Psychological Stress Increases Risk for Peptic Ulcer, Regardless of Helicobacter pylori Infection or Use of Nonsteroidal Anti-inflammatory Drugs

Susan Levenstein; Steffen Rosenstock; Rikke Kart Jacobsen; Torben Jorgensen

Clin Gastroenterol Hepatol. 2015;13(3):498-506.

Abstract and Introduction

Abstract

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.

Methods We collected blood samples and psychological, social, behavioral, and medical data in 1982–1983 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 1987–1988 (n = 2809) and 1993–1994 (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.

Results 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], 1.2–3.9; P < .01). The per-point odds ratio for the stress index (1.19; 95% CI, 1.09–1.31; 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, 1.07–1.29; P < .001) and still lower after further adjustments for smoking, use of nonsteroidal anti-inflammatory drugs, and lack of exercise (1.11; 95% CI, 1.01–1.23; 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.

Conclusions 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.

Introduction

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 drug–exposed individuals develop ulcers, however, and in 16%–31% of ulcers neither can be implicated, so co-factors and alternative pathways must be common.^[3–5] The concept that psychological factors contribute to ulcer etiology has not disappeared,^[6–8] 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 11–12 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.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Baseline Characteristics of Study Population in 1982
Categorical variables			Number (%)
Age (y)
30			892 (26.4)
40			892 (26.4)
50			841 (24.9)
60			754 (22.3)
Sex
Female			1694 (50.1)
Male			1685 (49.9)
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 (0–100 ELISA units)			1929 (57.1)
Borderline (101–400 ELISA units)			642 (19.0)
Positive (>400 ELISA units)			808 (23.9)
Nonsteroidal anti-inflammatory drugs^a (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)
Ex-smoker			626 (18.5)
Current, <15 g/day			863 (25.5)
Current, 15–24.999 g/day			839 (24.8)
Current, ≥25 g/day			197 (5.8)
Alcohol consumption (N = 3378)
None			439 (13.0)
Moderate (1–14 drinks/wk for women, 1–21 for men)			2488 (73.7)
Heavy (≥15 drinks/wk for women, ≥22 for men)			451 (13.4)
Leisure time exercise (N = 3378)
None			912 (27.0)
Walking regularly			1772 (52.5)
Intense exercise or competitive sport			694 (20.5)
Hours of sleep per day (N = 3299)
>8			117 (3.5)
8			844 (25.6)
7			1628 (49.3)
<7			710 (21.5)
Use of minor tranquilizers (N = 3377)
None in past 5 years			2751 (81.5)
Previous			252 (8.1)
Current			354 (10.5)
Current work status
Working			2733 (80.9)
Retired			292 (8.6)
Not in work force (students, housewives)			185 (5.5)
Unemployed			169 (5.0)
Hours of work per wk (N = 3357)
<37			712 (21.2)
37–40			1511 (45.0)
>40			488 (14.5)
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 index^b (N = 3338)
Low stress (index score = 0)			927 (27.8)
Medium stress (index score = 1–2)			1240 (37.1)
High stress (index score = 3–10)			1171 (35.1)
Continuous variables	25th percentile	Mean	Median	75th percentile
Mental Vulnerability, 12-item (N = 3365)	0	1.3	1	2
Stress index^b (N = 3338)	0	2.1	2	3

NOTE. N = 3379 except where otherwise specified.
^aCurrent use ≥ once/week of antirheumatic drugs or analgesics.
^bA 10-point scale combining Mental Vulnerability score (1 = 1 point, 2 = 2 points, 3–4 = 3 points, 5+ = 4 points); past or present tranquilizer use (2 points); economic, work, family, housing, or personal problems (1 problem area = 1 point, 2–5 problem areas = 2 points); unemployment (1 point); and working >40 hours/week (1 point).

Table 2. Risk for Incident Peptic Ulcer by 1993–1994 According to Baseline Characteristics in 1982, Multiple Logistic Regression
	Age-adjusted			Age- and SES-adjusted
	Odds ratio	95% CI	P value	Odds ratio	95% CI	P value
Age, per 10 y	1.07	0.87–1.32	.51	1.03	0.84–1.27	.76
Female sex	1.05	0.67–1.65	.83	1.01	0.64–1.60	.96
Stress index,^a per point	1.19	1.09–1.31	<.001	1.17	1.07–1.29	<.001
Stress index tertile (versus low)			.002			.004
Medium (1–2)	0.95	0.47–1.89		0.96	0.48–1.93
High (≥3)	2.24	1.23–4.05		2.16	1.19–3.92
Socioeconomic status^b	1.46	1.16–1.83	.001
Smoking (versus never-smoker)			.002			.004
Ex-smoker	1.66	0.65–4.25		1.64	0.64–4.19
Current smoker	3.32	1.58–6.98		3.10	1.47–6.53
Alcohol use (versus none)			.77			.88
Moderate	0.82	0.43–1.54		0.80	0.33–1.93
Heavy	0.74	0.31–1.77		0.91	0.48–1.74
NSAIDs^c	2.34	1.42–3.86	<.001	2.30	1.39–3.79	.001
Sleeping <7 h/day	1.25	0.74–2.11	.41	1.18	0.69–2.00	.55
Sedentary in leisure time	1.60	1.00–2.57	.05	1.48	0.92–2.39	.10
H pylori ^d	3.62	2.16–6.05	<.001	3.44	2.05–5.76	<.001

NOTE. N = 3379, number of ulcers = 76.
SES, socioeconomic status.
^aA 10-point scale combining Mental Vulnerability score (1 = 1 point, 2 = 2 points, 3–4 = 3 points, 5+ = 4 points); past or present tranquilizer use (2 points); economic, work, family, housing, or personal problems (1 problem area = 1 point, 2–5 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
None	1.19	1.09–1.31	<.001
Socioeconomic status	1.17	1.07–1.29	<.001
H pylori ^a	1.19	1.08–1.31	<.001
Alcohol (none, moderate, heavy)	1.19	1.09–1.31	<.001
Sleeping <7 h/day	1.19	1.08–1.31	<.001
Smoking (never-, ex-, current)	1.16	1.05–1.30	.002
NSAIDs^b	1.15	1.04–1.27	.005
Sedentary in leisure time	1.18	1.07–1.29	<.001
SES + smoking + NSAIDs + sedentary	1.11	1.01–1.23	.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.

Table 4. Multivariable Logistic Regression Model Including All Major Baseline Risk Factors in 1982 Versus Incident Peptic Ulcer by 1993–1994
	Odds ratio	95% CI	P value
Stress index, per point^a	1.12	1.01–1.23	.03
Socioeconomic status^b	1.29	1.02–1.62	.03
Smoking (reference: never smoked)			.008
Ex-smoker	1.57	0.61–4.04
Current smoker	2.91	1.38–6.16
H pylori ^c	3.39	2.02–5.69	<.001
Nonsteroidal anti-inflammatory drugs^d	1.77	1.03–3.03	.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.

Table 5. Possible Moderators of Association Between Stress and Peptic Ulcer: Age- and Socioeconomic Status–adjusted 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
Seronegative	21/1912	1.13	0.95–1.35	.17
Borderline or positive^a	55/1426	1.19	1.06–1.33	.003
NSAIDs^b
Less than once per week	53/2754	1.16	1.04–1.31	.01
At least once per week	23/507	1.07	0.90–1.28	.46
Both H pylori and NSAIDs	16/240	1.11	0.89–1.38	.35
Neither H pylori nor NSAIDs	14/1621	1.14	0.91–1.44	.26
Sex
Female	39/1673	1.12	0.98–1.27	.09
Male	37/1665	1.26	1.09–1.44	.001

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.