Pediatric Annals

Celiac Disease in the Pediatric Population

Daniel Gelfond, MD; Alessio Fasano, MD

Abstract

Celiac disease (CD) is an immune-mediated enteropathy triggered by inappropriate immune response to ingested gluten and gluten-related proteins found in wheat, rye, and barley. Genetic predisposition is an essential factor in the development of CD. Membrane receptors involved in preferential antigen presentation to CD4+ T cells play a crucial role in the immune response characteristic of CD. Genes located on the HLA region of chromosome 6, namely HLA-DQ2 or DQ8, are found in almost 100% of those affected with CD (Figure 1, see page 276). Once the inflammatory reaction is activated by gluten, CD4+ T cells produce cytokines, which are likely to contribute to the pathophysiology of the intestinal damage of CD that ultimately dictates the clinical outcome of the disease.

1. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163(3):286-292.

2. Catassi C, Fasano A. New developments in childhood celiac disease. Curr Gastroenterol Rep. 2002;4(3):238-243.

3. Fasano A, Catassi C. Coeliac disease in children. Best Pract Res Clin Gastroenterol. 2005;19(3):467-478.

4. Mora S, Barerà G, Beccio S, et al. A prospective, longitudinal study of the long-term effect of treatment on bone density in children with celiac disease. J Pediatr. 2001;139(4):516-521.

5. Hill ID, Dirks MH, Liptak GS; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40(1): 1-19.

6. Fasano A. European and North American populations should be screened for coeliac disease. Gut. 2003;52(2): 168-169.

7. Kumar PJ. European and North American populations should be screened for coeliac disease. Gut. 2003;52(2):170-171.

8. Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology. 2005;128(4 Suppl 1):S68-S73.

9. Arentz-Hansen H, Fleckenstein B, Molberg O, et al. The molecular basis for oat intolerance in patients with celiac disease. PLoS Med. 2004;l(l):el.

10. Kronholm K Adults with celiac disease can eat pure oat [in Norwegian]. Tidsskr Nor Laegeforen. 2001;121(3):364.

11. SoIUd LM, Khosla C. Future therapeutic options for celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2005;2(3): 140-147.

12. Hausch F, Shan L, Santiago NA, Gray GM, Khosla C. Intestinal digestive resistance of immunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol. 2002;283(4): G996-G1003.

13. Di Cagno R, De Angelis M Auricchio S, et al. Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appi Environ Microbiol. 2004;70(2): 1088-1096.

14. Fasano A, Not T, Wang W, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518-1519.

TABLE 1.

Conditions Associated With Celiac Disease

TABLE 2.

Clinical Manifestations of Untreated Celiac Disease in Pediatric Patients

TABLE 3.

Efficacy of Serologic Assays in Diagnosing Celiac Disease…

Celiac disease (CD) is an immune-mediated enteropathy triggered by inappropriate immune response to ingested gluten and gluten-related proteins found in wheat, rye, and barley. Genetic predisposition is an essential factor in the development of CD. Membrane receptors involved in preferential antigen presentation to CD4+ T cells play a crucial role in the immune response characteristic of CD. Genes located on the HLA region of chromosome 6, namely HLA-DQ2 or DQ8, are found in almost 100% of those affected with CD (Figure 1, see page 276). Once the inflammatory reaction is activated by gluten, CD4+ T cells produce cytokines, which are likely to contribute to the pathophysiology of the intestinal damage of CD that ultimately dictates the clinical outcome of the disease.

EPIDEMIOLOGY

CD is one of the most common lifelong disorders in Europe and United States, affecting approximately 1% of the general population.1 An increased frequency of CD is found in at-risk groups, such as family members of CD patients, patients with autoimmune disorders (eg, Type 1 diabetes, autoimmune thyroiditis), and genetic disorders, including Down syndrome, Turner syndrome, and IgA deficiency (Table 1, see page 277).

Projections based on epidemiological studies performed in United States suggest that 2 to 3 million people may be affected by CD, although only 70,000 to 80,000 carry the diagnosis.1·2 Considering that the clinical presentation of CD often is atypical or clinically silent, many cases may go undiagnosed for many years. Accordingly, these undiagnosed patients are exposed to the risk of long-term complications from untreated disease.

Figure !.The small-intestinal mechanism in patients with celiac disease. Fragments of proline-rich gluten are resistant to enzymatic digestion within the lumen and the brush-border. Zonulin-induced damage of the intercellular barrier maintained by tight junctions (zonula occludens) enables prolinerich gluten fragments to enter the lamina propria. Once in the lamina propria, gluten fragments are deamidated with the help of tissue transglutaminase (TTG). Only deamidated gluten can be recognized by the HLA-DQ2 or DQ8 of the antigen-presenting cells (APC) and be presented to a CD4+ T cell. Gluten-activated T cells can produce INF-? and cytokines via theTh-1 pathway and lead to production of anti-TTG antibody or anti-gliadin antibody via theTh-2 pathway.

Figure !.The small-intestinal mechanism in patients with celiac disease. Fragments of proline-rich gluten are resistant to enzymatic digestion within the lumen and the brush-border. Zonulin-induced damage of the intercellular barrier maintained by tight junctions (zonula occludens) enables prolinerich gluten fragments to enter the lamina propria. Once in the lamina propria, gluten fragments are deamidated with the help of tissue transglutaminase (TTG). Only deamidated gluten can be recognized by the HLA-DQ2 or DQ8 of the antigen-presenting cells (APC) and be presented to a CD4+ T cell. Gluten-activated T cells can produce INF-? and cytokines via theTh-1 pathway and lead to production of anti-TTG antibody or anti-gliadin antibody via theTh-2 pathway.

CLINICAL PRESENTATION IN CHILDREN

Although CD can present at any age, including in the elderly, typical cases manifest in early childhood. Classic symptoms in the pediatric population are characterized by gastrointestinal manifestations starting between age 6 months and 2 years, following introduction of gluten into the diet. Typically, children present with impaired growth, chronic diarrhea, abdominal distention, muscle wasting with hypotonia, poor appetite, and lack of energy (Table 2, see page 278). Progression of symptoms can be noticed within weeks to months of consuming gluten-containing products, starting with poor weight gain and ultimately manifesting as weight loss. Although rarely observed in developed countries, untreated CD can evolve into a clinical condition defined as celiac crisis, characterized by abdominal distention, explosive watery diarrhea, and dehydration with electrolyte imbalance, leading to hypotensive shock and lethargy.

Less typical presentation has been observed in older children (ages 5 to 7), presenting with delayed onset CD features. These children frequently experience unusual intestinal complaints (eg, recurrent abdominal pain, nausea, vomiting, bloating, constipation) or extraintestinal manifestations, including short stature, pubertal delay, iron deficiency, dental enamel defects, and abnormalities in liver function tests (Table 2).

Table

TABLE 1.Conditions Associated With Celiac Disease

TABLE 1.

Conditions Associated With Celiac Disease

CD-related complications once thought limited to the adult population also have been observed in children. For example, osteoporosis has been found in older children with untreated CD.3 Although the exact pathogenesis of the bone demineralization seen in children affected by CD has not been identified conclusively, prompt induction and adherence to a gluten-free diet in pediatric patients has led to a satisfactory recovery of bone mass.4 The importance of early recognition of poor bone mineralization and gluten-free diet implementation in childhood is emphasized by the observation that a delayed diagnosis may jeopardize the improvement of the osteoporotic damage in adults.4

One of the most controversial issues concerning the clinical presentation of CD in pediatrics is the association between the disease and other autoimmune disorders. Although the exact mechanism of this correlation has not been established, two main theories have been entertained: co-localization of CD genes and genes involved in pathogenesis of other autoimmune diseases on the same chromosome, or untreated CD causing conditions that predispose to the onset of other autoimmune diseases in genetically susceptible people. This clearly is a critical question, considering that, presumptively, many patients with CD are realtively asymptomatic and therefore undiagnosed (latent disease).

DIAGNOSIS

Several important components are involved in finalizing a diagnosis of CD, including clinical presentation, serologic markers, genetic factors, and tissue pathology. Commercially available serologic tests for CD include anti-gliadin antibodies (AGA) both of the IgA and IgG class, anti-endomysium IgA (EMA) antibodies, and anti-tissue transglutaminase IgA and IgG (TTG) antibodies (Table 3, see page 278). These tests are particularly helpful in those with silent disease or with the potential to develop CD beacuse of first-degree relatives with known CD cases or because of the presence of other associated conditions (Table 1).

Clinicians must be aware that false positive results are increasingly likely when a single serologic test is used, while multiple tests may yield higher positive predictive values for diagnosing CD. Patients with gastrointestinal disorders such as esophagitis, gastritis, gastroenteritis, inflammatory bowel disease (IBD), cystic fibrosis (CF), and cow's milk protein intolerance frequently test positive for AGA, particularly of the IgG class. EMA is more expensive, operatordependant and less accurate in children younger than 2.5 Use of TTG alone or in combination with other serologic markers has been shown to have higher correlation with biopsy-proven CD.5 Considering that the most reliable CD-related auto-antibodies are of the IgA class, appropriate evaluation includes ruling out total IgA deficiency to minimize false negative serologic results.

SCREENING

One of the most debated questions remains who should be screened for CD and what actions should be taken based on the results of the screening tests. There is ample evidence that untreated patients with CD are at an increased risk of severe, sometimes life-threatening complications, with increased mortality and morbidity as compared to the general population. The high estimated prevalence of the disease in North and South America, Europe, and North Africa emphasizes the importance of increased awareness among healthcare professionals to decrease the threshold for CD screening.

Table

TABLE 2.Clinical Manifestations of Untreated Celiac Disease in Pediatric Patients

TABLE 2.

Clinical Manifestations of Untreated Celiac Disease in Pediatric Patients

Table

TABLE 3.Efficacy of Serologic Assays in Diagnosing Celiac Disease

TABLE 3.

Efficacy of Serologic Assays in Diagnosing Celiac Disease

Whether the epidemiological data and high sensitivity and specificity of the serologic markers currently available support the notion of CD screening of the general population remains to be established.6,7 Nevertheless, large numbers of asymptomatic patients have been diagnosed through serologic screening. These patients generally belong to one of the two categories, as discussed previously: silent disease with potential for development of CD, or latent CD. Most important, because these patients, particularly those with silent disease, typically manifest no or minimal symptoms8 (Table 2), they remain at risk for longterm morbidity from CD-related complications. Serologic screening should therefore be carried out in patients with known CD-associated disorders (Table 1) and those who have first-degree relatives with CD. Based on both these considerations and evidence-based analysis, revised diagnostic algorithms for the evaluation of CD in children at risk of the disease have been developed (Figure 2, see page 279).

THERAPEUTIC INTERVENTIONS

Although the clinical spectrum of CD is wide and includes typical, atypical, silent, and latent presentations of the disease, its therapy remains centered on the implementation of a gluten-free diet. Dietary compliance presents many challenges to both children and their parents. With the increasing availability and proliferation of processed foods and higher dependence on fast-food services, gluten has become a frequent and often "hidden" ingrethent of many products. Even in children who embrace a strict glutenfree diet, social events, popular snacks, and peer influence on food intake can play a crucial role in their compliance to the diet. Inadequate labeling of food products or possible contamination with gluten can have tangible effects on CD patients, despite apparently compliance to the gluten-free diet.

Recent studies have focused on the debate regarding the relative safety versus toxicity of oats for patient with CD.9·10 Pure oats may be a safe alternative grain for consumption by many with CD. However, its cross-contamination with gluten-containing grains (especially wheat) during manufacturing, and recent reports suggesting that oats may be toxic to a small subgroup of patients with CD9,10 warrant some caution in allowing oats in the CD diet.

FUTURE DIRECTIONS

An increasing understanding of the molecular pathophysiology of CD has opened opportunities to explore novel therapeutic approaches aimed at interfering with the progression of the disease and at potentially reversing the damage in CD and other related conditions.11 Enzyme therapy targeting intraluminal degradation of gluten peptides using prolyl endopeptidases has the potential to eliminate harmful proteins before they reach the intestinal mucosal barrier. Thus, one proposal suggests that such therapy might counteract toxic effects of moderate quantities of ingested gluten.12

Novel approaches to pre-digesting gluten-containing products with probiotics capable of hydrolyzing wheat prolamines has been investigated and has resulted in improving the palatability of gluten-free products.13 Another strategy that has been explored is the prevention of gluten recognition by gut-associated antigen presenting cells by blocking the sites of HLA-DQ2 and DQ8.11 Inhibition of various steps in the host immune response has been also investigated, including silencing of gluten sensitized T cells, prevention of cytokine release or binding to their target receptors, and selective inhibition of leukocyte adhesions.11

The role of increased gut permeability as responsible for inappropriate passage of immune-reactive gluten fragments has been studied extensively.14 The discovery of zonulin, a modulator of intestinal permeability that is up-regulated during the acute phase of CD, provided the rationale for novel approaches aimed at preventing the gluten-induced structural derangement of the intestinal epithelial barrier and, consequently, its access to the gut-associated lymphoid tissue through the paracellular pathway.14 Whether current research will lead to the improvement of our current diagnostic tools, the development of novel therapeutic interventions, or will open new avenues for future investigators, the end result surely will have a positive effect on the quality of life of children affected by CD.

Figure 2. Suggested diagnostic algorithm for celiac disease.

Figure 2. Suggested diagnostic algorithm for celiac disease.

REFERENCES

1. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163(3):286-292.

2. Catassi C, Fasano A. New developments in childhood celiac disease. Curr Gastroenterol Rep. 2002;4(3):238-243.

3. Fasano A, Catassi C. Coeliac disease in children. Best Pract Res Clin Gastroenterol. 2005;19(3):467-478.

4. Mora S, Barerà G, Beccio S, et al. A prospective, longitudinal study of the long-term effect of treatment on bone density in children with celiac disease. J Pediatr. 2001;139(4):516-521.

5. Hill ID, Dirks MH, Liptak GS; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40(1): 1-19.

6. Fasano A. European and North American populations should be screened for coeliac disease. Gut. 2003;52(2): 168-169.

7. Kumar PJ. European and North American populations should be screened for coeliac disease. Gut. 2003;52(2):170-171.

8. Fasano A. Clinical presentation of celiac disease in the pediatric population. Gastroenterology. 2005;128(4 Suppl 1):S68-S73.

9. Arentz-Hansen H, Fleckenstein B, Molberg O, et al. The molecular basis for oat intolerance in patients with celiac disease. PLoS Med. 2004;l(l):el.

10. Kronholm K Adults with celiac disease can eat pure oat [in Norwegian]. Tidsskr Nor Laegeforen. 2001;121(3):364.

11. SoIUd LM, Khosla C. Future therapeutic options for celiac disease. Nat Clin Pract Gastroenterol Hepatol. 2005;2(3): 140-147.

12. Hausch F, Shan L, Santiago NA, Gray GM, Khosla C. Intestinal digestive resistance of immunodominant gliadin peptides. Am J Physiol Gastrointest Liver Physiol. 2002;283(4): G996-G1003.

13. Di Cagno R, De Angelis M Auricchio S, et al. Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients. Appi Environ Microbiol. 2004;70(2): 1088-1096.

14. Fasano A, Not T, Wang W, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355(9214):1518-1519.

TABLE 1.

Conditions Associated With Celiac Disease

TABLE 2.

Clinical Manifestations of Untreated Celiac Disease in Pediatric Patients

TABLE 3.

Efficacy of Serologic Assays in Diagnosing Celiac Disease

10.3928/0090-4481-20060401-12

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