Psychological Stress Increases Risk for Peptic Ulcer, Regardless of Helicobacter pylori Infection or Use of Nonsteroidal Anti-inflammatory Drugs
Susan Levenstein*, Steffen RosenstockЗ, Rikke Kart JacobsenІ, and Torben JorgensenІ
* Aventino Medical Group, Rome, Italy;
З Gastroenterology Department, Surgical Section, Hvidovre University Hospital, Hvidovre, Denmark;
І Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark
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Background & Aims:
There is controversy over whether psychological stress contributes to development of peptic ulcers. We collected data on features of life stress and ulcer risk factors from a defined population in Denmark and compared these with findings of confirmed ulcers during the next 11-12 years.
We collected blood samples and psychological, social, behavioral, and medical data in 1982Ц1983 from a population-based sample of 3379 Danish adults without a history of ulcer participating in the World Health Organization`s MONICA study. A 0- to 10-point stress index scale was used to measure stress on the basis of concrete life stressors and perceived distress. Surviving eligible participants were reinterviewed in 1987Ц1988 (n = 2809) and 1993Ц1994 (n = 2410). Ulcer was diagnosed only for patients with a distinct breach in the mucosa. All diagnoses were confirmed by review of radiologic and endoscopic reports. Additional cases of ulcer were detected in a search of all 3379 subjects in the Danish National Patient Register.
Seventy-six subjects were diagnosed with ulcer. On the basis of the stress index scale, ulcer incidence was significantly higher among subjects in the highest tertile of stress scores (3.5%) than the lowest tertile (1.6%) (adjusted odds ratio, 2.2; 95% confidence interval [CI], 1.2Ц3.9; P < .01). The per-point odds ratio for the stress index (1.19; 95% CI, 1.09Ц1.31; P < .001) was unaffected after adjusting for the presence of immunoglobulin G antibodies against Helicobacter pylori in stored sera, alcohol consumption, or sleep duration but lower after adjusting for socioeconomic status (1.17; 95% CI, 1.07Ц1.29; P < .001) and still lower after further adjustments for smoking, use of nonsteroidal anti-inflammatory drugs, and lack of exercise (1.11; 95% CI, 1.01Ц1.23; P = .04). The risk for ulcer related to stress was similar among subjects who were H pylori seropositive, those who were H pylori seronegative, and those exposed to neither H pylori nor nonsteroidal anti-inflammatory drugs. On multivariable analysis, stress, socioeconomic status, smoking, H pylori infection, and use of nonsteroidal anti-inflammatory drugs were independent predictors of ulcer.
In a prospective study of a population-based Danish cohort, psychological stress increased the incidence of peptic ulcer, in part by influencing health risk behaviors. Stress had similar effects on ulcers associated with H. pylori infection and those unrelated to either H. pylori or use of nonsteroidal anti-inflammatory drugs.
Psychosocial Factors, Epidemiology, Gastric, Duodenal
Helicobacter pylori and nonsteroidal anti-inflammatory drugs have long displaced stress as accepted causes of peptic ulcer, and authoritative sources now commonly discount or ignore a role for psychosocial factors.1, 2
Only a minority of H pylori or nonsteroidal anti-inflammatory drugЦexposed individuals develop ulcers, however, and in 16%Ц31% of ulcers neither can be implicated, so co-factors and alternative pathways must be common.3, 4, 5 The concept that psychological factors contribute to ulcer etiology has not disappeared,6, 7, 8 but no prospective studies have linked stress with incident medically confirmed ulcer in population-based data sets taking all major risk factors into consideration. Changes in ulcer epidemiology and medical practice since 1990, notably a drop in the prevalence of uncomplicated ulcer and the widespread empirical treatment of dyspepsia with H pylori eradication and/or using potent prescription and over-the-counter antisecretory agents without diagnostic confirmation, have made valid research increasingly difficult to perform. Thus, doubt remains whether the frequently reported association between stress and ulcer might be due to confounding, diagnostic bias, or the stressful effect of ulcer symptoms.
The present study sought to resolve this doubt by examining life stress at baseline among a defined Danish population cohort in relation to medically confirmed ulcers during the next 11Ц12 years; earlier analyses on a subject subset had suggested associations with psychological factors.9, 10 The availability of baseline data on a broad range of potential ulcer risk factors, collected in a period early enough to be free of potential confounding stemming from the recent innovations in medical practice just described, allowed exploration of the relative importance and interactions of psychological, social, behavioral, and bacteriologic factors.
It was hypothesized that life stress would be a predictor of documented incident ulcer, that the association between stress and ulcer would be attributable in part to health risk behaviors and in part to confounding by low socioeconomic status, and that psychological stress and H pylori would be additive, independent ulcer risk factors.
Subjects and Outcomes
In 1982 as part of the World Health OrganizationТs MONICA study on the risk and development of cardiovascular diseases,11 the Research Centre for Prevention and Health identified an age- and sex-stratified random sample of adults living in Western Copenhagen County who were born in 1922, 1932, 1942, or 1952. A total of 4807 persons were invited, and all 3785 interviewed subjects were considered for inclusion in the present analyses. Subjects were then excluded if they were not Danish, reported at baseline having had a peptic ulcer, or had missing baseline H pylori antibody measures, for a final sample of 3379 (Figure 1).
Figure 1. Flow chart of enrollment, procedures, and outcomes
Surviving Danish participants (110 had died in the interim) were reinvited in 1987Ц1988, and 2987 attended the interview, including 2809 subjects eligible for this study. All were asked whether since 1982 they had undergone gastroscopy or barium swallow, and whether an ulcer had been diagnosed. In 1993Ц1994, 4130 surviving subjects from the original cohort were reinvited, 2656 were reexamined and asked whether an ulcer had been diagnosed since 1982, and 2410 were eligible for the present project. Attempts were made to review reports of all 209 endoscopy and radiology examinations reported in 1987 and were successful in 170 cases including all cases of self-reported ulcer; diagnostic reports were also reviewed for all new ulcers self-reported in 1993. Additional ulcer cases were detected via a search performed on all 3379 subjects in the Danish National Patient Register, which since 1977 has listed discharge diagnoses for all patients admitted to non-psychiatric hospitals.12 Ulcer was diagnosed only in the presence of a distinct breach in the mucosa; gastroduodenal erosions without appreciable depth were not classified as ulcers.
Baseline socioeconomic status was calculated from education, occupation, and number of employees and classified according to the highest-rated family member. Unemployment was determined from respondentsТ descriptions of their current main activity. Other real-life stressors examined were working more than 40 hours a week and an ad hoc measure asking whether the subject had economic, work, family, housing, or personal problems.
Past and present cigarette, cigar, and pipe smoking were recorded as grams of tobacco consumed per day, alcohol consumption as drinks per week, leisure time physical activity as none, walking, or intense, and sleep duration as hours per day. Frequency of current and past use of 19 types of medication was ascertained; consumption of aspirin, arthritis medications, and minor tranquilizers (which did not include antidepressants) was examined for the present analyses.
Subjects answered 22 items from the Mental Vulnerability Scale (formerly called the Psychic Vulnerability Scale), a questionnaire constructed by the Danish Military Psychological Services in the 1960s with the purpose of detecting young men unsuitable for military service.13 The 12-item version used in the present analyses (Appendix) has been validated in the general Danish population, where it is predictive of both incident coronary disease and mortality and is associated (r = 0.41Ц0.67) with somatization, neuroticism, depression, and anxiety.14, 15, 16
A stress index with a theoretical range from 0 to 10 was designed a priori to combine baseline Mental Vulnerability (score of 1 = 1 point, 2 = 2 points, 3Ц4 = 3 points, ≥5 = 4 points); tranquilizer use (any, past or present = 2 points); economic, work, family, housing, or personal problems (1 problem area = 1 point, 2Ц5 problem areas = 2 points); unemployment (1 point)17; and working >40 hours/week (1 point).
Blood samples were drawn at baseline, and the sera were frozen. They were thawed in 1993, and immunoglobulin G H pylori antibodies were measured with a validated in-house indirect enzyme-linked immunosorbent assay (ELISA) (sensitivity 99%, specificity 54%, positive predictive value 76%, negative predictive value 96%) that classified antibody levels as negative (≤100 ELISA units), borderline (100Ц400 ELISA units), or positive (>400 ELISA units).18
Socioeconomic status and age were treated as continuous variables; leisure time exercise (sedentary versus other), nonsteroidal anti-inflammatory drug exposure (current ≥ once a week versus less or no use), tranquilizer use (ever during past 5 years versus never), H pylori status (borderline or positive versus negative), and sleep duration (<7 hours versus adequate) were dichotomized; and smoking categories were collapsed into never, ex, and current. Alcohol use was categorized as none, moderate (1Ц14 drinks/week for women, 1Ц21 for men), and heavy (>14 drinks/week for women, >21 for men) because of a possible U-shaped association with ulcer.9, 19 The stress index was usually treated as a continuous variable, but critical analyses were repeated, for heuristic reasons, with stress levels trichotomized into high (index score = 3Ц10), medium (1Ц2), and low stress (0).
The MONICA I study was approved by the Regional Research ethics committee of Copenhagen County. Present analyses fall under National Institutes of Health exemption 4 (study of existing data).
All statistical analyses were performed with logistic regression models by using the statistical package SAS, version 9.3 (SAS Institute Inc, Cary, NC). All P values were two-sided and interpreted with significance level of 5%. Model fit was evaluated with the Hosmer and Lemeshow goodness-of-fit test.
It was considered desirable to limit the number of degrees of freedom in any individual model following the rule of 10 outcome events per parameter. This condition was generally fulfilled, but occasionally we chose to construct larger models. Although some caution is necessary when interpreting results from these models, all the models converged, and the estimated odds ratios were in line with results from smaller models. In subgroup analyses with fewer events, we also conducted the nonparametric KruskalЦWallis test to compare participants with and without an ulcer. The results from these KruskalЦWallis tests were in line with results from the logistic regression models.
The stress index was initially examined as a predictor of incident ulcer to be adjusted for age and sex as indicated. This model was adjusted for socioeconomic class as a confounder and then for nonsteroidal anti-inflammatory drugs, smoking, heavy drinking, inadequate sleep, and lack of exercise, individually and collectively, as potential behavioral mediators. Possible effect modifiers were explored by examining the association of stress with ulcer in subgroupings according to H pylori and nonsteroidal anti-inflammatory drug status and according to sex and by examining interaction terms; the expected interaction between H pylori and smoking,20 potentially relevant to the causal mechanisms of stress, was similarly investigated.
One item of the Mental Vulnerability scale, УDo you often have pain in different parts of your body, eg, your stomach, neck, back or chest?Ф, could be affected by undiagnosed baseline ulcer, and another, УDo you often take medicine, such as headache tablets, sleeping pills, tranquilizers, or the like?Ф, creates double-counting issues. The impact of possible confounding on our results was investigated by creating versions of the Mental Vulnerability scale modified to omit each of these items in turn and then using them to construct modified stress indices. In sensitivity analyses, the modified stress indices were examined against incident ulcer.
The population attributable fraction was calculated for each risk factor by using age-adjusted and socioeconomic statusЦadjusted odds ratios and the prevalence of exposure.
Baseline data were collected on 3379 eligible subjects (Table 1). Forty-three percent were borderline or seropositive for H pylori immunoglobulin G antibodies, 16% were taking nonsteroidal anti-inflammatory drugs at least once a week, 56% were current smokers, and 39% were in the lower socioeconomic categories IV or V.
Table 1. Baseline Characteristics of Study Population in 1982
|Categorical variables ||Number (%)|
Household socioeconomic status
|Classes I-II (professional, managerial, technical)||926 (27.4)|
|Class III (skilled workers, manual or nonmanual)||1125 (33.3)|
|Class IV (partly skilled workers)||924 (27.4)|
|Class V (unskilled workers)||404 (12.0)|
H pylori immunoglobulin G antibody status
|Negative (0Ц100 ELISA units)||1929 (57.1)|
|Borderline (101Ц400 ELISA units)||642 (19.0|
|Positive (>400 ELISA units)||808 (23.9)|
Nonsteroidal anti-inflammatory drugsa (N = 3375)
|None in past 5 years||515 (15.3)|
|Moderate or past use||2325 (68.9)|
|Current, ≥ once/week||535 (15.9)|
Tobacco smoking (cigarettes, pipe, cigars)
|Never smoked||854 (25.3)|
|Current, <15 g/day||863 (25.5)|
|Current, 15Ц24.999 g/day||839 (24.8)|
|Current, ≥25 g/day||197 (5.8)|
Alcohol consumption (N = 3378)
|Moderate (1Ц14 drinks/wk for women, 1Ц21 for men)||2488 (73.7)|
|Heavy (≥15 drinks/wk for women, ≥22 for men)||451 (13.4)|
Leisure time exercise (N = 3378)
|Walking regularly||1772 (52.5)|
|Intense exercise or competitive sport ||694 (20.5)|
Hours of sleep per day (N = 3299)
Use of minor tranquilizers (N = 3377)
|None in past 5 years||2751 (81.5)|
Current work status
|Not in work force (students, housewives)||185 (5.5)|
Hours of work per wk (N = 3357)
|Not currently working||646 (19.2)|
Economic, work, family, housing, or personal problems (N = 3374)
|No problems||2189 (64.9)|
|Problems in 1 area||557 (16.5)|
|Problems in 2 areas||362 (10.7)|
|Problems in ≥3 areas||266 (7.9)|
Stress indexb (N = 3338)
|Low stress (index score = 0)||927 (27.8)|
|Medium stress (index score = 1Ц2)||1240 (37.1)|
|High stress (index score = 3Ц10)||1171 (35.1)|
Table 1. Baseline Characteristics of Study Population in 1982
|25th percentile||Mean||Median||75th percentile|
Mental Vulnerability, 12-item (N = 3365)
|Stress indexb (N = 3338)||0||2.1||2||3|
NOTE. N = 3379 except where otherwise specified.
The composite stress index, low socioeconomic status, H pylori, smoking, and nonsteroidal anti-inflammatory drugs were each significantly associated with subsequent ulcer; lack of leisure time physical exercise was marginally significant (Table 2). Adjustment for socioeconomic status decreased but did not eliminate most associations (Table 2). The incidence of documented ulcer was 1.6% among subjects with stress index scores in the bottom tertile, 1.5% among subjects in the middle tertile, and 3.5% among subjects with scores in the upper tertile, with an adjusted odds ratio for high- versus low-tertile stress of 2.2 (95% confidence interval [CI], 1.2Ц3.9; P = .004). Sex was not associated with ulcer. Among the 2774 subjects interviewed in 1987 who answered the item about interim upper gastrointestinal diagnostic testing, 3.8% of subjects in the low stress tertile, 5.4% of those in the middle tertile, and 10.2% of those in the upper tertile reported having been tested.
aCurrent use ≥ once/week of antirheumatic drugs or analgesics.
bA 10-point scale combining Mental Vulnerability score (1 = 1 point, 2 = 2 points, 3Ц4 = 3 points, 5+ = 4 points); past or present tranquilizer use (2 points); economic, work, family, housing, or personal problems (1 problem area = 1 point, 2Ц5 problem areas = 2 points); unemployment (1 point); and working >40 hours/week (1 point).
Medically confirmed ulcers with onset between 1982 and 1993Ц1994 were detected in 76 subjects (Figure 1). Thirty had gastric ulcers, 39 had duodenal ulcers, and 1 had both; in 6 cases the location was unknown. Diagnosis was made by endoscopy in 53 cases, by contrast radiology in 17 cases, and at surgery in 6.
Table 2. Risk for Incident Peptic Ulcer by 1993Ц1994 According to Baseline Characteristics in 1982, Multiple Logistic Regression
|Age- and SES-adjusted|
|Odds ratio||95% CI||P value||Odds ratio||95% CI||P value|
Age, per 10 y
Stress index,a per point
Stress index tertile (versus low)
Smoking (versus never-smoker)
Alcohol use (versus none)
Sleeping <7 h/day
Sedentary in leisure time
NOTE. N = 3379, number of ulcers = 76.
Crude rates of ulcer incidence increased fairly smoothly as scores on the 10-point stress index rose from 0 to 9 (data not shown). The odds ratio for incident ulcer per point of the stress index (1.19; 95% CI, 1.09Ц1.31) was unchanged by addition of H pylori, inadequate sleep, or alcohol consumption to the model (Table 3). It fell to 1.17 (95% CI, 1.07Ц1.29) with adjustment for socioeconomic status, suggesting some confounding. The odds ratio changed little with addition individually of smoking, lack of exercise, or nonsteroidal anti-inflammatory drug use, but when adjusted for all 3 health risk behaviors as well as socioeconomic status, the odds ratio per point of the stress index fell to 1.11 (95% CI, 1.01Ц1.23; P = .04). The socioeconomic statusЦadjusted per-point odds ratio of 1.17 indicates excess risk of 17% per point on the stress index, and the fully adjusted odds ratio of 1.11 indicates an 11% excess risk. Examining the relations among these odds ratios, it would appear that approximately one-third of the excess risk associated with stress is due to mediation by behavioral changes ((17%Ц11%)/17% = 6%/17% = 35%).
SES, socioeconomic status.
aA 10-point scale combining Mental Vulnerability score (1 = 1 point, 2 = 2 points, 3Ц4 = 3 points, 5+ = 4 points); past or present tranquilizer use (2 points); economic, work, family, housing, or personal problems (1 problem area = 1 point, 2Ц5 problem areas = 2 points); unemployment (1 point); and working >40 hours/week (1 point).
bPer step on 4-point scale: I-II, III, IV, V.
cNonsteroidal anti-inflammatory drugs; current use ≥ once/week of antirheumatic drugs or analgesics.
dSerum immunoglobulin G antibodies borderline or positive (>100 ELISA units).
Table 3. Possible Confounders and Mediators of Association Between Stress and Peptic Ulcer: Associations of Baseline Stress Index (per Point) With Incident Ulcer in Logistic Regression Models Including Known Ulcer Risk Factors
Variables in addition to stress and age
|Odds ratio per stress index point||95% CI||P value, OR of stress vs unity|
|Alcohol (none, moderate, heavy)||1.19||1.09Ц1.31||<.001|
|Sleeping <7 h/day||1.19||1.08Ц1.31||<.001|
|Smoking (never-, ex-, current)||1.16||1.05Ц1.30||.002|
|Sedentary in leisure time||1.18||1.07Ц1.29||<.001|
|SES + smoking + NSAIDs + sedentary||1.11||1.01Ц1.23||.04|
NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; SES, socioeconomic status.
aSerum immunoglobulin G antibodies borderline or positive (>100 ELISA units).
bCurrent use ≥ once/week of antirheumatic drugs or analgesics.
When baseline stress, socioeconomic status, smoking, H pylori, and nonsteroidal anti-inflammatory drug use were entered into a single age-adjusted multivariable model, all 5 risk factors remained significant predictors (Table 4), indicating that stress is predictive of ulcer even when the other major risk factors are taken into consideration. The socioeconomic statusЦadjusted population attributable fraction was 29.6% for high tertile stress, as compared with 50.7% for H pylori and 17.1% for nonsteroidal anti-inflammatory drugs.
Table 4. Multivariable Logistic Regression Model Including All Major Baseline Risk Factors in 1982 Versus Incident Peptic Ulcer by 1993Ц1994
|95% CI||P value|
Stress index, per pointa
Smoking (reference: never smoked)
|Nonsteroidal anti-inflammatory drugsd||1.77||1.03Ц3.03||.04|
NOTE. Odds ratios for each risk factor are adjusted for age and for all other risk factors. N = 3337, number of ulcers = 76.
aOn 0- to 10-point scale.
bPer step on 4-point scale: socioeconomic class I-II, III, IV, V.
cSerum immunoglobulin G antibodies borderline or positive (>100 ELISA units).
dCurrent use ≥ once/week of antirheumatic drugs or analgesics.
Stress increased the risk for both gastric and duodenal ulcers, with an adjusted odds ratio of 1.19 per point in gastric ulcers (95% CI, 1.03Ц1.37; P = .02) and 1.11 in duodenal ulcers (95% CI, 0.98Ц1.27; P = .10).
There was no significant effect modification by other ulcer risk factors on the association, meaning that the increase in ulcer risk in relation to stress was statistically similar regardless of H pylori or nonsteroidal anti-inflammatory drug status. Specifically, the per-point odds ratio for the stress index was 1.19 for H pyloriЦborderline or Цseropositive subjects, 1.13 for H pyloriЦseronegative subjects, 1.07 for nonsteroidal anti-inflammatory drug users, and 1.14 for subjects exposed to neither H pylori nor nonsteroidal anti-inflammatory drugs (Table 5; P for interaction > .2). Stress also had a statistically similar impact at all levels of socioeconomic status (data not shown) and in both sexes.
Table 5. Possible Moderators of Association Between Stress and Peptic Ulcer: Age- and Socioeconomic StatusЦadjusted Associations of Baseline Stress Index (per Point) With Subsequent Incident Ulcer in Selected Subgroups
|Number of ulcers/subjects ||Odds ratio per index point||95% CI||P value|
|H pylori status|
|Borderline or positivea||55/1426||1.19||1.06Ц1.33||.003|
|Less than once per week||53/2754||1.16||1.04Ц1.31||.01|
|At least once per week||23/507||1.07||0.90Ц1.28||.46|
Both H pylori and NSAIDs
Neither H pylori nor NSAIDs
NOTE. All group differences are nonsignificant (P for interaction with stress index > .2).
NSAIDs, nonsteroidal anti-inflammatory drugs.
aSerum immunoglobulin G antibodies borderline or positive (>100 ELISA units).
bCurrent use ≥ once/week of antirheumatic drugs and/or analgesics.
The interaction between smoking and H pylori was not significant (P = .08), and introduction of an interaction term did not change the associations of stress with ulcer.
When the stress index was modified to exclude the pain item or the medication item in the Mental Vulnerability scale, the results were substantially unchanged.
In these prospective analyses of a Danish population sample with no history of peptic ulcer, a composite stress index was associated with medically confirmed subsequent ulcers (whose definition excluded mere erosions). High tertile stress more than doubled the odds of developing an ulcer, with attributable risk of nearly 30%. Stress remained a significant predictor in a multivariable model including H pylori, nonsteroidal anti-inflammatory drugs, socioeconomic status, and smoking; odds ratios associated with established ulcer risk factors were similar to those in previous reports.21
A vast literature links peptic ulcer to stress, but its weaknesses are such that the National Institute of Diabetes and Digestive and Kidney Diseases Web site for the general public summarizes it as УPeptic ulcers are not caused by stress.Ф22 Some of the stronger evidence is indirect: surges in ulcer diagnoses after societal stressors such as wartime bombing or earthquake23, 24, 25 and worsening of prognosis by psychological factors.26, 27, 28 Cross-sectional studies are unconvincing, because their results may be inflated by recall bias and by the distressing effects of disease.29
Several longitudinal studies of defined epidemiologic cohorts have reported baseline stress to increase the risk of developing ulcer during a period of 5Ц15 years.17, 19, 30, 31, 32 Ulcer diagnoses in these studies have been based on self-report either exclusively17, 19, 31 or in part,30, 32 however, and differential self-reporting causing bias could arise from psychological characteristics. Furthermore, none have taken into account both H pylori and socioeconomic status. The present study has none of these weaknesses, and because its sample is population-based (although in an area slightly less rural than Denmark as a whole33), its results can be reliably generalized to other Western countries and, although with somewhat less confidence, also to populations with different rates of H pylori infection.
The data analyzed here were gathered 2 decades ago. This apparent limitation is potentially an advantage, however, considering the subsequent evolution of ulcer epidemiology and medical culture. At baseline, H pylori had not been discovered, excluding prior eradication therapy as a potential confounder.34 During the follow-up period, histamine-2 blockers (and later, proton pump inhibitors) were available only by prescription, H pylori was rarely tested for and was only treated if verified during gastroscopy, and dyspepsia was routinely evaluated by using endoscopic or radiologic studies, so that incident ulcers were likely to be accurately diagnosed. At present, dyspepsia is commonly treated or self-treated empirically, with definitive testing reserved for refractory or Уred flagФ symptoms.35, 36, 37, 38 Many ulcers thus probably remain undiagnosed, whereas psychological influences on dyspeptic symptoms, on health care seeking behavior, and on the decision to perform definitive testing constitute unavoidable sources of confounding (as they do to some extent, as demonstrated by the excess of upper gastrointestinal testing in high-stress subjects, in the earlier period covered by the present study).39, 40 Furthermore, performance of similar analyses on later cohorts could face serious power considerations, because the incidence of uncomplicated ulcers has fallen sharply.1, 38 Bleeding and perforated ulcers, which may be particularly linked to stress,23, 24, 25, 41 have decreased to a lesser extent, however, and continue to cause substantial morbidity and mortality in the United States as well as elsewhere.35, 42, 43, 44, 45 The statistical power of the present analyses sufficed to document a robust independent association between stress and ulcer but did not allow formal mediation analyses or full examination of effect modification and somewhat limited the reliability of larger multivariable models.
The stress index used in these analyses had the merit of taking into account objective life stressors such as unemployment as well as the subjective distress measured in the well-validated Mental Vulnerability scale. However, this index was developed ad hoc for the present study by using a priori weightings of its component items, with the aim of maximally exploiting relevant information available in a preexisting data base, and it has not undergone independent validation.
While often used for screening larger populations, serum immunoglobulin G antibodies are an imperfect measure of H pylori infection because antibodies can reflect either ongoing or past infection. In this study population, seropositivity likely reflected current H pylori infection, because the population was unexposed to eradication therapy; spontaneous clearance of infection is unusual in nonelderly adults.46 The proportion of subjects considered H pylori infected was slightly overestimated because of the inclusion of borderline as well as seropositive serologies.
Both gastric and duodenal ulcers were associated with stress; in the literature, risk factors including stress are quite similar for both types.24, 25, 31
No data were available regarding subjectsТ baseline use of antisecretory agents or of low-dose aspirin. Such use was likely to be minimal in 1982; fewer than 0.5% of MONICA I subjects without known ulcers were taking antisecretory agents even 11 years later,9 and aspirin use for primary cardiovascular prevention was uncommon before publication of the PhysiciansТ Health Study in 1989.
Finally, the observed 0.20% per-year rate of new ulcers during follow-up underestimates the true incidence rate, both because ulcers diagnosed as outpatients among subjects lost to follow-up were not included and because asymptomatic ulcers were unlikely to have been detected.
Stress may promote peptic ulcer through increased acid load, effects of hypothalamic-pituitary-adrenal axis activation on healing, altered blood flow, or cytokine-mediated impairment of mucosal defenses.47, 48, 49, 50 Behavioral mediators such as smoking account for approximately one-third of the ulcerogenic effect of psychological stress in the present analyses as in previous studies.19 Two previously reported behavioral mediators, heavy alcohol consumption and poor sleep, were not confirmed in the present analyses.19 Synergy between stress and H pylori3 and effect modification by socioeconomic status51 were also not observed. An impact of stress was at least as evident in H pyloriЦpositive as in УidiopathicФ ulcer, as 2 previous studies have suggested52, 53 but contrary to 1 recent report.25 Because various chronic diseases may be related to infection, either directly or via immune mechanisms, the ability of stress to affect the course of H pylori infection could extend to other conditions as well.54, 55, 56
Life stress at baseline increased the risk of subsequent confirmed peptic ulcer in a population-based cohort without a history of ulcer at baseline. The increased risk was not fully explained by confounding by socioeconomic status or by associations with nonsteroidal anti-inflammatory drugs and smoking, although the impact of stress on these health risk behaviors accounted for a portion of the increased risk. Stress affected H pyloriЦrelated ulcers at least as much as those related to neither H pylori nor nonsteroidal anti-inflammatory drugs. These results support a multicausal model of peptic ulcer etiology with intertwined biological and psychosocial components. Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors.
The authors thank Anne Helms Andreasen, MS, who at the time was Chief Statistician of the Research Centre for Prevention and Health, for her invaluable help in developing the statistical approach; the Capital Region of Denmark for its contribution of personnel and infrastructure; and the Kirby Family Foundation for its generous support.
Appendix. The 12-item Mental Vulnerability Scale
Instructions: We would like to ask you some questions regarding your personal well-being. Please do not think too much about the answers; just answer as you find most suitable.
- Do your hands easily shake?
- Do you often suffer from loss of appetite?
- Do you often suffer from sleeplessness?
- Do you often feel very tired?
- Do you often take medicine, such as headache tablets, sleeping pills, tranquilizers, or the like?
- Do you often have pain in different parts of your body, eg, your stomach, neck, back, or chest?
- Do you often suffer from fits of dizziness?
- Does your heart often beat very fast for no particular reason?
- Is it difficult for you to make friends?
- Do small things get on your nerves?
- Do you constantly have thoughts that trouble and worry you?
- Do you usually feel misunderstood by other people?
- Malfertheiner P, Chan FKL, McColl KEL. Peptic ulcer disease. Lancet 2009;374:1449Ц1461.
- Anand BS. Peptic ulcer disease: etiology. Available from: http://emedicine.medscape.com/article/181753-overview- aw2aab6b2b4aa. Accessed September 18, 2012.
- Graham DY. Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer: a model. Gastroenterology 1997;113:1983Ц1991.
- Jyotheeswaran S, Shah AN, Jin HO, et al. Prevalence of Helicobacter pylori in peptic ulcer patients in greater Rochester, NY: is empirical triple therapy justified? Am J Gastroenterol 1998; 93:574Ц578.
- Gisbert JP, Calvet X. Review article: Helicobacter pylorinegative duodenal ulcer disease. Aliment Pharmacol Ther 2009;30:791Ц815.
- Levenstein S. Stress and peptic ulcer: life beyond Helicobacter. Br Med J 1998;316:538Ц541.
- Levenstein S. The very model of a modern etiology: a biopsychosocial view of peptic ulcer. Psychosom Med 2000;62:176Ц185.
- Soll AH. Peptic ulcer disease: genetic, environmental, and psychological risk factors and pathogenesis. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate, 2012.
- Rosenstock S, Jorgensen T, Bonnevie O, et al. Risk factors for peptic ulcer disease: a population based prospective cohort study comprising 2416 Danish adults. Gut 2003;52:186Ц193.
- Rosenstock SJ, Jørgensen T, Bonnevie O, et al. Does Helicobacter pylori infection explain all socio-economic differences in peptic ulcer incidence? genetic and psychosocial markers for incident peptic ulcer disease in a large cohort of Danish adults. Scand J Gastroenterol 2004;39:823Ц829.
- Tunstall-Pedoe H, ed. MONICA: monograph and multimedia sourcebookЧworldТs largest study of heart disease, stroke, risk factors, and population trends 1979-2002. Geneva: World Health Organization, 2003.
- Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39(Suppl 7):30Ц33.
- Sabroe K, Kousgaard E, Knox-Seith B, et al. P-faktoren i FOUSHIP-klassificerings-systemet [in Danish, with English summaries]. Copenhagen: MPT, 1968Ц1970.
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Conflicts of interest
The authors disclose no conflicts.
Funding for statistician time was provided by the Kirby Family Foundation.
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