We had the unique opportunity to examine the relationship between ACEs and the likelihood of hospitalizations with AD identified through hospital discharge records. As the number of ACEs increased, the likelihood of hospitalizations with Th1, Th2, Th2-rheumatic, and any of 21 types of ADs also increased. Moreover, the relationship between the ACE Score and AD hospitalizations was stronger among younger adults. To our knowledge, this study is the first to demonstrate a relationship between multiple types of childhood adversity on hospitalizations for AD during adulthood.
Research on nervous, endocrine, and immune interactions has revealed that these systems are anatomically and functionally interconnected (11
). Stressors, such as infections, toxins, and/or psychological trauma, stimulate the hypothalamic-pituitary-adrenal axis to release corticoid-releasing hormone (CRH), resulting in elevated systemic levels of corticosteroids, such as glucocorticoids. Acute stress initially may increase inflammation through acute-phase mediators like IL-1, IL-6, and CRP that are eventually downregulated by glucocorticoids thereby maintaining homeostasis (46
). Chronic stress has the opposite effect and decreases glucocorticoid levels. A recent epidemiologic study confirmed the link between childhood abuse and long-term changes in immune response (36
); in this longitudinal study, childhood abuse was associated with elevated CRP levels, white blood cell counts, and other markers of inflammation 20 years later (36
Women and female rodents have higher systemic baseline levels of glucocorticoids than their male counterparts due to the transcriptional regulation of CRH by estrogen (11
). In a similar manner, estrogen increases IL-4 levels in females, resulting in a greater Th2-type immune response (7
). Increased glucocorticoid levels in females further enhance IL-4 production (11
). In contrast, testosterone reduces glucocorticoid and IL-4 levels in males, resulting in a predominantly IFN-γ, Th1-type immune response to infection or trauma (11
). Research in rodents (6
) and the observed immunopathology and sex prevalence of certain ADs (8
) suggests that sex-specific immune mechanisms may account for the observed differences. In our study, hospitalizations for Th1-associated ADs were more common in men in this cohort, whereas hospitalizations for Th2-associated ADs, such as rheumatoid disorders, were more common in women. This is the first epidemiological study confirming this immunopathologic relationship.
Rheumatic diseases are a group of inflammatory disorders in which autoantibodies and immune complex deposition produce tissue damage (44
). One of the characteristics of rheumatic diseases is the production of rheumatoid factor (RF), which is an autoantibody that binds other antibodies. RF is usually produced following viral infections (44
), suggesting that infections may contribute to the development of AD (49
). Fairweather and Frisancho-Kiss have found that social stress occurring before viral infection in rodents increased inflam matory heart disease in both sexes, but especially in females (unpublished results). These findings and the present study suggest that childhood stressful events may increase ADs independently as well as amplify the effect of other environmental factors, such as infections. Thus, a possible explanation for the increased prevalence of ADs in females is that females respond to similar stressful events differently than males due to sex differences in their physiology and neurobiology (i.e., greater Th2 and glucocorticoid levels that are further amplified by stress) (13
In addition, physiological and anatomical changes in the brains of individuals who have experienced childhood abuse have been documented. For example, Teicher et al. conducted electroencephalograms to measure limbic irritability and found the percentage of clinically significant brain-wave abnormalities to be higher among individuals who had a history of early trauma versus those who did not experience early trauma (51
). Magnetic resonance imaging has revealed reductions in hippocampal volumes among severely sexually abused women, and reductions in the intracranial and cerebral volumes among maltreated children compared with non-abused individuals (51
Although the effects cannot be defined to any specific area of the brain, it has been shown that the limbic system, which is responsible for emotional response, is adversely affected. Because ACEs rarely occur in isolation (14
), the cumulative effect of multiple ACEs shown in our study may have an even more powerful negative effect on a young child's developing brain via repeated activation of the stress response. This repeated “dosing” of the developing central nervous system by adrenal catecholamines and corticosteroids may contribute to central nervous system- and endocrine-mediated differences in immune function that result in an increased risk for AD.
There are several limitations to the present study. Inflammatory biomarkers, such as CRP or white blood cell counts, were not compared with ACE Scores because biological samples were not available. Our data cannot provide certainty about the temporal relationship between stress exposure (ACEs) and AD, because of the lack of information about the age at which ACEs occurred and also lack of information on the age at onset of the AD. However, given the age at onset for most ADs, it is likely that the ACEs antedated disease onset in most cases. Also, the lack of information about the exact age at which ACEs occurred potentially limits any specific inferences that might be made about the developmental pathway of ACEs on AD.
There are potential limitations with retrospective reporting of childhood experiences. Respondents may have difficulty recalling certain events. However, longitudinal follow-up of adults whose childhood abuse was documented has shown that their retrospective reports of childhood abuse are likely to underestimate actual occurrence (54
). Difficulty recalling childhood events likely results in misclassification (classifying persons truly exposed to ACEs as unexposed) that would bias our results toward the null (56
). This potential weakness may result in underestimates of the true strength of the relationships between ACEs and hospitalization for AD.
ADs were identified through hospitalizations and not outpatient data. Future studies may be strengthened through the use of clinical data because most ADs are diagnosed through outpatient visits. Finally, it is possible that other unmeasured factors at the time of hospitalizations that were not included in our analyses could have affected the strength of our estimates (either upward or downward) of association between ACEs and ADs. Despite this weakness, our data provide preliminary evidence of the association between ACEs and ADs.
It is important to note that the prevalence estimates for childhood exposures we report are nearly identical to those reported in surveys of the general population. We found that 16% of the men and 25% of the women met the case definition for contact sexual abuse; a national telephone survey of adults in 1990 conducted by Finkelhor et al., using similar criteria, estimated that 16% of men and 27% of women had been sexually abused (57
). As for physical abuse, 28% of the men from our study had experienced this abuse as boys, which closely parallels the percentage (31%) found in a population-based study of Ontario men that used questions from the same scales (58
). The similarity of the estimates from the ACE study to those of population-based studies suggests that our findings are likely to be applicable in other settings.
This is the first study to find an association between early childhood stressors and the development of AD decades later. Our epidemiological findings, coupled with the documented immunopathology of AD, provide preliminary evidence of the relationship between early childhood stress with the human physiological and immunological response, which may also contribute to and expand on the theory of developmental origins of adult disease and health (59
). Because childhood adverse events are common and ADs are chronic and often debilitating, expansion of research in this area may further elucidate the impact of stress on adult chronic disorders such as ADs.