Mechanisms of growth impairment in pediatric Crohn's disease

Abstract

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.

Acute Illness is Associated with Suppression of the Growth Hormone Axis in Zimbabwean Infants

“…For example, children with chronic inflammatory diseases, such as Crohn's disease and juvenile idiopathic arthritis, have reduced circulating IGF-1 concentrations caused by elevated pro-inflammatory cytokines. 17,18 Although chronic inflammatory conditions such as Crohn's disease are characterized by highly elevated inflammatory markers over long periods, leading to severe growth failure, they provide a proof of concept of the association between inflammation and reduced IGF-1; data from transgenic mice confirm that these associations are causal. 29 It therefore seems plausible that even a short illness associated with an acute-phase response, such as pneumonia, temporarily suppresses the GH-IGF-1 axis, and that recurrent infections may have a cumulative effect on growth through frequent, short-term reductions in IGF-1.…”

“…IGF-1 is a circulating hormone synthesized by the liver that mediates the effects of growth hormone (GH) by stimulating proliferation of chondrocytes at the epiphyseal growth plate; it is essential for healthy bone growth. 16 Individuals with chronic inflammatory conditions (e.g., juvenile idiopathic arthritis and Crohn's disease) commonly have suppressed concentrations of IGF-1, 17,18 which are inversely related to the level of circulating pro-inflammatory cytokines.…”

Exclusive enteral nutrition and induction of remission of active Crohn’s disease in children

“…As well as effects on weight gain, active CD also leads to impaired linear growth, which is consequent to the direct and indirect effects of proinflammatory cytokines, and also from in adequate nutritional intake [8]. Historically, such growth impairments often led to altered final adult height (i.e., shorter than their genetic potential).…”

“…Physical factors (such as early satiety, pain or enhanced gastrocolic reflex activity) may contribute to these reductions in intake. More importantly, however, weight loss is due to the anorexic effects of mucosally derived proinflammatory cytokines, especially TNF-α and IL-6 [8].…”

The Human Gut Microbiota and Undernutrition

“…T us, stunting usually ref ects the cumulative ef ects of poor nutrition and other insults that of en span several generations (2). Undernutrition during critical periods of development has been linked to insulin-like growth factor-I (IGF-I) and growth hormone signaling pathways, which appear to modulate height in response to an unfavorable environment, whether in utero or postnatally (7,8). T is may "program" the child's future growth, which may explain why reductions in stunting in response to nutritional interventions are typically rather modest.…”