Abnormalities in linear growth and the growth hormone-insulin like growth factor axis in children with chronic inflammatory disease

© 2015 Dr. Sze Choong WongPublications included in thesis:Wong, S. C., MacRae, V. E., McGrogan, P., & Ahmed, S. F. (2006). The role of pro-inflammatory cytokines on inflammatory bowel disease growth retardation. Journal of Pediatric Gastroenterology and Nutrition, 43(2), 144-155. DOI: 10.1097/01.mpg.0000226374.18494.14Wong, S. C., Smyth, A., McNeill, E., Galloway, P. J., Hassan, K., McGrogan, P. et al. (2010). The growth hormone-insulin like growth factor 1 axis in children and adolescents with inflammatory bowel disease and growth retardation. Clinical Endocrinology, 73, 220-228. DOI: 10.1111/j.1365-2265.2010.03799.xWong, S. C., MacRae, V. E., Gracie, J. A., McInnes, I. B., Galea, P., Garner-Medwin, J. et al. (2008). Inflammatory cytokines in juvenile idiopathic arthritis: effects on physical growth and the insulin like growth factor axis. Growth Hormone & IGF Research, 18(5), 369-378. DOI: 10.1016/j.ghir.2008.01.006MacRae, V. E., Wong, S. C., Farquharson, C., Ahmed, S. F. (2006). Cytokine actions in growth disorders associated with paediatric chronic inflammatory diseases (review). International Journal of Molecular Medicine, 18(6): 1011-1018. DOI: 10.3892/ijmm.18.6.1011MacRae, V. E., Wong, S. C., Smith, W., Gracie, A., McInnes, I. B., Galea, P. et al. (2007). Cytokine profiling and in vitro studies of murine bone growth using biological fluids from children with juvenile idiopathic arthritis. Clinical Endocrinology, 67(3), 442-448. DOI: 10.1111/j.1365-2265.2007.02908.xAhmed, S. F., Wong, J. S., & McGrogan, P. (2007). Improving growth in children with inflammatory bowel disease. Hormone Research, 68(Suppl. 5), 117-121. DOI: 10.1159/000110604Wong, S. C., Hassan, K., McGrogan, P., Weaver, L. T., & Ahmed, S. F. (2007).The effects of recombinant human growth hormone on linear growth in children with Crohn’s disease and short stature. Journal of Pediatric Endocrinology & Metabolism, 20, 1315-1324.Wong, S. C., Kumar, P., Galloway, P., Blair, J. C., Didi, M., Dalzell, A. M. et al. (2011). A preliminary trial of the effect of recombinant human growth hormone on short-term linear growth and glucose homeostasis in children with Crohn’s disease. Clinical Endocrinology, 74, 599-607 DOI: 10.1111/j.1365-2265.2011.03977.xImpaired linear growth is commonly encountered in children with chronic inflammatory conditions such as juvenile idiopathic arthritis (JIA) and inflammatory bowel disease (IBD), especially those with Crohn's disease (CD). Sub-optimal nutrition, prolonged use of glucocorticoid (GC) and chronic inflammation mediated by pro-inflammatory cytokines all play a role in contributing to the underlying aetiology of growth retardation by their effects on the secretion and sensitivity of systemic factors and directly at the level of target organs. In a group of children with JIA at acute relapse requiring intra-articular glucocorticoid injections, systemic IGF1 and IGFBP3 were noted to be normal but ALS was disproportionately low. Interleukin (IL5) and IL15 were noted to be associated with height in these children. In children with IBD and growth retardation who underwent evaluation of the GH axis with insulin tolerance test, my study demonstrated for the first time that a spectrum of abnormalities in secretion and sensitivity of GH and IGF1 may exist. Exposing fetal metatarsals to serum and synovial fluid of children with JIA at relapse show variable deficits in local bone growth not reversed by addition of blocking antibodies to TNFα, IL1β and IL6 did not reverse bone growth. In the first randomized controlled trial of rhGH at 0.067 mg/kg/day in children with IBD and growth retardation, my study showed that height velocity in the treated group improved by 140% over a 6 months period compared with only 17.4% in the control group. Similar to rhGH trials in other groups of children with chronic disease, reduction in insulin sensitivity was noted with no evidence of abnormalities in glucose homeostasis. Finally, systemic IGF1 increased in the rhGH treated group but remained within 2 standard deviation during the treatment period