Selective IgA deficiency, as defined by the total or severe deficiency of the IgA immunoglobulins in serum and secretions, is the most common of the immunodeficiency disorders (Lilic and Sewell, letter). Studies suggest that 1 in every 500 people may have selective IgA deficiency. Even though a large number of individuals with selective IgA deficiency are relatively healthy, there are many affected with various illnesses. These include recurrent infections, allergies, and autoimmune disorders (23
). The prevalence of IgA deficiency in patients with CD is 10 to 15 times higher than that in the general population (2
; H. R. Gillett, P. M. Gillett, K. Kingstone, T. Marshall, and A. Ferguson, Letter, J. Pediatr. Gastroenterol. Nutr. 25:
366-367, 1997). For this reason it is suggested that patients with IgA deficiency should be considered as an at-risk group for CD. Cataldo et al. (2
) have reported that the clinical presentation of patients with CD with selective IgA deficiency is different from that of patients with CD with normal IgA levels, demonstrating a greater incidence of the silent form. Because of the mild form of clinical presentation in IgA-deficient patients with CD, there may be an extended delay in recognizing such cases before an appropriate GFD therapy can be instituted.
Due to the varied clinical presentations and the fact that two-thirds of patients with CD have either the asymptomatic or silent form of CD, there has been much more emphasis on the serological methods for detecting all forms of CD. The serum antibody markers that are being used are AGA, ARA, EMA, and tTG antibody. These serological markers are highly sensitive and specific markers for CD, especially for IgA-based antibody tests. Of the various markers, EMA has proven to be the most specific and sensitive marker, with positive and negative predictive values approaching 100% (12
). Because of the high prevalence of IgA deficiency in patients with CD, attention has been focused on the problem of IgA-deficient patients with CD and the methods of diagnosing them. IgA deficiency can lead to false-negative serology, as most of the existing serological methods detect only IgA antibodies (21
). The only serological test that can detect IgG antibodies related to CD is the AGA test. However, as the AGA IgG antibody test has limited specificity (76 to 80%), this test alone may not reliably establish a definitive diagnosis. Some investigators have suggested that IgA levels be measured in all specimens submitted for CD and a biopsy be performed in on IgA-deficient patients. However, there is a concern that routine IgA testing of all suspected cases of CD may lead to unnecessary biopsy (14
In 1989, Beutner et al. (E. H. Beutner, V. Kumar, T. P. Chorzelski, and M. Szaflarska-Czerwionka, Letter, Lancet i:
1261-1262, 1989) reported the first case of an IgA-deficient CD patient found negative for EMA IgA antibodies but positive for EMA, ARA, and AGA IgG antibodies. The levels of these antibodies disappeared when the patient was on a GFD and reappeared upon gluten challenge. This study suggested that IgG EMA antibody levels could be used to monitor IgA-deficient patients with CD for their compliance to GFD. Since this report, at least 36 similar cases of IgA-deficient patients with CD have been reported (Table ). All tested positive for EMA IgG antibody, indicating the importance of EMA IgG antibody for diagnosing IgA-deficient patients with CD (2
). The results for AGA IgG and tTG antibodies were less reliable than those for EMA IgG antibodies, as a few cases were missed by the tTG antibody and AGA IgG tests that were convincingly positive for the EMA IgG antibodies. The specificity of the EMA test in all studies was 100% in comparison with AGA and tTG antibody assays, as a few false positives were reported with these assays in the hands of some investigators. This agrees with the findings of Lagerqvist et al. (13
) and others (10
), who found the EMA test to provide the highest reliability in its sensitivity and specificity, compared with AGA or tTG antibody tests. This could be due to various factors, including the quality and source of the antigen as well as method standardization. Most of the ELISAs utilize a cutoff of positivity that is 2 or 3 standard deviations of the mean of the value for specimens from healthy subjects, thus providing a confidence interval of 95% in the majority of cases. In comparison, EMA tests performed according to good laboratory practices can approach 100% specificity and sensitivity. In our laboratory, we were able to achieve much better correlation between the AGA and tTG antibody results with EMA, as all 14 IgA-deficient patients with CD on normal diets were positive for AGA IgG antibody, and all but one were also positive for tTG antibodies. For the subject for whom a negative tTG antibody result was obtained the assay was repeated and the result was still found to be negative, suggesting that there may be other antigens involved in CD or that certain epitopes on tTG are masked for reacting to the antibodies. Our group and others have observed a similar phenomenon with IgA-normal patients with CD (10
). Cataldo et al. (4
) reported all of their 24 patients to be positive for tTG antibodies; however, they also found 2 of the 10 IgA-deficient patients without CD to be positive for tTG antibodies, raising questions about the specificity of their tTG antibody assay.
Immunological antibody profile of patients with IgA deficiency
When patients are on a GFD, the antibody levels tend to decrease and eventually disappear. This is borne out by data for certain patients in our studies. In each study there was one patient with CD on GFD. In both cases the EMA and AGA IgG antibody levels were normal. The patient whose case is presented in this paper was also negative for tTG antibodies. This suggests that the level of these antibodies may be used to monitor the response of the patients to GFD, as is the case with IgA-normal patients with CD.
In conclusion, the data suggest that patients with CD with IgA deficiency have the IgG isotype of antibodies to the same antigens (EMA, AGA, and tTG antibody) as IgA-normal patients with CD. The use of these assays will enhance the reliability of the serological methods of detecting symptomatic, asymptomatic, and silent forms of CD, whether they are IgA normal or deficient. We provide an algorithm for serological investigation of patients suspected for CD (Fig. ).
Algorithm for serological screening of CD.