Celiac.com 09/01/2002 - Patients with celiac disease are 20 times more likely than the general population to have epilepsy and often have associated cerebral and cerebellar calcifications imaged by CT and MRI. Depression, dementia, and schizophrenia are all also common in persons with untreated celiac disease. Cerebellar degeneration with resulting ataxia (gluten-associated ataxia) is a known entity in Europe, and the National Institutes of Health (NIH) is currently recruiting subjects with ataxia to examine them for gluten sensitivity and celiac disease. Focal white matter lesions in the brain recently have been reported to occur in children with celiac disease and are thought to be either ischemic in origin as a result of vasculitis or caused by inflammatory demyelination. Parents of children with celiac disease have reported behavioral changes such as irritability, separation anxiety, emotional withdrawal, and autistic-like behaviors that all seemed to improve on a GFD. Although not scientifically validated, the GFD is now also being advocated for children with autism by several groups. Whether or not children with autism are at a higher risk for celiac disease or celiac children have a higher incidence of autism remains to be proven. However, children with Down syndrome, who often have autistic-like behaviors, are at higher risk for celiac disease. It has been hypothesized that gluten may be broken down into small peptides that may cross the blood-brain barrier and interact with morphine receptors, leading to alterations in conduct and perceptions of reality.

The serologic tests can be divided into 4 different types of antibodies: antigliadin (AGA), antireticulin, antiendomysium (AEA), and antitissue transglutaminase (tTG). Each antibody varies widely in its sensitivity, specificity, and positive and negative predictive values (Table 2).

Table 2 (from Pietzak et al, 2001, compiled data from multiple studies)

Test Sensitivity Specificity PPV NPD
AGA IgG 57-100 42-98 20-95 41-88
AGA IgA 53-100 65-100 28-100 65-100
AEA IgA* 75-98 96-100 98-100 80-95
Guinea pig tTG† 90.2 95
Human tTG† 98.5 98

* Patients older than 2 years of age.
† IgG +IgA antibodies.

The AEA IgA immunofluorecent antibody is an excellent screening test for celiac disease, with both a high sensitivity and specificity. This antibody was discovered in the early 1980s and rapidly gained use as part of a screening celiac panel by commercial laboratories in combination with AGA IgG and AGA IgA. Its major drawbacks are that it may be falsely negative in children under the age of 2 years, in patients with IgA deficiency, and in the hands of an inexperienced laboratory. Also, the substrate for this antibody was initially monkey esophagus, making it expensive and unsuitable for screening large numbers of people. Recently, the human umbilical cord has been used as an alternative to monkey esophagus. However, the subjective nature of the AEA assay may lead to false-negative values and unacceptable variability between laboratories.

Because tTG had been first described as the autoantigen of celiac disease in 1997, it has been used to develop innovative diagnostic tools. The tTG IgA ELISA test is highly sensitive and specific, using either the commercially available guinea pig tTG or human recombinant tTG. The tTG assay correlates well with AEA-IgA and biopsy. However, it represents an improvement over the AEA assay because it is inexpensive and rapid (30 minutes), is not a subjective test, and can be performed on a single drop of blood using a dot-blot technique. Therefore, this test is ideally suited for mass screenings and in the future could be performed in the general practitioners office, much like the now routine finger-stick hematocrit.

For the reasons outlined above, the IgA class human anti-tTg antibody, coupled with the determination of total serum IgA, currently seems to be the most cost-effective way to screen for celiac disease. AEA should be used as a confirmatory, pre-biopsy test, whereas AGA determinations should be restricted to the diagnostic work-up of younger children and patients with IgA deficiency, using the guidelines in Table 3.

Table 3
Probability of celiac disease based on three antibodies in combination

AEA IgA
AGA IgA
AGA IgG
Interpretation
+
+
+
Celiac disease 99% probable
+
-
+
probable
+
+
-
Celiac disease probable
+
-
-
Celiac disease probable
-
+
+
Celiac disease less likely*
-
-
+
Celiac disease less likely*
-
+
-
Celiac disease less likely
-
-
-
Celiac disease very unlikely+

* If patient is IgA sufficient: AGA IgG > 100 warrants work-up of enteropathy.
+ If patient is on a gluten-containing diet.
Celiac disease: AEA, antiendomysium antibodies: AGA, antigliadin antibodies.

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