancet. 2016; 387(10021): 825-7.
    CrossRef
76. Handjieva-Darlenska T, Łuszczki E, Torbahn G, et al. After 32 Years of Action and Engagement, the European Childhood Obesity Group Keeps Fighting for the Best Prevention and Treatment of Pediatric Obesity. Ann Nutr Metab. 2023 Aug 25;79(4):343-344. doi: 10.1159/000533575.
    CrossRef
77. Ruggiero A, Ariano A, Triarico S, et al. Cisplatin-induced nephrotoxicity in children: what is the best protective strategy? J Oncol Pharm Pract. 2021;27(1):180-186.
    CrossRef
78. Bondyra-Wiśniewska B, Harton A. Effect of the Nutritional Intervention Program on Body Weight and Selected Cardiometabolic Factors in Children and Adolescents with Excess Body Weight and Dyslipidemia: Study Protocol and Baseline Data. Nutrients. 2023 Aug 19;15(16):3646. doi: 10.3390/nu15163646.
    CrossRef
79. Sofia R, Melita V, De Vita A, et al. Cardiac Surveillance for Early Detection of Late Subclinical Cardiac Dysfunction in Childhood Cancer Survivors After Anthracycline Therapy. Front Oncol. 2021;11:624057.
    CrossRef
80. Xing Y, Zhang P, Li X, et al. New predictive models and indices for screening MAFLD in school-aged overweight/obese children. Eur J Pediatr. 2023 Aug 30. doi:10.1007/s00431-023-05175-x.
    CrossRef
81. Valdes DS, So D, Gill PA, Kellow NJ. Effect of Dietary Acetic Acid Supplementation on Plasma Glucose, Lipid Profiles, and Body Mass Index in Human Adults: A Systematic Review and Meta-analysis. J Acad Nutr Diet. 2021;121(5):895-914.
    CrossRef
82. Chiaretti A, Ruggiero A, Barbi E, et al. Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists. Pediatr Blood Cancer. 2011;57(7):1163-1167
    CrossRef
83. Gao XF, Wu BB, Pan YL, et al. Gut microbiome biomarkers in adolescent obesity: a regional study. Health Inf Sci Syst. 2023 Aug 17;11(1):37. doi: 10.1007/s13755-023-00236-9.
    CrossRef
84. Zemel BS, Shepherd JA, Grant SFA, et al. Reference Ranges for Body Composition Indices by Dual Energy X-ray Absorptiometry from the Bone Mineral Density in Childhood Study Cohort. Am J Clin Nutr. 2023 Aug 18:S0002-9165(23)66076-9. doi:10.1016/j.ajcnut.2023.08.006.
    CrossRef
85. Tong X, Liu C, Liang M, Ye X, Deng Z, Zhang X. Screening and validation of differentially expressed genes in adipose tissue of patients with obesity and type 2 diabetes mellitus. Biomol Biomed. 2023 Aug 17. doi: 10.17305/bb.2023.9498.
    CrossRef
86. Gavela-Pérez T, Parra-Rodríguez A, Vales-Villamarín C, et al. Relationship between eating habits, sleep patterns and physical activity and the degree of obesity in children and adolescents. Endocrinol Diabetes Nutr (Engl Ed). 2023 Sep;70 Suppl 3:10-17. doi: 10.1016/j.endien.2023.08.001.
    CrossRef
87. Falsini B, Chiaretti A, Barone G, et al. Topical nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology. Neurorehabil Neural Repair. 2011; 25: 512-520
    CrossRef
88. Yoong SL, Lum M, Wolfenden L, et al. Healthy eating interventions delivered in early childhood education and care settings for improving the diet of children aged six months to six years. Cochrane Database Syst Rev. 2023 Aug 22;8(8):CD013862. doi:10.1002/14651858.CD013862.pub3.
    CrossRef
89. Grey E, Griffin T, Jolly K, et al. Extended brief interventions for weight management and obesity prevention in children: A rapid evidence review. Obes Rev. 2023 Aug 21:e13633. doi: 10.1111/obr.13633.
    CrossRef
90. Ruggiero A, Rizzo D, Trombatore G, Maurizi P, Riccardi R. The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: real or not?. Cancer Chemother Pharmacol. 2016;77(1):19-26.
    CrossRef
91. Mainieri F, La Bella S, Rinaldi M, Chiarelli F. Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach. Eur J Pediatr. 2023 Aug 23. doi:10.1007/s00431-023-05159-x.
    CrossRef
92. Vandevijvere S, De Pauw R, Djojosoeparto S, et al. Upstream Determinants of Overweight and Obesity in Europe. Curr Obes Rep. 2023 Aug 18. doi:10.1007/s13679-023-00524-1.
    CrossRef
93. Ruggiero A, Rizzo D, Mastrangelo S, Battaglia D, Attinà G, Riccardi R. Interactions between antiepileptic and chemotherapeutic drugs in children with brain tumors: is it time to change treatment?. Pediatr Blood Cancer. 2010;54(2):193-198
    CrossRef
94. Aronsson CA, Tamura R, Vehik K, et al. Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort. Pediatr Diabetes. 2023;2023:3945064. doi:10.1155/2023/3945064.
    CrossRef
95. Ahern S, Marshall S, Wallbank G, et al. Communication strategies and effectiveness of early childhood obesity-related prevention programs for linguistically diverse communities: A rapid review. Obes Rev. 2023 Aug 22:e13634. doi: 10.1111/obr.13634.
    CrossRef
96. Falsini B, Ziccardi L, Lazzareschi I, et al. Longitudinal assessment of childhood optic gliomas: relationship between flicker visual evoked potentials and magnetic resonance imaging findings. J Neurooncol. 2008; 88: 87-96.
    CrossRef
97. Romano A, Capozza MA, Mastrangelo S, et al. Assessment and Management of Platinum-Related Ototoxicity in Children Treated for Cancer. Cancers (Basel). 2020;12(5):1266.
    CrossRef
98. Alfraidi A, Alafif N, Alsukait R. The Impact of Mandatory Food-Marketing Regulations on Purchase and Exposure: A Narrative Review. Children (Basel). 2023 Jul 25;10(8):1277. doi: 10.3390/children10081277.
    CrossRef
99. Pulungan AB, Puteri HA, Ratnasari AF, et al. Childhood Obesity as a Global Problem: A Cross-sectional Survey on Global Awareness and National Program Implementation. J Clin Res Pediatr Endocrinol. 2023 Aug 25. doi: 10.4274/jcrpe.galenos.2023.2023-7-5.
    CrossRef
100. Russo P, Lauria F, Sirangelo I, Siani A, Iacomino G. Association between Urinary AGEs and Circulating miRNAs in Children and Adolescents with Overweight and Obesity from the Italian I.Family Cohort: A Pilot Study. J Clin Med. 2023 Aug 18;12(16):5362. doi: 10.3390/jcm12165362.
     CrossRef
101. Fetoni AR, Ruggiero A, Lucidi D, et al. Audiological Monitoring in Children Treated with Platinum Chemotherapy. Audiol Neurootol. 2016;21(4):203-211.
     CrossRef
102. Peng L, Hu R, Feng Y, Shi W, Zhao L, Jiang L. The relationship between family diet consumption, family environment, parent anxiety and nutrition status children during the COVID-19 pandemic: a longitudinal study. Front Public Health. 2023 Aug 10;11:1228626. doi: 10.3389/fpubh.2023.1228626.
103. Kazeminasab F, Sharafifard F, Miraghajani M, Behzadnejad N, Rosenkranz SK. The effects of exercise training on insulin resistance in children and adolescents with overweight or obesity: a systematic review and meta-analysis. Front Endocrinol (Lausanne). 2023 Aug 10;14:1178376. doi:10.3389/fendo.2023.1178376.
     CrossRef
104. Giordano P, Lassandro G, Barone A, et al. Use of Eltrombopag in Children With Chronic Immune Thrombocytopenia (ITP): A Real Life Retrospective Multicenter Experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Front Med (Lausanne). 2020 Feb 28;7:66. doi: 10.3389/fmed.2020.00066.
     CrossRef
105. Trisciuzzi MT, Riccardi R,  Piccardi M, et al. A fast visual evoked potential method for functional assessment and follow-up of childhood optic gliomas. Clin Neurophysiol. 2004; 115: 217-226.
     CrossRef
106. Riccardi A, Mazzarella G, Cefalo G, et al. Pharmacokinetics of Temozolomide given three times a day in pediatric and adult patients. Cancer Chemother Pharmacol. 2003; 52: 459-464
     CrossRef
107. Wilson OWA, Thai M, Williams L, Nutter S, Myre M, Russell-Mayhew S. A scoping review of school-based anthropometric measurement. Obes Rev. 2023 Aug 31:e13610. doi: 10.1111/obr.13610.
     CrossRef
108. Lazzareschi I, Ruggiero A, Riccardi R, Attinà G, Colosimo C, Lasorella A. Hypersensitivity reactions to carboplatin in children. J Neurooncol. 2002; 58:33-37
     CrossRef
109. Ribeiro SM, Basso MB, Massignan C, Leal SC. Playful educational interventions in children and adolescents’ health literacy: a systematic review. Health Promot Int. 2023 Aug 1;38(4):daad089. doi: 10.1093/heapro/daad089.
     CrossRef
110. Flynn AC, Suleiman F, Windsor-Aubrey H, Wolfe I, O’Keeffe M, Poston L, Dalrymple KV. Preventing and treating childhood overweight and obesity in children up to 5 years old: A systematic review by intervention setting. Matern Child Nutr. 2022;18(3):e13354.
     CrossRef
111. Lioret S, Harrar F, Boccia D, et al. The effectiveness of interventions during the first 1,000 days to improve energy balance-related behaviors or prevent overweight/obesity in children from socio-economically disadvantaged families of high-income countries: a systematic review. Obes Rev. 2023 Jan;24(1):e13524. doi: 10.1111/obr.13524.
     CrossRef
112. Denstel KD, Beyl RA, Danos DM, et al. An examination of the relationships between the neighborhood social environment, adiposity, and cardiometabolic disease risk in adolescence: a cross-sectional study. BMC Public Health. 2023 Sep 1;23(1):1692. doi:10.1186/s12889-023-16580-0.
     CrossRef
113. Demirhan I, Oner E, Kurutas EB. Evaluation of the relationship between insulin resistance and 8-iso prostaglandin levels in obesity children. Folia Med (Plovdiv). 2023 Aug 31;65(4):589-596. doi: 10.3897/folmed.65.e81316.
     CrossRef
114. Danielsson P, Svensson V, Kowalski J, Nyberg G, Ekblom O, Marcus C. Importance of age for 3-year continuous behavioral obesity treatment success and dropout rate. Obesity Facts. 2012; 5(1): 34-44.
     CrossRef
115. Danielsson P, Kowalski J, Ekblom O, Marcus C. Response of severely obese children and adolescents to behavioral treatment. Arch Pediatr Adolesc Med. 2012; 166(12): 1103-8.
     CrossRef
116. Davoli AM, Broccoli S, Bonvicini L, et al. Pediatrician-led motivational interviewing to treat overweight children: an RCT. Pediatrics. 2013; 132(5): e1236-46.
     CrossRef

(Visited 218 times, 1 visits today)