Abnormal Body Composition Research Articles

Proton magnetic resonance spectroscopy and single photon emission computed tomography study of the brain in asymptomatic young hyperlipidaemic Asian Indians in North India show early abnormalities.

To evaluate brain metabolism and cerebral blood flow in young patients with hyperlipidaemia. Proton magnetic resonance spectroscopy ((1)H MRS) and single photon emission computed tomography (SPECT) of the brain was carried out in 19 asymptomatic young patients with hyperlipidaemia (mean age 32.6 +/- 6.0 years, range 22-45 years) and 21 age-matched healthy controls divided into the following three groups; (i) hyperlipidaemics on pharmacological treatment (group 1, n = 13), (ii) hyperlipidaemics not on pharmacological treatment (group 2, n = 6) and (iii) control group of healthy subjects (group 3, n = 21). No statistical difference was observed in the brain metabolite ratios between controls and hyperlipidaemic patients (both treatment naive and treated) in the (1)H NMR study. Two hyperlipidaemic patients showed a lactate peak and one had a lipid peak. The SPECT study was abnormal in seven hyperlipidaemic patients. In the pooled data, 50% subjects with high serum triglyceride (TG) levels as opposed to 14% subjects with normal serum TG levels showed cerebral hypoperfusion. The choline/creatine (Cho/Cr) ratio of the occipital region of the brain showed correlation with the excess percentage of body fat (%BF) and low levels of high density lipoprotein cholesterol (HDL-C) compared to those with normal %BF and normal HDL-C levels, respectively, in pooled data of all subjects. The N-acetyl aspartate (NAA)/Cho ratio also showed correlation with hypercholesterolaemia. Serum TG levels were positively correlated with the NAA/Cr ratio (r = 0.62, P < 0.05) and the Cho/Cr ratio (r = 0.63, P < 0.05) in the parieto-temporal area in group 1 patients. The study revealed no difference in the brain metabolite ratios between controls and hyperlipidaemic patients, while some hyperlipidaemic patients showed abnormalities of cerebral blood flow. Brain metabolite ratios were also influenced by certain parameters of body composition and lipids. As abnormal body composition, hypertriglyceridaemia and low levels of HDL-C are prevalent in Asian Indians, such data are important and indicate a need for further study.

Body composition and cardiovascular risk factors in pretransplant hemodialysis patients

Background: Obesity, hyperlipemia and cardiovascular complications contribute to a significant proportion of morbidity and mortality of renal transplant patients and have negative effects on renal survival. Aim of the present study was to evaluate the main abnormalities in body composition and the prevalence of some cardiovascular risk factors in a population of hemodialyzed (HD) patients awaiting renal transplantation. Methods: We studied 151 HD patients, all included in a waiting list for renal transplantation, 97 males and 54 females, with mean age 47.4±12 years. Patients were divided into three groups according to their body mass index (BMI) (kg/m 2): 18.5 to 24.9 (normoweight, NW); 25.0 to 29.9 (overweight, OW); ⩾30 (obese, OB). The body composition measurements were obtained the day after the mid-week HD session using bioelectrical impedance analysis (BIA). Results: We found that 47 patients were NW (31%), while 56 were OW (37%), and 48 were OB (32%). BIA-measured body cell mass was (BCM) significantly increased in the OW as compared with the NW group ( P<0.001), but, of note, no significant difference was found in OB group in comparison with the OW. Total cholesterol and triglycerides plasma levels were significantly elevated in OW and OB patients with respect to NW ( P<0.05) and an increased prevalence of diabetes was seen in OB patients (NW: 6%, OW: 5%, OB: 12%). Conclusions: These data show that a large proportion of patients awaiting renal transplant are overweight or obese and a consistent part of them have other cardiovascular risk factors associated. Furthermore, obese HD patients have a BCM lower than predicted on the basis of BMI and show an altered metabolic profile. A better understanding of the characteristics of patients included in the renal transplant waiting list is crucial in order to design prospective studies that aim to define the proper risk profile for the selection of patients.

HGH for short stature: ethical issues raised by expanded access

When the only source of therapeutic human growth hormone (hGH) was pituitary-derived GH, rationing of this precious resource was a necessity. Recombinant DNA technology made hGH abundant, but this abundance also brought uncertainty, controversy, and discomfort to practitioners trying to practice ethically responsible medicine. Early debates focused on two central questions: (1) If hGHwere proven effective at increasing the height of children without GH deficiency (GHD), would the diagnosis of GHD be morally relevant in determining entitlement to hGH treatment? (2) Regardless of underlying cause, should the treatment of short stature be considered a medical problem justifying medical treatment, and, if so, to what degree? We argued that hGH effectiveness and serious disability rather than the designation of GHD should guide access. Others countered that patients with GHD had a disease deserving treatment, whereas children short from other causes did not have a disease (at least not that of GHD) and that to treat them would constitute enhancement and not therapy. The intervening years have in some ways clarified and in some ways complicated this debate. hGH has been approved by the Food and Drug Administration (FDA) for treatment of non–GH-deficient children with Turner syndrome, chronic renal insufficiency, short stature caused by intrauterine growth retardation, and, most recently, children with severe familial or idiopathic short stature (ISS). Thus, there is now consensus that the cause of short stature is not morally relevant in deciding who is entitled to treatment. The utility of GHD as a necessary or sufficient criterion for eligibility for treatment is a priori problematic, since the definition and ascertainment of GHD is still controversial and elusive. Isolated GHD (as conventionally diagnosed) is usually neither complete nor permanent. A continuum of GH secretion spans the clinical presentations of ‘‘partial’’ versus ‘‘severe’’ isolated GHD versus ‘‘complete’’ (ie, multiple pituitary hormone deficiency state) GHD. Children with isolated GHD (IGHD) without identifiable central nervous system abnormalities or metabolic evidence indicative of severe GHD (eg, hypoglycemia or abnormal body composition) comprise the majority of and most controversial hGH-treated patients. In the discussion below, ‘‘GHD’’ refers to these patients, not to severe, permanent GHD associated with hypoglycemia, identifiable central nervous system malformations, or multiple pituitary hormone deficiencies. In addition to proving the irrelevance of underlying cause, this transformation in practice has unmasked the limited relevance of the treatment/enhancement distinction in determining who is entitled to treatment. Defenders of this distinction argued that the non-GHD child did not have a disease and that the use of hGH in such a situation constituted enhancement, implicitly an inappropriate goal of the practice of medicine. Today, it is acknowledged that the non–GH-deficient child’s central concern is identical to that of the child with GHD; namely, ‘‘I am short and I would like to be taller.’’ To the child and the parent, it is irrelevant whether the condition being treated is a well-characterized ‘‘disease’’ caused by GHD or a less well-understood process, as is the case in Turner syndrome and ISS. If ‘‘enhancement’’ refers to a desire for a child to be taller than he would be if left alone, then all children involved in this debate are seeking enhancement. The object of concern is not GH deficiency but short stature, and the only relevant question is whether there is safe, effective, affordable treatment. From the Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin. Dr Allen serves as a grant reviewer for the Genentech Center for Research and receives research grant support from Genentech, Inc, and Eli Lilly, Inc. Submitted for publication Sept 15, 2003; last revision received Jan 15, 2004; accepted Feb 18, 2004. Reprint requests: David B. Allen, MD, Professor of Pediatrics, H4/448 CSC– Pediatrics, 600 Highland Ave, Madison, WI 53792-4108. E-mail: dballen@wisc.edu. J Pediatr 2004;144:648–52. 0022-3476/$ see front matter Copyrighta 2004 Elsevier Inc. All rights reserved.

Abnormalities of Body Composition in Peritoneal Dialysis Patients

Body composition changes occur in peritoneal dialysis (PD) due to abnormalities in nutrition and hydration. We investigated abnormalities of nutrition and hydration in PD patients compared with healthy controls by measurement of total body potassium (TBK) and body water compartments. Cross-sectional comparison study. We measured TBK--an indicator of body cell mass--by whole body counting, total body water (TBW) by deuterium oxide dilution, and extracellular water (ECW) by bromide dilution in 29 PD patients and 32 controls. The absolute mean value of TBK for PD patients was not significantly lower than in controls. The ratios of observed TBK to predicted TBK from prediction formulas were compared. Equations used were those of Boddy, Bruce, Burkinshaw, and Ellis and our own equation derived from a local control database (Leeds). Observed/predicted ratios of TBK were significantly less in PD than in control subjects for all equations. Water volumes did not differ between PD and control groups. Observed/predicted ratios for TBK in PD patients correlated with serum potassium (Boddy r = 0.355, p = 0.06; Bruce r = 0.411, p < 0.05; Burkinshaw r = 0.457, p < 0.01; Leeds r = 0.412, p < or = 0.05; Ellis r = 0.356, p = 0.06) and tended to correlate with serum albumin (Bruce r = 0.343, p = 0.07; Burkinshaw r = 0.421, p < 0.05; Leeds r = 0.357, p = 0.06; Ellis r = 0.310, p = NS). There was no relationship with serum potassium in controls. Serum albumin in PD correlated with TBK (r = 0.445, p < 0.02), TBK/height (r = 0.419, p < 0.05), TBK/weight (r = 0.554, p = 0.002), and TBK/TBW (r = 0.586, p = 0.0001). Extracellular water/intracellular water (ECW/ICW) was inversely related to TBK (r = -0.455, p < 0.02 in PD; r = -0.387, p < 0.05 in controls) and to TBK/height (r = -0.446, p < 0.02 in PD; r = -0.411, p = 0.02 in controls). TBK/weight reduced with age in PD (r = -0.445, p < 0.02), as did TBK/TBW in PD (r = -0.463, p < 0.02). ECW/ICW tended to increase with age in PD (r = 0.351, p = 0.06). Observed/predicted ratio of TBK is reduced in PD patients relative to healthy controls, indicating reduced body cell mass. Serum albumin and potassium reflect TBK indices in PD. Body water volumes did not differ between PD and controls, implying no overall abnormality in hydration in the PD group. However, ECW is relatively increased compared to ICW with decreasing TBK indices, suggesting relative ECW expansion with reduction in body cell mass.

Place de l'impédancemétrie dans le dépistage de la dénutrition à l'hôpital

The prevalence of malnutrition is high in patients and tends to worsen during the hospital stay. In the absence of one reliable method to evaluate patients, the assessment of nutritional status is based on a global approach. Body composition measurement by bio-impedance analysis (BIA) is one of these approaches. Body composition measurements can detect malnutrition or abnormal hydration. Fat free mass, fat mass, and total body water are the main body compartments that are evaluated. Determination of abnormal body composition can then guide nutritional support. The reliability of BIA depends on the equation used to predict body composition and the parameters included in the formula (weight, height, sex, age, race, etc.). These parameters allow to minimize measurement errors. Thus, formula developed for specific populations allow to evaluate the nutritional status with reasonable error rates. BIA has been found to be inaccurate with abnormal distribution of body compartments (ascites, dialysis, lypodystrophy, etc.) or extreme weights (cachexia, obesity). Multi-frequency or segmental BIA was developed to overcome hydration abnormalities and variations in body geometry. However, these techniques require further validation. The BIA seems to have some limitations. This review aims to assess the reliability of BIA to detect protein-calorie malnutrition at hospital admission or during nutritional follow-up of patients.

Assessing body composition in gastrointestinal disorders.

The assessment of body composition and energy requirements is important for the nutrition of healthy and pathological states such as gastrointestinal disorders, which are known to be associated with abnormalities in body composition among persons with malnutrition and malabsorption. Careful monitoring of body composition is thus recommended for assessing body water compartments, predicting caloric needs and physical performance, and evaluating the development of muscle mass in persons with malabsorption. In the present review we briefly describe the basic body composition models and various techniques used for their assessment and discuss the utility of measuring caloric requirements in persons with gastrointestinal disorders. Assessing body composition may improve the prognosis of malnutrition caused by gastrointestinal disorders and may be useful in monitoring diet treatment.

Effects of GH replacement on metabolism and physical performance in GH deficient adults.

GH deficiency (GHD) in adults is associated with abnormalities in body composition, metabolic derangements, sub-optimal physical performance, high incidence of adverse cardiovascular risk factors and poor quality of life. GHD adults are insulin resistant and have reduced hepatic glycogen stores, reduced insulin stimulated glucose utilization and reduced glycogen synthesis in muscle. GH replacement results in either no change or slight reduction in insulin sensitivity. Hence, it is important to monitor for the development of glucose intolerance in patients on long-term GH replacement. GHD is associated with a lipid profile known to predispose to premature atherosclerosis and cardiovascular disease, i.e. increased total and LDL cholesterol, decreased HDL cholesterol, increased small dense LDL particles and increased triglycerides. LDL-cholesterol abnormalities appear to improve with GH replacement even if maintained within physiological dose range; the greatest improvement occurs in those subjects with higher baseline total and LDL cholesterol values and in female patients with adult onset GHD compared with male patients with childhood onset GHD. In contrast, hypertriglyceridaemia is not corrected by GH replacement. The majority of the reports suggest GH replacement increases Lipoprotein-a levels. Long-term observation will be required to determine whether GH replacement reduces cardiovascular morbidity and mortality in GHD adults. The reduced muscle mass and strength associated with GHD has been shown to improve after GH replacement. GH treatment also improves maximal and sub-maximal exercise performance in GHD adults. The effects on protein metabolism, energy expenditure and thyroid metabolism in GHD adults are also critical.

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

ObjectiveInfants 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 designSixteen 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. ResultsPercent 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. ConclusionCompared 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.

Insulin and carbohydrate dysregulation.

Patients with human immunodeficiency virus receiving highly active antiretroviral therapy (HAART) may experience abnormal body composition changes as well as metabolic abnormalities, including dyslipidemia, increases in triglycerides, low high-density lipoprotein cholesterol levels, and abnormal carbohydrate metabolism, ranging from insulin resistance with and without glucose intolerance to frank diabetes. Whether the body composition changes (i.e., increased visceral adiposity and fat wasting in the peripheral tissues) are linked to abnormalities in carbohydrate metabolism is unclear. The use of HAART with and without therapy with protease inhibitors (PIs) is related to carbohydrate abnormalities and changes in body composition. Regimens that include PIs appear to have a higher incidence of insulin resistance (up to 90%) and diabetes mellitus (up to 40%). The etiology of these abnormalities is not well understood; what is known about insulin and carbohydrate dysregulation with HAART is discussed.

Calculating energy requirements for men with HIV/AIDS in the era of highly active antiretroviral therapy.

1. To determine if resting energy expenditure (REE) adjusted for body composition is elevated in HIV-positive males when compared with healthy controls in the era of highly active antiretroviral therapy. 2. To examine the accuracy of prediction equations for estimating REE in people with HIV. 3. To determine if REE adjusting for body composition is significantly different between those HIV-positive subjects reporting lipodystrophy (LD) or weight loss (>or=5%) and those who are weight stable when compared to controls. Cross-sectional study. Tertiary referral hospital HIV unit and an outpatient clinic specializing in HIV care. HIV-positive males (n=70) and healthy male controls (n=16). REE was measured using indirect calorimetry. Body composition was assessed using bioelectrical impedance analysis. 1. REE when adjusted for fat-free mass and fat mass using the general linear model (analysis of covariance) was greater in HIV-positive subjects than controls (7258+/-810 kJ, n=70 vs 6615+/-695 kJ, n=16, P<0.05). 2. The Harris and Benedict, Schofield, Cunningham and the two equations previously published by Melchior and colleagues in HIV-positive subjects all gave an estimate of REE significantly different from the measured REE in the HIV-positive subjects, therefore a new prediction equation was developed. The inability of the published equations to predict REE in the different HIV-positive subgroups reflected the heterogeneity in body composition. 3. REE adjusted for fat-free and fat mass was significantly greater in the both the HIV patients who were weight stable and those with lipodystrophy compared with the healthy controls. REE is significantly higher in HIV-positive males when compared with healthy controls. Body composition abnormalities common in HIV render the use of standard prediction equations for estimating REE invalid. When measuring REE in HIV-positive males adjustment steps should include fat-free and fat mass.

Do all adults with growth hormone deficiency require growth hormone treatment?

Adult growth hormone (GH) deficiency results mainly from pituitary or peri-pituitary disease and/or its treatment and is frequently accompanied by other anterior pituitary hormone deficiencies. GH deficiency (GHD) results in a number of psychological and physical symptoms and signs which in combination constitute the adult 'GHD syndrome'. The psychological symptoms include decreased energy levels, social isolation, and lack of positive well being, depressed mood and increase in anxiety. The physical symptoms and signs include abnormal body composition with reduced lean body mass, increased central adiposity, and decreased extracellular fluid volume, decreased bone mineral density with an increased risk of fracture, reduced muscle strength, reduced exercise capacity, increased LDL cholesterol and reduced insulin sensitivity. Hypopituitarism and GHD are associated with an increased standardised mortality ratio. The diagnosis of GHD is confirmed by the insulin tolerance test or alternative stimulation test in the presence of structural pituitary disease and/or additional pituitary hormone deficiencies. Replacement with synthetic growth hormone by once daily subcutaneous injection can reverse many of the symptoms and signs of growth hormone deficiency, but the long-term effects are yet to be established. Whether or not all patients with GHD should receive GH replacement remains a matter for debate: a selective approach to therapy based on psychological well being and quality of life has been adopted in many centres.

Assessment of Fluid Status in Peritoneal Dialysis Patients

To assess the influence of abnormalities in fluid status and body composition on agreement between multifrequency bioimpedance analysis (MF-BIA), segmental BIA (sigmaBIA), the Watson formula, and tracer dilution techniques. Cross-sectional. Multicenter. 40 patients (29 males, 11 females) on peritoneal dialysis (PD). Agreement between the various techniques used to assess total body water (TBW) [MF-BIA, deuterium oxide (D2O), and the Watson formula] and extracellular water (ECW) [MF-BIA, bromide dilution (NaBr), and sigmaBIA], also in relation to the relative magnitude of the body water compartments [ECW (NaBr):body weight (BW) and TBW (D2O):BW] and body composition (DEXA). Second, the relation between body water compartments with echocardiographic parameters. Wide limits of agreement were observed between tracer dilution techniques and MF-BIA [TBW (D2O - MF-BIA) 2.0 +/- 3.9 L; ECW (NaBr - MF-BIA) -2.8 +/- 3.9 L], which were related to the relative magnitude of the body water compartments: r = 0.70 for ECW and r = 0.40 for TBW. sigmaBIA did not improve the agreement [ECW (NaBr-sigmaBIA): 3.7 +/- 2.9 L]. Also, wide limits of agreement were observed between D2O and the Watson formula (-2.3 +/- 3.3 L). The difference between D2O and Watson was related to hydration state and to percentage of fat mass (r = 0.70 and r = -0.53, p < 0.05). Both ECW and TBW as assessed by BIA and tracer dilution were related to echocardiographic parameters. Wide limits of agreement were found between MF-BIA and sigmaBIA with dilution methods in PD patients, which were related to hydration state itself. The disagreement between the Watson formula and dilution methods was related to both hydration state and body composition.

Avaliação do Metabolismo Glicídico e da Gordura Visceral em Adultos Deficientes de Hormônio de Crescimento

A síndrome da deficiência de hormônio de crescimento (DGH) no adulto e o conseqüente aumento no risco cardiovascular têm sido bastante estudados nos últimos anos. Com o objetivo de avaliar as alterações na composição corporal e a presença de resistência à insulina em adultos com DGH, estudamos 27 pacientes comparados a 27 indivíduos saudáveis pareados por idade, sexo e índice de massa corporal, através de tomografia computadorizada de abdômen para medida da gordura visceral e teste de tolerância oral à glicose (TTOG), com curva de glicose e insulina e estimativa da resistência à insulina pelo Homeostasis Model Assessment (HOMA). Observamos, nos pacientes, aumento do tecido adiposo visceral (p= 0,008) sem aumento da freqüência de alterações no TTOG. As glicemias e insulinemias basais e após 2 horas de sobrecarga oral de glicose e as áreas sob as curvas de glicose e insulina foram semelhantes ao grupo controle (p&gt; 0,05). Não houve diferença na sensibilidade à insulina pelo método HOMA (p= 0,989). Houve correlação positiva significativa da medida de gordura visceral nos pacientes com as dosagens de glicemia (r= 0,583; p= 0,001) e insulina (r= 0,728; p= 0,001) após sobrecarga de glicose e as áreas sob a curvas de glicose (r= 0,403; p= 0,040) e insulina (r= 0,713; p= 0,001), porém sem correlação significativa nos controles (r&lt; 0,40; p&gt; 0,05). Em conclusão, não houve alteração significativa no metabolismo glicídico, apesar do aumento da adiposidade visceral observada em adultos DGH.

Lipodystrophy syndrome and self-assessment of well-being and physical appearance in HIV-positive patients.

The lipodystrophy syndrome (LDS) is a growing problem in human immunodeficiency virus (HIV)-positive patients treated with highly active antiretroviral therapy (HAART). It is characterized by alterations of body composition and metabolic abnormalities. The goal of the study was to investigate attitudes toward health condition, well-being, and individual appearance in relation to LDS. Outpatients between July and October 2000 in an HIV-specialized unit at the University Hospital of Düsseldorf, Germany, underwent clinical evaluation and received a standardized written questionnaire. Of 389 patients eligible for analysis, 313 patients returned completed questionnaires (response rate, 80.5%). LDS was observed in 37.7%; the predominant manifestation was lipoatrophy of the face (32.9%). Individuals with and without LDS did not differ significantly in their attitude to the quality of their health condition and the amount of disturbance of their well-being by HIV infection. Participants with LDS felt recognizable as HIV-positive by physical appearance in 30.1%, compared to 18.3% in patients without LDS (p = 0.027). This difference became more pronounced after adjustment for gender, age, stage of disease, CD4 cell count, and duration of HAART (odds ratio, 2.04, 95%-confidence interval [CI] 1.09-3.84). In conclusion, LDS does not seem to disturb the general attitude toward health condition and well-being. However, patients presenting with lipodystrophy are about twice as likely to feel recognizable as HIV-positive by their physical appearance. LDS may thus be perceived as a characteristic mark of being HIV-positive by affected persons. A stigmatizing effect and social disadvantages may be the consequences.

Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study.

Obesity, poor growth, and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a GH-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While short-term benefits of treatment with GH have been shown, whether these beneficial effects are dose dependent and persist or wane with prolonged therapy remains uncertain. Effects of 24 additional months of GH treatment at varying doses (0.3, 1.0, and 1.5 mg/m(2).d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS, who had previously been treated with GH therapy (1 mg/m(2).d) for 12-24 months. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotient. A modified Bruininks-Oseretski test of physical performance evaluated strength and agility. During months 24-48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and REE occurred with GH therapy doses of 1.0 and 1.5 mg/m(2).d (P < 0.05), but not with 0.3 mg/m(2).d. BMD continued to improve at all doses of GH (P < 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. Salutary and sustained GH-induced changes in growth, body composition, BMD, and physical function in children with PWS can be achieved with daily administration of GH doses > or =1 mg/m(2). Lower doses of GH, (0.3 mg/m(2).d) effective in improving body composition in GHD adults, do not appear to be effective in children with PWS at sustaining improvement in body composition.

Resting metabolic rate, plasma leptin concentrations, leptin receptor expression, and adipose tissue measured by whole-body magnetic resonance imaging in women with Prader-Willi syndrome

Obesity in Prader-Willi syndrome (PWS) may be related to abnormalities in the adipocyte-leptin-hypothalamic pathway and may be exacerbated by reductions in the resting metabolic rate (RMR). We compared body composition, body-composition- adjusted RMR, and adiposity-adjusted plasma leptin between women with PWS and control women. We also examined leptin receptor expression in the PWS group. We studied body composition using whole-body magnetic resonance imaging and measured plasma leptin by radioimmunoassay in 45 control women aged 18-56 y and in 13 women with PWS aged 20-38 y. RMR was measured by indirect calorimetry in 41 control women and in 8 women with PWS. Age, body composition, and regional adipose tissue (AT) depots were corrected for by multiple regression analysis. Messenger RNA expression of the leptin receptor was examined by reverse transcriptase-polymerase chain reaction in lymphocytes. In the PWS group, fat mass was greater after correction for fat-free mass, and RMR was normal after correction for both fat-free mass and fat mass. Leptin was influenced primarily by subcutaneous AT volume in both subject groups. Leptin concentrations were not significantly different between the 2 groups after adjustment for age and AT content or distribution. Full-length leptin receptor messenger RNA was expressed in the lymphocytes of the PWS group. Differences in RMR in women with PWS are explained by abnormal body composition, suggesting that energy expenditure is normal at the tissue level in PWS. There is no evidence that defective leptin production causes obesity in PWS, and leptin receptor deficiency is not a primary consequence of the gene defects leading to leptin resistance.

Leptin concentrations in GH deficiency: the effect of GH insensitivity.

Disorders of GH secretion are known to impair the physiological lipostat and to affect the secretion of leptin, a sensitive marker of regional fat accumulation and total body composition. In both children and adults with GH deficiency (GHD), leptin levels are increased proportionately with enhanced adiposity. In GHI, mutations of the GH receptor gene result in a phenotype similar to GHD, with increased adiposity and unfavorable lipid profiles. To examine the impact of different forms of growth disorders on leptin production, we measured leptin levels in 22 GHI patients homozygous for the E180 splice mutation (15 females and 7 males, aged 8-37 yr) and compared results with those obtained in 20 subjects heterozygous for the mutation (11 females and 9 males, aged 7-54), 17 idiopathic GHD patients (6 females and 11 males, aged 3-34), and 44 normal subjects (25 females and 19 males, aged 7-45). After the baseline evaluation, all subjects received two 7-d GH treatments at doses of 0.025 and 0.050 mg/kg x d in random order. Leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3) were assayed by specific immunoassays. IGF-I and IGFBP-3 levels were significantly lower (P < 0.0001) in homozygous GHI and GHD patients compared with either controls or GHI heterozygotes. Circulating leptin levels were significantly higher in homozygous GHI patients than in normal controls (20.7 +/- 4.2 vs. 8.7 +/- 1.4 microg/liter) as well as when compared with heterozygous GHI subjects (14.4 +/- 3.4 microg/liter) and GHD patients (9.8 +/- 1.6 microg/liter; P < 0.01). Similar results were obtained when leptin was normalized for body mass index. When subjects were subgrouped by gender, leptin levels were significantly higher (P < 0.05) in GHI females than in females of all other groups and were significantly increased in GHD males (P < 0.01 vs. control males). Within the study groups, females had significantly higher leptin levels than males in controls (12.7 +/- 2 vs. 3.3 +/- 1 microg/liter; P < 0.001) and homozygous GHI patients (28.7 +/- 5.3 vs. 6.9 +/- 2.3 microg/liter; P < 0.05), but not in heterozygous GHI (20.1 +/- 5.4 vs. 7.3 +/- 2.4 microg/liter; P < 0.06) and GHD (10.9 +/- 2.6 vs. 9.2 +/- 2.1 microg/liter) patients. By multivariate analysis, log-normalized leptin levels were best predicted by gender and body mass index in homozygous GHI patients as well as in normal subjects. During the 1-wk courses of GH therapy, serum IGF-I and IGFBP-3 levels significantly increased (P < 0.0001) in GHD patients, heterozygous GHI patients, and control subjects at both GH doses. Inversely, leptin levels did not change significantly during either course of GH administration in the groups examined. These data demonstrate that leptin is increased in patients affected with long-standing homozygous GHI, probably reflecting abnormalities of body composition and metabolism typical of this condition.

Leptin Concentrations in GH Deficiency: The Effect of GH Insensitivity

Disorders of GH secretion are known to impair the physiological lipostat and to affect the secretion of leptin, a sensitive marker of regional fat accumulation and total body composition. In both children and adults with GH deficiency (GHD), leptin levels are increased proportionately with enhanced adiposity. In GHI, mutations of the GH receptor gene result in a phenotype similar to GHD, with increased adiposity and unfavorable lipid profiles. To examine the impact of different forms of growth disorders on leptin production, we measured leptin levels in 22 GHI patients homozygous for the E180 splice mutation (15 females and 7 males, aged 8–37 yr) and compared results with those obtained in 20 subjects heterozygous for the mutation (11 females and 9 males, aged 7–54), 17 idiopathic GHD patients (6 females and 11 males, aged 3–34), and 44 normal subjects (25 females and 19 males, aged 7–45). After the baseline evaluation, all subjects received two 7-d GH treatments at doses of 0.025 and 0.050 mg/kg·d in random order. Leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3) were assayed by specific immunoassays. IGF-I and IGFBP-3 levels were significantly lower (P < 0.0001) in homozygous GHI and GHD patients compared with either controls or GHI heterozygotes. Circulating leptin levels were significantly higher in homozygous GHI patients than in normal controls (20.7 ± 4.2 vs. 8.7 ± 1.4 μg/liter) as well as when compared with heterozygous GHI subjects (14.4 ± 3.4 μg/liter) and GHD patients (9.8 ± 1.6 μg/liter; P < 0.01). Similar results were obtained when leptin was normalized for body mass index. When subjects were subgrouped by gender, leptin levels were significantly higher (P < 0.05) in GHI females than in females of all other groups and were significantly increased in GHD males (P < 0.01 vs. control males). Within the study groups, females had significantly higher leptin levels than males in controls (12.7 ± 2 vs. 3.3 ± 1 μg/liter; P < 0.001) and homozygous GHI patients (28.7 ± 5.3 vs. 6.9 ± 2.3 μg/liter; P < 0.05), but not in heterozygous GHI (20.1 ± 5.4 vs. 7.3 ± 2.4 μg/liter; P < 0.06) and GHD (10.9 ± 2.6 vs. 9.2 ± 2.1 μg/liter) patients. By multivariate analysis, log-normalized leptin levels were best predicted by gender and body mass index in homozygous GHI patients as well as in normal subjects. During the 1-wk courses of GH therapy, serum IGF-I and IGFBP-3 levels significantly increased (P < 0.0001) in GHD patients, heterozygous GHI patients, and control subjects at both GH doses. Inversely, leptin levels did not change significantly during either course of GH administration in the groups examined. These data demonstrate that leptin is increased in patients affected with long-standing homozygous GHI, probably reflecting abnormalities of body composition and metabolism typical of this condition.

Long-term growth hormone replacement therapy in hypopituitary adults.

Growth hormone deficiency (GHD) in the adult has now been fully recognised as a clinical entity characterised by abnormal body composition, osteopenia, impaired quality of life, cardiac dysfunction and an adverse lipid profile. While short-term studies of GH replacement have demonstrated irrefutably a favourable effect on all if not most features of GHD, data on long-term administration spanning more than 2 years are still scarce. Experience of GH replacement up to 5 to 10 years indicate that the beneficial effects on body composition, predominantly a decrease in body fat and an increase in lean mass, is maintained during treatment. Long-term GH therapy also increases muscle strength and exercise performance. All data, with one exception, are consistent with a significant increase in bone mass during prolonged GH therapy. The most distinct effect on bone was observed in the worst affected individuals and in males. Improvement in quality of life is documented shortly after initiation of GH replacement and is maintained during long-term studies. This may explain the reduction in days of sick leave seen during GH therapy. The beneficial effect on cardiovascular risk factors is sustained over a prolonged period of time, revealing a reduction in intima wall thickness, and an improvement in serum lipid levels and clotting parameters. The increase in lipoprotein(a) levels with GH therapy in some studies may be disturbing, but difficulties in measuring this parameter and inconsistencies between the different studies makes it difficult to estimate its real impact. No data are yet available to show that GH replacement will normalise or even improve mortality rate and fracture rate. Adverse events associated with GH replacement therapy are mainly secondary to fluid retention as a result of excess dose administration. This can be adequately prevented by monitoring GH replacement according to serum insulin-like growth factor (IGF)-I levels. From what is currently known, GH replacement does not increase the prevalence of diabetes mellitus, and does not induce new neoplasms or recurrence of the primary brain tumour; however, longer follow-up studies are needed to provide definitive answers. In conclusion, it appears not only that long-term GH replacement therapy in adults with GHD is a procedure that can be safely used, but that GH replacement should be considered as a possible life-long therapy in order to maintain its benefits.

Pathophysiology of Body Composition and Metabolic Abnormalities in HIV-Infection: Therapeutic Implications

Changes in body composition and metabolism have been a central feature of HIV infection from the outset--initially, as the wasting syndrome and, more recently, as metabolic and body fat redistribution syndromes associated with antiretroviral (ARV) therapy. Here, advances in physiologic and biochemical understanding of these conditions are reviewed. First, the pathophysiology of wasting in HIV-1 infection is discussed, focusing on the failure of nutrients to increase lean tissue ("anabolic block") and the role of hypogonadism. Results of anabolic interventions, including recombinant growth hormone, testosterone, and progressive resistance exercise, are presented. Next, ARV-associated disorders are reviewed, including lipoatrophy and an hypothesized "mitochondrial toxicity." The possibility of establishing pathogenesis in vivo in humans, by direct measurement of mitochondrial DNA synthesis and adipocyte proliferation, is discussed. In summary, important advances have occurred toward the goal of explaining body composition and metabolic abnormalities associated with HIV disease.