Overdiagnosis of adrenal insufficiency in children with biliary atresia.

Serum cortisol mainly binds to the cortisol-binding globulin (CBG). Children with biliary atresia (BA) may have low serum CBG levels; thus, low serum total cortisol (TC) levels and adrenal insufficiency (AI) may be overdiagnosed. This study aimed to assess adrenal function in children with BA. All the patients underwent adrenocorticotropic hormone (ACTH) stimulation tests. Plasma ACTH, serum TC, and CBG levels were measured at baseline, with additional TC measurements at 30 and 60 min during testing. Free cortisol (FC) index (FCI) and calculated FC (cFC) were also calculated. AI was defined as peak TC <500 nmol/L (<18 µg/dL), peak FCI <12 nmol/mg, or peak cFC <33 nmol/L (<1.2 µg/dL). This study enrolled 71 children with BA. The Median (IQR) age of the patients was 5.5 (1.7-11.4) years. Twenty-five (35%) patients were diagnosed with AI based on the peak TC. In the AI group, the median serum CBG level was significantly lower than that in the non-AI group (481 vs. 533 nmol/L, p = 0.03). Only eight patients (11%) met all three AI criteria (six secondary AI and two primary AI). In conclusion, low serum CBG levels contribute to reduced peak TC and, consequently, overdiagnosing AI. Peak FCI and cFC could help reduce the overdiagnosis of AI.

Long-term outcomes of anti-thyroid drug treatment in childhood-onset Graves' disease.

OBJECTIVE: Outcomes of childhood-onset Graves' disease (GD) and suggested duration of anti-thyroid drug (ATD) therapy have been controversial. This study aimed to determine long-term outcomes following ATD therapy, including remission and relapse rates. DESIGN, PATIENTS AND MEASUREMENTS: A retrospective study of 265 paediatric patients with GD who were initially treated with ATD was conducted. Long-term outcomes were analysed. RESULTS: Median (IQR) age at diagnosis was 11.5 (9.4, 13.7) years. Duration of ATD treatment was 4.3 (2.3, 6.7) years and time since diagnosis to the enrolment was 7.1 (3.8, 10.9) years. There were 77, 93 and 95 patients who underwent definitive treatment, had ATD discontinuation, and were still being treated with ATD, respectively. The remission rate was 21% (56 out of 265 patients) and relapse rate was 40% (37 out of 93 patients). Cumulative incidence of first remission increased with the duration of ATD treatment with maximum remission rate at 5.3 years following ATD therapy. Among patients who experienced relapse, approximately 50% had disease relapse which occurred within 1 year after ATD discontinuation. Patients with goitre size of less than 3.5 cm, thyroid-stimulating hormone receptor antibody of less than 10 IU/L, no ophthalmopathy at diagnosis and methimazole dose requirement of less than 0.25 mg/kg/day at 1 year after treatment were more likely to achieve remission. CONCLUSIONS: Remission rate of childhood-onset GD was relatively low following ATD treatment. Longer-term ATD therapy was associated with increased remission rate. Approximately 50% of patients with relapse had disease relapse within 1 year following ATD discontinuation.

Glucose metabolism in systemic juvenile idiopathic arthritis.

BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is a chronic systemic inflammatory disease in children. Overproduction of inflammatory cytokines in SJIA resembles that in adult onset Still disease. Chronic inflammation causes insulin resistance and consequently leading to abnormal glucose metabolism. Adults with rheumatoid arthritis (RA) have increased risks of abnormal glucose metabolism and diabetes. To date, glucose metabolism in patients with SJIA has not been elucidated. METHODS: Patients with SJIA aged 4-25 years were recruited. All patients underwent an oral glucose tolerance test (OGTT). Indices of insulin sensitivity [homeostasis model assessment for insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)] and ß-cell function [insulinogenic index (IGI) and disposition index (DI)] were calculated. Obese children with normoglycemia who underwent the OGTT were served as a control group. RESULTS: A total of 39 patients with SJIA, aged 4-25 years, median (IQR) BMI SDS was 0.1 (-0.5 to 1.7). Patients were divided into 2 groups, overweight/obese (OW/OB) (n = 11) and lean (n = 28). Only one obese patient had prediabetes and none had diabetes. In comparison with sex- and age-matched OW/OB controls (n = 33), OW/OB patients with SJIA had higher insulin resistance [median (IQR) HOMA-IR: 2.6 (2.1-3.3) vs 1.5 (0.8-2.0), p = 0.001], lower insulin sensitivity [median (IQR) WBISI: 3.7 (2.7-5.9) vs 5.4 (4.5-8.7), p = 0.024], and higher insulin secretion [median (IQR) IGI: 2.5 (2.0-3.5) vs 1.0 (0.8-1.9), p = 0.001]. In lean patients with SJIA, insulin sensitivity indices seemed to be comparable with those of lean controls. CONCLUSIONS: Overweight/obese children with SJIA seemed to have increased insulin resistance and thus may have an increased risk for developing diabetes.

Beta cell function, incretin hormones, and incretin effect in obese children and adolescents with prediabetes.

BACKGROUND: Defects of incretin hormones and incretin effect may be underlying mechanisms of abnormal glucose metabolism in youth. OBJECTIVE: To assess incretin hormone dynamics during an oral glucose tolerance test (OGTT) and incretin effect in obese children with prediabetes in comparison with those with normal glucose tolerance (NGT). METHODS: Overweight and obese children were enrolled and classified according to OGTT results as NGT and prediabetes. Insulin sensitivity, insulin secretion, incretin hormone concentrations during OGTT; and incretin effect derived from OGTT and intravenous glucose tolerance test were determined and compared between NGT and prediabetes groups. RESULTS: Sixty-three patients (43 NGT and 20 prediabetes) were enrolled. Their median (interquartile range) age was 12.5 (11.1, 13.8) years. Peak glucagon-like peptide-1 (GLP-1) was demonstrated at 30 min during OGTT and was higher in the prediabetes group (49.2 [35.6, 63.6] versus 36.5 [27.6, 44.2] pmol/L, p = 0.009). However, incremental areas under the curves (iAUCs) of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were not different between the two groups. There was no difference in incretin effect between NGT and prediabetes (NGT: 66.5% [60.2%, 77.5%] vs. prediabetes: 70.0% [61.5%, 75.0%], p = 0.645). Incretin effect had positive correlations with iAUCs of both GLP-1 and GIP (GLP-1: r = 0.40, p = 0.004 and GIP: r = 0.37, p = 0.009). CONCLUSIONS: Comparing between obese children with prediabetes and NGT, there were no differences in overall incretin hormone changes during OGTT and incretin effect. Incretin effect was positively correlated with iAUCs of GLP-1 and GIP.

Short-term effects of gonadotropin-releasing hormone analogue treatment on leptin, ghrelin and peptide YY in girls with central precocious puberty.

OBJECTIVES: To determine appetite-regulating hormone levels in girls with central precocious puberty (CPP) before and after 20 weeks of gonadotropin-releasing hormone analogue (GnRH-A) treatment. METHODS: Eighteen newly diagnosed CPP girls were enrolled. Body composition measured by bioelectrical impedance analysis and GnRH-A test were performed with fasting serum leptin, ghrelin and peptide YY (PYY) measurements at baseline (before) and after 20 weeks of GnRH-A treatment. RESULTS: Following GnRH-A treatment, all patients had prepubertal gonadotropin and estradiol levels. Mean (SD) fat mass index (FMI) was significantly increased from 4.5 (1.7) to 5.0 (1.8) kg/m2 after treatment. Also, median (IQR) serum leptin level was significantly increased from 6.9 (4.2-8.6) to 7.4 (5.3-13.1) ng/mL. FMI had a positive correlation with serum leptin level (r=0.64, p=0.004). In contrast, no significant changes of serum ghrelin and PYY levels were observed. CONCLUSIONS: Decreased estrogen following short-term GnRH-A treatment in CPP girls may cause an increase in appetite and consequently an elevation of FMI. Increased serum leptin may be a result of having increased FMI secondary to an increase in appetite.

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients.

OBJECTIVE: To identify the genetic etiologies of congenital primary hypothyroidism (CH) in Thai patients. DESIGN AND METHODS: CH patients were enrolled. Clinical characteristics including age, signs and symptoms of CH, pedigree, family history, screened thyroid-stimulating hormone results, thyroid function tests, thyroid imaging, clinical course and treatment of CH were collected. Clinical exome sequencing by next-generation sequencing was performed. In-house gene list which covered 62 potential candidate genes related to CH and thyroid disorders was developed for targeted sequencing. Sanger sequencing was performed to validate the candidate variants. Thyroid function tests were determined in the heterozygous parents who carried the same DUOX2 or DUOXA2 variants as their offsprings. RESULTS: There were 118 patients (63 males) included. Mean (SD) age at enrollment was 12.4 (7.9) years. Forty-five of 118 patients (38%) had disease-causing variants. Of 45 variants, 7 genes were involved (DUOX2, DUOXA2, TG, TPO, SLC5A5, PAX8 and TSHR). DUOX2, a gene causing thyroid dyshormonogenesis, was the most common defective gene (25/45, 56%). The most common DUOX2 variant found in this study was c.1588A>T. TG and TPO variants were less common. Fourteen novel variants were found. Thyroid function tests of most parents with heterozygous state of DUOX2 and DUOXA2 variants were normal. CONCLUSIONS: DUOX2 variants were most common among Thai CH patients, while TG and TPO variants were less common. The c.1588A>T in DUOX2 gene was highly frequent in this population.

Serum Kisspeptin and Its Relation to Metabolic Parameters and Glucose Metabolism in Prepubertal and Pubertal Obese Children.

OBJECTIVE: Kisspeptin, a puberty control neuropeptide, has been discovered to have an additional role in metabolism and glucose homeostasis regulation. This study aimed to determine the association of serum kisspeptin with metabolic parameters and glucose metabolism in obese children. Design, Patients and Measurements. A cross-sectional study of 270 obese children was conducted. All children underwent an oral glucose tolerance test and had serum kisspeptin, glycated hemoglobin (HbA1c), and lipid profile measurements. Body fat mass was assessed by bioelectrical impedance analysis. Serum kisspeptin levels of both prepubertal and pubertal children with two HbA1c ranges, <5.7% (normal range) and 5.7-6.4% (prediabetes range), were analyzed and correlated with metabolic parameters and glucose metabolism status. RESULTS: The median (IQR) serum kisspeptin level of only pubertal (not prepubertal) children with prediabetes HbA1c was higher than those with normal HbA1c (53.2 (33.9, 69.8) and 37.8 (29.6, 67.5) pg/mL; p = 0.015, respectively). There were no differences in serum kisspeptin levels among children with different glucose metabolism status. During pubertal progression, serum kisspeptin reached the highest level at Tanner stage II only in obese boys. Additionally, there was a positive correlation between serum kisspeptin and HbA1c after adjusting for puberty (ß = 12.87; p = 0.001). No correlations between serum kisspeptin and insulin sensitivity indices, insulin secretion indices, lipid profile, blood glucose, as well as percentage of body fat were demonstrated. CONCLUSIONS: Serum kisspeptin levels in pubertal obese children with prediabetes HbA1c were greater than those with normal HbA1c. Serum kisspeptin was positively associated with HbA1c, but not with glucose metabolism status.

Skewed X chromosome inactivation in girls and female adolescents with autoimmune thyroid disease.

OBJECTIVE: Skewed X chromosome inactivation (XCI) was associated with female predominance in adult autoimmune thyroid disease (ATD). In normal females, skewed XCI is increased with age. Whether early-onset skewed XCI is associated with childhood ATD remains unknown. This study aimed to determine XCI skewing in paediatric ATD. DESIGN, PATIENTS AND MEASUREMENTS: Ninety-one female ATD patients, aged 3-20 years and 57 age-matched, female controls were enrolled. XCI was analysed by enzymatic digestion of DNA with methylation-sensitive enzymes followed by PCR of the polymorphic CAG repeat in the androgen receptor gene. Skewed XCI was defined as having 80% or greater of the cells preferentially inactivated on the same X chromosome. XCI pattern of the enrolled patients and parental origin of the skewed XCI were determined. RESULTS: After exclusion of samples with homozygous CAG repeats, skewed XCI was analysed in 83 patients (57 Graves' disease and 26 Hashimoto thyroiditis) and 52 controls. There was an increased frequency of skewed XCI in ATD patients as compared with the controls (23% vs 8%, P = 0.022). Patients with Hashimoto thyroiditis had greater frequency of skewed XCI than patients with Graves' disease (38% vs 16%, P = 0.023). There were no differences in clinical parameters between patients with skewed and random XCI. Analysis of 7 patients with skewed XCI showed a preferential inactivation of paternal X chromosome in 6 patients (86%). CONCLUSIONS: Frequency of skewed XCI was increased in childhood ATD. This observation suggests a possible association of skewed XCI in the development of paediatric ATD.

Acute Effects of Blood Transfusion on Insulin Sensitivity and Pancreatic ß-Cell Function in Children with ß-Thalassemia/Hemoglobin E Disease.

OBJECTIVE: To assess the acute effects of blood transfusion on insulin sensitivity and pancreatic ß-cell function in thalassemia patients. METHODS: Fifty children and adolescents with ß-thalassemia/HbE disease were enrolled in a prospective cohort study. Hemoglobin, serum ferritin and oral glucose tolerance test (OGTT) were performed prior to, and one week after blood transfusion. Insulin sensitivity indices [homeostatic model assessment (HOMA) of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and ß-cell function indices [HOMA of ß-cell function (HOMA-ß), insulinogenic index (IGI), and disposition index (DI)] were calculated from glucose and insulin levels obtained during the OGTT. RESULTS: Following blood transfusion, hemoglobin and serum ferritin increased significantly; 8.5 to 10.1 g/dL (p<0.001) and 1764 to 2160 ng/mL (p<0.001), respectively. ß-Cell function indices also increased significantly [median HOMA-ß: 74.3 vs. 82.7 (p=0.033); median IGI: 59.6 vs. 79.3 (p=0.003); median DI: 658 vs. 794 (p=0.01)]. However, the insulin sensitivity index (WBISI) tended to decrease and the insulin resistance index (HOMA-IR) tended to increase although this did not reach significance. Multivariate analysis showed that pre-transfusion serum ferritin was the major factor negatively associated with WBISI and positively associated with HOMA-IR, but pre-transfusion hemoglobin had no significant association with insulin sensitivity indices post-transfusion. CONCLUSION: This study demonstrated that acute increases in serum ferritin and hemoglobin following blood transfusion in patients with thalassemia might contribute to an increase in insulin secretion and to a trend towards increased insulin resistance.

Serum glypican 4 level in obese children and its relation to degree of obesity.

OBJECTIVE: Previous adult studies have demonstrated associations of serum glypican 4 (Gpc4) and obesity parameters and insulin sensitivity. However, an association of serum Gpc4 and glucose metabolism remains contradictory. Study of serum Gpc4 in obese children has not been conducted. We aimed to determine serum Gpc4 levels in obese children with various degrees of obesity. DESIGN, PATIENTS AND MEASUREMENTS: Up to 370 overweight and obese children, aged 6-18 years were enrolled in this cross-sectional study. Oral glucose tolerance test (OGTT) was performed with fasting serum Gpc4, lipid profiles, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) measured. Insulin sensitivity and ß-cell function indices were calculated from plasma glucose and serum insulin levels derived from the OGTT. Bioelectrical impedance analysis was performed for body fat determination. Comparisons of serum Gpc4 levels among the groups of children with various degrees of obesity were performed. RESULTS: Serum Gpc4 levels progressively increased in children with increasing body mass index standard deviation score (BMI SDS) tertiles [median (interquartile range, IQR): 2.3 (1.8, 3.2), 2.6 (1.9, 3.4) and 3.2 (2.4, 3.8) µg/L, P<.001]. There were no differences in serum Gpc4 levels among children in the different glucose metabolism categories. Log serum Gpc4 levels were positively correlated with SDSs of weight and BMI, cholesterol, AST and ALT. No associations of log serum Gpc4 and insulin sensitivity and ß-cell function indices were demonstrated. CONCLUSIONS: Serum Gpc4 levels were increased with increasing degrees of obesity. There were no differences in serum Gpc4 levels among glucose metabolism categories.

Serum fibroblast growth factor 21 in overweight and obese Thai children and adolescents: its relation to glucose metabolism and its change after glucose loading.

OBJECTIVES: Fibroblast growth factor 21 (FGF21) has been demonstrated to be beneficial for glucose metabolism in animal and in vitro studies. However, its role in humans is still unclear. This study aimed to determine serum FGF21 in relation to glucose metabolism in obese children and to evaluate serum FGF21 changes during an oral glucose tolerance test (OGTT). DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study of 301 obese children was conducted in a tertiary hospital. All children underwent an OGTT and had their fasting serum FGF21 and adiponectin measured. A subgroup of 71 children had their serum FGF21 levels serially measured at 0, 60 and 120 min during the OGTT. RESULTS: Serum FGF21 levels were progressively increased in children with normal glucose tolerance without hyperinsulinaemia, normal glucose tolerance with hyperinsulinaemia and abnormal glucose tolerance [median (IQR): 72 (34-148), 96 (55-182), 122 (75-220) pg/ml, respectively, P = 0·003]. Log serum FGF21 was associated with homoeostatic model assessment of insulin resistance (r = 0·174, P = 0·002). There was no correlation between log serum FGF21 and serum adiponectin level. During the OGTT, there were changes in serum FGF21 levels with a decrease in FGF21 at 60 min from the baseline and an increase above the baseline at 120 min. CONCLUSIONS: Serum FGF21 level was highest in obese children with the highest insulin resistance or abnormal glucose tolerance. Log serum FGF21 was not correlated with serum adiponectin. Changes in serum FGF21 levels during the OGTT were observed.