Ulcerative Colitis: Walters T

Heuschkel R, Salvestrini C, Beattie RM, Hildebrand H, Walters T, Griffiths A. · Royal Free Hampstead NHS Trust, Centre for Paediatric Gastroenterology, Hampstead, London, UK. · Inflamm Bowel Dis. · Pubmed #18266237 links to  free full text

Abstract: Around 1 in 4 patients with inflammatory bowel disease (IBD) present in childhood, the majority around the time of their pubertal growth spurt. This presents challenges over and above those of managing IBD in adults as this period is a time of dramatic psychological and physical transition for a child. Growth and nutrition are key priorities in the management of adolescents and young adults with IBD. Growth failure in IBD is characterized by delayed skeletal maturation and a delayed onset of puberty, and is best described in terms of height-for-age standard deviation score (Z score) or by variations in growth velocity over a period of 3-4 months. Growth failure is common at presentation in Crohn's disease (CD), but less common in ulcerative colitis (UC). The etiology of growth failure is multifactorial. Principal determinants, however, include the inflammatory process per se, with proinflammatory cytokines (e.g., IL-1beta, IL-6) being directly implicated. Furthermore, poor nutrition and the consequences of prolonged corticosteroid use also contribute to the significant reduction in final adult height of almost 1 in 5 children. Initially a prompt, where possible steroid-free, induction of remission is indicated. The ideal is then to sustain a relapse-free remission until growth is complete, which is often not until early adulthood. These goals can often be achieved with a combination of exclusive enteral nutrition (EEN) and early use of immunosuppressants. The advent of potent and efficacious biological agents considerably improves the range of growth-sparing interventions available to children around puberty, although well-timed surgery remains another highly effective means of achieving remission and significant catch-up growth. We carried out a systematic review of publications to identify the best available evidence for managing growth failure in children with IBD. Despite the paucity of high-quality publications, sufficient data were available in the literature to allow practical, evidence-based where possible, management guidelines to be formulated. Although there is clear evidence that exclusive enteral nutrition achieves mucosal healing, its effect on growth has only been assessed at 6 months. In contrast to corticosteroids, EEN has no negative effect on growth. Corticosteroids remain the key therapy responsible for medication-induced growth impairment, although the use of budesonide in selected patients may minimize the steroid effect on dividing growth plates. Immunosuppressants have become a mainstay of treatment in children with IBD, and are being used earlier in the disease course than ever before. However, there are currently no long-term data reporting better growth outcome if these agents are introduced very soon after diagnosis. In comparison, recent data from a large prospective trial of infliximab in children with moderate to severe CD suggested significant catch-up growth during the first year of regular infusions. The only other intervention that has documented clear catch-up growth has been surgical resection. Resection of localized CD, in otherwise treatment-resistant children, early in the disease process achieves clear catch-up growth within the next 6 months. There are no data available that growth hormone improves final adult height in children with CD. In conjunction with expert endocrinological support, pubertal delay, more common in boys, may be treated with parenteral testosterone if causing significant psychological problems. The optimal management of children and adolescents requires a multidisciplinary approach frequently available within the pediatric healthcare setting. Dedicated dietetic support, along with nurse-specialist, child psychologist, and with closely linked medical and surgical care will likely achieve the best possible start for children facing a lifetime of chronic gut disease.

Muise AM, Walters T, Wine E, Griffiths AM, Turner D, Duerr RH, Regueiro MD, Ngan BY, Xu W, Sherman PM, Silverberg MS, Rotin D. · Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, 555 University Ave, Toronto, Ontario, Canada. · Curr Biol. · Pubmed #17614280 No free full text.

Abstract: Inflammatory bowel disease (IBD), a relatively common chronic debilitating intestinal illness, is composed of two broadly defined groups, Crohn's disease (CD) and ulcerative colitis (UC). Although several susceptibility genes for CD have been recently described, susceptibility genes exclusive for UC have not been forthcoming. Here, we show that receptor protein-tyrosine phosphatase sigma (PTPRS-encoding PTPsigma) knockout mice spontaneously develop mild colitis that becomes severe when challenged with two known inducers of colitis. We also demonstrate that E-cadherin and beta-catenin, two important adherens junction proteins involved in maintenance of barrier defense in the colon, act as colonic substrates for PTPsigma. Furthermore, we show that three SNPs (rs886936, rs17130, and rs8100586) that flank exon 8 in the human PTPRS gene are associated with UC. The presence of these SNPs is associated with novel splicing that removes the third immunoglobulin-like domain (exon 9) from the extracellular portion of PTPsigma, possibly altering dimerization or ligand recognition. We propose that polymorphisms in the human PTPRS gene lead to ulcerative colitis.