Omar Ibrahim Saadah  ( Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Saudi Arabia. )

Objective: To assess the growth pattern of children with coeliac disease after the introduction of a gluten-free diet.

Methods: The retrospective study was conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, and comprised data from January 2015 to December 2018 of children aged 2-16 years with biopsy-proven coeliac disease. Serial measurements of height-for-age and weight-for-age z-scores were recorded at 0, 4, 8, 12 and 16 months. Data on insulin-like growth factor-1 and insulin-like growth factor binding protein-3 obtained at diagnosis and during follow-up was retrieved. Clinical, demographic, and laboratory data was extracted from the patients' medical files. Data was analysed using SPSS 22.

Results: Of the 47 patients, 25(53.2%) were boys and 22(46.8%) were girls. The overall mean age was 8.7±3.4 years. There was a significant time effect for weight-for-age and height-for-age z-scores (p<0.001). There was significant increase in the secretion of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 (p<0.05) during the first 8 months of a gluten-free diet.

Conclusion: The administration of gluten-free diet for Saudi children with coeliac disease normalized growth parameters and improved the endogenous secretion of growth factors.

Keywords: Celiac disease, Growth, Child, Saudi Arabia. (JPMA 71: 1388; 2021)

DOI: https://doi.org/10.47391/JPMA.1308

 

Introduction

 

Coeliac disease (CD) is an immune-related enteropathy elicited by dietary gluten and related prolamins in genetically-susceptible individuals carrying human leukocyte antigen (HLA) DQ2 or DQ8 alleles and is characterised by a range of non-specific symptoms and signs, including faltering linear growth, stunting and poor weight-gain.¹ CD prevalence 1.5-2.2% has been reported in children in Saudi Arabia.^2,3 Growth impairment can be a significant manifestation of the disease in Saudi children; it is often an indication to look for CD.⁴ Indeed, a significant proportion of Saudi Arabian children with CD present with isolated short stature.^5,6 The linear growth of children tends to improve solely with gluten-elimination from the diet, but a lack of response after one year of strict gluten-elimination should be investigated for the possibility of combined CD and growth hormone deficiency.⁷ Many guidelines recommend screening for CD using serological tests in children with symptoms suggestive of CD, such as growth failure.^1,8,9

Regardless of the mode of presentation, growth impairment in children with CD remains an important concern for most patients and their families.¹⁰ Malnutrition resulting from malabsorption is the main determinant of growth failure, but impaired growth hormone (GH) secretion because of suppressed hypothalamic pituitary axis may also play a role in the mechanism of growth failure.¹¹ Anti-pituitary antibodies have been reported to contribute to linear growth impairment in children with newly-diagnosed CD, likely mediated via insulin-like growth factor-1 (IGF-1).¹² The secretion of IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3) is significantly affected in patients with active CD following long-term gluten exposure.^13,14 A gluten-free diet (GFD) is reported to stimulate the secretion of IGF-1 and IGFBP-3 that may play a role in the catch-up growth process following the institution of a strict GFD.¹⁵

Life-long provision of GFD often reverses CD manifestation and stimulates linear growth through improvement of nutritional status and through recovery of the GH pituitary axis.^16-18

To the best of our knowledge, there are currently no studies on the trend of growth pattern following the introduction of a GFD in Saudi children with CD. The current study was planned to fill the gap by assessing the pattern of linear growth of CD children following GFD, and by evaluating the association with GH and GH-related factors that can be utilised for monitoring linear growth response.

 

Patients and Methods

 

The retrospective study was conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia after approval from the institutional ethics review committee, and comprised data from January 2015 to December 2018. Data collection was commenced and completed between 1st and 31st of August 2019. Data was related to children with documented regular attendance at the paediatric gastroenterology clinic for the first 16 months post-diagnosis. Data of patients with associated co-morbidities affecting growth, such as chronic illnesses, endocrine disorders, and genetic and chromosomal abnormalities was excluded. Growth data comprising serial measurements of weight and height was extracted from the hospital's health information system. Clinical, demographic and laboratory data was collected from patients' medical charts.

CD diagnosis was based on the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) criteria1: having positive antibody testing to tissue transglutaminase-Immunoglobulin-A (tTG-IgA), followed by small intestinal biopsy obtained through upper gastrointestinal endoscopy for confirmation. The assessment of the adherence to GFD was based on dietary history and the normalisation of the initial tTG-IgA level following GFD commencement. Histopathology was graded using the Marsh-Oberhuber classification.¹⁹

Anthropometric measures, including serial measurements of height and weight, were collected at 0, 4, 8, 12, 16 months and converted to standard deviation (z) scores. Weight-for-age z-score (WAZ) and height-for-age z-score (HAZ) were calculated using Epi-Info 7.2.

Available results of investigations of GH or growth-related factors by the paediatric endocrinologist for patients with severe short stature were also recorded. The GH provocation test at the institution is usually performed using two pharmacological tests. Clonidine (150 micrograms/m2 body surface area orally) and glucagon (15 micrograms/kg intramuscular [IM]) stimulation tests were performed on two different occasions, followed by a timely collection of blood samples at 0, 30, 60, 90, 120, 150, 180 and 210 minutes post-stimulation. The diagnosis of GH deficiency (GHD) was based on low GH response (peak GH level <10ng/mL) after the results of two different pharmacological tests. IGF-1 was measured in plasma by radioimmunoassay (RIA) after acid-alcohol extraction. IGFBP-3 was measured by RIA in diluted serum. Data was analysed using SPSS 22. A one-way repeated-measure analysis of variance (ANOVA) with post-hoc analysis was used to compare changes of repeated anthropometric and growth factor measures over time, and a mixed-design ANOVA was used when testing the repeated growth measures between categories, such as gender and level of adherence. Data were checked for normality prior to application of ANOVA. P<0.05 was taken as statistically significant.

 

Results

 

Of the 47 patients, 25(53.2%) were boys and 22(46.8%) were girls. The overall mean age was 8.7±3.4 years (range: 2.4-16 years). The most commonly presented symptoms were abdominal pain 17(36%), abdominal distention 17(36%), sever stunting 17(36%), loss of appetite 16(34%), weight-loss 14(30%), diarrhoea 12(25.5%), and vomiting 9(19%) (Table-1).

 

 

Overall mean WAZ at diagnosis was -2.8±1.9; for boys -2.4±1.9, and for girls -3.2±1.9. Significant time-based effects were noted (Figure-1).

 

 

HAZ <-2 indicating stunting was found in 40(85%) patients. The mean HAZ at diagnosis was -3±0.99. Significant changes with time were noted (Figure-2).

 

 

Pairwise comparison showed significant differences between each time period (p<0.001).

Apart from the gender difference in the estimated means of HAZ linear trend (p=0.002), there was no difference between males and females (p>0.05). The degree of adherence to GFD did not differ in either WAZ or HAZ trends between patients in any of the corresponding groups (Table-2).

 

 

GH assessment using two pharmacological agents was performed on 30(63.8%) patients at the time of diagnosis. GHD was found in 11(23%) patients. The peak GH secretion occurred at 60 minutes for most children with normal GH secretion (Figure-3).

 

 

There was statistically significant difference in either mean weight change (p=0.45) or mean height change (p=0.15). None of the patients required GH treatment.

Mean IGF-1 was 133.4±96.8ng/ml (range: 25-382ng/ml) and mean IGFBP-3 was 3174±1081ng/ml (range: 913-5280ng/ml).

IGF-1 changes after the introduction of GFD during follow-up was performed for 17(36%) patients and showed significant increase from the baseline (p=0.01). The difference was mainly between baseline and 8 months (p=0.01), and between baseline and 12 months (p=0.02) (Figure-4).

 

 

Mean IGFBP-3 showed a significant trend over time following the introduction of GFD (p=0.004). The difference was significant between baseline and 8 months (p=0.02), and between baseline and 12 months (p=0.006) (Figure-5).

 

 

There was no significant differences in the mean weight (p=0.766) or height (p=0.916) changes in relation to low haemoglobin (Hb). Similarly, no significant differences were found between high CD serology and mean weight (p=0.07) or mean height (p=0.190).

 

Discussion

 

Growth impairment is one of the most significant manifestations that occur commonly in CD patients. The growth impairment may reflect various nutritional deficiencies resulting from nutrient malabsorption, which occurs following villous atrophy of the small intestinal mucosa after prolonged exposure to gluten.²⁰ Impairment of GH production from the pituitary glands and lack of response to GH have been implicated as possible contributing mechanisms of growth failure.^13,14

Growth failure may precede CD diagnosis in the absence of gastrointestinal symptoms in many patients.²⁰ This provokes researchers to advocate universal auxological screening for CD in all children to identify children with possible CD,²¹ especially in the context of frequent recommendations against mass screening of children using serological testing in Europe and the United States.^1,22,23

Catch-up growth is defined by the WHO as rapid, compensatory growth during rehabilitation from prior nutritional deficit or illness.²⁴ Nutritional rehabilitation of children with CD leads to acceleration of growth,^17,18,24-27. The current study demonstrated exponential increase in WAZ and HAZ growth parameters following the introduction of GFD over a period of 16 months. This increase did not differ between GH-deficient children and children with normal GH levels. Children normalised their growth parameters by 8-10 months of nutritional rehabilitation with overshot after 12 months of GFD (Figures-1, 2). This pattern has been consistent with earlier studies.^25,28 Different studies reported variable growth patterns in CD patients, finding both complete^17,25,27-29 and incomplete catch-up growth.^18,30,31 This variation may be attributed to differences in the studied population, degree of adherence to GFD, and the growth status at the time of diagnosis.³² The current study found no significant differences according to the degree of GFD adherence on catch-up growth parameters probably because of the small number of patients in the non-adherent group. The finding, however, is consistent with literature¹⁷ and may be explained by a lack of a clear relationship between GFD adherence and recovery of the small intestinal mucosa, which may lag behind in some patients despite good adherence.

The improvement in growth parameters shown in the current study is in line with earlier studies.^13,14

The current study has limitations, including retrospective design, relatively small sample size, lack of formal sample size power calculation, and a lack of long-term follow-up data.

 

Conclusion

 

CD children had normalised growth parameters and improved endogenous secretion of growth factors with the administration of GFD.

 

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

 

References

 

1.      Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54:136-60. doi: 10.1097/MPG.0b013e31821a23d0.

2.      Al-Hussaini A, Troncone R, Khormi M, AlTuraiki M, Alkhamis W, Alrajhi M, et al. Mass Screening for Celiac Disease Among School-aged Children: Toward Exploring Celiac Iceberg in Saudi Arabia. J Pediatr Gastroenterol Nutr 2017;65:646-51. doi: 10.1097/MPG.0000000000001681.

3.      Aljebreen AM, Almadi MA, Alhammad A, Al Faleh FZ. Seroprevalence of celiac disease among healthy adolescents in Saudi Arabia. World J Gastroenterol 2013;19:2374-8. doi: 10.3748/wjg.v19.i15.2374.

4.      Saadah OI. Celiac disease in children and adolescents at a singe center in Saudi Arabia. Ann Saudi Med 2011;31:51-7. doi: 10.4103/0256-4947.75779.

5.      Assiri AM. Isolated short stature as a presentation of celiac disease in Saudi children. Pediatr Rep 2010;2:e4. doi: 10.4081/pr.2010.e4.

6.      Saadah OI, ALNosani NM. Celiac disease in Saudi children with isolated short stature: is it rare or are we not screening rigorously enough? J Pediatr Endocrinol Metab 2020;33:89-93. doi: 10.1515/jpem-2019-0348.

7.      Qutub LM, Saadah OI. Prevalence of combined growth hormone deficiency and celiac disease among Saudi Arabian children with short stature: a tertiary care center experience. Chin Med J (Engl) 2020;133:729-31. doi: 10.1097/CM9.0000000000000715.

8.      Mäki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, et al. Prevalence of Celiac disease among children in Finland. N Engl J Med 2003;348:2517-24. doi: 10.1056/NEJMoa021687.

9.      Ravikumara M, Nootigattu VK, Sandhu BK. Ninety percent of celiac disease is being missed. J Pediatr Gastroenterol Nutr 2007;45:497-9. doi: 10.1097/MPG.0b013e31812e5710.

10.    Coburn SS, Puppa EL, Blanchard S. Psychological Comorbidities in Childhood Celiac Disease: A Systematic Review. J Pediatr Gastroenterol Nutr 2019;69:e25-33. doi: 10.1097/MPG.0000000000002407.

11.    Argente J, Pozo J, Hernández M. The growth hormone axis in malnutrition. An Esp Pediatr 1993;39(Suppl 55):173-80.

12.    Delvecchio M, De Bellis A, Francavilla R, Rutigliano V, Predieri B, Indrio F, et al. Anti-pituitary antibodies in children with newly diagnosed celiac disease: a novel finding contributing to linear-growth impairment. Am J Gastroenterol 2010;105:691-6. doi: 10.1038/ajg.2009.642.

13.    Ferrante E, Giavoli C, Elli L, Redaelli A, Novati E, De Bellis A, et al. Evaluation of GH-IGF-I axis in adult patients with coeliac disease. Horm Metab Res 2010;42:45-9. doi: 10.1055/s-0029-1241169.

14.    Street ME, Volta C, Ziveri MA, Zanacca C, Banchini G, Viani I, et al. Changes and relationships of IGFS and IGFBPS and cytokines in coeliac disease at diagnosis and on gluten-free diet. Clin Endocrinol (Oxf) 2008;68:22-8. doi: 10.1111/j.1365-2265.2007.02992.x.

15.    Boersma B, Houwen RH, Blum WF, van Doorn J, Wit JM. Catch-up growth and endocrine changes in childhood celiac disease. Endocrine changes during catch-up growth. Horm Res 2002;58(Suppl 1):57-65. doi: 10.1159/000064771.

16.    Barera G, Mora S, Brambilla P, Ricotti A, Menni L, Beccio S, et al. Body composition in children with celiac disease and the effects of a gluten-free diet: a prospective case-control study. Am J Clin Nutr 2000;72:71-5. doi: 10.1093/ajcn/72.1.71.

17.    Damen GM, Boersma B, Wit JM, Heymans HS. Catch-up growth in 60 children with celiac disease. J Pediatr Gastroenterol Nutr 1994;19:394-400. doi: 10.1097/00005176-199411000-00005.

18.    De Luca F, Astori M, Pandullo E, Sferlazzas C, Arrigo T, Sindoni A, et al. Effects of a gluten-free diet on catch-up growth and height prognosis in coeliac children with growth retardation recognized after the age of 5 years. Eur J Pediatr 1988;147:188-91. doi: 10.1007/BF00442220.

19.    Marsh MN, Johnson MW, Rostami K. Rebutting Oberhuber- Again. Gastroenterol Hepatol Bed Bench 2015;8:303-5.

20.    Holtmeier W, Caspary WF. Celiac disease. Orphanet J Rare Dis 2006;1:3. doi: 10.1186/1750-1172-1-3.

21.    Saari A, Harju S, Mäkitie O, Saha MT, Dunkel L, Sankilampi U. Systematic growth monitoring for the early detection of celiac disease in children. JAMA Pediatr 2015;169:e1525. doi: 10.1001/jamapediatrics.2015.25.

22.    Murch S, Jenkins H, Auth M, Bremner R, Butt A, France S, et al. Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children. Arch Dis Child 2013;98:806-11. doi: 10.1136/archdischild-2013-303996.

23.    Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013;108:656-76. doi: 10.1038/ajg.2013.79.

24.    World Health Organization. Physical status: The use of and interpretation of anthropometry: Report of a WHO Expert Committee. Geneva, Switzerland: WHO Press; 1995.

25.    Barr DG, Shmerling DH, Prader A. Catch-up growth in malnutrition, studied in celiac disease after institution of glutenfree diet. Pediatr Res 1972;6:521-7. doi: 10.1203/00006450-197205000-00006.

26.    Boersma B, Wit JM. Catch-up growth. Endocr Rev 1997;18:646-61. doi: 10.1210/edrv.18.5.0313.

27.    Bosio L, Barera G, Mistura L, Sassi G, Bianchi C. Growth acceleration and final height after treatment for delayed diagnosis of celiac disease. J Pediatr Gastroenterol Nutr 1990;11:324-9. doi: 10.1097/00005176-199010000-00007.

28.    Greco L, Tipo V, Di Donato F, Mayer M. Pulsatile growth pattern during catch-up growth in childhood coeliac disease. Acta Paediatr 1994;83:724-9. doi: 10.1111/j.1651-2227.1994.tb13127.x.

29.    Hernández M, Argente J, Navarro A, Caballo N, Barrios V, Hervás F, et al. Growth in malnutrition related to gastrointestinal diseases: coeliac disease. Horm Res 1992;38(Suppl 1):79-84. doi: 10.1159/000182576.

30.    Cataldo F, La Tona D, Mirto G, La Monaca P, Albeggiani A. Behavior of the auxologic status and various nutritional indices in a group of celiac children. Minerva Pediatr 1987;39:187-90.

31.    Gemme G, Vignolo M, Naselli A, Garzia P. Linear growth and skeletal maturation in subjects with treated celiac disease. J Pediatr Gastroenterol Nutr 1999;29:339-42. doi: 10.1097/00005176-199909000-00018.

32.    Catassi C, Fasano A. Celiac disease as a cause of growth retardation in childhood. Curr Opin Pediatr 2004;16:445-9. doi: 10.1097/01.mop.0000133637.64414.20.