This study yielded 2 major findings. First, undiagnosed CD was associated with a nearly 4-fold increased risk of death compared with subjects without serologic evidence of CD. Second, the prevalence of CD appears to have increased dramatically in the United States during the past 50 years.
These results are important because, by testing a unique collection of sera obtained from 1948 to 1954, we were able to study the long-term natural history of CD. Our results confirm recent data (19
) showing that undiagnosed CD is associated with a significant excess mortality over time. Thus, early detection and treatment of presymptomatic CD appear logical if we assume that strict adherence to a gluten-free diet has the same positive effect in undiagnosed CD as previously shown in symptomatic CD (11
). Exploring the potential benefits of early detection and intervention with a gluten-free diet is also important because undiagnosed CD results in excess mortality during middle age. However, both the low number of cases with undiagnosed CD and the missing data render specific comparison unreliable on cause of death between subjects with seronegative results and subjects with undiagnosed CD. Whether treatment actually improves survival in patients with clinically silent CD remains unknown. The benefits, if any and cost-effectiveness of treatment should be prospectively assessed, including any influences on cumulative morbidity, quality of life, and mortality in silent CD (20
). For ethical reasons, it is unlikely that a subject found to have CD, albeit silent, can be randomized to no treatment.
This study suggests that the prevalence of CD has dramatically increased more than 4-fold in the United States during the past 50 years, consistent with the finding in a recent study from Europe (21
). Reasons for the increased prevalence of CD over time are unknown. However, because human genetic changes in response to environmental challenges are extremely slow, the most likely explanation may be environmental, such as a change in quantity, quality, or processing of cereal. Several major changes in wheat genetics, bread processing, and enzymatic modification of wheat prolamins as a result of industry food processing have occurred in the past 40 years (22
). Changing patterns of early childhood infection may also affect the prevalence of autoimmune diseases (“hygiene hypothesis”) (24
), but the host immune system-microbial interactions are complex and some infections (ie, rotavirus) may increase the risk of CD autoimmunity in genetically predisposed children (26
). The hygiene hypothesis is likely only a partial explanation for the increasing prevalence because CD is a global health problem that affects both developed and developing countries (5
For the cohort of subjects with a similar year of birth (older present-day cohort), the higher prevalence of CD compared with that in the historical WAFB cohort cannot be solely explained by a higher detection rate as a result of using modern serologic testing (27
), because the same modern serologic tests were used for diagnosis in both. This finding further supports our theory that an unidentified environmental factor or factors are responsible for the changing prevalence of CD in the United States over time. The potential role of highly processed nutrients as modifiers of gene expression (nutrigenomics) that may alter the risk for development of CD in genetically susceptible individuals is intriguing but difficult to prove experimentally (28
). Because our data are cross-sectional, the exact point in time when the change in prevalence occurred and the actual trend over time are unknown.
Particular strengths of our study included use of a unique collection of 50-year-old sera, availability of 45-year follow-up data, and overall large sample size. Several potential limitations of this study should also be considered, including the lack of diagnostic confirmation of CD by intestinal biopsy. However, the very high specificity of the sequential testing paradigm strongly supports the serologic-based diagnosis of CD and makes false-positive results due to disorders associated with single-antibody positivity (especially tTGA) very unlikely (19
). Survival estimates should be interpreted cautiously because they are based on a limited number of cases of undiagnosed CD and because the deaths are known through only March 1997. Moreover, potential confounders were not systematically evaluated (especially smoking habits, in that some deaths in persons with undiagnosed CD could be smoking-related); thus, the effect of those factors in risk of death in persons with undiagnosed CD is unknown. However, most studies have reported an inverse association between cigarette smoking and CD (30
The major limitation of this study is that the historical WAFB cohort and the present-day cohorts are heterogeneous, although every effort was made to make the cohorts comparable in terms of sex and age. Clinically diagnosed CD is more common in women (female:male ratio, 2–3:1) (1
), but screening-detected CD was equally prevalent in men and women (7
). Although our analysis is limited to male subjects, it is therefore unlikely that our results are biased by sex selection. In addition, the WAFB cohort is composed of male subjects from various parts of the United States, and the present-day cohorts are from the Upper Midwest. The incidence of clinically detected CD has increased recently in Olmsted County, Minnesota (27
), but serologic evidence of CD in the present-day cohorts (~1%) was similar to that in other settings in the United States and Europe (5
). Thus, the difference in the prevalence of undiagnosed CD between the WAFB cohort and present-day cohorts is not explained by a higher risk for CD in the Olmsted County cohorts. African American participation was also higher in the WAFB cohort than in both present-day cohorts, but none of the WAFB subjects with undiagnosed CD were known to be African American, and only 1 subject with undiagnosed CD was known to be African American in both present-day cohorts combined. Therefore, we believe that this imbalance is not confounding the prevalence rate comparisons. In fact, excluding known African Americans in a post-hoc analysis, we found that the rate of undiagnosed CD among WAFB subjects was still substantially less than in the present-day cohorts (data not provided). Finally, we cannot assess the impact that a potential shift in age at onset of CD during the past 50 years may have had on the observed differences in prevalence because all subjects were adults at the time of sampling in the WAFB cohort and the present-day cohorts. However, this possibility seems unlikely as the rate of diagnosis of CD during childhood in Olmsted County has been consistently low for the past 50 years (27
Thus, using a unique collection of sera with the longest follow-up to date, we showed that undiagnosed CD was associated with a nearly 4-fold increased risk of death compared with that in subjects without serologic evidence of CD. This result is clinically relevant. Moreover, our finding that the prevalence of CD seems to have increased dramatically during the past 50 years suggests that CD is emerging as a substantial public health concern in the United States.