Faculty Bibliography

PURPOSE OF REVIEW:Despite advances in type 1 diabetes (T1D) management, mortality is still increased, with cardiovascular disease (CVD) as the leading cause. Dyslipidemia is a highly prevalent modifiable CVD risk factor. We reviewed the existing literature on CVD mortality in T1D to highlight CVD risk in pediatric patients with T1D. RECENT FINDINGS:Pathophysiology of T1D and premature CVD risk is still not fully understood. Dyslipidemia remains a highly prevalent and undertreated CV risk factor in T1D. Statins have been shown to be safe and effective to improve CVD risk in adults with T1D, and in children with familial hypercholesterolemia, in addition to improving lipids levels in children with T1D. SUMMARY:T1D is associated with premature CVD mortality, and dyslipidemia is still a highly prevalent and undertreated CVD risk factor. We aim to educate and empower pediatric providers to optimize management of dyslipidemia in pediatric patients with T1D to potentially decrease the CVD risk.

INTRODUCTION/BACKGROUND:Gonadotropin releasing hormone analogs (GnRHas) are used for treatment of precocious puberty. Over the last decade, several new formulations have been approved. METHODS:The Drugs and Therapeutics Subcommittee of the Pediatric Endocrine Society (PES) undertook a review to ascertain the current treatment options, prescribing behaviors, and practices of GnRHas among pediatric endocrinologists practicing within the USA. The survey consisted of four main subsections: (1) description of clinical practice; (2) self-assessment of knowledge base of pediatric and adult GnRHa formulations; (3) current practice for treating central precocious puberty (CPP); and (4) utilization of healthcare resources. RESULTS:There were 223 survey respondents. Pediatric endocrine practitioners were most familiar with the pediatric one-monthly preparation, the 3-month preparation, and the histrelin implant (Supprelin®) (88%, 96%, and 91%, respectively), with lower familiarity for 24-week triptorelin intramuscular (Triptodur®) (65%) and 6-month subcutaneous leuprolide (Fensolvi®) (45%). Only 23% of the respondents reported being extremely familiar with the availability of adult formulations, and 25% reported being completely unaware of cost differences between pediatric and adult GnRHa preparations. The implant was the most preferred therapy (44%), but in practice, respondents reported a higher percentage of patients treated with the 3-month preparation. While family preference/ease of treatment (87%) was the key determinant for using a particular GnRHa preparation, insurance coverage also played a significant role in the decision (64%). Responses regarding assessment for efficacy of treatment were inconsistent, as were practices and criteria for obtaining an MRI. CONCLUSIONS:The survey indicated there is more familiarity with older, shorter acting GnRHas, which are prescribed in greater numbers than newer, longer acting formulations. There is lack of consensus on the need for central nervous system (CNS) imaging in girls presenting with CPP between 6 and 8 years of age and use of laboratory testing to monitor response to treatment. Insurance requirements regarding CNS imaging and laboratory monitoring are highly variable. Despite having similar constituents and bioavailability, there are substantial cost differences between the pediatric and adult formulations and lack of evidence for safe use of these formulations in children. The survey-based analysis highlights the challenges faced by prescribers while reflecting on areas where further research is needed to provide evidence-based practice guidelines for pediatric endocrinologists.

OBJECTIVES/OBJECTIVE:Obesity-induced insulin resistance (IR) is known to influence hepatic cytokines (hepatokines), including fibroblast growth factor (FGF-21), fetuin-A, and chemerin. This study aimed to investigate the association between hepatokines and markers of endothelial dysfunction and vascular reactivity in obese adolescents. METHODS:A total of 45 obese adolescents were categorized into three groups based on glucose tolerance: normal glucose tolerance (NGT), prediabetes (PD), and type 2 diabetes (T2D). We examined the relationships between FGF-21, fetuin-A, and chemerin with endothelial markers (plasminogen activator inhibitor-1 [PAI-1], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion marker-1 [VCAM-1]) and vascular surrogates (brachial artery reactivity testing [BART] and peak reactive hyperemia [PRH]). RESULTS:Obese adolescents (age 16.2±1.2 years; 62 % female, 65 % Hispanic) with NGT (n=20), PD (n=14), and T2D (n=11) had significant differences between groups in BMI; waist-hip ratio (p=0.05), systolic BP (p=0.008), LDL-C (p=0.02), PAI-1 (p<0.001). FGF-21 pg/mL (mean±SD: NGT vs. PD vs. T2D 54±42; 266±286; 160±126 p=0.006) and fetuin-A ng/mL (266±80; 253±66; 313±50 p=0.018), were significantly different while chemerin ng/mL (26±5; 31±10; 28±2) did not significantly differ between the groups. Positive correlations were found between chemerin and both PAI-1 (r=0.6; p=0.05) and ICAM-1 (r=0.6; p=0.05), FGF-21 and PAI-1 (r=0.6; p<0.001), and fetuin-A with TNFα (r=-0.4; p=0.05). Negative correlations were found between chemerin and PRH (r= -0.5; p=0.017) and fetuin-A and PRH (r=-0.4; p=0.05). CONCLUSIONS:In our cohort, IR predicted higher FGF-21 levels suggesting a linear relationship may exist between the two parameters. Hepatokines can augment alterations in the microvascular milieu in obese adolescents as demonstrated by their associations with the markers PAI-1, ICAM-1, and PRH.

UNLABELLED:One hour plasma glucose (1-hr PG) concentration during an oral glucose tolerance test (OGTT) is steadily emerging as an independent predictor of type 2 diabetes (T2D). METHODS/UNASSIGNED:We applied the current cut off thresholds reported in the pediatric literature for the 1-hr PG, 132.5 (7.4 mmol/l) and 155 mg/dL (8.6 mmol/l) during an OGTT, to report abnormal glucose tolerance (AGT) using ROC curve analyses. We determined the empirical optimal cut point for 1-hr PG for our multi ethnic cohort using the Youden Index. RESULTS/UNASSIGNED: CONCLUSION/UNASSIGNED:Our cross-sectional study affirms that the 1-hr PG can identify obese children and adolescents at increased risk for prediabetes and/or T2D with almost the same accuracy as a 2-hr PG. In our multi-ethnic cohort, a 1-hr PG ⩾ 155 mg/dL (8.6 mmol/l) serves as an optimal cut-point, using the estimation of the Youden index with AUC of 0.86 and sensitivity of 80%.We support the petition to consider the 1-hr PG as integral during an OGTT, as this adds value to the interpretation of the OGTT beyond the fasting and 2-hr PG.

PURPOSE OF REVIEW/OBJECTIVE:Lipoprotein(a) has emerged as a strong independent risk factor for cardiovascular disease. Targeted screening recommendations for Lp(a) measurement exist for adults and youth known to be at high-risk. However, Lp(a) measurements are not included in universal screening guidelines in the US; hence, most families in the US with high Lp(a) levels who are at risk of future atherosclerotic heart disease, stroke, or aortic stenosis are not recognized. Lp(a) measurement included as part of routine universal lipid screening in youth would identify those children at risk of ASCVD and enable family cascade screening with identification and early intervention for affected family members. RECENT FINDINGS/RESULTS:Lp(a) levels can be reliably measured in children as young as two years of age. Lp(a) levels are genetically determined. The Lp(a) gene is inherited in a co-dominant fashion. Serum Lp(a) attains adult levels by two years of age and is stable for the lifetime of the individual. Novel therapies that aim to specifically target Lp(a) are in the pipeline, including nucleic acid-based molecules such as antisense oligonucleotides and siRNAs. Inclusion of a single Lp(a) measurement performed as part of routine universal lipid screening in youth (ages 9-11; or at ages 17-21) is feasible and cost effective. Lp(a) screening would identify youth at-risk of ASCVD and enable family cascade screening with identification and early intervention for affected family members.

PURPOSE OF REVIEW:Non-invasive measurements such as arterial stiffness serve as proxy surrogates for detection of early atherosclerosis and ASCVD risk stratification. These surrogate measurements are influenced by age, gender, and ethnicity and affected by the physiological changes of puberty and somatic growth in children and adolescents. RECENT FINDINGS:There is no consensus of the ideal method to measure surrogate markers in youth (< 18 years of age), nor standardized imaging protocols for youth. Currently, pediatric normative data are available but not generalizable. In this review, we provide rationale on how currently used surrogates can help identify subclinical atherosclerosis in youth and affirm their role in identifying youth at risk for premature CVD.

PURPOSE OF REVIEW/OBJECTIVE:Atherosclerosis and associated cardiovascular risk factors originate in childhood; hence, early management of dyslipidaemia is vital. However, hypercholesterolemia remains untreated or undertreated in many youths. We review current therapies, drugs under investigation and consider potential future directions for the management of paediatric dyslipidaemia to highlight the recent evidence and new therapeutic options for future use. RECENT FINDINGS/RESULTS:Cardiovascular disease (CVD) risk factors in childhood, including dyslipidaemia, are associated with CVD risk and clinical CVD events in adulthood. Recent data show that initiation of statin therapy in childhood in children with familial hypercholesterolemia reduces the risk of CVD in adulthood. Several well tolerated and efficacious treatment options have become available in recent times for the management of dyslipidaemia in youth. Many new lipid-lowering drugs are under investigation to widen the available choices. Some of these drugs are now available for use in paediatrics, while some remain targets for future use. SUMMARY/CONCLUSIONS:We review available treatment options for paediatric dyslipidaemia management, discuss potential limitations and propose future directions. We also acknowledge the need for continued research in paediatrics for optimal paediatric dyslipidaemia management.

Objectives The COVID-19 pandemic caused stress, social isolation and physical inactivity in many. We proposed to review anthropometric/biochemical profiles in girls seen for precocious puberty (PP) (ages 5-8 years) during the pandemic (3/2020- 3/2021) compared to girls seen in the prior 2 years (2/2018-2/2020) and look at environmental and psychosocial impacts. Methods A retrospective chart review of the girls prepandemic (Pre-PD) were compared to those seen during the pandemic (PD). Criteria for PP: luteinizing hormone (LH range: 0.02-0.3 mIU/L, ECLIA, Esoterix) with >0.3 defined as pubertal; estradiol (range <36 pg/ml for age 7-9 years, LCMS, ARUP) with >=36.0 pg/ml defined as pubertal; follicle stimulating level (FSH 0.4- 6.5 IU/L ECLIA, ARUP). Girls with isolated adrenarche were excluded. Pelvic ultrasound with ovarian volumes (OVs>1cc considered pubertal) and MRI pituitary were done as indicated. Bone age/chronological age ratio (BA/CA) >1 was considered advanced. A Covid-19 impact survey was sent via a HIPAA compliant REDCap link to assess activity, sleep, and psychosocial stressors, distress on 0-10 scale (mild 0-4, moderate 5-7, severe 8-10) to families. T-tests and bivariate correlations were run (SPSS Ver 21). Results In total 56 subjects were included (pre-PD=23 vs. PD=33). A 30% increase in puberty referrals was noted during the pandemic. Weight (mean+ SD: Pre-PD vs. PD: 26.8+/-5 vs. 26.9+/-5.7 kg) and BMI (17.3+/-2.3 vs.16.8+/-2.3kg/m²). Estradiol (9.7+/-7.5 vs.21.9+/-16.6 pg/ml; p-value =0.006), random LH (1 vs. 15) were pubertal. OVs (1.75+/-1.1 vs. 2.75 cc) and BA/CA (1.1+/- 0.4 vs. 1.0+/-0.5) were seen in the two groups respectively. There was a correlation between estradiol levels and OVs in PD group (r= 0.5; p=.05). Survey results showed 61% of subjects used remote learning, 55% spent >4 hours on social media (Tik Tok, WhatsApp, etc.), 50% reported no exercise and 33% reported no social interaction. Stress was moderate with a parental report of 5.4/10, (50%essential workers, 18% lost jobs) & children reported stress level of 4.8/10. Conclusions We report an increased incidence of PP during the pandemic (perhaps due to a delay in evaluation) and a more advanced puberty (higher estradiol levels and greater OVs) compared to Pre-PD patients. Though weight gain, potentially due to inactivity, did not appear to contribute, we believe that stress, excessive social media use and/or isolation could be factors which contributed to the increased incidence of PP during the pandemic

OBJECTIVES/OBJECTIVE:To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents. METHODS:; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP). RESULTS:Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3-0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=-0.4, p=0.005) and SpO2 nadir (r=-0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance. CONCLUSIONS:Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO2 nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.