Pathophysiology and Management of Abnormal Growth in Children with Chronic Inflammatory Bowel Disease

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1 Shamir R, Turck D, Phillip M (eds): Nutrition and Growth. World Rev Nutr Diet. Basel, Karger, 2013, vol 106, pp (DOI: / ) Pathophysiology and Management of Abnormal Growth in Children with Chronic Inflammatory Bowel Disease S.F. Ahmed a C. Farquharson b P. McGrogan a R.K. Russell a a Royal Hospital for Sick Children, University of Glasgow, Glasgow, and b Bone Biology Group, Division of Developmental Biology, Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, UK Abstract Many children with a variety of chronic diseases suffer from a variable component of chronic inflammation and often have co- existing growth retardation. The aetiology of this growth retardation may be multifactorial and in a condition such as inflammatory bowel disease it includes the effects of the disease on nutrition as well as the effect of drugs such as glucocorticoids. Growth is primarily regulated through the endocrine and paracrine component of the GH/IGF- 1 axis which may be modulated by other factors such as sex steroids. There is increasing evidence that this axis may be affected in children with chronic inflammation. An improved understanding of the GH/IGF- 1 axis and how it is affected in chronic inflammation will lead to an improved rationale for developing therapeutic regimens that can improve growth in those children whose growth does not improve despite optimal management of the disease. This review will illustrate these aspects by concentrating primarily on the pathophysiology of growth retardation in inflammatory bowel disease and possible interventions for improving growth. Copyright 2013 S. Karger AG, Basel Inflammation and its adverse effects on skeletal development are observed in a number of chronic diseases such as cystic fibrosis, chronic kidney disease, rheumatological conditions and inflammatory bowel disease (IBD). As the mechanisms that regulate growth in childhood are age and maturity dependent, the effect that these conditions exert on growth will depend on when children develop and clinically present with these conditions. However, whilst it is very likely that there are other condition- specific issues that may also play a major role, inflammation remains a common factor in all these conditions. Given that chronic infection and stunting are commonly encountered in developing countries, inflammation may also play a wider, global role in contributing to poor growth which may, itself, be a marker of the effects of disease on other aspects such as body composition [1]. As an example

2 of a chronic inflammatory disease that affects a number of growth regulatory mechanisms, IBD occurs in children and adults and its prevalence is estimated at 1 in 500 with about 10,000 affected children in the UK [2]. Growth retardation can be a presenting symptom in over 30% of these children and subsequent short stature in adulthood may occur in over 15% of cases [3]. Both adults and children with chronic inflammatory conditions such as IBD are now living longer and the adverse effects of chronic inflammation on growth and skeletal development have been ranked as one of the top areas by the Crohn s and Colitis Foundation of America that require further research [4]. IBD and Puberty Children with IBD and, particularly Crohn s disease (CD), often present during early adolescence and have been reported to display delayed puberty and associated growth retardation [5]. A recent retrospective study which utilized serial height measurements over the period of adolescence in children with IBD showed that an altered pubertal growth spurt is not uncommon in this age group, particularly in boys, and may be related to disease severity and poor nutritional status [6]. In adolescents with IBD, the aetiology of pubertal delay is multifactorial [7] and hypogonadism may encompass a range of abnormalities of the hypothalamic/pituitary/ gonadal/end organ axis, including hypogonadotrophic hypogonadism, abnormality of sex steroid synthesis or an abnormality of sex steroid action. In addition, there is a concern that those with CD who present in adolescence may have more profound short stature than expected simply for delayed puberty [5]. Generally, adults with a past history of pubertal delay are often shorter as adults than their predicted height. However, the discrepancy between target height and final height seems to be greater in adults with childhood- onset CD compared to healthy adults with a history of delayed puberty [8, 9]. As sex steroid- induced growth acceleration is dependent on increased GH and IGF- 1 production [10], it is possible that the poorer growth and final height may be due to the combined effect of inflammation on the GH/IGF- 1 axis as well as puberty. Interaction between Inflammatory Cytokines and the GH/IGF- 1 Axis The GH/IGF- 1 pathway is critical for regulating bone growth; circulating GH can act independently of hepatic IGF- 1 and directly initiate an increase in growth plate chondrocyte proliferation, matrix production and differentiation as well as stimulate the local production of IGF- 1 [11]. Circulating IGF- 1 can also rescue the growth in IGF- 1 null mice but the levels required are supraphysiological [12]. Although, poor growth may also be secondary to poor nutrition, in experimental models of colitis, 40% of Growth and Chronic Disease 143

3 linear growth impairment may occur as a direct result of inflammation [13]. This may be due to a direct adverse effect of circulating pro- inflammatory cytokines on the systemic hypothalamic- pituitary- growth axis and also due to their effects on the growth plate. In children with chronic inflammation, there is an association between individual circulating concentrations of proinflammatory cytokines and growth but the relationship is not strong especially as individual cytokine concentrations are highly variable at any one time point in children with the same disease [14]. Recent data from our group suggests that the systemic GH/IGF- 1 axis is affected to a variable extent in poorly growing children with IBD [15]. Peak GH levels following insulin induced hypoglycaemia were very variable but IGF- 1 concentrations were almost universally low. The finding of subnormal GH secretion in some cases is consistent with other studies in this field [16]. Previous investigators have also highlighted the possibility of reduced IGF- 1 bioavailability possibly due to an alteration in IGF- binding proteins [17, 18]. Current research suggests that the actions of some proinflammatory cytokines such as TNF- α may be independent of systemic or circulating IGF- 1 action and may be exerted directly on growth plate chondrogenesis through local GH/IGF- 1- dependent effects as well as independent effects on proteoglycan synthesis and the microarchitecture of the growth plate [19]. On the other hand, in experimental colitis, immunoneutralisation of IL- 6 increased both systemic IGF- 1 concentrations and linear growth but immunoneutralisation of TNF- α had no effect on systemic IGF- 1 concentrations [20]. Furthermore, IL- 6 does not seem to generally exert any deleterious direct effects on growth plate chondrogenesis [21, 22]. It is possible that there may also be other mechanisms of how proinflammatory cytokines exert an effect on the GH/IGF- 1 axis. There is increasing evidence that proinflammatory cytokines can induce the tissue- specific expression of suppressors of cytokine signalling (SOCS) proteins which are a group of signalling proteins characterised by their ability to downregulate cytokine signalling [11]. SOCS2 is uniquely identified as a primary GH receptor signalling inhibitor in vivo by its overgrowth knockout phenotype in mice which are 30 40% larger than normal littermates and have increased long bone length and these effects seem to be mediated by increased signalling through the JAK/STAT pathway [23]. It is currently unclear whether at the level of the growth plate, the SOCS proteins can alter tissue sensitivity to proinflammatory cytokines [24]. General Management of Growth Impairment in Children with IBD The single most important risk factor for reduced height at diagnosis and follow- up is the time from symptom onset to diagnosis [25]. Early identification of growth deterioration is, therefore, of the utmost importance in the IBD clinic to ensure prompt intervention. This requires regular measurement of height and assessment of puberty. A close working relationship with a paediatric endocrinologist would facilitate appropriate management of these children when there are concerns about growth, puberty 144 Ahmed Farquharson McGrogan Russell

4 and skeletal development. The first- line management of growth failure in IBD is optimising control of the active disease, which may be occult in parallel with providing adequate nutritional support. In the clinical setting, this should include thorough history and examination to reveal subtle symptoms and signs of disease activity coupled with laboratory investigations for inflammatory markers as well as dietetic assessment. Primary management should also involve correcting poor nutritional status; improving the disease and nutritional status of children with CD has been shown to be associated with beneficial changes in growth and markers of the systemic GH/IGF- 1 axis [26] and consideration should also be given to the early introduction of second- line immunomodulating therapy (thiopurines or methotrexate), thereby reducing the use of corticosteroids. In the future, the possibility of using drugs such as selective glucocorticoids receptor modulators which can exert the anti- inflammatory effect but not the growth inhibitory effect holds promise [27]. Significant improvements in height velocity (HV), pubertal progress and IGF- 1 levels may also follow surgery for localised disease or resectable disease. Infliximab, a chimeric monoclonal antibody against TNFα, has been shown to be effective in childhood onset CD and its use has been associated with an improvement in growth [28, 29]. Adalimumab has also recently been reported to be associated with an improvement in disease and growth [30]. Although an evaluation of the GH/IGF- 1 axis may be justified in a child who fails to grow despite optimisation of their disease management, the results of pituitary function tests need to be interpreted with caution [15]. There may be a role for growth- promoting agents including treatment with sex steroids and rhgh but these would generally only be considered in conjunction with IBD therapies in a short child who is growing poorly and is out with the target range. The appropriate timing to consider growth- promoting agents is still unclear but it is anticipated that any growthpromoting agent would only be used as an adjunct to aggressive management of the disease process. Although sex steroid treatment is often used and recommended in children with IBD, there are limited data on their effectiveness [31]. Given the possibility that children with IBD may have a concomitant alteration in the GH/IGF- 1 axis, the sole use of sex steroids requires careful monitoring and the change in HV needs to be compared with that reported in otherwise healthy children. Whilst rhgh is a therapeutic possibility in children with IBD who grow slowly, its efficacy remains unclear. Studies of rhgh treatment in children with other inflammatory diseases such as juvenile arthritis have clearly shown a cessation in deterioration of HV and may have added benefits on bone mineral content and body composition [16, 32]. An improvement in growth that is independent of disease activity and steroid dose over a relatively short period of rhgh has also been demonstrated in two randomised controlled trials [33, 34]. There is also a possibility that rhgh treatment may have a beneficial effect on the disease process and, thereby, improve growth [35], but this requires further investigation. Considering that the defect in the GH/IGF- 1 axis may be at multiple levels, the role of other forms of growth- promoting agents such as rhigf- 1 needs further investigation [36]. This may be particularly important as patients with Growth and Chronic Disease 145

5 chronic inflammation who receive rhgh may be predisposed to impairment of glucose homeostasis [33, 37] and the use of rhigf- 1 children with chronic disease has been reported to be associated with an improvement in glucose homeostasis [38]. Conclusion The pathophysiology of poor growth in children with IBD is multifactorial and has parallels to many other chronic inflammatory conditions. The assessment of growth is an effective marker of disease itself and in many cases improving disease and nutrition will lead to an improvement in growth. In the small number of cases, where there is persistent growth retardation, there is a need for close involvement of a paediatric endocrinologist with experience in managing children with chronic disease to consider other forms of growth- promoting therapy. Acknowledgements S.F.A. is supported by the Chief Scientist Office of Scotland and Ipsen. C.F. acknowledges the support of the Biotechnology and Biological Sciences Research Council UK through Institute Strategic Programme Grant Funding. R.K.R. is supported by a NHS Research Scotland career fellowship award. The work of the IBD team at Yorkhill is supported by the Catherine McEwan Foundation and the Yorkhill IBD fund. References 1 Kruger HS, Pretorius R, Schutte AE: Stunting, adiposity, and low- grade inflammation in African adolescents from a township high school. Nutrition 2010;26: Armitage EL, Aldhous MC, Anderson N, Drummond HE, Riemersma RA, Ghosh S, Satsangi J: Incidence of juvenile- onset Crohn s disease in Scotland: association with northern latitude and affluence. Eur J Gastroenterol Hepatol 2001;13: 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: Bousvaros A, Sylvester F, Kugathasan S, Szigethy E, Fiocchi C, Colletti R, Otley A, Amre D, Ferry G, Czinn SJ, Splawski JB, Oliva- Hemker M, Hyams JS, Faubion WA, Kirschner BS, Dubinsky MC, Challenges in Pediatric IBD Study Groups: Challenges in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2006;12: Brain CE, Savage MO: Growth and puberty in chronic inflammatory bowel disease. Baillières Clin Gastroenterol 1994;8: Mason A, Malik S, Russell RK, Bishop J, McGrogan P, Ahmed SF: The impact of inflammatory bowel disease on pubertal growth. Horm Res Paediatr 2011;76: Ballinger AB, Savage MO, Sanderson IR: Delayed puberty associated with inflammatory bowel disease. Pediatr Res 2003;53: Sawczenko A, Ballinger AB, Croft NM, Sanderson IR, Savage MO: Adult height in patients with early onset of Crohn s disease. Gut 2003;52: Kelly BP, Paterson WF, Donaldson MD: Final height outcome and value of height prediction in boys with constitutional delay in growth and adolescence treated with intramuscular testosterone 125 mg per month for 3 months. Clin Endocrinol (Oxf) 2003; 58: Ahmed Farquharson McGrogan Russell

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7 32 Touati G, Prieur M, Ruiz JC, et al: Beneficial effects of one year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab 2004; 83: Denson LA, Kim MO, Bezold R, Carey R, Osuntokun B, Nylund C, Willson T, Bonkowski E, Li D, Ballard E, Collins M, Moyer MS, Klein DJ: A randomized controlled trial of growth hormone in active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2010;51: Wong SC, Kumar P, Galloway PJ, Blair JC, Didi M, Dalzell AM, Hassan K, McGrogan P, Ahmed SF: 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. Clin Endocrinol (Oxf) 2011;74: Slonim AE, Bulone L, Damaore MB, et al: A preliminary study of growth hormone therapy for Crohn s disease. N Engl J Med 2000;342: Savage MO, Camacho- Hubner C, Dunger DB: Therapeutic applications of insulin- like growth factors. Growth Horm IGF Res 2004;14: Bismuth E, Chevenne D, Czernichow P, Simon D: Moderate deterioration in glucose tolerance during high- dose growth hormone therapy in glucocorticoid- treated patients with juvenile idiopathic arthritis. Horm Res Paediatr 2010;73: 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: Prof. S. Faisal Ahmed, MD, FRCPCH Section of Child Health Royal Hospital for Sick Children Glasgow, G3 8SJ (UK) faisal.ahmed@glasgow.ac.uk 148 Ahmed Farquharson McGrogan Russell