Review

Nature Reviews Gastroenterology and Hepatology 6, 513-523 (September 2009) | doi:10.1038/nrgastro.2009.124

Subject Categories: Inflammatory bowel disease | Pediatric gastroenterology

Mechanisms of growth impairment in pediatric Crohn's disease

Thomas D. Walters1 & Anne M. Griffiths1  About the authors

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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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Introduction

Crohn's disease manifests during childhood or adolescence in up to 25% of patients.1 Varied phenotypic features and a spectrum of clinical severity are observed in children with the disease, as among adults. Unique to pediatric patient populations, however, is the potential for linear growth impairment as a complication of chronic intestinal inflammation. This complication is commonly present before Crohn's disease is diagnosed but also occurs during the subsequent years, so that height at maturity is often compromised.2 The challenge in treating each child with Crohn's disease is to use pharmacologic, nutritional, and (where appropriate) surgical interventions to not only decrease mucosal inflammation and thereby alleviate symptoms, but also to optimize growth and normalize associated pubertal development. A summary of studies that characterized linear growth in children with Crohn's disease who were treated during the previous 30 years was presented in 2008.2 While older studies provide a benchmark for linear growth outcomes with traditional therapies, the introduction of biologic agents provides optimism for reducing the prevalence of this otherwise common complication.

Several reviews have addressed the prevalence of growth impairment in pediatric Crohn's disease and the efficacy of specific treatments in ameliorating linear growth. This Review focuses on the mechanisms of growth impairment and the general principles of disease management that are based on knowledge of these mechanisms. We will begin with an overview of the mechanisms involved in normal growth.

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Normal growth and pubertal development

Healthy children grow at very different rates. A child's growth is dependent on both genes and the environment; growth seems to be principally mediated by hormones and nutrition.3 Linear growth can be represented by stature (attained height) or by the rate of growth (height velocity). A child's attained height represents the culmination of growth in all the preceding years; height velocity reflects their growth status at a particular point in time.

Normal growth patterns

Height velocity decreases from birth onwards, punctuated by a short period of growth acceleration (the adolescent growth spurt) just before completion of growth. Healthy children grow at a consistent rate in the range of 4–6 cm annually from 6 years of age until the onset of puberty.4 A rapid alteration in body size and shape occurs during puberty; height velocity approximately doubles for 1 year or more. The age of onset of puberty and the pubertal growth spurt varies among healthy individuals and between ethnic groups. Puberty begins earlier in girls than in boys. Moreover, the pubertal growth spurt occurs in mid-puberty (before menarche) in girls but in late puberty (after Tanner stage 4) in boys.4 The occurrence of menarche in girls is an indication that linear growth is nearing completion; usually they gain only 5–8 cm more in height in the 2 years following menarche.4

To understand the mechanisms by which growth is inhibited in children with Crohn's disease, comprehension of the normal physiology and regulation of growth is necessary. The growth hormone–insulin-like growth factor I (GH–IGF-I) axis has a pivotal role in normal postnatal growth. Thyroxine and the sex steroids are also implicated in the maintenance of normal linear growth.

The GH–IGF-I axis

The somatomedin hypothesis

In 1956, Daughaday and Salmon5 proposed that an intermediate hormone they termed somatomedin C mediated all the growth-promoting effects of growth hormone (GH). Somatomedin C was subsequently purified and renamed IGF-I;5, 6, 7 it was found to act in an endocrine fashion, via its hepatic generation and subsequent release into the circulation, as well as in an autocrine and paracrine fashion, through its local generation within target organs.8, 9 More-recent work has determined that both GH and IGF-I can directly stimulate longitudinal growth by acting on different cell types. GH induces differentiation of precursor cells of the growth plate (the hyaline cartilage plate found in growing bones) towards chondrocytes, which in turn become responsive to IGF-I, and IGF-I stimulates the clonal expansion of differentiated chondrocytes (Figure 1).9, 10

Figure 1 | The GH–IGF-I axis and its role in linear growth.
Figure 1 : The GH|[ndash]|IGF-I axis and its role in linear growth. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comHypothalamic release of GHRH stimulates the pulsatile release of GH from the pituitary gland. Somatostatin has the opposite effect on the pituitary gland and inhibits the GHRH-stimulated release of GH. The GH receptor is widely expressed throughout the body, including within the liver and at the growth plate. GH binds to the extracellular domain of the GH receptor and induces upregulation of various anabolic target genes, including IGFI. The majority of circulating IGF-I protein forms a ternary complex with ALS and IGFBP-3. IGF-I acts in an endocrine fashion (1) as well as in an autocrine and paracrine fashion (2). In addition to upregulating IGF-I production, GH contributes directly to linear growth by inducing differentiation of the precursor cells within the growth plate towards chondrocytes (3). IGF-I stimulates mitosis of epiphyseal chondrocytes (4) and also mediates negative feedback of GH (5).

GH and IGF-I

The precise mechanism by which GH is released and subsequently stimulates the release of IGF-I is now well established (Figure 2).11, 12, 13, 14, 15 In humans, most circulating IGF-I is synthesized in the liver, although a low level of GH-dependent and GH-independent IGF-I expression does occur in extrahepatic tissues.

Figure 2 | GH receptors and the JAK2–STAT5 signaling pathway.
Figure 2 : GH receptors and the JAK2|[ndash]|STAT5 signaling pathway. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com(1) GH binds to the extracellular domain of the GH receptor within its various target tissues, which induces intracellular autophosphorylation (2) of JAK2. (3) In turn, phosphorylated JAK2, in association with activated GH receptors, leads to the phosphorylation of STAT5. (4) Activated STAT5 dimerizes and then translocates to the nucleus (5), which results in upregulation of various anabolic target genes including IGFI and ALS.12, 13, 14 (6) IGF-I and ALS enter the circulation and form ternary complexes with IGFBPs, such as IGFBP-3. (7) SOCSs are postreceptor inhibitors of cell signaling that mediate their effect via the JAK2–STAT5 pathway.15 GH rapidly and prominently induces expression of SOCS-3 and CIS-1 within the liver as part of a negative-feedback loop that functions by blocking the phosphorylation of STAT5. SOCS-3 inhibits JAK2 by a mechanism that requires GH receptors.

Sex differences in the GH–IGF-I pathway

GH is released in a pulsatile pattern that is sex-specific; male individuals experience higher peaks and deeper troughs in circulating levels of GH than do female ones.16 Interestingly, signal transducer and activator of transcription protein 5 (STAT5) exists in two genetically distinct, although highly homologous, forms (STAT5A and STAT5B),17 which differ somewhat in their tissue distribution.18 Of note, while STAT5A and STAT5B are both required for normal GH-dependent growth, STAT5B is responsive to pulsatile GH whereas STAT5A is not. Indeed, STAT5B-deficient male mice have pronounced growth impairment and tend to grow at a rate similar to that of healthy females.12 Thus, the complex regulation of sexually dimorphic growth patterns seems to be mediated, at least in part, by STAT5B, which 'interprets' the different GH pulsatile secretion patterns of male versus female individuals.17 Given this finding, any interference with the GH–STAT5B–IGF-I signaling pathway is likely to have a more pronounced effect on growth patterns in male than female individuals.

Insulin-like growth factor binding proteins

The bioavailability of IGF-I depends on the amount of its unbound or free fraction. Six specific high-affinity IGF-I binding proteins (IGFBPs; IGFBP-1 to IGFBP-6) are present within the circulation and can each bind IGF-I with an affinity at least equal to that of IGF-I for the IGF receptor.19 The IGFBPs are each regulated by specific proteases that dramatically reduce their IGF-I binding affinity. The specific function and structure of the six IGFBPs differ considerably.20 IGFBP-1, IGFBP-2, IGFBP-4 and IGFBP-6 primarily inhibit IGF-I by tightly binding to it and preventing it from binding to its receptor.19, 21, 22 Conversely, IGFBP-3 potentiates the action of IGF-I by loosely binding to it, which prolongs the time it is available within the circulation to interact with its receptor. About 75% of IGF-I circulates as a 150 kDa ternary complex composed of IGF-I, the IGFBP complex acid-labile chain (also known as acid-labile subunit [ALS]), and IGFBP-3.19 This large complex, which cannot cross the endothelial barrier,23 significantly increases the half-life of IGF-I from less than 10 min to more than 16 h.19 Caloric and protein restriction can cause a reduction in the levels of IGFBP-3.24, 25

Growth plate proliferation, senescence and fusion

The normal age-dependent decrease in growth rate is related primarily to the senescence of growth plate chondrocytes, which causes a decrease in the rate of proliferation of these cells.26, 27 This process is referred to as growth plate senescence.28, 29, 30 The proliferative capacity of the stem-like cells within the resting zone of the growth plate is finite. Thus, senescence is not a function of age per se, but of proliferative cycle number. Given this finite capacity for proliferation, interventions that slow the proliferation rate of growth plate chondrocytes, such as glucocorticoid exposure, will also defer growth plate senescence.29, 31 That is to say, following transient growth inhibition, growth plates are less senescent and retain a greater proliferative capacity than expected for age. Thus, in the postinhibitory period, the growth plate will show a greater growth rate than expected for age. This catch-up growth is an apparent acceleration off linear growth that occurs after resolution of a growth-inhibiting condition.30, 32

The pubertal growth spurt is primarily induced by estrogen, which acts to increase the activity of the GH–IGF-I axis.33, 34 In addition, sex steroids, especially androgens, seem to stimulate growth by a direct effect on growth plate chondrocytes.35, 36, 37 Estrogen is also the key hormone that promotes growth plate fusion.28

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Pathophysiology of growth impairment

As described above, IGF-I, produced by the liver in response to GH stimulation, is the key mediator of GH's effects at the growth plate of bones. An association between impaired growth and low IGF-I levels is well recognized in children with Crohn's disease.38 However, GH production is normal in such children,39 which suggests that a considerable degree of resistance to the effects of GH is present in this setting.

Early studies tended to emphasize the role of undernutrition in the suppression of IGF-I production.38 Both protein and calorie intake regulate IGF-I production, either by decreasing GH receptor density or through postreceptor mechanisms.40, 41 However, as summarized in Table 1, several interrelated factors contribute to the growth impairment seen in pediatric Crohn's disease: undernutrition, the inflammatory process per se and steroid therapy seem to be its principal (and potentially reversible) determinants. Chronic undernutrition has long been implicated in growth retardation and remains an important and remediable cause of it.42 Nevertheless, a simple nutritional hypothesis, where adequate caloric delivery would correct any growth impairment, fails to explain all the observations related to growth patterns among children with Crohn's disease.


Chronic caloric insufficiency

Growth requires energy. Multiple factors contribute to undernutrition in Crohn's disease, but reduced energy intake, rather than excessive energy losses or increased needs, is generally the major cause of growth impairment.

Caloric intakes of growth-impaired pediatric patients with Crohn's disease are reported to be, on average, 54% of those recommended for children of similar height and age.43 Deliberate food restriction avoids symptoms. A more important factor is that cytokine-mediated, disease-related anorexia can be profound. Work in a rat model suggests that tumor necrosis factor (TNF) has a prominent role in the suppression of caloric intake through an interaction with the hypothalamic appetite pathways.44 While clinical studies have demonstrated that substantial intestinal malabsorption of fat is uncommon in patients with Crohn's disease,45 leakage of protein is frequent.46 In general, resting energy expenditure does not differ from that of healthy individuals in patients with inactive Crohn's disease; however, it can be increased in patients with fever and sepsis.47 Moreover, malnourished adolescents with Crohn's disease fail to reduce their resting energy expenditure as efficiently as similarly malnourished patients with anorexia nervosa.47 This relative failure of a compensatory mechanism has been attributed to the effects of proinflammatory cytokines.

Interplay between nutrition and cytokines

The relative contributions of undernutrition and inflammation to linear growth delay were explored by Ballinger et al., who used a rat model of colitis induced by trinitrobenzene sulfonic acid.48 Two control groups were used: healthy rats with free access to food, and a pair-fed group of healthy animals whose daily food intake was restricted to match that of rats with colitis.48 In the rats with colitis, IGF-I levels decreased to 35% of control values. Comparison with the healthy but undernourished pair-fed rats suggested that undernutrition accounted for 53% of the total suppression of IGF-I in rats with colitis, with the remaining 47% reduction of IGF-I attributable to inflammation.48

Direct cytokine effects

A variety of cytokines have been implicated in the pathogenesis of Crohn's disease including TNF, interferon gamma (IFN-gamma), and multiple interleukins (including IL-6, IL-12, IL-17 and IL-23). Within the past decade the direct growth-inhibitory effects of proinflammatory cytokines released from the inflamed intestine have been increasingly recognized and are now the focus of intriguing research.48, 49, 50, 51

Disruption of the GH–IGF-I axis

As mentioned above, GH production remains normal in growth-impaired children with Crohn's disease,39 which suggests that a substantial degree of resistance to this hormone is present in such children. The molecular mechanisms by which cytokines and other factors induce this state of GH resistance have not yet been completely elucidated. Conceptually, however, these mechanisms could involve downregulation of the growth hormone receptor (GHR), upregulation of postreceptor inhibitory proteins, reduced protein synthesis and/or increased protein degradation. Information from both animal models and human studies supports each of these potential mechanisms (Figure 3).14, 15, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64

Figure 3 | Molecular mechanisms of GH resistance in Crohn's disease.
Figure 3 : Molecular mechanisms of GH resistance in Crohn's disease. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com(1) LPS reduces GH receptor density by inducing GH receptor proteolysis and shedding of GHBP.52 (2) TNF downregulates GH receptor formation via inhibition of Sp1 and Sp3's ability to transactivate GHR.53 IL-1 suppresses GHR promoter activity.53 (3) LPS inhibits GHR expression via a cytokine-independent mechanism (the TLR-4–MD2 pathway) that reduces GHR promoter activity. Anti-TNF therapy does not abrogate this effect.54 (4) IL-6 and TNF upregulate SOCS-3 and CIS-1 expression,14, 55 which inhibits GH signaling by blocking STAT5 phosphorylation.15, 56, 57 (5) IL-1beta reduces IGF-I messenger RNA levels. This reduction does not seem to result from upregulation of SOCS nor impairment of JAK2–STAT5 signaling.58 (6) IL-6 is implicated in a reduction of circulating IGFBP-3 levels owing to reduced production and/or increased proteolysis.59 Low IGFBP-3 levels are associated with accelerated clearance and thus reduced serum levels of IGF-I.59 (7) TNF and IL-1 increase chondrocyte death, which may restrict growth.50 Cytokines apparently impair end-organ responsiveness to testosterone.59 IL-6 promotes osteoclast maturation and activation, affects osteoblasts, is associated with osteoclast–osteoblast uncoupling and results in thinning of the growth plate.49, 61, 62, 63, 64 Laboratory evidence suggests that IL-6 acts independently of IGF-I.61 Abbreviations: ECD, extracellular domain; ICD, intracellular domain.

IGF-I-independent mechanisms

Inflammatory cytokines inhibit linear growth through pathways other than IGF-I production. Animal experiments have shown that TNF and IL-1 increase chondrocyte death and thus may have a deleterious effect on growth.50 In an organ culture model of fetal rat parietal bone, marked impairment of osteoblast function and bone growth was observed with the addition of serum from children with Crohn's disease, but not with serum from children with ulcerative colitis, nor that from healthy controls.51 Finally, cytokines seem to impair end-organ responsiveness to circulating testosterone, and thereby compound the effects of undernutrition in delaying progression through puberty.60

The role of IL-6 in growth impairment

As in a number of chronic inflammatory conditions, levels of IL-6 are increased in the serum of pediatric patients with active Crohn's disease, and this increase is predictive of clinical relapse.65 IL-6 activates signal transducer and activator of transcription protein 3 (STAT3) via the IL-6 receptor subunit beta (also known as glycoprotein 130 or gp130); a process that is negatively regulated by suppressor of cytokine signaling protein 3 (SOCS-3).66, 67, 68 As shown in the accompanying figures (Figures 2 and 3), SOCS-3 is also a negative regulator of the GH signaling pathway. In 2008, the activation of STAT3 by IL-6 was confirmed to correlate with mucosal inflammation in patients with active, pediatric-onset Crohn's disease.69, 70

Similar to pediatric Crohn's disease, children with juvenile idiopathic arthritis also present with linear growth failure,71, 72 and IGF-I levels negatively correlate with serum IL-6 levels in this group of patients.49 The exact mechanism that underlies this observation, however, is not completely clear. Of note, transgenic mice with defective growth overexpress IL-6. Interestingly, antibodies to IL-6 partially corrected this growth defect, whereas administration of IL-6 led to a decrease in IGF-I.49 While these and other data73 suggest an underlying IL-6-mediated decrease in IGF-I production,49 work by De Benedetti et al. in 2001 suggests that the primary mechanism for the decrease in IGF-I serum concentration is a reduction in IGFBP-3 levels owing to reduced production and/or increased proteolysis of this binding protein.59 Low levels of IGFBP-3 have been associated with accelerated clearance of IGF-I, and hence with a reduction in the serum level of IGF-I.59

Studies in pediatric patients with Crohn's disease or juvenile idiopathic arthritis have demonstrated a significant 'uncoupling' of osteoblast and osteoclast activities.59, 74, 75, 76 Experimental data suggest that this uncoupling may also be a consequence of increased serum IL-6 levels. Concurrent mouse and human studies have shown that chronic IL-6 exposure promotes osteoclast maturation and activation, affects osteoblasts, is associated with osteoclast and osteoblast uncoupling and results in thinning of the growth plate.49, 61, 62, 63, 64 Again, while the underlying mechanism is yet to be determined, laboratory evidence suggests that this process is independent of IGF-I.61

Taken together, these data suggest that increased serum levels of IL-6 may represent a major generalized mechanism by which chronic inflammation affects the developing skeleton. This finding would imply that anti-IL-6 therapeutic approaches, which have shown promising anti-inflammatory efficacy in Crohn's disease, rheumatioid arthritis and systemic juvenile idiopathic arthritis,77, 78, 79, 80 may also specifically address the problem of growth impairment.

Cytokine-independent mechanisms

Impaired intestinal barrier function is a recognized feature in some patients with Crohn's disease and may predispose them to chronic, subclinical, endotoxin exposure, specifically exposure to bacterial lipopolysaccharide (LPS).81 LPS can induce a state of GH insensitivity that is characterized by downregulation of GHR messenger RNA expression and upregulation of SOCS-3 messenger RNA expression.82 These effects might simply be secondary to LPS-induced cytokine generation14, 53 (Figure 3 and 4); however, various groups are investigating whether LPS can interfere with the GH–IGF-I axis via cytokine-independent mechanisms. To date, in vivo data from a mouse model has demonstrated that LPS exposure reduces GHR density by inducing GHR proteolysis, probably via the metalloprotease cleavage site, and results in increased shedding of GH-binding protein (GHBP; Figure 5).52 LPS signals via a membrane-bound complex of the lipid-binding protein lymphocyte antigen 96 (also known as MD-2) and Toll-like receptor 4 (TLR4). Recent in vitro data generated by Dejkhamron et al.54 demonstrate that the downregulation of the GHR promoter region by LPS is mediated via its interaction with TLR4, that the MD-2 protein is essential for this interaction and that inhibition of GHR promoter activity indeed occurs via activation of the usual cognate signaling pathways of the receptor complex.54 Both mechanisms are seemingly independent of the inflammatory cytokine cascade, and the addition of anti-TNF antibody failed to abrogate this effect.52 Although certainly intriguing, the clinical significance of these findings and their relative importance as a mechanism in the setting of growth impairment and Crohn's disease is yet to be determined.

Figure 4 | Proposed mechanism for blockade of IL-6–STAT3 activation by GH.
Figure 4 : Proposed mechanism for blockade of IL-6|[ndash]|STAT3 activation by GH. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comIL-6 stimulation induces the expression of a number of proinflammatory gene products via activation of the JAK2–STAT3 pathway. GH inhibits STAT3-mediated IL-6 activity by increasing binding of SHP-2 to gp130, which directly inhibits IL-6 activation of STAT3. The mechanism by which GH promotes association of SHP-2 and gp130 is not yet apparent, although it is thought to be related to GH receptor signaling, independent of IGF-I.115 Of note, data from experimental models of colitis suggest that while GH administration may alleviate colonic inflammation, this treatment does not reverse local inflammatory resistance to GH-mediated upregulation of IGF-I.115 SOCS-3 inhibits both JAK2–STAT3 and JAK2–STAT5 pathways.

Figure 5 | GH receptor cleavage and formation of GH-binding protein.
Figure 5 : GH receptor cleavage and formation of GH-binding protein. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comThe GH receptor has both intracellular and extracellular domains. GHBP, present within the circulation, is produced by the inducible metalloproteolytic cleavage of the GH receptor extracellular domain. Serum concentrations of GHBP are thought to reflect GH receptor density.117 Abbreviations: ECD, extracellular domain; ICD, intracellular domain.

Corticosteroid suppression of linear growth

Short-term administration of corticosteroids is commonly used as a rapid treatment for active inflammatory disease, but adverse effects, including growth inhibition, preclude their long-term use. The growth-suppressive effects of glucocorticoids are multifactorial and can occur at virtually any point along the growth axis.83 In general, exogenous corticosteroids are considered to create a state of functional GH deficiency.84 The dose, preparation and administration schedule of glucocorticoids all influence the degree of growth suppression observed. The concentration of glucocorticoid required to exert direct suppression on the growth plate seems to be lower than that required to suppress GH secretion. Growth, particularly in prepubertal children, can be impaired by relatively modest daily doses of prednisone (3–5 mg/m2).83 This effect may be reduced, but is not necessarily eliminated, by administration of this therapy on alternate days. Selective elimination of evening doses may avoid blunting of both nocturnal GH secretion and/or adrenocorticotropic hormone-induced adrenal androgen production.83 Catch-up growth after cessation of glucocorticoid therapy does not always fully compensate for growth deficits, particularly when treatment occurs during puberty. Although chronic daily dosing and frequent induction courses of steroids can lead to bone demineralization, at present no good evidence exists that occasional, short-term use of steroids for the induction of remission in Crohn's disease is detrimental to long-term growth.

Pathogenesis of pubertal delay

Puberty is frequently delayed in pediatric patients with Crohn's disease.84 Although undernutrition has been frequently considered the main reason for delayed puberty in children with Crohn's disease, a subgroup of patients with persistently active disease do not enter puberty despite an adequate energy intake.85 Experimental colitis models demonstrate that inflammatory mediators potentiate the puberty-delaying effects of undernutrition84 via alterations in gonadotropin-releasing hormone secretion patterns. However, the specific inflammatory cytokines that influence puberty are yet to be determined. Both human and experimental data suggest that an element of gonadotropin resistance is evident in pubertal delay, and in vitro studies implicate TNF in the downregulation of androgen gene expression.86 Although Cushing disease has been associated with pubertal delay,87 whether the doses of corticosteroid used in the management of Crohn's disease are sufficient to delay either the onset or progression of puberty is not known.84

Influence of genetic factors

A number of genetic polymorphisms have been implicated in susceptibility to and pathogenesis of Crohn's disease, the most prominent of which lie within the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. While some investigators88, 89 have suggested that Crohn's-disease-associated NOD2 polymorphisms may be determinants of growth impairment, none of the analyses controlled for disease location. A subsequent careful analysis of growth before and following diagnosis found no such association.90 Data from a Scottish pediatric study in 2006 suggest an association between polymorphisms in the IBD5 susceptibility locus and low anthropometric percentiles at diagnosis.91

Common genetic polymorphisms that alter cytokine expression may contribute to growth impairment, although they do not influence overall susceptibility to Crohn's disease. A 2005 study of Israeli patients suggests that relatively common variations in the TNF promoter region may have an independent effect on linear growth outcomes.92 Similarly, data from Sawczenko et al. demonstrate a potential causal relationship between genetic variation in the promoter region for IL6, alterations in subsequent IL-6 expression and differential effects on linear growth impairment during inflammation.73 Confirmation of these and similar findings is awaited and may help to elucidate the complex molecular interactions pertinent to the pathophysiology of growth impairment.

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Management of growth impairment

Assessment and monitoring of linear growth

Linear growth disturbance associated with Crohn's disease may be part of or even dominate a patient's presentation, may precede the onset of luminal symptoms, or may manifest only during the subsequent disease course. A summary of techniques that should be used to assess and monitor linear growth from childhood through to adulthood are presented in Box 1.2 Pre-illness and parental heights are important to obtain at the time of diagnosis so that the effect of chronic intestinal inflammation on linear growth can be fully appreciated. The greater the growth impairment that is evident before disease recognition, the greater the requirement for catch-up growth if predicted adult stature is to be attained. Following diagnosis and initiation of treatment, regular measurement and charting of height are central to growth management. Height velocity, appraised in the context of pubertal stage, is the most sensitive parameter by which to recognize impaired growth. Delayed radiographic bone age and/or puberty suggests that a greater potential exists for catch-up growth than may be anticipated by the patient's age. Conversely, in patients with growth failure and a normal bone age, the potential window to achieve any catch-up growth may be very small.

Effects of specific treatments on growth

Before the recognition that proinflammatory cytokines directly influence linear growth, management of growth-impaired children with Crohn's disease focused on nutritional restitution.42, 43 Improved growth following supplementary enteral or parenteral nutrition is well documented.93, 94, 95 However, a subset of patients fail to grow despite nutritional repletion, presumably because intestinal inflammation remains chronically active. Thus, in the management or prevention of growth impairment, attention needs to focus on both providing adequate nutritional support and on treating inflammatory disease with the most appropriate pharmacologic, nutritional or surgical interventions (Box 2).2, 96 In addition, separation of anti-inflammatory and nutritional effects on growth is somewhat artificial because of the important interactions between cytokines and nutrition.

The efficacy of specific medical therapies in pediatric Crohn's disease may be extrapolated from data accrued from randomized, controlled trials in adults. Evidence of the efficacy of such therapies for enhancing linear growth, however, requires pediatric studies. Until recently, such data were largely retrospective. The importance of persistent inflammation in the pathogenesis of growth impairment intuitively suggests that therapies that achieve mucosal healing are likely to facilitate normal growth.

Enteral nutrition

Administration of formulated food as the sole source of nutrition in pediatric patients with Crohn's disease has been an important alternative to conventional corticosteroids in the treatment of active disease. Such exclusive enteral nutrition decreases mucosal cytokine production and, particularly when compared with corticosteroid therapy, frequently induces endoscopic healing.97, 98 Changes in serum IGF-I levels have been observed within 14 days of initiating exclusive enteral nutrition; clearly, this therapy has a more rapid and direct anti-inflammatory effect than might be expected from simple nutritional restitution and support alone. Furthermore, exclusive enteral nutrition is associated with improved height velocity compared with steroid therapy.99

One of the limitations of exclusive enteral nutrition has been the tendency for symptoms to recur promptly following its cessation.100 Both cyclical regimens (elemental diet for 1 month out of four) and nocturnal supplemental regimens (exclusive enteral nutrition four nights per week with an unrestricted daytime diet) have been associated with prolonged disease quiescence and improved growth.94, 95, 101 Maintenance exclusive enteral nutrition, however, is not always well tolerated by patients.

Corticosteroids

As mentioned above, conventional corticosteroids are still commonly used as initial therapy for active pediatric Crohn's disease. Chronic daily administration and frequent induction courses directly inhibit growth through the mechanisms discussed above and must be avoided. Moreover, clinical response to corticosteroids is often not associated with mucosal healing98, 102 and probably leads to continued cytokine interference with linear growth.

Immunomodulatory drugs

The steroid-sparing roles of immunomodulatory drugs—azathioprine, mercaptopurine and methotrexate—are well documented.103, 104 Sustained clinical remission and decreased steroid requirements were, however, not associated with improved linear growth in a randomized, placebo-controlled trial of mercaptopurine in children and adolescents with newly diagnosed Crohn's disease.103 Retrospective data published in 2007, however, showed enhancement of linear growth when methotrexate was given to young patients who were intolerant of or had disease refractory to thiopurine therapy.104

Anti-TNF therapy

The efficacy of anti-TNF agents in pediatric patients is well established.105 Considering the role that cytokines, including TNF, have in growth impairment and the ability of anti-TNF antibodies to achieve mucosal healing, both observational106, 107, 108, 109 and clinical trial110 data have unsurprisingly demonstrated a beneficial effect of anti-TNF therapy on linear growth, as long as treatment is undertaken early enough before or during puberty. Ongoing monitoring of long-term safety issues will determine whether anti-TNF agents and other biologic therapies developed in the future should have a special place in pediatric treatment regimens to improve disease-related outcomes such as linear growth.

Surgical treatment

Timely surgical intervention may be the optimal management for some young patients with Crohn's disease, notably for those with localized, internally penetrating or stricturing disease. Despite the almost inevitable endoscopic and subsequent clinical recurrence of Crohn's disease, the period of postoperative remission enables important catch-up growth to occur in patients who have been appropriately selected for surgery and who undergo it before or during early puberty.111, 112, 113

Hormonal interventions

Although serum IGF-I levels clearly decrease during active disease, the fact should be emphasized that no data are yet available to suggest that supplemental GH therapy will alter the final adult height of children with Crohn's-disease-associated growth disturbance. Some experience of the supplemental use of GH during ongoing steroid therapy has been reported in a number of pediatric conditions60 including steroid dependent Crohn's disease.114

GH therapy may have a direct anti-inflammatory effect in patients with IBD. Such therapy can reduce mucosal inflammation in experimental colitis via an IGF-I-independent mechanism that downregulates IL-6 and STAT3,115 but does not reverse local inflammatory resistance to the upregulation of IGF-I by GH (Figure 4).115 Limited data suggest a similar effect of GH therapy in adults with Crohn's disease.116 Further clinical data are awaited. Given the variety of potential risks and complications, GH therapy should be considered experimental in the setting of IBD and is still best limited to formal, investigative, study settings.

Although no controlled clinical studies of testosterone therapy have been conducted in the setting of Crohn's disease, 3–6 months of such treatment carefully supervised by pediatric endocrinologists has been used in boys with Crohn's disease who had an extreme delay of puberty; this therapy was associated with a growth spurt.84

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Conclusions

Chronic undernutrition and proinflammatory cytokines released from the inflamed intestine are key and interrelated contributory factors in the growth impairment that commonly complicates childhood-onset Crohn's disease. Both factors act via interference with the GH–IGF-I axis. Injudicious, chronic use of corticosteroids may compound disease-related growth impairment. Genetic factors may also influence the degree of growth retardation associated with inflammation. Early recognition of disease, optimal control of intestinal inflammation and provision of adequate nutrition are the means by which to prevent or remedy growth delay. Normal growth is a marker of the success of therapy. Contemporary biologic agents that have the potential to achieve mucosal healing provide optimism that these therapies will reduce the prevalence of growth impairment.

Review criteria

A PubMed search was performed in November 2008 using the terms: "Crohn's disease", "complications", "etiology", "immunology", "physiology", "physiopathology", "therapy", "growth", "analysis", "immunology", "pathology", "physiology", "growth disorders/exp", "human growth hormone/exp", "insulin-like growth factor/exp", "interleukin-6/exp", "tumor necrosis factor-alpha/exp", "STAT transcription factors/exp". The reference lists for the papers identified in the initial search were also reviewed for relevant publications. Full-length original articles, meta-analyses, guidelines, and review articles written by respected authorities were all considered. Only English language articles were reviewed.

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Acknowledgments

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.

Competing interests statement

The authors declare competing interests.

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References

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Author affiliations

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

Correspondence to: A. M. Griffiths, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada
Email: anne.griffiths@sickkids.ca

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