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Background
Celiac disease (CD) is characterized by an abnormal proximal small intestinal mucosa, and it is associated with a permanent intolerance to gluten. Removal of gluten from the diet leads to a full clinical remission and restoration of the small intestinal mucosa to normality. It is a lifelong disorder and affects both children and adults. It may present for the first time in either childhood or adult life.
Gluten, which is the protein responsible for CD, is found in the grain of wheat, rye, oats, and barley. The toxic effects of gluten most likely result from an immunologic mechanism. Circulating antibodies to wheat fractions and other dietary proteins have been detected in the sera of patients with CD. Increased density of the intraepithelial lymphocytes in the small intestinal mucosa is a hallmark of the disease.
The hallmark of CD is permanent gluten intolerance, requiring a lifelong, gluten-free diet. Spontaneous recovery in children has been reported, but it is not yet known whether these children will eventually relapse. A disorder of transient gluten intolerance has been described in early infancy, with clinical features that are indistinguishable from CD. This is rare, but this syndrome has made it necessary to demonstrate that gluten intolerance persists by means of gluten challenge in children presenting before 2 years of age.
Age at onset of symptoms varies, but most children present between 1 and 2 years of age. Recently, symptoms seem to be appearing at a later age, possibly because gluten is being introduced into the diet in most Western countries at an older age.
Diarrhea, which may be acute or insidious in onset, is the most common presenting symptom. The stool characteristically is pale, loose, and very offensive. The child may have 2 or 3 such stools a day but often passes just 1 large, bulky stool. Recurrent attacks of more severe diarrhea with watery stools may occur. However, a few children present with constipation and may have a dilated colon or, occasionally, rectal prolapse. Failure-to-thrive is common, and children may present with short stature alone. Celiac disease must be considered in every child with failure-to-thrive and short stature regardless of whether diarrhea is present.
Emotional symptoms are common, although they are not often the mode of presentation. Anorexia classically is said to be present, but sometimes appetite is increased. In countries such as Finland, where the disease is presenting at a later age, anorexia, delayed puberty, or unexplained nutritional deficiencies such as iron deficiency may be the earliest symptom. Although the classic appearance of a miserable child with a distended abdomen, wasted buttocks, and shoulder girdles still occurs, physical examination may show little abnormality apart from abdominal protuberance. Muscle wasting, hypotonia, and a delay in motor milestones may be present in severe cases. Height and weight at the time of diagnosis often are below the 10th percentile, and weight is sometimes below the 3rd percentile.
Diagnosis of CD is based on the demonstration of characteristic features on small intestinal biopsy and on a clinical response to withdrawal of gluten from the diet. Accepted guidelines indicate that a gluten-free-diet trial should not be initiated before obtaining a small bowel biopsy. Strict adherence to this diet is generally viewed as difficult and more stressful than undergoing a diagnostic biopsy. Clinical response is demonstrated by significant weight gain and relief of all symptoms. The European Society of Pediatric Gastroenterology and Nutrition has established criteria for definitive diagnosis of CD. In children younger than 2 years of age, the criteria state diagnosis would be made only when reintroduction of gluten into the diet, after the intestinal mucosa has become normal, causes the mucosa again to become abnormal, with or without symptoms. In children older than 2 years of age, the criteria state a second challenge with gluten is not required if the initial biopsy is positive.
Circulating IgA-gliadin, anti-reticulin, and anti-endomysial antibodies have a high degree of sensitivity and specificity for the diagnosis of CD. The presence of 2 of these antibodies at the time of diagnosis, with a typical small intestinal mucosa and their disappearance with a clinical response to a gluten-free diet and return on challenge, establishes the diagnosis. Although anti-endomysial antibodies have a high degree of specificity, particularly in adult patients, false-positive results may occur in children. Accepted guidelines indicate that antibody estimations on their own should not be relied on for the final diagnosis of CD. Accepted guidelines indicate that small intestinal biopsy is still mandatory.
It has also been suggested that these tests can be used to screen first-degree relatives of affected individuals to diagnose subclinical (latent) CD. These tests have also been shown to be useful in determining compliance with a gluten-free diet.
According to a NIH Consensus Panel Statement on celiac disease (2004), serological testing is the first step in pursuing a diagnosis of CD. The Consensus Statement said that the best available tests are the IgA anti-human tissue transglutaminase (TTG) and anti-endomesial IgA antibodies (EMA). According to the NIH Consensus Statement, the anti-gliadin IgA and IgG antibody tests are no longer routinely recommended because of their lower sensitivity and specificity.
According to the NIH Consensus Statement (2004), if an individual has suggestive symptoms and negative serologies, it may be necessary to measure serum IgA to detect a selective IgA deficiency. If an IgA deficiency is identified, an IgG-TTG or IgG-EMA test should be performed.
An assessment by the Ontario Ministry of Health Medical Advisory Secretariat (MAS, 2010) on the use of serologic testing for CD in symptomatic persons found that the clinical validity and clinical utility of serologic tests for CD was considered high in subjects with symptoms consistent with the disease as they aid in the diagnosis of CD and some tests present a high accuracy, and a CD diagnosis leads to treatment with a gluten-free diet. The assessment found that study findings suggest that IgA TTG is the most accurate and the most cost-effective test, and that IgA AGA has a lower accuracy compared to other IgA-based serologic celiac disease tests. Serologic test combinations appear to be more costly with little gain in accuracy. The assessment found that IgA deficiency seems to be uncommon in patients diagnosed with CD. The assessment stated that the generalizability of study results is contingent on performing both the serologic test and biopsy in subjects on a gluten-containing diet, since the avoidance of gluten may affect test results.
An assessment by the Ontario Ministry of Health Medical Advisory Secretariat (MAS, 2011) of the use of serologic testing for CD found that, based on a review of the literature, there is an increased risk of asymptomatic CD in patients with type 1 diabetes. The assessment found, based on low quality evidence, in patients with idiopathic short stature and asymptomatic celiac disease there is an acceleration in growth once a gluten-free diet is introduced. With the exception of idiopathic short stature, there was no published evidence of clinical utility of CD testing in asymptomatic patients with respect to a gluten-free diet intervention in the other conditions evaluated. The report also found, based on low to very low quality evidence, asymptomatic CD does not confer an increased risk of lymphoma or mortality. Similarly, in patients with lymphoma there is no increased risk of asymptomatic celiac disease
The CeliaGENE test (Prometheus Laboratories, Inc., San Diego, CA) is a genetic test for HLA-DQ2 and HLA-DQ8. Kaukinen and associates (2002) investigated whether HLA-DQ2 and HLA-DQ8 typing is helpful when diagnosis of CD is uncertain because of the absence of unequivocal small bowel villous atrophy. The authors concluded that HLA-DQ2 and HLA-DQ8 determination is useful in exclusion, probably lifelong, of CD in individuals with an equivocal small bowel histological finding. According to the NIH Consensus Statement, when the diagnosis of CD is uncertain because of indeterminate results, testing for certain genetic markers (HLA haplotypes) can stratify individuals to high or low risk for CD. The Consensus Statement noted that greater than 97 % of patients with CD have the DQ2 and/or DQ8 marker, compared to about 40 % of the general population. Therefore, an individual negative for DQ2 or DQ8 is extremely unlikely to have CD (high negative-predictive value).
There is strong evidence for an increased occurrence of celiac disease in children with type 1 diabetes (Hill et al, 2005; Dretzke et al, 2004). It has been estimated that 6 to 8 % of children with type 1 diabetes have concomitant CD (American Gastroenterological Association, 2001). Guidelines from the American Diabetes Association (Silverstein et al, 2005) recommend that children and adolescents with type 1 diabetes should be screened for celiac CD. The ADA recommends celiac disease testing soon after the diagnosis of diabetes and subsequently if growth failure, failure to gain weight, weight loss, or gastroenterologic symptoms occur. The ADA also states that consideration should be given to periodic re-screening of children and adolescents with negative antibody levels. Guidelines from the National Collaborating Centre for Women's and Children's Health (2004) recommend screening children and adolescents with type 1 diabetes for CD at diagnosis and at least every 3 years thereafter.
Treatment consists of excluding wheat, rye, barley, and oats from the diet for life. In the short-term, clinical studies have shown that this will permit normal growth, with achievement of the child's full growth potential. There is evidence that, in the long-term, a gluten-free diet may prevent complicating malignancy. Available literature suggests that patients with CD who receive a reduced-gluten or a normal diet have increased risk for lymphoma and for cancers of the mouth, pharynx, and esophagus. However, available evidence suggests that strict adherence to a gluten-free diet for 5 years or more decreases the risk of these malignancies in adults to rates similar to that of the unaffected population.
The addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, provided the same measures of test performance as either testing strategy alone (Hadithi et al, 2007). Hadithi et al (2007) prospectively examined the performance of serologic testing and HLA-DQ typing. Patients referred for small-bowel biopsy for the diagnosis of CD underwent celiac serologic testing (AGA, TGA, and EMA) and HLA-DQ typing. Diagnostic performance of serologic testing and HLA-DQ typing compared with a reference standard of abnormal histologic findings and clinical resolution after a gluten-free diet were carried out. Sixteen of 463 participants had celiac disease (prevalence, 3.46 % [95 % confidence interval [CI]: 1.99 % to 5.55 %). A positive result on both TGA and EMA testing had a sensitivity of 81 % (CI: 54 % to 95.9 %), specificity of 99.3 % (CI: 98.0 % to 99.9 %), and negative- predictive value of 99.3 % (CI: 98.0 % to 99.9 %). Testing positive for either HLA-DQ type maximized sensitivity (100 % [CI: 79 % to 100 %]) and negative-predictive value (100 % [CI: 98.6 % to 100 %]), whereas testing negative for both minimized the negative likelihood ratio (0.00 [CI: 0.00 to 0.40]) and post-test probability (0 % [CI: 0 % to 1.4 %]). The addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, did not change test performance compared with either testing strategy alone. The authors concluded that a patient population referred for symptoms and signs of CD with a prevalence of CD of 3.46 %, TGA and EMA testing were the most sensitive serum antibody tests and a negative HLA-DQ type excluded the diagnosis. However, the addition of HLA-DQ typing to TGA and EMA testing, and the addition of serologic testing to HLA-DQ typing, provided the same measures of test performance as either testing strategy alone.
In an editorial that accompanied the afore-mentioned paper, Rashtak and Murray (2007) stated that "Hadithi and colleagues' study illustrate the importance of considering the pretest probability of celiac disease and the performance and limitations of each test when deciding which diagnostic tests to use for celiac disease. In most circumstances, physicians should use TGA-IgA but not AGA as the initial diagnostic test, referring patients who test positive and those with reasons to suspect other diagnoses for duodenal biopsies. The principal role of HLA testing is trying to rule out celiac disease in diagnostically challenging circumstance, such as discrepant serologic and histopathologic findings and refractory symptoms despite a gluten-free diet, or when patients with an uncertain diagnosis have already begun a gluten-free diet".
In a review on diagnosis, monitoring, and risk assessment of celiac disease, Setty et al (2008) stated that "[c]urrently, serological screening tests are utilized primarily to identify those individuals in need of a diagnostic endoscopic biopsy. The serum levels of immunoglobulin (Ig)A anti-tissue transglutaminase (or TG2) are the first choice in screening for celiac disease, displaying the highest levels of sensitivity (up to 98 %) and specificity (around 96 %). Anti-endomysium antibodies-IgA (EMA), on the other hand, have close to 100 % specificity and a sensitivity of greater than 90 %. The interplay between gliadin peptides and TG2 is responsible for the generation of novel antigenic epitopes, the TG2-generated deamidated gliadin peptides. Such peptides represent much more celiac disease-specific epitopes than native peptides, and deamidated gliadin peptide antibodies (DGP) have shown promising results as serological markers for celiac disease".
A systematic review of the evidence for DGP for celiac disease conducted by the Institute for Clinical Effectiveness and Health Policy (Pichon-Rivere et al, 2009) found the evidence supporting its use to be controversial. Of the 11 studies of sufficient quality to be included in the review, 10 were of case-control design, and only 1 study of a consecutive series of patients. Using biopsy results as a gold standard, the sensitivity values reported for the IgA DGP ranged from 74 % to 98.3 % while the specificity values ranged from 90 % to 99.1 %. For IgG DGP tests, sensitivity values ranged from 65 % to 96.7 % and specificity values ranged from 95 % to 100 %. The assessment concluded that whether DGP is superior to ATG antibodies in the diagnosis of CD is controversial, with studies reporting conflicting results. The assessment also noted that, given the case-control nature of most of the studies, the patients included in these studies may not be representative, in terms of clinical presentation and stage of disease, of the patients for whom the test would be used in clinical practice.
Prause and colleagues (2009) examined investigated the performance of new assays for antibodies against deamidated gliadin (anti-dGli) in childhood CD. These investigators retrospectively compared children (142 with active CD and 160 without CD, diagnosis confirmed or excluded by intestinal biopsy) concerning (immunoglobulin [Ig] G and IgA) anti-nGli, anti-tTG, and 2 different anti-dGli assays. IgG-anti-dGli1, IgG-anti-dGli2, and IgA-anti-tTG performed similarly. Area under the receiver-operating characteristic curve (AUC) was 98.6 %, 98.9 %, and 97.9 %; accuracy was 94.7 %, 95.7 %, and 96.7 %. Anti-dGli1 and anti-dGli2 (IgG and IgA) and IgA-anti-tTG performed significantly better than IgA-anti-nGli and IgG-anti-nGli. Both IgG-anti-dGli showed higher AUC and accuracy than IgA-anti-dGli and IgG-anti-tTG. Combined evaluation of IgA-anti-tTG with one of the IgG-anti-dGli tests reduced the rate of falsely classified patients. At enhanced cut-off (specificity greater than 99 %), sensitivity was above 67 % for both IgG-anti-dGli and IgA-anti-tTG. If IgA-anti-tTG assay was combined with one of the IgG-anti-dGli tests, then the fraction of patients identified with more than 99 % specificity as celiacs increased significantly above 84.5 %. Combined evaluation of the 2 IgG-anti-dGli tests did not improve the performance. The authors concluded that the new IgA and IgG-anti-dGli tests out-perform conventional anti-nGli assays. The validity of IgG-anti-dGli can not be distinguished from IgA-anti-tTG. They stated that whether antibody assays could replace biopsy in diagnosis of CD in a substantial segment of children should be studied prospectively.
Lewis and Scott (2010) compared the performance of the DGP antibody test with the current standard, the TTG antibody test, through a meta-analysis of published studies. Databases from 1998 to 2008 were searched for relevant studies. These were assessed for methodological quality and standard statistical tests were applied to compare particularly the sensitivity and specificity of the 2 tests for the diagnosis of CD. Most studies had methodological flaws, especially ascertainment bias. The pooled sensitivities for the DGP antibody and TTG antibody tests were 87.8 % (95 % CI: 85.6 to 89.9) and 93.0 % (95 % CI: 91.2 to 94.5), respectively and the pooled specificities were 94.1 % (95 % CI: 92.5 to 95.5) and 96.5 % (95 % CI: 95.2 to 97.5), respectively. The authors concluded that although both tests performed well, the TTG antibody test out-performed the DGP antibody test and remains the preferred serological test for the diagnosis and/or exclusion of CD.
Parizade and Shainberg (2010) noted that reports from their clinical laboratory database show that 75 % of children less than 2 years old tested for celiac serology who were found positive for DGP antibodies had negative results for IgA-TTG. Levels of DGP were shown to decline and disappear without a gluten-free diet. This observation questions DGP's specificity for diagnosis of CD.
Vecsei et al (2009) ascertained which non-invasive follow-up investigation -- serological tests or intestinal permeability test (IPT) -- correlated best with histology and whether the interval between diagnosis and follow-up affects the accuracy of these tests. Data from adult patients with CD (followed up with biopsy, IPT, and serological tests [IgG anti-gliadin antibodies (AGA-IgG), AGA-IgA, and endomysial antibodies (EMA)] were retrieved from a computerized database. Results of non-invasive tests were compared with the persistence of villous atrophy on biopsy. Patients were divided into 2 groups: Group A (comprised patients followed-up within 2 years after diagnosis), and Group B (comprising patients followed-up later than 2 years). A total of 47 patients were evaluable. The lactulose/mannitol (L/M) ratio had a sensitivity of 85 % and a specificity of 46.2 % for mucosal atrophy, whereas saccharose excretion showed a sensitivity of 60 % and a specificity of 52.6 %. The sensitivities of AGA-IgA and AGA-IgG were 15 % and 20 %, respectively, while specificity was 100 % for both. Validity of AGA was limited due to low number of positive results. Endomysial antibodies assay was 50 % sensitive and 77.8 % specific. In group A (n = 23) L/M ratio performed best in terms of sensitivity (88.9 %), whereas EMA achieved a higher specificity (71.4 %). In group B, the sensitivity of the L/M ratio decreased to 85.7 %, while the specificity of EMA increased to 91.7 %. The authors concluded that in this study, none of the non-invasive tests was an accurate substitute for follow-up biopsy in detecting severe mucosal damage.
Armstrong and colleagues (2011) stated that IgA-TTG is the single most efficient serological test for the diagnosis of CD. It is well-known that IgA-TTG levels correlate with the degree of intestinal damage, and that values can fluctuate in patients over time. Serological testing can be used to identify symptomatic individuals that need a confirmatory biopsy, to screen at-risk populations or to monitor diet compliance in patients previously diagnosed with CD. Thus, interpretation of serological testing requires consideration of the full clinical scenario. Anti-gliadin tests are no longer recommended for the diagnosis of classical CD. However, the understanding of the pathogenesis and spectrum of gluten sensitivity has improved, and gluten-sensitive irritable bowel syndrome patients are increasingly being recognized. The authors noted that studies are needed to determine the clinical utility of anti-gliadin serology in the diagnosis of gluten sensitivity.
Kurppa et al (2011) noted that the widely used serum endomysial (EmA) and transglutaminase 2 (TG2-ab) antibodies predict forthcoming villous damage and CD when the small-bowel mucosa structure is still normal. However, these autoantibodies may remain negative in this early stage of the disease. These researcehers hypothesized that the antibodies against DGP (DGP-AGA) might appear before the other antibodies and would thus be useful in the diagnosis and follow-up of patients with early-stage CD. Serum DGP-AGA, TG2-ab, and EmA were measured at baseline and after 1 year on a gluten-free diet in 42 adults proven to have early-stage CD despite normal small-bowel mucosal morphology (Marsh I-II), and in 20 celiac subjects evincing villous atrophy (Marsh III); 39 subjects with no signs of CD served as non-celiac controls. Sensitivity to detect early-stage CD was 79 % for DGP-AGA, 64 % for TG2-ab, and 81 % for EmA. Specificities were 95 %, 100 %, and 100 %, respectively. The corresponding efficiencies of the tests were 89 % for DGP-AGA, 81 % for TG2-ab, and 91 % for EmA. All 3 antibodies were significantly decreased on a gluten-free diet. The authors concluded that this study showed that the sensitivity of DGP-AGA was superior to TG2-ab and comparable to EmA in celiac patients having early-stage CD with normal villous morphology. They stated that, on the basis of these results, DGP-AGA would seem to offer a promising new method for case-finding and follow-up in this entity.
Sakly et al (2012) evaluated the usefulness of anti-DGP antibodies (a-DGP), in the diagnostic of celiac disease. A total of 103 untreated CD patients (67 children and 36 adults) and 36 CD patients under gluten-free diet were studied; and 274 subjects served as controls (114 healthy blood donors, 80 healthy children and 80 patients with primary biliary cirrhosis). Anti-DGP antibodies (IgG and IgA) and anti-tissue transglutaminase antibodies (AtTG) were detected by enzyme-linked immunosorbent assay (Elisa). Anti-endomysium antibodies (AEA) were detected by indirect immunofluorescence on human umbilical cord. The sensitivitiy of IgG and IgA a-DGP were 94 % and 97 % respectively, compared to 96 % for AEA and AtTG. The specificity of a-DGP was 93.6 % for IgG and 92 % for IgA. The specificity of AEA and AtTG were 100 %. The frequency of IgG and IgA a-DGP was significantly higher in patients with CD than in control group (94 % versus 4.4 %, p < 10(-7); 97 % versus 8 %, p < 10(-7)). The frequency of IgG a-DGP was the same in children and adult (94 %). The frequency of IgA a-DGP were similar in children and adults (95.5 % versus 100 %). The authors concluded that the findings of this study showed that a-DGP increases neither the sensitivity nor the specificity of AEA and AtTG.
Hojsak et al (2012) compared the performance of 3 serological tests (IgA + IgG DGP, IgA TTG, and IgA + IgG EMA) for CD in young children younger than 3 years of age. These investigators identified all subjects younger than 3 years of age (n = 6,074) that were tested for CD serology and included those with biopsy data. Patients were classified as group 1 (n = 47): patients with confirmed CD, or group 2 (n = 12): patients with normal biopsy findings. There was statistically significant difference between group 1 and group 2 with regard to number of patients with positive IgA TTG (97.87 % versus 50 %, p < 0.001), IgA + IgG DGP (100 % versus 77.78 %, p = 0.007), and IgA + IgG EMA (95.65 % versus 9.09 %, p < 0.001). There was a significantly positive correlation between Marsh-Oberhuber score on the small duodenal biopsies and all tests. Analysis of sensitivity and specificity showed that manufacturer's levels had high sensitivity for all tests (IgA TTG 97 %, IgA + IgG DGP 100 %, IgA + IgG EMA 96 %), however specificity was low for IgA + IgG DGP (44 %) and IgA TTG (50% ) but not for IgA + IgG EMA (91 %). The authors concluded that for children younger than 3 years of age, IgA + IgG EMA is highly sensitive and specific. Use of IgA + IgG DGP or IgA TTG as a single serological marker is insufficient for definite diagnosis of CD in this age group. Based on these findings, it might be reasonable to postpone the biopsy for asymptomatic children with negative EMA.
Olen et al (2012) evaluated diagnostic performance and actual costs in clinical practice of immunoglobulin (Ig)G/IgA DGP as a complement to IgA-TTG for the diagnosis of pediatric CD. All of the consecutive patients younger than 18 years tested for TTG and/or DGP, who underwent duodenal biopsy because of suspected CD in Stockholm and Gothenburg, Sweden, from 2008 to 2010, were included. Medical records were reviewed. Of 537 children who underwent duodenal biopsy, 278 (52 %) had CD. A total of 71 (13 %) were younger than 2 years and 16 (4 %) had IgA deficiency. Sensitivity and specificity for TTG were 94 % and 86 %, respectively. Corresponding values for DGP were 91 % and 26 %. Positive-predictive values (PPV) were 88 % for TTG and 51 % for DGP. There were 148 children who were TTG-negative and DGP-positive, of which only 5 % (8/148) had villous atrophy. Among children younger than 2 years with normal IgA, PPV was 96 % (25/26) for TTG and 48 % (24/50) for DGP. In 16 IgA-deficient children, 11 were DGP positive, of which 5 had CD (PPV 45 %). Eight of 278 cases of CD would possibly have been missed without DGP. The cost of adding DGP and consequently more biopsies to be able to detect 8 extra cases of CD was Euro 399,520 or Euro 49,940 per case. The authors concluded that for diagnosing CD, TTG is superior to DGP, even in children younger than 2 years. Combining TTG and DGP does not provide a better trade-off between number of missed cases of CD, number of unnecessary duodenal biopsies, and cost than TTG alone.
Neves et al (2013) described the first electrochemical immunosensor (EI) for the detection of antibodies against DG. A disposable nano-hybrid screen-printed carbon electrode modified with DGP was employed as the transducer's sensing surface. Real serum samples were successfully assayed and the results were corroborated with an ELISA kit. The authors stated that the EI is a promising analytical tool for the diagnosis of CD.
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