Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in susceptible individuals (1). Clinical manifestations of CD vary markedly with the age of the patient and the duration and extent of disease. The onset of symptoms in the classic form generally occurs between 6 and 18 months of age. This form is typically characterized by chronic diarrhea, failure to thrive, anorexia and muscle wasting. In recent years there has been a noticeable change in the age of onset of symptoms and the clinical presentation of CD. Maki et al. (2) reported that the mean age of onset in Finland has increased to 5 to 6 years. Celiac disease may first present in adulthood. Diarrhea is the main presenting feature of CD in adults (3). Although CD was once thought to be a rare disease (4), recent screening studies indicate that CD is one of the more frequent genetically based diseases, occurring in 1 in 130 to 300 Europeans (5,6). The frequency in Finish school-aged children is 1 in 99 (7). In Iran the prevalence has been shown to be 1 in 166 apparently healthy blood donors (8). In a study in Kuwait, CD accounted for 18.5% of cases of chronic diarrhea in children (9). Little is known about the prevalence of CD in children with chronic diarrhea in the Middle East, especially in Iran. In this study we evaluated the prevalence of CD among 825 children in Iran with chronic watery diarrhea comparing them to controls.
MATERIALS AND METHODS
From June 1997 to March 2003 we studied 825 consecutive patients with small bowel type chronic diarrhea (voluminous watery diarrhea lasting 6 weeks or more) attending the Department of Gastroenterology of Mofid Medical Center in Tehran. Patients with bloody diarrhea, renal failure (serum creatinine >2 mg/dL) and previous diagnosis of CD were excluded. A control group was selected from patients who attended the pediatrics clinics of Mofid Medical Center with non-gastrointestinal symptoms who agreed to participate in the study. Informed consent was obtained from all parents after a full discussion of risks, benefits and alternatives. The Ethics Committee for Medical Research at Shahid Beheshti University of Medical Sciences reviewed and approved the study.
The patients underwent a thorough interview and physical examination by a pediatric gastroenterologist. Then 10 mL venous blood was drawn from each patient. Serum total immunoglobulin (Ig)A was measured for all patients. A commercial enzyme-linked immunosorbent assay was used (Biosystem®, Madrid, Spain) to measure the IgA antibody titers against gliadin. A serum dilution of 1/100 was used and the results were reported in terms of arbitrary units (AU/mL). An IgA antigliadin antibodies result of >20 AU/mL was considered positive. Serum IgA antibody against endomysium was measured for all patients by the immunofluorescence method using commercial kits (Biosystem®).
Patients with positive serologic tests for CD (IgA endomysial autoantibodies [EMA] or IgA antigliadin antibodies) underwent upper gastrointestinal endoscopy, and three biopsy samples from the second portion of duodenum were taken. The samples were evaluated by an expert pathologist and were graded using modified Marsh classification (10). Hematologic and biochemical tests including complete blood count, serum iron, total iron binding capacity, serum ferritin level, serum alanine aminotransferase, and serum aspartate aminotransferase were also measured in patients with positive serologic tests of CD. Small intestinal barium study was also performed in these patients. In patients with histologic evidence of CD, a gluten-free diet (GFD) was prescribed for 6 months and clinical symptoms and serologic and biochemical tests were evaluated thereafter.
Among 1230 patients with chronic watery diarrhea, 825 cases (389 girls and 436 boys) agreed to participate in the study and were enrolled. Mean age was 8.5 years (range, 3 months to 14 years). The control group consisted of 825 patients (395 girls and 430 boys) with a mean age of 9.2 years (range, 2 months to 14 years). Total serum IgA was within normal limits in all patients.
IgA EMA was positive in 57 (6.9%) patients (25 boys and 32 girls) in the case group and in seven (0.8%) patients (two boys and five girls) in the control group. IgA antigliadin antibody testing was positive in 41 (4.9% ) cases and in no controls. One patient tested positive for IgA antigliadin antibodies but had a negative IgA EMA. He had a normal duodenal biopsy. Of the 57 patients testing positive for IgA EMA, duodenal biopsies revealed stage 0 in three, stage I in 11, stage II in two, stage IIIa in 21, stage IIIb in seven and stage IIIc in 13 patients according to the modified Marsh classification. Thus, the diagnosis of celiac disease (based on positive IgA EMA and compatible duodenal biopsy) was made in 54 of 825 cases (8.96%). Among seven patients in the control group testing positive for IgA EMA, duodenal biopsies revealed stage 0 in two, stage I in three and stage II in two. The diagnosis of celiac disease was made in five of 825 controls (0.61%), which is significantly lower than in the case group (P < 0.001, Student t-test). Patients in the control group were not followed and further evaluation was not done for them; only cases were followed and further evaluated.
Other symptoms in patients with CD include abdominal discomfort and bloating, weight loss, nocturnal diarrhea, nausea, vomiting and oral aphthous ulcers. Laboratory findings revealed iron deficiency anemia in 39 patients (72.2%), elevated serum aminotransferase levels in 11 (20.3%) and thrombocytopenia in five patients (9.2%). After 6 months of GFD, 41 (76.1%) patients had complete clinical and laboratory response, six patients (11.1%) had good response (four or less bowel movements per day) and one (5%) had partial response (five to six bowel movements per day). Six patients did not follow the GFD. IgA EMA became negative in 19 of 38 patients (50%) in whom the test was repeated after 6 months of observing GFD.
Twelve patients with CD had elevated serum aspartate aminotransferase levels (mean, 55.2; range, 55 to 76 U/L). Serum aspartate aminotransferase returned to normal after 6 months of GFD in these patients (mean, 22.9 U/L; P < 0.0001). Six patients had elevated serum alanine aminotransferase levels (mean, 78.5; range, 58 to 97 U/L). Serum alanine aminotransferase became normal after introduction of GFD (mean, 19 U/L; P < 0.01). In 39 patients with iron deficiency anemia after GFD with supplementary diet, their anemia resolved (mean hemoglobin level increasing to 12.88 g/dL from 9.82 g/dL, P < 0.01) without any iron supplementation. Mean plasma ferritin level also increased in these individuals (from 3 to 65.1 ng/mL; P < 0.01).
In this study, we assessed the prevalence of CD among 825 children with small bowel type chronic diarrhea. Those diagnosed with CD were followed for 6 months after introduction of GFD. Our data show that CD is a common diagnosis in Iranian children referred for evaluation of chronic diarrhea. Our findings are consistent with a previous study finding a similar prevalence of CD in hospitalized patients with chronic diarrhea in the Middle East (11). Shaltout et al reported a prevalence of 18.5% for CD among Kuwaiti children with chronic diarrhea (9). The classic form of CD is characterized by chronic diarrhea, failure to thrive, anorexia, abdominal distension and muscle wasting. This form generally occurs between 6 and 18 months of age. However, after introduction of serologic tests for diagnosis of CD, it has become apparent that oligosymptomatic forms of CD are much more prevalent than its typical form, and that CD is not limited to the pediatric population; the onset of disease may occur at any age, after years of silent disease (1). There is a case report of CD first diagnosed in a 67-year-old woman (12).
Our study also showed that GFD can eliminate or reduce the severity of diarrhea in most patients with celiac disease. If diarrhea persists after introduction of GFD, ongoing gluten ingestion is the most plausible cause. However, other coexisting diseases such as microscopic colitis, exocrine pancreatic insufficiency and dietary lactose or fructose malabsorption should be considered (13).
Another interesting finding from our study is that in three patients with positive IgA EMA and normal duodenal biopsy (Marsh 0) GFD resulted in complete resolution of diarrhea. In fact, a patient may have celiac disease and the normal duodenal biopsy may be attributable to patchy involvement of the duodenum by CD. Another possibility is that a patient may have latent CD together with some degrees of gluten sensitivity. In a recent study, Wahnschaffe et al. showed that some patients with diarrhea predominant irritable bowel syndrome who have CD-associated antibodies in duodenal aspirate respond to GFD (14).
In our study small intestinal Crohn disease and idiopathic enteropathy (15) were also relatively common and should be considered in the differential diagnosis of small bowel type chronic diarrhea in Iran. Except for tuberculosis, other infectious causes were relatively uncommon in the studied population.
In conclusion, IgA EMA should be included as one of the first diagnostic tests for evaluating of chronic diarrhea. GFD can eliminate or reduce diarrhea in a substantial proportion of patients with CD.
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