Caterina Anania

Nonalcoholic fatty liver disease and carotid atherosclerosis in children

Nonalcoholic fatty liver disease (NAFLD) is closely associated with several metabolic syndrome features, including obesity, dyslipidemia, insulin resistance, and increased cardiovascular risk. The present study was undertaken to assess whether NAFLD in children is associated with increased carotid artery intima-media thickness (IMT), a marker of early-generalized atherosclerosis. We analyzed carotid IMT along with serum triglycerides, total, low-density lipoprotein and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), aminotransferases, leptin, and adiponectin in 29 obese children with NAFLD, 33 obese children without liver involvement, and 30 control children. The diagnosis and severity of NAFLD was based on ultrasound scan, after exclusion of infectious and metabolic disorders. Obese children with NAFLD had significantly increased carotid IMT [mean 0.58 (95% confidence intervals 0.54–0.62 mm)] than obese children without liver involvement [0.49 (0.46–0.52) mm; p = 0.001] and control children [0.40 (0.36–0.43) mm; p < 0.0005]. In a stepwise multiple regression model, after adjusting for age, gender, Tanner stage, and cardiovascular risk factors, the severity of fatty liver was significantly associated with maximum IMT (b = 0.08; p < 0.0005). Our results suggest that NAFLD is strongly associated with carotid atherosclerosis even in childhood.

Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk.

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.

MRI and ultrasound for hepatic fat quantification:relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease

Objective: The aims of this study were to evaluate hepatic steatosis severity in a series of obese children through both magnetic resonance imaging (MRI) and ultrasound, and to correlate imaging findings to clinical and metabolic characteristics of the study population.

Low 25(OH)D3 levels are associated with total adiposity, metabolic syndrome, and hypertension in Caucasian children and adolescents

OBJECTIVES Evidence of the association between vitamin D and cardiovascular risk factors in the young is limited. We therefore assessed the relationships between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and metabolic syndrome (MetS), its components, and early atherosclerotic changes in 452 (304 overweight/obese and 148 healthy, normal weight) Caucasian children. METHODS We determined serum 25(OH)D(3) concentrations in relation to MetS, its components (central obesity, hypertension, low high-density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, glucose impairment, and/or insulin resistance (IR)), and impairment of flow-mediated vasodilatation (FMD) and increased carotid intima-media thickness (cIMT) - two markers of subclinical atherosclerosis. RESULTS Higher 25(OH)D(3) was significantly associated with a reduced presence of MetS. Obesity, central obesity, hypertension, hypertriglyceridemia, low HDL-cholesterol, IR, and MetS were all associated with increased odds of having low 25(OH)D(3) levels, after adjustment for age, sex, and Tanner stage. After additional adjustment for SDS-body mass index, elevated blood pressure (BP) and MetS remained significantly associated with low vitamin D status. The adjusted odds ratio (95% confidence interval) for those in the lowest (<17 ng/ml) compared with the highest tertile (>27 ng/ml) of 25(OH)D(3) for hypertension was 1.72 (1.02-2.92), and for MetS, it was 2.30 (1.20-4.40). A similar pattern of association between 25(OH)D(3), high BP, and MetS was observed when models were adjusted for waist circumference. No correlation was found between 25(OH)D(3) concentrations and either FMD or cIMT. CONCLUSIONS Low 25(OH)D(3) levels in Caucasian children are inversely related to total adiposity, MetS, and hypertension.

Serum uric acid and its association with metabolic syndrome and carotid atherosclerosis in obese children

OBJECTIVE The association between hyperuricemia, metabolic syndrome (MS), and atherosclerotic vascular disease has been reported in adults, but very little is known about this association in children. The aims of our study were to ascertain the correlates of uric acid (UA) in a sample of obese children, and to investigate whether UA is associated with carotid intima-media thickness (IMT) independently from classical risk factors including MS. METHODS We analyzed carotid IMT along with serum triglycerides, total and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), alanine aminotransferase, gamma-glutamyltransferase, creatinine, and UA in 120 obese children and 50 healthy control children. RESULTS UA concentrations were significantly higher in obese children compared with controls; moreover, they correlated with the most established cardiovascular risk factors. In the group of obese children, after adjustment for age, sex, pubertal stage, and creatinine, an independent association between UA levels and the presence of MS syndrome was observed (unstandardized coefficient, 0.044 (95% confidence intervals (CI) 0.015-0.072); P<0.01). Carotid IMT significantly increased in the fourth quartile of UA compared with that in the first, second, and third quartile (0.49 (0.46-0.53), 0.53 (0.49-0.56), and 0.55 (0.52-0.59) vs 0.61 (95% CI, 0.58-0.64); P<0.01). When multivariate analysis was performed after adjusting for age, gender, pubertal stage, creatinine, and MS (considered as a single clinical entity), or the individual components of MS simultaneously included, the association between UA and carotid IMT was significant (P<0.01). CONCLUSIONS In obese children and adolescents, increased UA levels are associated with carotid atherosclerosis.

Acylated and nonacylated ghrelin levels and their associations with insulin resistance in obese and normal weight children with metabolic syndrome

BACKGROUND Ghrelin, a peptide mainly derived from the stomach, plays a pivotal role in the regulation of food intake, energy metabolism, and storage, as well as in insulin sensitivity. Ghrelin circulates in acylated (A-Ghr) and nonacylated (NA-Ghr) forms, and their potential differential associations with insulin resistance (IR) in childhood obesity remain undefined. OBJECTIVE We investigated the associations of ghrelin forms with IR in normal weight and obese children and the impact of metabolic syndrome (MS) on their plasma values. DESIGN A total of 210 children in four subgroups of normal weight/obese children with and without components of MS were studied. Fasting blood glucose, insulin, lipid profile, and acylated and total ghrelin were examined. IR was determined by a homeostasis model assessment (HOMA) of IR. RESULTS In the entire population, plasma insulin and HOMA-IR were associated negatively with T-Ghr and NA-Ghr, but positively with the ratio of A/NA-Ghr after adjustment for age, gender, and Tanner stage. Obese metabolically abnormal children had lower T-Ghr and NA-Ghr, but comparable A-Ghr and a higher A/NA-Ghr ratio than obese metabolically normal subjects. Compared with lean healthy children, lean metabolically abnormal subjects had higher A-Ghr and the A/NA-Ghr ratio, but comparable T-Ghr and NA-Ghr. A multiple regression analysis showed that A-Ghr and the A/NA-Ghr ratios were positively associated with HOMA-IR, independent of age, gender, Tanner stage, and body mass index (or waist circumference) and other components of MS. CONCLUSIONS A-Ghr excess may negatively modulate insulin action in obese and nonobese children, and may contribute to the association of IR and MS.

Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has been consistently found to be associated with features of the metabolic syndrome (MS), a condition carrying a high risk of cardiovascular events. The present study aimed to determine whether, in children and adolescents, NAFLD is atherogenic beyond its association with MS and its components. We assessed both flow‐mediated dilation of the brachial artery (FMD) and carotid intima‐media thickness (cIMT), along with lipid profile, glucose, insulin, insulin resistance, and high‐sensitivity C‐reactive protein (CRPHS), in 250 obese children, 100 with and 150 without NAFLD, and 150 healthy normal‐weight children. NAFLD was diagnosed by ultrasound examination and persistently elevated alanine aminotransferase, after exclusion of infectious and metabolic disorders. Compared to controls and children without liver involvement, those with ultrasound‐diagnosed NAFLD (and elevated alanine aminotransferase) demonstrated significantly impaired FMD and increased cIMT. Patients with NAFLD had more features of MS and elevated CRPHS levels. In addition, percent FMD was remarkably reduced, whereas cIMT was increased in obese children with MS compared to those without MS. Using logistic regression analysis, the presence of NAFLD was found to be an independent predictor of low percent FMD (odds ratio, 2.25 [95% confidence interval, 1.29 to 3.92]; P = 0.004) as well as of increased cIMT (1.98 [1.16 to 3.36]; P = 0.031), after adjustment for age, gender, Tanner stage, and presence of MS. When we analyzed the relations between cIMT and measures of FMD in patients with NAFLD, the disease was associated with increased cIMT in children with impaired FMD status. Conclusion: The presence of liver disease entails more severe functional and anatomic changes in the arterial wall. Its detection may help identify individuals with increased cardiometabolic risk. (HEPATOLOGY 2010.)

Management of metabolic syndrome in children and adolescents.

Concomitantly with the increasing prevalence of childhood obesity, the prevalence of metabolic syndrome (MS) is rising among children and adolescents, leading to fears for future epidemics of type 2 diabetes mellitus and cardiovascular disease in the young. This makes the accurate identification and the appropriate treatment of children and adolescents with MS an important priority for health care systems. This review will focus on the management of each component of MS, including the nonalcoholic fatty liver disease (NAFLD), which is currently considered as the hepatic component of the syndrome. The most relevant target of treatment of MS in children and adolescents is the abdominal obesity. To this end, we will discuss the efficacy of dietary approaches, possibly coupled with regular physical activity, on eliciting visceral fat reduction. We will also highlight several aspects of the treatment of the high triglyceride/low high-density lipoprotein cholesterol phenotype, including the use of non-pharmacological measures, and indications for instituting drug therapies. Part of this review will address treatment of glucose abnormalities, including the benefits of lifestyle modification alone, and the potential adjunctive role of hypoglycemic drugs. The treatment of hypertension in children with MS also requires a multifaceted approach and the available data of this topic will be examined. The remainder of this review will address treatment to reverse NAFLD and prevent progression to end-stage disease.

Long-term effects of Helicobacter pylori eradication on circulating ghrelin and leptin concentrations and body composition in prepubertal children

BACKGROUND Helicobacter pylori, and the chronic gastric inflammation that it causes, may compromise the function and survival of ghrelin-producing cells, resulting in a decrease of circulating ghrelin levels. This finding raises the possibility that the infection might affect growth in children by reducing the ghrelin production. AIMS To determine baseline circulating levels of ghrelin and leptin in prepubertal children with and without H. pylori infection and to evaluate the long-term effects of H. pylori eradication on circulating levels of ghrelin and leptin as well as on body composition. PATIENTS Thirty children with H. pylori-associated gastritis, 35 children with H. pylori-negative gastric mucosa, and 20 healthy controls were studied. RESULTS At baseline, while leptin levels were significantly lower in H. pylori-positive patients, ghrelin concentrations did not differ among the three study groups. However, a significant inverse correlation between ghrelin concentrations and histological severity of gastritis was found. Eradication of the organism was associated with a progressive decrease in ghrelin concentrations over baseline at both 6- and 12-month follow-ups. SDS-body mass index (BMI), lean and fat mass, as well as leptin concentrations, significantly increased over baseline at both follow-ups. CONCLUSIONS In prepubertal children, serum ghrelin concentrations are inversely related to the severity of H. pylori-associated gastritis. In these youngsters, long-term eradication of H. pylori infection is associated with a significant increase in BMI, lean and fat mass along with a significant decrease in circulating ghrelin levels and an increase in leptin levels.

T1-weighted dual-echo MRI for fat quantification in pediatric nonalcoholic fatty liver disease

AIM To determine in obese children with nonalcoholic fatty liver disease (NAFLD) the accuracy of magnetic resonance imaging (MRI) in assessing liver fat concentration. METHODS A case-control study was performed. Cases were 25 obese children with biopsy-proven NAFLD. Controls were 25 obese children matched for age and gender, without NAFLD at ultrasonography and with normal levels of aminotransferases and insulin. Hepatic fat fraction (HFF) by MRI was obtained using a modification of the Dixon method. RESULTS HFF ranged from 2% to 44% [mean, 19.0% (95% CI, 15.1-27.4)] in children with NAFLD, while in the controls this value ranged from 0.08% to 4.69% [2.0% (1.3-2.5), P < 0.0001]. HFF was highly correlated with histological steatosis (r = 0.883, P < 0.0001) in the NAFLD children. According to the histological grade of steatosis, the mean HFF was 8.7% (95% CI, 6.0-11.6) for mild, 21.6% (15.3-27.0) for moderate, and 39.7% (34.4-45.0) for severe fatty liver infiltration. With a cutoff of 4.85%, HFF had a sensitivity of 95.8% for the diagnosis of histological steatosis ≥ 5%. All control children had HFF lower than 4.85%; thus, the specificity was 100%. After 12 mo, children with weight loss displayed a significant decrease in HFF. CONCLUSION MRI is an accurate methodology for liver fat quantification in pediatric NAFLD.