Background: Growth in children with inflammatory bowel disease (IBD) is affected through a number of mechanisms; controlling disease activity and supporting poor nutritional status are paramount in these patients. Further understanding of the basic mechanisms by which cytokines influence growth will facilitate the development of therapeutic modalities to improve growth. Conclusions: Clinical management that addresses growth and puberty in children with IBD should be a partnership between paediatric gastroenterologists and endocrinologists. Well-designed studies of growth-promoting hormonal treatment may answer questions regarding the efficacy and safety of treating growth retardation in the subgroup of patients who continue to fail to grow despite optimal management of their IBD.

Keywords:
Cytokines, Growth hormone, Inflammation, Puberty, Stature
1.
Savage MO, Beattie RM, Camacho-Hubner C, Walker-Smith JA, Sanderson IR: Growth in Crohn’s disease. Acta Paediatr suppl 1999;88:89–92.
2.
Paerregaard A, Uldall Urne F: Anthropometry at the time of diagnosis in Danish children with inflammatory bowel disease. Acta Paediatr 2005;94:1682–1683.
3.
Sawczenko A, Sandhu BK: Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child 2003;88:995–1000.
4.
Saha MT, Ruuska T, Laippala P, Lenko HL: Growth of prepubertal children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1998;26:310–314.
5.
Ahmed SF, Horrocks IA, Patterson T, Zaidi S, Ling SC, McGrogan P, Weaver LT: Bone mineral assessment by dual energy x-ray absorptiometry in children with inflammatory bowel disease: evaluation by age or bone area. J Pediatr Gastroenterol Nutr 2004;38:276–281.
6.
Wong SC, Macrae VE, McGrogan P, Ahmed SF: The role of pro-inflammatory cytokines in inflammatory bowel disease growth retardation. J Pediatr Gastroenterol Nutr 2006;43:144–155.
7.
Sawczenko A, Ballinger AB, Savage MO, Sanderson IR: Clinical features affecting final adult height in patients with pediatric-onset Crohn’s disease. Pediatrics 2006;118:124–129.
8.
Martensson K, Chrysis D, Savendahl L: Interleukin-1β and TNF-α act in synergy to inhibit longitudinal growth in fetal rat metatarsal bones. J Bone Miner Res 2004;19:1805–1812.
9.
Macrae VE, Farquharson C, Ahmed SF: The restricted potential for recovery of growth plate chondrogenesis and longitudinal bone growth following exposure to pro-inflammatory cytokines. J Endocrinol 2006;189:319–328.
10.
Macrae VE, Wong SC, Smith W, Gracie A, McInnes I, Galea P, Gardner-Medwin J, Farquharson C, Ahmed SF: Cytokine profiling and in vitro studies of murine bone growth using biological fluids from children with juvenile idiopathic arthritis. Clin Endocrinol 2007;67:442–448.
11.
Hong CY, Park JH, Ahn RS, Im SY, Choi HS, Soh J, Mellon SH, Lee K: Molecular mechanism of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha. Mol Cell Biol 2004;24:2593–2604.
12.
Rettori V, Belova N, Kamat A, Lyson K, McCann SM: Blockade by IL-1-α of the nitrocoxidergic control of luteinizing hormone-releasing hormone release in vivo and in vitro. Neuroimmunomodulation 1994;1:86–91.
13.
Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald TT: Serum concentrations of tumour necrosis factor α in childhood chronic inflammatory bowel disease. Gut 1991;32:913–991.
14.
Street ME, de’Angelis G, Camacho-Hubner C, Giovannelli G, Ziveri MA, Bacchini PL, Bernasconi S, Sansebastiano G, Savage MO: Relationship between serum IGF-I, IGFBP-2, interleukin-1β and interleukin-6 in inflammatory bowel disease. Horm Res 2004;61:159–164.
15.
de Jager W, te Velthuis H, Prakken BJ, Kuis W, Rijkers GT: Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells. Clin Diagn Lab Immunol 2003;10:133–139.
16.
Wong SC, MacRae VE, Smith W, Gracie JA, McInness IB, Galea P, Gardner-Medwin J, Ahmed SF: Inflammatory cytokines in juvenile idiopathic arthritis: effects on physical growth and the insulin-like-growth factor axis. Submitted.
17.
Mushtaq T, Ahmed SF: The impact of corticosteroids on growth and bone health. Arch Dis Child 2002;87:93–96.
18.
Kelts DG, Grand RJ, Shen G, Watkins JB, Werlin SL, Boehme C: Nutritional basis of growth failure in children and adolescents with Crohn’s disease. Gastroenterology 1979;76:720–727.
19.
McHugh KJ, Collins SM, Weingarted HP: Central interleukin-1 receptors contribute to suppression of feeding after acute colitis in the rat. Am J Physiol 1994;266:1659–1663.
20.
Strobel CT, Byrne WJ, Ament ME: Home parenteral nutrition in children with Crohn’s disease: an effective management alternative. Gastroenterology 1979;77:272–279.
21.
Bannerjee K, Camacho-Hubner C, Babinska K, Dryhurst KM, Edwards R, Savage MO, Sanderson IR, Croft NM: Anti-inflammatory and growth stimulating effects precede nutritional restitution during enteral feeding in Crohn’s disease. J Pediatr Gastroenterol Nutr 2004;38:270–275.
22.
Beattie RM, Camacho-Hubner C, Wacharasindhu S, Cotterill AM, Walker-Smith JA, Savage MO: Responsiveness of IGF-1 and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn’s disease. Clin Endocrinol 1998;49:483–489.
23.
Ballinger AB, Azooz O, El-Haj T, Poole S, Farthing MJ: Linear growth retardation in experimental colitis is induced through a decrease in insulin-like growth factor-1 which is independent of malnutrition. Gut 2000;46:695–700.
24.
McLain BI, Davidson PM, Stokes KB, Beasley SW: Growth after gut resection for Crohn’s disease. Arch Dis Child 1990;65:760–762.
25.
Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM: Growth and clinical course of children with Crohn’s disease. Gut 1993;34:939–943.
26.
Motil KJ, Grand RJ, Davis-Kraft L, Ferlic LL, Smith EO: Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105:681–691.
27.
Markowitz J, Grancher K, Rosa J, Aiges H, Daum F: Growth failure in pediatric inflammatory bowel disease. J Ped Gastroenterol Nutr 1993;16:373–338.
28.
Burnham JM, Shults J, Semeao E, Foster B, Zemel BS, Stallings VA, Leonard MB: Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation and body composition. J Bone Miner Res 2004;19:1961–1968.
29.
Hammond A, Andus T, Gierend M, Ecker KW, Scholmerich J, Herfarth H, German Budesonide Foam Study Group: Controlled, open, randomized multicenter trial comparing the effects of treatment on quality of life, safety and efficacy of budesonide foam and betamethasone enemas in patients with active distal ulcerative colitis. Hepatogastroenterology 2004;51:1345–1349.
30.
Issenman RM, Atkinson SA, Radoja C, Fraher L: Longitudinal assessment of growth, mineral metabolism, and bone mass in pediatric Crohn’s disease. J Pediatr Gastroenterol Nutr 1993;17:401–406.
31.
Mushtaq T, Bijman P, Ahmed SF, Farquharson C: Insulin-like growth factor-I augments chondrocyte hypertrophy and reverses glucocorticoid-mediated growth retardation in fetal mice metatarsal cultures. Endocrinology 2004;145:2478–2486.
32.
Anonymous: Deflazacort – an alternative to prednisolone? Drug Ther Bull 1999;37:57–58.
33.
Rosen J, Miner JN: The search for safer glucocorticoid receptor ligands. Endocr Rev 2005;26:452–464.
34.
Owen HC, Miner JN, Ahmed SF, Farquharson C: The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438. Mol Cell Endocrinol 2007;264:164–170.
35.
Escher JC, Taminiau JA, Nieuwenhuis EE, Büller HA, Grand RJ: Treatment of inflammatory bowel disease in childhood: best available evidence. Inflamm Bowel Dis 2003;9:34–58.
36.
Markowitz J, Grancher K, Kohn N, Lesser M, Daum F: A multicentre trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895–902.
37.
Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, Kelnar CJ, Wallace WH: Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab 1998;83:3121–3129.
38.
Cezard JP, Nouaili N, Talbotec C, Hugot JP, Gobert JG, Schmitz J, Mougenot JF, Alberti C, Goulet O: A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (Remicade) in severe pediatric Crohn’s disease. J Pediatr Gastroenterol Nutr 2003;36:632–636.
39.
Borrelli O, Bascietto C, Viola F, Bueno de Mesquita M, Barbato M, Mancini V, Bosco S, Cucchiara S: Infliximab heals intestinal inflammatory lesions and restores growth in children with Crohn’s disease. Dig Liver Disease 2004;36:342–347.
40.
Walters TD, Gilman AR, Griffiths AM: Linear growth improves during infliximab therapy in children with chronically active severe Crohn’s disease. Inflamm Bowel Dis 2007;13:424–430.
41.
Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, Liu G, Travers S, Heuschkel R, Markowitz J, Cohen S, Winter H, Veereman-Wauters G, Ferry G, Baldassano R, REACH Study Group: Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology 2007;132:863–873.
42.
Tenore A, Berman WF, Parks JS, Bongiovannie AM: Basal and stimulated serum growth hormone concentrations in inflammatory bowel disease. J Clin Endocrinol Metab 1977;44:622–628.
43.
Chong SK, Grosssman A, Walker-Smith JA, Rees LH: Endocrine dysfunction in children with Crohn’s disease. J Pediatr Gastroentrol Nutr 1983;3:529–534.
44.
Thomas AG, Holly JM, Taylor F, Miller V: Insulin like growth factor-1, insulin like growth factor binding protein-1 and insulin in childhood Crohn’s disease. Gut 1993;34:944–947.
45.
Farthing MJ, Campbell CA, Walker-Smith J, Edwards CR, Rees LH, Dawson AM: Nocturnal growth hormone and gonadotrophin secretion in growth retarded children with Crohn’s disease. Gut 1981;22:933–938.
46.
Cezard JP, Touati G, Alberti C, Hugot JP, Brinon C, Czernichow P: Growth in paediatric Crohn’s disease. Horm Res 2002;58(suppl 1):11–15.
47.
Walker-Smith JA: Management of growth failure in Crohn’s disease. Arch Dis Child 1996;75:351–354.
48.
Kara E, Sungurtekin H, Sungurtekin U, Alkanat M, Ilkgul O: The effect of recombinant human growth hormone (rhGH) on trinitrobenzene sulfonic acid-induced colitis in rats: an experimental study. Inflamm Bowel Dis 2004;10:112–115.
49.
Slonim AE, Bulone L, Damore MB, Goldberg T, Wingertzahn MA, McKinley MJ: A preliminary study of growth hormone therapy for Crohn’s disease. N Engl J Med 2000;342:1633–1637.
50.
Theiss AL, Fuller CR, Simmons JG, Liu B, Sartor RB, Lund PK: Growth hormone reduces the severity of fibrosis associated with chronic intestinal inflammation. Gastroenterology 2005;129:204–219.
51.
Han X, Sosnowska D, Bonkowski EL, Denson LA: Growth hormone inhibits signal transducer and activator of transcription 3 activation and reduces disease activity in murine colitis. Gastroenterology 2005;129:185–203.
52.
Andiran N, Yordam N: TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy. Growth Horm IGF Res 2007;17:149–153.
53.
Mauras N, George D, Evans J, Milov D, Abrams S, Rini A, Welch S, Haymond MW: Growth hormone has anabolic effects in glucocorticoid dependent children with inflammatory bowel disease: a pilot study. Metabolism 2002;51:127–135.
54.
van Beek R, van der Sluis I, Bouquet J, De Muinck Keizer-Schrama SM: First year results of additional treatment with recombinant human growth hormone for growth retardation and osteopenia in children with inflammatory bowel disease. Horm Res 2002;58(suppl 2):55–56.
55.
Calenda KA, Schornagel IL, Sadeghi-Nejad A, Grand RJ: Effect of recombinant growth hormone treatment on children with Crohn’s disease and short stature: a pilot study. Inflamm Bowel Dis 2005;11:435–441.
56.
Wong SC, Hassan K, McGrogan P, Ahmed SF: The effects of recombinant human growth hormone (rhGH) on linear growth in children with Crohn’s disease (CD) and severe growth retardation. J Pediatr Endocrinol Metab. In Press.
57.
Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, GH Insensitivity Syndrome Collaborative Group: Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab 2007;92:902–910.
58.
Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D: Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 1999;96:7324–7329.
59.
Bucuvalas JC, Chernausek SD, Alfaro MP, Krug SK, Ritschel W, Wilmott RW: Effect of insulin like growth factor-1 treatment in children with cystic fibrosis. J Pediatr Gastroenterol Nutr 2001;33:576–581.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.