Manipulation pharmacologique de l'anabolisme : l'exemple de l'hormone de croissance

Optimal enteral or parenteral nutrition is not sufficient to correct protein catabolism during major metabolic stress or to systematically improve protein anabolism in chronic malnutrition. The administration of anabolic factors is therefore logical. The availability of human recombinant growth hormone (rhGH) and Insulin-like Growth Factor-I (rhIGF-I) permits their utilization in cases of metabolic stress and muscle catabolism. Their efficiency has been globally demonstrated. On the other hand, the data regarding possible clinical benefits are practically non-existent and the risk-benefit and cost-benefit ratios require further evaluation.This review summarizes the main clinical studies of rhGH and rhIGF-I and the relationship with catabolism or protein deficit. The main pathophysiological bases are presented.     

Effect de l'hGH sur le métabolisme des protéines et des acides aminés chez l'homme

The increased availability of human Growth Hormone (rhGH) as a result of recombinant molecular biology has provided the opportunity to explore its actions and potential utility in humans. rhGH administration is associated with an increase in the resting energy expenditure of GH-deficient adults, but has little effect on the resting energy expenditure of GH-sufficient individuals. By mechanisms which remain to be elucidated, rhGH increases the oxidation of fat, decreases the oxidation of protein, and has little effect on the oxidation of carbohydrate. The net effect of these changes in substrate oxidation is a reduction in fat mass and an increase in muscle mass in GH-deficient adults, and increased linear growth in GH-deficient children. The primary mechanism of rhGH on whole body protein would appear to increase the whole body rate of protein synthesis with little effect on the rates of proteolysis in both the fasting and intracibal conditions. rhGH appears to increase acutely the rates of protein synthesis in forearm tissues, but has little effect on muscle mass or strength following 3 months of treatment in GH-sufficient adults. The effects of rhGH on two experimental models of protein catabolism in humans (caloric restriction and glucocorticosteroid treatment) are reviewed. Our knowledge of the actions and utility of rhGH as a therapeutic agent has increased tremendously over the last decade. However, a great deal remains to be discovered about the specific genes induced or suppressed as a result of rhGH treatment before we will be knowledgeable in all of its potential clinical applications.     

Long-term risk of gastrointestinal tumor recurrence after postoperative treatment with recombinant human growth hormone

BACKGROUND: Recombinant human growth hormone (rhGH) promotes protein synthesis, accelerates wound healing, and maintains immune function in the catabolic state. It has also been claimed that rhGH may promote the activation of residual tumor cells, and therefore, increases the risk of tumor recurrence. This study aimed to investigate whether postoperative administration of rhGH increases the long-term risk of tumor recurrences in patients undergoing major gastrointestinal surgery for malignancy. METHODS: Patients (n =104) received three different doses of rhGH (0.075 IU/kg, 0.150 IU/kg, and 0.300 IU/kg) during 5 postoperative days in a placebo-controlled trial. Follow-up was performed for 56-70 months after radical tumor resection. Mean survival period and relapse-free survival were compared with the control group. RESULTS: Complete data were available for 75 patients. Thirty-five percent (n = 20) of all patients treated with rhGH showed tumor recurrences in comparison to 44% (n = 8) of patients given placebo. Mean survival period for rhGH-treated patients was 46 months (median 59 months); in controls, 42 months (median 58 months). The length of relapse-free survival tended to be longer in rhGH-treated patients (2-47 months; median, 21 months) compared with the patients who were given placebo (2-18 months; median, 13 months). CONCLUSIONS: The results demonstrate no evidence for an increased risk of tumor recurrence after rhGH treatment for a short period of time after removal of a gastrointestinal adenocarcinoma. Therefore, the positive metabolic effects of rhGH application can be used safely in the treatment of the postoperative catabolic state in the patient groups investigated.     

Modifications des pratiques d’élevage : conséquences pour la viande de porcs et autres monogastriques

The monogastric meat of today differs from that produced by the animals 50 years ago. The selection of animals according to growth performance has modified the sensorial and nutritional qualities of the meat. The carcass is less fat and the animals are slaughtered younger at the same weight. The lipid content of the meat is thus decreased. However, in the medical world, meat still has a negative image of being a fat meat whereas this is no longer the case. The rearing conditions influence the quality of monogastrics meat. The feeding level and the fat matter in the diet determine the rate and composition of growth (lipids/proteins) and influence the fatty acids composition. The lipid composition of tissues highly depends on the lipid composition of the diet. Therefore, the fatty acid profile of meat (n-3 fatty acid content for example) can be easily modified through feeding, thereby improving the meat quality for the consumer and meeting the nutritionist's requirements.     

Les effets métaboliques de l'hormone de croissance

Human growth hormone (GH) metabolism and the roles of this hormone in the body are becoming increasingly understood. Numerous factors regulate GH release by the pituitary gland in humans, including nutritional status, age, drugs and activity level. GH action in tissues is modulated by production of insulin-like growth factor-I (IGF-I), IGF binding proteins (IGFBPs), which may act as endocrine, paracrine or autocrine regulators, and other as yet poorly understood molecular events. GH has well described effects on carbohydrate, fat and protein metabolism: GH causes insulin resistance, enhances lipolysis and induces protein anabolism. In addition to routine use in children with GH deficiency, recombinant GH has been recently approved for use in many countries to enhance somatic growth in pediatric renal failure, to improve body composition and physical/mental function in adults with GH deficiency and to counteract wasting in AIDS patients. The anabolic effects of GH are also being studied in other catabolic states, including patients requiring specialized feeding in the hospital and home setting.     

Aspects métaboliques de la dénutrition au cours de la maladie VIH

The Wasting Syndrome (WS) is one of the major aspects of the acquired immunodeficiency syndrome (AIDS). Fat free mass, the amount of functionnal protoplasm in non adipose tissue is an independent predictor of death in AIDS patients.The deficit of the energy balance could be the result of decreased caloric intake and/or increased energy expenditure. Elevated Resting Energy Expenditure (REE) has been reported in the early stage of the HIV infection. Patients with AIDS who had active secondary infection had a striking average weight loss resulting of the combination of anorexia and dramatic elevated REE. The role of cytokines in the WS was proposed in reason of the in vitro and in vivo metabolic disturbances induced by these cytokines. The difference studies suggest that synergistic interactions between cytokines may be necessary for developping the WS.     

Stratégies de dépistage de la dénutrition chez l''enfant hospitalisé

Metabolic stress modifies homeostasis, therefore nutrient's metabolism and nutritional needs. Stress is a risk factor of malnutrition, which increases morbidity and short-term mortality, and, in the child, can threaten long-term growth. Nutritional assessment is difficult in critically ill children. Nutritional support must be undertaken early as possible, especially in malnourished children and with severe agression. Enteral nutrition must be privileged. Parenteral nutrition is indicated when enteral nutrition is impossible, badly supported or insufficient to satisfy needs. Monitoring must be rigorous because aggression increases the risk of metabolic complications.     

Nutrition et insuffisance rénale chronique de l'enfant

The nutritional management of the uremic child depends on the residual glomerular filtration rate. When it has dropped to 25% of the normal range, one can observe decreased growth velocity, anemia, hyperparathyroidism, poor tolerance to changes in water and sodium intake and anorexia. The assessment of the nutritional status is based on anthropometric measurements by using standard deviation scores — i.e. body weight, height, growth velocity, head circumference and skinfold thickness —, on some biochemical parameter — i.e. serum proteins, calcium, phosphorus, parathyroid hormone and urea: creatinine ratio — and sometimes on biophysical methods (dual energy X ray absorptiometry). The current nutritional practices of the uremic child are less restrictive than in adults due to energy and protein requirements for both cerebral maturation and statural growth. Such uremic children should therefore be fed according to recommended dietary allowances, that often require tube feeding in infants. In addition to diet, some other treatments have a nutritional impact, like recombinant human growth hormone and erythropoietin. Such strategies should be adapted to the type of treatment — i.e. conservative, transplantation, haemodialysis, peritoneal dialysis.     

Place des facteurs de croissance dans le traitement de la dénutrition des patients dialysés

Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are two endogenous growth factors necessary for growth in children and maintenance of normal body composition in adults. The anabolic effects of these substances have been confirmed in vitro and in vivo since they are now available from recombinant synthesis. Chronic renal failure is associated with an impaired GH/IGF-1 axis responsible for abnormal growth in children and potentially involved in the frequent loss of muscle mass that occurs in adults undergoing chronic dialysis. Treatments with recombinant GH and/or IGF-1 induce strong anabolic responses in both adult and children suffering from renal failure. These encouraging results support the future use of these substances in the treatment of malnutrition in chronic renal failure patients.     

Troubles nutritionnels lors de la sclérose latérale amyotrophique (SLA)

Amyotrophic lateral sclerosis (ALS) is a rare neuromuscular disease, with a severe prognostic. Its consequences are not only neurological, but also nutritional, linked with a decrease of feeding, caused by swallowing and salivation disorders, a frequent anorexia or constipation, troubles due to a possible respiratory insufficiency, and sometimes important difficulties for going shopping, cooking and more simply putting the food into the mouth. Although fat-free mass is usually decreased during ALS, a paradoxical hypermetabolism is present in 50 to 70% cases, favouring nutritional alterations. The tools used for assessment, sometimes specific to the disability, are anthropometric criteria, body impedance analysis (BIA), dietetic surveys, dual X-ray absorptiometry and indirect calorimetry. Alimentary intakes, weight, fat-free mass and body mass index are progressively reduced, leading to malnutrition. BIA phase angle is largely decreased, reflecting severe cellular alterations. Disorders of lipid status are possible but inconsistent across studies and perhaps linked with cultural feeding habits. The loss of weight at diagnosis and malnutrition during evolution are independent prognostic factors for survival, justifying early nutritional assessment and care. During evolution of ALS, a higher level of fat mass seems to be a positive factor for survival. French, European and American recommendations give precisions on follow-up, modalities of fight against the causes of malnutrition, nutritional care, mainly including the use of oral energy and protein-enriched nutritional supplements and enteral nutrition.     

Mesures objectives de l’environnement bâti et statut pondéral des enfants et adolescents : revue de la littérature

In the framework of the study of the Environmental links to physical activity, nutrition and health (ELIANE), we performed a systematic review of the associations between objective spatial measurements of the built environment and weight status in youth. Of the 25 identified papers, 18 reported at least one significant relationship, although only almost one-third of the associations tested were significant. Inverse relationships of weight with different walkability indices were the most consistent (7/9 papers). Weight was also positively related to spatial accessibility to convenience stores (3/6 papers), and inversely to the accessibility to recreational physical activity facilities (4/9 papers). Relationships with parks, other food retail outlets and restaurants were inconsistent. Reasons for such discrepant results are discussed. Better-built environment measures are needed. The challenge lies also in better understanding the complex pathways through which the built environment, the socioeconomic context, and the perception of their environment by the subjects impact childhood behaviors and weight status.     

Polluants environnementaux et troubles de la reproduction masculine : les phtalates au cœur du débat

Two major functions are assumed by the testis: the production of male gametes (i.e. spermatozoa), and the production of steroid hormones. Those two functions are established during fetal life and are essentials for the adult fertility and the masculinization of the internal tract and genitalia. For many years, our laboratory has been interested in the ontogeny of those two functions in rodents and since 2003, in collaboration with Gynecology and Obstetrics service of Professor R. Frydman in A. Béclère hospital, we have studied them in human. The first aim of this work was to improve the global knowledge of the human fetal testis development by using both our experimental data and the literature. Then we focused on the different defects that can occur during the fetal testis development. Indeed, male reproductive abnormalities have been steadily increasing since the last decades and are thought to be related to the concomitant increase of the concentration of contaminants and particularly of endocrine disruptors in the environment. Thus, we decided to study the effect of endocrine disruptors on human fetal testis, and more particularly the effect of phthalates, by using an organ culture system developed for human. In contrast to the data obtained in rat, mono (ethylhexyl)-phthalate (MEHP), an active metabolite of the most widespread phthalate in the environment, does not disturb the steroidogenic function. On the other hand, it has a negative effect on the male germ cells number. This study is the first experimental demonstration of a negative effect of phthalates directly on human reproductive functions. Using a molecular approach, our aim is now to understand the mechanisms of phthalate's action.     

Prévalence et conséquences de la dénutrition dans l'insuffisance respiratoire chronique

From large series of patients with COPD, the prevalence of malnutrition can be estimated at 25% taking a cut-off value for Body Mass Index (BMI) less than 20 kg/m², and 35% for a body weight less than 90% of the ideal body weight. Data are very scarce for the other causes of respiratory failure. Malnutrition is a feature of emphysema. There is a well established correlation between height related body weight and FEV1, and TCO: it is not possible to assert that malnutrition is lither a cause or a consequence of the altered respiratory function. Nutritional status is a predictor for the capacity of exercise, independently of the alteration of respiratory function. There is probably a link between malnutrition and the performance of respiratory muscles. The prognostic influence of malnutrition in chronic respiratory failure is well established, with the best survival rates for overweight patients.     

Quelques aspects de la motivation à manger en fonction de l’index de masse corporelle (de la maigreur à l’obésité massive) dans un groupe de 2 509 adultes

This study examines how chronic dietary restraint, disinhibition, and hunger, as assessed by the Eating Inventory (also called the “Three Factor Eating Questionnaire”), vary over a broad range of Body Mass Index (BMI) values from leanness to massive obesity, in subjects with family obesity. EI factors were also studied as a function of personal weight history. Subjects were 2509 participants in a genetic study of obesity. BMIs ranged from 15 to 87kg/m². Multivariate analyses showed that restraint and disinhibition were significantly associated with the BMI in men, while only disinhibition was in women. Further analyses were performed after subdividing the population in 6 BMI groups. Disinhibition scores correlated strongly with hunger scores in both genders in all BMI categories; dietary restraint tended to correlate with the other two factors positively in leaner subjects, and negatively in highest BMI categories. The highest restraint scores were observed in nonobese adult women with previous obesity in childhood and/or adolescence, suggesting a beneficial influence of restraint on body weight loss. The role of behaviors associated with disinhibition in the development of body adiposity deserves further investigation.     

Measurement of Body Composition in Burned Children: Is There a Gold Standard?

Background: Maintaining lean body mass (LBM) after a severe burn is an essential goal of modern burn treatment. An accurate determination of LBM is necessary for short‐ and long‐term therapeutic decisions. The aim of this study was to compare 2 measurement methods for body composition, whole‐body potassium counting (K count) and dual x‐ray absorptiometry (DEXA), in a large prospective clinical trial in severely burned pediatric patients. Methods: Two‐hundred seventy‐nine patients admitted with burns covering 40% of total body surface area (TBSA) were enrolled in the study. Patients enrolled were controls or received long‐term treatment with recombinant human growth hormone (rhGH). Near‐simultaneous measurements of LBM with DEXA and fat‐free mass (FFM) with K count were performed at hospital discharge and at 6, 9, 12, 18, and 24 months post injury. Results were correlated using Pearson's regression analysis. Agreement between the 2 methods was analyzed with the Bland‐Altman method. Results: Age, gender distribution, weight, burn size, and admission time from injury were not significantly different between control and treatment groups. rhGH and control patients at all time points postburn showed a good correlation between LBM and FFM measurements (R ² between 0.9 and 0.95). Bland‐Altman revealed that the mean bias and 95% limits of agreement depended only on patient weight and not on treatment or time postburn. The 95% limits ranged from 0.1 ± 2.9 kg for LBM or FFM in 7‐ to 18‐kg patients to 16.3± 17.8 kg for LBM or FFM in patients >60 kg. Conclusions: DEXA can provide a sufficiently accurate determination of LBM and changes in body composition, but a correction factor must be included for older children and adolescents with more LBM. DEXA scans are easier, cheaper, and less stressful for the patient, and this method should be used rather than the K count.     

Effets physiopathologiques des mélanges de pesticides

Pesticides are considered as risk factors for human health. Indeed, epidemiological studies often show a positive correlation between occupational exposure and the risk of developing diseases for users and/or their descendants. The exposure of the general population is different from the exposure of professionals. Indeed, the consumer is exposed through the diet to mixtures of pesticides at low doses and during a long-term period. Now the question raised is what may be the impact of such an exposure on the health of consumers or their descendants. The hypothesis that compounds at doses corresponding to their No Observable Adverse Effect Level (NOAEL), which act via different mechanisms of action, could not exert an effect even when they are present in combination is today rebutted. Studies on endocrine disrupters or on pesticides mixture in general, as we develop in our laboratory, show that the effects of mixtures cannot be predicted from the effect of the single molecule. The effects of mixtures can be cumulative, antagonistic, additive or synergistic depending on the function or the parameter of the studied physiological function. Even if it is difficult to evaluate experimentally all possible combinations to which consumers may be exposed, it is essential to evaluate the effects of representative mixtures for a better understanding of the risk assessment of consumers.     

Mécanismes de la dénutrition au cours de l'insuffisance respiratoire chronique

The study of the mechanisms of denutrition during chronic obstructive pulmonary disease is useful because this common evolutive complication has severe functional consequences and is associated with a poor prognosis, irrespective of respiratory functional status. Conversely, renutrition improves the prognosis in these patients. Adaptation to hypoxia, the basis of which is oxygen conformance, is described. Denutrition during chronic obstructive pulmonary disease is linked to the imbalance arising from increased energy expenditure and inadequate food intake. The origins of the imbalance are discussed. The clinical implications of knowing the mechanisms of denutrition are set out and perspectives for both experimental and applied research are proposed.     

La réaction de Maillard dans les aliments : quels enjeux pour la santé humaine ?

The Maillard reaction is a complex mixture of temperature-dependent reactions between carbonyl compounds derived from sugars, lipids, and vitamins heat degradation products, and amino groups of amino acids, proteins or DNA. Among the numerous Maillard products (MP) formed, some are considered to raise safety problems because of their carcinogenicity, or pro-oxidant and inflammatory bioactivity. MP are produced in severely heat-treated food and partially absorbed, while reaching the endogeous pool of MP formed from glucose and lipid metabolites and biological proteins or DNA. If uncompletely degraded and/or excreted, they accumulate and promote the secretion of cytokines which are involved in the development of degenerative processes. The specific contribution of dietary MP in those physiopathological phenomena remains unknown. However, risk prevention supposes to control MP formation in food, while maintaining satisfactory sensorial quality.     

Fréquence et gravité des troubles du comportement alimentaire chez les jeunes diabétiques de type 1 : revue de la littérature

Eating disorders (ED) of young diabetics have been the subject of many publications for the last twenty years. They have been especially studied in the case of young girls in the pre-adolescent period or during adolescence. These eating disorders are part of DSM-IV classification: anorexia nervosa, bulimia nervosa or non other specified disorders (NOSD) where a clinical sign in the above mentioned diseases is lacking. An example of NOSD is “binge eating disorder”. Other more moderate ED, not classified in the DSM-IV have also been described. Ten case-control studies showed that anorexia nervosa does not appear frequently with diabetes, but when it does appear, mortality is very frequent. All the other ED are statistically more frequent with diabetes, especially binge eating disorder and the moderate ED which are not included in the DSM-IV. Purging behaviour, including insulin omission is equally frequent with young diabetics when weight must be controlled. This, will result in an increase of the HbA₁C and more of chronic complications, especially retinopathy. Two principal factors seem to enter into the appearance of the ED. First, weight, often higher than in control cases, where regulation can contribute to the apparition of ED to compensate for insulin omission. Then, bad familial environment, without really knowing if this is found more often with diabetes, or with ED control subjects. Several studies have shown that a follow up of ED is possible and efficient, but also, that ED are not always necessary in a certain number of cases, when more care is taken with young diabetics when the metabolic control is and continues to be mediocre.