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Metabolic syndrome (MS) and hepatic steatosis (HS) have been described in patients with celiac disease (CD) after starting a gluten-free diet (GFD), but data on predictive factors for these conditions are scarce. Recently, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 has been identified as a key factor for HS development in the general population. The aim of the study was to evaluate the role of PNPLA3 rs738409 in the development of MS and HS in CD patients after starting GFD. Between June 2014 and September 2016, we consecutively enrolled CD patients with HS, while those without steatosis served as a control group. All patients underwent anthropometric and serologic investigations, ultrasonography (US) to assess the degree and severity of HS, and genotyping of the PNPLA3 rs738409 polymorphism. Finally, 370 subjects were enrolled (136 with and 234 without HS). At genotyping assays, the CC genotype was found in 194 subjects (52.4%), the CG genotype in 138 subjects (37.3%), and the GG genotype in 38 subjects (10.2%). At binary logistic regression, only CG and GG alleles were predictive for the development of HS (odds ratio (OR) 1.97; p < 0.01 for CG and OR 6.9; p < 0.001 for GG). Body mass index (BMI) (OR 3.8; p < 0.001) and waist circumference (OR 2.8; p = 0.03) at CD diagnosis were the only independent factors for the development of MS. Intergroup comparisons showed that the severe grade of HS was more frequently observed in GG than in CC carriers (74% vs. 11.3%, p < 0.001, OR 21.8). PNPLA3 CG and GG carriers with CD have a higher susceptibility to hepatic steatosis, but not to metabolic syndrome. Moreover, patients with GG alleles display more severe forms of HS based on ultrasound.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aims: Insulin-like growth factor (IGF)-I is related to cardiometabolic risk in adults, whereas the metabolic role of IGF-II is unclear. The aim of this study was to assess IGFs in obese children and correlate them with metabolic syndrome (MetS) components., Methods: This is a retrospective study including 574 obese children (11.34 ± 3.16 years). All subjects underwent complete anthropometry and biochemical assessment. In a subgroup of 136 subjects, body composition was evaluated. IGF-I was measured in 300 obese subjects and IGF-II in 77 obese and 15 lean children. 177 subjects were divided according to the presence of 1 or more MetS criteria: group 1, subjects with 1 MetS criterion; group 2, subjects with 2 components; and group 3, subjects with MetS diagnosis., Results: IGF-I, IGF-II, and IGF-I/insulin-like growth factor-binding protein-3 ratio were not different among subjects with an increasing number of MetS criteria and were not associated with single components of MetS as well as with body composition parameters. In children younger than 10 years, IGF-I directly correlated with high-density lipoprotein cholesterol (p < 0.005) even after controlling for confounders. IGF-II was significantly higher in obese children and correlated with parameters of insulin sensitivity (p < 0.05)., Conclusion: IGFs were neither related to MetS nor to body composition parameters in obese children. Further studies are needed to clarify the mechanisms underlying the relationship between IGF-II and insulin sensitivity., (© 2017 S. Karger AG, Basel.)

Nonalcoholic fatty liver disease (NAFLD) is one of the main chronic noncommunicable diseases in Westernized societies; its worldwide prevalence has doubled during the last 20 years. NAFLD has serious health implications not only for adults, but also for children. However, pediatric NAFLD is not only an important global problem in itself, but it is likely to be associated with increases in comorbidities, such as metabolic syndrome and cardiovascular diseases. There are several differences between NAFLD in children and adults, and it is not clear whether the disease observed in children is the initial phase of a process that progresses with age. The increasing prevalence of pediatric NAFLD has serious implications for the future adult population requiring appropriate action. Studies of NAFLD progression, pathogenesis, and management should evaluate disease phenotypes in children and follow these over the patient's lifetime. We review the similarities and differences of NAFLD between children and adults., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Pediatric nonalcoholic fatty liver disease (NAFLD) histology demonstrates variable amounts of portal inflammation, which may be associated with more severe liver disease and fibrosis. We assessed the relationship between portal inflammation, hepatic fibrosis, and the metabolic syndrome in pediatric NAFLD. Children with biopsy-proven NAFLD were eligible for inclusion. Histology was assessed using Kleiner fibrosis stage and the Nonalcoholic Steatohepatitis Clinical Research Network system for portal inflammation. Patients were divided by histology into type 1, type 2, and overlap NAFLD. Multivariable ordinal logistic regression was used to determine factors associated with fibrosis and portal inflammation. The 430 Caucasian children were divided into 52 with type 1, 95 with type 2, and 283 with overlap NAFLD. Those with type 2 had a more severe metabolic phenotype, with higher body mass index z score (2.0 versus 1.6, P < 0.0001), waist circumference centile (96th versus 90th, P < 0.0001), and triglycerides (84 versus 77 mg/dL, P = 0.01) and lower high-density lipoprotein (46 versus 60 mg/dL, P = 0.004) than those with type 1. Similarly, those with overlap NAFLD had a more severe phenotype. Stage 2-3 fibrosis was present in 69/283 (24%) with overlap NAFLD. Portal inflammation was associated with stage 2-3 fibrosis on multivariable analysis (95% confidence interval 1.4-5.2, odds ratio = 3.7). Waist circumference centile was associated with portal inflammation (95% confidence interval 1.2-3.4, odds ratio = 2.0)., Conclusion: Portal inflammation is associated with more advanced pediatric NAFLD and features of the metabolic syndrome., (© 2015 by the American Association for the Study of Liver Diseases.)

During the last decade, paediatricians have observed a dramatic increase of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children. Furthermore, several lines of evidence have reported that a large part of children with NAFLD presents one or more traits of MS making plausible that, in the coming years, these subjects may present a rapid course of disease towards more severe cirrhosis and cardiovascular disease. Genetic susceptibility and the pressure of intrauterine environment and lifestyle are all crucial to activate molecular machinery that leads to development of NAFLD and MS in childhood. In this scenario, central obesity and consequent adipose tissue inflammation are critical to promote both MS-associated metabolic dysfunctions and NAFLD-related hepatic damage. An excessive dietary intake may in fact cause a specific lipid partitioning and induce metabolic stressors, which in turn promote insulin resistance and the release of several circulating factors. These molecules, on the one hand, trigger steatosis and the inflammatory response that characterize liver damage in NAFLD, and on the other hand contribute to the onset of other features of MS. This review provides an overview of current genetic, pathogenetic and clinical evidence of the vicious circle created by NAFLD and MS in children., (2014 S. Karger AG, Basel)

Liver transplantation (LT) is a standard treatment for children with end-stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so-called post-transplant metabolic syndrome (PTMS). During the post-transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non-alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long-term health outcomes and acceptable graft survival can be achieved., (© 2013 John Wiley & Sons A/S.)

Background: The prevalence of obesity and its metabolic consequences has dramatically increased in the last two decades urging physicians to find a reliable definition for early detection, treatment and possibly prevention of metabolic syndrome (MS). MS could be diagnosed in adult patients in the presence of a large waist circumference and ≥2 of the following features: high serum triglycerides, low serum high-density lipoprotein cholesterol, high blood pressure and high fasting glucose. The definition of MS in children is more problematic, and the potential role of its single components on metabolic risk remains largely undefined. Recent evidence strongly suggests not only a relationship between non-alcoholic fatty liver disease (NAFLD) and MS in obese children, adolescents and adults, but also the key role exerted by liver fat deposition in the pathogenesis of MS., Conclusion: We propose that NAFLD should be routinely checked in obese subjects because early lifestyle changes may be effective in reducing the overall risk of MS., (© 2012 The Authors. Pediatric Obesity © 2012 International Association for the Study of Obesity.)

Atherosclerosis is a complex inflammatory disease comprising multiple plaque phenotypes. The development of advanced atheromatous plaques with necrotic core represents the result of the invasion of lipid pools by macrophages. The release of activated proteolytic enzymes degrades the surrounding tissue and contributes to the formation of vulnerable plaque. Thinning of the fibrous cap and necrotic core expansion are considered to be critical for the progression toward plaque rupture and acute thrombosis. The pathogenic mechanisms leading the progression of atherosclerotic lesions are various and involve endothelial cells, inflammatory cells, and platelets. Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis (NASH) and may progress to cirrhosis and hepatocellular carcinoma. The prevalence of this pathology is quite high in the general population and is one of the most important causes of liver-related morbidity and mortality in children. NAFLD is considered the hepatic feature of the metabolic syndrome and this has stimulated interest in its possible role in the atherosclerosis development. Clinical observations indicated that NAFLD might be an independent risk factor for coronary artery disease. Moreover, NASH may increase atherosclerotic and cardiovascular risks by local overexpression of inflammatory mediators, endothelial damage, and regulators of blood pressure. NASH development is correlated with hepatic progenitor cell activation and the release of proatherogenic adipokines. These aspects suggest the necessity for an early therapeutic intervention in NASH patients, not only for ameliorating the liver injury, but also for improving the systemic proatherogenic state.

In the last three decades the incidence of metabolic syndrome (MetS) has been growing worldwide along with an increase of obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). In children and adolescents such epidemics are particularly worrisome, since the metabolic consequences in adulthood will significantly burden the health care system. Although the definition of MetS in childhood is still controversial, there is agreement with respect to NAFLD being the hepatic manifestation of MetS. However, the molecular pathogenesis of MetS and its contribution to NAFLD is complex and closely related to the pre- and postnatal environment as well as to genetic predisposing factors. The analysis of the possible relationships between NAFLD and MetS is particularly interesting, not only from an epidemiological point of view, but also to better understand the genetic and environmental factors contributing to the development of both diseases. We here summarize the most recent epidemiological data on the incidence of both diseases in adolescents, and several aspects linking MetS with NAFLD, discussing the possible role played by genetics and intrauterine environment.

A growing number of studies focusing on the developmental origin of health and disease hypothesis have identified links among early nutrition, epigenetic processes and diseases also in later life. Different epigenetic mechanisms are elicited by dietary factors in early critical developmental ages that are able to affect the susceptibility to several diseases in adulthood. The studies here reviewed suggest that maternal and neonatal diet may have long-lasting effects in the development of non-communicable chronic adulthood diseases, in particular the components of the so-called metabolic syndrome, such as insulin resistance, type 2 diabetes, obesity, dyslipidaemia, hypertension, and CVD. Both maternal under- and over-nutrition may regulate the expression of genes involved in lipid and carbohydrate metabolism. Early postnatal nutrition may also represent a vital determinant of adult health by making an impact on the development and function of gut microbiota. An inadequate gut microbiota composition and function in early life seems to account for the deviant programming of later immunity and overall health status. In this regard probiotics, which have the potential to restore the intestinal microbiota balance, may be effective in preventing the development of chronic immune-mediated diseases. More recently, the epigenetic mechanisms elicited by probiotics through the production of SCFA are hypothesised to be the key to understand how they mediate their numerous health-promoting effects from the gut to the peripheral tissues.

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

Objective: We conducted a systematic review in order to: i. summarize the relationship between low birth weight, catch-up-growth and the metabolic syndrome, from publications during the past 10 years; and ii. study the potential role of an alternative nutritional approach to side effects of catch-up-growth., Methods: We reviewed all papers published in the past ten years assessing the possible association between low birth weight, catch-up-growth and the occurrence of some components of the metabolic syndrome, including insulin resistance, type 2 diabetes, dyslipidemia and non-alcoholic fatty liver disease., Results: We found 57 studies which described the relationship between metabolic syndrome associated features and low birth weight and catch-up-growth. The majority of the studies in children, adolescents and adults born small for gestational age (SGA) suggested that insulin resistance could represent the prelude to other metabolic disorders., Conclusions: Both low birth weight and catch-up-growth seem to correlate with some aspects of a later metabolic syndrome.

Background 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. Objective The aim of the study is to evaluate the efficacy of Obalon Intragastric Balloon on weight loss and on metabolic and cardiovascular parameters in a pediatric population with severe obesity. Methods We enrolled 10 children with severe obesity. In all patients anthropometric parameters, biochemical tests, ultrasound liver examination and blood pressure monitoring were evaluated at the time of insertion and after removal of device. Results The Obalon had a positive effect on decrease of weight, body mass index and percentage of excess body weight within 3 months from placement. Moreover, this safe minimally invasive device improves the cardio-metabolic profiles of obese children. Conclusions The Obalon could be a useful tool in the difficult management of pediatric patients with morbid obesity, inducing in short-term a meaningful weight loss. [ABSTRACT FROM AUTHOR]

Objective:Our aim was to estimate prevalence of metabolic syndrome (MS), obesity and comorbidities in a cohort of 120 children (3–18 years) with biopsy-proven non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) and to evaluate correlations between clinical or biochemical variables and liver histology.Research methods and procedures:MS was diagnosed according to the adapted National Cholesterol Education Program criteria. Homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI); and ISI composite, insulin secretion (insulin response at 30 min after a glucose load; HOMA-β cell; insulinogenic index) were all estimated. BMI z-score and total body fat (dual-energy X-ray absorptiometry) were evaluated as indexes of obesity.Results:MS was diagnosed in 66% of children. About 92% had weight above the 85th percentile, of which 42% were obese with weight above 97th percentile. Prevalence of hypertriglyceridaemia was 63%, low HDL cholesterol 45%, hypertension 40% and impaired glucose tolerance 10%. Levels of aminotransferases were higher as the number of comorbidities increased, the highest values being found in subjects with MS (P0.05). Prevalence of a grade of steatosis 2 (P=0.05) and fibrosis (P0.01) was higher in subjects with MS. Histology was associated significantly with higher values of a number of clinical and biochemical parameters (steatosis 2 with BMI z-score (P=0.04), fasting insulin (P=0.02), HOMA-IR (P=0.03), β-cell secretion (P=0.04); necroinflammation with BMI z-score (P=0.007), glucose (P0.0001), cholesterol (P0.04) and white blood cells (P=0.025); fibrosis with body weight (P=0.05), BMI z-score (P=0.03), cholesterol (P=0.05), triglycerides (P=0.05), fasting insulin (P0.0001) and mean values of the hormone at the OGTT (P=0.03), HOMA-IR (P0.0001)).Conclusion:Presence of MS or clinical and biochemical variables associated with the syndrome seems to be strictly related to histological features of NASH in paediatric fatty liver disease. Thus, routinely liver biopsy should be encouraged in these children.International Journal of Obesity (2008) 32, 381–387; doi:10.1038/sj.ijo.0803711; published online 18 December 2007 [ABSTRACT FROM AUTHOR]

Objective: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease characterised by accumulation of large-droplet fat in hepatocytes with possible progression to inflammation and fibrosis. Breastfeeding has benefits for child health, both during infancy and later in life, reducing the risk of manifestations of the metabolic syndrome. Here we investigated the association between early type of feeding (breastfed versus formula-fed and duration of breastfeeding) and later NAFLD development. Study design: We investigated 191 young Caucasian children (3-18 years old) with NAFLD consecutively enrolled between January 2003 and September 2007 in our centre. 48% of these children (n = 91) had been breastfed for a median (interquartile range) time of 8 (7) months. Results: After correction for age, waist circumference, gestational age and neonatal weight, the odds of non-alcoholic steatohepatitis (NASH) (OR 0.04, 95% CI 0.01 to 0.10) and fibrosis (OR 0.32, 95% CI 0.16 to 0.65) were lower in breastfed versus not breastfed infants. Moreover, the odds of NASH (OR 0.70, exact 95% CI 0.001 to 0.87) and fibrosis (OR 0.86, exact 95% CI 0.75 to 0.98) decreased for every month of breastfeeding. Conclusions: This observational study suggests that earlier feeding habits might affect the clinical expression of NASH from 3 to 18 years later, with an apparent drug-like preventive effect of breastfeeding. [ABSTRACT FROM AUTHOR]