Objective: To evaluate the growth response to growth hormone (GH) replacement therapy during a gluten-free diet in patients with celiac disease (CD) associated with GH deficiency (GHD).
Patients and Methods: A total of 14 prepubertal children affected by CD and GHD with no catch-up growth after ≥12 months of gluten-free diet and a reversion to seronegativity for antiendomysium antibodies and 10 age-matched prepubertal children with idiopathic GHD (IGHD) entered the study. All of the patients were treated with the same GH dosage (0.25 mg/kg subcutaneously each week). Height, growth rate, and body mass index were measured at the time of diagnosis of CD, at the time of endocrinological evaluation, and after the first, second, and third year of GH replacement therapy.
Results: Growth rate strikingly increased (P < 0.005) during the first year of therapy in a similar way in subjects with CD/GHD and IGHD (from a median standard deviation score [SDS] of −2.34 to an SDS of 3.25 and from an SDS of −1.29 to an SDS of 2.79, respectively). During the second and third years of GH treatment, the growth rate tended to decrease but the values at the third year were always positive (CD/GHD, median SDS, 1.10; IGHD, median SDS, 0.11), indicating continued catch-up growth.
Conclusions: In patients with CD with GH deficiency confirmed after ≥12 months of gluten-free diet, GH replacement therapy should be started to allow complete catch-up growth in children. In addition, the effect of GH treatment in patients who comply with a gluten-free diet seems to be comparable to that observed in children with IGHD.
*Department of Pediatric Science, Università degli Studi di Pavia, Fondazione IRCCS San Matteo, Pavia
†Pediatrics Department, Ospedale “F. Ferrari,” Lecce
‡Clinica Pediatrica Monteluce, Perugia
§Pediatric Unit, Ospedali Riuniti, Foggia
||Pediatric Unit, Ospedale di Foligno, Foligno
#Endocrinology Unit, Ospedale San Carlo, Potenza
¶Department of Developmental Biomedicine, Università degli Studi di Bari, Bari
**Departments of Pediatrics and Rehabilitation, Azienda Ospedaliera Pediatrica “Santobono-Pausilipon,” Napoli, Italy
Received 2 February, 2006
Accepted 1 May, 2007
Address correspondence and reprint requests to Mauro Bozzola, MD, Dipartimento di Scienze Pediatriche, Università di Pavia, Fondazione IRCCS San Matteo, Piazzale C. Golgi 2, 27100 Pavia, Italy (e-mail: firstname.lastname@example.org).
Celiac disease (CD), an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible subjects, is one of the most common lifelong disorders in Europe and the United States (1,2). Because CD is often atypical and silent on clinical grounds, many cases remain undiagnosed and exposed to the risk of long-term complications such as osteoporosis or cancer (3). In unselected children and adolescent subjects referred for serological analysis for growth failure, including antibodies against endomysium (EMAs) and serum antitransglutaminase (tTG) immunoglobulin (Ig) A, and jejunal biopsy if necessary, may be carried out to exclude CD. In fact, short stature can be considered a dominant feature, and sometimes the only symptom, of CD (4,5). In patients with CD, before a gluten-free diet is instituted, an apparent GH deficiency can be observed that generally normalizes after the institution of the diet (6). Adherence to a gluten-free diet generally leads to catch-up growth. In particular, weight reaches full catch-up 6 months after the start of a gluten-free diet and height catches up 2 years later (7). In a prospective study of the incidence of childhood CD, subjects with positive CD serology were slightly shorter and weighed less than matched controls (8). A poor growth response to gluten withdrawal was minimal despite satisfactory control. It has been clearly shown that persistent growth stunting occurs only among patients with CD with major transgressions (9). Studies on the hypothalamic-pituitary-somatomedin axis have shown normal or blunted GH response to pharmacological stimuli and insulin-like growth factor-I (IGF-I) concentrations have been reported to be low (10). We previously reported isolated and multiple growth hormone (GH) deficiency (GHD) in patients who showed no catch-up growth after the introduction of a gluten-free diet despite reversion to seronegativity for EMA (11,12). It could be possible that in these patients the effect of GH treatment on growth rate could be affected by the coexistence of malabsorption. The aim of the present study was to evaluate the growth response to GH replacement therapy during gluten-free diet in patients with CD associated with GHD (CD/GHD).
PATIENTS AND METHODS
We studied 14 prepubertal short children (7 boys, 7 girls) affected by GHD and CD with no catch-up growth after ≥12 months of gluten-free diet and a reversion to seronegativity for EMA. We also evaluated 10 age-matched prepubertal children (4 boys, 6 girls) with idiopathic GHD (IGHD).
The diagnosis of CD was made on the basis of the presence of EMA and anti-tTG IgA and the subsequent endoscopic examination of the upper gastrointestinal tract with ≥4 biopsies of the distal duodenal mucosa. Villous atrophy (Marsh type 3), infiltrative changes (Marsh type 1), and crypt hyperplasia (Marsh type 2) were considered characteristic histopathological features of CD (13,14). Because these children did not show catch-up growth after a gluten-free diet, they were investigated for GH secretion. In all of the patients, the diagnosis of GHD was established when GH response to ≥2 pharmacological stimuli was <10 ng/mL in the presence of short stature, reduced growth velocity, and delayed bone age (15). None of the patients had diabetes insipidus, chromosomal abnormalities, dysmorphic syndromes, or acquired GHD after careful clinical evaluation. All of the subjects showed normal thyroid function and normal circadian cortisol rhythm. Magnetic resonance imaging of the hypothalamus and pituitary region was performed in all of the patients. The auxological data from children with CD/GHD or IGHD at the time of diagnosis of CD and GHD are shown in Table 1.
According to the recommendations for the use of GH in children, GH therapy was administered at the weekly dose of 0.25 mg/kg subcutaneously subdivided in 6 daily doses in the evening in children with CD/GHD and IGHD. The patients' height, growth velocity, and body mass index were evaluated before and every 6 months during GH replacement therapy. At present, all of the subjects with IGHD have completed the third year of treatment. All of the patients with CD/GHD completed the first year of treatment, and 11 of 14 subjects completed the second year. In addition, at the end of the second year of GH treatment, 2 patients with CD/GHD interrupted therapy because they started puberty. Only 5 patients with CD/GHD completed the third year of therapy.
Height was measured using a Harpenden stadiometer and expressed as standard deviation score (SDS) for chronological age. The weight and height standards of Tanner et al (16) were used. Pubertal stages were evaluated according to Marshall and Tanner classification (17). Bone age was evaluated according to the method of Greulich and Pyle (18) and expressed as SDS. Target height was calculated as sex-corrected midparental height expressed as SDS score. The study was approved by the ethics committees of the multicenter study, and written informed consent was obtained from the children's parents.
Serum GH, free thyroxine, and thyroid-stimulating hormone concentrations were measured with a commercial time-resolved fluoroimmunoassay (AutoDELFIA; Wallacoy, Turku, Finland), based on the direct sandwich technique in which 2 monoclonal antibodies are directed against specific antigenic determinants on the molecule. EMAs were detected by indirect immunofluorescence on sections from the distal portion of monkey esophagus as an antigenic substrate. Serum anti-tTG IgA and IgG were determined by a commercially available enzyme-linked immunosorbent assay kit (Eu-tTG IgA and IgG, Eurospital, Trieste, Italy).
Data are reported as medians and interquartile ranges (IQRs; 25th to 75th percentiles). The analysis was performed with Statistica software (version 6.0; StatSoft, Tulsa, OK). Nonparametric tests were used in the statistical analysis. The Mann-Whitney U test was used to compare unpaired data between the 2 groups, and Friedman tests (in cases of >2 groups), analyses of variance and Wilcoxon tests (in cases of comparison of the same group at 2 different times) were used to compare paired data. All of the tests were 2-sided. P < 0.05 was deemed statistically significant.
As shown in Table 1, children affected by CD/GHD and children with only GHD had comparable chronological age, bone age, and growth velocity at the time of endocrinological evaluation. In addition, the mean values of GH peak after 2 pharmacological stimuli were similar between the 2 groups of patients. They only differed for the height, which was statistically lower in children with CD/GHD than in children with IGHD (P < 0.05). In patients with CD/GHD, height at the time of the endocrinological investigation was significantly lower (P < 0.05) than that at CD diagnosis (Table 1).
Imaging studies showed pituitary hypoplasia in 2 cases and ectopic posterior hypophysis in another 2 patients in the CD/GHD group. Furthermore, among patients with IGHD, an ectopia of the posterior hypophysis was found. These data indicate a congenital origin of GHD in some patients in both groups.
During the first 3 years of therapy, patients with CD/GHD showed a significant (P < 0.05) improvement in height, from a median value of −2.69 SDS to −0.69 SDS (Fig. 1A). These values are not significantly different from those of patients with IGHD treated with the same dose of GH (from −2.07 SDS to −1.34 SDS; Fig. 1B). The height pretreatment values of patients with CD/GHD and IGHD were significantly lower than the values at the first, second, and third years of GH therapy.
Growth rate also significantly increased (P < 0.005) during the first year of therapy in a similar way in patients with CD/GHD and those with IGHD (from a median value of −2.34 SDS to 3.25 SDS and from −1.29 SDS to 2.79 SDS, respectively; Fig. 2). During the second and third years of GH treatment, the growth rate tended to decrease but the values at the third year were always positive (CD/GHD, median, 1.10 SDS; IGHD, 0.11 SDS), indicating continued catch-up growth. On the contrary, body mass index values did not significantly change during the first 3 years of GH therapy in both groups of subjects and were comparable between the 2 groups at any time of the study (data not shown).
Short stature can be the only presenting clinical feature of CD, mainly in older children and adolescent subjects. In fact, in unselected cases admitted for short stature, the prevalence of the disease varies from 2.9% to 8.3% (19,20). The pathogenesis of CD-associated short stature is still unclear. Withdrawal of gluten from the diet constitutes the best effective treatment for CD. In particular, the gluten-free diet leads to a rapid catch-up growth of body weight within the first year of therapy, whereas height catches up somewhat more gradually, reaching target height within 2 to 3 years (21). The period for catch-up growth appears to have a great variation in duration and appears to depend mainly on the extent of the disease, the age at which it occurs, and the extent of the height deficit compared with target height (21,22); however, most reports indicate that final height in CD is generally normal (23–25). Serum IGF-I increases during the early phase of catch-up growth, but it appears unlikely that this is the steering mechanism of catch-up growth (22).
Catch-up growth is not always complete, however, suggesting other additional causes of short stature. It has been reported that a blunted GH response to pharmacological stimuli normalizes during a gluten-free diet (26). It is not known whether the impaired GH secretion is related to malnutrition.
Our previous studies have suggested that GH secretion should be evaluated in patients with CD who show no catch-up growth after a period of a gluten-free diet despite reversion to seronegativity for EMA (11,12). In fact, in a population of short children we found 0.23% of subjects with CD and blunted GH secretion after pharmacological stimuli (12). It is well known that, in a small proportion of patients with CD, a gluten-free diet fails to induce clinical and/or histological recovery. In a large percentage of these patients, even if an improvement of histological lesions has been reported after gluten-free diet, diarrhea may persist because of some conditions including microscopic colitis and, more rarely, bacterial overgrowth, coexisting inflammatory bowel disease, or irritable bowel syndrome (27,28). On the contrary, there are patients who show persisting villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes despite a strict gluten-free diet for >12 months. This condition is defined as “true refractory CD” (29). Our patients should not be considered affected by refractory CD because they showed a positive response to gluten-free diet and showed reversion to seronegativity of EMA after 1 year of gluten-free diet. Furthermore, after the first year of gluten-free diet, they did not exhibit any more diarrhea or other clinical symptoms of CD. They exhibited persistent reduced height and growth rate as a result of the GH deficit.
In these patients, it could be important to start GH replacement therapy. Recently, Iughetti et al (30) showed the presence of antipituitary autoantibodies in children with CD without catch-up growth after a period of a gluten-free diet.
In the present study, we followed 14 children with CD/GHD during the first 3 years of GH therapy to evaluate whether there is an improvement in growth rate and whether this is comparable with that obtained in GH-treated subjects with IGHD. The 2 groups of patients were similar in terms of chronological age, bone age, and growth velocity before the start of GH treatment. Only height values were significantly different, with children with CD/GHD being shorter than those with IGHD. This is probably a result of the fact that the diagnosis of GHD was made ≥2 years after the diagnosis of CD and the start of the gluten-free diet. During this period, the growth velocity of the children was reduced and the height values became extremely low.
In our patients with CD/GHD, height and growth velocity significantly improved during the first 3 years of GH replacement therapy, confirming that the absence of catch-up growth after gluten-free diet was not caused by a nutritional insufficiency, but presumably by blunted GH and IGF-I secretion. The height at the end of the third year of therapy is still slightly below average for age, but it has almost attained the target height. Our present results are in agreement with recent data by Salardi et al (31) that suggest a short course of hormonal replacement therapy in such patients. Furthermore, the pattern of height and growth rate of patients with CD/GHD or IGHD during GH therapy is comparable. Height velocity increases the most during the first year of therapy and then gradually wanes as height SDS approaches target height SDS. These data suggest that the nutritional imbalance that could persist in patients with CD on a gluten-free diet does not influence the effect of GH treatment on height and growth velocity. Interestingly, we can speculate that if a chronic disease such as CD is under control, then the growth pattern of the subjects depends only on GH–IGF-I axis functionality.
In conclusion, in patients with CD and GHD confirmed after ≥12 months of a gluten-free diet, GH replacement therapy should be started to allow complete catch-up growth in children. Furthermore, the effect of GH treatment in patients who comply with a gluten-free diet seems to be comparable to that observed in children with IGHD.
The authors thank Susan West for the English revision of the manuscript.
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