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Belly Fat Accumulation in Children
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In light of the recent discussions surrounding FRAM & belly fat accumulations, here is data on belly fat accumulation in children.
"Longitudinal Evaluation and Risk Factors of Lipodystrophy and Associated Metabolic Changes in HIV-Infected Children"
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 40(2) 1 October 2005
Definition of Lipodystrophy
The definition of lipodystrophy was based on skinfold thickness measurements. Values obtained for each skinfold were transformed into z-scores for gender and age.
Hypertrophic lipodystrophy is made up of accumulation of fat in the central truncal region. To identify the redistribution of fat depots, this lipodystrophy was defined by at least 1 abnormal central skinfold measurement (>3 standard deviations [SDs] for age and gender), together with an increased ratio of central/peripheral skinfolds (>3 SDs) with no major evidence of obesity (BMI <3 SDs).
Atrophic lipodystrophy is made up of loss of limb tissue and peripheral subcutaneous tissue. It was defined as sunken cheeks and/or any thin peripheral skinfold (<-3 SDs) with BMI in the normal range for age and gender (between -2 SDs and +2 SDs) so as to exclude wasting syndrome.
According to the definitions given previously, 32 (24.6%) children presented with evidence of fat redistribution at the time of the first observation: 14 with peripheral atrophy and 18 with central hypertrophy (Table 2). As shown in Table 3, BMI and waist circumferences, expressed as z-scores for age and gender, significantly differed between children with atrophy, hypertrophy, or no lipodystrophy; in contrast, percentage of fat mass did not differ between the 3 groups, attesting to a clear fat redistribution without any drastic change in fat mass.
Risk Factors for Lipodystrophy (bivariate analysis)
Thirty-two children presented with any type of lipodystrophy. In our population, 2 factors were found as significant predictors of lipodystrophy. Being of African origin was associated with a reduced risk in comparison to being white (OR = 0.19; P = 0.001). A longer NRTI treatment during the 4 years preceding the observation was associated with an increased risk of lipodystrophy (OR = 1.8 per year; P = 0.001). Although not statistically significant, a longer duration of the disease was also associated with an increased risk of lipodystrophy (OR = 1.1; P = 0.07).
DISCUSSION
Lipodystrophy and metabolic disturbances, such as dyslipidemia and insulin resistance, have been reported in HIV-infected children receiving intensive antiretroviral therapy, but the natural history of these complications is still poorly known. Using an objective assessment based on the measurement of 4 skinfold thicknesses, we observed a proportion of 25% of children being affected by lipodystrophy. This finding is in agreement with a previous observation reported by our group, where the frequency of lipodystrophy was evaluated to be 33% in a smaller independent group of children using the same methodology.6 It is similar (26%) to what was observed in a large retrospective cohort of 477 children, where fat redistribution was based on clinical observation.5
A recent study aimed at introducing an objective and sensitive definition of lipodystrophy.19 This study did not include children, however. The study showed that the definition of lipodystrophy was more sensitive when including an imaging measurement of fat mass by biphotonic absorptiometry. In our study, dual-energy x-ray absorptiometry (DEXA) could not be used for 2 reasons: restricted availability of the tool and the lack of reference values in children for the measurement of fat compartments. Instead, we used another objective measurement of fat mass based on the measurement of skinfold. For this parameter, French reference values for gender and age were available in children, allowing each value to be quantified calculating a z-score. The fact that no case of fat redistribution was observed in the small group of children (n = 5) who had never received any antiretroviral therapy points to the relevance of the measurement of skinfold thickness in the detection of fat redistribution in children. The extensive use of this method in clinical practice is hindered by the fact that it is tedious, however. The question of measurement of fat mass is crucial in children, because adiposity naturally changes with growth in terms of mass and distribution. It may be difficult to distinguish between natural changes or changes indicative of lipodystrophy using only clinical observation.
By contrast, we found a much larger proportion of children presenting with one of the metabolic disturbances (42%) already described as HAART associated. Usually, dyslipidemia is the most frequently documented complication in children, although HDL cholesterol is not frequently measured in children. We found a significant proportion of children (19%) with low HDL cholesterol values, however, indicating that here also the metabolic disturbances induced in children may not be different from those reported in adults. In the same line of evidence, fasting insulin levels, interpreted with respect to the physiologic insulin resistance induced by puberty,20 revealed that 13% of the children were indeed insulin resistant. When the OGTT was performed, only a few children were identified as having impaired glucose tolerance, whereas none of the 130 children showed overt diabetes. These results indicate that the complications of glucose metabolism may be rare but do exist in HIV-infected children.
The remarkable observation in this study is the great stability over 2 years of fat redistribution and metabolic disorders in HIV-infected children on HAART, except for insulin resistance (the proportion of which doubled over 2 years). This observation can be interpreted as an increase of the physiologic insulin resistance induced by puberty itself and amplified in this case by the interaction with the drugs.
Although based on cross-sectional observation at baseline, the present study identified factors associated with lipodystrophy or metabolic disturbances similar to those already reported in adults and children: severity of HIV infection, duration of treatment, NRTI use for lipodystrophy, and PI use for metabolic changes. We found a lesser proportion of African children affected by lipodystrophy, and they did not seem to progress rapidly. A large European pediatric study that included African children did not find ethnicity to be a risk factor of lipodystrophy as assessed by clinical observation.5 This difference may be attributable to methodologic differences only or may point to individual or genetic factors that influence lipodystrophy.
Our observations have 2 major clinical implications. First, puberty seems to be the time when children are most likely to develop lipodystrophy and metabolic complications, especially in children with severe underlying HIV infection; consequently, screening for metabolic changes should be reinforced at this age. Second, once developed, lipodystrophy and metabolic changes seem to be extremely stable over time. A better understanding of the pathogenesis of these disorders is necessary, however, so as to propose interventions to reduce the impact of these complications in HIV-infected children.
Authors: Beregszaszi, Marta MD; Dollfus, Catherine MD; Levine, Martine MD; Faye, Albert MD, PhD; Deghmoun, Samia; Bellal, Nassima MD; Houang, Muriel; Chevenne, Didier PhD; Hankard, Regis MD, PhD; Bresson, Jean-Louis MD#; Blanche, Stephane MD, PhD; Levy-Marchal, Claire MD
From INSERM Unit 690, Hopital Robert Debre, Paris France; Service d'Hemato-Immunologie, Hopital Trousseau, Paris, France; Service d'Hemato-Immunologie, Hopital Robert Debre, Paris, France; Unite d'Immunologie et d'Hematologie, Hopital des Enfants Malades, Paris, France; Laboratoire d'Hormonologie, Hopital Robert Debre, Paris, France; #Centre d'Investigations Cliniques, Hopital des Enfants Malades, Paris, France; Centre d'Investigations Cliniques, Hopital Robert Debre, Paris, France; and Laboratoire d'Endocrinologie, Hopital Trousseau, Paris, France.
Abstract
Objective: To assess the rate of progression of lipodystrophy and the associated metabolic disturbances over a 2-year period in children and to assess risk factors associated with lipodystrophy and metabolic disturbances.
Design: Multicenter 2-year prospective study with a standardized evaluation.
Methods: One hundred thirty children (median age = 10 years, 64 boys and 66 girls) receiving antiretroviral therapy were recruited in 3 pediatric clinics. Lipodystrophy was defined based on 4 skinfold thickness measurements. Fasting lipids and glucose profile were measured in all children.
Results:
The proportion of children presenting with lipodystrophy was 24.6%. Nineteen percent of children had high-density lipoprotein values less than 1 mmol/L. Twenty-two percent and 15% of children had values greater than 2 standard deviations for age and gender for cholesterol and triglycerides, respectively.
A total of 13.2% showed insulin resistance. A total of 42.7% showed at least 1 of these biologic disturbances. Prospective follow-up showed no progression at all over 2 years, except for a doubling of the number of children with insulin resistance. In multivariate analyses, ethnicity, previous severe clinical condition, duration of HIV infection, and nucleoside reverse transcriptase inhibitor treatment were significantly associated with lipodystrophy. Tanner stage V of puberty, severe clinical symptoms and protease inhibitor treatment were independently associated with the risk of metabolic disturbances.
Conclusions: Puberty seems to be the time when HIV-infected children taking potent antiretroviral therapy are more likely to develop lipodystrophy and metabolic complications, especially in children with a severe underlying HIV infection. Once developed, lipodystrophy and metabolic changes seem to be extremely stable with time.
BACKGROUND:
Lipodystrophy develops in the course of HIV infection under intensive treatment, such as highly active antiretroviral therapy (HAART). Fat redistribution, including peripheral atrophy and central hypertrophy, was first described in adults but has also been reported in children.1-11 The frequency of children presenting with lipodystrophy is variable (10%-33%) in the series of patients under study. As in adults, the assessment of lipodystrophy is hampered by the lack of a consensus on the definition.
Several serious metabolic complications have been described in association with fat redistribution, such as insulin resistance and dyslipidemia. The mechanisms underlying these changes are not yet elucidated. Although drug toxicity has been strongly suspected and can be influenced by individual susceptibility, the role of the virus itself has also been suggested. For several authors, these complications are mostly viewed as adverse effects of HAART. Protease inhibitors (PIs) have been strongly suspected in the development of insulin resistance and hypertriglyceridemia, and it has been shown that short-term administration of PIs in healthy volunteers can indeed induce insulin resistance.12 Some clinical studies have reported that administration of stavudine, a nucleoside reverse transcriptase inhibitor (NRTI), induces lipoatrophy. The metabolic disturbances (which can induce long-term cardiovascular toxicity) as well as the morphologic changes can affect adherence to treatment and quality of life.
In children, there are few reports documenting these complications of HIV infection. The frequency and severity of lipodystrophy and metabolic disturbances are still poorly understood in the pediatric population. It seems that lipodystrophy is indeed detectable in children, although the clinical picture of fat redistribution may be more subtle and more difficult to identify than in adults. If the definition of lipodystrophy is still controversial in adults, it is even more so in children, where patients are less numerous and adiposity itself is changing with physiologic growth. Moreover, the rate of progression and the factors associated with the evolution of these complications need to be documented.
The aim of the present study was first to assess the rate of progression of lipodystrophy and the associated metabolic disturbances based on a prospective and standardized evaluation over a 2-year period in a large multicenter sample of HIV-infected children. The second aim was to assess risk factors associated with lipodystrophy and metabolic disturbances.
Patients
Patients were enrolled in this study from December 2000 to April 2002 in the Clinical Immunology Departments of 3 different university children's hospitals in Paris. Eligibility criteria were proven HIV infection, age from 2 to 18 years, and not receiving treatment of any other chronic disease. Exclusion criteria were a severe clinical illness in the weeks before the observation and administration of steroids.
A total of 130 children were included, and 89 were seen for a new evaluation 24.7 ± 1.7 months after the first observation.
Children were included after receipt of informed parental consent, and the study protocol was approved by the Comite Consultatif de Protection des Personnes dans la Recherche Biomedicale (CCPPRB) Paris/St. Louis (Paris, France). Consent from the children was also obtained whenever possible.
Protocol
At each visit, the children were evaluated at the time of an outpatient medical visit. All patients were seen by the same investigator at each center.
Puberty was rated using Tanner stages. To describe fat distribution, 3 parameters were used: body mass assessed by body mass index (BMI), percent fat assessed by bioimpedancemetry for the overall fat mass, and skinfold thickness for the distribution of adiposity. BMI was calculated as the weight (kg)/height2 (m2) ratio and was expressed as a z-score according to reference values established in French children.13
Percent of body fat mass was measured using bioelectrical impedance measurement at 50 kHz and standard electrode positions (RJL Systems, Clinton Township, NJ), and calculations were made using the equation by Schwenk et al14 in children. An independent investigator blinded to the children's treatment performed evaluation of the lipodystrophy. Skinfold thicknesses (biceps, triceps, suprailiac, and subscapular) were measured twice by Harpenden skinfold calipers (Chambly-Medical, Chambly, France) at 5-minute intervals at each site. Subsequently, the 2 individual values for each site were averaged, and results were expressed as a z-score of the normal distribution for gender and age according to the French growth standard curve for each site.15 The central-to-peripheral ratio was calculated as the ratio of subscapular skinfold plus suprailiac skinfold to biceps skinfold plus triceps skinfold and similarly expressed as a z-score.
Waist circumference was measured as the smallest circumference at the level of the umbilicus and was expressed as a z-score for gender and age.
Serum samples were collected after a 10-hour fast, and total cholesterol, triglycerides, free thyroxine (T4), thyroid stimulating hormone (TSH), and cortisol concentrations were measured. Some children underwent an oral glucose tolerance test (OGTT) according to the World Health Organization's guidelines for children. Plasma glucose and serum insulin concentrations were measured at fasting and 30 and 120 minutes after loading. Results were interpreted according to the Word Health Organization's criteria,16 which identify 4 categories: normal tolerance to glucose, impaired fasting glycemia, impaired tolerance to glucose, and diabetes. Elevated fasting insulinemia together with normal glycemia was considered indicative of insulin resistance.
Antiretroviral treatment (medication and dosage) was recorded from the medical charts of the children from 4 years before inclusion onward. This time lag covers the whole period of prescription of PIs widely used since 1996 but not the period of prescription for all antiretroviral drugs in the study population; indeed, in most children, treatment had been given for much longer than 4 years.
Nadir values of CD4 T-lymphocyte percentage and highest plasma HIV RNA levels were recorded from the chart, and current values were measured at the time of observations. Severity of the disease was classified according to the Centers for Disease Control and Prevention's (CDC) revised pediatric classification17 identifying for classes of severity (N = less severe; A, B, and C = more severe).
Analytic Methods TOP
Glucose, cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured by automated enzymatic methods.
Serum insulin concentrations were measured using an immunoradiometric method (Bi-Insulin IRMA; Sanofi-Diagnostic Pasteur, Nanterre, France). Cross-reactivity with proinsulin and derived metabolites was less than 1%.
Serum free T4, TSH, and cortisol concentrations were measured using an automated chemoluminescence system (ACS 180 Chiron Diagnostic; Bayer Diagnostic, Cergy-Pontoise, France).
Values for HIV RNA and CD4 T-lymphocyte percentages were taken from the medical charts of the children.
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