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Background
Celiac disease 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 celiac disease, 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 celiac disease. Increased density of the intraepithelial lymphocytes in the small intestinal mucosa is a hallmark of the disease.
The hallmark of celiac disease 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 celiac disease. 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 two or three such stools a day but often passes just one 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 tenth percentile, and weight is sometimes below the third percentile.
Diagnosis of celiac disease 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 celiac disease. 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 celiac disease. The presence of two 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 celiac disease. 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) celiac disease. 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 celiac disease. 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.
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 celiac disease 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 celiac disease in individuals with an equivocal small bowel histological finding. According to the NIH Consensus Statement, when the diagnosis of celiac disease is uncertain because of indeterminate results, testing for certain genetic markers (HLA haplotypes) can stratify individuals to high or low risk for celiac disease. The Consensus Statement noted that greater than 97% of patients with celiac disease 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 celiac disease (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 percent of children with type 1 diabetes have concomitant celiac disease (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 disease. 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 rescreening 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 celiac disease 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 celiac disease 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 celiac disease 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 % 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 celiac disease with a prevalence of celiac disease 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".
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