The historical prevalence and long-term outcome of undiagnosed [CD] are unknown, write Alberto Rubio-Tapia, from the Mayo Clinic in Rochester, Minnesota, and colleagues. We investigated the long-term outcome of undiagnosed CD and whether the prevalence of undiagnosed CD has changed during the past 50 years.

The study collected sera from 9133 healthy young men at Warren Air Force Base (WAFB) between 1948 and 1954 and from 12,768 matched subjects from 2 recent cohorts in Olmsted County. They were matched by sex and by either similar years of birth (n = 5558) or age at sampling (n = 7210). Sera was also tested for endomysial antibodies if found with abnormal values of tissue transglutaminase. Over a 45-year follow-up survival was measured in the WAFB cohort and the prevalence of undiagnosed CD was compared in the WAFB cohort vs the recent matched cohorts.

Of 9133 persons, undiagnosed CD was present in 14 (0.2%) in the WAFB cohort. Those with undiagnosed CD had greater all-cause mortality during 45 years of follow-up (hazard ratio, 3.9; 95% confidence interval, 2.0 – 7.5; P < .001) than those who were seronegative.

For the 2 recent cohorts, 68 (0.9%) of those with similar age at sampling had undiagnosed CD, as did 46 (0.8%) of those with similar years of birth, yielding a 4.5-fold and 4-fold greater rate of undiagnosed CD in the recent cohorts, respectively, than in the WAFB cohort (both P < .0001).

During 45 years of follow-up, undiagnosed CD was associated with a nearly 4-fold increased risk of death, the study authors write. The prevalence of undiagnosed CD seems to have increased dramatically in the United States during the past 50 years.

The study limitations include heterogeneity of the cohorts, failure to systematically evaluate potential confounders, and cross-sectional data precluding determination of the exact point in time when the change in prevalence occurred and the actual trend over time. Moreover, survival estimates are based on a limited number of cases of undiagnosed CD and on deaths recorded only through March 1997.

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, because the same modern serologic tests were used for diagnosis in both, the study authors conclude. 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.