Circulating levels of miR-122 and nonalcoholic fatty liver disease in pre-pubertal obese children.

OBJECTIVES: The liver-specific miR-122 was proposed as biomarker for NAFLD in adults. Here, we investigated the relationship between miR-122 levels, parameters of liver metabolism and NAFLD in pre-pubertal obese children. METHODS: Parameters of liver metabolism (ALT, AST and GGT) of three European cohorts were included (German cohort [n = 71; age: 11.53 ± 1.29 years; BMI z-score: 2.96 ± 0.64], Italian cohort [n = 45; age: 9.60 ± 2.11 years; BMI z-score: 3.57 ± 1.16], Slovenian cohort [n = 31; age: 7.53 ± 1.47 years; BMI z-score: 3.66 ± 0.88]). MiR-122 levels and CK18 concentrations were measured in fasting blood samples. In the German and Italian cohort, the diagnosis of NAFLD and grading of NAFLD was assessed by ultrasound. RESULTS: NAFLD was diagnosed in n = 50 patients of the German cohort (29.6%) and in n = 29 patients (72.5%) of the Italian cohort. In all three cohorts, miR-122 was positively correlated with ALT and AST as well as with CK18 concentrations. MiR-122 levels were higher in children with NAFLD compared with healthy controls. CONCLUSIONS: MiR-122 levels in pre-pubertal obese children could be a potential biomarker for paediatric NAFLD.

Thyroid dysfunction and hepatic steatosis in overweight children and adolescents.

BACKGROUND: Overt or subclinical hypothyroidism is a common finding in adult populations affected by non-alcoholic fatty liver disease (NAFLD). Currently, there are only sparse data available on the association of thyroid dysfunction and NAFLD in obese children and adolescents. OBJECTIVE: The study aims to investigate the association of thyroid function test values with NAFLD and metabolic risk factors in a population of obese children and adolescents. METHODS: A total of 332 overweight and obese children and adolescents (170 girls) aged between 10 and 19 years were analysed. Subjects underwent ultrasound examination of the liver. Thyroid function was evaluated by laboratory determination of thyroid-stimulating hormone (TSH), total triiodothyronine (T3) and total thyroxine levels. All included subjects were either euthyroid or had subclinical hypothyroidism (TSH > 4 µU mL-1 , normal thyroxine). Further metabolic profiling included the determination of lipid status, insulin and liver function tests. Anthropometric parameters body mass index, waist and hip circumference were documented. RESULTS: The prevalence of hepatic steatosis was 29.8%. Subjects with NAFLD had significantly higher TSH levels than those without (p = 0.0007). After dividing TSH values into quartiles, both univariate and multivariate analyses (adjusted for age, body mass index-standard deviation scores and stage of puberty) showed a significant association with hepatic steatosis (p < 0.05). CONCLUSION: Taking possible variables into consideration, our results show that there is a significant association between hepatic steatosis and the TSH levels in obese children and adolescents. Mild thyroid dysfunction may therefore have a role in determining an unfavourable metabolic profile in obese children and adolescents.

Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort.

OBJECTIVE: We aimed to determine the prevalence of melanocortin-4 receptor (MC4R) variants in a large German cohort of children with obesity in a pediatric outpatient clinic and to ascertain whether there is a specific phenotype associated with loss-of-function variants as previously reported. STUDY DESIGN: Eight hundred and ninety-nine patients from our pediatric obesity clinic were screened for MC4R variants by DNA sequencing after PCR amplification. Retrospective statistical analysis of anthropometric and metabolic characteristics was performed, comparing patients with and without MC4R variants across the entire cohort (n=586) as well as in case-control analysis using patients with common sequence MC4R individually matched for age, sex and body mass index standard deviation score (SDS) (n=11 case-control pairs). RESULTS: We identified heterozygous variants within the coding region of the MC4R gene in n=22 (2.45%) patients. Fourteen (1.56%) had a variant that impaired receptor function. One new frameshift (p.F152Sfs), an yet unpublished nonsense mutation (p.Q156X) and one nonsynonymous variation (p.V65E) described in the Mouse Genome Database were detected. Across the whole cohort, at all ages, mean height SDS in subjects with impaired receptor function was higher than in patients with common sequence MC4R. In matched individuals, this trend persisted (8 of the 11 pairs) within the case-control setting. No differences were found regarding metabolic characteristics. CONCLUSIONS: The observed prevalence of mutations causing impaired receptor function in this large cohort is comparable to other pediatric cohorts. MC4R deficiency tends to lead to a taller stature, confirming previous clinical reports. The association of MC4R mutations with a distinct phenotype concerning metabolic characteristics remains questionable.

Sonographically measured suprailiac adipose tissue is a useful predictor of non-alcoholic fatty liver disease in obese children and adolescents.

OBJECTIVE: The objective of the present study was to identify ultrasonographic and anthropometric parameters that are highly associated with the presence of non-alcoholic fatty liver disease (NAFLD) in overweight children and adolescents. METHODS: A total of 447 overweight children and adolescents (body mass index, 32.4 ± 5.2 kg m(-2) ; mean age, 14.2 ± 1.9 years; range 10.1-20.3 years) were analysed. Subjects underwent ultrasound examination of the liver as well as ultrasonographic measurement of the amount of adipose tissue overlying the biceps brachii and triceps brachii muscles, and of subscapular, suprailiac and abdominal subcutaneous adipose tissue and intra-abdominal depth. Anthropometric parameters such as body mass index, waist and hip circumference were documented. RESULTS: The prevalence of NAFLD was 27.1%; it was significantly associated with the above-cited anthropometric parameters (P < 0.001). Ultrasonographic findings identified a significant association between NAFLD and the amount of subscapular, suprailiac and abdominal subcutaneous adipose tissue (P < 0.001) as well as between NAFLD and intra-abdominal depth (P < 0.001). Stepwise logistic regression analysis showed only intra-abdominal depth for both gender and the deposit of subcutaneous suprailiac adipose tissue in females to be independent predictors of NAFLD. CONCLUSIONS: In overweight children and adolescents, we identified intra-abdominal depth for both gender and the ultrasonographically easily determined subcutaneous suprailiac adipose tissue in females as independent predictor of NAFLD.

[Non-alcoholic fatty liver disease in obese children and adolescents]. / Nichtalkoholische Fettlebererkrankung bei adipösen Kindern und Jugendlichen.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adolescents in industrialized countries. Recent studies have demonstrated a prevalence rate of NAFLD in overweight and obese children and adolescents in Germany of up to 30%. The spectrum of NAFLD ranges from pure fatty infiltration (simple steatosis) to inflammation (steatohepatitis, synonymous NASH) to fibrosis and cirrhosis. Age, gender, ethnicity, insulin resistance, and sex steroids are implicated in the pathogenesis of NAFLD in childhood and adolescence. Moreover, NAFLD in the pediatric age group is associated with marked cardiovascular comorbidities. This review focuses on current data regarding epidemiology, pathophysiology, comorbidities, and treatment of NAFLD in children and adolescents.

Gallstone prevalence and risk factors for gallstone disease in an urban population of children and adolescents.

BACKGROUND: At present only a few sonography-based studies have assessed gallstone prevalence and associated risk factors in children and adolescents in randomly selected urban population samples. The aim of the present study was to analyze the prevalence of cholecystolithiasis and associated risk factors in children and adolescents. METHODS: From a randomly selected urban population sample a total of 307 children and adolescents (157 girls, 150 boys; age 12 - 18 years, mean age 15.1 +/- 2.0 years) were studied using ultrasonography, standardized questionnaires and blood samples. RESULTS: Three adolescents (one girl, two boys), corresponding to a prevalence of 1.0 %, showed gallstones. One 14-year-old girl and one 17-year-old boy were overweight using Cole's classification. A positive family history and female gender could not be confirmed as risk factors. CONCLUSION: Obesity appears to be a risk factor in the development of gallstones in childhood and adolescence.

Pubertal development in obese children and adolescents.

OBJECTIVE: To investigate clinical and laboratory markers of pubertal development in a large sample of obese children and adolescents. METHODS: Analysis of parameters of sexual maturation in 1232 obese individuals (582 boys) aged 6-18 years (mean 13.0+/-2.42 years). Clinical evaluation of pubertal stage and determination of bone age in a subset (227 patients). RESULTS: Mean Height--standard deviation scores (height-SDS) was positive during childhood and reached zero approximately at age 14 years followed by a turn to negative mean height-SDS in both genders. Accordingly, bone age was accelerated until age 14. No significant differences in average time points of occurrence of pubic hair stages PH 2 to PH 4 in boys and PH 2 to PH 5 in girls were observed as compared to references of the First Zurich Longitudinal Study. In girls, breast stage B 3 was reached earlier (11.6 vs 12.2 years, P=0.03). In boys, mean volume of testis revealed no significant deviation from reference. Mean dehydroepiandrosterone sulfate (DHEAS) levels were elevated in boys (within age ranges 8-10 years and 12-16 years, P<0.02) and in girls (within age ranges 6-8 years and 12-18 years, P<0.005) and mean testosterone levels in boys >12 years were lower as compared to reference ranges (all P-values <0.0001). CONCLUSION: The study data suggest normal development of pubarche and gonadarche in obese German boys and normal timing of pubarche in girls. Breast development in obese girls seems to be slightly advanced. In obese boys, an obvious dissociation of clinical and laboratory parameters of pubertal development was observed. Despite significantly increased height-SDS and increased DHEAS levels, gonadal development was normal and testosterone levels were decreased. Elevated DHEAS levels in both genders may contribute to the acceleration of bone maturation, a lower final body height and could increase cardiovascular risk.