Introduction

This article reviews issues related to identifying the appropriate patient to test for celiac disease (CD), the performance characteristics of serologic testing, the role of gene testing for human leukocyte antigen (HLA) DQ2 and DQ8 haplotypes, and issues related to the performance of small intestinal biopsy. The article concludes with a review of special diagnostic considerations in pediatric patients.

Identifying the appropriate patient to test for celiac disease

Diagnoses of CD are increasing in the United States and worldwide. In a population-based study of individuals in Olmsted County, Minnesota, the annual incidence of CD increased dramatically from 0.9 per 100,000 individuals in the years before the availability of serologic tests (1950–1989) to 9.1 per 100,000 in the years 2000 to 2001. Analysis of claims data from a national insurance company found that diagnoses of CD continued to increase through the year 2003, the last year of the analysis.

Despite evidence of increasing rates of diagnosis, the majority of patients in the United States remain undiagnosed. Population-based data are sparse, but inferences on the ratio of undiagnosed to diagnosed individuals can be made based on what is known regarding the seroprevalence of CD in the general population (0.8%–1%). In 2001, the point prevalence of diagnosed CD in Olmsted County was 0.04%. If the seroprevalence of CD is 0.8%, then approximately 95% of patients with CD were undiagnosed at that time. While diagnosis rates are increasing, the fact that the seroprevalence of CD is also increasing may result in a persistently high undiagnosed-to-diagnosed ratio. The high fraction of undiagnosed patients in the United States stands in contrast to parts of Europe, including Italy and Finland, where the threshold to test for CD is lower and thus the fraction of diagnosed patients is substantially higher.

One approach to address the relatively low rates of CD diagnosis in the United States is to institute a program of population screening, whereby all individuals regardless of symptoms undergo serologic testing for CD, and those who screen positive subsequently undergo esophagogastroduodenoscopy (EGD) with small intestinal biopsy. Advocates for this approach note that CD meets World Health Organization criteria for diseases that warrant mass screening: early clinical detection is difficult; the condition is common; screening tests are highly sensitive and specific; effective treatment is available; and untreated disease can lead to complications. Given the reduction in mortality risk that occurs in the years after diagnosis and institution of the gluten-free diet (GFD), and the reduced health care expenditures after diagnosis of CD, screening for CD may be cost effective, and was found to be so in 3 quantitative analyses.

Despite calls for general population screening, problems with this approach have led to targeted case finding becoming the preferred method of increasing diagnosis rates. Apart from unresolved questions regarding the logistics of screening (such as deciding on the appropriate age and interval of screening), limitations of the currently available serologic tests pose a significant problem. Given that the prevalence of CD in the general population is 1%, any test with an imperfect specificity will result in a large number of false positives. Assuming that the specificity of tissue transglutaminase (TTG) immunoglobulin A (IgA) is 98%, its positive predictive value when used in the general population is only 34%; as a result, two-thirds of screened individuals who have a positive result will undergo EGD with biopsy and not be diagnosed with CD. This false-positive rate may be reduced by performing a biopsy only on patients with dual positive serologies of TTG endomysial antibody (EMA), but difficulties with the latter serology (see later section Serologic and Genetic Testing ) makes this approach less than ideal.

In addition to the technical limitations of serologic screening and its attendant false-positive rate, one objection to routine screening for CD is based on the persistent uncertainty regarding the long-term prognosis of asymptomatic, undiagnosed CD. A major argument for screening is that CD is associated with an increased mortality risk, which declines in the years following diagnosis, a decrease that is attributed to the protective effects of the GFD. The evidence for a mortality risk in undiagnosed CD is less consistent. In an analysis of thawed serum, Rubio-Tapia and colleagues identified individuals with positive CD serologies (both TTG and EMA) in 14 out of 9133 (0.2%) participants in the Warren Air Force cohort. With a follow-up period of 45 years, the patients with seropositivity (who all remained undiagnosed) had a nearly 4-fold risk of death compared with seronegative individuals (hazard ratio [HR] 3.9; 95% confidence interval [CI] 2.0–7.5). In a second cohort study, healthy volunteers with a positive TTG had an increased mortality compared with seronegative subjects (HR 2.53; 95% CI 1.50–4.25). However, in 4 other studies in England, Finland, Ireland, and individuals older than 50 years in Olmsted county, no increase in mortality was noted in undiagnosed seropositive individuals in comparison with their seronegative counterparts. A recent meta-analysis found a modestly increased mortality risk in patients with CD based on serology alone (odds ratio [OR] 1.16; 95% CI 1.02–1.31), but this pooled analysis included seropositive patients who underwent small intestinal biopsy that was normal, raising the possibility of confounding by indication.

The conflicting data with regard to mortality risk in undiagnosed CD are likely due to differences in age, definitions of seropositivity, and follow-up time, but given this residual uncertainty in magnitude of risk, if any, these data do not justify population screening. Although enteropathy-associated T-cell lymphoma appears to be rising in incidence in the United States, possibly as a result of the increased number of patients with undiagnosed CD, given the rarity of this condition it would not justify population screening for CD based on this consideration alone. At the other end of the spectrum of clinical severity, apparently asymptomatic patients may report improved quality of life after screen-detected diagnosis of CD, but data on this topic are insufficient to establish that widespread screening of the population is cost effective.

The favored alternative to population screening at this time is a case-finding approach, whereby health care providers order serologic testing for CD in patients who exhibit one or more of the symptoms, signs, or other diseases closely associated with CD. In this approach, the problem of high false-positive rates of serologic tests is reduced, because the underlying prevalence of CD in a symptomatic or high-risk group is likely to be higher than that of the general population. The feasibility and effectiveness of the case-finding approach was demonstrated in a multicenter study in which adult patients attending a primary care office were given a questionnaire soliciting symptoms (such as diarrhea, abdominal pain, chronic fatigue, and infertility), abnormal laboratory values (including anemia and abnormal liver tests), or associated diseases (such as irritable bowel syndrome, any autoimmune disease, Down syndrome, and Turner syndrome). Individuals responding affirmatively to 1 or more of these items were offered serologic testing for CD and, if positive, EGD with small intestinal biopsy. During the 3-year period, 976 of 2568 eligible patients (38%) responded affirmatively and agreed to serologic testing. Of these 2568 patients, 22 (2.3%) were ultimately diagnosed with CD based on serology and biopsy. Of note, the overall diagnosis rate markedly increased. Compared with the 12-month period preceding the case-finding initiative, the diagnosis rate increased from 0.27 cases per 1000 visits to 8.6 cases per 1000 visits. Such an approach, while increasing diagnosis rates, may still leave the majority of patients undiagnosed.

Although the case-finding approach is the favored strategy, it remains a matter of controversy as to which symptoms and associated diseases should prompt evaluation for CD. Given the protean clinical manifestations of CD and the expanding list of associated conditions, the strategy of testing for CD for one associated symptom or condition may approach that of screening the general population, because nearly 100% of respondents may respond affirmatively to at least one item. For example, in the case-finding study by Catassi and colleagues, 64% of all participants were eligible for CD testing, and this questionnaire did not include additional items that may be justifiably included in a CD symptom checklist, such as peripheral neuropathy, migraines, gastroesophageal reflux, low bone density, and low levels of high-density lipoprotein.

A recent study set at a health fair in Caspar, Wyoming sheds light on the fine line between case finding and screening of the general population. In this study, 3850 individuals attending the health fair submitted a blood sample that was tested for TTG, and serum with positive results then underwent confirmatory EMA testing. These individuals also completed a questionnaire querying respondents for gastrointestinal symptoms including bloating, abdominal pain, heartburn, nausea, diarrhea, and constipation. Of the 3850 subjects, 34 had a positive TTG and EMA, yielding a prevalence of 0.8%. (Thirty-one of these 34 had not been previously diagnosed with CD, yielding an undiagnosed-to-diagnosed ratio of 10:1.) When comparing seropositive to seronegative individuals with regard to gastrointestinal symptoms, none of these symptoms were predictive of seropositivity. This null finding was due in part to these symptoms being quite common; more than 80% of all respondents had at least one such symptom. Thus, an aggressive case-finding strategy may closely resemble a de facto mass screening approach.

At present, there is no universally accepted threshold for testing for CD among physicians who have adopted this recommended strategy of case finding. Consensus statements from the United States and Europe broadly agree with the need to test for CD in scenarios such as chronic diarrhea and unexplained iron deficiency. However, there is less agreement on whether screening asymptomatic patients in high-prevalence groups (such as first-degree relatives or patients with autoimmune thyroiditis) should be recommended or merely offered with the caveat that the benefits of diagnosing asymptomatic patients are unclear. Because a low threshold (ie, a long list of symptoms that would prompt testing) may result in a testing a large proportion of patients seeking health care, it is imperative that physicians using this strategy have a solid understanding of the performance characteristics of serologic tests.

Identifying the appropriate patient to test for celiac disease

Diagnoses of CD are increasing in the United States and worldwide. In a population-based study of individuals in Olmsted County, Minnesota, the annual incidence of CD increased dramatically from 0.9 per 100,000 individuals in the years before the availability of serologic tests (1950–1989) to 9.1 per 100,000 in the years 2000 to 2001. Analysis of claims data from a national insurance company found that diagnoses of CD continued to increase through the year 2003, the last year of the analysis.

Despite evidence of increasing rates of diagnosis, the majority of patients in the United States remain undiagnosed. Population-based data are sparse, but inferences on the ratio of undiagnosed to diagnosed individuals can be made based on what is known regarding the seroprevalence of CD in the general population (0.8%–1%). In 2001, the point prevalence of diagnosed CD in Olmsted County was 0.04%. If the seroprevalence of CD is 0.8%, then approximately 95% of patients with CD were undiagnosed at that time. While diagnosis rates are increasing, the fact that the seroprevalence of CD is also increasing may result in a persistently high undiagnosed-to-diagnosed ratio. The high fraction of undiagnosed patients in the United States stands in contrast to parts of Europe, including Italy and Finland, where the threshold to test for CD is lower and thus the fraction of diagnosed patients is substantially higher.

One approach to address the relatively low rates of CD diagnosis in the United States is to institute a program of population screening, whereby all individuals regardless of symptoms undergo serologic testing for CD, and those who screen positive subsequently undergo esophagogastroduodenoscopy (EGD) with small intestinal biopsy. Advocates for this approach note that CD meets World Health Organization criteria for diseases that warrant mass screening: early clinical detection is difficult; the condition is common; screening tests are highly sensitive and specific; effective treatment is available; and untreated disease can lead to complications. Given the reduction in mortality risk that occurs in the years after diagnosis and institution of the gluten-free diet (GFD), and the reduced health care expenditures after diagnosis of CD, screening for CD may be cost effective, and was found to be so in 3 quantitative analyses.

Despite calls for general population screening, problems with this approach have led to targeted case finding becoming the preferred method of increasing diagnosis rates. Apart from unresolved questions regarding the logistics of screening (such as deciding on the appropriate age and interval of screening), limitations of the currently available serologic tests pose a significant problem. Given that the prevalence of CD in the general population is 1%, any test with an imperfect specificity will result in a large number of false positives. Assuming that the specificity of tissue transglutaminase (TTG) immunoglobulin A (IgA) is 98%, its positive predictive value when used in the general population is only 34%; as a result, two-thirds of screened individuals who have a positive result will undergo EGD with biopsy and not be diagnosed with CD. This false-positive rate may be reduced by performing a biopsy only on patients with dual positive serologies of TTG endomysial antibody (EMA), but difficulties with the latter serology (see later section Serologic and Genetic Testing ) makes this approach less than ideal.

In addition to the technical limitations of serologic screening and its attendant false-positive rate, one objection to routine screening for CD is based on the persistent uncertainty regarding the long-term prognosis of asymptomatic, undiagnosed CD. A major argument for screening is that CD is associated with an increased mortality risk, which declines in the years following diagnosis, a decrease that is attributed to the protective effects of the GFD. The evidence for a mortality risk in undiagnosed CD is less consistent. In an analysis of thawed serum, Rubio-Tapia and colleagues identified individuals with positive CD serologies (both TTG and EMA) in 14 out of 9133 (0.2%) participants in the Warren Air Force cohort. With a follow-up period of 45 years, the patients with seropositivity (who all remained undiagnosed) had a nearly 4-fold risk of death compared with seronegative individuals (hazard ratio [HR] 3.9; 95% confidence interval [CI] 2.0–7.5). In a second cohort study, healthy volunteers with a positive TTG had an increased mortality compared with seronegative subjects (HR 2.53; 95% CI 1.50–4.25). However, in 4 other studies in England, Finland, Ireland, and individuals older than 50 years in Olmsted county, no increase in mortality was noted in undiagnosed seropositive individuals in comparison with their seronegative counterparts. A recent meta-analysis found a modestly increased mortality risk in patients with CD based on serology alone (odds ratio [OR] 1.16; 95% CI 1.02–1.31), but this pooled analysis included seropositive patients who underwent small intestinal biopsy that was normal, raising the possibility of confounding by indication.

The conflicting data with regard to mortality risk in undiagnosed CD are likely due to differences in age, definitions of seropositivity, and follow-up time, but given this residual uncertainty in magnitude of risk, if any, these data do not justify population screening. Although enteropathy-associated T-cell lymphoma appears to be rising in incidence in the United States, possibly as a result of the increased number of patients with undiagnosed CD, given the rarity of this condition it would not justify population screening for CD based on this consideration alone. At the other end of the spectrum of clinical severity, apparently asymptomatic patients may report improved quality of life after screen-detected diagnosis of CD, but data on this topic are insufficient to establish that widespread screening of the population is cost effective.

The favored alternative to population screening at this time is a case-finding approach, whereby health care providers order serologic testing for CD in patients who exhibit one or more of the symptoms, signs, or other diseases closely associated with CD. In this approach, the problem of high false-positive rates of serologic tests is reduced, because the underlying prevalence of CD in a symptomatic or high-risk group is likely to be higher than that of the general population. The feasibility and effectiveness of the case-finding approach was demonstrated in a multicenter study in which adult patients attending a primary care office were given a questionnaire soliciting symptoms (such as diarrhea, abdominal pain, chronic fatigue, and infertility), abnormal laboratory values (including anemia and abnormal liver tests), or associated diseases (such as irritable bowel syndrome, any autoimmune disease, Down syndrome, and Turner syndrome). Individuals responding affirmatively to 1 or more of these items were offered serologic testing for CD and, if positive, EGD with small intestinal biopsy. During the 3-year period, 976 of 2568 eligible patients (38%) responded affirmatively and agreed to serologic testing. Of these 2568 patients, 22 (2.3%) were ultimately diagnosed with CD based on serology and biopsy. Of note, the overall diagnosis rate markedly increased. Compared with the 12-month period preceding the case-finding initiative, the diagnosis rate increased from 0.27 cases per 1000 visits to 8.6 cases per 1000 visits. Such an approach, while increasing diagnosis rates, may still leave the majority of patients undiagnosed.

Although the case-finding approach is the favored strategy, it remains a matter of controversy as to which symptoms and associated diseases should prompt evaluation for CD. Given the protean clinical manifestations of CD and the expanding list of associated conditions, the strategy of testing for CD for one associated symptom or condition may approach that of screening the general population, because nearly 100% of respondents may respond affirmatively to at least one item. For example, in the case-finding study by Catassi and colleagues, 64% of all participants were eligible for CD testing, and this questionnaire did not include additional items that may be justifiably included in a CD symptom checklist, such as peripheral neuropathy, migraines, gastroesophageal reflux, low bone density, and low levels of high-density lipoprotein.

A recent study set at a health fair in Caspar, Wyoming sheds light on the fine line between case finding and screening of the general population. In this study, 3850 individuals attending the health fair submitted a blood sample that was tested for TTG, and serum with positive results then underwent confirmatory EMA testing. These individuals also completed a questionnaire querying respondents for gastrointestinal symptoms including bloating, abdominal pain, heartburn, nausea, diarrhea, and constipation. Of the 3850 subjects, 34 had a positive TTG and EMA, yielding a prevalence of 0.8%. (Thirty-one of these 34 had not been previously diagnosed with CD, yielding an undiagnosed-to-diagnosed ratio of 10:1.) When comparing seropositive to seronegative individuals with regard to gastrointestinal symptoms, none of these symptoms were predictive of seropositivity. This null finding was due in part to these symptoms being quite common; more than 80% of all respondents had at least one such symptom. Thus, an aggressive case-finding strategy may closely resemble a de facto mass screening approach.

At present, there is no universally accepted threshold for testing for CD among physicians who have adopted this recommended strategy of case finding. Consensus statements from the United States and Europe broadly agree with the need to test for CD in scenarios such as chronic diarrhea and unexplained iron deficiency. However, there is less agreement on whether screening asymptomatic patients in high-prevalence groups (such as first-degree relatives or patients with autoimmune thyroiditis) should be recommended or merely offered with the caveat that the benefits of diagnosing asymptomatic patients are unclear. Because a low threshold (ie, a long list of symptoms that would prompt testing) may result in a testing a large proportion of patients seeking health care, it is imperative that physicians using this strategy have a solid understanding of the performance characteristics of serologic tests.

Serologic and genetic testing

Clinical Use of Serologic Tests

Serologic tests are useful to evaluate patients with suspected CD, and may be helpful in monitoring adherence to the GFD. Among adult patients with chronic abdominal symptoms, IgA TTG and IgA EMA have high accuracy for the diagnosis of CD. The initial serologic test of choice for CD diagnosis is IgA TTG. Sequential testing (IgA TTG–positive followed by IgA EMA) has been an effective strategy for detection of CD in large epidemiologic studies but its accuracy in clinical practice may require further study, especially if the intention is to avoid an intestinal biopsy for confirmation of CD. Testing for CD is accurate only if the patient continues to follow a gluten-containing diet; therefore, it is important to inform patients that they should not start a GFD until the diagnostic process is completed. Indeed, all serologic tests could become negative after gluten withdrawal. False-negative serologic testing should be strongly considered in patients with selective IgA deficiency. In this scenario, cascade testing or, alternatively, concurrent measurement of total IgA should be considered. IgA- deficient patients should be evaluated by measurement of immunoglobulin G (IgG) TTG, IgG deamidated gliadin peptides (DGP), and/or IgG EMA. In addition, a false-negative test result is more likely in young children (<2 years of age) and among patients with nonatrophic lesions. Further assessment is needed when serology tests are negative but clinical suspicion of CD is high; approximately 10% of patients with CD are seronegative. Intestinal biopsy to confirm or exclude CD is indicated in people with (1) a positive serologic result from any TTG, deamidated gliadin antibodies, or EMA test; and (2) seronegative patients if celiac disease is highly suspected and genetic testing is positive. A cascade testing algorithm used at Mayo Clinic for the diagnosis of CD is summarized in Fig. 1 .

The Mayo Clinic celiac disease diagnostic testing algorithm. Serology and genetic testing are part of an automated laboratory cascade testing, meaning that a sequence of tests driven by real-time results is used to diagnose celiac disease using a single blood draw. This cascade testing is intended for adults on a gluten-containing diet.

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