From the Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” Naples, Italy.
Address correspondence and reprint requests to Prof Riccardo Troncone, Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University “Federico II,” via S. Pansini 5, I-80131 Naples, Italy (e-mail: firstname.lastname@example.org).
The authors report no conflicts of interest.
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. The association between CD and AI disorders may be secondary to the linkage disequilibrium of genes predisposing for both CD and other AI diseases or to the existence of shared epitopes between gliadin and antigens of “self” structures. Some studies demonstrated a remarkable prevalence of positive anti-pituitary antibodies (APA) in newly diagnosed patients with CD. High APA titers are associated with height impairment, likely mediated by a reduction of IGF-I, thus suggesting that AI pituitary process could induce a linear growth impairment. In fact, APA are associated with lower levels of IGF-I and their presence may help in identifying subjects with short stature who are prone to develop GH deficiency (GHD) (4).
Catch-up growth, a discontinuous process made up of a sequence of bursts of growth followed by a resting phase (5), is defined as rapid, compensatory growth during rehabilitation from prior nutritional deficit. During catch-up growth, the child may grow in height at up to 4 times the average rate for his or her chronological age. Velocity decreases as the child approaches his or her genetically predisposed channel growth. Catch-up growth is maximal in the first 6 months on a GFD. In patients with CD, after GFD starts, weight catches up more quickly than height. The increments in height may be influenced by age at the time of diagnosis of CD because children with an early diagnosis demonstrated higher increments in height than children who were diagnosed late (6). However, there are conflicting results concerning final height attained by patients with CD; some authors suggest that growth recovery is not always complete and final height may remain 1.5 SD less than the mean despite early treatment, careful follow-up, and good adhesion to dietary restrictions, whereas others conclude that the final height of patients with CD is similar to that of the general population. Some authors demonstrated that delayed diagnosis of CD had an influence on the final adult height in men, with an inverse correlation between the age at diagnosis and the final attained height (7). Diet compliance seems not to influence the height.
Some patients with CD do not show catch-up growth during GFD, despite reversion of seronegativity for CD markers including anti-endomysial and anti-tTG. The absence of catch-up growth requires evaluation of compliance, endocrinological evaluation, and possible concurrent GH deficiency. In a few cases, incomplete catch-up growth could be caused by persistent nutritional defects or by the marked acceleration in bone maturation that parallels the rapid increase in growth velocity. In patients with CD with no catch-up growth after at least 1 year of GFD, GHD was found in 0.23% of them (2). In these patients, GH replacement therapy should be started to allow complete catch-up growth. Growth rate strikingly increases during the first year of recombinant human GH therapy in patients with CD-GHD and then gradually wanes as height approaches its target. Furthermore, the effect of GH treatment in patients who comply with a GFD seems to be comparable with that observed in children with idiopathic GHD (8).
It is important to mention that Turner syndrome (TS) is another important cause of short stature in girls and it is frequently associated with CD (6%–18% of patients). Thus, subjects with TS require screening for CD, which should occur as soon as possible after the diagnosis of TS and be repeated periodically. It could be advantageous to treat subjects already screened for CD with GH to improve the response to treatment (9).
In conclusion, short stature is 1 of the most common clinical manifestations of CD and should be considered in all children with short stature. Catch-up growth is observed on GFD, mostly in the first 6 months from diagnosis. The absence of catch-up growth requires the evaluation of compliance and endocrinological evaluation. Patients should be tested for GH reserve, particularly if APA is positive.
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