DOI: 10.1097/MPG.0b013e3181f1dd66

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PMID: 21088537

Issn Print: 0277-2116

Publication Date: 2010/12/01


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Short Stature and Catch-up Growth in Celiac Disease

Riccardo Troncone; Roberta Kosova

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Celiac disease (CD) is an immune-mediated systemic disorder elicited by gluten and related proteins in genetically (mainly human leukocyte antigen) susceptible individuals, characterized by a variable combination of gluten-dependent clinical manifestations, anti-tissue transglutaminase (anti-tTG) antibodies, and enteropathy. It presents with increasing incidence worldwide and depends on both genetic and environmental factors. Intestinal damage is the end-stage lesion of an inappropriate T-cell–mediated immune response against gluten peptides that are modified in the lamina propria by transglutaminase enzymes. The clinical spectrum of CD includes symptomatic, silent, latent, and potential forms of the disease. Symptomatic CD can be characterized by classic gastrointestinal manifestations such as diarrhea, weight loss, muscle wasting, failure to thrive, vomiting, and constipation, or by extragastrointestinal manifestations such as short stature, iron-deficiency anemia, hypertransaminasemia, delayed puberty, dermatitis herpetiformis, and others. CD is defined as silent whenever typical intestinal histopathology is found in a patient who is apparently free of symptoms. A potential form of CD is diagnosed in patients who are positive for anti-endomysial and/or anti-tTG, the typical human leukocyte antigen–predisposing genotype, but present with normal mucosal architecture at the intestinal biopsy.
The prevalence of the atypical/silent form has increased significantly recently both in adults and children. In atypical/silent CD the most frequent age of diagnosis coincides with school age and adolescence. This increase appears more likely due to a greater diagnostic awareness and to a better use of screening tests than to a higher number of atypical/silent cases. Both in adults and children, iron-deficiency anemia appears to be the most frequent extraintestinal symptom, followed by short stature in children (1). Thus, short stature is 1 of the main extraintestinal presentations of CD, and CD should be considered in all children with short stature. In these patients the prevalence of CD varies from 2.9% to 8.3%, and CD is by far the most common causal agent, much more than growth hormone deficiency or any other organic disorder (2).
The pathogenesis of CD-associated short stature is still unclear. Growth retardation traditionally has been attributed to generalized or selective malnutrition, but many report a dysfunction of the endocrine growth axis in children with CD. The insulin-like growth factor (IGF) system is crucial for growth because it regulates cell proliferation, differentiation, and apoptosis. Changes in this system have been described in CD at diagnosis; in particular, patients with CD had reduced or normal levels of basal growth hormone (GH), low GH levels during induced hypoglycemia examination, lower IGF-I, lower IGF-II, similar IGF-binding protein (IGFBP)-1, lower IGFBP-3, and higher IGFBP-2 compared with that of controls. In untreated CD, partial GH insensitivity is also present because exogenous administration of human GH does not restore normal IGF-I levels. Patients with CD also had increased concentrations of interleukin (IL)-6, tumor necrosis factor-α, interferon-γ, IL-1β, IL-8, IL-18, IL-4, and IL-10 in serum compared with that of controls, suggesting that inflammation can contribute to the dysregulation of the IGF system in CD. Upon institution of a gluten-free diet (GFD), various parameters of the somatotropic axis change: sensitivity to GH increases and levels of IGF-I, IGF-II, and IGFBP-3 rise, whereas levels of IGFBP-2 decrease (3). At the same time, catch-up growth takes place. Changes reflect the recovery toward a normally functioning somatotropic axis. It is possible that changes were dependent on the reduction in inflammatory cytokines, as the negative correlation of IL-6 with IGF-I would suggest, or were directly related to improved nutritional conditions on GFD.
The possible autoimmune (AI) involvement of the pituitary gland in patients with CD has been suggested, but demonstrated in only a few patients receiving GFD.

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