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Celiac Disease in Children With Diarrhea in 4 Cities in China

Wang, Xin-qiong*; Liu, Wei*; Xu, Chun-di*; Mei, Hong; Gao, Yuan; Peng, Han-ming; Yuan, Lan§; Xu, Jun-jie

Journal of Pediatric Gastroenterology and Nutrition: October 2011 - Volume 53 - Issue 4 - p 368–370
doi: 10.1097/MPG.0b013e31822a0128
Invited Review

Objective: The aim of the study was to investigate whether celiac disease (CD) could be the cause of chronic diarrhea in Chinese patients.

Patients and Methods: During the period of January 2005 to December 2008, patients with chronic diarrhea in pediatric hospitals from 4 major cities (Shanghai, Wuhan, Jinan, and Chengdu) in China were included in the study. The clinical history, physical findings, and laboratory data were collected and analyzed.

Results: Among 199 patients with chronic diarrhea, 118 were enrolled in the study. Fourteen (11.9%) were diagnosed as being affected by CD.

Conclusions: The 14 patients are the first reported cases of CD in Chinese patients with chronic diarrhea.

*Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai

Department of Gastroenterology, Qilu Children's Hospital, Shandong University, Jinan, Shandong

Department of Gastroenterology, Wuhan Children's Hospital, Wuhan, Hubei

§Department of Gastroenterology, Chengdu Children's Hospital, Chengdu, Sichuan, China.

Address correspondence and reprint requests to Xu Chun-di, Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (e-mail:

Received 16 July, 2010

Accepted 19 April, 2011

The present study is partly supported by the IPSEN Fund.

The authors report no conflicts of interest.

See “Another Brick in the (Great) Wall: Celiac Disease in Chinese Children” by Catassi and Alarida on page 359.

Celiac disease (CD) is an autoimmune disorder of the small intestine occurring in genetically predisposed patients of all ages, from infancy to adulthood. Symptoms may include diarrhea, failure to thrive in infants and children, and fatigue, but it may be entirely symptomless. With the advent of noninvasive laboratory tests, more individuals without symptoms are diagnosed as having the illness. The illness is 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 histologic alterations of the small bowel mucosa (1).

The vast majority of patients with CD have 1 of 2 types of human leukocyte antigen DQ (HLA-DQ). These genes are parts of the major histocompatibility complex (MHC) class II antigen–presenting receptor (also called the human leukocyte antigen) system and distinguish cells between self and nonself for the purposes of the immune system. The genes are located on the short arm of the sixth chromosome. In European white populations, >90% of celiacs carry the HLA-DQ2 heterodimer. The DQ8 heterodimer is common in celiacs who do not carry the DQ2 haplotype. Only a small number of celiacs are negative for both DQ2 and DQ8, and many of them have been reported to encode just 1 chain of the DQ2 heterodimer (2). Although CD has never been reported in China, it has been reported in other Asian populations, including various parts of the Indian subcontinent, Arabian countries, and central Asian countries. In addition to the intrinsic genetic diversity of the vast Han population, intermarriage is now common between the Han and other Chinese ethnic groups as well as people of neighboring countries. The long-held assumption that CD is not found in China may be self-perpetuating by deterring clinicians from considering the diagnosis. It is with this notion in mind that we designed the present study to look for the existence of CD in our patients with chronic diarrhea.

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The present study was a multicenter prospective study. It was conducted on patients with chronic diarrhea ages 0 months to 18 years in the children's hospitals of 4 cities (Shanghai, Jinan, Wuhan, and Chengdu) during the period January 2005 to December 2008. The consecutive patients with chronic diarrhea seen at the participant hospitals were eligible for inclusion in the study and supplied informed consent to participate in the study. The present study was approved by a medical ethical committee. Chronic diarrhea was defined as having 3 or more bowel movements per day, without blood or mucus in the stool, for a period of not less than 2 months. There were 199 patients who satisfied this definition, and after excluding those who do not have gluten in their diet (most of them were infants <6 months old), we enrolled a total of 118 patients in our study, 85 boys (72%) and 33 girls (28%).

A thorough clinical history and physical examination were conducted on each patient. Relevant laboratory data were collected. Total IgA, anti-tissue transglutaminase IgA (tTGA), and human anti-endomysial antibody IgA (EMA) were determined in all of the patients. For IgA-deficient subjects, a tTG-IgG antibody test was performed (3), The anti-tTG-IgA was determined using an enzyme-linked immunosorbent assay produced by Biohit Oyj. A value of <15 arbitrary units was considered negative, 15 to 20 arbitrary units was considered weakly positive, >20 arbitrary units was considered positive, and >100 arbitrary units strongly positive. The human EMA enzyme-linked immunosorbent assay kit produced by ADL was used for EMA. A cutoff value of 15 ng/mL was used to define positivity for EMA.

Patients with positive serologic tests for CD (either positive in EMA and tTGA or strongly positive in tTGA) underwent upper gastrointestinal endoscopy, and at least 3 biopsy samples were taken from the second part of the duodenum. The samples were evaluated by an expert pathologist and were graded using modified Marsh classification (grade 0, I, II, IIIa, IIIb, IIIc) (4).

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Diagnosis of CD was based on the guideline published by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition in 2005 and the diagnostic criteria suggested by Catassi et al (5). The diagnosis of CD is confirmed if the following 2 criteria are satisfied: either positive in EMA and tTGA or strongly positive in tTGA, and celiac enteropathy at the small-bowel biopsy (grade I–III or worse).

Growth charts published by the World Health Organization (0–5 years old, 2006 (6) and 5–18 years old, 2007 (7)) were used. The children in the study were divided into 2 groups according to their z scores: those who are at or lower than 2 standard deviations below the mean (z ≤ −2) and those who are between −1 and −2 standard deviations from the mean (−2 < z <−1). Malnutrition was defined as any child with z ≤ −2 for either weight or height. Stunting was defined as z ≤ −2 for the height-for-age chart, underweight if z ≤ −2 for the weight-for-age chart, and wasting if z ≤ −2 for the weight-for-height chart.

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Statistical Analysis

Discrete variables are expressed as numbers and percentages, quantitative variables of normal distribution are expressed as means ± standard deviations, and quantitative variables of skewed distribution were expressed as medians. Data were analyzed by t test and χ 2 test to compare categorical data between children with CD and other children with diarrhea. Differences were considered statistically significant at P < 0.05. SPSS version 11.5 (SPSS Inc, Chicago, IL) was used throughout.

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One hundred eighteen patients with chronic diarrhea and gluten-containing diets were recruited in the study. IgA EMA was positive in 19 patients and tTGA was positive in 27 (including 6 weak positives, 9 positives, and 12 strong positives) patients. Both EMA and tTGA were positive in 10 patients. Using the definition of positive serology outlined above, 18 patients underwent upper gastrointestinal endoscopy for further investigation.

Duodenal biopsies were consistent with CD in 14 patients (14/118, or 11.9%). Stratifying by Marshall classification, no villous atrophy was found in 2 (grade 0 in Marshall classification), grade I changes in 1, grade II changes in 2, IIIa in 7, IIIb in 3, and IIIc in 1. Other diseases identified were intestinal lymphangiectasia in 1 patient and eosinophilic duodenitis in 1 patient.

Among the 14 patients with CD, there were 12 boys and 2 girls. Ages ranged from 6 months to 12 years (Table 1). All of the children had been introduced to gluten-containing food before diarrhea. The younger children took gluten panda as part of their complementary foods from 4 to 6 months old. Six patients (42.8%) had malnutrition, including stunting, in 3 (22.2%), underweight in 4, and wasting in 4 (28.6%). The average hemoglobin of the 14 children was 113.8 ± 13.1 g/L; 4 (28.6%) had anemia. All of the patients had a low prealbumin value, with an average of 172.5 ± 23.2 mg/L. The percentage of malnutrition is higher in children with CD than in the other children with diarrhea. There was no difference in sex distribution between the 2 groups (Table 2). Five children felt uncomfortable after taking gluten-containing food: 2 had simple diarrhea, 1 developed rash, and 2 had abdominal pain or abdominal distention. Ten patients (71.4%) had symptoms that included abdominal pain (4 patients), vomiting (3 patients), abdominal distension (2 patients), mouth ulcers (1 patient), edema (1 patient), rash (1 patient), and fever (1 patient). One had family history of diarrhea (brother died of refractory diarrhea).





All 14 patients with CD were prescribed a gluten-free diet (GFD) and provided supplements of trace elements and energy supplementation when needed. All of them demonstrated clinical improvement, and the diarrhea diminished after 1 month. Diarrhea returned in 6 patients when they failed to adhere to a GFD. One of them returned to a GFD and was retested for EMA and tTGA 6 months later; both tests were negative. Diarrhea recurred after the gluten-containing diet was reintroduced.

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In the present study, 14 patients (11.9%) were diagnosed as having CD. In southern India, Kuwait, and Iran, in children with chronic diarrhea, the incidence of CD was, respectively, >40%, 18.5%, and 8.69% (8–10). In our study, boys were more likely than girls to have CD, which contradicts other reports (11–13). This is difficult to interpret given the high percentage of boys in the initial cohort (68%). Serologic testing is the mainstay of clinical screening for CD. The main tests used include EMA, anti-gliadin antibodies, and tTGA (14). EMA and tTGA tests are of high sensitivity and specificity, although it has been reported that their accuracy in the clinical setting may not be as good as those reported in research studies (15–18).

The advent of serologic tests of reasonably high sensitivity and specificity is helpful in the diagnosis of CD but cannot replace the intestinal biopsy, which is still believed to be the criterion standard in diagnosis. The understanding of the histopathology of CD has changed over the years. Marsh and Crowe (19,20) put forward the proposal that the small-bowel mucosal lesion of CD is an evolutionary process, which may be present in various histologic forms. In developing countries, especially in countries in which CD is rarely seen, it is not routinely considered a likely diagnosis in children presenting with chronic diarrhea and mild-to-moderate proximal small intestinal mucosal lesions. More likely, it is assumed that such a lesion may be caused by tropical sprue, persistent enteric infection or infestation, postinfection complications, or protein energy malnutrition with associated small-bowel bacterial overgrowth (21,22).

In the present study, although we can diagnose 14 cases of CD in our cohort of children with chronic diarrhea, we had 2 patients with positive serology but no mucosal lesions. They could have latent CD and still may ultimately need GFD implementation. Careful follow-up will be required so that a definitive diagnosis can be made. Recently, a study demonstrated that CD-related histologic lesions are always present in the bulb and that sometimes this specific site is the only one affected (23). Because the present study did not take biopsies from these sites, it is possible that some cases may be missed. Whether one should place children without histologic evidence of CD on GFD is controversial. Because treatment of GFD is a lifelong process, follow-up and reevaluating the clinical symptomatology, serologic testing, and repeating the intestinal biopsy could be helpful in establishing a definitive diagnosis at a later time.

Experience in other countries identified that the HLA haplotype HLA-DQ2 and HLA-DQ8 are important in the pathogenesis of CD: 95% of people with CD have genes that include HLA-DQ2 and 5% have genes with HLA-DQ8. Although these 2 haplotypes are common in Western populations, their frequency in the Chinese population is unknown. A review of the Chinese literature shows that the predominant HLA-DQ CD risk alleles and haplotypes are present in China (24). We were unable to perform HLA typing in our patients and this may be a useful future study. The fact that we had a significant group of patients with CD suggests that it may be important to establish the frequency of these haplotypes in a Chinese population. We believe these are the first reported cases of CD in Chinese children. CD has been considered extremely rare in the ethnic Han Chinese population. The present study shows otherwise and demonstrates that CD must be considered in Chinese children with chronic diarrhea. It is interesting that Wu et al (25) reported 6 CD-positive (no biopsy confirmed) adults in Jiangsu, a province next to Shanghai in China. With the help of sensitive and specific serologic tests and general availability of small-bowel biopsies via the endoscope in China, we hope that we shall be able to diagnose CD in Chinese patients with relevant clinical symptomatology.

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We thank the medical and nursing staff of the units for their help, as well as the parents and patients. We are also thankful to Dr Ying Kit Leung and Michael Stephens for help in the preparation of this manuscript.

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celiac disease; children; China; chronic diarrhea; digestive endoscopy

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