The Role of Ghrelin in Weight Gain and Growth in Epileptic Children Using Valproate

Abstract

Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulin-like growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased ( P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period.

Keywords

ghrelin valproate body weight

Get full access to this article

View all access options for this article.

References

Bebin M. Pediatric partial and generalized seizures. J Child Neurol. 2002;17:65-69.

Biton V. , Mirza W. , Montouris G. , et al. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology. 2001 ;56:172-177.

Jallon P. , Picard F. Body weight gain and anticonvulsants. Drug Saf. 2001;24:969-978.

Corman CL , Leung NM , Guberman AH Weight gain in epileptic patients during treatment with valproic acid: a retrospective study. Can J Neurol Sci. 1997 ;24:240-244.

Gale SM , Castracane D. , Mantzoros CS Ghrelin and the regulation of energy homeostasis. Clin Lab Int. 2003;27:12-14.

Greco R. , Latini G. , Chiarelli F. , et al. Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid. Neurology. 2005;65:1808-1809.

Sun Y. , Ahmed S. , Smith RG Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol. 2003;23:7973-7981.

Asakawa A. , Inui A. , Kaga T. , et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003;52:947-952.

Cummings DE , Purnel JQ , Weigle DS , et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001 ;50:1714-1719.

10.

Bagnasco M. , Dube MG , Katz A. , et al. Leptin expression in hypothalamic PVN reverses dietary obesity and hyperinsulinemia but stimulates ghrelin. Obes Res. 2003;11:1463-1470.

11.

Lee PA Disorders of puberty. In: Lifshitz F , ed. Pediatric Endocrinology. 3rd ed. New York: Marcel Dekker; 1996:175-195.

12.

Mathews DR , Hasker JP , Rudenski AS , et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man. Diabetelogia. 1985;28:412-419.

13.

Anderson G. Children versus adults: pharmacokinetic and adverse-effect differences. Epilepsia. 2002 ;43:53-59.

14.

Coulter DL Carnitine deficiency: a possible mechanism for valproate hepatotoxicity . Lancet. 1984;24:689.

15.

Verrotti A. , Basciani F. , Morresi S. , et al. Serum leptin changes in epileptic patients who gain weight after therapy with valproic acid. Neurology. 1999;53:230-232.

16.

Nakazato M. , Murakarni N. , Date Y. , et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.

17.

Yıldız BO , Suchard MA , Wong ML , et al. Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity . Proc Natl Acad Sci USA. 2004;101:10434-10439.

18.

Whatmore AJ , Hall CM , Jones J. , et al. Ghrelin concentrations in healthy children and adolescents. Clin Endocrinol. 2003;59: 649-654.

19.

Wren AM , Seal LJ , Cohen MA , et al. Ghrelin enhances appetite and increases food intake in humans . J Clin Endocrinol Metab. 2001;86:5992-5995.

20.

Isojarvi JIT , Tauboll E. , Pakarinen AJ , et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med. 2001;111:290-296.

21.

Pylvanen V. , Knip M. , Pakarinen A. , et al. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia. 2002 ;43: 514-517.

22.

Vainionpaa LK , Rattya J. , Knip M. , et al. Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy. Ann Neurol. 1999;45:444-450.

23.

Rattya J. , Vainionpaa L. , Lanning P. , Isojarvi JIT. The effects of valproate, carbamazepine, oxcarbazepine on growth and sexual maturation in girls with epilepsy. Pediatrics. 1999;103:588-593.

24.

Malik IA , English PJ , Ghatei MA , et al. The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency. Clin Endocrinol. 2004;60:137-141.