Prevalence of Combined Growth Hormone Deficiency and Celiac Disease Among Saudi Arabian Children with Short Stature: A Tertiary Care Center Experience
Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten in genetically susceptible individuals. It is characterized by a range of symptoms, including chronic diarrhea, abdominal distention, and poor weight gain. In some cases, short stature (SS) may be the sole manifestation of CeD, without any gastrointestinal symptoms. This highlights the importance of considering CeD as a potential underlying cause in children presenting with SS. Additionally, transient dysfunction of the endocrine growth axis has been reported in CeD, leading to apparent growth hormone deficiency (GHD). This dysfunction is often reversible with the introduction of a gluten-free diet (GFD). However, in some cases, the impairment of the growth hormone (GH) axis may persist despite strict adherence to a GFD, necessitating treatment with GH therapy.
The coexistence of GHD and CeD has been documented in several studies, with prevalence rates ranging from 0.23% to 0.28%. This study aimed to determine the prevalence of combined GHD and CeD in Saudi Arabian children with SS at a university teaching hospital and to evaluate the response to GH therapy. The study was conducted as part of a larger research project investigating the impact of screening high-risk populations for CeD and was approved by the Research Committee/Biomedical Ethics Unit at King Abdulaziz University.
The study was retrospective in design and included children diagnosed with CeD and SS between October 2006 and December 2018 at King Abdulaziz University Hospital. Patients were identified using the hospital’s medical records through the Health Information Coding System and manual chart review. The diagnosis of CeD was based on the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criteria, which involve measuring antibodies to tissue transglutaminase (tTG) followed by intestinal biopsy in positive cases to confirm the diagnosis. Only biopsy-proven cases of CeD were included in the analysis. SS was defined according to World Health Organization (WHO) criteria, with a height-for-age Z score (HAZ) less than 2 standard deviations below the mean. The Z score was calculated using the Epi Info software program.
Children with known genetic conditions, chronic diseases, and skeletal dysplasia were excluded from the study. The diagnosis of GHD was based on a low GH response (less than 10 ng/mL) after at least two different pharmacological stimulation tests. The tests included clonidine (150 mg/m² body surface area orally) and glucagon (15 mg/kg intramuscular injection) stimulation tests, performed on two separate occasions. Blood samples were collected at 0, 30, 60, 90, 120, 150, 180, and 210 minutes after stimulation. GH-dependent peptide factors, including insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3), were also measured. Treatment with recombinant human GH (rhGH) was initiated in patients who showed no improvement in linear growth after 12 months of strict adherence to a GFD.
Out of 683 children with SS identified during the study period, 91 (13.3%) had positive serology for CeD, 31 (4.5%) had biopsy-proven CeD, and 5 (0.7%) had combined CeD and GHD. The median age at diagnosis of patients with combined GHD and CeD was 7 years, with a range of 4 to 13 years. All patients were treated with subcutaneous injections of rhGH at a daily dose of 35 mg/kg/day in addition to a GFD. The treatment resulted in significant improvement in linear growth, with the HAZ score increasing from -2.77 ± 0.65 to -1.27 ± 1.63. Serum levels of IGF-1 also showed a significant increase from baseline (9.3 ± 59.3 vs. 282.6 ± 161.5). All patients demonstrated good compliance with the GFD, as evidenced by a decline in tTG serum levels (147.5 ± 60.6 vs. 80.5 ± 62.4).
The study highlights the importance of ruling out CeD in children with SS, as it may be the sole manifestation of the disease. The association of SS with other autoimmune diseases has been demonstrated in children with CeD, with some studies reporting high titers of anti-pituitary antibodies, suggesting an autoimmune process. It has been postulated that autoantibodies against the pituitary gland could cause pituitary hypophysitis, leading to suppression of GH production. This may explain the mechanism underlying the association between CeD and GHD.
The coexistence of CeD and GHD has been described in a limited number of studies. For example, Giovenale et al. found that 16 out of 7066 children (0.23%) with SS had both CeD and GHD, while Bozzola et al. reported 14 out of 1066 children (0.28%) with the same condition. In this study, the prevalence of combined CeD and GHD was 0.7%, which is higher than the rates reported in previous studies. This difference may be attributed to the higher prevalence of consanguineous marriages in Saudi Arabia and the relatively high prevalence of stunted growth in the region.
Following GH therapy, significant improvement in linear growth was observed, consistent with the findings of previous studies. Serum IGF-1 levels, which serve as an important biomarker of rhGH treatment, increased in response to therapy. This rise in IGF-1 levels may also contribute to improved intestinal barrier function, as reflected by the decline in tTG levels. The correlation between the increase in IGF-1 and the decrease in tTG levels suggests a better response to a GFD following the effects of rhGH on intestinal integrity.
The study also noted a predominance of female patients among those with combined CeD and GHD, with four girls and one boy included in the cohort. This contrasts with the findings of Giovenale et al., who reported an equal gender distribution, and Bozzola et al., who found only male patients affected. However, these studies collectively suggest that there is no clear gender association with this condition. The median age at diagnosis in this study was 7 years, compared to 6.1 years in Giovenale’s study. The growth response was assessed using the HAZ score, which showed significant improvement from a median value of -2.52 SDs to -1.58 SDs following GH therapy. Previous studies used growth velocity calculations to demonstrate the response to GH treatment.
The study has several limitations, including its retrospective design, small cohort size, and lack of long-term follow-up. These limitations highlight the need for prospective, multi-center studies to further investigate the prevalence and treatment outcomes of combined CeD and GHD in children with SS.
In conclusion, the prevalence of combined CeD and GHD in Saudi Arabian children with SS was higher than reported in many other studies. GH therapy in these patients led to significant improvement in linear growth, suggesting that it may be an effective treatment for achieving catch-up growth. The findings underscore the importance of screening for CeD in children with SS and considering GH therapy in cases where growth impairment persists despite adherence to a GFD.
doi.org/10.1097/CM9.0000000000000715
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