OBJECTIVE: The goal was to evaluate the impact of immunoglobulin A endomysial antibody testing on the incidence and clinical presentation of childhood celiac disease.
METHODS: The incidence and clinical presentation of celiac disease in patients <18 years of age in 1990–1996 (pretesting group) versus 2000–2006 (testing group) were compared.
RESULTS: The median age at diagnosis was 2 years (95% confidence interval: 2–4 years) in the pretesting group (N = 36), compared with 9 years (95% confidence interval: 8–10 years) in the testing group (N = 199; P < .001); the female/male ratios (1.6:1) were similar (P = .982). The incidence of celiac disease increased from 2.0 cases per 100000 children (pretesting group) to 7.3 cases per 100000 children (testing group; P = .0256). The frequency of classic celiac disease presentations decreased from 67% (pretesting group) to 19% (testing group; P < .001), but the incidence of classic celiac disease did not differ (0.8 vs 1.6 cases per 100000; P = .154). In the testing group, 13 previously unrecognized clinical presentations were observed in 98 children, including 35 with family history, 18 with abdominal pain, and 14 with type 1 diabetes mellitus. The frequency of Marsh IIIc lesions decreased from 64% (pretesting group) to 44% (testing group; P = .0403). In the testing group, classic celiac disease remained predominant (67%) in young children (<3 years), whereas atypical gastrointestinal and silent presentations predominated in older children.
CONCLUSIONS: Antibody testing for celiac disease tripled the incidence of celiac disease and quadrupled the median age at diagnosis.
The introduction into clinical practice of serological testing to detect the presence of circulating antibodies against endomysium and tissue transglutaminase is largely responsible for our understanding of celiac disease as a multisystem disorder with myriad presentations.1 The prevalence of celiac disease is estimated to be 0.3% to 1.0% in North American children, and most cases remain undiagnosed.2,3 Children may present with atypical or extraintestinal symptoms or with celiac disease-associated conditions.4–8
Current North American guidelines recommend testing for celiac disease in a wide variety of ailments, including gastrointestinal symptoms, chronic fatigue, short stature, delayed puberty, dental enamel defects, elevated liver transaminase levels, dermatitis herpetiformis, and nutritional anemias.9 Testing is also recommended for patients with celiac disease-associated conditions, such as type 1 diabetes mellitus, autoimmune thyroiditis, immunoglobulin A (IgA) deficiency, Down syndrome, Turner syndrome, and a family history of celiac disease.9 Evidence for these recommendations comes mostly from European studies. Our understanding of the clinical picture of childhood celiac disease in North America is limited.8,10,11 Telega et al8 provided preliminary evidence for the changing face of celiac disease by describing the clinical presentation in Wisconsin. The only report of the clinical features of consecutive cases of celiac disease in Canadian children is 40 years old.10 More recently, Rashid et al11 retrospectively studied clinical presentations among Canadian children in a celiac disease support group.
Children with undiagnosed celiac disease remain at risk for complications, including growth failure, delayed puberty, anemia, decreased bone mineralization, and autoimmune disease, as well as infertility and malignancy in later years.1,9 Currently, a diagnostic approach that uses serological testing for patients with symptoms and those in at-risk groups is recommended.1 Therefore, clinicians from all specialties must recognize the variable presentations of celiac disease. The aim of this study was to evaluate the impact of serological testing with a case-finding strategy on the incidence and clinical presentations in a North American population, and to acquaint clinicians with the multisystem diversity of celiac disease.
Case Identification and Data Collection
Data for consecutive patients (<18 years of age) who were referred with symptoms and/or positive celiac disease serological findings and were diagnosed as having celiac disease through intestinal biopsy at the Alberta Children's Hospital between January 1, 1990, and December 31, 2006, were entered into a database. This hospital is the only pediatric gastroenterology referral center in southern Alberta. Patients diagnosed as having celiac disease were identified through a search of the Calgary Laboratory Services surgical pathology database for diagnostic terms consistent with celiac disease (“villus atrophy,” “villus blunting,” “celiac disease,” “sprue,” or “gluten-sensitive enteropathy”) for biopsies performed during this time period. A second search of clinic records was performed to ensure completeness of the database. The clinic charts and small-bowel pathology reports were reviewed, and data on the following variables were extracted: (1) clinical information, including patient demographic features, symptoms, associated conditions, indication for intestinal biopsy, and date of biopsy; (2) laboratory abnormalities at diagnosis, including iron deficiency, anemia, hypoalbuminemia, elevated liver transaminase levels, IgA deficiency (IgA level of <0.06 g/L),12 and IgA-endomysial antibody (EMA) test results13; and (3) small-intestinal biopsy results at diagnosis, including the modified Marsh score.14 Biopsies were interpreted by 1 of 2 pediatric pathologists and were rereviewed for assignment of modified Marsh scores.14 The diagnosis of celiac disease was based on the current North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines.9 Seropositive children with symptoms who had Marsh I to III lesions on biopsy and had clinical and serological responses to a gluten-free diet (GFD) were diagnosed as having celiac disease. Seropositive children without symptoms with associated conditions who had Marsh I to III lesions on biopsy and had serological responses to GFD were diagnosed as having celiac disease. Seronegative children with symptoms who had Marsh III lesions on biopsy and had clinical and histologic responses to GFD were diagnosed as having celiac disease. Children were monitored for ≥1 year to determine responses to GFD.
Patients were assigned 1 primary symptom, sign, or indication (associated condition) leading to intestinal biopsy (ie, the reason for referral), on the basis of chart documentation. The clinical presentations were grouped into 4 categories, that is, (1) classic celiac disease, defined on the basis of diarrhea with failure to thrive15 or weight loss of >10%; (2) atypical gastrointestinal presentation, defined on the basis of any gastrointestinal symptom, including abdominal pain, gastroesophageal reflux, vomiting, constipation, and diarrhea, without failure to thrive or weight loss; (3) extraintestinal presentation, defined on the basis of signs or symptoms outside the gastrointestinal tract, such as iron deficiency anemia or short stature; and (4) silent presentation. Children with the silent mode of presentation were identified through testing because of a family history of celiac disease or celiac disease-associated condition. They reported no symptoms, even in response to direct questioning, before the establishment of GFD. Associated conditions included type 1 diabetes mellitus, trisomy 21, and hypothyroidism. Direct questioning during follow-up visits over 1 year identified symptoms that were recognized retrospectively after initiation of GFD.
IgA-EMA testing was introduced in 1997. Children were divided into the pretesting group (1990–1996) and the testing group (2000–2006) on the basis of the year of diagnosis. Because altering physician practice patterns takes time, the years 1997–1999 were considered transition years and the 21 diagnoses made in those years were not considered for comparison. The incidence and clinical presentation of celiac disease (including signs/symptoms, Marsh scores, and laboratory abnormalities) were compared between the pretesting and testing groups, and age- and gender-related differences in the mode of presentation of childhood celiac disease were examined in the testing group. Incidence was determined by averaging annual incidence data for each study period, using population data (age: 0–17 years) provided by Alberta Health Services, Health Outcomes Office.
Statistical analyses were performed with SPSS 16.0 (SPSS, Chicago, IL). Continuous variables were summarized as medians with 95% confidence intervals (CIs), because of nonnormal distribution. The Mann-Whitney U test was used to detect differences in continuous variables, and Pearson's χ2 test, or Fisher's exact test when appropriate, was used to detect differences between categorical variables. Spearman's rank correlation was used to test associations when variables were measured on an ordinal scale. P < .05 was accepted as statistically significant. The conjoint medical research ethics board of the University of Calgary approved this study.
A total of 266 children (161 female; 61% [95% CI: 55%–66%]) were diagnosed as having celiac disease through intestinal biopsy at the Alberta Children's Hospital between 1990 and 2006. The annual number of diagnoses of celiac disease increased fourfold over these 16 years, from 6 to 28 cases per year. Between 1990 and 1996 (pretesting group), 36 children (22 female; 61% [95% CI: 45%–75%]) were diagnosed as having celiac disease; this increased to 199 patients (122 female; 61% [95% CI: 54%–68%]) between 2000 and 2006 (testing group). The female/male ratio (1.6:1) remained unchanged (P = .982). The median age at diagnosis increased from 2 years (95% CI: 2–4 years) in the pretesting group to 9 years (95% CI: 8–10 years) in the testing group (P < .001) (Table 1). The population-based estimate of the incidence of celiac disease increased from 2.0 cases per 100 000 per year in the pretesting group to 7.3 cases per 100 000 per year in the testing group (P = .0256).
Comparison of Clinical Presentations
The primary symptoms, signs, or associated conditions that led to intestinal biopsy for each child are presented in Table 1. The frequency of classic celiac disease decreased from 67% (24 of 36 children) in the pretesting group to 19% (39 of 199 children) in the testing group (P < .001) (Table 1). However, the incidence of classic celiac disease did not differ between the pretesting group (0.8 cases per 100 000 per year) and the testing group (1.6 cases per 100 000 per year; P = .154).
The frequency of presentation with atypical gastrointestinal symptoms, especially nonspecific abdominal pain, was increased in the testing group, compared with the pretesting group, and the silent mode of presentation occurred only in this group (Table 1). Furthermore, 13 previously unrecognized clinical presentations were observed in 98 (49%) of 199 children in the testing group, including a family history of celiac disease (n = 35 children), isolated abdominal pain (n = 18), type 1 diabetes (n = 14), endoscopy for other reasons before celiac disease serological testing (n = 8), and short stature (n = 6) (Table 1). Previously unobserved extraintestinal presentations included short stature (n = 6), dermatitis herpetiformis (n = 2), elevated transaminase levels (n = 1), and dental enamel defects (n = 1), whereas failure to thrive with no diarrhea and iron deficiency with or without anemia occurred at similar frequencies in the 2 groups (Table 1). Serological testing for children without symptoms led to diagnosis for 21 (75%) with a family history of celiac disease, 6 (21%) with type 1 diabetes, and 1 (4%) with hypothyroidism. A Marsh I lesion and a Marsh II lesion were observed in 2 seropositive children without symptoms with a family history of celiac disease. Serological results normalized with GFD for both children. Among the 55 patients with a silent mode of presentation in the testing group, 27 patients (49%; 14 female) had symptoms that were recognized only retrospectively and 28 (51%; 16 female) had no symptoms.
An evaluation of the entire spectrum of symptoms documented at the time of diagnosis revealed that diarrhea occurred for 28 (78%) of 36 patients in the pretesting group and 59 (30%) of 199 in the testing group (P < .001), failure to thrive/weight loss for 26 patients (72%) in the pretesting group and 71 (36%) in the testing group (P < .001), and abdominal distention for 11 patients (31%) in the pretesting group and 28 (14%) in the testing group (P = .025). In contrast, abdominal pain occurred for 5 patients (14%) in the pretesting group and 77 (39%) in the testing group (P = .007). Of the children who underwent laboratory testing, iron deficiency with or without anemia occurred for 6 patients (17%) in the pretesting group and 35 (18%) in the testing group (P = .893), whereas hypoalbuminemia occurred for 3 patients (8%) in the pretesting group and 5 (3%) in the testing group (P = .107).
Age- and Gender-Related Differences in the Presentation of Celiac Disease
In the testing group, the median age at diagnosis was 8 years (95% CI: 7–9 years) for girls and 10 years (95% CI: 8–11 years) for boys (P = .054). The classic mode of presentation was inversely associated with the age at diagnosis (P < .001) (Fig 1). Atypical gastrointestinal (P < .01) and silent (P < .001) modes of presentation were directly associated with the age at diagnosis (Fig 1). The extraintestinal mode of presentation occurred with similar frequencies among the age groups (P = .650). No significant association between the mode of presentation and gender was observed, overall (P = .397) (Fig 1) or within age groups (data not shown). In addition, the classic presentation was associated with higher Marsh scores (P = .003) (Fig 2). Nonclassic presentations (atypical gastrointestinal, extraintestinal, and silent) were not associated with Marsh scores (P = .132) (Fig 2). The frequency of Marsh IIIc biopsy lesions was higher in the pretesting group (64%) than in the testing group (44%; P = .0403).
In the testing group, 191 (96%) of 199 children underwent serological testing before intestinal biopsy; positive IgA-EMA results were found for 185 children (97%), including 2 with IgA deficiency (titers of 1:1280 for a 6-year-old child and 1:320 for a 9-year-old child). Among the 191 children tested, 5 children with IgA sufficiency (3%; 1, 2, 9, 13, and 16 years of age) and 1 child with IgA deficiency (0.5%), all with gastrointestinal symptoms, had negative IgA-EMA results. The 8 patients who had positive biopsy findings before IgA-EMA testing underwent serological testing immediately after physicians received the pathology reports. All IgA-EMA serological test results were positive. The IgA-EMA titer strength correlated directly with the severity of the small-intestinal lesion, as measured with the Marsh score (Spearman's ρ = 0.387; P < .001), and correlated inversely with the age at diagnosis (Spearman's ρ = −0.373; P < .001) (Fig 3).
Our findings demonstrate that the incidence and median age at diagnosis of childhood celiac disease tripled and quadrupled, respectively, after the introduction of IgA-EMA testing. Furthermore, the introduction of serological testing broadened the clinical spectrum of celiac disease recognized by physicians, as evidenced by the identification of 13 previously unrecognized presentations in one half of all cases diagnosed between 2000 and 2006. Although the frequency of children presenting with classic celiac disease decreased by more than one third between the pretesting and testing groups, the incidence of classic celiac disease remained unchanged. To our knowledge, the stable incidence of classic celiac disease has not been reported previously. The marked increase in the incidence of celiac disease between time periods can be attributed to the improved detection of nonclassic presentations, particularly in older children. Improved physician awareness through educational programs and increased emphasis on celiac disease in the medical literature likely contributed to this. Furthermore, positive celiac disease serological results may persuade caregivers to consent to biopsy for children with mild symptoms.
Although we observed many atypical clinical manifestations of celiac disease, gastrointestinal symptoms remained the most frequently observed clinical presentations after the introduction of serological testing. However, these gastrointestinal symptoms were increasingly diverse and were associated with milder intestinal injury, as evidenced by decreased biopsy Marsh scores. Consistent with results from European studies, the classic presentation remains common in younger children and frequently is associated with Marsh IIIc lesions, whereas older children frequently present with atypical gastrointestinal symptoms.4,7,16,17 Interestingly, the frequency of laboratory abnormalities, including iron deficiency, with or without anemia, and hypoalbuminemia, did not decrease between time periods, despite the decreased severity of intestinal lesions. The anemia observed in nonclassic celiac disease with milder intestinal lesions may be attributable to chronic inflammation.18
The direct correlation between IgA-EMA titers and Marsh scores is consistent with the results of a previous study.19 Although the reliability of the IgA-EMA assay in children <3 years of age has been questioned,9 we observed an inverse correlation between IgA-EMA titer and age at diagnosis of celiac disease. This likely reflects the fact that the majority of young children present with classic celiac symptoms. We and others19 have demonstrated that the classic presentation is associated with higher IgA-EMA titers and more-severe intestinal injury than are nonclassic presentations. Furthermore, only 2 of 5 IgA-sufficient children with false-negative serological results were <3 years of age. Children of all ages with symptoms suggesting celiac disease should undergo intestinal biopsy, despite negative celiac serological findings.
The frequency of the classic presentation observed in our testing group (20%) was lower than values for European children diagnosed during the serological testing era.5–7,16,20 This may be attributable to differences in infant feeding practices, which influence the incidence, age at diagnosis, and clinical presentation of celiac disease.16 Physician awareness, thresholds for serological testing, endoscopy availability, and differences in case-identification methods also may account for differences between studies. Our study and others suggest that the clinical presentation of celiac disease is changing irrespective of testing.21–23 In the pretesting group, 44% of patients were >3 years of age at diagnosis, compared with 17% in the 4-decade-old Toronto study.10 A possible explanation for these observations is related to an increase in the prevalence of breastfeeding in Canada, from 25% in 1965 to 85% in 2003, with 35% of mothers breastfeeding for ≥3 months.24 Breastfeeding and an older age of gluten introduction are associated with delayed onset of celiac disease and atypical symptoms.16,25
Current practice guidelines for children presenting with chronic abdominal pain in the absence of other symptoms do not recommend testing for celiac disease26 or recommend testing only if alarm symptoms are present.27 Notably, nearly 1 in 10 children diagnosed as having celiac disease in our testing group presented with chronic abdominal pain and no other symptoms or signs. To our knowledge, this is the only study to document celiac disease in children with abdominal pain without any other symptoms, signs, or associated conditions that would warrant testing for celiac disease. Two studies examined the prevalence of celiac disease in children with chronic abdominal pain, and both concluded that testing is not warranted.28,29 Those studies had small sample sizes, however, and only 1 included control subjects. Both studies were performed before the recognition that celiac disease occurs in 0.3% to 1.0% of children.2,3 Further investigation is needed to ascertain the prevalence of celiac disease in children with chronic abdominal pain without alarm symptoms and to assess the value of testing for this subgroup.
In the past 7 years, >1 in 4 children were diagnosed as having celiac disease in southern Alberta as a result of case-finding of associated conditions, consistent with data from the United Kingdom.6 Although current guidelines recommend testing for children with associated conditions for celiac disease, the short- and long-term benefits of treating such children is not fully understood. Children with testing-detected celiac disease have significantly lower weight and height, compared with control subjects.30,31 We and others have observed that children with “asymptomatic,” testing-detected disease who begin GFD often report improvement in symptoms that were not recognized before diagnosis.30–34 It is not known whether asymptomatic or retrospectively recognized celiac disease carries the long-term risks associated with symptomatic untreated celiac disease.35 In addition, children with testing-detected celiac disease may not perceive any benefit from GFD, which may increase the burden of illness and decrease dietary compliance.11,36–40
Potential limitations of this retrospective study include incomplete reporting of symptoms and laboratory data in clinic charts, as well as incomplete identification of all cases because of clerical error, changes in referral patterns, and evaluation of older children by adult gastroenterologists. Our clinic remained the only pediatric referral center in southern Alberta throughout the duration of the study.
The introduction of serological testing led to a marked increase in recognition of the diversity of celiac disease clinical presentations, particularly in older children. This study is the first to report the frequencies of clinical presentations of celiac disease observed in clinical practice before and after the introduction of serological testing in North American children. Although the incidence of classic celiac disease did not decrease, many children with atypical gastrointestinal presentations and those in high-risk groups with mild symptoms were recognized because of serological testing. Further educational efforts are required to improve the detection of nonclassic celiac disease, and long-term follow-up studies are needed to understand the impact of celiac disease and GFD on the health and well-being of children, particularly those identified through serological testing.
This research was supported by grants from the Calgary Chapter of the Canadian Celiac Association and the Canadian Association of Gastroenterology. Calgary Laboratory Services provided access to pathology, IgA, and IgA-EMA results.
- Accepted June 16, 2009.
- Address correspondence to J. Decker Butzner, MD, Division of Gastroenterology and Nutrition, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada. E-mail:
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject:
European data demonstrated that celiac disease is a multisystem disorder, occurring in 0.3% to 1.0% of children. Serological testing facilitates the recognition of children presenting with atypical or extraintestinal symptoms or with celiac disease-associated conditions.
What This Study Adds:
Serological testing tripled the incidence, quadrupled the age at diagnosis, and led to the recognition of diverse presentations of celiac disease in a North American population. Classic celiac disease predominated in younger children, whereas atypical presentations predominated in older children.
- ↵Ravikumara M, Tuthill DP, Jenkins HR. The changing clinical presentation of coeliac disease. Arch Dis Child.2006;91 (12):969– 971
- ↵Hamilton JR, Lynch MJ, Reilly BJ. Active coeliac disease in childhood: clinical and laboratory findings of forty-two cases. Q J Med.1969;38 (150):135– 158
- ↵Rashid M, Cranney A, Zarkadas M, et al. Celiac disease: evaluation of the diagnosis and dietary compliance in Canadian children. Pediatrics.2005;116 (6). Available at: www.pediatrics.org/cgi/content/full/116/6/e754
- ↵Latiff AH, Kerr MA. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem.2007;44 (2):131– 139
- ↵McGowan KE, Lyon ME, Loken SD, Butzner JD. Celiac disease: are endomysial antibody test results being used appropriately? Clin Chem.2007;53 (10):1775– 1781
- ↵Bauchner H. Failure to thrive. In: Kliegman RM, Behrman RE, Jenson HB, eds. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, PA: Saunders Elsevier; 2007;184–187
- ↵Ascher H, Holm K, Kristiansson B, Mäki M. Different features of coeliac disease in two neighbouring countries. Arch Dis Child.1993;69 (3):375– 380
- ↵Millar W, McLean H. Statistics Canada: breastfeeding practices. Health Reports.2005;16 (2). Available at: www.statcan.gc.ca/bsolc/english/bsolc?catno=82-003-X20040027787. Accessed July 28, 2008
- ↵Ivarsson A, Hernell O, Stenlund H, Persson LA. Breast-feeding protects against celiac disease. Am J Clin Nutr.2002;75 (5):914– 921
- ↵American Academy of Pediatrics, Subcommittee on Chronic Abdominal Pain. Chronic abdominal pain in children. Pediatrics.2005;115 (3):812– 815
- ↵Berger MY, Gieteling MJ, Benninga MA. Chronic abdominal pain in children. BMJ.2007;334 (7601):997– 1002
- ↵Bingley PJ, Williams AJ, Norcross AJ, et al. Undiagnosed coeliac disease at age seven: population based prospective birth cohort study. BMJ.2004;328 (7435):322– 323
- ↵Hoffenberg EJ, Emery LM, Barriga KJ, et al. Clinical features of children with screening-identified evidence of celiac disease. Pediatrics.2004;113 (5):1254– 1259
- ↵Hansen D, Brock-Jacobsen B, Lund E, et al. Clinical benefit of a gluten-free diet in type 1 diabetic children with screening-detected celiac disease: a population-based screening study with 2 years' follow-up. Diabetes Care.2006;29 (11):2452– 2456
- ↵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 (8):916– 920
- Mayer M, Greco L, Troncone R, Auricchio S, Marsh MN. Compliance of adolescents with coeliac disease with a gluten free diet. Gut.1991;32 (8):881– 885
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