Table of Contents  

Belsha and Thomson: Coeliac disease in the paediatric population

Introduction

Coeliac disease (CD) is an immune-mediated systemic disease elicited by exposure to gluten in genetically susceptible individuals, with the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, human leukocyte antigen (HLA)-DQ2 and -DQ8 haplotypes, and enteropathy.1

Pathogenesis

In CD, gluten peptides, after crossing the small intestinal epithelium into the lamina propria, are deaminated by the enzyme tissue transglutaminase and presented by HLA-DQ2- or HLA-DQ8-positive antigen-presenting cells to activated T cells. Once activated, the T cells produce interferon-γ and other cytokines, leading to a higher expression of the HLA-DQ molecules and thereby increased gluten peptide presentation. This inflammatory process mediated by T cells leads to mucosal damage of the small bowel.

Diagnoses of CD are increasing with the increased awareness of the disease. Serological testing across a large cohort random sample from a US population estimated a prevalence of CD to be as high as 1 : 133 (0.8%); oesophago-gastroduodenoscopy is now not indicated in every symptomatic child with positive serology and HLA positivity.24

According to recent British Society of Paediatric Gastroenterology, Hepatology and Nutrition and European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines, a diagnosis of CD can be made in symptomatic patients with tissue transglutaminase (tTG) more than 10 times the upper limit of normal levels without endoscopic assessment, providing that genetic testing (HLA-DQ2/DQ8) and anti-endomysial antibodies are positive. This group accounts for up to 59% of paediatric patients with CD.5 Other symptomatic patients with positive tTG but not fitting the criteria should have endoscopic assessment.

Endoscopic assessment is indicated in asymptomatic patients at risk of developing CD if their tTG is more than three times the upper limit of normal levels, and they are HLA-DQ2/DQ8 positive, or if tTG is positive but less than three times the upper limit of normal, ant-endomysial antibodies are present and genetic testing is positive for HLA-DQ2 and -DQ8. Care should be taken regarding the expertise of the local genetic laboratory in interpreting coeliac genetics. A genotyping result that has resolved all common and well-documented HLA alleles (HLA-DQ2.5, -DQ2.5/8, -DQ8, -DQ2.2 or -DQA1*05) is preferred. It should be remembered, however, that HLA-DQ2/DQ8 risk-associated haplotypes are common, carried by 20–30% of the general population. CD is very unlikely (< 1%) if these risk alleles are absent (negative predictive value > 99%).4,68

Recently HLA-DQ2.2 has been used to further improve the true negative value of this test. Discussion with a gastroenterologist is recommended before making the diagnosis. HLA genetic testing can be helpful as well in the following situations:

  1. small bowel histological findings are equivocal (Marsh 1–2) in seronegative patients;

  2. patients on a gluten-free diet in whom testing for CD was not carried out before starting the gluten-free diet;

  3. patients with discrepant coeliac-specific serology and histology;

  4. patients in whom refractory CD is suspected but in whom the original diagnosis of coeliac remains in question;

  5. patients with immunoglobulin A (IgA) deficiency and negative serological markers.

Conditions associated with CD that benefit from genetic testing of CD and serology (if necessary) include: juvenile chronic arthritis, Down’s syndrome, Williams syndrome, Turner syndrome, IgA nephropathy, IgA deficiency, autoimmune thyroid disease and autoimmune liver disease.

Histology

Histology depends on the modified Marsh criteria for a diagnosis of CD, with Marsh 1 being defined as an increase in intraepithelial lymphocytes (IELs), Marsh 2 as increased IELs and crypt hyperplasia and Marsh 3 as increased IELs and crypt hyperplasia with a variable degree of villous atrophy.

Multiple biopsies, including biopsies from the duodenal bulb, are recommended. It is important to consider biopsy from the duodenal cap (DI), as recent studies suggested that up to 21% of coeliac diagnoses were dependent on changes in DI.9

Treatment and follow-up

Children with CD and their families should receive dietetic advice and counselling for a GFD. Patients should be seen regularly to assess growth and nutrition, check nutrient levels, assess for other autoimmune diseases, such as thyroid disease, and monitor autoantibodies, which usually normalize within the first year of life. Of interest, recent studies showed children with CD have a less-balanced diet in terms of excessive intake of sugar and fat, and poor micronutrient intake than children without CD.10 Lactose-free milk should be considered in young patients with Marsh 3 CD and significant villous atrophy in view of the potential deficiency of lactase following villous atrophy.

Refractory coeliac disease

Refractory CD is rare in children but is associated with an increased risk of ulcerative jejunitis and T-cell small bowel lymphoma. Clinically the patient shows normalization of serological markers but abnormal histological findings. Refractory CD is usually due to abnormalities in IELs. Measurement of anti-endomysial and anti-transglutaminase antibodies along with a thorough dietary review is recommended when reviewing this specific group of patients.11

Differential diagnosis of villous atrophy

Many disorders, such as giardiasis, autoimmune enteropathy, tropical sprue, common variable immunodeficiency and intolerance to non-gluten dietary proteins, may show histological findings that are very similar, but not necessarily identical, to CD and therefore should be considered and excluded.

When to consider a gluten rechallenge

If the genetic testing is positive, i.e. the child has the genetic predisposition to develop CD, a gluten challenge should be considered in cases of diagnostic uncertainty, supervised by a dietitian and paediatrician. Exposure to gluten should be approximately 15 g per day for a period of 6–8 weeks. A patient should be considered to have CD if changes in serological markers and histological changes are reported.

Non-coeliac gluten hypersensitivity

Non-coeliac gluten hypersensitivity (NCGH) encompasses a wide spectrum of ill-defined symptoms related to wheat/gluten intake. A differential diagnosis, such as wheat intolerance or proper CD, should be excluded prior to this diagnosis.

A recent systematic review estimated the prevalence of food allergy in Europe and reported self-reported lifetime prevalence of allergy to wheat in all age groups of 3.6%, slightly lower than the prevalence of cow’s milk allergy of 6.0%. The prevalence of IgE-mediated allergy to cow’s milk and wheat was 0.6% and 0.1%, respectively.13

In children, NCGH tends to manifest with gastrointestinal symptoms, such as abdominal pain and chronic diarrhoea; systemic manifestations are less frequent than in adults, the most common systemic symptom being tiredness.12,13

References

1. 

Husby S, Koletzko S, Korponay-Szabó IR, 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. [Erratum published in J Pediatr Gastroenterol Nutr 2012; 54:572.] http://dx.doi.org/10.1097/MPG.0b013e31821a23d0

2. 

Whyte LA, Jenkins HR. The epidemiology of coeliac disease in South Wales: a 28-year perspective. Arch Dis Child 2013; 98:405–7. http://dx.doi.org/10.1136/archdischild-2012-303113

3. 

White LE, Merrick VM, Bannerman E, et al. The rising incidence of coeliac disease in Scotland. Pediatrics 2013; 132:e924–31. http://dx.doi.org/10.1542/peds.2013-0932

4. 

Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of coeliac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med 2003; 163:286–92. http://dx.doi.org/10.1001/archinte.163.3.286

5. 

Belsha D, Morris MA. Potential Impact of revised ESPGHAN guidelines of coeliac disease. British Society of Paediatric Gastroenterology, Hepatology and Nutrition, Nottingham, January 2012.

6. 

Murch S, Jenkins H, Auth M, 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. http://dx.doi.org/10.1136/archdischild-2013-303996

7. 

Lionetti E, Castellaneta S, Francavilla R, et al. Introduction of gluten, HLA status, and the risk of coeliac disease in children. N Engl J Med 2014; 371:1295–303. http://dx.doi.org/10.1056/NEJMoa1400697

8. 

Tye-Din JA, Cameron DJ, Daveson AJ, et al. Appropriate clinical use of human leucocyte antigen typing for coeliac disease: an Australasian perspective. Intern Med J 2015; 45:441–50. http://dx.doi.org/10.1111/imj.12716

9. 

Kaur Bilkhoo H, Ducruet T, Marchand V, et al. Revisiting pathological criteria for earlier diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2016; 62:734–8. http://dx.doi.org/10.1097/MPG.0000000000001026

10. 

Babio N, Alcázar M, Castillejo G, et al. Patients with coeliac disease reported higher consumption of added sugar and total fat than healthy individuals [published online ahead of print 26 April 2016]. J Pediatr Gastroenterol Nutr 2016. http://dx.doi.org/10.1097/MPG.0000000000001251

11. 

Mubarak A, Oudshoorn JH, Kneepkens CM, et al. A child with refractory coeliac disease. J Pediatr Gastroenterol Nutr 2011; 53:216–18. http://dx.doi.org/10.1097/MPG.0b013e318214553a

12. 

Francavilla R, Cristofori F, Castellaneta S, et al. Clinical, serologic, and histologic features of gluten sensitivity in children. J Pediatr 2014; 164:463–7. http://dx.doi.org/10.1016/j.jpeds.2013.10.007

13. 

Nwaru BI, Hickstein L, Panesar SS, et al. Prevalence of common food allergies in Europe: a systematic review and meta-analysis. Allergy 2014; 69:992–1007. http://dx.doi.org/10.1111/all.12423




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