Celiac Disease Among Children and Adolescents M. Luisa Mearin, MD, PhD

eliac disease (CD) is a chronic disorder caused by an inflammatory T-cell response to the storage proteins in wheat (gliadin), rye (secalin), and barley (hordein), which are collectively called “gluten” and characterized by the presence of typical autoantibodies and histological alterations of the small bowel mucosa. Genetic, immunological, and environmental factors are necessary for the expression of the disease. Ingestion of gluten by genetically predisposed people precipitates an uncontrolled T-cell-driven inflammatory response that leads to disruption of the structural and functional integrity of the small bowel mucosa. CD is treated with a gluten-free diet (GFD), which leads to resolution of the clinical disease and restoration of the histological abnormalities. CD was once thought to be a rare condition, but at the present time it is accepted that CD is the most common form of food hypersensitivity in children and adults. The first description of CD is attributed to Aretaeus the Cappadocian, who lived in the second century AD.1 He noted the characteristic stool and chronic nature of the condition and observed that children could also be affected by the disease. In 1888, Samuel Gee, a physician working at the St. Bartholomew Hospital in London, provided a thorough description of the clinical features of childhood CD.2 During the first half of the past century, it was generally agreed that the treatment for CD was rest and diet. In 1924 Sidney Haas described his treatment of childhood CD with a banana diet,3 but there was hardly any form of diet not frequently discussed at that time as a treatment

C

From the Department of Pediatrics, Leiden University Medical Center and Free University Medical Center, Amsterdam, The Netherlands. The author has no commercial interest in the subject and no financial relationships or other relationships that would contribute to a conflict of interest. Curr Probl Pediatr Adolesc Health Care 2007;37:86-105 1538-5442/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.cppeds.2007.01.001

86

for the disease. However, the relationship between gluten ingestion and the symptoms of CD was discovered by the Dutch pediatrician Willem-Karel Dicke (1905-1962).4 He became the medical director of the Juliana Children’s Hospital in The Hague (The Netherlands) at the age of 31. Long before the start of the Second World War (1934-1936) he started experiments with wheat-free diets. At the end of World War II, during the 1944-1945 winter of starvation, the delivery of normal food such as bread to his young patients in his hospital was endangered. This period and dietary studies convinced him even more that eating less cereals and more uncommon food products such as tulip bulbs improved the clinical condition of his patients and that a wheat-free diet had favorable effects on children with CD. After World War II, in collaboration with Van de Kamer, a biochemist from the Netherlands’ Central Institute for Nutritional Research TNO in Utrecht, and with Weyers, a pediatrician from the Wilhelmina Children’s Hospital in Utrecht, he extended his research and demonstrated that gliadins, ie, the alcohol-soluble fractions of gluten (wheat protein), produced fat malabsorption in patients with CD.5 His experiences with the wheat-free diet were at first published in “Het Nederlands Tijdschrift voor Geneeskunde” (Dutch Journal of Medicine) in 1941.6 In his PhD dissertation, published in 1950, he described a dietary study over a period of several years at the Juliana Children’s Hospital in patients with CD.7 In his PhD thesis Dicke wrote: “The starting point of this treatment (gluten-free diet) was to me an observation of M.E. van Dusseldorp and H. A. Stheemann, during the treatment of a celiac patient” (chapter 3: treatment with a diet free of corn). Dicke refers to a child with CD who went through three attacks of “gastrointestinal catarrh” after eating corn-containing products during a stay in the hospital. This observation was presented by Dr. Stheemann (the supervisor of Dicke in The Hague) in The Medical Society of The Hague in 1932. Van Dusseldorp would

Curr Probl Pediatr Adolesc Health Care, March 2007

succeed Dicke as one of the first women directors of a Hospital in The Netherlands. A few years after Dicke’s discovery, the advent of the peroral intestinal mucosal biopsy led to confirmation of the characteristic intestinal histopathology of CD.8

Clinical Spectrum and the Iceberg of CD CD occurs largely in Caucasians. The disease has been well documented in Asians from India, Pakistan, and Iran,9 but it is rare or nonexistent among native Africans, Japanese, and Chinese. Using simple serological tests, it has gradually become clear that the prevalence of CD in different countries in the Middle East, North Africa, and India where wheat has been the major staple food for many centuries is almost the same as that in Western countries. Clinical studies showed that presentation with nonspecific symptoms or no symptoms is as common in the Middle East as it is in Europe. A high index of suspicion for CD should be maintained in all developing countries for patients who present with chronic diarrhea or iron-deficiency anemia.10 CD is a common, but frequently unrecognized, disease. The disease is more frequent among females, with a female-to-male ratio of 2-3:1. Screening studies have shown that CD is severely underdiagnosed, with a prevalence of 0.5 to 1% among the white population,11 both in adults12,13 and in children.14-16 Assuming a conservative prevalence of 0.5%, this corresponds to about 2.5 million CD cases in Europe. Approximately 85% of these cases are unrecognized and thus also untreated. Findings from mass screening studies in the USA show a prevalence of the disease similar to that reported in Europe and suggest that CD is a much greater problem in the United States than has previously been appreciated.17 CD is also a frequent condition in South America, as shown by the prevalence of undiagnosed CD of 1:681 among apparently healthy blood donors in Brazil18 and of 1:167 among the general urban population in Argentina, presenting with a heterogeneous clinical picture and a predominance of asymptomatic cases.19 CD is frequently unrecognized by physicians, in part because of its variable clinical presentation and symptoms.20 CD is easily diagnosed in children with a symptomatic malabsorption syndrome, but most of the

Curr Probl Pediatr Adolesc Health Care, March 2007

children with CD do not have malabsorption and the clinical picture at presentation is very variable. Not all CD patients are equal. While some develop CD very early in life, others may eat gluten for many years before the disease becomes apparent. The clinical picture of CD is very heterogeneous with a broad spectrum of symptoms, from malabsorption, chronic diarrhea, and failure to thrive (the classic “triad”) to abdominal pain, lassitude, iron-deficiency anemia, delayed puberty, nonspecific arthritis, depression, ataxia, low bone mineral density, or dental enamel hypoplasia without gastrointestinal complaints.11,20 This heterogeneity in the clinical presentation is one of the causes of poor diagnosis of the disease. At present it is not known what causes these differences in the clinical expression of CD, but there is some evidence that both genetic and environmental factors may be involved.21,22 The relationship between the different HLA-DR and -DQ haplotypes of the children with CD and their clinical presentation has been thoroughly investigated. Some researchers have found a significant relationship between the gene dose effect and the heterogeneity of the clinical disease,21-23 but others have not noted an association.24 Congia and coworkers22 found that a double dose of DQ2 (␣1*0501, ␤1*0201) predisposes for an early onset and more severe disease manifestations. The differences in outcome can be partially explained by the fact that, for statistical analysis in this latter study, the groups were divided in double-, single-, or no-dose HLA-DQ2, and the authors also limited the phenotypic distribution to fully expressed disease versus mono-/oligosymptomatic. We have recently shown that children with the DR3DQ2-DR5DQ7 and DR5DQ7-DR7DQ2 genotype are presented with CD at an earlier age and have a more severe clinical picture, which suggests a link between the genotype and phenotype. A correlation between disease severity and the HLA-DQ2 gene dose was not observed (Vermeulen B, Hogen Esch C, Yuksel Z, et al., unpublished data). It is possible that other, non-HLA genetic factors also play a role in the different phenotypic expression of CD. The iceberg is a model frequently used to explain the clinical spectrum of CD (Fig 1). ● The tip of the iceberg is formed by the children with clinically diagnosed CD, among others, those with clear gastrointestinal symptoms such as chronic diarrhea and malabsorption (Table 1), those with so-called “classic CD.” The symptoms

87

FIG 2. Frequency of diagnosis of childhood celiac disease in the Netherlands.

FIG 1. The iceberg of celiac disease.

TABLE 1. Some clinical manifestations of celiac disease in children and adolescents

System

Manifestation

(Possible) Cause

Gastrointestinal

Diarrhea Distended abdomen Vomiting Anorexia Weight loss Failure to thrive Aphthous stomatitis Anemia Rachitis Osteoporosis Enamel hypoplasia of the teeth Atrophy Peripheral neuropathy Epilepsy Irritability Short stature Pubertas tarda Secondary hyperparathyroidism Dermatitis herpetiformis Alopecia areata Erythema nodosum Idiopathic pulmonary hemosiderosis

Atrophy of the small bowel mucosa Malabsorption

Hematology Skeleton

Muscular Neurology

Endocrinology

Dermatology

Respiratory

Iron malabsorption Calcium/vitamin D malabsorption

Malnutrition Thiamine/vitamin B12 deficiency Malnutrition Calcium/vitamin D malabsorption Autoimmunity

start typically after the introduction of gluten into the diet of babies or toddlers, but they may also present later in life. The severe clinical condition in young children, known as “celiac-crisis,” accompanied by skin bleeding, hypocalcemic tetany, hypoalbuminemia, and edema is nowadays very rare.

88

● In the Netherlands, as in most countries, the majority of CD diagnoses are in children with the “classic” symptoms. However, the results of a prospective national study of all the newly diagnosed cases of CD throughout the country from 1993 to 2000 show that the recognition of childhood CD in the Netherlands has increased significantly during the last few years20 (Fig 2), and that the clinical picture has changed as well with a decrease in the frequency of “classic” symptoms (Fig 3). The overall crude incidence rate of CD for 1993 to 2000 was 0.81/1000 live births. We found a significant linear increase of the crude incidence rate from 0.55 per 1000 live births in 1993 to 1.10 per 1000 live births in 2000. From 1996 onward, there was a greater increase in incidence of CD among children older than 2 years than among the younger children. ● This increasing frequency of diagnosis seems to be true worldwide,25,26 including the USA.17 An open question is whether the increase in diagnosed childhood CD is due to more children developing CD or whether it reflects a greater awareness of the disease among the physicians who increasingly recognize more subtle expressions of the disease. ● Under the water level in the CD iceberg, we find the children with unrecognized or nondiagnosed CD. These children have the typical CD histological alterations in their small bowel mucosa and they may or may not have health complaints or symptoms. In the Netherlands, for every child with diagnosed CD, there are at least seven children with unrecognized CD.15 Identification of these children

Curr Probl Pediatr Adolesc Health Care, March 2007

FIG 3. Presenting clinical picture (% of symptoms) of childhood celiac disease in the Netherlands 1993 to 2000 (*P ⬍ 0.05).

TABLE 2. Some diseases associated with childhood celiac disease (CD)

Disease

Frequency of CD (%)

Reference

Down’s syndrome Turner’s syndrome Diabetes mellitus type I Auto-immune hepatitis Selective IgA-deficiency Auto-immune thyroidisme Dermatitis herpetiformis Idiopathic pulmonary hemosiderosis

8-15 5-7 2-8 5 2-3 5-6 ? ?

Csizmadia 200032 Ivarsson 199933 Green 200311 Green 200311 Green 200311 Ansaldi 200327 Lemberg 200531 Ertekin 200629

after mass screening programs in the general population in different countries has shown that about 0.5 to 1% of the children have CD14-16 and that CD is the most common form of food intolerance in children, adolescents, and adults. Children with unrecognized CD may be asymptomatic, but they frequently have symptoms such as chronic abdominal pain or lassitude that is frequently a cause of consultation with a pediatrician. CD may also be unrecognized if it is associated with other, frequently autoimmune diseases such as type 1 diabetes mellitus, anemia, arthritis, and osteoporosis even in the absence of gastrointestinal symptoms11 (Table 2). A link between CD and asthma has been supported by some studies but not by others. Greco and coworkers found no difference in the prevalence of atopy in cases affected by CD and their relatives compared with controls and their relatives.28 On the other hand, an important study on the Finnish Medical Birth Register data of the

Curr Probl Pediatr Adolesc Health Care, March 2007

whole 1987 birth cohort (n ⫽ 60,254 births) showed a significant increased cumulative incidence of asthma in children with CD (24.6%) than in children without CD (3.4%) during the first 7 years of life, indicating that TH1 and TH2 immunological mediated diseases can coexist and may have a common environmental denominator.29 Another associated disease is idiopathic pulmonary hemosiderosis, a rare condition of unknown autoimmune etiology mainly affecting children and adolescents, in which a GFD may be very effective for the regression of the pulmonary hemosiderosis.30 ● An important associated disease is dermatitis herpetiformis, a dermatology disease also known as “CD of the skin,” with a high frequency of CD in adults,31 but with a much lower frequency in childhood CD.32 Down syndrome is strongly associated with CD,33 and to a lesser degree, Turner’s syndrome is associated with the disease.34 Underdiagnosis is common in children with Down syndrome and we found only two cases of Down syndrome among 225 children with CD diagnosed in the Netherlands between 1975 and 1990, while CD was identified by screening in 7% of the children with Down syndrome in the same area.35 The health complaints present in children with Down syndrome and CD are frequently and repeatedly attributed to Down syndrome, but in most of the children the health status improves after a GFD. Another possible manifestation of CD is short stature. In two British population-based studies on short stature, where CD was not specifically inves-

89

tigated, the prevalence of CD was 2:18036 and 0:149,37 respectively. In children with short stature and no gastrointestinal symptoms investigated for CD, the prevalence increases to 2 to 8%. When other (endocrine) causes for short stature are excluded, the prevalence could rise to 59%.38 ● CD may be asymptomatic both above and below the water level of the CD iceberg, for example, among family members of CD patients (approximately 3 to 10% asymptomatic)39 and among young children with CD identified by mass screening (approximately 50% asymptomatic).15 Normal growth does not exclude CD in children as it was demonstrated in a mass screening program in the Netherlands: all the children from the general population identified with CD had normal growth for both weight and height.15 ● The bottom of the CD iceberg is formed by the children with the genetic predisposition for CD who may or may not develop CD during their lives.

Complications of CD CD is an important health problem for the individual and the community, because of its high prevalence, association with nonspecific morbidity, and long-term complications. The health burden of CD is considerable. CD is an immune-mediated disease that can affect any organ.11 The broad spectrum of symptoms varies considerably between children and within a single child over time, often resulting in delayed or missed diagnosis. Many undiagnosed children accept a chronic state of vague ill health as normal. Paradoxical constipation and symptoms more typical of peptic or reflux disease are common.40 Health problems due to untreated CD include anemia, delayed puberty, elevated serum transaminases, depression, epilepsy with cerebral calcifications, low bone mineral density, and dental enamel hypoplasia. CD subjects also have an increased risk for other autoimmune diseases, depending on the duration of gluten exposure.41 Two severe eventual complications of CD are malignancy and osteoporosis. CD and Malignancy. In adults, CD has been considered a premalignant condition, which could progress to lymphoma.42 Evidence that treatment of CD with a GFD might reduce the risk of malignancy was established by Holmes and coworkers.43 In adults, increased frequency for lymphoma (6%),44 small bowel adenocarcinomas, and esophageal and oropha-

90

ryngeal squamous carcinomas45 have been described. However, these prevalence figures represent probably an overestimation of the frequency of malignancy in CD since the studies were performed in centers for CD. Recent population-based studies indicate that the increased risk of malignancy associated with CD is less than previously thought with an odds ratios (OR) for non-Hodgkin lymphoma of 2.6 to 6.3.46-48 There is a form of cancer, the enteropathy-associated T-cell lymphoma (EATL), with a very high association with CD, but this in general is a rare condition with an absolute risk of only 1:1000 based on the local prevalence of CD.49 Small bowel lymphoma and EATL are very rare diseases, but CD is the most important risk factor for these conditions. An inquiry among the members of ESPGHAN found 25 cases of children with cancer and CD, suggesting that an association between CD and cancer in childhood is not likely,50 but it showed also that the combination of cancer and CD in childhood is underreported. The children described with CD and cancer were found only through a limited number of highly specialized pediatricians in Europe. Six of the 25 children reported had malignant disease localized in the small bowel [4 of them a non-Hodgkin lymphoma (NHL)], suggesting that in children and adults there is an association between CD and small bowel malignancy. However, NHL is a common cancer in childhood and small bowel localization frequently occurs. To get more data on this subject, the importance of reporting all cases of CD and cancer in children to the literature should be stressed. The role of the pediatrician in counseling the parents of a child with CD regarding the long-term risks of cancer should be to reassure them, since, in the big series of CD complicated by cancer, there were no patients in whom CD has been diagnosed during childhood CD,46-48 suggesting that the association of childhood CD with cancer may be very low. Osteoporosis. Osteoporosis is characterized by a low bone mass with an increase in bone fragility and susceptibility to fracture.51 Intestinal malabsorption may cause loss of bone mass and mineral metabolism alteration. In CD the main mechanisms of osteoporosis are malabsorption and the production of proinflammatory cytokines, activating osteoclasts. Osteoporosis may complicate CD, in both adults52 and children53 and it is mostly present in patients with overt malabsorption at diagnosis, but it may also be present in subclinical or in asymptomatic CD.54 However, the

Curr Probl Pediatr Adolesc Health Care, March 2007

risk of bone fracture in CD seems to be lower that previously presumed.55 Bone density improves after following a GFD,56,57 but in adult CD this improvement does not reach the normal sex- and age-matched values for the control population. In contrast, in childhood CD with a very early treatment, gluten exclusion prevents bone loss and most children reach a normal bone mass.58 This discrepancy can be explained by the fact that bone loss has an irreversible component (disappearance of trabeculae and thinning of the cortex) and a reversible component (increased intracortical tunneling, thinning of trabeculae). While late treatment in adulthood may revert only the reversible bone loss, very early treatment during infancy could prevent both the irreversible and the reversible bone loss.58 Consequently, there is no need to perform bone mass measurement in children if fully compliant with GFD.54 The question is weather bone mass should be assessed at diagnosis in cases of subclinical or silent disease in older children. Following the advice for adult CD, the evaluation of bone mass after the first year of strict adherence to GFD seems to be of more clinical use, since the treatment with mineral-active drugs may be started on the basis of the results of gluten exclusion. Risk factors for fractures have not been specifically identified in CD, but are likely to include, in addition to noncompliance with GFD, steroid treatment, untreated hypogonadism, age, low body mass index, and previous fragility fracture.54 The role of lifestyle factors should be not underestimated in the prevention of osteoporosis and adolescent patients with CD should be encouraged to follow a calcium-rich diet, to maintain a high level of exercise, and to stop smoking.54

Genetics, Gluten, and Immunology CD is a familial disorder: first-degree relatives of CD patients have an increased risk of 5 to 10% of developing the disease.57 Twin studies are very useful to assess the genetic and environmental components to disease susceptibility. Both monozygotic and dizygotic twin pairs share the same environmental factors, but differ by sharing 100 and 50% of genetic variability, respectively.59 In CD the concordance in monozygotic twins is approximately 83% and this is only 17% in dyzygotic twins.60 By way of comparison monozygotic concordance rates are 25%

Curr Probl Pediatr Adolesc Health Care, March 2007

in multiple sclerosis, 36% in type I diabetes, and in 33% in Crohn’s disease, showing that CD has one of the highest concordance rates of the complex multifactorial diseases.59 The sibling relative risk (RR, defined as the risk for CD to a sibling of a CD patient divided by the risk for CD in the general population) is also useful to measure the heritability of CD. Population studies estimate sibling RR for CD between 30 and 48, also suggesting a stronger genetic component in CD than in many other complex diseases.59

The Human Leukocyte Antigen (HLA) Complex CD is strongly associated with genetic factors coded by the HLA complex, which occupies a 4-Mb region on chromosome 6p21 and contains some 200 genes of which over half are known to have immunological function.60 Around 95% of patients with CD express HLA-DQ2 (␣1*0501/␤1*0201), either in the cis- (encoded by HLA-DRB1*03-DQA1*05DQB1*03) or in the trans- (encoded by HLADRB1*11/12-DQA1*05-DQB1*0301/DRB1*07-DQA1 *0201-DQB1*02) configuration and most of the remainder express HLA-DQ8 (␣1*0301/␤1*0302) encoded by HLA-DRB1*04-DQA1*03-DQB1*0302, showing that the chance to develop CD in absence of HLA-DQ2 and/or HLA-DQ8 is very small61 (Table 3). However, HLA-DQ2 and DQ8 are frequently present in the white population (approximately 30%), implying that HLA-DQ2 and DQ8 are very important, but not enough, to explain the genetics of CD. This knowledge has triggered the search for other non-HLA genetic variants predisposing to CD, but currently no other genetic variants have been found that exert a major influence similar to the HLA. The primary function of the HLA-DQ molecules is to present exogenous peptide antigens (in CD gluten peptides) to helper T-cells. The strong relationship between the HLA genetic factors and CD is illustrated by the impact of the HLA-DQ2 gene dose on the chance of disease development: HLA-DQ2 homozygous individuals have an at least five times higher risk of disease development compared with HLA-DQ2 heterozygous individuals.62,63 It is likely that the large HLA effect size is related to the essential permissive role of DQ2 peptide presentation in disease pathogenesis. The level of HLA-DQ2 expression influences the magnitude of the gluten-specific T-cell response: it has been demonstrated that gluten presentation by HLA-DQ2 ho-

91

TABLE 3. Comparison of the distribution of the HLA-DR/DQ genotypes in Dutch children with celiac disease (CD) and in the Dutch general population

Risk for CD High Medium Medium Low

DR DQ genotype

CD (n ⴝ 149) (%)

General population (n ⴝ 2307) (%)

Relative risk RR (95% CI)

40

5

8.0 (6.1-10.5)*

15

5

3.1 (2.1-4.7)*

36

18

2.0 (1.6-2.6)*

9

72

0.1 (0.07-0.2)*

Homozygote DR3 DQ2 DR3 DQ2/DR7 DQ2 DR3 DQ2/DR5 DQ7 DR5 DQ7/DR7 DQ2 DR3 DQ2/DRX DQX** DR3 DQ2/DR4 DQ8 DR7 DQ2/DRY DQY** DR4 DQ8/DRZ DQZ** DRX DQX/DRX DQX**

*P ⬍ 0.05. **DRX DQX ⫽ not DR3DQ2, DR4DQ8, DR5DQ7, or DR7DQ2. DRY DQY ⫽ DR7DQ2 of DRXDQX. DRZ DQZ ⫽ DR4DQ8 or DRXDQX.

mozygous antigen-presenting cells is superior to presentation by HLA-DQ2/non-DQ2 heterozygous antigen-presenting cells and this correlates with the risk of disease development.64 The question is if there may be additional alleles in the HLA region in addition to DQ2 and DQ8 that confer risk for CD. Although the association between CD and another HLA gene, such as and TNF and MICA, may be explained by the linkage disequilibrium across the HLA; at the moment there is no evidence for additional HLA risk factors.

Genome-Wide Linkage Studies Several genome-wide searches have been performed in CD. Genome-wide linkage studies aim to identify broad genomic regions that contain disease-predisposing variants and are successful to identify loci for monogenic disorders (eg, cystic fibrosis, hemochromatosis), but they are less useful to identify loci in the more common polygenic diseases. Outside the HLA region there are at least three genomic areas related to CD: CELIAC2 on 5q31 to 33, CELIAC3 on 2q33, and CELIAC4 on 19p13. From two of these regions the responsible genes have been identified: CTLA4 on 2q65 and Myosin IXB on 19p,66 but their mode of action is unclear. T-lymphocyte regulatory genes CD28, CTLA4, and ICOS are found in a 300-kb block of chromosome 2q33. All three genes control different aspects of the T-cell response, and their close genetic proximity likely allows for integrated control of expression.59 Chromosome 6q21-22 (distinct from the HLA) has been reported to be related to CD in type I diabetes, rheumatoid arthritis, and multiple sclerosis and it is possible that a common variant at this locus might predispose to autoimmune diseases in general (as

92

demonstrated by the HLA A1-B8-DR3-DQ2 haplotype).59 Newer methods including gene expression analysis will provide further insight in the genetic susceptibility for CD.

Gluten Gluten, the antigenic protein mixture for CD patients, present in wheat and related cereals, is the water-insoluble material in wheat flour that gives dough its elasticity. The major components are the glutenins and the gliadins, both representing complex families of proteins (Koning F, Mearin ML. Manuscript submitted for publication, 2006). In a single wheat variety dozens of distinct gluten proteins are found.67 Gluten contains a high amount of the amino acid proline, which renders gluten resistant to degradation in the gastrointestinal tract. Together with the fact that gluten is a very much used protein in the food industry—the daily consumption of gluten is estimated to be between 10 and 15 g—this indicates that gluten exposure is high and continuous.

Immunology In celiac patients, gliadin and glutenin peptides are presented by HLA-DQ2 or -DQ8 expressed on antigen-presenting cells to gluten-specific CD4⫹ T-cells. This generates a mixed Th0 and Th1 response. Antigenic protein fractions (peptides) binding to HLA is in part mediated by interactions between particular amino acids in the bound peptide and pockets in the HLA molecule. In the case of HLA-DQ2 and -DQ8 it is well established that negatively charged amino acids are required for these interactions.68,69 As gluten contains very few negatively charged amino acids, gluten peptides were therefore predicted to poorly bind

Curr Probl Pediatr Adolesc Health Care, March 2007

to HLA-DQ2 and -DQ8. This paradox was solved by the observation that the enzyme tissue transglutaminase (tTG) can convert the amino acid glutamine in gluten into glutamic acid, which introduces the negative charge(s) required for strong binding to HLADQ2/8.70,71 Several studies have investigated the specificity of the gluten-specific T-cell response in CD and revealed that polyclonal T-cell responses to multiple gluten peptides are almost invariably found in patients.72,73 Most responses are specific for tTG-modified gluten peptides. These peptides can be derived from all types of gliadins as well as glutenins. However, some peptides are immunodominant; in particular, a proline-rich stretch in alphagliadin is found in the large majority of patients, while other peptides are less frequently recognized.74,75 Similar peptides are found in the gluten-like molecules in barley and rye and T-cells specific for gluten peptides can cross-react with those homologous peptides in these other cereals.76 However, it is clear that HLA-DQ2/8 and tTG are not the only factors that contribute to disease development since the physiological role of tTG is tissue repair and approximately 40% of the white population expresses HLA-DQ2 and/or -DQ8 and only 1% develop CD. Therefore, it is possible that, although enhanced by tTG modification, gluten is in itself immunogenic. One proposed model for the pathogenesis of CD states that tTG drives the diversification of the gluten-specific T-cell response: once a glutenspecific T-cell response is initiated, the accompanying tissue damage will lead to the release of intracellular tTG which, in turn, allows the generation of additional gluten peptides that can trigger T-cell responses, more tissue damage, more T-cell activation, etc. A vicious circle is initiated that is driven by gluten intake.76 In a healthy situation the role of the intestinal mucosal immune system is the maintenance of tolerance and, even though HLA-DQ2 and/or -DQ8-positive individuals are prone to the development of gluten-specific T-cell responses, such responses will generally be suppressed. However, stress situations, like, for example, intestinal infections, would force the immune system to raise an inflammatory response accompanied by the production of IFN␥. This would increase the HLA-DQ expression and, combined with the fact that due to the high gluten intake gluten peptides are almost continuously present in the intestine, and that inflammation can raise tTG levels, this

Curr Probl Pediatr Adolesc Health Care, March 2007

may lead to a situation where gluten specific T-cell responses are initiated instead of suppressed.66 In addition, it has also been shown that gluten activates the innate immune system. A particular ␣-gliadin peptide, p31-43, which is not known to bind to HLA-DQ2/8 and stimulate T-cells, has been shown to upregulate natural killer cells (NKG2D) and induce MICA expression in biopsies of patients.77,78 The cytokine IL-15 appears to be a key factor in the inflammatory intestinal response in CD. IL-15 promotes the maturation of intestinal dendritic cells and might stimulate the recognition of gluten-peptidesderived T-cell epitopes by lamina propria CD4⫹ T-cells.79 In addition, IL-15 stimulates the effector properties of intra epithelial lymphocytes (IEL), their synthesis of ␥-interferon, and their cytotoxicity and can license IEL to kill enterocytes by signaling delivered by their NKG2D receptor and by inducing the epithelial target of this receptor on enterocytes, the MHC Ib molecule MICA.78-81

Diagnosis In 1970 the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) established the criteria for the diagnosis of CD in childhood, based on the recovery of the characteristic histological alterations of the small intestinal mucosa after following a GFD and on the histological relapse following a gluten-challenge (the reintroduction of gluten into the diet).82 At least three small intestine biopsies (SIB) were necessary to diagnose CD. Currently SIB is still the gold standard for the diagnosis of CD. SIB can be taken blindly with peroral suction biopsy tubes or at the time of upper endoscopy from descending duodenum83: both techniques are considered relatively safe.84 Because the intestinal lesions in CD may be patchy, it is recommended that multiple biopsy specimens be obtained. In 1990 a working group of the ESPGHAN published revised criteria for the diagnosis of childhood CD based on a retrospective study of the diagnosis procedure in a large group of celiac children.85 According to the revised criteria, gluten-challenge should only be necessary in those children who were younger than 2 years when the first SIB was performed. In this group of young children a number of diseases other than CD may produce histological small intestinal alterations similar to the typical CD lesions (Table 4). However, in some cases

93

TABLE 4. Some enteropathies different from celiac disease that may cause villous atrophy of the small bowel gastroenteritis and postenteritis syndromes

Giardiasis Cow’s milk protein allergy Autoimmune enteropathy Immunodeficiencies HIV/AIDS Tropical sprue Protein energy malnutrition

patients whose small bowel mucosa is unresponsive to gluten withdrawal: the so-called refractory CD. Marsh type 3 is accepted as a clear feature of CD, but whether the hyperplasic changes of Marsh type 2 lesions should be considered as distinctive for CD is still controversial. In addition to the small intestine alterations, a lymphocytic gastritis has been described in CD.89

Serology Tests in the Diagnosis of CD gluten-challenge may be needed to prove the necessity of continuing lifelong GFD or to confirm the diagnosis in those patients on a GFD who did not have a diagnostic SIB. The typical histological lesion of the SIB of a celiac child eating gluten is the subtotal villous atrophy with elongated and hypertrofic crypts and a chronic inflammatory infiltration in the mucosa (Fig. 4). The lamina propria contains an increased number of lymphocytes, plasma cells, and some eosinophils and histiocytes. The crypts contain an increased number of cells in mitosis, Paneth cells, and argentaffin cells. There is a reduction in the number of goblet cells and an increased number of intraepithelial gamma/delta Tlymphocytes. A widely used classification of the histological alterations in CD was introduced by Marsh in 1992 and it ranges from type 0 (Marsh 0) to Marsh type 486: ● Type 0 concerns the normal stage of the small bowel mucosa. ● Marsh type 1 or infiltrative lesion comprises normal mucosal architecture in which the villous epithelium is infiltrated by small, nonmitotic intraepithelial lymphocytes and it is characteristically present in first-degree relatives of children with celiac disease.87 ● Type 2, or hyperplasic lesion, consists of a type 1 lesion with enlarged crypts. ● Marsh type 3 or destructive lesion is synonymous with the typical flat mucosa of CD and it is subclassified according to the different degrees of villous atrophy present: Marsh type 3a, with partial villous atrophy; Marsh type 3b, in the presence of subtotal villous atrophy; and Marsh type 3c, when total villous atrophy is present.88 ● Marsh type 4 or hypoplastic lesion (total villous atrophy with crypt hypoplasia) represents the extreme end of the gluten-sensitivity spectrum and an irreversible lesion is present in some adult CD

94

For more than 25 years it has been possible to use serological markers to identify CD with high sensitivity and specificity. The most useful are the IgA antibodies to endomysium (EMA) and to human tissue transglutaminase (tTGA). The EMA is an immunofluorescence test that requires expertise in the subjective interpretation of the results and the use of monkey’s primate esophagus or human umbilical cord as substrate.90 According to the evidence Report/Technology Assessment performed by the Agency for Healthcare Research and Quality in 2004, the determination of EMA has a high sensitivity for CD of approximately 90% and a very high specificity approaching 100%.91 The titer of EMA correlates with the degree of mucosal damage; accordingly, the sensitivity increases with higher prevalence of subtotal villous atrophy in the CD population studied.92 The recognition of the enzyme tTG as the substrate for the EMA formed the basis for the development of an enzyme-linked immunoassay (ELISA) for the determination of tTGA.93,94 Assays using human tTG, either recombinant or derived from human red cells, have better results than these using guinea pig tTG.95 The sensitivity of tTGA is greater than 90%, but the specificity is lower than the one of the EMA.91 It has been shown that TGA results may be positive in other diseases different from CD, such as in type 1 diabetes, chronic liver disease, or rheumatoid arthritis, although small bowel biopsy was not always performed to exclude CD in the cases described.96 A controlled European multicenter study performed in biopsy-proven CD cases and control with other diseases different from CD controls to evaluate the value of IgA antibody measurement to human recombinant tTG in comparison to IgA-EMA in the diagnosis of CD found that tTGA measurement were effective and at least as good as EMA in the case-finding of CD.97 Considering the time it spares, the quantitative character of

Curr Probl Pediatr Adolesc Health Care, March 2007

FIG 4. Characteristic subtotal villous atrophy of the small bowel mucosa in a child with celiac disease consuming gluten (A) and improvement of the histological lesions after gluten-free diet (B). (Color version of figure is available online.)

the tTGA ELISA method, and its lower price, it is likely that, of all serological screening tests, tTGA determination will be the first choice. Selective IgA deficiency (SIgAD) occurs more frequently in children with CD than in the general population.97 These patients with CD lack IgA-EMA and IgA-tTG.98 To avoid missing CD in children with SIgAD, it is advisable to determine the total IgA level in serum when testing for CD. Children with already known SIgAD should be tested with an IgG antibodybased tTG test, the IgG-tTG.99 Figure 5 shows the scheme that is usually followed in the clinical diagnosis of CD in children.

Who Should Be Tested for Celiac Disease? The availability of such sensitive and specific serological tests to identify CD, together with the increasing knowledge of the heterogeneous character of the clinical picture, opens the question about who should be tested for CD. Nowadays, these serological tests are advised for active case-finding, among children who seek medical advice for health problems that suggest CD (Table 1). Targeted screening is also widespread, aiming at high-risk groups such as relatives of CD patients or individuals with associated conditions like type I diabetes mellitus or Down syndrome (Table 2). According to the official recommendations of the North American Society for Pediatric Gastroenterol-

Curr Probl Pediatr Adolesc Health Care, March 2007

FIG 5. Flowchart for the diagnosis of celiac disease. (Color version of figure is available online.)

ogy, Hepatology and Nutrition on the diagnosis and treatment of CD in children and adolescents, CD should be considered early in the differential diagnosis of children with failure to thrive and persistent diarrhea. In addition, it is recommended that CD be considered in the differential diagnosis of children with other persistent gastrointestinal symptoms, including recurrent abdominal pain, constipation, and vomiting. Testing is recommended for children with nongastrointestinal symptoms of CD (dermatitis her-

95

petiformis, dental enamel hypoplasia of permanent teeth, osteoporosis, short stature, delayed puberty, and iron-deficient anemia resistant to oral iron). Testing is also recommended for asymptomatic children who have conditions associated with CD (type 1 diabetes mellitus, autoimmune thyroiditis, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, and first-degree relatives of celiac patients). It is recommended that testing of asymptomatic children who belong to groups at risk begin around 3 years of age provided they have had an adequate gluten-containing diet for at least 1 year before testing.100

The Use of HLA-DQ Typing in the Diagnosis of CD Because CD is very unusual in the absence of HLA-DQ2 or HLA-DQ8, the determination of these haplotypes may be used in the identification of CD, among others, in high-risk groups for CD whose members may develop the disease at a certain moment in their lives, but in whom it is not known how often CD should be tested. This is especially the case among first-degree relatives of CD children: in these families there is frequently anxiety to know who may or may not develop CD. However, HLA-DQ2 and -DQ8 are not specific for CD since they are present in about 40% of the general white population, and their contribution to the identification of the disease resides in their high negative-predictive factor.91 Using HLA-DQ typing, a two-step model has been proposed to identify CD in children with high risk for CD.32 The first step should consist of the typing for the molecularly defined HLA-DQ2 and -DQ8, which has to be performed only once in life, because it does not change in time. This will help to exclude the children without HLA-DQ2 and/or HLA-DQ3 from further unnecessary tests for CD. The second step should consist of total IgA and IgA-tTGA and/or IgA EMA determinations in serum in the children selected by HLA-typing. Individuals with positive serological tests should be offered a small bowel biopsy, and in the case of histological alterations treatment with a GFD should be provided. The children with normal serological tests or normal small bowel biopsies should be further investigated for CD, for example, every 1 to 2 years.

To Screen or not to Screen? CD is a hidden public health problem worldwide. Many studies have shown that CD affects about 1.0%

96

of children of white ancestry,14-16 but most cases remain undiagnosed. The prevalence of CD thus exceeds by far that of a number of diseases for which screening programs are currently applied such as congenital hearing loss (1/1000), congenital hypothyroidism (1/3400), and phenylketonuria (1/18,000).39 Mass screening is the only way to identify the majority of people with CD. Mass screening for CD, ie, screening of the general population, is a controversial issue. To decide whether mass-screening programs for CD would be performed, the principles for early disease detection as elaborated by Wilson and Jungner should be taken into account.101 These principles are as follows: (1) The condition should be an important health problem; (2) There should be an accepted treatment for the disease; (3) Facilities for diagnosis and treatment should be available; (4) There should be a recognizable latent or early symptomatic stage; (5) There should be a suitable test for disease detection; (6) The test should be acceptable for the population; (7) The natural history of the condition, including development from latent to declared disease, should be understood; (8) There should be an agreed policy of whom to treat as a patient; (9) The costs of case-finding should be economically balanced in relation to possible expenditure on medical care as a whole; and (10) Case-finding should be a continuous process. Nine of the 10 principles for mass-screening are met by CD, but the natural history of CD is not well known and it is not clear if the children with none of subtle symptoms of CD identified by mass screening have the same health risks and long-term complications that the children with clinical diagnosed CD. Assuming a standardized mortality ratio of 1.5 or higher for untreated CD patients, mass screening for CD has been shown to be cost-effective in populations with a relatively high prevalence of CD over a wide range of ages at screening.102 To answer this question, limited screening programs in well-defined regions should be initiated with continuous and prospective evaluation of their costs and benefits in comparison with control populations.38

Treatment A lifelong strict GFD with exclusion of gluten from wheat, rye, and barley is the treatment of CD.7 Wheat, rye, and barley are the predominant grains containing

Curr Probl Pediatr Adolesc Health Care, March 2007

the peptides known to cause CD. Triticale (a combination of wheat and rye), kamut, and spelt are also known to be harmful. Other forms of wheat are semolina (durum wheat), farina, einkorn, bulgur, and couscous. Malt is also harmful because it is a partial hydrolysate of barley prolamins. In general, any ingredient with malt in its name (barley malt, malt syrup, malt extract, malt flavorings) is made from barley.100 The ingestion of very small amounts of gluten, even without the accompaniment of clinical or serological responses, induces changes that are detectable at the small bowel level.103 The clinical response of children with CD after starting a GFD may be observed within days or weeks. The histological recovery of the small bowel mucosa after GFD takes longer, but the recovery in children is much quicker and complete than in adults and 95% of the children show histological recovery after 2 years on a GFD.88 Initially, oats were considered to be harmful for CD patients, but more recently it has been shown that, in general, oats are safe both for adults and for children with CD.104-110 One concern about oats consumption in a GFD is the frequent contamination of oats with gluten during the harvesting and milling process.111 In addition, some CD patients have avenin-reactive mucosal T-cells that can cause mucosal inflammation and clinical follow-up of CD patients eating oats is advisable.112 Recently, in vitro experiments showing the absence of gluten-derived T-cell epitopes in tef, suggest that this cereal may be suitable for use in the diet of patients with CD.113 Tef (Eragrostis tef), a cereal traditionally grown in Ethiopia and used to make flat bread, can substitute for wheat flour in almost all applications and has a nutritional value similar to that of wheat. Studies on tef consumption by patients with CD are needed to determine whether tef is safe for these patients. In principle, a GFD appears simple; in practice, it represents a challenge to children and their families, dieticians, and physicians, since wheat products are added to many processed foods in the Western diet. Several helpful books distributed by the National Celiac Societies provide excellent dietary instructions and gluten-free recipes. Adherence to the GFD diets is difficult, because sources of unintentional gluten intake are so numerous; among others:

Curr Probl Pediatr Adolesc Health Care, March 2007

1. Contamination with wheat flour of foods that are “naturally” gluten-free, 2. Residual gluten in gluten-free wheat starch used for bread mixes, 3. Mislabeling of foods Lists of gluten-free food are available for patients. General awareness should be promoted to keep these lists updated. The Codex Alimentarius Committee on Nutrition and Food for Special Dietary Uses (CCNFSDU) in 1982 set the limit of gluten allowed in raw materials to produce gluten-free food to 0.05 g nitrogen per 100 g dry matter. Recently an R5 ELISA method for gluten/ gliadin determination in food has become available based on a monoclonal antibody reacting with the specific gliadin pentapeptide glutamine-glutamineproline-phenylalanine-proline (QQPFP) with a sensitivity and limit of detection (1.5 ppm gliadin), which is superior to older methods of detection.114 At the moment a provisional level of [20 ppm] gluten for food gluten-free by nature and [200 ppm] for food rendered gluten-free has been accepted (Draft Revised Standard for Gluten-free Foods (ALINORM 04/27/26) CCNFSDU). The problem is that this standard refers to the amount contained in a food and not to the amount of food that can be taken by a person who is sensitive to it. Patients with CD need careful support to provide them with up-to-date facts about a GFD. This may in part be given by the many Celiac Patients Societies around the world, among others the Association of European Celiac Societies (www.aoecs.org) and the American Celiac Sprue Association (www. csaceliacs.org). Nonadherence to the GFD may lead to complications such as diarrhea, abdominal pain, anemia, and osteoporosis.11 For many patients adherence to the diet may be difficult to achieve.115 This seems to be particularly true among adolescent patients with CD, with a reported compliance with the GFD between 52 and 81%.116-122 Determination of celiac antibodies in serum has been reported as a reliable way to monitor the compliance with the GFD.123 However, in a study among young celiacs in the Netherlands we did not find a correlation between the self-reported compliance with the diet and the results of the celiac antibodies in serum. Neither did we find a relation between the amount of gluten consumed and the level of antibodies (EMA, tTGA).122 It is also possible that the determination of the antibodies in serum is not an

97

adequate method to detect adherence to the GFD, both in adults and in adolescents, as it has been suggested by others.124-126 In addition, adherence to a GFD may have negative nutritional consequences.127,128 Mariani and coworkers121 reported overweight and an unbalanced diet rich in fat and protein, poor in carbohydrate, and deficient in calcium, iron, and fiber in 72% of the Italian CD adolescents adhering strictly to the GFD. In a prospective study performed in Dutch adolescents and young adults, we found a high dietary compliance (75%) with a median gluten intake of 44 mg per day (2-6382 mg). The nutritional state was adequate, with normal scores for height and body mass index, but the nutrient intake was not adequate. The fiber and iron intake were significantly lower, and the saturated fat intake was significantly higher than recommended, but comparable with the general population. Most of the patients (61%) found the diet easy to follow. Regular medical controls were reported by 86%, but regular dietary controls were reported by only 7% of the patients.122 Better medical and dietary support is necessary to prevent long-term complications and to achieve an ongoing satisfying management in this group of young patients with a chronic disorder. Most young patients with CD thought that avoiding cancer was the most important reason to adhere to the GFD. It has been found that when patients with CD adhere to a GFD for five consecutive years or more, their risk of malignancy is not increased compared with that of the general population.42,129 On the other hand, over the last few years it has become clear that, although CD patients have a higher risk of developing cancer than the general population, the risk is much lower than previously presumed.45-47 At present the GFD is the only effective treatment for CD and it is prudent to recommend strict adherence to the diet to all celiac patients. However, the fear of developing malignancy is not necessarily the most important reason for advising a strict diet to CD patients.48 Physicians should mainly stress the advantages of the diet with regard to the prevention of other complications of CD, such as osteoporosis49 and autoimmune disorders.42 They should also point out the relation between adherence to the GFD and improvement of fertility and birth outcomes.50,130,131

Quality-of-Life Decreased quality-of-life (QOL) has been described in adults with CD, especially in females.128 Having a

98

chronic illness like CD may reduce a child’s QOL. Not only can physical function be affected, but also a child’s emotional and social world may change. The illness can therefore be an important factor in the evaluation of QOL of a child.132 Health-related QOL (HRQOL) is a multidimensional concept containing physical, emotional, social, and cognitive domains, variable over time, and is getting increasing attention in medical and health care settings.133 What matters in HRQOL is the way patients feel about their functioning, not their functioning itself.134 HRQOL can be measured by generic, disease-generic, and diseasespecific instruments. These instruments can be seen as having a pyramid structure, with, at the bottom, the generic QOL questionnaires such as the DUX25135 and the TACQOL.136 In the second layer of the pyramid, disease-generic questionnaires are found, which can be administered to children with any disease, including chronic diseases. Finally, diseasespecific questionnaires complete the top layer. These questionnaires can be given to children, healthy and ill. Generic HRQOL instruments offer specific possibilities in the assessment of the QOL of patients with a particular disease: they allow comparison with normative data and across disease populations. Most QOL instruments are designed as top-down instruments. This means that they are developed by researchers and physicians who used their own experience as guidelines. In the last few years there has been an increasing interest in the development of generic and diseasespecific HRQOL instruments developed from the bottom-up approach such as the KIDSCREEN and DISABKIDS questionnaires. These questionnaires used a focus group based bottom-up approach.137 A bottom-up approach allows us to perceive the situation from the child’s point of view. It can be seen as a child-centered methodology, designed to ensure that the children, rather than their parents or health care professionals, generate, prioritize, and explain the issues of interest to them. It can produce data that adult investigators and even parents have never considered. The HRQOL of children with CD has been previously assessed, making use of the TACQOLCD, a questionnaire especially designed for CD and based on the generic instrument TACQOL, in which the child’s well-being was estimated by the researchers and attending physicians.138 The TAQOLCD did not provide information about the children’s view, nor that of their parents, and it contained only symptomatic questions mainly useful for the investigation of physical

Curr Probl Pediatr Adolesc Health Care, March 2007

complaints. In the absence of complaints, thanks to compliance with the GFD or to coping with the disease, the results gave an optimal score which may not give an accurate view of the HRQOL. Recently, together with the Dutch foundation Doctors for Children, a foundation that works for the improvement of the QOL of children with chronic illness, an improved questionnaire developed from the bottom up, to assess the QOL of children with CD has been developed (van Doorn RK, Winkler LMF, Zwinderman KH, Mearin ML, Hendrik M, Koopman HM. Manuscript submited for publication.): the Celiac Disease DUX (CDDUX). Using the CDDUX children with CD appears to have a lower QOL than the healthy reference group. Children with a better health status have a higher score on the CDDUX questionnaire. The new disease-specific questionnaire CDDUX provides information about how children with CD think and feel about their illness. The use of a similar questionnaire enables researchers and clinicians to determine the consequences of CD on the daily living of the children. In this context the results of an important study aimed to evaluate the impact of the GFD on the 5240 members of the Canadian Celiac Association shows that the QOL in those with CD could be increased with early diagnosis, increased availability of gluten-free foods, improved food labeling, and better dietary instruction.139 Education of physicians and dieticians about CD and its treatment is essential.

Future Prospects Prevention There is some evidence suggesting that prevention of CD may be possible. One observation is that the level of HLA-DQ2 expression is linked to the probability of disease development: a double gene dose leads to an at least fivefold increased risk.61,76 Usually children are exposed to high levels of gluten. The question is what will happen when we lower the amount of gluten in the diet. It is conceivable that this may have a similar effect as the HLA-DQ2 gene dose: lower gluten exposure would decrease the risk to develop CD. Epidemiological studies from Sweden suggest that early nutrition patterns may have a significant impact on the later risk of developing CD. The occurrence of “epidemics” of CD after changes in the Swedish infant feeding during the 1980s and 1990s suggested that the disease may be preventable by improving early nutri-

Curr Probl Pediatr Adolesc Health Care, March 2007

tion and inducing tolerance to gluten in predisposed individuals. The “Swedish epidemic of CD” started in 1983 when gluten introduction was postponed from month 4 to 6 by changed national recommendations for gluten introduction into the diet of young children. Carefully performed studies exploring the epidemic in detail suggest that the causal factors of the epidemic were whether breastfeeding was ongoing or not while gluten was introduced and also the amount of gluten then given.140,141 Thus, when introduction of gluten in 1983 was postponed, it also implied that more infants had ended breastfeeding, and that gluten was introduced by larger amounts. Moreover, the epidemic subsided in1996 when gluten introduction was once again “allowed” from 4 months of age when more of the infants were still breastfed and gluten was introduced in smaller amounts. Thus, the Swedish studies strongly support that ongoing breastfeeding during the period of gradual introduction of gluten-containing foods into the infant diet reduces the risk of symptomatic CD.140,141 Based on an estimate of the attributable fraction, half of the CD cases during the Swedish epidemic might have been avoided if all infants had been introduced to gluten in small amounts while still being breastfed. The latter finding opens the way to possible prevention strategies. It is possible that gradual introduction of antigens will lead to the development of oral tolerance.142,143 It is also likely that the response of the immune system to gluten may be modified by breastfeeding.144,145 Several studies have been performed in different European countries on gluten consumption and breastfeeding,143,146-150 but the methods used to assess gluten intake were mostly time consuming and differed from each other. An important American study has published the findings on a cohort of 1560 children who had an increased risk of developing CD or type 1 diabetes, as defined by possessing either HLA-DR3 or DR4 alleles, or having a first-degree relative with type 1 diabetes, derived from the Diabetes Autoimmunity Study in the Young project.150 At a mean follow-up of 4.8 years the authors concluded that (1) there is a “window of opportunity” of introducing gluten into the diet when the child is aged between 4 and 6 months with regard to the risk of developing CD; and (2) that the contribution of breastfeeding was to be disregarded in this respect. However, the authors did not make specific attempts to calculate the gluten amount ingested by the children or to correlate this important early nutrition event with the presence or absence of

99

breastfeeding. A systematic review and a meta-analysis of observational studies published between 1966 and June 2004 that examined the association between breastfeeding and the development of CD showed that breastfeeding seemed to protect against CD.151 Prospective cohort studies may shed light on the importance of the quantity of exposure to gluten in early life in the development of CD.152 One problem in this respect is that, until now, there were no validated instruments to quantify gluten intake by young infants. The instruments available were work intensive, time consuming, and difficult to use in population studies. Recently we have developed and validated food frequency questionnaires for this purpose, using the 2-day food record as a reference (Hopman EG, Kiefte-de Jong JC, le Cessie S, et al., unpublished data). This instrument may be used in collaborative studies to assess the role of the quantity of gluten consumption in the development of CD. The actual guidelines for infant nutrition recommend introducing gluten into the diet no earlier than at the age of 6 months,153 and at this age, only a low percentage of the children, ranging from 1 to 46% in the different European countries, receive breastfeeding.154 On the other hand, the Swedish study only investigated the effect of the early dietary history on symptomatic CD in children. It may be that the nutritional factors only have an effect on the symptoms of CD and/or on the time of presentations of the symptoms. In addition, there is no information on the biological mechanisms involved in the effect of early nutrition in the development of CD. Prospective intervention nutritional studies in high-risk populations are necessary to provide parents with sensible advice to prevent CD in their children.

Safer Foods Gluten is a complex mixture of proteins that contains a multitude of immunogenic peptides. This is because bread wheat and pasta wheat are hexaploid and tretraploid species, containing three and two entire wheat genomes, respectively. These wheat varieties have been selected for good crop yield and superior baking qualities. However, there are many wheat varieties and not all of those appear to be equally toxic to patients.155 This offers two opportunities for the generation of safer wheat strains. In addition, other cereals can be selected that do not contain harmful gluten or gluten-like molecules, like the Ethiopian cereal tef.155

100

Novel Treatments? A GFD is at present the only possible treatment for CD children, but there are a number of drawbacks to a lifelong diet. At present there are four options that can be explored, as follows: (1) Enzymatic degradation of gluten before it reaches the small intestine; (2) Blocking of peptide binding to HLA-DQ2/8; (3) Blocking of tTG; (4) Blocking of IL-15.66 Of these four options, the latter two may be dangerous. tTG is important for the maintenance of tissue integrity, while IL-15 is required for normal functioning of the immune system. The fist two options, however, may provide opportunities. However, due to its high proline content, gluten is resistant to enzymatic degradation. Oral supplementation with a postproline cutting enzyme has therefore been proposed as a potential way to destroy gluten before it can do damage in the small intestine.156 Blocking HLA-DQ would also be highly selective as it would block the gluten-specific T-cell response but would leave non-HLA-DQ-mediated Tcell responses intact. These two and other possible options deserve further study.

Practice Points ● Celiac disease is a common, but frequently unrecognized disease. Consequently, celiac disease is severely underdiagnosed. ● The health burden of celiac disease is considerable. Two important complications of celiac disease are malignancy and osteoporosis. ● Recent population-based studies indicate that the increased risk of malignancy associated with celiac disease is less that previously thought. ● There is no need to perform bone mass measurement in children if fully compliant with the GFD. ● Celiac disease is strongly associated with genetic factors coded by the HLA complex. Around 95% of the patients express HLA-DQ2 and most of the remainders express HLA-DQ8. The risk of developing celiac disease in the absence of HLA-DQ2 and/or HLA-DQ8 is very small. ● It is possible to use serological markers to identify celiac disease with high sensitivity and specificity. The most useful are the IgA antibodies to EMA and to human tTGA. ● At the present time small bowel biopsy is the gold standard for the diagnosis of celiac disease.

Curr Probl Pediatr Adolesc Health Care, March 2007

● CD should be considered early in the differential diagnosis of children with failure to thrive and persistent diarrhea and in children with other persistent gastrointestinal symptoms in children with nongastrointestinal symptoms of CD and in conditions associated with CD. ● At present a GFD is the only effective treatment for celiac disease. ● Better medical and dietary support is necessary to prevent long-term complications and to achieve satisfying management in children and young patients with celiac disease.

17.

18.

19.

20.

References 1. Adams F. The extant works of Aretaeus the Cappadocian. London: London Sydenham Society; 1856. p. 350. 2. Gee SJ. On the coeliac affection. St. Bartholomew’s Hospital Report 1888;24:17-20. 3. Haas SV. The value of the banana in the treatment of coeliac disease. Am J Dis Child 1924;24:421-37. 4. van Bergen-Henegouwen GP, Mulder CJ, Dicke WK. Pioneer in the gluten free diet: Willem-Karel Dicke 1905-1962, over 50 years of gluten free diet. Gut 1993;34:1473-5. 5. Van de Kamer JH, Weijers HA, Dicke WK. Coeliac disease IV. An investigation into the injurious constituents of wheat in connection with coeliac disease. Acta Paediatr 1953;42:223-31. 6. Dicke WK. Simple dietary treatment for the syndrome of Gee-Herter. Ned Tijdschr Geneeskd 1941;85:1715-6 (in Dutch). 7. Dicke WK. Coeliac disease: investigation of the harmful effects of certain types of cereal on patients with celiac disease (Thesis). University of Utrecht, the Netherlands, 1950 (in Dutch). 8. Shiner M. Duodenal biopsy. Lancet 1956;i:17-9. 9. Masjedizadeh R, Hajiani E, Hashemi J, Shayesteh AA, Moula K, Rajabi T. Celiac disease in South-West of Iran. World J Gastroenterol 2006;12:4416-9. 10. Malekzade H, Sachdev A, Fahid AS. Coeliac disease in developing countries: Middle East, India and North Africa. Best Pract Res Clin Gastroenterol 2005;19:351-8. 11. Green PHR, Jabri B. Coeliac disease. Lancet 2003;362: 383-91. 12. Johnston SD, Watson RG, McMillan SA, Sloan J, Love AH. Prevalence of coeliac disease in Northern Ireland. Lancet 1997;350:1370. 13. Kolho KL, Farkkila MA, Savilahti E. Undiagnosed coeliac disease is common in Finnish adults. Scand J Gastroenterol 1998;33:1280-3. 14. Catassi C, Ratsch IM, Fabiani E, Rossini M, Bordicchia F, Candela F, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994;343:200-3. 15. Csizmadia CG, Mearin ML, von Blomberg BM, Brand R, Verloove-Vanhorick SP. An iceberg of childhood coeliac disease in the Netherlands. Lancet 1999;353:813. 16. Maki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti

Curr Probl Pediatr Adolesc Health Care, March 2007

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

M, Karttunen T, et al. Prevalence of Celiac disease among children in Finland. N Engl J Med 2003;348:2517-24. Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, 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;163:286-92. Gandolfi L, Pratesi R, Cordoba JCM, Tauil PL, Gasparin M, Catassi C. Prevalence of celiac disease among blood donors in Brazil. Am J Gastroenterol 2000;95:689-92. Gomez JC, Selvaggio GS, Viola M, Pizarro B, la Motta G, de Barrio S, et al. Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area. Am J Gastroenterol 2001;96:2700-4. Steens RFR, Csizmadia CGDS, George EK, Ninaber MK, Hira Sing RA, Mearin ML. Better recognition of childhood celiac disease in the Netherlands and its changing clinical picture: a national prospective study 1993-2000. J Pediatr 2005;147:239-42. Mearin ML, Koninckx CR, Biemond I, Polanco I, Pena AS. Influence of genetic factors on the serum levels of antigliadin antibodies in celiac disease. J Pediatr Gastroenterol Nutr 1984;3:373-7. Congia M, Cucca F, Frau F, Lampis R, Melis L, Clemente MG, et al. A gene dosage effect of the QA80501/ DQB1*0201 allelic combination influences the clinical heterogeneity of celiac disease. Hum Immunol 1994;40:138-42. Ploski R, Ek J, Thorsby E, Sollid M. On the HLA-DQ (␣1*0501, ␤1*0201)-associated susceptibility in celiac disease: a possible gene dosage effect of DQB1*0201. Tissue Antigens 1993;41:173-7. Greco L, Percopo S, Clot F, Bouguerra F, Babron MC, Eliaou JF, et al. Lack of correlation between genotype and phenotype in celiac disease. J Pediatr Gastroenterol Nutr 1998;26:286-90. Dickey W, McMillan SA. Increasing numbers at a specialist coeliac clinic: contribution of serological testing in primary care. Dig Liver Dis 2005;37:928-33. Sood A, Midha V, Sood N, Avasthi G, Sehgal A. Prevalence of celiac disease among school children in Punjab, North India. J Gastroenterol Hepatol 2006;21:1622-5. Ansaldi N, Palmas T, Corrias A, Barbato M, D’Altiglia MR, Campanozzi A, et al. Autoimmune thyroid disease and celiac disease in children. J Pediatr Gastroenterol Nutr 2003;37:63-6. Greco L, De Seta L, D’Adamo G, Baldassarre C, Mayer M, Siani P, et al. Atopy and coeliac disease: bias or true relation? Acta Paediatr Scand 1990;79:670-4. Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol 2001;108:781-3. Ertekin V, Selimoglu MA, Gursan N, Ozkan B. Idiopathic pulmonary hemosiderosis in children with celiac disease. Respir Med 2006;100:568-9. Hervonen K, Hakanen M, Kaukinen K, Collin P, Reunala T. First-degree relatives are frequently affected in coeliac disease and dermatitis herpetiformis. Scand J Gastroenterol 2002;37:51-5.

101

32. Lemberg D, Day AS, Bohane T. Coeliac disease presenting as dermatitis herpetiformis in infancy. J Paediatr Child Health 2005;41:294-6. 33. Csizmadia CGDS, Mearin ML, Oren A, Kromhout A, Crusius JB, von Blomberg BM, et al. Accuracy and costeffectiveness of a new strategy to screen for celiac disease in children with Down syndrome. J Paediatr 2000;137:756-61. 34. Ivarsson SA, Carlsson A, Bredberg A, Alm J, Aronsson S, Gustafsson J, et al. Prevalence of coeliac disease in Turner syndrome. Acta Paediatr 1999;88:933-6. 35. George EK, Mearin ML, Bouquet J, von Blomberg BM, Stapel SO, van Elburg RM, et al. High frequency of celiac disease in Down syndrome. J Paediatr 1996;128:555-7. 36. Voss LD, Mulligan J, Betts PR, Wilkin TJ. Poor growth in school entrants as an index of organic disease: the Wessex growth study. BMJ 1992;305:1400-2. 37. Ahmed ML, Allen AD, Sharma A, Macfarlane JA, Dunger DB. Evaluation of a district growth screening programme: the Oxford Growth Study. Arch Dis Child 1993;69:361-5. 38. Van Rijn JCW, Grote FK, Oostdijk W, Wit JM. Short stature and the probability of coeliac disease, in the absence of gastrointestinal symptoms. Arch Dis Child 2004;89:882-3. 39. Mustalahti K, Sulkanen S, Holopainen P, Laurila K, Collin P, Partanen J, et al. Coeliac disease among healthy members of multiple case coeliac disease families. Scand J Gastroenterol 2002;37:161-5. 40. Mearin ML, Ivarsson A, Dickey W. Coeliac disease: is it time for mass screening? Best Pract Res Clin Gastroenterol 2005;19:441-52. 41. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in celiac patients. Gastroenterology 1999;117:303-10. 42. Gough KR, Reade AE, Nash JM. Intestinal reticulosis as a complication of idiopathic steatorrhoea. Gut 1962;3:232-9. 43. Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease— effect of a gluten free diet. Gut 1989;30:333-8. 44. Cooper BT, Holmes GKT, Cooke WT. Lymphoma risk in coeliac disease of later life. Digestion 1982;23:89-92. 45. Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983;1:111-5. 46. Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA 2002;287:1413-9. 47. Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis in Sweden. Gastroenterology 2002;123:142835. 48. Mearin ML, Catassi C, Brousse N, Brand R, Collin P, Fabiani E, et al. European multicenter study on coeliac disease and non-Hodgkin lymphoma. Eur J Gastroenterol Hepat 2006;18:187-94. 49. Johnston SD, Watson RG. Small bowel lymphoma in unrecognized coeliac disease: cause for concern? Eur J Gastroenterol Hepatol 2000;12:645-8. 50. Schweizer JJ, Oren A, Mearin ML, and the Working Group on Celiac Disease and Malignancy of the European Society for Paediatric Gastroenterology Hepatology and Nutricion.

102

51. 52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

Cancer in children with celiac disease: a survey of the European Society for Paediatric Gastroenterology Hepatology and Nutricion. J Pediatr Gastroenterol Nutr 2001;33:97-9. Wood AJJ. Treatment of postmenopausal osteoporosis. N Engl J Med 1998;336:736-46. Meyer D, Stavropolous S, Diamond B, Shane E, Green PH. Osteoporosis in a North American adult population with CD. Am J Gastroenterol 2001;96:112-119. Hartman C, Hino B, Lerner A, Eshach-Adiv O, Berkowitz D, Shaoul R, et al. Bone quantitative ultrasound and bone mineral density in children with celiac disease. J Pediatr Gastroenterol Nutr 2004;39:504-10. Corazza GR, Di Stefano M, Mauriño E, Bai JC. Bones in coeliac disease: diagnosis and treatment. Best Pract Res Clin Gastroenterol 2005;19:453-65. West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with CD: a population-based cohort study. Gastroenterology 2003;125:429-36. Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996;38:322-7. Babron MC, Nilsson S, Adamovic S, Naluai AT, Wahlstrom J, Ascher H, et al. European Genetics Cluster on Coeliac Disease. Meta and pooled analysis of European coeliac disease data. Eur J Hum Genet 2003;11:828-34. Mora S, Weber G, Barera G, Proverbio MC, Weber G, Bianchi C, et al. Effect of gluten-free diet on bone mineral content in growing patients with celiac disease. Am J Clin Nutr 1993;57:224-30. van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:323-39. Nistico L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG, et al. Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 2006;55:803-8. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med 1989;169:345-50. Mearin ML, Biemond I, Pena A, Polanco I, Vazquez C, Schreuder GT, et al. HLA-DR phenotypes in Spanish coeliac children: their contribution to the understanding of the genetics of the disease. Gut 1983;24:532-7. Mearin ML, Bouquet J, Mourad N, Schoorel E, Sinaasappel M, Biemond I, et al. HLA-DR antigens and phenotypes in Dutch coeliac children and their families. Clin Genet 1985;27:45-50. van Belzen MJ, Mulder CJJ, Zhernakova A, Pearson PL, Houwen RHJ, Wijmenga C. CTLA4⫹49 A/G and CT60 polymorphisms in Dutch coeliac disease patients Eur J Hum Genet 2004;12:782-5. Monsuur AJ, de Bakker PIW, Alizadeh BZ, Zhernakova A, Bevova MR, Strengman E, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nat Genet 2005;37:1341-4. Shewry PR, Tatham AS. The prolamin storage proteins of

Curr Probl Pediatr Adolesc Health Care, March 2007

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

cereal seeds: structure and evolution. Biochem J 1990;267:1-12. van de Wal Y, Kooy YMC, Drijfhout JW, Amons R, Koning F. Peptide binding characteristics of the coeliac diseaseassociated DQ(␣1*0501,␤1*0201) molecule. Immunogenetics 1996;44:246-53. Johansen BH, Vartdal F, Eriksen JA, Thorsby E, Sollid LM. Identification of a putative motif for binding of peptides to HLA-DQ2. Int Immunol 1996;8:177-82. Molberg Ø, McAdam S, Körner R, Quarsten H, Kristiansen C, Madsen L, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut derived T cells in celiac disease. Nat Med 1998;4:713-7. van de Wal Y, Kooy YMC, van Veelen P, Pena S, Mearin L, Papadopoulos G, et al. Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998;161:1585-8. Arentz-Hansen H, McAdam SN, Molberg Ø, Fleckenstein B, Lundin KE, Jorgensen TJ, et al. Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 2002;123:803-9. Vader W, Kooy Y, van Veelen P, de Ru A, Harris D, Benckhuijsen W, et al. The gluten response in children with recent onset celiac disease. A highly diverse response towards multiple gliadin and glutenin derived peptides. Gastroenterology 2002;122:1729-37. Arentz-Hansen H, Körner R, Molberg Ø, Quarsten H, Vader W, Kooy YM, et al. The intestinal T cell response to ␣-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 2000;191:603-12. Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med 2000;6:337-42. Vader W, Stepniak D, Bunnik EM, Mearin L, Thompson A, van Rood JJ, et al. Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterology 2003;125:1105-13. Vader W, Stepniak D, Kooy Y, de Haan W, Drijfhout JW, Van Veelen PA, et al. The HLA-DQ2 gene dose effect in Celiac Disease is directly related to the magnitude and breadth of gluten-specific T-cell responses. Proc Natl Acad Sci USA 2003;100:12390-5. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Auricchio S, et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 2003;362:30-7. Hüe S, Mention J-J, Monteiro RC, Zhang S, Cellier C, Schmitz J, et al. Role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 2004; 21:367-77. Koning F, Schuppan D, Cerf-Bensussan N, Sollid LM. Pathomechanisms in celiac disease. Best Pract Res Clin Gastroenterol 2005;19:373-87. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, et al. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL

Curr Probl Pediatr Adolesc Health Care, March 2007

81.

82. 83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

into lymphokine-activated killer cells in celiac disease. Immunity 2004;21:357-66. Mention JJ, Ben Ahmed M, Begue B, Verkarre V, Asnafi V, Colombel JF, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 2003;125:730-45. Meeuwisse GW. Diagnostic criteria in coeliac disease. Acta Paediatr Scand 1970;59:461-3. Branski D, Faber J, Freier S, Gottschalk-Sabag S, Shiner M. Histologic evaluation of endoscopic versus suction biopsies of small intestinal mucosae in children with and without celiac disease. J Pediatr Gastroenterol Nutr 1998;27:6-11. Hogberg L, Nordwall M, Stenhammar L. One thousand small-bowel biopsies in children. A single-port versus a double-port capsule. Scand J Gastroenterol 2001;36:1230-2. Walker-Smith JA, Guandalini S, Schmitz J, Schmerling DH, Visakorpi JK. Revised criteria for the diagnosis of coeliac disease. Report of the working group of the European Society for Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990;65:909-11. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology 1992;102:330-54. Marsh MN, Bjarnason I, Shaw S, Ellis A, Baker R, Peters TJ. Studies of intestinal lymphoid tissue. XIV-HLA status, mucosal morphology, permeability and epithelial lymphocyte population in first degree relatives of patients with coeliac disease. Gut 1990;31:32-6. Wahab PJ, Meijer JW, Mulder CJ. Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery. Am J Clin Pathol 2002;118:459-63. De Giacomo C, Gianatti A, Negrini R, Perotti P, Bawa P, Maggiore G, Fiocca R. Lymphocytic gastritis: a positive relationship with celiac disease. J Pediatr 1994;124:57-62. Chan KN, Phillips AD, Mirakian R, Walker-Smith JA. Endomysial antibody screening in children. J Pediatr Gastroenterol Nutr 1994;18:316-20. Rostom A, Dubé C, Cranney A, Saloojee N, Sy R, Garritty C, et al. Evidence Report/Technology Assessment No. 104. (Prepared by the University of Ottawa Evidence-based Practice Center, under Contract No. 290-02-0021.) AHRQ Publication No. 04-E029-2. Rockville, MD: Agency for Healthcare Research and Quality; July 2004. Abrams J, Diamond B, Rotterdam H, Green PHR. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci 2004;49:546-50. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3:797-801. Dieterich W, Laag E, Schöpper H, Volta U, Ferguson A, Gillett H, et al. Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology 1998;115: 1317-21. Wong RC, Wilson RJ, Steele RH, Radford-Smith G, Adelstein S. A comparison of 13 guinea pig and human anti-tissue transglutaminase antibody ELISA kits. J Clin Pathol 2002;55:488-94. Lock RJ, Stevens S, Pitcher MC, Unsworth DJ. Is immuno-

103

97.

98.

99.

100.

101. 102.

103. 104.

105.

106. 107.

108.

109.

110.

111.

112.

104

globulin A anti-tissue transglutaminase antibody a reliable serological marker of coeliac disease? Eur J Gastroenterol Hepatol 2004;16:467-70. Collin P, Kaukinen K, Vogelsang H, Korponay-Szabo I, Sommer R, Schreier E, et al. Anti-endomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease. A biopsy-proven European multicentre study. Eur J Gastroenterol 2005;17:85-91. Rittmeyer C, Rhoads JM. IgA deficiency causes falsenegative endomysial antibody results in celiac disease. J Pediatr Gastroenterol Nutr 1996;23:504-6. Korponay-Szabo IR, Dahlbom I, Laurila K, Koskinen S, Woolley N, Partanen J, et al. Elevation of IgG antibodies against tissue transglutaminase as a diagnostic tool for coeliac disease in selective IgA deficiency. Gut 2003;52:1567-71. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guidelines 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;40:1-19. Wilson JM, Jungner G. Principles and Practice of Screening for Disease. Geneva: World Health Organisation; 1968. Shamir R, Hernell O, Leshno M. Cost-effectiveness analysis of screening for celiac disease in the adult population. Med Decis Making 2006;26:282-93. Ellis HJ, Ciclitira PJ. In vivo gluten challenge in celiac disease. Can J Gastroenterol 2001;15:243-7. Janatuinen EK, Pikkarainen PH, Kemppainen TA, Kosma VM, Jarvinen RM, Uusitupa MI, et al. A comparison of diets with and without oats in adults with celiac disease. N Engl J Med 1995;333:1033-7. Janatuinen EK, Kemppainen TA, Julkunen RJ, Kosma VM, Maki M, Heikkinen M, et al. No harm from five year ingestion of oats in coeliac disease. Gut 2002;50:332-5. Kumar PJ, Farthking MGJ. Oats and celiac disease. N Engl J Med 1995;333:1075-6. Hardman CM, Garioch JJ, Leonard JN, Thomas HJ, Walker MM, Lortan JE, et al. Absence of toxicity of oats in patients with dermatitis herpetiformis. N Engl J Med 1997;337: 1884-7. Hoffenberg EJ, Haas J, Drescher A, Barnhurst R, Osberg I, Bao F, et al. A trial of oats in children with newly diagnosed celiac disease. J Pediatr 2000;137:361-6. Picarelli A, Di Tola M, Sabbatella L, Gabrielli F, Di Cello T, Anania MC, et al. Immunologic evidence of no harmful effect of oats in celiac disease. Am J Clin Nutr 2001;74:137-40. Holm K, Maki M, Vuolteenaho N, Mustalahti K, Ashorn M, Ruuska T, et al. Oats in the treatment of childhood coeliac disease: a 2-year controlled trial and a long-term clinical follow-up study. Aliment Pharmacol Ther 2006;15:1463-72. Hernando A, Mujico JR, Juanas D, Mendez E. Confirmation of the cereal type in oat products highly contaminated with gluten. J Am Diet Assoc 2006;106:665-6. Arentz-Hansen H, Fleckenstein B, Molberg Ø, Scott H, Koning F, Jung G, et al. The molecular basis for oat

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

intolerance in patients with celiac disease. PLoS Med 2004;1:e1. [Epub 2004 Oct 19]. Spaenij-Dekking L, Kooy-Winkelaar Y, Koning F. The Ethiopian cereal tef in celiac disease. N Engl J Med 2005;353:1748-9. Mendez E, Vela C, Immer U, Janssen FW. Report of a collaborative trial to investigate the performance of the R5 enzyme linked immunoassay to determine gliadin in glutenfree food. Eur J Gastroenterol Hepatol 2005;17:1053-63. Lamontagne P, West GE, Galibois I. Quebecers with celiac disease: analysis of dietary problems. Can J Diet Prac Res 2001;62:175-81. Kumar PJ, Walker-Smith J, Milla P, Harris G, Colyer J, Halliday R. The teenage coeliac: follow up study of 102 patients. Arch Dis Child 1988;63:916-20. Anson O, Weizman Z, Zeevi N. Celiac disease: parental knowledge and attitudes of dietary compliance. Pediatrics 1990;85:98-103. Mayer M, Greco L, Troncone R, Auricchio S, Marsh MN. Compliance of adolescents with coeliac disease with a gluten free diet. Gut 1991;32:881-5. Ljungman G, Myrdal U. Compliance in teenagers with coeliac disease—a Swedish follow-up study. Acta Paediatr 1993;82:235-8. Fabiani E, Catassi C, Villari A, Gismondi P, Pierdomenico R, Ratsch IM, et al. Dietary compliance in screeningdetected coeliac disease adolescents. Am J Clin Nutr 1996;412(Suppl):65-7. Mariani P, Viti MG, Montuori M, La Vecchia A, Cipolletta E, Calvani L, et al. The gluten-free diet: a nutritional risk for adolescents with celiac disease. J Pediatr Gastroenterol Nutr 1998;27:519-23. Hopman GD, le Cessie S, von Blomberg BME, Mearin ML. Nutritional management of the gluten-free diet in young people with celiac disease in the Netherlands. J Pediatr Gastroenterol Nutr 2006;43:102-8. Burgin-Wolff A, Dahlbom I, Hadziselimovic F, Petersson CJ. Antibodies against human tissue transglutaminase and endomysium in diagnosing and monitoring coeliac disease. Scand J Gastroenterol 2002;37:685-91. Troncone R, Mayer M, Spagnuolo F, Maiuri L, Greco L. Endomysial antibodies as unreliable markers for slight dietary transgressions in adolescents with celiac disease. J Pediatr Gastroenterol Nutr 1995;21:69-72. Sategna-Guidetti C, Grosso S, Bruno M, Grosso SB. Reliability of immunologic markers of celiac sprue in the assessment of mucosal recovery after gluten withdrawal. J Clin Gastroenterol 1996;23:101-4. Vahedi K, Mascart F, Mary JY, Laberenne JE, Bouhnik Y, Morin MC, et al. Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol 2003;98:1079-87. Kemppainen T, Uusitupa M, Janatuinen E, Jarvinen R, Julkunen R, Pikkarainen P. Intakes of nutrients and nutritional status in coeliac patients. Scand J Gastroenterol 1995;30:575-9. Hallert C, Grännö C, Hultén S, Midhagen G, Strom M, Svensson H. Living with coeliac disease. Scand J Gastroenterol 2002;37:39-42.

Curr Probl Pediatr Adolesc Health Care, March 2007

129. Lewis HM, Reunala TL, Garioch JJ, Leonard JN, Fry JS, Collin P, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol 1996;135:363-7. 130. Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P. Infertility and coeliac disease. Gut 1996;39:382-4. 131. Nørgård B, Fonager K, Sørensen HT, Olsen J. Birth outcomes of women with celiac disease: a nationwide historical cohort study. Am J Gastroenterol 1999;94:2435-40. 132. Eiser C, Morse R. Can parents rate their child’s healthrelated quality of life? Results of a systematic review. Qual Life Res 2001;10:347-57. 133. Petersen C, Schmidt S, Power M, Bullinger M. The DISABKIDS Group. Development and pilot-testing of a health-related quality of life chronic generic module for children and adolescents with chronic health conditions: a European perspective. Qual Life Res 2005;14:1065-77. 134. Gill TM, Feinstein AR. A critical appraisal of the quality of life measurements. JAMA 1994;272:619-26. 135. Koopman HM, Theunissen NCM, Vogels TGC, Kamphuis RP, Verrips EGH. The DUX-25, a short form questionnaire for measuring health related quality of life of children with chronic illness. Qual Life Res 1998;7:619. 136. Loonen HJ, Grootenhuis MA, Last BF, Koopman HM, Derkx HHF. Quality of life in paediatric inflammatory bowel disease measured by a generic and a disease specific questionnaire. Acta Paediatr 2002;91:348-54. 137. Peterson C, Schmidt S, Power M, Bullinger M: The DISABKIDS Group. Development and pilot-testing of a health-related quality of life chronic generic module for children and adolescents with chronic health conditions: a European perspective. Qual Life Res 2005;14:1065-77. 138. Kolsteren MMP, Koopman HM, Schalekamp G, Mearin ML. Health-related quality of life in children with celiac disease. J Pediatr 2001;138:593-5. 139. Zarkadas M, Cranney A, Case S, Molloy M, Switzer C, Graham ID, et al. The impact of a gluten-free diet on adults with coeliac disease: results of a national survey. J Hum Nutr Diet 2006;19:41-9. 140. Ivarsson A, Persson LÅ, Nyström L, Ascher H, Cavell B, Danielsson L, et al. Epidemic of celiac disease in Swedish children. Acta Paediatr 2000;89:65-71. 141. Ivarsson A, Hernell O, Stenlund H, Persson LÅ. Breastfeeding protects against celiac disease. Am J Clin Nutr 2002;75:914-21. 142. Brandtzaeg PE. Current understanding of gastrointestinal immunoregulation and its relation to food allergy. Ann NY Acad Sci 2002;964:13-45.

Curr Probl Pediatr Adolesc Health Care, March 2007

143. Strobel S. Oral tolerance, systemic immunoregulation and autoimmunity. Ann NY Acad Sci 2002;968:47-58. 144. Falth-Magnusson Franzen L, Jansson G, Laurin P, Stemhammer L. Infant feeding history shows distinct differences between Swedish celiac and reference children. Pediatr Allergy Immunol 1996;7:1-5. 145. Hanson, LA. Breastfeeding provides passive and likely long-lasting active immunity. Ann Allergy Asthma Immunol 1998;81:523-37. 146. Boom van den SAM, Kimber AC, Morgan JB. Weaning practices in children up to 19 months of age in Madrid. Acta Paediatr 1995;84:854-8. 147. Ascher H, Holm K, Kristiansson B, Mäki M. Influence of infant feeding and gluten intake on coeliac disease. Arch Dis Child 1997;76:113-7. 148. Challacombe DN, Mecrow IK, Elliott K, Clarke FJ, Wheeler EE. Changing infant feeding practices and declining incidence of celiac disease in West Somerset. Arch Dis Child 1997;77:206-9. 149. Mitt K, Uibo O. Low cereal intake in Estonian infants: the possible explanation for the low frequency of coeliac disease in Estonia. Eur J Clin Nutr 1998;52:85-8. 150. Norris JM, Barriga K, Hoffenberg EJ. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA 2005;293: 2343-51. 151. Akobeng AK, Ramanan AV, Buchan I, Heller RF. Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch Dis Child 2006;91:39-43. 152. Farrel RJ. Infant gluten and celiac disease: too early, too late, too much, too many questions. JAMA 2005;293:2410-2. 153. WHO. The optimal duration of exclusive breastfeeding. Systematic Review, March 2001, Geneva, 28-30. 154. Cattaneo A, Yngve A, Koletzko B, Guzman LR. Promotion of Breastfeeding in Europe Project. Protection, promotion and support of breast-feeding in Europe: current situation. Public Health Nutr 2005, 8:39-46. 155. Spaenij-Dekking L, Kooy-Winkelaar Y, van Veelen P, Drijfhout JW, Jonker H, van Soest L, et al. Natural variation in toxicity of wheat accessions for celiac disease patients. Potential for selection and breeding of non-toxic wheat varieties. Gastroenterology 2005;129:797-806. 156. Shan L, Molberg Ø, Parrot I, Hausch F, Filiz F, Gray GM, et al. Structural basis for gluten intolerance in celiac sprue. Science 2002;297:2275-9.

105