Association between non-alcoholic fatty liver disease and subclinical hypothyroidism in children with obesity.

PURPOSE: We aimed (i) evaluating the relationship between non-alcoholic fatty liver disease (NAFLD) and thyroid function tests, (ii) testing if the relationship between NAFLD and thyroid dysfunction could be driven by the obesity and the IR degree, and (iii) exploring the influence of the patatin-like phospholipase domain-containing protein-3 (PNPLA3) I148M and the transmembrane 6 superfamily member 2 (TM6SF2) E167K polymorphisms on the association between NAFLD and thyroid function in children. METHODS: We examined 2275 children and adolescents with obesity. Subclinical hypothyroidism (SH) was defined by thyroid-stimulating hormone (TSH) > 4.2 µUI/ml with normal fT3 and fT4. RESULTS: Children with NAFLD showed higher SH prevalence than those without NAFLD (15.7% Vs 7.4%;p = 0.001) and showed an adjusted odds ratio (aOR) to have SH of 1.68 (95% CI:1.01-2.80;p = 0.04) while patients with SH had an aOR to show NAFLD of 2.13(95% CI:1.22-3.73;p = 0.008). Patients having severe obesity and IR degree presented an aOR to show both NAFLD and SH of 3.61 (95% CI:1.78-7.33;p < 0.0001). Subjects with NAFLD carrying the TM6SF2 167 K allele had lower TSH levels than non-carriers (p = 0.03) and showed an aOR to have SH of 0.10 (95% CI: 0.01-0.79;p = 0.02). No differences were found in carriers of the PNPLA3 148 M allele. A general linear model for TSH variance showed a significant association of TSH with TM6SF2 genotypes only in the NAFLD group (p = 0.001). CONCLUSION: Children with obesity and NAFLD presented increase risk of SH and vice versa likely due to the adverse effect of duration of obesity, obesity degree, and IR. The TM6SF2 E167K exerts a protective role against SH in children with obesity and NAFLD.

Screening for hypertension in young people with obesity: Feasibility in the real life.

BACKGROUND AND AIM: Screening for pediatric hypertension (HTN) is based on several measurements of blood pressure (BP) in different visits. We aimed to assess its feasibility in outpatient youths with overweight/obesity (OW/OB) in terms of adherence to two-repeated measurements of BP and to show the features of youths who missed the follow-up and the predictive role of clinical and/or anamnestic features on confirmed HTN. METHODS AND RESULTS: Six hundred, eighty-eight youths (9-17 years) with OW/OB, consecutively recruited, underwent a first measurement of BP. Those exhibiting BP levels within the hypertensive range were invited to repeat a second measurement within 1-2 weeks. Confirmed HTN was diagnosed when BP in the hypertensive range was confirmed at the second measurement. At entry, 174 youths (25.1%) were classified as hypertensive. At the second visit, 66 youths (37.9%) were lost to follow-up. In the remaining 108 participants, HTN was confirmed in 59, so that the prevalence of confirmed HTN was 9.5% in the overall sample; it was higher in adolescents than children (15.9% vs 6.8%, P = 0.001). HTN at first visit showed the best sensitivity (100%) and a good specificity (91%) for confirmed HTN. The association of HTN at first visit plus familial HTN showed high specificity (98%) and positive predictive value of 70%. CONCLUSION: The high drop-out rate confirms the real difficulty to obtain a complete diagnostic follow up in the obese population. Information about family history of HTN may assist pediatricians in identifying those children who are at higher risk of confirmed HTN.

Phenotypes of prediabetes and metabolic risk in Caucasian youths with overweight or obesity.

PURPOSE: To assess the prevalence of pre-diabetes phenotypes, i.e., impaired fasting glucose (IFG), impaired glucose tolerance (IGT), increased HbA1c (IA1c), and their association with metabolic profile and atherogenic lipid profile in youths with overweight/obesity (OW/OB). METHODS: This cross-sectional study analyzed data of 1549 youths (5-18 years) with OW/OB followed in nine Italian centers between 2016 and 2020. Fasting and post-load measurements of glucose, insulin, and HbA1c were available. Insulin resistance (IR) was estimated by HOMA-IR and insulin sensitivity (IS) by reciprocal of fasting insulin. The atherogenic lipid profile was assessed by triglycerides-to-HDL ratio or cholesterol-to-HDL ratio. Insulinogenic index was available in 939 youths, in whom the disposition index was calculated. RESULTS: The prevalence of overall pre-diabetes, IFG, IGT and IA1c was 27.6%, 10.2%, 8% and 16.3%, respectively. Analyzing each isolated phenotype, IGT exhibited two- to three-fold higher odds ratio of family history of diabetes, and worse metabolic and atherogenic lipid profile vs normoglycemic youths; IFG was associated only with IR, while IA1c showed a metabolic and atherogenic lipid profile intermediate between IGT and IFG. CONCLUSION: Prevalence of pre-diabetes was high and IA1c was the most prevalent phenotype in Italian youths with OW/OB. The IGT phenotype showed the worst metabolic and atherogenic lipid profile, followed by IA1c. More studies are needed to assess whether HbA1c may help improving the prediction of diabetes.

High uric acid, reduced glomerular filtration rate and non-alcoholic fatty liver in young people with obesity.

OBJECTIVE: To evaluate the association between high uric acid (UA), reduced estimated glomerular filtration rate (eGFR), and non-alcoholic fatty liver disease (NAFLD) in outpatient children and adolescents with overweight (OW) or obesity (OB). METHODS: Anthropometric, biochemical, hepatic ultrasound and eGFR data were available from 2565 young people with OW/OB (age 5-18 years). eGFR was calculated using the Schwartz's bedside formula and reduced eGFR (ReGFR+) was defined by a value < 90 mL/min/1.73 m2. High UA was defined as ≥ 75th percentile by sex in children and adolescents. RESULTS: The population was stratified in four categories: (1) normal eGFR and absence of NAFLD (ReGFR-/NAFLD-) (n = 1,236); (2) ReGFR+ and absence of NAFLD (ReGFR+/NAFLD- (n = 155); (3) normal eGFR and presence of NAFLD (ReGFR-/NAFLD+) (n = 1019); (4) presence of both conditions (ReGFR+/NAFLD+) (n = 155). Proportions of youth with high UA across the four categories were 17%, 30%, 33% and 46%, respectively (P < 0.0001). Young people with high levels of UA had odds ratio (95% CI) of 2.11 (1.43-3.11) for ReGFR+; 2.82 (2.26-3.45) for NAFLD+; and 5.04 (3.45-7.39) for both conditions (P < 0.0001 for all), independently of major confounders. CONCLUSIONS: High levels of UA were independently associated with ReGFR, NAFLD and the combination of both conditions in young people with OW/OB. The strength of this association was the highest in cases presenting both reduced eGFR and NAFLD. UA may serve as marker to identify patients at risk for these conditions.

Subclinical hypothyroidism and myocardial function in obese children.

BACKGROUND AND AIMS: Pediatric obesity is an important health problem representing a major public health concern worldwide in the last decades. An isolated elevation of Thyroid Stimulating Hormone (TSH) with normal levels of thyroid hormones is frequently found in obese children. It has been named Isolated Hyperthyreotropinemia or Subclinical Hypothyroidism (SCH) and may be considered a consequence of obesity. Evidence exists that SCH is related to impairment of both systolic and diastolic myocardial function in the adult population. The aim of our study is to establish if obesity-related SCH influences myocardial function in children. METHODS AND RESULTS: We examined 34 obese children and adolescents with SCH and 60 obese children with normal TSH levels who underwent Doppler echocardiographic to evaluate myocardial function. Global systolic function as assessed by Ejection Fraction (EF) was comparable between groups, however Right Ventricle pressure global systolic function and pressure were significantly reduced in SCH group. Mitral annulus peak systolic (MAPSE) excursion lateral and MAPSE septum resulted significantly reduced in SCH group. Tissue Doppler imaging peak systolic motion (TDI-S) was reduced in SCH group. Diastolic function also showed significant modifications in SCH group. CONCLUSION: These results suggest possible involvement of cardiac function in obese children with SCH resulting in both abnormal diastolic function and reduced longitudinal systolic function. This new insight into cardiovascular consequences of obesity-related SCH in children could influence clinical approach to such patients by pediatric endocrinologists.

New treatment modalities for obesity.

The treatment of childhood obesity represents a greater challenge for pediatricians. To date, it is multidisciplinary, including behavioral, dietary, pharmacological, and surgical options. Given the limited efficacy of available treatments, scientific research on finding new solutions is very active. Several drugs comprising Metformin, Glucagon-like peptide- 1 receptor agonists, Naltrexone-bupropion, Phentermine-Topiramate, and Lorcaserin have been studied as pediatric antiobesity agents. Findings from clinical trials showed a modest but significant effect of these drugs on weight loss, but long-term studies are needed to better define their exact role. Bariatric surgery is also promising for extremely obese adolescents. Moreover, a novel approach to treat obesity might be represented by compounds inducing browning of white adipose tissue, a complex process involved in body energy homeostasis, but at present evidence in humans is lacking. We aimed to review the current knowledge regarding the available new options for pediatric obesity treatment.

TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children.

BACKGROUND: The Glu167Lys (E167K) transmembrane 6 superfamily member 2 (TM6SF2) variant has been associated with liver steatosis, high alanine transaminase (ALT) levels and reduced plasma levels of liver-derived triglyceride-rich lipoproteins. OBJECTIVES: The objectives of this study were to investigate in a group of obese children the association among the 167K allele of TM6SF2 gene and ALT, cholesterol and triglycerides levels, and hepatic steatosis, and to evaluate the potential interaction between this variant and the I148M patatin like phospholipase 3 gene (PNPLA3) polymorphism on liver enzymes. METHODS: We genotyped 1010 obese children for TM6SF2 E167K and PNPLA3 I148M polymorphisms. Anthropometrical and biochemical data were collected. Ultrasound imaging of the liver was performed. RESULTS: The 167K allele showed an association with steatosis (P < 0.0001), higher ALT levels (P < 0.001) and lower total cholesterol (P < 0.00001), low-density lipoprotein cholesterol (P < 0.0001), triglycerides (P = 0.02) and non-high-density lipoprotein cholesterol levels (P < 0.000001). The subjects homozygous for the PNPLA3 148M allele carrying the rare variant of TM6SF2 showed an odds ratio of 12.2 (confidence interval 3.8-39.6, P = 0.000001) to present hypertransaminasaemia compared with the remaining patients. CONCLUSION: Although the TMS6SF2 E167K variant predisposes the obese children to non-alcoholic fatty liver disease, there is an association between this variant and lower levels of cardiovascular risk factors. Overall, the data suggest differential effects of TMS6SF2 E167K variant on liver and heart health.