The coexistence of celiac disease (CD) and insulin-dependent diabetes mellitus (IDDM) has been known for more than 46 years (1). Several studies worldwide have demonstrated an increased prevalence (0.7–16.4%) of CD in children and adolescents with IDDM (2–25). Only one study in the United States has reported the prevalence of CD in diabetic children (26). In this study, 10 of 211 patients with IDDM (4.1%) in Buffalo, New York, were found to have endomysial antibody (EMA). Only 3 of these 10 patients underwent small bowel biopsy and were diagnosed with CD (1.4%). The prevalence of CD in diabetic children in the United States is unknown.
Celiac disease is characterized by loss of the normal villous structure in the small bowel, often associated with symptoms related to malabsorption. Malignancy, particularly of the small bowel, may occur in untreated or undiagnosed patients (27–32). Silent forms of CD in children with IDDM have been detected by serologic screening. Early identification and the treatment of CD therefore are important to prevent the development of symptoms and to reduce long-term morbidity (33–34).
The aim of this study was to determine the prevalence and the clinical presentation of CD in children and adolescents with IDDM in Wisconsin using serum EMA as a screening test.
PATIENTS AND METHODS
All children attending the Diabetes Clinic at Children's Hospital of Wisconsin between December 1996 and December 1998 were offered testing for EMA. Children's Hospital of Wisconsin is the primary pediatric referral hospital in eastern Wisconsin and offers the only pediatric diabetes clinic in the region. Two hundred eighteen children and adolescent with IDDM (113 males, 105 females) agreed to participate. The mean age was 13.7 years (range, 4–21 years). One hundred seventeen age-and gender-matched control participants were tested also. The control participants consisted of children without gastrointestinal symptoms undergoing laboratory testing at Children's Hospital of Wisconsin. A standardized questionnaire regarding abdominal pain, diarrhea, and growth failure was filled out by the parents, the patients, or both.
A blood sample was taken from participants during a routine outpatient visit. The serum was stored at −20°C until testing. The sera were analyzed for EMA immunoglobulin A by indirect immunofluorescence test on commercially available tissue sections of monkey esophagus (Immco Diagnostic, Buffalo, NY). The presence of EMA is demonstrated by an apple-green fluorescence staining of the endomysial lining of smooth muscle bundles. For this procedure, serum was diluted at 1:2.5. A positive serum in the screening test was tested further to determine the titer of the antibody by testing serial twofold dilutions starting at 1:5, 1:10, 1:20, and 1:40 for one slide. If positive at a 1:40 dilution, the titer was reported as more than 40 or additional slides were used to obtain endpoints. The reciprocal of the highest dilution producing a positive reaction is the titer.
Patients testing positive for EMA were offered small bowel biopsy. Two or three mucosal biopsies were obtained at endoscopy from the distal duodenum, oriented on mesh and placed in formalin. Histopathologic examination was performed by pediatric pathologists. The diagnosis of CD was made by the following criteria: villous atrophy, inflammation in the lamina propria with increased intraepithelial lymphocytes, and hyperplasia of the crypts. Biopsy specimens were classified as partial or total villous atrophy. The specimens were read by the pediatric pathology service consisting of four pediatric pathologists. Patients diagnosed with CD were treated with a gluten-free diet and followed up in the Gastroenterology Clinic.
This study was approved by The Research and the Publications Committee of the Children's Hospital of Wisconsin and the Institutional Review Board of the Medical College of Wisconsin. Informed consent or assent was obtained from parents, patients, or both.
Seventeen of the 218 patients with IDDM (7.7%) were positive for EMA (Fig. 1). All the control participants were EMA negative.
Fourteen of the 17 patients underwent biopsy, and 10 showed changes compatible with CD (Table 1). Of the 10 newly diagnosed patients with CD, one with mild villous architectural alterations and increased intraepithelial lymphocytes had total villous atrophy on a second biopsy. Two patients with minor histologic changes (increased intraepithelial lymphocytes, focal acute inflammation, and mild architectural changes of villous) were not diagnosed with CD and are being observed. Two patients had normal mucosal morphologic features. With 10 newly diagnosed patients, the prevalence of CD in our population of diabetic children was 4.6%. The mean duration of diabetes was 6.06 years (range, 0.8–12 years) in the EMA-positive patients and 4.3 years (range, 0.2–15 years) in the EMA-negative patients. The male-to-female ratio in EMA-positive children was 1:1.4, compared with 1:0.93 in the EMA-negative children. All newly diagnosed children were white. White children compromise 79.9% of the population observed in the Diabetes Clinic.
Only 3 of 10 patients (30%) with CD were symptomatic (Table 1). After treatment with a gluten-free diet, the gastrointestinal symptoms resolved in all symptomatic patients except one, who continued to have abdominal pain 1 year after treatment with a gluten-free diet. A repeat endoscopy in this patient revealed normal villous architecture. Twelve percent of EMA-negative diabetic children had the following symptoms: abdominal pain (n = 19), diarrhea (n = 4), growth failure (n = 6). Two diabetic patients with CD had Down syndrome and hypothyroidism.
In the group of patients who declined to undergo small bowel biopsy, one converted a positive EMA titer to negative in 1 year and another had a decrease in EMA titer from 1:2560 to 1:20 in 2 years. These patients were on a normal diet.
The minimal prevalence of CD in children with juvenile diabetes in Wisconsin is 4.6%, which is higher than that reported in Buffalo, New York (1.4%), Germany (2.3%), the Czech Republic (3.6%), France (1.7%), and Austria (3%), but is comparable with Canadian studies (5.1%) (3,13,23–26). The true prevalence of CD in diabetic children in this study may be even higher for two reasons: 1) three patients with EMA who declined small bowel biopsy also may have CD, and 2) total immunoglobulin A was not measured in our study population. Selective immunoglobulin A deficiency is seen in approximately 3% of the patients with CD and is a known cause of false-negative EMA results (35–37).
There have been very few studies on the prevalence of CD in the United States. Rossi et al. (26) reviewed the charts of symptomatic children with a definitive diagnosis of CD between 1980 and 1990. By their estimates, the crude incidence rate of CD in western New York was 1:5464. Talley et al. (38) retrospectively evaluated the records of cases who had a small bowel biopsy consistent with CD in Olmstead County, Minnesota. The authors identified only three children and calculated the incidence rate of CD 0.4 per 100,000 person years. Based on these results, CD has been considered less common in the United States than in Europe. However, Berti et al. (39) recently reported the prevalence of CD in healthy children and adults as 1:163 and 1:150, respectively. The same prevalence has been reported in Europe, which supports the concept that CD in the United States is more common than previously realized. Based on these results, the prevalence of CD in our diabetic population (1:22) far exceeds the prevalence in the ethnically diverse population of the United States.
Patients with latent celiac disease have normal intestinal biopsy results on a normal diet but have had or will have gluten sensitive enteropathy (40,41). This has been previously reported in patients with IDDM (42,43) and was also observed in our IDDM population. One patient with initial small bowel biopsy showing mild inflammatory changes and normal villous had total villous atrophy on a repeat biopsy 2 years later. Thus, EMA measurement may detect gluten sensitivity in IDDM patients before development of overt villous atrophy. Of the remaining EMA-positive patients, two with mild villous architectural changes and two with normal biopsy results may also have latent CD, and long-term follow-up is required to ascertain a definitive diagnosis. Tissue transglutaminase, which has recently been identified as the antigen recognized by the antiendomysial antibodies, may be useful in diagnosing latent CD in patients with IDDM (43,44).
In this study, only 3 of 10 patients (30%) with CD were symptomatic (abdominal pain, diarrhea, and growth failure), in agreement with the previous reports that CD in some IDDM patients is clinically silent (45). All the patients with growth failure had Down syndrome, which has been reported to be associated strongly with diabetes and with CD (46). Untreated patients with CD have an increased risk of malignancy, especially small bowel lymphoma, infertility, or osteoporosis, which could be prevented by a strict gluten-free diet (32–34). Thus, to prevent complications, early diagnosis and treatment of CD in diabetic children is crucial.
It has been suggested that IDDM may trigger the development of CD in genetically predisposed individuals. A recent North American study suggested that initial screening of asymptomatic children should begin 1 to 2 years after the diagnosis of NIDDM (23). Schober et al. (25) reported that one third of the patients with diagnosed CD had EMA at the time of the manifestation of diabetes. None of our patients were screened at the time of the diagnosis; the earliest diagnosis of CD was 10 months after the onset of diabetes.
In conclusion, because of the high prevalence and silent cases of CD in IDDM patients, we suggest that North American children with diabetes be screened for CD. Patients with normal villous architecture and intraepithelial lymphocytes on small bowel biopsy may have latent or presymptomatic CD; thus, close clinical monitoring and follow-up biopsies should be considered in these patients.
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