World Perspective on Celiac Disease

Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in genetically susceptible individuals. The gliadin and glutenin fractions of wheat gluten and similar alcohol-soluble proteins in other grains (rye and barley) are the primary environmental factors responsible for the development of the intestinal damage. The genetic predisposition is related to human leukocyte antigen (HLA) class II genes: most of the patients with CD are HLA-DQ2–positive, and the remaining patients are mostly HLA-DQ8–positive. The typical intestinal damage is characterized by loss of absorptive villi and hyperplasia of the crypts, and it completely resolves upon elimination of gluten-containing grains from the patient's diet (1,2). Improvement of symptoms following the gluten-free diet (GFD) is not pathognomonic of CD. Nonceliac gluten sensitivity is a recently described clinical entity that will not be covered in this article, particularly because of uncertainty on its clinical presentation and frequency in the pediatric age group (3). In the past, CD was considered a rare disorder, mostly affecting individuals of European origin, and usually characterized by onset during the first years of life. At that time, diagnosis was entirely based on the detection of typical gastrointestinal symptoms and confirmation by the small intestinal biopsy. The availability of highly sensitive and specific serological tools, first the anti-gliadin and later the anti-endomysium and the anti-transglutaminase (tTG) antibodies, clearly showed that (1) the prevalence of CD is much higher than previously thought because of the high percentage of clinically atypical or even silent forms of CD; (2) CD shows a worldwide distribution and is common in many developing areas, given the widespread distribution of gluten consumption and genetic HLA-related predisposition. Recent understanding of the pathophysiology of this autoimmune disorder paved the way to new therapeutic and preventive strategies, which are presently under scrutiny. The course of the recent progress in CD basic and clinical research is huge. Its pace has accelerated in the last 15 years, even when compared with other research on gastrointestinal disease, for example, inflammatory bowel disorders. The global nature of CD research is reflected in the wide geographic distribution of CD research productions. Noteworthy, the Journal of Pediatric Gastroenterology and Nutrition was the number 1 highest-publishing CD research journal during the time period of 1995–2009 by a number of PubMed publications (4). In this article, we review the recent advances on CD epidemiology, diagnosis, and treatment, with a special emphasis on the different geographical scenarios. WHAT'S NEW IN EUROPE: FOCUS ON DIAGNOSIS AND PREVENTION STRATEGIES Two important issues have absorbed European clinicians and researchers on CD during the last decade: The increasing incidence of CD with major differences between countries and possible environmental risk factors with the opportunity for intervention How to diagnose CD with a high degree of certainty but the with least burden to the patient The availability of highly sensitive and specific antibody tests allowed screening persons at increased risk and from the general population in different European countries, disclosing that ∼1% of the population is affected by CD (5,6). Clinically overt CD represents only the tip of the iceberg and most celiac cases in Europe have not been discovered so far; however, there was another interesting finding connected to studies on celiac epidemiology: apparently prevalence rates differ significantly between European countries, although the applied diagnostic tools had been identical (6). In Finland, the prevalence of CD was as high as 2.4%, whereas in Italy 0.7% and in Germany as few as 0.3% of the population of comparable age had CD. One of the highest prevalence of CD (∼3%) in Europe was reported in Swedish children born during the so-called epidemic of CD in the early 1990s (7). This prevalence is almost 6 times higher than the 0.53% reported in unselected Swedish adults screened in 1994 (8). What are the causes for the huge differences in prevalence between countries and for the increasing incidence found during the last decades in the same populations? Genetic differences between European populations appear to be an unlikely cause for the extent of the difference because HLA types at risk for CD are similarly distributed in the different countries. Likewise, genetic factors do not explain the rising incidence during the last decades, which goes in parallel with the epidemiology of other autoimmune or immune-mediated diseases, such as type 1 diabetes mellitus (T1D) (9). Therefore, environmental or lifestyle factors may be responsible for the differences between European countries and changes over time. The Swedish epidemic of CD allowed investigating the role of early feeding habits such as the continuation of breast-feeding at the time of gluten introduction, the age at first feeding of gluten, and the amount of gluten given at the time of weaning. Several cohort studies confirmed the relevance of early feeding practices on the manifestation of CD in children at risk for CD (10). It has been estimated that 50% of celiac cases could be prevented when gluten is introduced in small amounts while the mother is still breast-feeding. Too early (within the first 3 months of life) or too late (after 6–7 months of life) introduction of gluten seems to increase the risk. This knowledge gained from retrospective or prospective observational cohort studies formed the basis of a large randomized controlled trial funded by the European Union within the 6th framework program (www.preventceliacdisease.com). Around 1000 infants with at least 1 first-degree family member with CD and positive HLA type DQ2 and/or DQ8 are randomized to receive either 100-mg gluten or placebo during the 5th and 6th month of life. Thereafter, all of the children gradually increase their gluten intake. The study will not be unblinded until 2013 when the youngest child will turn 3 years. Another prospective study is presently ongoing in Italy to investigate the relation between the age at gluten introduction and risk of CD development in infants at family risk of CD (11). The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort, including >6000 children in Europe and United States, is one of the studies aimed to identify potential risk or protective factors for the development of CD and T1D (12). Since the previous guidelines for the diagnosis of CD of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition had been published in 1990 (13), the understanding of disease pathology has substantially increased. So far the histological examination of biopsies had the highest effect on final diagnosis, but the unambiguousness of duodenal biopsies had been questioned because lesions may be patchy or sometimes only occur in the duodenal bulb and histological findings are not always CD-specific. In addition, interpretation depends not only on orientation of the tissue but is also prone to high interobserver variability. New diagnostic guidelines had been developed and were presented to the scientific community at the annual European Society of Pediatric Gastroenterology, Hepatology and Nutrition meeting in Istanbul in 2010 and published recently (14). A systematic review on the performance of CD-specific serological tests showed that endoscopy may be omitted in a subgroup of children with symptoms of malabsorption with high titers for tissue transglutaminase IgA antibodies (>10 times cutoff values) (15). No such data are available for asymptomatic or oligosymptomatic children with high risk for CD (first-degree relative with CD or history of other CD-associated disorders). A large multicenter trial, the ProCeDE study (Prospective Celiac Disease Diagnostic Evaluation), is under way to provide prospective data to assure that the suggested diagnostic procedure is valid also in clinical practice with specificity >99%. LESSONS FROM EPIDEMIOLOGY: THE NATURAL HISTORY OF GLUTEN SENSITIZATION IS VARIABLE The natural history of CD shows a wide variation among patients. When CD is diagnosed in adulthood, it is often impossible to establish whether the patient has a long-standing or newly developed disease. There is usually a sequential development of appearance of CD antibodies, intestinal enteropathy, onset of symptoms, and (sometimes) complications; however, the duration of each step ranges from a few weeks to decades. It was previously thought that loss of gluten tolerance leading to immunological and mucosal changes typical of CD usually developed early in life, soon after exposure to the environmental trigger (ie, at weaning), while the onset of clinical manifestations of the disease occurred much later. This concept has recently been challenged by long-term studies showing that seroconversion to CD autoimmunity may occur at any time (16). This observation suggests that genetic susceptibility and ingestion of gluten-containing grains are necessary but not sufficient conditions to lose tolerance to gluten and develop CD. Identifying both the mechanism responsible for gluten tolerance and how this tolerance is lost in subjects genetically susceptible to CD can pose the basis for breakthrough discoveries for preventing other autoimmune diseases. The progression of gluten sensitization is not necessarily a 1-way process. Maintenance of a normal villous architecture has been described in a few adults spontaneously abandoning treatment of childhood-diagnosed CD (17); however, fluctuation from serum CD autoimmunity positivity to normal values is not rare in at-risk subjects, for example, children with T1D (18). Potential CD, characterized by a serum celiac-type antibody response associated with a normal or minimally abnormal intestinal mucosa at the biopsy, is more common than previously appreciated in children with a family history of CD and positivity of serologic CD markers. During a 2-year follow-up serum, CD markers disappeared in most young children with potential CD despite a regular diet. These “fluctuating” or “latent” cases require periodical reassessment because a proportion of them develop overt intestinal damage over time (11). THE AMERICAN POINT OF VIEW Recognition of CD in North America (NA) has increased markedly in the last decade. Physicians are now more aware of the condition and appreciate that it occurs in approximately 1% of the population (19). The increased awareness is partly because of a national CD education campaign conducted by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Foundation based on evidenced-based guidelines for diagnosis and treatment of CD in children developed by NASPGHAN (20). Children with CD in NA are usually identified on the basis of symptoms. These are variable and include both gastrointestinal and nongastrointestinal manifestations. Young children present predominantly with typical gastrointestinal symptoms, whereas less typical and nongastrointestinal symptoms occur more often in older children and adolescents. Asymptomatic children at increased risk for CD because of an associated condition may be identified by means of serological screening tests. In NA it is recommended the tTG be used to test for CD. Because tTG may be less reliable in young children, it should be combined with either anti-gliadin or antideamidated gliadin peptides when testing those younger than 2 years (20). It is recommended that all of the children with typical gastrointestinal symptoms be tested for CD. Those with nontypical or nongastrointestinal manifestations should be tested if no other cause for the symptoms is found. The need to test asymptomatic children at increased risk for CD is under debate. NASPGHAN recommends testing all such cases even though no good studies have demonstrated benefits of treating asymptomatic cases. In contrast, the American Gastroenterology Association recommends only testing those at increased risk if they have a symptom associated with CD (21). In NA it is recommended that CD be confirmed by means of an intestinal biopsy before starting treatment (20,21). Biopsies should be taken from both the duodenal bulb and more distally to increase diagnostic accuracy (22). Characteristic histological changes, symptom resolution on a GFD, and subsequent negative serological tests over time confirm the diagnosis beyond doubt (20). Nonbiopsy diagnosis of CD remains a goal and may be possible in certain cases (14); however, most physicians in NA are unwilling to diagnose CD with serological tests alone because there is no laboratory standardization of commercial tests for CD in NA and marked variability in test results between laboratories has been documented (21–23). Recommended treatment for CD in NA is lifelong adherence to a diet that excludes all wheat, barley, and rye referred to as a GFD (20). Oats appear safe but are not generally recommended because of frequent contamination with wheat. Because the diet is burdensome, a number of novel therapies are under investigation as possible alternatives (24). To date, none has yet proven to be as effective and safe as the GFD. In NA children at risk for CD still face a number of challenges. Despite progress made in raising awareness of the condition, there are still many who remain undiagnosed or experience prolonged diagnostic delays because of failure to use appropriate serological tests. Further education in this regard is needed. The necessity of screening asymptomatic children who belong to at-risk groups for CD also needs clarification. This speaks directly to the principle of “first, do no harm.” Finally, an emerging problem is the growing number of children who are being placed on a GFD without any testing or before the diagnosis of CD being confirmed. A GFD has become the latest fad in NA fanned by celebrities, sports stars, and others who claim health benefits from the diet. Although some may have the entity of nonceliac gluten sensitivity, (25) others may simply from a more diet and not need a GFD. 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