stress and peptic ulcers

Older studies have shown an association between stress and peptic ulcer disease. At least the ones I've seen have not controlled for the use of NSAIDs or the presence of H pylori. However, from newer data, 16-31% of ulcers are not associated with either of these precipitating factors. The current prospective population-based study was done in Denmark, in which the researchers collected blood samples as well as an inventory of psychological, social, behavioral and medical data in 1982-3, and reinterviewed these patients in 1987-8 and 1993-4, finding that psychological stress did indeed increase the risk of ulcers (see peptic ulcer dz and stress clin gastro 2014 in dropbox, or doi.org/10.1016/j.cgh.2014.07.052​).

details:
--3379 adults without prior history of ulcer disease were enrolled, with subsequent data on 2809 of them in 1987-8 and 2410 in 1993-4. Pretty evenly distributed in the 30-60 year age range.
--socioeconomic status (SES) was calculated from education, occupation, employment status. Stressors included working more than 40 hours/week and an assessment if the person had economic, work, family, housing , or personal problems. Subjects also answered 22 items from the Mental Vulnerability Scale (a questionnaire used by the military to screen potential recruits), a validated scale which assesses "somatization, neuroticism, depression, and anxiety."
--a stress index was calculated which combined the baseline Mental Vulnerability; tranquilizer use; economic, work, family, housing or personal problems; unemployment; and working >40 hours/week -- with a score of 0-10.​

results:
--43% were H pylori positive, 16% were taking NSAIDs, 56% were current smokers, 39% in the lower two SES categories
--76 people were diagnosed with an ulcer over the course of the study (documented on endoscopy/radiology exam): 39 duodenal ulcers and 30 gastric ulcers
--ulcers were significantly more common in those in the highest tertile of stress scores (3.5%) vs the lowest (1.6%), with adjusted odds ratio of 2.2 (CI 1.2-3.9, p<.01). This did not change after adjusting for IgG antibodies to H pylori, alcohol consumption, or sleep duration, with a per-point odds ratio for the stress index being 1.19 (CI 1.09-1.31, p<0.001), and a clear dose-response (the higher the stress score, the more likely to have an ulcer)
--the adjusted stress relationship was lower after controlling additionally for SES, with per-point odds ratio for the stress index being 1.17 (CI 1.07-1.29, p<0.001), and further by controlling for smoking, use of NSAIDs and lack of exercise, with per-point odds ratio for the stress index being 1.11 (CI 1.01-1.23, p=0.04).
--there was  a similar risk of ulcer related to stress in those who were H pylori positive or negative, or in those both H pylori negative and not on NSAIDs.
--in multivariate analysis, stress, SES, smoking, H pylori infection, and use of NSAIDs were independent predictors of ulcers.

one big plus for this study was its timing: it predated H pylori testing (and treatment), either H₂-blockers and subsequently proton-pump inhibitors were available only as prescriptions and not over-the-counter, and the study was done largely before widespread use of low-dose aspirin; all of these factors significantly decrease the confounding that would exist if the study were done now. Purported mechanisms by which stress could cause ulcers include by increases in stomach acid secretion, effects on the hypothalamic-pituitary-adrenal axis (essentially all hormones are affected by stress, many of them mediated by the stress-related cortisol elevations) which can affect healing, hormone-mediated changes in blood flow to the stomach, or cytokine-mediated impairment of mucosal defenses. Some of the stress effect is likely mediated by smoking (which in one study accounted for one-third of the ulcerogenic effect of stress), alcohol or poor sleep (though these latter 2 were not confirmed in the Danish study above). Of note, there was no synergy in the Danish study between stress and H pylori in ulcer development. To me, this is a pretty impressive study despite its being observational, given the quality of the data they collected prospectively, the fact that there is a dose-response curve with each increase in their stress scale associated with increased likelihood of ulcer disease, and their controlling for many known or likely associations for ulcers.

So, not so shocking a finding (i think most of my patients are aware of the link between stress and ulcers....). However, the National Institute of Diabetes and Kidney Diseases of the NIH in 2012 notes "peptic ulcers are not caused by stress". so, i guess my patients were right all along...