To the Editor: Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of dietary gluten, resulting in inflammation and villous atrophy of the small intestine in genetically predisposed individuals. It frequently manifests with gastrointestinal symptoms in children and is strongly associated with the human leukocyte antigen (HLA)-DQ2 and HLA-DQ8 genetic markers. Historically perceived as predominantly affecting Caucasian populations, CD is now acknowledged as a global disorder with increasing incidence rates, a trend attributed in part to heightened public awareness and advanced diagnostic methodologies. Recent research in China suggests a higher prevalence of CD than previously estimated, however, comprehensive nationwide studies are lacking, and findings remain inconsistent across different regions. The aim of this study is to evaluate the prevalence and characteristics of CD in Chinese children who present with unexplained gastrointestinal symptoms across multiple provinces. This prospective multicenter study, conducted from January 1, 2018 to December 31, 2020, included 11 tertiary medical centers specializing in pediatric gastroenterology across 10 regions. Children with unexplained chronic gastrointestinal symptoms were enrolled according to predefined inclusion and exclusion criteria Supplementary Material, https://links.lww.com/CM9/C839. The attending physicians collected data using standardized questionnaires. Ethical approval for this study was granted by the Ethical Committees of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (Approval No. 2013-47). Informed consent was obtained from all the subjects and their legal guardians. The participants underwent serological testing for endomysial antibodies (EMAs), tissue transglutaminase (TTG) and deaminated gliadin peptide (DGP) antibodies. CD-associated haplotypes (HLA-DQ2 and HLA-DQ8) were identified using genomic DNA extracted from peripheral blood leukocytes. Participants who screened positive for any of the serological biomarkers indicative of CD were recommended to undergo a small intestinal biopsy. CD was diagnosed on the basis of a combination of serological and histological criteria in accordance with the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) diagnostic guidelines for CD.1,2 A total of 400 children were screened, with 321 cases ultimately included in the study Supplementary Figure 1, https://links.lww.com/CM9/C839. The cohort included 197 males (61.4%) and 124 females (38.6%), with a median age of 6.1 years (interquartile range: 6.7 years). Most (96.3%, 309/321) participants were of Han Chinese ethnicity, and the remaining 3.7% (12 individuals) were from various ethnic minorities. All participants presented with gastrointestinal symptoms: diarrhea in 145 cases (45.2%), abdominal pain in 80 cases (24.9%), abdominal distension in 63 cases (19.6%), and recurrent nausea/vomiting in 33 cases (10.3%); 17.1% demonstrated growth retardation (height standard deviation score SDS Z score ≤–2). Geographically, 75 participants (23.4%) were from northern China, whereas 246 participants (76.6%) were from southern China; these two regions are separated by the Qinling Mountains-Huaihe River Line. Among the total cohort, 22 participants (6.9%) were positive for at least one CD-specific antibody, with positivity rates of 2.8% (9/321) for TTG, 2.2% (7/321) for EMA, and 5.6% (18/321) for DGP. The interrelationships among the positive results for the TTG, DGP, and EMA are illustrated in a Venn diagram Supplementary Figure 2A, https://links.lww.com/CM9/C839. Correlation analysis revealed a significant association between the presence of CD-specific antibodies and both growth retardation (P = 0.013) and ethnicity (P = 0.041). By contrast, no statistically significant differences were identified with respect to sex, age, or symptoms such as diarrhea, abdominal pain, vomiting, or abdominal distension. Among the 22 individuals with positive antibody tests, three individuals opted not to undergo biopsies. Among the 19 patients who underwent biopsy, four received a histopathological confirmation of CD. The correlations between positive results for the DGP, TTG, and EMA among the 19 participants are displayed in a Venn diagram Supplementary Figure 2B, https://links.lww.com/CM9/C839. A nonbiopsied participant who was positive for the TTG, DGP, and EMA and carried the HLA-DQ2.5 gene was diagnosed with CD according to the serological diagnostic criteria in the 2020 ESPGHAN guidelines.2 The diagnostic performance of the EMA, TTG, and DGP for CD screening was assessed using receiver operating characteristic (ROC) curves and precision–recall curves Supplementary Figure 2C and D, https://links.lww.com/CM9/C839. The study reported a CD prevalence of 1.6% (5/321) among Chinese children presenting with unexplained gastrointestinal symptoms, including a biopsy-confirmed CD prevalence of 1.2% (4/321). The five children diagnosed with CD had a median age of 5.9 years (interquartile range: 9.8 years), with a female preponderance of 60% (3/5). We compared the CD group with the seropositive group (without CD confirmation) and the antibody-negative group, focusing on demographic characteristics and clinical manifestations Table 1. Children with CD demonstrated significant weight loss and growth retardation, with a height Z score of –2.6 and a weight Z score of –2.0, both of which were markedly lower than those of the other two groups. The height Z score of the CD group was significantly lower than that of both the seropositive (P = 0.048) and antibody-negative groups (P = 0.031). Z scores for both height and weight Z scores ≤–2 of the CD group were significantly different from those of the antibody-negative group (P = 0.037 and P = 0.003, respectively), and the height Z score ≤–2 was significantly different from that of the seropositive group (P = 0.039). Table 1 - Comparison of demographic and clinical characteristics among the CD group, seropositive group without CD confirmation, and antibody-negative participants. Parameter Antibody-positive (n = 22) Statistics value (Z value) P value Antibody-negative (n = 299) Statistics value (Z value)* P value* CD (n = 5%) Not CD (n = 17) Age (years) 5.9 (9.8) 8.1 (5.3) –0.588 0.595 6.0 (6.6) –0.041 0.967 Weigh SDS –2.0 (2.0) –0.5 (2.2) –1.841 0.071 –0.8 (1.8) –1.752 0.080 ≤–2 3 (60.0) 3 (17.6) – 0.100 49 (16.4) – 0.037 Height SDS –2.6 (3.1) –0.4 (2.1) –1.998 0.048 –0.6 (1.8) –2.157 0.031 ≤–2 4 (80.0) 4 (23.5) – 0.039 47 (15.7) – 0.003 Gender – 0.624 – 0.377 Male 2 (40.0) 7 (41.2) 185 (61.9) Female 3 (60.0) 10 (58.8) 114 (38.1) Ethnic group – 0.006 – <0.001 Han 2 (40.0) 17 (100.0) 290 (97.0) Non-Han 3 (60.0) 0 (0) 9 (3.0) Region – 0.039 – 0.011 North 4 (80.0) 4 (23.5) 67 (22.4) South 1 (20.0) 13 (76.5) 232 (77.6) Gastrointestinal symptoms Diarrhea 4 (80.0) 7 (41.2) – 0.311 134 (44.8) – 0.180 Abdominal pain 0 (0) 5 (29.4) – 0.290 75 (25.1) – 0.338 Distended abdomen 1 (20.0) 3 (17.6) – 1.000 59 (19.7) – 1.000 Recurrent nausea/vomiting 0 (0) 2 (11.8) – 1.000 31 (10.4) – 1.000 HLA-DQ genotypes HLA-DQ 2.5/8/2.2 positive 5 (100) 12 (70.6) – 0.290 90 (30.1) – 0.003 HLA-DQ 2.5 positive 3 (60.0) 5 (29.4) – 0.309 40 (13.4) – 0.022 HLA-DQ 8 positive 1 (20.0) 6 (35.3) – 1.000 26 (8.7) – 0.371 HLA-DQ 2.2 positive 1 (20.0) 1 (5.9) – 0.411 24 (8.0) – 0.351 Data are presented as the n (%) or median (interquartile range). Nonnormally distributed variables were analyzed using the Mann–Whitney U test. Categorical variables were analyzed using Fisher’s exact test. Statistics: Z value for the Mann–Whitney U test; “–” indicates that no test statistic is applicable for Fisher’s exact test, as the P value is calculated directly via exact probability. P value for the comparison between the CD and non-CD groups; *Statistics value and P value for the comparison between the CD and antibody-negative groups. CD: Celiac disease; SDS: Standard deviation score, which was the score based on age and sex. Four of the five CD cases (4/5) originated from northern China, primarily Xinjiang. The prevalence of CD was higher in the northern region than in the southern region (5.3% 4/75 vs. 0.4% 1/246, P = 0.011). Regarding ethnic distribution, the proportion of ethnic minorities in the CD group (60.0% 3/5, two Kazakh and one Uyghur) was significantly higher than that in the seropositive (non-CD) group (0% 0/17, P = 0.006) and the antibody-negative group (3.0% 9/299, P <0.001). The incidence of CD among ethnic minorities was as high as 25.0% (3/12), which is much greater than the occurrence (0.6%, 2/309) among Han participants. Notable statistical disparities were observed among the ethnic groups (P <0.001). In this study, 33.3% (107/321) of Chinese children with unexplained gastrointestinal symptoms carried HLA-DQ2/8 genotypes, with HLA-DQ2.5, HLA-DQ8, and HLA-DQ2.2 representing 44.9% (48/107), 30.9% (33/107), and 24.3% (26/107) of the cases, respectively. The proportion of HLA-DQ2/8 genotypes among children with CD was significantly greater than that in the antibody-negative groups (100.0% 5/5 vs. 30.1% 90/299, P = 0.003), with a particularly pronounced difference for HLA-DQ2.5 (60.0% 3/5 vs. 13.4% 40/299, P = 0.022). No statistically significant differences were observed for HLA-DQ8 or HLA-DQ2.2 between the CD and seropositive groups. This study revealed that the prevalence of CD in children with gastrointestinal symptoms in China is significantly lower than that in European children.3 Notably, both this study and prior regional research in China have demonstrated a higher CD prevalence in northern regions than in southern regions.4,5 Apart from the dietary intake of gluten, the results of this study also imply that this disparity is associated with the frequency of susceptible genotypes and racial dissimilarities. The observed frequency of CD susceptibility genotypes in our study aligns with those reported in European populations and is markedly higher than previous estimates for the Chinese population. Particularly in the northwestern region of China and among its ethnic minorities, the frequency of CD susceptibility genotypes is significantly greater. This study also evaluated the efficacy of various antibody combinations for the screening of CD. We determined that the concurrent detection of EMA and TTG antibodies was highly effective. However, the inclusion of DGP led to an increased rate of false-positive results. Given the low prevalence of CD in China, performing simultaneous testing for the EMA, TTG, and total immunoglobulin A (IgA) during the initial diagnostic workup is recommended. This strategy improves the precision of the screening process and reduces the necessity for repeated blood sampling in pediatric populations. To summarize, in our multicenter study, a comprehensive screening of Chinese children who presented with suspected unexplained gastrointestinal symptoms revealed a prevalence of CD of 1.6%. This research further highlights disparities in CD prevalence across different geographical regions and among various ethnic groups within China. Considering the low incidence of CD in China, this study advocates the incorporation of TTG and EMA assays as primary screening methods for pediatric patients suspected of having CD. Acknowledgments The authors thank all the human participants who volunteered to participate in the study and the medical professionals who actively participated in the research at each research center. Funding This work was supported by grants from the National Natural Science Foundation of China (Nos. 81400588 and 81741103). Conflicts of interest None.
Xu et al. (Tue,) studied this question.