Aaron L. Carrel

Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study

BACKGROUND Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition and diminished energy expenditure resembling a growth hormone deficient state. Hypothalamic dysfunction in PWS often includes decreased growth hormone (GH) secretion, suggesting a possible therapeutic role for exogenous GH treatment. OBJECTIVES AND METHODS After 6 months of observation to determine baseline growth rate, and with the use of a 12-month randomized controlled study design, the effects of GH treatment (1 mg/m2/d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 54 children with PWS (n = 35 treatment and n = 19 control). Percent body fat and bone mineral density were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotients. RESULTS Stimulated levels of GH in response to clonidine testing were low in all patients (peak, 2.0 ng/mL). After 12 months, GH-treated subjects showed significantly increased height velocity Z scores (mean, 1.0 1.7 to 4.6 2.9; P <.001), decreased percent body fat (mean, 46.3% 8.4% to 38.3% 10.7%; P <.001), and improved respiratory muscle function, physical strength, and agility (sit-ups, weight-lifts, running speed, and coordination). A significant decline in respiratory quotients occurred during GH therapy (0.81 to 0.77, P <.001), but total REE did not change. CONCLUSIONS GH treatment of children with PWS accelerated growth, decreased percent body fat, and increased fat oxidation but did not significantly increase total REE. Improvements in respiratory muscle strength, physical strength, and agility also occurred, suggesting that GH treatment may have value in reducing some physical disabilities experienced by children with PWS.

Glucocorticosteroid Therapy in Childhood Acute Lymphoblastic Leukemia

Treatment of childhood acute lymphoblastic leukemia has included glucocorticosteroids for almost 50 years. Glucocorticoids are the subject of renewed interest. In one randomized trial, deferral of glucocorticosteroids from the initial month of induction therapy to the second month of therapy decreased event free survival despite preservation of remission induction rate. Dexamethasone in induction and maintenance provides a better event free survival than prednisone for standard risk patients in an isotoxic comparison even though all patients received dexamethasone in Delayed Intensification (protocol II). In a third report, patients with prior glucocorticosteroid therapy who achieved remission with subsequent multiagent therapy had a relapse rate similar to that of patients in second remission after failure of multiagent therapy. In vitro and in vivo response of leukemic cells to glucocorticosteroids is highly predictive of outcome. At relapse, loss of in vitro sensitivity to glucocorticosteroids is common and out of proportion to the loss of sensitivity to other agents. Glucocorticoid induced cell kill does not require p53 function. Investigation of leukemic cell lines finds that glucocorticosteroid resistance is most commonly linked to altered receptor number or function. Not all ligands are equivalent. Cortivazol, a pyrazolosteroid, may bind to altered receptor in some cases and induce apoptosis in dexamethasone resistant leukemic cells. Host response to exogenous glucocorticosteroid also varies. Associations between host sensitivity, disease sensitivity, and glucocorticosteroid side effects like avascular necrosis of bone remain to be investigated.

Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits.

Infants with Prader–Willi syndrome (PWS) typically display failure to thrive and decreased muscle mass with excess body fat for age. Growth hormone (GH) therapy in children with PWS improves, but does not normalize, body composition and muscle strength and agility. The objective of this study was to determine the effects of earlier GH therapy on anthropometric measurements, body composition, and psychomotor development in affected PWS infants and toddlers. Twenty‐five subjects, ages 4–37 months, were randomized to 2 years of GH therapy (1 mg/m2/day) or 1 year of observation without GH treatment and then placed on GH (1.5 mg/m2·day) for 1 year only. Anthropometric measurements were obtained by standard methods: percent body fat, lean body mass, and total body bone mineral density by dual x‐ray absorptiometry; motor constructs of mobility and stability by the Toddler Infant Motor Evaluation; and cognitive and language function by the Capute Scales of Infant Language and Cognitive Development. GH‐treated PWS subjects demonstrated normalization of length/height standard deviation scores (SDS), faster head growth, increased lean body mass accrual, and decreased percent body fat (P < 0.005 for all parameters), as well as improved language (P = 0.05) and cognitive (P = 0.02) quotient Z‐scores compared with similarly aged untreated PWS subjects after 1 year into the study. PWS subjects treated before their first birthday spoke their first words at a mean age of 14.4 ± 2.8 months and walked independently at 23.3 ± 4.8 months. GH therapy was well‐tolerated; however, one PWS subject experienced scoliosis progression. As greater benefits were seen in our study with early treatment, prompt referral to a pediatric endocrinologist for consideration of GH therapy is recommended for PWS at an early age.

Long-Term Growth Hormone Therapy Changes the Natural History of Body Composition and Motor Function in Children with Prader-Willi Syndrome

BACKGROUND Children with Prader-Willi syndrome (PWS) have decreased muscle mass, hypotonia, and impaired linear growth. Recombinant human GH (hGH) treatment reportedly improves body composition and physical function in children with PWS, but these studies lack long-term control data. To assess the impact of hGH therapy begun early in life on the natural history of PWS, we compared height, body composition, and strength in similar-age children with PWS naïve to hGH with those treated with hGH for 6 yr. OBJECTIVES Forty-eight children with PWS were studied: 21 subjects (aged 6-9 yr) treated with hGH for 6 yr (beginning at 4-32 months, mean 13 +/- 6 months) were compared with 27 children of similar age (5-9 yr) prior to treatment with hGH. Percent body fat, lean body mass, carbohydrate/lipid metabolism, and motor strength were compared using analysis of covariance. RESULTS PWS children treated with hGH demonstrated lower body fat (mean, 36.1 +/- 2.1 vs. 44.6 +/- 1.8%, P < 0.01), greater height (131 +/- 2 vs. 114 +/- 2 cm; P < 0.001), greater motor strength [increased standing broad jump 22.9 +/- 2.1 vs. 14.6 +/- 1.9 in. (P < 0.001) and sit-ups 12.4 +/- 0.9 vs. 7.1 +/- 0.7 in 30 sec (P < 0.001)], increased high-density lipoprotein cholesterol (58.9 +/- 2.6 vs. 44.9 +/- 2.3 mg/dl, P < 0.001), decreased low-density lipoprotein (100 +/- 8 vs. 131 +/- 7 mg/dl, P < 0.01), and no difference in fasting glucose or insulin. CONCLUSIONS hGH treatment in children with PWS, begun prior to 2 yr of age, improves body composition, motor function, height, and lipid profiles. The magnitude of these effects suggests that long-term hGH therapy favorably alters the natural history of PWS to an extent that exceeds risks and justifies consideration for initiation during infancy.

Effect of conjugated linoleic acid on body fat accretion in overweight or obese children

BACKGROUND Conjugated linoleic acid (CLA) is a supplemental dietary fatty acid that decreases fat mass accretion in young animals. OBJECTIVE The aim of this study was to determine CLAs efficacy with regard to change in fat and body mass index (BMI; in kg/m(2)) in children. DESIGN We conducted a 7 +/- 0.5-mo randomized, double-blind, placebo-controlled trial of CLA in 62 prepubertal children aged 6-10 y who were overweight or obese but otherwise healthy. The subjects were randomly assigned to receive 3 g/d of 80% CLA (50:50 cis-9,trans-11 and trans-10,cis-12 isomers) or placebo in chocolate milk. RESULTS Fifty-three subjects completed the trial (n = 28 in the CLA group, n = 25 in the placebo group). CLA attenuated the increase in BMI (0.5 +/- 0.8) compared with placebo (1.1 +/- 1.1) (P = 0.05). The percentage change in body fat measured by dual-energy X-ray absorptiometry was smaller (P = 0.001) in the CLA group (-0.5 +/- 2.1%) than in the placebo group (1.3 +/- 1.8%). The change in abdominal body fat as a percentage of total body weight was smaller (P = 0.02) in the CLA group (-0.09 +/- 0.9%) than in the placebo group (0.43 +/- 0.6%). There were no significant changes in plasma glucose, insulin, or LDL cholesterol between groups. Plasma HDL cholesterol decreased significantly more (P = 0.05) in the CLA group (-5.1 +/- 7.3 mg/dL) than in the placebo group (-0.7 +/- 8 mg/dL). Bone mineral accretion was lower (P = 0.04) in the CLA group (0.05 +/- 0.03 kg) than in the placebo group (0.07 +/- 0.03 kg). Reported gastrointestinal symptoms did not differ significantly between groups. CONCLUSIONS CLA supplementation for 7 +/- 0.5 mo decreased body fatness in 6-10-y-old children who were overweight or obese but did not improve plasma lipids or glucose and decreased HDL more than in the placebo group. Long-term investigation of the safety and efficacy of CLA supplementation in children is recommended.

Environment and obesity in the National Children's Study.

Objective In this review we describe the approach taken by the National Children’s Study (NCS), a 21-year prospective study of 100,000 American children, to understanding the role of environmental factors in the development of obesity. Data sources and extraction We review the literature with regard to the two core hypotheses in the NCS that relate to environmental origins of obesity and describe strategies that will be used to test each hypothesis. Data synthesis Although it is clear that obesity in an individual results from an imbalance between energy intake and expenditure, control of the obesity epidemic will require understanding of factors in the modern built environment and chemical exposures that may have the capacity to disrupt the link between energy intake and expenditure. The NCS is the largest prospective birth cohort study ever undertaken in the United States that is explicitly designed to seek information on the environmental causes of pediatric disease. Conclusions Through its embrace of the life-course approach to epidemiology, the NCS will be able to study the origins of obesity from preconception through late adolescence, including factors ranging from genetic inheritance to individual behaviors to the social, built, and natural environment and chemical exposures. It will have sufficient statistical power to examine interactions among these multiple influences, including gene–environment and gene–obesity interactions. A major secondary benefit will derive from the banking of specimens for future analysis.

Effects of growth hormone on body composition and bone metabolism

Physiologic effects of growth hormone (GH) extend beyond the stimulation of linear growth during childhood and adolescence. These effects include building and sustaining lean body mass, facilitating the utilization of fat mass for energy needs, and maintaining bone mineral density. These nongrowth effects of GH appear to be important throughout life. Children and adults with severe GHD demonstrate marked reductions in lean body mass, increases in percent body fat, and subnormal bone mineral density. Replacement of GH attenuates these abnormalities, though it remains unknown whether it does so completely. Children with body composition abnormalities resembling the GHD state (e.g., Prader-Willi syndrome) also appear to respond fovorably to administration of GH treatment, and demonstrate concomitant improvements in strength and agility. Long-term body composition benefits of GH supplementation in these and other non-GHD individuals remain unproven.

Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: Changes during development

Background  Prader–Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with hyperghrelinaemia and increased insulin sensitivity. The role of ghrelin excess in the pathogenesis of obesity is unclear.

Decreased energy expenditure is caused by abnormal body composition in infants with Prader-Willi Syndrome

OBJECTIVE Infants with Prader-Willi syndrome (PWS) are hypotonic and underweight before the onset of childhood obesity. This study evaluates body composition in the PWS infant and its relationship to energy expenditure. STUDY DESIGN Sixteen infants and toddlers with PWS (mean age, 12.4+/-6 months; eight female subjects) underwent analysis of body composition with dual-energy x-ray absorptiometry and deuterium dilution, and energy expenditure with both doubly labeled water and indirect calorimetry. RESULTS Percent body fat was significantly increased (male subjects, P<.001; female subjects, P<.001) and fat-free mass (FFM) was significantly decreased (male subjects, P<.001; female subjects, P=.04) in infants with PWS when compared with age-matched published data for normal infants. Meanwhile, total energy expenditure was significantly decreased (male subjects, P=.025; female subjects, P<.001) in infants with PWS when compared with published normative data. There was a normal relationship between FFM and total energy expenditure in infants with PWS. CONCLUSION Compared with published data for infants without PWS, infants with PWS demonstrate increased percent body fat, decreased FFM, and decreased energy expenditure. Importantly, total energy expenditure per kilogram of FFM appears similar in infants with and without PWS. We conclude that lower energy expenditure in infants with PWS is caused by decreased FFM.

Childhood Obesity and Medical Neglect

The incidence of childhood obesity has increased dramatically, including severe childhood obesity and obesity-related comorbid conditions. Cases of severe childhood obesity have prompted the following question: does childhood obesity ever constitute medical neglect? In our opinion, removal of a child from the home is justified when all 3 of the following conditions are present: (1) a high likelihood that serious imminent harm will occur; (2) a reasonable likelihood that coercive state intervention will result in effective treatment; and (3) the absence of alternative options for addressing the problem. It is not the mere presence or degree of obesity but rather the presence of comorbid conditions that is critical for the determination of serious imminent harm. All 3 criteria are met in very limited cases, that is, the subset of obese children who have serious comorbid conditions and for whom all alternative options have been exhausted. In these limited cases, a trial of enforced treatment outside the home may be indicated, to protect the child from irreversible harm.