What Is Known
- Tissue transglutaminase immunoglobulin A antibody is a highly sensitive and the best initial screening test for celiac disease.
- Selective immunoglobulin A deficiency is associated with celiac disease, and the current recommendations suggest that either total serum immunoglobulin A or both tissue transglutaminase immunoglobulin A antibody and tissue transglutaminase immunoglobulin G antibody should be measured to account for selective immunoglobulin A deficiency in the initial testing strategy.
- What Is New
- Does isolated tissue transglutaminase immunoglobulin G antibody have utility in initial testing for celiac disease?
- Does isolated tissue transglutaminase immunoglobulin G antibody positivity predict immunoglobulin A deficiency?
Celiac disease (CD) is an immune disorder that occurs as a reaction to gluten consumption in genetically susceptible individuals (1,2). Serologic screening in diverse populations suggests that CD often remains undiagnosed and the prevalence, which is anywhere from 0.2% to 2% in different parts of the world, has increased dramatically during the past 50 years (3–9). Moreover, in recent years, the proportion of children presenting with diarrhea, weight loss, and abdominal distention (typical CD) has decreased while patients presenting with extraintestinal manifestations (atypical CD) and asymptomatic patients (silent CD) identified by targeted screening of high-risk groups (positive family history of CD, presence of type 1 diabetes mellitus, immunoglobulin A [IgA] deficiency, and Down syndrome) have increased (10). The reason for this increased prevalence and changed clinical presentation over time is not clearly understood. Increased awareness and utilization of highly sensitive serologic tests could, however, be responsible for these changes (11,12).
According to the North American guidelines for diagnosing CD in both adults and children, serologic testing with IgA to tissue transglutaminase (tTG) is the test of choice for initial evaluation for suspected CD, followed by confirmatory intestinal biopsy (13).
This recommendation of tTG IgA as an initial test of choice is based on its overall accuracy, cost, and reliability. The result of this test may, however, be affected in the presence of selective IgA deficiency (14). The prevalence of IgA deficiency or partial deficiency is similar among adults and children with CD (2.1% and 1.9%, respectively) (15). Thus, the current recommendations are to routinely test for total serum IgA before selecting which isotype to look for or to use both tTG IgG and tTG IgA as a part of the initial test strategy in symptomatic patients (13,16). In patients with selective IgA deficiency, IgG antibodies to tTG have shown diagnostic utility and are used to determine whether the patient needs a confirmatory intestinal biopsy (17,18). The alternative approach to counter the possibility of selective IgA deficiency in patients with symptoms suggestive of CD may involve including both tTG IgA and tTG IgG in the initial screening strategy, bypassing the need for measuring total serum IgA (16). The accuracy of an isolated positive result of IgG to tTG (coexisting negative result of IgA to tTG) in diagnosing CD is, however, unknown. In the present study, we aimed to determine the positive predictive value of an isolated positive result of IgG to tTG in diagnosing CD, which would help us evaluate this alternative approach.
The present study was approved by the Mayo Clinic Institutional Review Board. We conducted a retrospective review of the Mayo Clinic electronic medical record database for the period between January 1997 and June 2014 using the Advanced Cohort Explorer. We did not restrict inclusion of patients on the basis of age and sex. All patients (1–80 years of age and of either sex) who had a positive IgG to tTG and a negative IgA to tTG result were deemed appropriate for inclusion. All patients who had positive results for both IgA and IgG to tTG were excluded from the study. Moreover, all patients who had any other positive CD-specific serologic findings, such as anti-endomysial IgA antibodies and anti–deamidated gliadin antibodies, were excluded. Demographic data, clinical presentation, and results of the diagnostic tests, including intestinal biopsy, were recorded. Descriptive statistics were used in summarizing the available data.
We reviewed the records of 2911 patients with positive celiac serology results and then identified 243 patients with a negative tTG IgA and a positive IgG tTG result. After excluding 10 patients due to deamidated gliadin antibodies IgG positivity, we had 233 patients with isolated positivity to tTG IgG. The demographic data showed that 68% (159/233) were females and 12% (28/233) were children younger than 18 years at time of testing. Mean (SD) age was 43 (19.5) years. Many patients had more than 1 indication for checking their celiac serology, but the most common indications were gastrointestinal symptoms in 74% (172/233) of cases, iron deficiency anemia in 5% (12/233) of cases, and high-risk screening in 20% (48/243) of cases. Of 233 patients with a positive tTG IgG result, 41 (18%) had other disorders, which are documented in Table 1. It is important to note the presence of autoimmune conditions that are known to coexist with CD (diabetes mellitus type 1 and thyroid disease) in Table 1; thus, rescreening may be considered in these high-risk patients.
A confirmatory small bowel biopsy (SBB) was performed in the evaluation of 76% (178/233) of cases. SBB findings were normal in 90% (160/178) of cases, and only 18 cases (10%) had histologic changes suggestive of enteropathy. Of the 18 cases with histologic changes on SBB, 9 had only increased intraepithelial lymphocytes with normal villous architecture and 9 had partial villous atrophy. Of the 9 patients with villous atrophy, 6 were given a diagnosis of CD despite reporting of suboptimally oriented biopsies in 3 of these patients; the remaining 3 patients were found to have other diagnoses (dermatomyositis, collagenous sprue, and autoimmune enteropathy). The average age for patients with positive histologic findings on SBB was 32 years (range 7–68) with 17 adults and 1 child ages 7 years. The average age for the patients who were ultimately diagnosed with CD was 46 years, and none of these patients were younger than 18 years. Based on that the utility of isolated tTG IgG in diagnosing CD was low at 2% (3/178), or at most 3% (6/178) if we consider the 3 cases with the suboptimally oriented biopsies as confirmed CD (Fig. 1). The concordance analysis value was 0.49, which suggests no strong association between the tTG IgG value and the biopsy findings.
Human Leukocyte Haplotype Testing
Human leukocyte haplotype for the celiac permissive gene DQ2 or DQ8 was checked in 34 patients (15%), and only 19 carried the permissive gene for CD. All 19 patients with permissive celiac genotype underwent confirmatory SBB, and only 4 (21%) were diagnosed as having CD (2 had partial villous atrophy and 2 had intraepithelial lymphocytes). This suggests that providers involved in these cases felt that isolated tTG IgG positivity together with permissive celiac genotype is an adequate indication for performing SBB to exclude CD, even though a small number of these patients were found to have CD.
Immunoglobulin A Deficiency
Total serum IgA level was measured in 72 of the 233 patients with isolated tTG IgG positivity. Of the 72 patients, 9 adults had serum IgA levels ranging from 1 to 50 mg/dL, which is lower than the reference range for serum IgA at our laboratory (61–356 mg/dL) for adults. None of the pediatric patients in this cohort had true selective IgA deficiency (serum IgA <5 mg/dL). Of these 9 patients, only 3 were completely deficient (IgA level of <5 mg/dL) and none of them were diagnosed with CD. The diagnosis of CD was confirmed in 3 (4%) of the 72 patients whose serum IgA was checked, and none of them had a low level. In this cohort the isolated positivity to tTG IgG did not predict CD in the setting of a low serum IgA level in our cohort of patients.
Family History of Celiac Disease
Out of 233 patients only 9 patients (4%) had positive family history of CD. None of the 18 patients with histologic finding on the SBB had positive family history of CD documented in the electronic medical records.
Although the advent of celiac-specific serology, such as endomysial and more recently tTG IgA, has revolutionized the approach to the detection and, ultimately, the diagnosis of CD, an identified weakness in that approach is the possibility of serum IgA deficiency (19).
Approximately 0.3% of the healthy blood donors in North America have selective IgA deficiency (20), and the prevalence is even higher in patients with CD (15). Thus, in symptomatic individuals highly suspected of having CD, it has been recommended that total serum IgA be measured routinely as a part of the screening process so that the importance of a negative screening serologic test result can be determined (13,16). An alternative approach is to include IgG to tTG routinely in initial testing, and thus bypassing the need for measuring total serum IgA (16,21).
Serologic tests involving measurement of tTG IgG have been used in symptomatic patients with selective IgA deficiency to determine whether they need an intestinal biopsy. In the setting of a low serum IgA level, there are conflicting data about whether positivity of endomysial antibodies or anti-gliadin antibodies to IgG has a higher predictive value for the need for confirmatory SBB (22,23).
Since the recommendation of tTG as a screening test, IgG to tTG has shown diagnostic utility and helped determine whether confirmatory SBB is necessary in patients with selective IgA deficiency (17,18). In this specific context, the sensitivity and specificity of IgG to tTG in the setting of symptoms suggestive of CD and selective IgA deficiency range from 84% to 97% and 91% to 93%, respectively, with a reasonable positive predictive value of 63% (17,24,25).
In our study, we found that the utility of isolated tTG IgG in the setting of unknown serum IgA status for the diagnosis of CD was low at 3%. Thus, in this cohort of patients, the presence of symptoms along with an isolated tTG IgG had a low predictive value for the presence of CD. This is in accordance with the notion that except for some well-defined clinical clues, little information is available as to what symptoms predict the presence of CD (26). Out of the 72 patients with normal serum IgA, 3 patients with CD would have been missed if tTg IgG was not done as part of their serologic screening. Larger studies are needed to assess the sensitivity of isolated tTG IgG in diagnosing CD.
Our study has some limitations. First, this is a retrospective chart review, which provides a lower level of evidence than a prospective study. The purpose of conducting a retrospective study is, however, to guide the undertaking of a larger prospective study examining the accuracy of a cascade approach using IgA measurement initially. Second, only 77% of the symptomatic patients underwent upper gastrointestinal endoscopy for performing an SBB. Thus, we may have underestimated or overestimated the results by the lack of availability of SBB for 23% of the cases identified through the present study.
In this cohort of patients, the utility of isolated tTG IgG in diagnosing CD was low at 3%, and that an isolated positive tTG IgG may not predict CD in the setting of a low serum IgA level.
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