Triggered by the ingestion of gluten in genetically predisposed individuals, celiac disease is the most common genetically based food intolerance in the world, with a prevalence among approximately 1% of the general population. This enteropathy may appear at any age and is characterized by a wide variety of clinical signs and symptoms that go well beyond the gastrointestinal tract. In young children, gastrointestinal presentations are common and include chronic diarrhea, failure to thrive, and abdominal distention; however, extraintestinal manifestations are becoming increasingly more common. They include numerous conditions such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, recurrent oral aphthae, short stature, osteoporosis, arthritis, neurologic problems, unexplained elevation of transaminase levels, and female infertility. Therefore, diagnosing celiac disease requires a high degree of suspicion, followed by correct screening and a confirmatory test with an intestinal biopsy. After diagnosis, a strict gluten-free diet must be followed, which in most cases will bring a marked improvement of symptoms. However, there are important compliance and quality-of-life problems, especially in adolescents.
Celiac disease (CD) is a permanent sensitivity to gluten, resulting in a disorder of the small intestine associated with the involvement of other organs. It occurs in individuals carrying the HLA class II haplotype DQ2 or DQ8 and is characterized by a variable combination of elevated titers of celiac-specific autoantibodies, an inflammatory enteropathy with various degrees of severity, and a wide range of gastrointestinal and extraintestinal problems.1,2
After the original description in 1888 by Gee,3 Dicke4 identified the central role of gluten in the 1940s. Once the capsule to obtain biopsy specimens from the small intestine became available, the typical changes caused by gluten in the duodenal mucosa of affected individuals were found. During the 1980s, it became clear that CD reached far beyond the intestine and was associated with many nongastrointestinal signs and symptoms such as dermatitis herpetiformis, short stature, osteoporosis, iron deficiency anemia, arthritis, headaches, fatigue, liver function abnormalities, myalgias, adverse pregnancy outcomes, dental enamel defects, and others. A strong association with autoimmune conditions, such as type 1 diabetes mellitus, was observed, and its link with some congenital disorders, such as IgA deficiency, Down syndrome, and others, was discovered.5 Celiac disease can affect any age but adolescents experience the most hardship in dealing with this condition.
The availability and widespread use of specific and sensitive serological markers has resulted in remarkable advances in our understanding of the true prevalence of CD and of its increase. In fact, the prevalence of CD seems to have been increasing at a remarkable pace during the past few decades.6- 11 A heightened awareness, especially in the United States, is responsible for the increased diagnostic rates, but reliable epidemiological data document a true increase in prevalence worldwide, with rates doubling approximately every 20 years.8,12,13 Uncertainty remains about which environmental factors are responsible for such a rapid increase, and it is likely that several are involved, including higher consumption of wheat and early-life infections.14 Taking into account studies from the United States5 and Europe,15 it is estimated that the incidence of CD is 3 to 13 cases per 1000, with a higher prevalence among first-degree relatives of patients with CD. Although the overall prevalence of CD is approximately 1% of the general population, evidence suggests that only about 10% to 15% of this population (including children and adults) have been diagnosed and treated.16 Most of the advances in our understanding of the epidemiological data and population disease distribution have been obtained from serological markers. In fact, serum tissue transglutaminase (tTG) IgA antibody levels have been used worldwide as a powerful screening tool.17
Celiac disease develops in genetically predisposed individuals as a result of the influence of environmental factors. The genetic components needed to develop CD are known in part. The HLA class II haplotypes DQ2 and DQ8 have been found to be necessary predisposing variables, contributing about 40% to the risk of developing CD. In addition to the only necessary factor of gluten ingestion, multiple environmental factors are known to be components. Chief among these are feeding patterns as well as early infections,14 gut microbiota in infants,18,19 and the amount20 and timing21 of the gluten initial exposure.
The HLA class II genes HLA-DQ2 and HLA-DQ8 are the best-characterized and most important genetic susceptibility factors in CD. These molecules are expressed on the surface of antigen-presenting cells in the gut lamina propria and are responsible for contributing gliadin peptides (after their deamidation by the intracellular enzyme tTG) to CD4+ T cells, eliciting a gliadin-specific immune response.22 Gluten is a heterogeneous molecule; the toxic fractions in gluten are a mixture of alcohol-soluble proteins called gliadins, which are rich in glutamine and proline residues that even the healthy human intestine cannot fully digest.23 As a result, intact gliadin peptides are left in the lumen, and some cross the intestinal barrier. These fragments come in contact with tTG, which deamidates them; this process modifies glutamine residues into glutamic acid residues, increasing the negative charges and generating peptides ideally suited to interact with the HLA DQ2 or DQ8 molecules.24 Once bound to DQ2 or DQ8, gliadin peptides are presented to the CD4+ T cells, triggering the inflammatory reaction. Abadie et al25 give a full review of the pathogenesis of CD.
The end result of these pathogenetic processes is an inflammatory state of the small intestine, causing a derangement in the architecture of the mucosa, with flattening of the villi, infiltration of lymphocytes in the epithelium, and increased density and depth of the crypts. These changes occur in a continuum from normal to complete flattening of the villi in a slow progression, as described in 1992 by Marsh26 and now widely used after the modified version introduced by Oberhuber27 in 2000 to grade the intensity of intestinal damage as follows: type 0 preinfiltrative stage (normal), type 1 infiltrative stage (increased intraepithelial lymphocytes), type 2 hyperplastic stage (type 1 plus hyperplastic crypts), and type 3 destructive stage (type 2 plus villous atrophy of progressively more severe degrees, subcategorized as 3a [partial atrophy], 3b [subtotal atrophy], and 3c [total atrophy]).
Celiac disease is characterized by the presence of autoantibodies that are generated as a result of the immunological response to gluten and that are highly specific to this condition. As such, they have also been extensively validated and used for diagnostic and follow-up purposes. The 2 major autoantibodies are anti-tTG IgA and antiendomysium IgA.28 The wide use of such diagnostic tools has revealed that patients with CD may have minor degrees of intestinal damage (type 1 or 2) or may have normal mucosa (type 0), with the latter referred to as potential or latent CD,1 described in greater detail herein.
Recently, a third antibody has been identified, produced against deamidated gliadin peptides (DGPs) and thought to be specific to active CD.29 The sensitivity and specificity of DGPs for CD diagnosis have been studied during the past few years, with the general conclusion that they (especially DGP-IgG) have diagnostic value similar to that of anti-tTG IgA,28 but they may have an advantage in very young children in whom the sensitivity seems to be somewhat superior.30Table 1 compares these 3 serological tests.
Although CD is basically an inflammatory condition of the small intestine and gastrointestinal symptoms are prominent, they may, in many cases, be minor or absent, while the signs and symptoms outside of the intestinal tract can be major. During the past decades, a progressive shift of presentation symptoms from gastrointestinal (still called typical) to extraintestinal (atypical) has been observed in many geographic areas and seems to be a common trend, along with a larger proportion of patients identified as having potential CD and a shift toward older ages at presentation.31- 33 Originally thought to affect only children by causing diarrhea and presenting a malabsorptive picture,34 CD was later proven to affect adults as well,35 and it may occur at any age. Table 2 summarizes the main symptoms of CD presentation in its gastrointestinal and extraintestinal or atypical forms. In children, the prevalence of symptoms seems to change according to the age at presentation,31,36,37 with extraintestinal manifestations becoming more prevalent as age increases.
As mentioned, because CD primarily affects the gastrointestinal tract, the clinical presentation still defined as typical involves gastrointestinal symptoms. The various interplay of symptoms, serological markers, and duodenal pathologic conditions has prompted the CD classifications now in use, which are summarized in Table 3.
Abdominal pain is probably the most common symptom of patients diagnosed as having CD worldwide; in Canadian children, it has been reported in as many as 90%.38 Chronic or intermittent diarrhea is another of the most common symptoms in patients with CD. However, chronic constipation is surprisingly present in a significant number of pediatric and adult patients, among whom a prevalence of 1% to 8% has been reported in a recently published multicenter international study.39 Other presenting symptoms related to the gastrointestinal tract are vomiting, weight loss, abdominal distention, and (particularly in the case of delayed diagnosis) cachexia and severe malnutrition. More rarely, other disorders such as electrolyte disturbances, hypotension, and lethargy can accompany the clinical picture.5 While most young children are seen with gastrointestinal signs and symptoms, these may occur at all ages.
Table 2 summarizes the most common extraintestinal manifestations of CD. Fatigue is common in all forms of symptomatic CD; however, iron deficiency anemia, especially when resistant to oral iron supplementation, is the most common nongastrointestinal sign and is considered the most frequent presentation among teenagers and adults.40- 44
Dental enamel hypoplasia is more common in patients with CD compared with the general population,45 and its prevalence in CD ranges from 10% to 97%.46 It seems to be more prevalent among children compared with adults having CD and is thought to be secondary to nutritional deficiencies and immune disturbances during enamel formation in the first 7 years.47 Aphthous ulcers can also be present in children and adults with CD, and they often regress once the patients are on a gluten-free diet (GFD).48 Dermatitis herpetiformis is the skin presentation of CD, with symmetrical itchy blisters that develop primarily on the extensor surfaces of the elbows and knees and on the buttocks.
Low bone mineral density is commonly found in newly diagnosed children and teenagers with CD,49- 53 and in some cases it has advanced to osteoporosis and can be associated with fractures. In adults, approximately one-third of patients at their diagnosis of CD have osteoporosis, one-third have osteopenia, and one-third have normal bone mineral density.53
Isolated, unexplained elevation of aminotransferase levels (sometimes referred to as transaminitis) can be frequently found in CD across all ages; in the pediatric age group, approximately one-third of patients with CD have elevated aspartate aminotransferase and alanine aminotransferase levels.54,55 Although uncommon, joint involvement has been described in children and adults with CD.56,57
From an endocrinologic standpoint, short stature, delayed puberty, and unexplained infertility and miscarriages in women have been described in association with CD.37 Neurologic presentations include cerebellar ataxia, idiopathic epilepsy, peripheral neuropathy, and (especially common) recurrent headaches.
Frequent symptoms in adolescents with CD are psychiatric issues, including depression, hallucinations, and anxiety (often with recurrent panic attacks), leading to a slightly higher prevalence of suicidal behavior among these patients.58 Some evidence suggests that the GFD may help in alleviating depression in adolescents with CD.59
Because all such manifestations can occur in the absence of gastrointestinal signs and symptoms, physicians require a high degree of suspicion to diagnosis CD. This is especially crucial in light of the fact that almost all these ailments can be effectively reversed by a strict GFD.
Celiac disease is associated with other conditions, including autoimmune diseases; the most notable is found in patients with type 1 diabetes mellitus, among whom approximately a 10% prevalence of CD is found.60 In addition, CD has an association with selective IgA deficiency and with chromosomal disorders such as Down syndrome, Turner syndrome, and Williams syndrome.5
During the past few years, a body of data has been accumulating from epidemiological investigations conducted among large samples of individuals (patients with CD and control subjects) predominantly in Sweden. These findings have allowed the detection of an increased risk of adverse conditions in patients with CD, even among those adhering to a GFD. The following are worth mentioning: adrenal insufficiency,61 asthma,62 IgA nephropathy,63 systemic lupus erythematosus,64 pancreatitis,65 primary hyperparathyroidism66 (a risk diminishing with adherence to a GFD), endometriosis,67 cataract,68 ischemic heart disease,69 and dilated cardiomyopathy.70
Of particular interest for physicians caring for adolescents, a recent study71 documented a possible increased risk of early atherosclerosis among young adults with CD. Among other variables, the study examined lipid metabolism and ultrasonographic measurement of carotid artery thickness at diagnosis and at 6 to 8 months after adherence to a GFD among young adult patients and healthy control subjects. At baseline, the low-density lipoprotein cholesterol levels and carotid thickness appeared to be increased in those with CD compared with the controls, and these measurements returned to normal after adherence to the GFD.
No increased risk has been found for lung cancer among individuals with CD.72 A reduced risk of breast, endometrial, and ovarian cancer has been documented in women with CD.73
The first step in a correct diagnosis of CD is to have a high degree of suspicion for it and a knowledge that CD may come in many different forms and shapes. The present rate of diagnosis in the United States is approximately 15%,16 leaving 85% of all patients undiagnosed and exposed to the risks of complications in the absence of a GFD.
Table 4 lists the indications for CD screening. In addition to patients whose symptoms, whether gastrointestinal or extraintestinal, may suggest the existence of CD, we also recommend screening individuals who may be asymptomatic but have risk factors for CD. However, recommendations supported by European1 and North American5 specialty societies are not universally endorsed. Recent guidelines from the American College of Gastroenterology74 indicate a reluctance to recommend testing asymptomatic individuals.
Reliable serological screening tests (Table 1) should be used primarily to identify individuals in need of a diagnostic biopsy. Testing the serum levels of anti-tTG IgA is generally acknowledged as the first choice in screening for CD, displaying the highest levels of sensitivity (up to 98%) and specificity (approximately 96%). Antiendomysium IgA testing has close to 100% specificity and a sensitivity exceeding 90%.28 This test has some drawbacks, including high interobserver variability.28 As mentioned, DGPs (DGP-IgG and DGP-IgA) are also used as screening tools, and they seem to be especially useful in very young children; they may be more sensitive than anti-tTG IgA in children younger than 2 years.30,75
The diagnosis of CD still rests on the demonstration of histologic changes in the small intestinal mucosa as documented by biopsy specimens from the duodenum via an endoscopy.76 However, minor changes (type 1 CD, also referred to as lymphocytic enteritis or lymphocytic duodenosis) are not unique to CD and can be seen in Crohn disease, Helicobacter pylori gastritis, some parasitic and bacterial infections, nonsteroidal anti-inflammatory drug use, and food allergies (particularly children’s allergies to cow’s milk and soy protein).77- 79 Therefore, we must reinforce that the diagnosis of CD should take into account the clinical presentation, an evaluation of serological markers within the context of gluten exposure, and response to a strict GFD.
Recent guidelines from the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition1 suggest the possibility of avoiding duodenal biopsies. They state that a combination of the following elements offers almost a 100% positive predictive value for CD in the presence of suggestive symptoms in a child or teenager: a consistent HLA haplotype, a positive titer of antiendomysium IgA, and an elevated tTG value more than 10 times the normal level. Although this is supported by evidence, the possibility remains (as one of us has recently demonstrated in a retrospective analysis of children and adolescents with biopsy-proven CD80) that in a substantial portion of patients, forgoing the biopsy may mean that associated conditions may be overlooked, such as eosinophilic esophagitis, peptic esophagitis, gastritides, and others. Therefore, patients in whom biopsies are not performed should be monitored closely.
What is the diagnostic value of HLA typing? In the clinical setting, HLA typing can be used to identify whether a patient carries the haplotype DQ2 or DQ8 that is necessary for CD to develop. In fact, the absence of HLA-DQ2 and HLA-DQ8 excludes the possibility of CD.81 Therefore, a negative test result (negative predictive value of close to 100%) should be used only as a tool to rule out the possibility of such a diagnosis, while the predictive value of a positive test result (positive predictive value of less than 3%) is negligible.
Lifelong adherence to a strict GFD remains the only available treatment for patients with CD and typically results in a complete return to health, as was recently shown in a large epidemiological study82 in Sweden. The researchers found that a GFD reduces symptoms and health care use in adults with CD. Along with many other sources, the Academy of Nutrition and Dietetics provides resources about the GFD (www.eatright.org). An e-book created by our team at the University of Chicago Celiac Disease Center is available for free download to help jump-start the diet (http://www.cureceliacdisease.org/living-with-celiac/resources/jump-start-your-gluten-free-diet-ebook).
Compliance with a GFD is difficult at all ages but particularly for teenagers because of several factors. In this age group, the diet may prove challenging psychologically and socially. Occasions such as birthday parties, sleepovers, eating out, and even snack time at school can be difficult to navigate. A survey among college students with CD revealed that they were motivated to adhere to the diet but that they experienced challenges related to dining services and social situations.83 Despite this, a survey among teenage boys and girls with CD showed that the nutrient intake of this age group with CD was comparable to that of healthy control subjects.84
What about the quality of life for teenagers with CD? Among adolescents, the quality of life may be affected not only by the disease but also by its treatment. In a recent study85 of children with CD and their parents, quality-of-life total scores were similar between the groups of children with and without CD, but the scores in the leisure dimension of the children with CD were significantly lower than those of the controls. Similarly, the authors found significantly lower scores in the social dimension for the parents of children who had CD compared with the parents of children who did not have CD. A recent survey of patients with CD showed that those younger than 29 years and those having extraintestinal symptoms (or those who are asymptomatic and detected by screening among at-risk groups) experienced a more deleterious effect of the disease on their daily life and greater difficulty in adherence to a GFD than those having classic symptoms of CD.86 The former groups more frequently reported dietary lapses and a bad attitude toward the disease. Negative perceptions were associated with younger age at diagnosis and with dissatisfaction about the quality of physician-patient communication.
These findings emphasize that effective communication between physician and patient is essential in minimizing the disease burden of CD, particularly in young patients and in screen-detected asymptomatic patients. Consequently, regular, periodic follow-up care of these patients is a necessary component of efficacious long-term treatment for children and adolescents with CD. However, this does not seem to be commonplace. A recent study87 in Minnesota estimated that by 1 year after diagnosis, less than half of the patients with CD had attended follow-up visits, and only one-third had been assessed for compliance with a GFD (with a minute fraction of them having met with a registered dietitian). When extending the observation for a full 5 years after diagnosis, almost one-third of the patients had failed to undergo serological testing.
Accepted for Publication: August 9, 2013.
Corresponding Author: Stefano Guandalini, MD, Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Mail Code 4065, 5841 S Maryland Ave, Chicago, IL 60637 (email@example.com).
Published Online: January 6, 2014. doi:10.1001/jamapediatrics.2013.3858.
Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Drafting of the manuscript: Guandalini.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: Assiri.
Study supervision: Guandalini.
Conflict of Interest Disclosures: None reported.
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