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Mechanisms of growth impairment in pediatric Crohn's disease

Nature Reviews Gastroenterology & Hepatology volume 6, pages 513–523 (2009)Cite this article

Abstract

Crohn's disease manifests during childhood or adolescence in up to 25% of patients. The potential for linear growth impairment as a complication of chronic intestinal inflammation is unique to pediatric patient populations. Insulin-like growth factor I (IGF-I), produced by the liver in response to growth hormone (GH) stimulation, is the key mediator of GH effects at the growth plate of bones. An association between impaired growth in children with Crohn's disease and low IGF-I levels is well recognized. Early studies emphasized the role of malnutrition in suppression of IGF-I production. However, a simple nutritional hypothesis fails to explain all the observations related to growth in children with Crohn's disease. The direct, growth-inhibitory effects of proinflammatory cytokines are increasingly recognized and explored. The potential role of noncytokine factors, such as lipopolysaccharides, and their potential to negatively influence the growth axis have recently been investigated with intriguing results. There is now reason for optimism that the modern anticytokine therapeutic agents available for treating children and adolescents with Crohn's disease will reduce the prevalence of this otherwise common complication. As our understanding of the mechanisms that underlie growth impairment advance, so too should the opportunity for developing further novel and targeted therapies.

Key Points

  • Chronic undernutrition and direct effects of proinflammatory cytokines are the two major and interrelated factors responsible for the impairment of linear growth in children with Crohn's disease

  • The mechanisms by which cytokines impede linear growth are complex and involve, but are not limited to, disruption of growth hormone–insulin-like growth factor I pathways

  • The potential effects that other noncytokine molecular factors may have on the growth axis are an evolving focus of research

  • Normal growth is a marker of the success of therapy in children with Crohn's disease

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Figure 1: The GH–IGF-I axis and its role in linear growth.
Figure 2: GH receptors and the JAK2–STAT5 signaling pathway.
Figure 3: Molecular mechanisms of GH resistance in Crohn's disease.
Figure 4: Proposed mechanism for blockade of IL-6–STAT3 activation by GH.
Figure 5: GH receptor cleavage and formation of GH-binding protein.

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Acknowledgements

T. D. Walters receives joint fellowship funding from The Crohn's and Colitis Foundation of Canada, AstraZeneca Canada, The Canadian Association of Gastroenterology, and the Canadian Institutes of Health Research.

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  1. Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Thomas D. Walters & Anne M. Griffiths

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  1. Thomas D. Walters
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Correspondence to Anne M. Griffiths.

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Competing interests

A. M. Griffiths has been a Consultant for Abbott, Centocor, Schering-Plough and UCB, and has received research support from Schering Plough Canada.

T. D. Walters has been a Consultant for Schering-Plough Canada and UCB.

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Walters, T., Griffiths, A. Mechanisms of growth impairment in pediatric Crohn's disease. Nat Rev Gastroenterol Hepatol 6, 513–523 (2009). https://doi.org/10.1038/nrgastro.2009.124

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