World Perspective on Celiac Disease (2012)

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 benefit from a more healthful diet and not need a GFD. The GFD has both social and economic consequences. The diet is not only burdensome with potential quality-of-life implications, but also more expensive and therefore should not be imposed lightly. AFRICA IS ON THE CELIAC MAP In north African countries, many screening studies, using appropriate serological test methods, have supported the high prevalence of CD. For instance, the prevalence of subclinical CD in children was 0.53% in Egypt (n = 1500 children) (26), 0.6 % in Tunisia (n = 6286 schoolchildren), (27) and 1% in Libya (2920 children) (28). It is worth mentioning that one of the few mass screening studies conducted in Africa, including 989 schoolchildren, highlighted that the highest CD prevalence in the world, 5.6%, occurs in the African population of Sahrawis. The high intake of gluten-containing food, the high level of consanguinity, and the high frequency of HLA-2 and -DQ8 haplotypes in this population, genetically close and isolated, could explain this huge prevalence (29). Turning to the burden of typical CD, it varies widely within countries and within populations. For instance, a 4.7% prevalence (7/150 children) was reported in the Egyptian study (25), compared with 22.5% (18/80 children) reported in Sudan (30). The prevalence of CD in high-risk north African population, because of immune disorder diseases, is consistent with literature data. In this case, studies have been performed particularly in T1D. A CD prevalence of 6.4% and 16.4% was reported in Egyptian and Algerian patients with T1D, respectively (26,31). In summary, mass screening CD studies in north Africa found nearly the same prevalence of subclinical CD than in western European population. The true prevalence of symptomatic CD is more difficult to estimate, because of its clinical variability and the many immune disorder diseases associated to CD. This frequency depends on variable clinical symptoms and degree of severity of the disease, and on the accessibility to screening tests in the clinical practice; however, most studies suggested that CD is rare in sub-Saharan Africa. The few reported studies are sporadic case reports or small sample of patients with digestive and malnutrition symptoms, such as chronic diarrhea, poor appetite, weight loss, pallor, and proximal muscle wasting (32). The prevalence of CD has not been ascertained in many African countries. Studies among African immigrant communities in developed countries have shown controversial results. Some studies report that CD may be a rare disorder, or underdiagnosed. For example, in United States, only 9 (1.3%) African American patients with CD were identified among a group of 700 biopsy-proven CD patients from 1981 to 2004 (33). No positive test was identified using mass serological screening test among 860 African Brazilian individuals from 10 African countries (34). CD shows a variable prevalence in Africa, but the poor living condition and the limited availability of diagnostic facilities could result in the lack of awareness and low suspicion of the disease. Therefore, assessing the true prevalence of CD through mass screening test studies in general population of sub-Saharan countries is needed. Moreover, genetic studies to identify risk factors or even specific genetic protective factors should be beneficial for young children in term of prevention. Overall, improving the management of CD in Africa is still challenging; it needs an appropriate CD IEC (information, education, communication) strategy to increase the clinical awareness of all doctors, and to implement diagnoses guidelines tests, enabling the treatment of all of the celiac patients in at-risk groups. Because of limited economic resources, an easy, efficient, and affordable diagnostic approach and methods should be developed for Africa. Additionally, CD treatment is based on GFD. This diet is mostly based on local food in African countries. Consequently, research is needed for the assessment of the risk of macro- or micronutrients deficiencies, for a nutritional support in patients with CD, and for the transfer of technology and knowledge for the manufacturing of affordable gluten-free product. REFEEDING SYNDROME IS A COMPLICATION OF PEDIATRIC CD IN INDIA CD is being increasingly recognized in India both in children and in adults. During the last 3 years, research thrust has been mostly focused on prevalence, identification of nondiarrheal variety, family studies, dietary compliance, and recognition of refeeding syndrome. In a large community-based cross-sectional study in Northern India, an overall prevalence of CD was found to be 1.04%. Prevalence of 0.56% has been found among healthy blood donor from Chandigarh, India (35). In 189 children with T1D, 11% had concomitant CD, 90.5% of whom were asymptomatic and diagnosed only on screening (36). In children suffering from Down syndrome, 6% prevalence of CD was shown, with statistical in those with In children with from north India, were found to have CD. gastrointestinal endoscopy in patients with chronic disease changes in which was confirmed as CD by positive and abnormal In with primary and in with of IgA tTG was and of previous and were higher in compared with was found in of children with CD screened in a pediatric The prevalence of CD among first-degree family of children with CD was A of cases of CD and all first-degree were positive for of the first-degree were negative for In 1 report CD was shown to be associated with without of and These after 6 weeks of GFD. the youngest patient reported so had an of on GFD was in 3 patients to patients with CD are at risk for developing refeeding syndrome, which may celiac in developing countries. In an observation from north India, of patients with CD were mass and were identified as refeeding syndrome. celiac but with introduction of GFD. were by of and feeding without the need for In another randomized of of weeks with GFD was shown to however, at the same time was shown to the that should be after a course of and have a good with CD and can be used as reliable markers for from GFD. to GFD was in cases in north India, more common among children living in and those with more number of have effect on social and are in the dietary group The of has CD as a thrust with emphasis upon finding prevalence and NEW The GFD is a safe and effective treatment for CD; however, this diet is often difficult to to small of gluten contamination in food and the social burden imposed by the GFD. In a of patients with so-called the disease not to treatment with a GFD. Therefore, in the last researchers have become increasingly in therapeutic alternatives for or use of a GFD in patients with CD developed treatment for CD are based on presently available the of the disease. These therapies on gluten-free of gliadin peptides that intestinal by in intestinal by of the of intestinal by transglutaminase of gluten presentation or of and of tolerance to gluten (24). The history of a possible CD will be described In in CD. Around of western and and of patients with CD the 2 that it is one of a family of on that the specificity of immune by peptides to on the role for DQ8 and present in patients negative for also a role for in the of CD. In laboratory confirmed the of intestinal in and showed almost all are by the gluten peptides recognized by in CD now and important because food tests, more and even preventing immune recognition or tolerance to gluten may be For and to identify peptides mostly focused on the first gluten even though of gluten and and proteins are by wheat, barley, and was reported to be an and shown to cause villous when the of patients These could not be and subsequent studies this has when with patient biopsies and The the role of highlighted in the relevance of in A highly sensitive of from patients was but if the only of was intestinal A to gluten peptides was that and -DQ8 peptides in and and yet gluten in have few This was in by and finding that from intestinal biopsies to gliadin and gluten peptides including to by tissue transglutaminase an in intestinal mucosa and also a for in CD for gluten in blood had been because of reports by the laboratory and others that and gliadin using blood do not the specificity of intestinal however, in reported that wheat in patients following GFD specific for gliadin at without in When screened with peptides with blood are focused on the same 2 after in antigen an of and introduced by in antigen presentation and long-term of including from wheat and and rye with blood from after wheat, barley, or rye reported in 2010 that specific for 3 peptides for most in patients. How could this new knowledge be used to benefit The first of to exposure of the immune to gluten are increasingly as potential to GFD. understanding of the specificity of a therapeutic is now under development with the of immune tolerance to gluten and an diet. of upon clinical development of for and of concept studies in an of is by some of tissue from the can be can be in and exposure to the antigen through gluten or dietary to be safe and Although much will be of development of to not benefit patients with CD, but could also as a for and development of therapeutic for other autoimmune diseases. In summary, treatment of CD is presently under by basic research and clinical The way to for is still and of The GFD is still the only CD treatment of the social is effective and any (24). CD is not only a common clinical problem but it is also worldwide research as before from those in a of including clinical epidemiology, and food Further studies are needed to the incidence of CD in apparently areas, as sub-Saharan Africa and the far In many developing countries, the frequency of CD is to increase in the given the to a dietary Because most cases presently diagnosis all over the world, an should be made to increase the awareness of CD clinical A could significantly the and associated with disease. The new guidelines will the diagnostic process. Although for CD are presently under the GFD remains the effective and safe treatment for patients affected with this