Faculty Bibliography

BACKGROUND: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed "minipuberty" of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. METHODS: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1-6 months, and in 12 adolescents, aged 11-17 years. RESULTS: Total serum T in all infants was, as expected, high (172 +/- 78 ng/dL) while salivary T was low (7.7 +/- 4 pg/mL or 0.45 +/- 0.20%). In contrast, salivary T in the adolescents was much higher (41 +/- 18 pg/mL or 1.3 +/- 0.36%) in relation to their total serum T (323 +/- 117 ng/dL). We provide for the first time reference data for salivary T in infants. CONCLUSION: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance..

We present the clinical phenotype of a toddler who presented with vitamin D-resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D).

This review highlights the presentations of myopathy in children in both hypothyroid and hyperthyroid states with an emphasis on the pathophysiology, diagnosis and treatment. Based on our review of the literature data, myopathy should be considered in all children presenting with muscular weakness or altered muscle enzymes in the context of thyroid disease.

CONTEXT: Insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 have been linked to cardiovascular disease (CVD) risk and pathophysiology in adults, but there are limited data in youth. OBJECTIVE: The aim of the study was to examine the relationship between IGF and IGFBP-1 with traditional and non-traditional CVD risk factors including inflammatory markers and body composition in an obese pediatric cohort. DESIGN: A cross-sectional study. SETTING: The study was carried out at a university children's hospital. SUBJECTS: Sixty-one obese non-diabetic adolescents. OUTCOMES: Fasting IGF-I, IGFBP-1, lipoprotein profiles, high-sensitivity C-reactive protein (hsCRP), and total adiponectin as well as insulin sensitivity measures, blood pressure (BP), and anthropometrics. RESULTS: IGFBP-1 was negatively associated with insulin sensitivity measures, body mass index (BMI), and diastolic BP in males. IGF-I was negatively associated with hsCRP (r = -0.479, p < 0.0005), and IGFBP-1 was positively associated with adiponectin (r = 0.545, p < 0.0005). The IGF-I/CRP and IGFBP-1/adiponectin associations remained significant when controlling for both BMI and insulin sensitivity index (SI ). Both IGF-I and IGFBP-1 were negatively associated with waist circumference (r = -0.327 and r = -0.275, respectively) and sagittal abdominal diameter (r = -0.333 and r = -0.371, respectively), while IGFBP-1 was negatively associated with fat mass (r = -0.347, p = 0.01) as well as neck circumference and fat-free mass in males. Controlling for BMI z-score and SI , IGFBP-1 remained negatively associated with diastolic blood pressure (r = 0.706, p = 0.001 and neck circumference (r = -0.548, p = 0.15) in males. CONCLUSIONS: IGF-I and IGFBP-1 associate with CVD risk markers and may add to clinical assessments of cardiometabolic dysfunction in youth.

Introduction: Acute myopathy occurs in both hyperthyroid and hypothyroid states, the mechanism of which is not clearly understood (1). Some cases of myopathy are attributed to a relative hypothyroid state at the cellular level (2). Elevated levels of creatine kinase (CK) are observed in hypothyroid myopathy but not in hyperthyroid myopathy. However, CK elevations have been associated with antithyroid drug treatment (3). We report an adolescent with Graves' disease who had CK elevation on methimazole (MMI) treatment and after radioactive iodine ablation. Case report: 13 year old female diagnosed with Graves' disease who on diagnosis had the following labs: Free T4: 5.6 ng/dl (Normal range: 0.9-1.9 ng/dl), Free T 3: 19 pg/ml (2.3-4.2pg/ml), TSH: <0.008 uIU/ml (0.35-4.8 uIU/ml), TSI: 338% (<140 %) and she was started on methimazole (MMI: 30mg/day) and propranolol. The teenager reported muscle aches 4 months after starting MMI and on testing CK levels were elevated at 516 U/L (35-155 U/L) (3X normal) and MMI was discontinued. The patient tested negative for rheumatologic conditions like polymyositis where testing included ANA, anti Smith ab, dsDNA ab, anti RNP ab, Jo-1 ab, Scl- 70 ab and centromere B ab. The teenager experienced rapid and marked improvement in her muscle symptoms and CK levels decreased to 153 U/L (35-155 U/L) in a week. As thyroid hormones rebounded rapidly on discontinuation of MMI: Free T4: 2.03 (0.9-1.9ng/dl), Free T3: 8.4 (2.3-4.2pg/ml)), the treatment options were restarting MMI at a lower dose or radioablation and the family opted for the latter. The patient underwent radioactive iodine ablation (131I) with 12.5millicuries. Two months status post radio ablation, the patient became hypothyroid: Free T4:0.33 (0.9-1.9 ng/dl), TSH: 102 uIU/ml (0.35-4.8 uIU/ml)) and she developed acute myopathic symptoms which were again associated with CK elevation (higher than preablation) of 1093 U/L (35-155 U/L). On initiation of levothyroxine at 50mcg daily, CK levels decreased to 266 U/L (35-155U/L) in 10 weeks and symptoms improved. Conclusion: True incidence of acute myopathy associated with pediatric Graves' disease is higher than described in literature. Learning points from our case are: a) Pediatric Graves' disease families should be counseled about muscle symptoms and CK levels be measured when warranted by clinical history; b) Trending CK levels during the course of treatment may be prudent as our case demonstrates reemergence of myopathy in the hypothyroid state status post radio ablation; c) Addition of levothyroxine along with antithyroid medication may offset the local hypothyroid state within the muscle tissue resulting in CK augmentation

BACKGROUND: Circulating levels of 25 (OH) vitamin D (VD) mediate deterioration of beta cell function in vitamin D deficiency (VDD) states. Higher parathyroid hormone (PTH) levels have a negative impact on the beta cell function and insulin sensitivity (1, 2). Understanding the independent effect of VD and PTH on different aspects of glucose homeostasis may be paramount, especially when treating obese adolescents with VDD. OBJECTIVE: To study the independent effects of VD and PTH on surrogates (sensitivity and secretory indices derived from oral glucose tolerance test: OGTT) before and after Rx for VDD. METHODS: In a single blinded randomized placebo controlled study (cross over design with sample size= 7) obese adolescents with VDD (25 (OH) < 20 ng/dl) were recruited. Adolescents received 50,000 IU of ergocalciferol (group A) once weekly or placebo (group B) for 6 weeks. At week 7, subjects were reassigned to receive VD if they were in group B or placebo if they were in Group A. Study subjects had an OGTT and screening labs (25 (OH) Vitamin D, PTH, CMP, calcium, phosphorous and urine calcium/creatinine ratio) at baseline, week 7 and then again at week 12 on the completion of study. OGTT indices: Insulin sensitivity was assessed by homeostatic model assessment index of insulin resistance (HOMA-IR) (3) and Whole body insulin sensitivity index (WBISI) (4), while B cell function was evaluated by insulinogenic index (IGI) (5) derived from an OGTT. RESULTS: Six of the seven patients were female(mean +/- SD): age 15.4+/-1.9 years, BMI 34 +/- 3.7, preRx VD 17.8+/- 2, postRx VD 22 +/- 5.7(> 19ng/ml); preRx PTH 58 +/- 20.8, postRx PTH 51 +/- 12.6 (15-75 pg/mL). When stratified by changes in VD postRx (group1= increase of 30% or more in VD level; group 2= <30 % change) indices derived from OGTT were: WBISI4.3 +/- 0.5 vs. 3.4 +/- 1.9, HOMA-IR: 2.7 +/- 0.4 vs. 4.1 +/- 3, IGI: 1.9+/- 0.6 vs. 1.6+/- 1. IGI to be statistically significant between groups (independent sample t test: p= 0.031). When stratified by change in PTH levels postRx (group 1= decrease in PTH level n=4 vs. group 2 increase in PTH level n=3) indices derived from OGTT were: WBSI 4.1 +/- 0.7 vs. 3 +/- 2.2 HOMA-IR: 3+/- 0.3 vs. 4.1+/- 3.7, IGI: 1.6+/- 1 vs. 1.8+/- 0.6. HOMA-IR and WBISI were found to be different between groups (p= 0.010 and p=0.07 respectively) CONCLUSIONS: VD and PTH work synergistically in bone health though they likely influence glucose metabolism through independent mechanism. a) Optimization of vitamin D may require using 2-3 fold higher doses (as suggested by the Endocrine society for adults) to achieve levels of 25(OH) D levels >30 ng/ml thereby maximizing the beneficial effects of vitamin D on glucose homeostasis. b) Preliminary results show that VD levels postRx correlate with secretory index IGI and PTH levels postRx with sensitivity indices: HOMA-IR and WBISI. The relative contributions of VD and PTH on aspects of glucose metabolism may have unique therapeutic implications for glucose dysregulation

Background. Increased prevalence of type 2 diabetes mellitus (T2DM) makes it important for pediatricians to use effective screening tools for risk assessment of prediabetes/T2DM in children. Methods. Children (n = 149) who had an oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) were studied. American Diabetes Association recommended screening criteria-HbA1c >/=5.7% and fasting plasma glucose (FPG) >/=100 mg/dL-were compared against OGTT. The homeostatic model assessment of insulin resistance (HOMA-IR), a mathematical index derived from fasting insulin and glucose, was compared with OGTT. We studied whether combining screening tests (HbA1c and fasting glucose or HbA1c and HOMA-IR) improved accuracy of prediction of the OGTT. Results. HbA1c of >/=5.7% had a sensitivity of 75% and specificity of 57% when compared with the OGTT. Combining screening tests (HbA1c >/=5.7% and FPG >/=100 mg/dL; HbA1c >/=5.7% and HOMA-IR >/=3.4) resulted in improved sensitivity (95.5% for each), with the HbA1c-FPG doing better than the HbA1c-HOMA-IR combination in terms of ability to rule out prediabetes (likelihood ratio [LR]) negative. 0.07 vs 0.14). Conclusions. HbA1c of >/=5.7% provided fair discrimination of glucose tolerance compared with the OGTT. The combination of HbA1c and FPG is a useful method for identifying children who require an OGTT.

Background: The childhood obesity epidemic had led to an exponential rise in the prevalence of pre diabetes and /or Type 2 diabetes. Vitamin D deficiency results in decreased insulin sensitivity (ability of insulin to promote peripheral glucose uptake) and fasting hyperglycemia has been correlated with Vitamin D deficiency in obese adolescents and children.1,2 Aims: To study insulin sensitivity and secretory indices derived from an oral glucose tolerance test (OGTT) in obese adolescents with vitamin D deficiency before and immediately after normalization of serum 25(OH) vitamin D levels. Methods: In a single blinded randomized placebo controlled study (cross over design with planned sample size= 20) obese adolescents with vitamin D deficiency; 25 (OH) vitamin D < 20 ng/dl (50 nmol/L) were recruited. Adolescents were assigned to receive 50,000 IU of ergocalciferol (group A) once weekly or placebo (group B) for 6 weeks. At week 7, subjects were reassigned to receive vitamin D if they were in group B or placebo if they were in Group A. Study subjects had an OGTT and screening labs (25 (OH) Vitamin D, PTH, CMP, calcium, phosphorous and urine calcium/ creatinine ratio) at baseline, week 7 and then again at week 12 on the completion of study. Indices derived from OGTT were: 1) Whole body sensitivity index (WBISI):10,000/(fasting glucose(mg/dL)x fasting insulin(uIU/mL)x(mean glucose (mg/dL) x mean insulin (uIU/mL) 2) Insulinogenic index: 30 min insulin- fasting insulin (uIU/mL) / 30 min glucose- fasting glucose (mg/dL) Results: To date four subjects have completed the study: Hispanic females (mean +/- SD) age 16.1+/- 1years, BMI 34.5+/- 4.5. Baseline labs were: HbA1c 5.3+/- 0.2, fasting glucose 81+/- 5.1, and fasting insulin 16.5+/- 5.3uIU/ml. PTH 48.5+/- 13.8 ng/dl (15- 75), calcium 9.1+/- 0.1 mg/dl (8.3- 10.3), phosphorous 4.3+/- 0.2mg/dl ( 2.7- 4.5), alkaline phosphatase 95+/- 19 mg/dl (39- 390) and urine calcium/creatinine were normal at baseline and on completion as we monitored for hypercalcemia. Mean 25 (OH) Vit D was 19.4+/- 1.4 ng/dl before treatment. In 3 of 4 subjects vit D did not normalize to >30 ng/dl (23+/- 6.7 mg/dl) on completion of the study, while it did in one patient (30.2 ng/dl). The mean insulin during OGTT (total of six levels during OGTT) decreased by 57% from 88+/- 36 to 51+/- 10 IU/L from start to completion of the study, while mean glucose values and HbA1c remained unchanged. WBISI improved significantly from 2.2+/- 0.3 to 4.3+/- 0.6, a 51% increase in this sensitivity index. Conclusions: These results, though preliminary, suggest that even marginal increases in the Vitamin D levels in deficient insulin resistant obese adolescents appears to improve their hyperinsulinemia. More intriguing is that insulin sensitivity index WBISI improved after 6 weeks of vitamin D treatment, which if confirmed at study completion could have important therapeutic implications for insulin resistance

Background: Obese adolescents are at high risk for vitamin D deficiency (VDD) because Vitamin D is sequestrated in adipose tissue. Vitamin D deficiency is defined as 25 (OH) D levels < 20 ng/ml; 50 nmol/L. Observational studies in adolescents support an association between VDD, Type 2 diabetes and metabolic syndrome. Objective: a) To determine the prevalence of VDD in an inner city multi ethnic cohort of obese adolescents and b) to study the efficacy of 50,000 IU of weekly PO vitamin D2 (Ergocholecalciferol) X 6 weeks in normalizing 25 (OH) D levels (based on published Endocrine Society guidelines, 2011) Methods: In a retrospective design from July 2011- 2013, we reviewed metabolic profile, pre and post treatment 25(OH) D levels of obese adolescents with VDD (> 95% weight for age). Though different regimens for vitamin D supplementation were used only obese adolescents who received 50,000 IU once weekly for either 4- 6 weeks were studied. Results: Of the 53 obese adolescents identified (56% were female, age: 11.7+/- 4.4 years; BMI: 32.3+/- 7.7; mean+/- SD) only 3 adolescents had 25 (OH) D levels which were sufficient (>30 ng/ml; 75 nmol/L). Average 25 (OH) D levels in this obese cohort was 21+/- 8 ng/dl. 40 subjects had a record of being treated and the pretreatment 25 (OH) D level was 15.9+/- 4.6 ng/dl. While 83% received treatment for 6 weeks, a subset were treated for 4 weeks. Of those adolescents, post treatment 25 (OH) D levels were available in only 34%. 8 (44%) normalized their 25 (OH) D levels and this level went above 30 ng/ml (34.8+/- 4.4 ng/dl) while 10 adolescents (56%) failed to optimize their level to above > 30 ng/ml. Conclusions: These results illustrate the following points: 1. Obese adolescents have invariably VDD and correction of their deficiency should be considered an effective addition to the management of their obesity to maximize non skeletal benefits of Vitamin D such as its role in glucose homeostasis. 2. Obese adolescents may require 2-3 fold higher doses (as suggested by the Endocrine society for adults) to optimize levels of 25(OH) D levels (>30 ng/dl) and this treatment course may need to be repeated 2-3 times/year to maintain optimal levels. 3. We suggest that adipose tissue is dynamically altered in obese adolescents which affects local metabolism of Vitamin D, it's reentry into the circulation and metabolic clearance rates, an area that deserves investigation