Intervention for Growth Failure in Children with IBD

Impairment of linear growth and pubertal development is an important potential complication of inflammatory bowel disease (IBD), particularly Crohn disease, developing during childhood and early to mid-adolescence. Normal growth is a marker of success of therapy. “Normal” children, however, grow at very different rates. Patterns of growth and pubertal progression in young patients with IBD can only be accurately recognized as pathologic, if the variations in normal development of healthy children and adolescents are first appreciated. Prompt recognition of IBD is important in avoiding a long period of growth retardation due to untreated inflammation. The greater the height deficit at diagnosis, the greater is the demand for catch-up growth. In caring for children with IBD, it is important to obtain pre-illness heights, so that the impact of the chronic intestinal inflammation can be fully appreciated. Following diagnosis and institution of treatment, regular measurement and charting of height, together with calculation of height velocity, are central to management. Increased understanding of the mechanisms of linear growth impairment associated with chronic inflammatory disease points the way toward better management. IGF-1, produced by the liver in response to growth hormone (GH) stimulation, is the key mediator of GH effects at the growth plate of bones. The role of genes in influencing the phenotypic expression of IBD, including its propensity for growth impairment, is an intriguing focus of research. Chronic undernutrition has long been implicated and remains an important and remediable contributing factor in the observed growth impairment. Inflammatory cytokines similarly inhibit linear growth through interference with hepatic release of IGF-1 and additionally via direct effects on growing bone. Cytokines also appear to impair end-organ responsiveness to circulating testosterone, thereby compounding the effects of undernutrition in delaying progression through puberty. Chronic daily corticosteroid administration in children augments the growth impairment associated with inflammatory disease. The growth suppressive effects of glucocorticoids are multifactorial, and include central suppression of GH release, decreased hepatic transcription of GH receptor, such that production of IGF-1 is decreased, and decreased IGF-1 binding in cartilage. Hence exogenous corticosteroids create a state of functional GH deficiency. Current pediatric treatment regimens aimed at facilitating growth limit use of corticosteroids via optimization of immunomodulatory drugs, use of enteral nutrition in Crohn disease, and, if necessary, surgery for ulcerative colitis and for intestinal complications of localized Crohn disease. Biologic agents with the potential for mucosal healing hold promise of growth enhancement even among patients with otherwise refractory disease, whose growth was previously compromised. For all interventions, there is a window of opportunity, which must be taken advantage of before puberty is too advanced. Few interventions, however, have been tested in the randomized controlled trial setting in children; the comparative effects of therapies on growth have seldom been rigorously assessed. Instead, growth outcomes have been reported mainly in observational studies. These include retrospective accounts of improved linear growth following intestinal resection, initiation of enteral nutrition, and during infliximab maintenance therapy. Two long-term randomized, controlled maintenance trials have examined the effects of, respectively, cyclical enteral nutrition and 6-mercaptopurine on linear growth. In a multi-center Canadian study, children achieving clinical remission with either prednisone or enteral nutrition, were randomized to receive longterm low dose prednisone on alternate days or exclusive enteral nutrition one month out of four. In this eighteen month study, linear growth was better in the children receiving liquid diet therapy. In the well-known study of Markowitz and colleagues, children with moderate to severe Crohn disease treated with an initial course of prednisone were randomized to receive either concomitant 6-mercaptopurine or placebo. A beneficial effect of 6-mercaptopurine on linear growth was not clearly apparent in this study in spite of the steroid-sparing effect and improved control of intestinal inflammation, perhaps a function of sample size and difficulties inherent in comparing growth rates among patients of varying ages and pubertal stages. Improvement in IGF-1 levels and height velocity have been observed following growth hormone therapy in small numbers of steroid-dependent children with Crohn's disease. Three to six months of testosterone therapy, carefully supervised by paediatric endocrinologists, has been used in boys with extreme delay of puberty and its associated growth spurt. Experience with both these adjunctive hormonal therapies is very limited. Treatment of intestinal inflammation and assurance of adequate nutrition remain of prime importance.

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