Fighting for growth in paediatric Inflammatory Bowel Disease
Amit Assa, P-ECCO Member
Fighting for growth in paediatric Inflammatory Bowel Disease
Growth retardation is commonly seen in children diagnosed with Inflammatory Bowel Disease (IBD), mainly those with Crohn's Disease (CD). The aetiology of poor growth in children with IBD is multifactorial and includes malnutrition, poor intake, increased nutritional needs, elevated inflammatory cytokines, genetic factors (parental height, CD susceptibility genes) and corticosteroid therapy. Growth retardation may be present years before diagnosis of IBD, and it commonly persists despite disease-specific treatments, with implications for final adult height and consequent social and psychological burden.
Linear growth failure in children is defined as height below the 3rd percentile or a height z-score of below a standard deviation score (SDS) of -2 whereas growth impairment is defined as height velocity SDS below -1 . Linear growth can also be expressed as height velocity, which represents growth status at a particular point in time.
The rate of growth retardation in paediatric IBD at diagnosis varies with the type of disease [CD vs Ulcerative Colitis (UC)], gender and the time of diagnosis [2, 3]. Apparently, the age and pubertal stage at diagnosis are key factors for growth potential. Malik et al.  have demonstrated that children with CD at a pre-pubertal age do not show improvement in their height velocity while most children diagnosed at pubertal age do achieve a normal height velocity SDS during follow-up. Other risk factors include diagnostic delay  proximal small bowel disease location, positive ASCA, GM-CSF auto-antibodies and CBir antibodies in children with CD [6–8].
It is clear that CD affects growth more profoundly than UC. Lee et al.  reported that 88% of children with CD suffer from growth impairment at diagnosis compared to 12% of children with UC. Malik et al.  reported that the percentage of children with height velocity SDS between -1 and -2 was 49% at CD diagnosis. Unfortunately, the natural course of CD results in decreased adult height in 11%–35% of paediatric patients [6, 9]. Data on final height in paediatric UC patients is limited but it is evident that final height is less frequently affected .
The aetiology of growth impairment in children with IBD is multifactorial and includes undernutrition (poor intake and malabsorption) , a relative catabolic state (increased nutritional needs and losses) , genetic factors (parental height, CD susceptibility genes and cytokine polymorphism) , effects of inflammatory cytokines on the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis , delayed puberty  and chronic or recurrent corticosteroid therapy . Most probably, a complex interplay exists which interrupts the normal regulation of growth.
Interestingly, children with IBD have normal GH secretion, either stimulated or spontaneous . However, these children manifest reduced plasma concentrations of IGF-1 and IGF binding proteins , implying "GH resistance". The reduction in IGF-1 has been shown to be correlated with increase in multiple inflammatory cytokines, mainly IL-6 and TNFα, and chronic glucocorticoid therapy has been shown to further decrease IGF-1 production, thereby contributing to growth impairment ; however, limited usage of glucocorticoids for remission induction is probably not detrimental to long-term growth.
Based on the described pathophysiology of growth impairment it is intuitive that optimisation of growth should rely on restoration of appropriate nutrition, minimisation of inflammation and avoidance of long-term or frequent corticosteroid therapy. There is a clear correlation between treatment success and normalisation of growth . The importance of sustained remission early in the course of disease is magnified by the rather narrow window for growth that exists until adult height is achieved.
In children, exclusive enteral nutrition (EEN) has been demonstrated to be as effective as corticosteroids in inducing remission and superior in inducing mucosal healing . EEN downregulates pro-inflammatory cytokines, including TNFα and IL-6 , with a consequent increase in IGF-1 and IGFBP-3 within 14 days of treatment . Indeed, it has been shown that EEN is associated with short-term improvement in height velocity in comparison to steroid therapy . The long-term effect of inducing remission with EEN on growth is limited and Cameron et al. reported that EEN induces long-term improvement in body mass index but not in linear growth .
The effect of immunomodulator treatment on growth is limited. The only paediatric CD randomised, placebo-controlled trial on this issue, reported by Markowitz et al. , failed to demonstrate any beneficial impact of 6-mercaptopurine growth parameters compared to placebo after 18 months of follow-up. A retrospective study by Turner et al.  showed a significant effect of methotrexate on linear growth whereas Malik et al.  found height SDS to be associated negatively with the use of either azathioprine or methotrexate.
Anti-TNFα agents hold promising potential for improving growth as they have been shown to induce prompt mucosal healing , reverse the pro-inflammatory cytokine cascade  and enable prolonged corticosteroid withdrawal . Numerous studies suggest an increase in height velocity and height z-score following prolonged anti-TNFα treatment, providing treatment is undertaken early enough, prior to or during puberty [29–32]. The REACH randomised controlled trial demonstrated that infliximab can induce an increase in height z-score of 0.5 at one year of treatment  with a greater beneficial effect in children with at least a one-year delay in bone age. A post hoc analysis of the IMAgINE1 trial  also demonstrated that adalimumab therapy significantly improves and normalises growth rate at weeks 26 and 52 in patients with growth impairment (from -3.25 at baseline to 0.21 at one year), but not in patients with normal growth. Walters et al.  published results from the prospective observational RISK study, which highlighted the benefit of early institution of anti-TNFα therapy for the resumption of growth in paediatric patients with CD. In comparison to early treatment with an immunomodulator or no early immunotherapy, early anti-TNFα treatment resulted in an increase in the height z-score at 12 months.
In children with short segment CD and growth failure, limited ileo-caecal resection should be considered. Despite almost inevitable recurrence, the period of remission induced by surgery allows significant catch-up growth if the surgery is performed prior to or at early puberty  and if no residual disease remains. Mechanistically, resection of the inflamed segment reduces the inflammatory burden of the disease, thus enabling reinstitution of growth.
As spontaneous and stimulated levels of GH in children and adolescents with IBD appear to be normal, a rationale for GH treatment in order to promote growth seems to be lacking. Nevertheless, two randomised controlled trials which examined the effect of rhGH on linear growth in children with CD succeeded in demonstrating a significant beneficial effect at 6 and 12 months [37, 38], with an increase in height velocity from 4.5 to 10.8 cm/year and in height z-score from -1.1 to -0.4. Thus, GH treatment should be considered in children with growth failure who do not show improvement in growth velocity despite optimal biologic or surgical treatment.
In conclusion, children with IBD who present with significant growth retardation during the course of their disease pose a particular challenge for the treating physician. Timely and prompt recognition of growth impairment combined with an aggressive therapeutic approach offers the best chance for catch-up growth. This approach should include avoidance of corticosteroid treatment and a preference for EEN as first-line induction treatment for children with CD. Patients with significant growth retardation should be offered early introduction of anti-TNFα therapy for induction and maintenance. In patients with severe, steroid-dependent UC and in selected patients with CD, surgery may be the most suitable therapeutic option, and it should not be delayed until the late stages of puberty when the "interventional window of opportunity" is being closed. Growth hormone treatment should also be considered in selected patients.
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