Faculty Bibliography

Summary/UNASSIGNED:We describe a case of an infant who presented with clinical features of hyperthyroidism. The child was found to be tachycardic, hypertensive and diaphoretic, she was noted to have poor weight gain and difficulty in sleeping. The child was admitted to the pediatric intensive care unit for care. She was found to have biochemical evidence of hyperthyroidism with positive thyroid stimulating immunoglobulin. She responded well to methimazole and propranolol and had a remarkable recovery. She is the youngest patient to be diagnosed with Graves disease in the English literature, at 12 months of life. Learning points/UNASSIGNED:Hyperthyroidism must always be considered even at very young age, for patient presenting with poor weight gain and hyperdynamic state. Autoimmune diseases are becoming more common in infancy. Craniosynostosis and increased height for age are well-documented consequences of untreated hyperthyroidism in developing children.

BACKGROUND:The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS:We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS:Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.

BACKGROUND:It is unknown that dysglycemia in obese adolescents has effects on myocardial deformation that are more pronounced when compared to obesity alone. We hypothesized that obesity associated abnormal glucose tolerance (dysglycemia) would have adverse effects on two-dimensional speckle tracking echocardiography derived longitudinal, radial and circumferential strain (LS, RS, CS) compared to age and gender lean controls. We also examined if changes in deformation would be reflected in abnormal ventricular vascular coupling indices (VVI). METHODS:In a prospective cross-sectional design 39 obese adolescents (15.9 ± 1.7 years; 101.5 ± 39 kg; female - 58%) were compared to age and gender matched lean controls (15.7 ± 1.8 yrs, 60 ± 12.8 kg). Based on results from an oral glucose tolerance test (OGTT), obese adolescents were categorized as obese normoglycemic (ONG, n = 25) or obese dysglycemic (ODG, n = 14). Left ventricular (LV) global and average LS, CS, RS and strain rate were measured. LV ejection fraction and mass index were measured and VVI approximated as ratio of arterial elasticity (Ea) and end-systolic elastance (Ees). RESULTS:Adolescents with ODG had significantly (P = 0.005) impaired global LS (- 20.98% ± 2.8%) compared to controls (- 23.01% ± 2.3%). A similar (P = 0.0027) reduction was observed in average LS for adolescents with ODG (18.87% ± 2.5%) compared to controls (20.49% ± 2%). Global CS was also decreased (P = 0.03) in ODG (- 23.95%) compared to ONG (- 25.80). A similar trend was observed in average CS after multivariate regression for BMI and blood pressure. CS correlated with HbA1c in both groups (P = 0.05). VVI had a negative correlation with both LS (r = - 0.4, P = 0.025) and CS rate (r = - 0.36, P = 0.04). CONCLUSIONS:Myocardial strain and strain rate were significantly altered in obese adolescents. Unfavorable subclinical reductions in global and average CS were more pronounced in adolescents with dysglycemia compared to obese adolescents with normoglycemia and controls. These data indicate progressive worsening of subendocardial function across the spectrum of glucose tolerance. Strain rate was predictive of VVI in obese adolescents, suggesting strain rate may be a sensitive marker for cardiac remodeling in abnormal glucose homeostasis states.

Background Prolonged neonatal hyperinsulinism (PHI) causes hypoglycemia in the neonatal period and is associated with perinatal stress. Even though diazoxide is an effective treatment option for PHI, it has serious adverse effects making an argument for safe yet expeditious wean off of diazoxide while ensuring normoglycemia. The objective of this study was to characterize clinical course, dose requirement and duration of treatment with diazoxide in our cohort of infants diagnosed with PHI. Methods A retrospective chart review of infants diagnosed with PHI during a 6-year period was done documenting the diagnostic workup and the duration of treatment with diazoxide. Results PHI was diagnosed (n = 20; mean ± standard deviation [SD]) at 14.3 ± 22.4 days. Elevated insulin (8.3 ± 8.4 mIU/L), normal cortisol (15.5 ± 6.6 μg/dL [6-21]), normal growth hormone (18.8 ± 15.7 ng/mL [0.1-6.2]) and inappropriate low serum free fatty acids (0.3 ± 0.2 mmol/L [>1.5]) levels were measured during hypoglycemia (plasma glucose <50 mg/dL). Detectable insulin at the time of hypoglycemia was measured in 17 of 20 infants while the same number (17/20) of infants had a positive glucagon stimulation test (GST). The dose of diazoxide was 10 ± 3.7 mg/kg/day and duration of treatment was 44.9 ± 27.9 days. Conclusions This study illustrates that the duration of treatment with diazoxide in infants with PHI can be shorter than previously reported in the literature. We speculate that active tapering of diazoxide started within a week after discharge from hospital as well an outpatient tapering of diazoxide based on glucose monitoring were possible reasons for this outcome.

PURPOSE OF REVIEW/OBJECTIVE:The purpose of this review is to present recent data that defines our current understanding of the role of the gut microbiome in the development of T2DM. RECENT FINDINGS/RESULTS:Recent studies focus on the physiology and molecular pathways of the gut microbiome-host interaction. Short-chain fatty acids (SCFAs) derived from the fermentation of plant-based nonsoluble fiber bind to G-protein-coupled receptors (GPR) GPR 41 and GPR 43 to induce enteroendocrine molecules that control appetite, and to upregulate intestinal gluconeogenesis gene expression that controls glucose regulation. "Metabolic endotexemia" reflects a state of low-grade systemic inflammation that results from lipopolysaccharide (LPS) release from the gut into the systemic circulation in response to a high-fat diet. Inflammatory pathways induced by LPS, activation of toll-like receptor-4 (TLR-4), and other inflammatory signaling pathways are mediators of systemic inflammation, insulin resistance and type II diabetes mellitus. SUMMARY/CONCLUSIONS:Recent scientific data support that derangements in the composition of the microbiota, termed "microbiome dysbiosis" is a factor in the development of "metabolic endotoxemia" and T2DM. Therapeutic options that target the gut microbiome in the treatment of T2DM are explored.

Objective Persistent hypoglycemia (PH) beyond 3 days of life warrants investigation which includes a critical sample. We report our case series of five neonates who presented with PH as the first sign of congenital hypopituitarism. Design This is a case series. Methods/Results This is a case series of five neonates evaluated at our academic institution in a 3-year period (2013-2016), who presented with persistent severe hypoglycemia and were subsequently diagnosed with congenital hypopituitarism. All neonates were full term (mean gestational age 39.8 ± 1.4 weeks) born by caesarian section with a mean weight of 3.5 ± 0.16 kg and a mean length of 51.2 ± 1.2 cm at birth. All five neonates had PH beyond 3 days with an average blood glucose (BG) <35 mg/dL at presentation, requiring a mean glucose infusion rate (GIR) of 7.22 ± 1.98 mg/kg/min. The average BG during the critical sample was 42 ± 0.16 mg/dL (three patients). The mean duration of requirement of the glucose infusion was 6.2 ± 3 days during the immediate neonatal period. Diagnosis of the hypopituitarism took 2-52 days from the initial presentation of hypoglycemia. Besides growth hormone (GH) deficiency, cortisol deficiency was diagnosed in all the five neonates. Neuroimaging findings in all the neonates were consistent with pituitary stalk interruption syndrome (hypoplastic anterior pituitary, ectopic posterior pituitary [EPP] and interrupted pituitary stalk). Conclusions Hypoglycemia is a common metabolic complication affecting an infant in the immediate neonatal period. Delay in the diagnosis of hypopituitarism presenting as hypoglycemia is the result of the lack of awareness among neonatologists and/or pediatricians. We propose that providers be cognizant that PH can be the only presentation of hypopituitarism in the neonatal period. Therefore, having a high index of suspicion about this condition can avoid a delay in the evaluation, diagnosis and treatment of hypopituitarism.

The modalities currently employed to screen for type 2 diabetes mellitus (T2DM)/prediabetes are HbA1c, fasting plasma glucose (FPG), and 2-hour plasma glucose (PG) during an oral glucose tolerance test (OGTT). The purpose of this review is to highlight the positive qualities and pitfalls of these diagnostic modalities and reflect on the most reasonable and effective approach to screen high risk youth. Given its inherent preanalytical advantages, glycated hemoglobin (HbA1c) continues to be the preferred diagnostic modality used by pediatricians to screen high risk youth. However, when the three aforementioned tests are performed in youths of different races/ethnicities, discrepant results for T2DM/prediabetes are observed. The prevalence rates for T2DM vary from 0.53% in Chinese youth (including youth of all body mass indexes) to 18.3% in high-risk, overweight, obese Korean youth. Moreover, the FPG is abnormal (>100 less than <126 mg/dL) in 15% of Korean youth versus 8.7% of Chinese youth. The prevalence rates for prediabetes are 1.49% in Chinese youth versus 21% in Emirati youth (HbA1c, 5.7%-6.4%). The coefficient of agreement, k, between these screening tests for T2DM are fair, 0.45-0.5 across all youth. However, using HbA1c as a comparator, the agreement is weak with FPG (k=0.18 in German youth versus k=0.396 in Korean youth). The American Diabetes Association (ADA) Standards of Medical Care Guidelines define "high risk youth" who need to be tested for T2DM and/or prediabetes. OGTT and HbA1c do not always detect T2DM in similar individuals. HbA1c may not be an ideal test for screening Hispanic and African American youth. FPG and OGTT are suitable screening tests for youth of ethnic minorities and those with cystic fibrosis or hemoglobinopathies. Performing all three tests either together or sequentially may be the only way to encompass all youth who have aberrations in different aspects of glucose homeostasis.

Diagnosis of adrenal insufficiency (AI) in infants can be difficult. While a low random cortisol can signal AI, often confirmatory tests are required when clinical suspicion is strong but the cortisol levels are equivocal. Several studies have demonstrated that in sick preterm infants, there is relative adrenal insufficiency (RAI) defined as an inadequate cortisol production relative to the degree of stress or illness, a condition which can last for several weeks, while in term infants the adrenal axis is mature at birth (Bagnoli F, Mori A, Fommei C, Coriolani G, Badii S, et al. ACTH and cortisol cord plasma concentrations in preterm and term infants. J Perinatol 2013;33:520-4). Adrenocorticotrophic hormone (ACTH) and corticotrophin releasing hormone (CRH) stimulation tests have been validated in infants in several studies. In light of recent reports of false-negative results of stimulation tests, it is imperative to highlight the pitfalls of these tests. The purpose of this communication is to bring attention to the accuracy of timing of these tests in infants.

PURPOSE/OBJECTIVE:Premature adrenarche (PA) often leads to polycystic ovary syndrome (PCOS). Higher anti-mullerian hormone (AMH) levels are reported in PCOS. We studied the androgen profile and AMH profiles in Hispanic girls with PA (aged 5-8 years) and age and body mass index (BMI) matched controls. METHODS:Retrospective review of electronic medical records of girls who met the inclusion criteria for premature adrenarche were done. RESULTS:PA girls (n=76) were matched to control girls (n=12) for age (mean±standard deviation) (6.7±1 years vs. 6.2±1.3 years) and BMI (20±10 kg/m2 vs. 17.8±2.7 kg/m2). Dehydroepiandrostenedione sulfate (63.3±51.3 μg/dL vs. 29.8±17.3 μg/dL, P&lt;0.001) and testosterone levels (11.4±4.8 ng/dL vs. 8.2±2.9 ng/dL, P=0.001) were significantly higher in the PA group than controls. AMH values (&lt;14 years: reference range, 0.49-3.15 ng/mL) were 3.2±2.2 ng/mL vs. 4.6± 3.2 ng/mL respectively in the PA and control groups and were not different (P=0.4). AMH did not show a correlation with bone age (P=0.1), and testosterone (P=0.9) in the PA group. 17-hydroxyprogesterone levels (17-OHP ng/dL) were 39.5±30.5 ng/dL vs. 36.8±19.8 ng/dL in PA versus control girls. The concentration of 17-OHP was not statistically different between the control and PA groups. CONCLUSION/CONCLUSIONS:Higher AMH was not observed in PA girls and no correlation with BA and androgen levels was observed.

OBJECTIVE:To study the effect of using a one time high dose "stoss therapy" of vitamin D2 (ergocalciferol: VD2) on indices of insulin sensitivity {whole body sensitivity index: WBISI} and secretion {insulinogenic index: IGI} measured during an oral glucose tolerance test (OGTT) in obese adolescents with VDD (25 OHD; serum metabolite of vit D: < 30 ng/dL). SUBJECTS AND METHODS/METHODS:In a randomized placebo controlled cross over design 20 obese adolescents with vitamin D deficiency (VDD) had baseline OGTT. Arm A received one time high dose 300,000 IU of ergocalciferol and Arm B received placebo. After 6 weeks the adolescents were reassigned to Arm A if they were in Arm B and vice versa. 25OHD, calcium, parathyroid hormone, comprehensive metabolic panel, urine calcium creatinine ratio were measured at each study visit. OGTTs to assess indices of sensitivity and secretion were done at baseline, 6 weeks and 12 weeks respectively. RESULTS:Adolescents were obese and insulin resistant (mean ± SD: mean age = 15.1 ± 1.9 years; BMI: 32.7 ± 9.8; homeostatic model of insulin resistance: HOMA-IR: 4.2 ± 2.8). Stoss therapy with VD2 increased 25OHD from baseline (16.7 ± 2.9 to 19.5 ± 4.5; p = 0.0029) when compared to the placebo. WBISI (2.8 ± 1.9) showed a trend towards improvement in Rx group (p = 0.0577) after adjustment for covariates. IGI (3 ± 2.2) showed an improvement in both Rx and placebo groups. CONCLUSIONS:Our study demonstrated that using a high dose of VD2 (300,000 IU) did not have any beneficial effect on insulin sensitivity (whole body sensitivity index {WBISI}) and secretory indices (insulinogenic index {IGI}) in obese adolescents. High dose "stoss therapy" of VD2 did not appear to have any beneficial effect on glucose homeostasis on obese adolescents.