The Agency for Healthcare Research and Quality has issued a systematic review of the evidence regarding screening patients for celiac disease, a small-bowel malabsorption disorder that results in mucosal inflammation, villous atrophy, and crypt hyperplasia, which occur on exposure to gluten, and clinical and histologic improvement when gluten is withdrawn from the diet. The full report is available at http://www.ahrq.gov/downloads/pub/evidence/pdf/celiac/celiac.pdf; a shorter summary is available at http://www.ahrq.gov/clinic/epcsums/celiacsum.htm. While the report does not make specific recommendations, it provides the best available evidence so physicians and patients can make their own decisions.

Celiac disease—also referred to as celiac sprue, gluten-sensitive enteropathy, and non-tropical sprue—is thought to result from the activation of both a cell-mediated (T cell) and humoral (B cell) immune response on exposure to the glutens (prolamins and glutenins) of wheat, barley, rye, and oats in a genetically susceptible person. The diagnosis of celiac disease in adults is classically made on the basis of clinical suspicion (i.e., isolated iron deficiency, combined iron and folate deficiency, osteoporosis) and findings of a duodenal biopsy while the patient is on a gluten-containing diet, followed by clinical and histologic improvement after a gluten-free diet (GFD) is initiated.

Untreated celiac disease is associated with a number of complications, including nutritional problems, anemia, reduced bone-mineral density, and intestinal lymphoma. Most patients are treated successfully with a GFD. However, mounting evidence implies that celiac disease is much more common than previously was thought, so patients at risk should be screened.

In this report, investigators assessed the literature to systematically review five areas of celiac disease: (1) sensitivity and specificity of serologic tests; (2) prevalence and incidence of celiac disease; (3) celiac disease–associated lymphoma; (4) consequences of testing for celiac disease; and (5) interventions to institute a GFD.

Sensitivity and Specificity of Serologic Tests

Several serologic markers have become available that may help diagnose celiac disease. The sensitivity of IgA anti-gliadin antibodies is reported to range from 70 to 85 percent; the specificity ranges from 70 to 90 percent. IgA anti-endomysial and anti-tissue transglutaminase antibodies have sensitivities that exceed 90 percent and specificities of more than 95 percent.

Human leukocyte antigen DQ2/DQ8 testing also may be useful in diagnosing celiac disease. The test has high sensitivity (exceeding 90 to 95 percent), but because about 30 percent of the general population, and an even higher proportion of high-risk persons (e.g., those with diabetes), also carry these markers, the specificity of this test is not ideal. The best use of this test is its negative predictive value. That is, when negative, it rules out the diagnosis, but when positive, it requires confirmation.

Biopsy itself, when used with a strict cutoff requiring villous atrophy, appears to have high specificity but poor sensitivity. Thus, it is helpful at confirming a suspected diagnosis when positive, but a negative result does not rule out the diagnosis. The use of a lower-grade cutoff improves sensitivity, but then the specificity suffers. The use of histomorphometric measures such as quantification of gamma delta positive intraepithelial lymphocytes is likely to allow for the use of lower-grade cutoffs while maintaining reasonable specificity.

Prevalence and Incidence of Celiac Disease

The prevalence of celiac disease is hard to estimate because of the variable presentation of the disease and because many patients do not exhibit symptoms. However, the disease occurs most often in Celtic populations. Celiac disease can affect persons of various ethnic backgrounds, but it rarely affects persons of purely Chinese, Japanese, or Afro-Caribbean descent. Several high-risk groups who have a prevalence of celiac disease greater than that of the general population have been identified and include first-degree family members of patients with celiac disease, and persons with type 1 diabetes, iron-deficiency anemia, low bone-mineral density (i.e., osteoporosis, osteopenia), Down syndrome, short stature, or infertility.

The crude incidence of celiac disease in adults varied from lows of 1.3 per 100,000 patient-years in Denmark and 3.1 per 100,000 patient-years in England to a high of 17.2 cases per 100,000 patient-years in Finland, where specific efforts had been undertaken to encourage screening for celiac disease.

The prevalence studies that were reviewed had important differences, including execution, tests for prevalence assessment, and patient sampling. Thus, results have to be interpreted in light of some of the limitations of the testing for celiac disease. Nonetheless, the data suggest that celiac disease is a common disorder, with a prevalence in the general population that is likely close to 1:100 (1 percent).

Celiac Disease–Associated Lymphoma

There is a strong association between celiac disease and gastrointestinal lymphoma. Lymphoma is four to 40 times more common, and death from lymphoma is 11 to 70 times more common, in patients with celiac disease. Delay in diagnosis—and possibly a diagnosis of celiac disease in adulthood as opposed to in childhood—may be associated with poorer outcomes. Several studies suggest that adherence to a GFD reduces the risk of lymphoma in patients with celiac disease.

The major complications of celiac disease include intestinal and extraintestinal malignancies, ulcerative jejunoileitis, and collagenous sprue. Lymphomas associated with celiac disease appear to be most commonly of T-cell origin. Unfortunately, the prognoses for patients with celiac disease–associated T-cell lymphomas, ulcerative jejunoileitis, and collagenous sprue appear grim. It is widely believed that strict adherence to a GFD reduces the risk of these complications. It is suggested that by five years of dietary adherence, the risk of lymphoma in patients with celiac disease approaches that of the general population.

Consequences of Testing for Celiac Disease

The consequences of testing for celiac disease are not well known because there is almost a complete absence of studies of interventions for the promotion of adherence to a GFD, which is the main treatment for celiac disease. One major consequence is the well-established relationship between celiac disease and gastrointestinal lymphoma. The consequences of testing for celiac disease in at-risk and symptomatic patients are straightforward, because these patients tend to be more compliant with a GFD and would be expected to benefit from this intervention. The data are less clear for asymptomatic screen-identified patients, particularly those who have truly silent celiac disease or who do not have fully developed villous atrophy. The outcome for such patients has not been studied extensively, but compliance with a GFD appears to be problematic, particularly for those diagnosed in adulthood.

Interventions to Institute a GFD

No specific interventions have been identified that promote adherence to a GFD, but education of patients and family members about celiac disease and about the intricacies of a GFD, and participation in local celiac societies, has been shown to improve compliance.

Biopsy monitoring of adherence to a GFD appears to be important: improvement in histologic grade has been associated with improved bone-mineral density, iron-deficiency anemia, and nutritional status. The serologic markers appear to be adequate for detecting patients who fail grossly to adhere to a GFD, but they appear to have poor sensitivity for detecting lesser degrees of dietary indiscretion, and they inadequately correlate with histologic improvement. However, children show more rapid and complete histologic improvement on a GFD, so monitoring adherence by using serology is reasonable in this age group.

No study has objectively determined the level of histologic improvement that would be associated with improved outcomes. Nonetheless, it appears that follow-up biopsy at least one year after initiation of a GFD in adults to document improvement of the histologic grade would be valuable.

Conclusion

The most important need in the study of patients with celiac disease is the development of a consensus on the definition of celiac disease in an era of advanced serologic testing. A new gold standard of diagnosis is needed—perhaps one that includes a combination of serology, biopsy, and human leukocyte antigen testing. Because the incidence of celiac disease has been underreported, it needs to be decided whether the general population should be screened; before that can be done, markers have to be better identified, and more sensitive and specific testing needs to be created. However, the number of studies that report histologic improvement of patients on a GFD is encouraging—assuming that patients will adhere to such a diet.