[Show abstract][Hide abstract] ABSTRACT: Recombinant human growth hormone (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety including; cancer risk, impact on glucose homeostasis and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk and the need for longterm surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
European Journal of Endocrinology 11/2015; DOI:10.1530/EJE-15-0873 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
The aim of this study was to investigate the degree to which waist circumference (WC), body mass index (BMI), and magnetic resonance imaging (MRI)-measured abdominal fat deposition predict insulin resistance (IR) in nonobese girls of diverse racial and ethnic backgrounds.
Fifty-seven nonobese girls (12 African-American, 16 Hispanic White, and 29 non-Hispanic White girls) aged 11-14 years were assessed for WC, MRI hepatic proton density fat fraction, visceral and subcutaneous adipose tissue volume, BMI Z-score, fasting insulin, homeostasis model of assessment (HOMA)-IR, adiponectin, leptin, sex hormone-binding globulin, high-density lipoprotein cholesterol, and triglycerides.
Univariate and multivariate analyses adjusted for race and ethnicity indicated that only WC and visceral adipose tissue volume were independent predictors of fasting insulin and HOMA-IR, while hepatic proton density fat fraction, BMI Z-score, and subcutaneous adipose tissue volume were dependent predictors. Hispanic White girls showed significantly higher mean fasting insulin and HOMA-IR and lower sex hormone-binding globulin than non-Hispanic White girls (p < 0.01).
In nonobese girls of diverse racial and ethnic backgrounds, WC, particularly when adjusted for race or ethnicity, is an independent predictor of IR comparable to MRI-derived measurements of fat and superior to the BMI Z-score.
Hormone Research in Paediatrics 09/2015; 84(4). DOI:10.1159/000439130 · 1.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare complex quantitative magnetic resonance imaging (MRI) with MR spectroscopy (MRS) for quantification of hepatic steatosis (HS) and determine clinically significant MRI-based thresholds of HS in female youths.
This prospective, cross-sectional study was conducted in 132 healthy females (11-22 years, mean 13.3 ± 2). Proton density fat-fraction (PDFF) was measured using complex quantitative MRI and MRS. Body mass index (BMI), fasting labs [glucose, insulin, alanine aminotransferase (ALT), and other metabolic markers] were obtained. Outcomes were measured using regression analysis, Spearman-rank correlation, and receiver operator characteristics (ROC) analysis. HS was defined as MRI-PDFF >5.6 %.
HS was detected by MRI-PDFF in 15 % of all subjects. Linear regression demonstrated excellent correlation and agreement [r(2) = 0.96, slope = 0.97 (95 %CI: 0.94-1.00), intercept = 0.78 % (95 %CI: 0.58-0.98 %)] between MRI-PDFF and MRS-PDFF. MRI-PDFF had a sensitivity of 100 % (95 %CI: 0.79-1.00), specificity of 96.6 % (95 %CI: 0.91-0.99), and a kappa index of 87 % (95 %CI: 0.75-0.99) for identifying HS. In overweight subjects with HS, MRI-PDFF correlated with ALT (r = 0.84, p < 0.0001) and insulin (r = 0.833, p < 0.001), but not with BMI or WC. ROC analysis ascertained an optimal MRI-PDFF threshold of 3.5 % for predicting metabolic syndrome (sensitivity = 76 %, specificity = 83 %).
Complex quantitative MRI demonstrates strong correlation and agreement with MRS to quantify hepatic triglyceride content in adolescent girls and young women. A low PDFF threshold is predictive of metabolic syndrome in this population.
• Confounder-corrected quantitative MRI (ccqMRI) effectively measures hepatic triglyceride content in adolescent girls. • MRS and ccqMRI strongly correlate in liver proton density fat-fraction (PDFF) detection. • A PDFF threshold of 3.5 % may be predictive of paediatric metabolic syndrome.
European Radiology 04/2015; 25(10). DOI:10.1007/s00330-015-3724-1 · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Urban environments can increase risk for development of obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM) by limiting physical activity. This study examined, in a cohort of urban Hispanic youth, the relationship between daily physical activity (PA) measured by GPS, insulin resistance and cardiovascular fitness.
Hispanic middle school children (n = 141) were assessed for body mass index (BMI), IR (homeostasis model [HOMA-IR]), cardiovascular fitness (progressive aerobic cardiovascular endurance run [PACER]). PA was measured (GPS-PA) and energy expenditure estimated (GPS-EE) utilizing a global positioning mapping device worn for up to 7 days.
Students (mean age 12.7 ± 1.2 years, 52% female) spent 98% of waking time in sedentary activities, 1.7% in moderate intensity PA, and 0.3% in vigorous intensity. GPS analysis revealed extremely low amounts of physical movement during waking hours. The degree of low PA confounded correlation analysis with PACER or HOMA-IR.
Levels of moderate and vigorous intensity PA, measured by GPS, were extremely low in these urban Hispanic youth, possibly contributing to high rates of obesity and IR. Physical movement patterns suggest barriers to PA in play options near home, transportation to school, and in school recess time. GPS technology can objectively and accurately evaluate initiatives designed to reduce obesity and its morbidities by increasing PA.
International Journal of Pediatric Endocrinology 12/2014; 2014(1):25. DOI:10.1186/1687-9856-2014-25
[Show abstract][Hide abstract] ABSTRACT: Objective:
To develop a risk assessment model for early detection of hepatic steatosis using common anthropometric and metabolic markers.
This was a cross-sectional study of 134 adolescent and young adult females, age 11-22 years (mean 13.3±2 years) from a middle school and clinics in Madison, Wisconsin. The ethnic distribution was 27% Hispanic and 73% non-Hispanic; the racial distribution was 64% Caucasian, 31% African-American, and 5% Asian, Fasting glucose, fasting insulin, alanine aminotransferase (ALT), body mass index (BMI), waist circumference (WC), and other metabolic markers were assessed. Hepatic fat was quantified using magnetic resonance imaging proton density fat fraction (MR-PDFF). Hepatic steatosis was defined as MR-PDFF>5.5%. Outcome measures were sensitivity, specificity, and positive predictive value (PPV) of BMI, WC, ALT, fasting insulin, and ethnicity as predictors of hepatic steatosis, individually and combined, in a risk assessment model. Classification and regression tree methodology was used to construct a decision tree for predicting hepatic steatosis.
MR-PDFF revealed hepatic steatosis in 16% of subjects (27% overweight, 3% nonoverweight). Hispanic ethnicity conferred an OR of 4.26 (95% CI, 1.65-11.04; P=.003) for hepatic steatosis. BMI and ALT did not independently predict hepatic steatosis. A BMI>85% combined with ALT>65 U/L had 9% sensitivity, 100% specificity, and 100% PPV. Lowering the ALT value to 24 U/L increased the sensitivity to 68%, but reduced the PPV to 47%. A risk assessment model incorporating fasting insulin, total cholesterol, WC, and ethnicity increased sensitivity to 64%, specificity to 99% and PPV to 93%.
A risk assessment model can increase specificity, sensitivity, and PPV for identifying the risk of hepatic steatosis and guide the efficient use of biopsy or imaging for early detection and intervention.
Journal of Pediatrics 05/2014; 165(2). DOI:10.1016/j.jpeds.2014.04.019 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: To provide information that will assist clinicians in assessing and addressing risk for obesity-related comorbidities in adolescents. Methods: Review of the literature. Results: Childhood obesity is a major public health concern. Prevention of obesity or early detection of its health consequences are important responsibilities or opportunities for primary care clinicians. While body mass index (BMI) screening is valuable, insulin resistance and other obesity-related comorbidities can develop even when BMI falls below the 95th percentile threshold for obesity. Detailed history and physical examination can help identify comorbidities and guide diagnostic evaluation. Referral to multidisciplinary clinics specializing in childhood obesity is warranted when obesity is particularly severe, comorbidities are present at baseline, or no improvement is noted after 6 months of intense lifestyle intervention. Conclusion: For optimal health outcomes, management of adolescent obesity and associated comorbidities is should be adapted based on an individual's overall risk rather than BMI alone.
Journal of clinical outcomes management: JCOM 02/2014; 21(2):87-96.
[Show abstract][Hide abstract] ABSTRACT: Objective:
In nonobese youth, to investigate whether hepatic fat deposition and its metabolic consequences vary between ethnic groups.
Design and methods:
Thirty-two nonobese girls (12 Hispanic White [H] and 20 non-Hispanic White [NHW] girls), aged 11-14 years old were recruited. Outcome measures were MRI measured hepatic proton density fat fraction (hepatic PDFF), BMI Z-score, waist circumference, fasting insulin, glucose, adiponectin, sex hormone-binding globulin [SHBG], ALT, AST, triglycerides, and HOMA-IR.
There were no significant differences in mean BMI Z-scores (P = 0.546) or hepatic PDFF (P = 0.275) between H and NHW girls; however, H girls showed significant correlations between hepatic PDFF and markers of IR (fasting insulin, HOMA-IR, adiponectin, SHBG, triglycerides; all P < 0.05), while NHW girls showed no significant correlations. Matched by hepatic PDFF or BMI Z-score, H girls had more evidence of IR for a given hepatic PDFF (mean insulin, HOMA-IR, and SHBG; all P < 0.05) or BMI Z-score (mean insulin and HOMA-IR; all P < 0.01) than NHW girls.
In nonobese female youth, ethnicity-related differences in effects of hepatic fat on IR are evident, so that in H girls, a given amount of hepatic fat appears to result in a more predictable and greater degree of IR than in NHW girls.
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
Recombinant human growth hormone (hGH) therapy in children with Prader-Willi syndrome (PWS) improves linear growth, body composition, physical strength and agility, and other metabolic parameters. These benefits must be weighed against potential adverse effects, including rare occurrences of sudden death. This review summarizes recent evidence important to a benefit-risk analysis of hGH use in children with PWS.
Studies consistently show that hGH improves stature, body composition, fat percentage and distribution, and other metabolic markers in children with PWS. Preliminary reports of improved cognitive development during hGH have also emerged. Scoliosis progression is influenced by growth rate, but frequency of occurrence and severity are not increased by hGH exposure. PWS genotype does not appear to affect response to hGH. Concerns about hGH-associated sudden death persist, but recent studies show either absence of change in sleep-disordered breathing or improved sleep cardiovascular function during hGH therapy.
Recent studies confirm and expand reported benefits of hGH therapy in children with PWS, including a possible salutary role in cognitive development. These findings support previous assertions that hGH can reduce morbidity and improve function in children with PWS, and suggest that potential risks of such treatment are favorably balanced by its benefits.
Current opinion in pediatrics 06/2013; 25(4). DOI:10.1097/MOP.0b013e328362c7a2 · 2.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context:rhGH therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the US in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge which includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events.Objective:To formulate recommendations for the use of rhGH in children and adult patients with PWS.Evidence:A systematic review of the clinical evidence in the pediatric population, including randomized controlled trials (RCTs), comparative observational studies and long term studies (>3.5 years). Adult studies included RCTs of rhGH treatment for [mteq] 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials and pharmaceutical registries.Methodology:Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (www.evidem.org/praderwilli).Conclusions:Following a multi-disciplinary evaluation preferably by experts, rhGH treatment should be considered for patients with genetically-confirmed PWS in conjunction with dietary, environmental and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.
The Journal of Clinical Endocrinology and Metabolism 03/2013; 98(6). DOI:10.1210/jc.2012-3888 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A family seeks evaluation and treatment of short stature in their 11.5-year-old son. He previously was in the 3rd percentile for height, but his growth rate has slowed during the past 2 years, and his height is now just below the 1st percentile (Fig. 1). His mother is 5 ft 0 in. (152 cm), and his father is 5 ft 6 in. (167 cm). The child's size at birth was normal. His medical history and a review of systems are unremarkable. His physical examination is normal and shows prepubertal development. The complete blood count, erythrocyte sedimentation rate, thyrotropin, tissue transglutaminase antibody, and insulin-like growth factor I (IGF-I) levels and growth hormone levels after provocative testing are normal. His skeletal maturation (bone age) is approximately 9 years, and his predicted adult height is 5 ft 5 in. (165 cm) plus or minus 1.3 in. (3.3 cm).(1) How should his condition be managed?
New England Journal of Medicine 03/2013; 368(13):1220-1228. DOI:10.1056/NEJMcp1213178 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prader-Willi syndrome (PWS), initially described by Prader, Willi, and Labhart in 1956, is characterized by obesity, hypotonia, hyperphagia, delayed motor skill acquisition, short stature, mental retardation, hypothalamic dysfunction, and hypogonadism. This article reviews current knowledge regarding causes of and potential treatments for impaired growth, body composition, and physical function observed in children with PWS. Growth failure due to PWS has become an approved indication for growth hormone (GH) therapy. However, treatment of these children has raised awareness of other potential benefits of GH therapy, which in this particular group of patients may exceed linear growth promotion in importance. These include improvements in body composition, which leads to improved physical strength and function and increased energy expenditure.
[Show abstract][Hide abstract] ABSTRACT: Caloric intake that exceeds energy expended and its consequences, particularly development of type 2 diabetes mellitus, is emblematic of a climate change for modern medicine - a phenomenon so complex, embedded in culture and economics, and intertwined with conflicts between individual freedom and societal health that solutions are difficult to envision. Chronic caloric surplus (rather than obesity itself) is a central cause of epidemic type 2 diabetes,(1) but differences in response to energy excess,(2)-(4) disproportionately present among disadvantaged youth, increase susceptibility to type 2 diabetes in early life. Indeed, the percentage of type 2 diabetes in cases of new-onset . . .
New England Journal of Medicine 04/2012; 366(24):2315-6. DOI:10.1056/NEJMe1204710 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing obesity and poor cardiovascular fitness (CVF) contribute to higher rates of type 2 diabetes mellitus (T2DM) in children. While the relative contributions of fitness and body fat on development of insulin resistance (IR) in children and adolescents remains unresolved, gender- and race-specific differences likely exist in the degree to which CVF influences IR and risk for T2DM. Better understanding of how gender and race affect interactions between body fat, CVF, and metabolic health would be helpful in designing effective and targeted strategies to reduce obesity-associated disease risk. We evaluated whether metabolic benefits of fitness on reducing inflammation and insulin resistance (IR) are affected by gender and race.
This cross-sectional study included 203 healthy children (mean age 12.2 y, 50% male, 46% non-Hispanic white (NHW), 54% racially diverse (RD)). Fasting insulin, glucose, hsCRP, and adiponectin were measured; race was self-reported; cardiovascular fitness (CVF) was evaluated by the Progressive Aerobic Cardiovascular Endurance Run. Associations between inflammation and gender, race, and CVF were evaluated using analysis of covariance. Multivariate regression analysis identified independent predictors of IR.
Fitness and inflammation were inversely related in both males and females (p < 0.01); this effect was marginally stronger in RD children (p = 0.06) and non-overweight males (p = 0.07). High BMI (p < 0.001), low fitness (p = 0.006), and (female) gender (p = 0.003) were independently associated with higher HOMA-IR. In males, BMI and fitness, but not race independently predicted HOMA-IR. In females, BMI and race, but not fitness independently predicted HOMA-IR.
In middle school children, the beneficial effects of fitness vary based on gender and race. High CVF has an enhanced anti-inflammatory effect in male and RD children. While BMI is the strongest predictor of IR in the study group as a whole, fitness is a significant predictor of IR only in males, and race is a significant predictor of IR only in females.
International Journal of Pediatric Endocrinology 03/2012; 2012(1):4. DOI:10.1186/1687-9856-2012-4
[Show abstract][Hide abstract] ABSTRACT: To develop a statewide school-based program of measuring and reporting cardiovascular fitness levels in children, and to create age- and sex-specific cardiovascular fitness percentile-based distribution curves.
A pilot study validated cardiovascular fitness assessment with Progressive Aerobic Cardiovascular Endurance Run (PACER) testing as an accurate predictor of cardiovascular fitness measured by maximal oxygen consumption treadmill testing. Schools throughout the state were then recruited to perform PACER and body mass index (BMI) measurement and report de-identified data to a centralized database.
Data on 20 631 individual students with a mean age 12.1 ± 2.0 years, BMI of 21.4 ± 5.1, and a cardiovascular fitness measured with PACER of 29.7 ± 18.2 laps (estimated maximal oxygen consumption of 36.5 mL/kg/min) were submitted for analysis. Standardized fitness percentiles were calculated for age and sex.
This study demonstrates the feasibility of performing, reporting, and recording annual school-based assessments of cardiovascular fitness to develop standardized childhood fitness percentiles on the basis of age and sex. Such data can be useful in comparing populations and assessing initiatives that aim to improve childhood fitness. Because health consequences of obesity result from both adiposity and physical inactivity, supplementation of BMI measurement with tracking of cardiovascular fitness adds a valuable tool for large-scale health assessment.
The Journal of pediatrics 02/2012; 161(1):120-4. DOI:10.1016/j.jpeds.2012.01.036 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recombinant human growth hormone (rhGH) is approved in the United States for treatment of idiopathic short stature (ISS). The occurrence of adverse events (AEs) and the long-term safety of rhGH treatment in this patient population are reviewed. Data were analyzed from postmarketing surveillance studies that included ISS patients, prospective ISS treatment trials and studies of specific AEs in smaller groups of rhGH-treated children. Frequency rates of targeted AEs (i.e., scoliosis, slipped capital femoral epiphysis, intracranial hypertension, pancreatitis) in patients with ISS are similar to or lower than the rates observed in other rhGH-treated conditions. At dosages of 0.24-0.37 mg/kg/week, rhGH treatment in children with ISS does not adversely affect blood glucose levels. At dosages ≥ 0.3 mg/kg/week, a dose-dependent increase in mean fasting and stimulated insulin levels is observed. Current evidence derived from 'on-treatment' surveillance studies suggests that rhGH does not increase the risk for new malignancies in children with ISS.The safety profile of rhGH at doses ≤ 0.37 mg/kg/week for the treatment of children with ISS is similar to or better than the profile seen in other rhGH-treated conditions and is not associated with any predictable AEs. Due to a continuing trend toward dose escalation to achieve greater height-promoting effects and the possibility of delayed post-treatment effects of hyperinsulinemia and/or heightened GH and insulin-like growth factor I exposure on cancer risk, caution and ongoing scrutiny of risks versus benefits are warranted.
Hormone Research in Paediatrics 09/2011; 76 Suppl 3(Suppl. 3):45-7. DOI:10.1159/000330159 · 1.57 Impact Factor