The Incidence and Risk of Celiac Disease in a Healthy US Adult Population

Mark S. Riddle, MD, DrPH; Joseph A. Murray, MD; Chad K. Porter, PhD


Am J Gastroenterol. 2012;107(8):1248-1255. 

In This Article


This study demonstrates a substantial increased incidence and diagnosis rate of CD in a large, generally healthy young adult population for which there is excellent capture of diagnosis and ready access to health care. This rise in incidence is consistent with what has been reported in other western industrialized population-based studies[9,16] and likely represents a combination of both increased diagnoses due to increased suspicion but also may reflect a true increase in incidence possibly related to environmental changes in cereal processing including wheat genetics, bread processing, and enzymatic modification of wheat prolamins resulting from changes in industry processes.[17] It is interesting that this increase in incidence seemed to be more marked in individuals in the third, fourth, and fifth decades in life, among those who would have already been in the military service for many years, suggesting that this is a true new onset of disease or the emergence of longstanding silent disease. We did not have data available on secular trends for number of serological CD tests performed, which should be done to inform the potential bias associated with increased testing that could partially explain the increased incidence (studies planned).[16]

Clearly, environmental, genetic, and immunological factors have a role in the pathogenesis of CD. It is well accepted that the common HLA genotype encoding HLA types DQ2 or DQ8 is necessary for CD to occur.[18] However, as almost 30% of the Caucasian population carries these genotypes, and virtually all eat gluten, there must be other factors including genetics, immune dysfunction, and environmental exposures that trigger the disease. Extensive genetic analysis has revealed a large number of other genes that all have very small attributable risks that cumulatively only add 10% of risk.[19] The balance of genetic and environmental influences in risk of disease is also supported by the 75% concordance in monozygous twin studies.[20] Although the only well-documented environmental trigger is gliadin, it has been proposed that the clinical expression of CD can be modulated by environmental factors. It is possible that in genetically susceptible patients, an infectious insult may contribute to trigger overt CD through increased intestinal permeability, or adjuvant effects of infection or inflammation, latent CD may be unmasked.

Given the potential for infections to act as triggers for developing gluten intolerance through molecular mimicry or other immune modulation mechanisms, efforts to identify an infectious association have be made. However, to date, there is no compelling evidence for such an association.[21] Neonatal infections have been associated with increased risk of CD, and the role of adenovirus 12 virus remains controversial. Based on the 12 amino-acid homology sequence of adenovirus type 12 E1B protein and α-gliadin, it has been suggested that exposure to adenovirus type 12 E1B may sensitize individuals to gliadin and trigger CD. However, it is difficult to establish a causative relationship between adenovirus type 12 E1B and gliadin, because adenovirus type 12 E1B is also highly prevalent in the duodenal tissue of normal individuals.[22] CD is epidemiologically associated with other viral infections, such as chronic hepatitis C, non-viral disorders including insulin-dependent diabetes, thyroid disease and cardiomyopathy, and HIV.[22,23] This suggests that the association may involve chronic immune stimulation, which in turn triggers an autoimmune reaction.

In the present study, we found an increased odds ratio of exposure to prior IGE twice as high among CD cases compared with matched controls (OR: 2.0, 95% CI: 1.4, 2.8). Non-viral IGE exposure odds were relatively higher (OR: 3.0, 95% CI: 1.9, 4.8), and odds of exposure were higher when looking at temporal proximity to CD diagnosis. Unfortunately, we do not have specific pathogen etiologies associated with these infections, and while these results are intriguing, the potential for misclassification of exposure given the conflated symptomatology of infectious diarrhea and CD confounds the potential association in this study. While much is known about the pathogenic adaptive and innate immune responses associated the disease process, less is known about the initiating steps that are involved in disease onset. As demonstrated in animal models of gluten sensitivity,[24,25] gastrointestinal infection may trigger or facilitate the onset of clinical CD, either by increasing intestinal permeability or by enhancing uptake and dysfunctional anti-gliadin immune response in the genetically susceptible host.[26,27] It is reasonable to suspect that acute gastrointestinal infections could result in the translocation of luminal antigens, including incompletely digested gluten peptides, which in the background of pro-inflammatory anti-bacterial responses could trigger a maladaptive immune response.[2] Campylobacter jejuni, a leading cause of enterocolitis worldwide, has been shown experimentally to permit the translocation of normal, non-invasive microflora via novel processes that implicate epithelial lipid rafts and M-cell transport and induce a pro-inflammatory response.[28–30] Thus, similarly to the epidemiological studies observing Campylobacter and Salmonella infections as a trigger of inflammatory bowel disease[31,32] it is possible that such infections could also trigger luminal antigens, including gluten peptides, across the intestinal barrier, and in certain susceptible individuals prime a mucosal immune response toward such antigens resulting in loss of tolerance to these antigens due to an inappropriate inflammatory response.[33,34]

With regard to what is known about infectious diarrhea as a trigger for CD there are a few anecdotal reports and case series suggesting an association whereby some patients with CD often attribute the onset of classic symptoms to a stressful episode or gastroenteritis,[35] and cases of CD have been reported as presenting as persistent travelers' diarrhea when no infectious cause could be documented.[36,37] It has also been described that exposure to three or more IGE events in young children at or around the time of introduction of follow-on formula was associated with a substantial increased risk of childhood diagnosis of CD.[38] In addition, a birth cohort followed in Denver suggested that rotovirus infection in the first year of life was associated with subsequent risk for CD.[3] More recently, a case of a healthy subject who developed sudden irritable bowel syndrome-like symptoms after a confirmed episode of C. jejuni enteritis was subsequently diagnosed with new onset CD.[39] It is interesting that in this study, we found a higher risk of CD in subjects who were diagnosed with a "non-viral" IGE episode. While the ICD-9-based diagnosis is non-specific, it would suggest that bacterial infections could be more associated with subsequent diagnosis of CD. In total, the results we found lend support to the infectious trigger hypothesis, though this study relied on non-specific (and potentially misclassified) infectious gastrointestinal exposures, which needs confirmation through studies evaluating risk after pathogen-specific exposures.

While CD is known to predominantly affect Caucasians, less is known about the incidence of CD in non-Caucasians. As this cohort of active military service personnel incorporates large numbers of individuals who are non-Caucasian, with unhindered access to medical care, the low incidence seen in non-Caucasians likely reflects a true difference in biologic predisposition, although rates increased during the study period that may implicate secular trends in environmental influences which has been seen in inflammatory bowel disease rates among non-whites.[40] It is unlikely that there would be significant differences in environmental exposures or diet due to common food and preparation and provision with the military service, though it is possible that there may be inherently lower suspicion for CD by the medical personnel caring for individuals who are non-Caucasian. Future active surveillance study should be considered including sampling of non-Caucasians to verify that incidence is truly lower and not simply undiagnosed. Other US military population specific differences were noted. The association of CD with officer rank and higher educational level begets the positive association with socioeconomic status. This has been suggested in an epidemiologic study from Finland wherein there is a higher rate of CD in the more developed population of Finland than the adjacent less developed population.[41] It is, however, possible that educational levels may have lead to increased awareness of this diagnosis, and also there may be a negative association with smoking for which we could not control.

Interestingly, we found that deployment decreased the risk of CD that may be counterintuitive given the known high risk of infectious exposures, including gastrointestinal infections, and stress while deployed. Unfortunately, capture of deployment-related illness and injury into the Defense Medical Surveillance System (DMSS) medical encounter databases is not complete; therefore, assessment of deployment-related illness effects (particularly minor ones) is incomplete. Furthermore, military members with underlying medical illness may not be deployed resulting in a type of "healthy worker" effect, which might also explain the lower rate of CD in deployed personnel compared with their non-deployed counterparts. Surgical stress has been described to trigger CD,[42] and future studies should be designed to capture these data to further evaluate deployment-related infectious and non-infectious exposures of interest.

This study has several limitations. First, an important limitation is that CD diagnoses were based on a medical encounter database, and while we believe our strategy for determining case status is robust based on prior experience with other complex diseases[12,43–45] it is not possible to review individual medical records to confirm. Additional studies are needed (and being planned) that use clinical procedure codes associated with upper endoscopy and histology, as well as serological evidence from linked Department of Defense serum repository specimens. Furthermore, given our reliance on clinically diagnosed CD, our incidence estimates should be considered as a gross underestimate of the true incidence in the population, though we feel the secular trends and differential rates among demographic subgroups are relevant observations. Second, as mentioned, the precise identification of enteropathogens associated with IGE visits was not described, due to the fact that laboratory work-up of these infections is infrequently carried out in US military as well as in civilian clinics and emergency rooms. Furthermore, our stratification of IGE into viral and non-viral categories is imprecise. It is further possible that these gastroenteritis episodes that were called IGE may actually have represented short-lived symptom events associated with subsequently diagnosed CD. To assess for such an effect, we utilized a 6-month exposure exclusion period before initial CD diagnosis (or control censoring) to prevent misclassification of initial CD presentation as an episode of IGE, and we did not see such effect (data not shown). However, if the duration between exposure and disease onset is short, then we may have underrepresented the true association biasing the results toward the null. Additionally, to minimize potential misclassification, this study excluded functional gastrointestinal disorders among controls and did not include such medical encounter visits before onset of incident CD. While not directly addressing this potential source of bias, excluding CD cases with functional gastrointestinal disorders co-diagnoses in this study did not change in the primary effect estimate of any IGE exposure (adjusted-OR: 2.00, 95% CI: 1.37–2.90). Finally, this study cohort does not address CD in the elderly or in the very young, and indeed individuals with chronic ill health are generally not admitted into military service; hence, this study may underestimate the true incidence in the general population.

In summary, our study shows a substantial increase in the rate of CD diagnosis in adult healthy Caucasian population with a much lower but increasing incidence in non-Caucasians. The disease is more likely to be diagnosed after a proximate IGE event of a non-viral nature and contribute to the emerging body of data that warrants further prospective or seroepidemiological studies linking pathogen-specific infectious diarrhea exposure attribution to incident CD. Studies that aim to evaluate the instigating exposures and mechanisms of CD-related antibody development, or initiation of disease in those who were previously asymptomatic but with pre-existence of positive celiac serology are needed (planned).