See “Celiac Disease in Children With Diarrhea in 4 Cities in China” by Wang et al on page 368.
There are plenty of data showing that celiac disease (CD), or genetic gluten intolerance, is a common disorder in many areas of the world, for example, Europe, North America, north Africa, and the Middle East, affecting 1% of the general population on average (1). CD epidemiology in the Asian continent is largely unknown, however. With >1.3 billion people, China is the most populous nation and the second largest by land area in the world. Despite the size of China, evidence indicating the existence of CD in this population has been poor.
In a series of 14 patients of Asian descent with biopsy-defined CD seen during the period 1982–2002, Freeman (2) found only 1 Chinese case, a 69-year-old woman who had been living in Canada for 20 years. In 2009, Jiang et al (3) reported on 4 of 62 adult Chinese patients with chronic diarrhea living in the Zhejiang province (southern China) who were eventually diagnosed as having CD, based on the histological pattern at the small intestinal biopsy (villous atrophy) and the clinical response to treatment with the gluten-free diet (GFD). Specific serological CD markers, such as the IgA-class anti-transglutaminase (TTG) and anti-endomysial antibodies (EMA), however, were not investigated in these patients (3). Recently, Wu et al (4) performed the anti-gliadin (AGA) and the anti-TTG tests in 78 Han Chinese adults at risk of CD (5 with type 1 diabetes and 73 with irritable bowel–like symptoms). They found positivity for immunoglobulin G (IgG)-AGA in 6 and borderline positivity for IgA-TTG in 2 of 78 Han Chinese adults, respectively. Diagnosis of CD was not confirmed by small intestinal biopsy and none of these cases showed a typical CD serology pattern (eg, high level of serum IgA anti-TTG) (4).
In this issue of JPGN, Wang et al (5) describe the first series of CD cases in Chinese children, with diagnosis confirmation based on clinical, serological, and histological evidences. During the period January 2005 to December 2008, 118 patients with chronic diarrhea admitted in pediatric hospitals from 4 major cities (Shanghai, Wuhan, Jinan, and Chengdu) in China were included in the study. All of these children underwent anti-TTG and EMA determination, and small intestinal biopsy was performed in patients with antibody positivity. Interestingly, EMA antibodies were determined by an enzyme-linked immunosorbent assay method rarely used in the literature that had been reported to show good agreement (98%) with the conventional immunofluorescence assay (6). Serology and duodenal biopsy results were consistent with CD diagnosis in 14 patients, 12 boys and 2 girls (11.9%), ages 6 months to 12 years. Six patients (42.8%) had malnutrition with features of stunting in 3 (22.2%) and wasting in 4 (28.6%). All 14 patients were prescribed a GFD and demonstrated reduction of diarrhea within the first month of treatment. Diarrhea returned in 6 patients when they failed to adhere to a GFD (5).
In our opinion, doubts about the diagnosis of CD can be raised for some of the patients described in the article by Wang et al First, 3 of 14 patients were diagnosed at age 6 months, which is unusual for CD, even in infants introduced to gluten-containing food early in life. We wonder whether other disorders that could mimic CD, such as cow's-milk protein allergy or postenteritis syndrome, were definitely excluded in these 3 infants with early-onset chronic diarrhea and enteropathy. Second, CD is notoriously more common in girls than in boys. The higher prevalence of CD among boys in this series of children with CD (12/14) is an unexpected finding, although it could be explained by sex unbalance in the studied sample (68% boys) and small sample size. Third, TTG is the major autoantigen responsible for EMA positivity in subjects with CD (7). For this reason, anti-TTG and EMA antibodies usually give parallel results, particularly when the TTG antibody titer is high. It looks, therefore, strange that 5 of 14 patients had a high titer of anti-TTG antibodies but a normal EMA level, a finding raising concerns about possible analytical problems.
Keeping the above limitations in mind, the present study is important because it describes the first cases of CD in Chinese children with chronic diarrhea and malnutrition, a result assuming greater significance because of the multicenter design of the survey. Is this a surprising finding? Not at all.
The most important determinants of CD prevalence in any population are the frequency of major histocompatibility complex class II alleles that encode for human leukocyte antigen (HLA)-DQ and exposure to dietary products that contain gluten. The contribution of HLA type to the genetic risk for CD has been estimated at 30% to 50%. Approximately 90% of patients are found to be positive for HLA-DQ2, whereas most of the remainder have HLA-DQ8. The distribution of HLA-DQ2 in the general population is therefore a marker of population predisposition to CD. With genetic testing, DQ2 is almost synonymous with DQB1*02. The frequency of DQ2 in white populations in western Europe has been estimated at 20% to 30% and relatively high frequencies also occur in northern and western Africa, the Middle East, and central Asia (8,9). DQ2 is somewhat less common in China (10%–20%) than in Europe, but it is frequently found in the general population, particularly in northern provinces (10). The other factor of the celiac equation, that is, gluten, is also well rooted in Chinese history and territory, particularly in the northern part of the country. Noodles are currently one of the most common gluten-rich foods eaten in the world. Interestingly, the oldest noodles discovered were found in Qinghai, China, during excavation at a Neolithic site along the Yellow River; however, those 4000-year-old noodles were likely to be harmless for CD-predisposed individuals, being made with gluten-free ingredients (foxtail millet and broomcorn millet). In northern China, wheat became a significant crop between 1600 BC and 1300 BC. Since the North Song dynasty (960 AD–127 AD), wheat also was introduced in southern parts of China. Presently, wheat is the second leading cereal in China (after rice) in terms of both harvested area and production. According to the 2007 Food and Agriculture Organization/World Health Organization data, the mean wheat supply in China is 67 kg per capita per year compared with 108 kg per capita per year in Europe (11). Chinese people consume various kinds of wheat products, for example, noodles, steamed bread, and dumplings. The Chinese have a long history of consuming “mianjin” or “kaofu,” which are basically gluten products. More than 90% of wheat grain is used to make steamed bread and noodles (3). Given the presence of both the genetic background and the environmental trigger, CD can be expected to be a common disorder in China.
The identikit of the celiac child is changing over time. In the classic textbook published in 1975, Paediatric Gastroenterology, the typical celiac patient was described as “usually fair-haired, blue-eyed” (12). Subsequent developments in CD epidemiology proved that this description was incorrect. As a matter of fact, the world's highest rate of CD has been discovered in the Saharawi, a black-eyed, black-haired African population (13), and CD has been found to be common in countries populated by nonwhite people, such as in India (14). The Wang et al article puts a missing brick in the wall of celiac epidemiology, showing that CD is on the map in China, too. With the more widespread diffusion of Western dietary habits and an increasing consumption of gluten-containing cereals, CD could be on the rise in the Eastern world. Further studies are therefore required to quantify the effect of CD on children's health in China and in other Eastern countries.
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