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

doi:10.1016/j.cgh.2014.07.052

Clinical Gastroenterology and Hepatology

Volume 13, Issue 3, March 2015, Pages 498-506.e1

https://doi.org/10.1016/j.cgh.2014.07.052 Get rights and content

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.

Section snippets

Subjects and Outcomes

In 1982 as part of the World Health Organization’s 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

Results

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.

Medically confirmed ulcers with onset between 1982 and 1993–1994 were detected in 76 subjects (Figure 1). Thirty had gastric ulcers, 39 had duodenal ulcers, and 1 had both; in 6

Findings

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

Conclusions

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 pylori–related ulcers at least as much as those related to neither H

Acknowledgments

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.

References (56)

P. Malfertheiner et al.
Peptic ulcer disease
Lancet
(2009)
D.Y. Graham
Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer: a model
Gastroenterology
(1997)
S. Jyotheeswaran et al.
Prevalence of Helicobacter pylori in peptic ulcer patients in greater Rochester, NY: is empirical triple therapy justified?
Am J Gastroenterol
(1998)
L.F. Eplov et al.
Mental vulnerability: a risk factor for ischemic heart disease
J Psychosom Res
(2006)
C.C. Spicer et al.
Perforated peptic ulcer during the period of heavy air raids
Lancet
(1944)
N. Aoyama et al.
Peptic ulcers after the Hanshin-Awaji earthquake: increased incidence of bleeding gastric ulcers
Am J Gastroenterol
(1998)
S. Levenstein et al.
Long-term symptom patterns in duodenal ulcer: psychosocial factors
J Psychosom Res
(1996)
B.J. Marshall et al.
Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration
Lancet
(1984)
J.D. Lewis et al.
Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications
Am J Gastroenterol
(2002)
R.S. Sandler et al.
The burden of selected digestive diseases in the United States
Gastroenterology
(2002)

M.N. Peters et al.

Stressful life events, acid hypersecretion, and ulcer disease

Gastroenterology

(1983)

K. Takeuchi et al.

Induction of duodenal ulcers in rats under water-immersion stress conditions: influence of stress on gastric acid and duodenal alkaline secretion

Gastroenterology

(1986)

J.K. Kiecolt-Glaser et al.

Slowing of wound healing by psychological stress

Lancet

(1995)

Anand BS. Peptic ulcer disease: etiology. Available from: http://emedicine.medscape.com/article/181753-overview-...

J.P. Gisbert et al.

Review article: Helicobacter pylori-negative duodenal ulcer disease

Aliment Pharmacol Ther

(2009)

S. Levenstein

Stress and peptic ulcer: life beyond Helicobacter

Br Med J

(1998)

S. Levenstein

The very model of a modern etiology: a biopsychosocial view of peptic ulcer

Psychosom Med

(2000)

A.H. Soll

Peptic ulcer disease: genetic, environmental, and psychological risk factors and pathogenesis

S. Rosenstock et al.

Risk factors for peptic ulcer disease: a population based prospective cohort study comprising 2416 Danish adults

Gut

(2003)

S.J. Rosenstock 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)

E. Lynge et al.

The Danish National Patient Register

Scand J Public Health

(2011)

Sabroe K, Kousgaard E, Knox-Seith B, et al. P-faktoren i FOUSHIP-klassificerings-systemet [in Danish, with English...

L.F. Eplov et al.

Mental vulnerability as a predictor of early mortality

Epidemiology

(2005)

L.F. Eplov et al.

The mental vulnerability questionnaire: a psychometric evaluation

Scand J Psychol

(2010)

S. Levenstein et al.

Sociodemographic characteristics, life stressors, and peptic ulcer: a prospective study

J Clin Gastroenterol

(1995)

L.P. Andersen et al.

Isolation and preliminary evaluation of a low molecular (LMW) antigen preparation for improved detection of Helicobacter pylori IgG antibodies

Clin Diagnostic Lab Immunol

(1995)

S. Levenstein et al.

Psychological predictors of peptic ulcer incidence in the Alameda County Study

J Clin Gastroenterol

(1997)

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: Conflicts of interest The authors disclose no conflicts.

: Funding Funding for statistician time was provided by the Kirby Family Foundation.

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

Background & Aims

Methods

Results

Conclusions

Section snippets

Subjects and Outcomes

Results

Findings

Conclusions

Acknowledgments

Lancet

Gastroenterology

Am J Gastroenterol

J Psychosom Res

Lancet

Am J Gastroenterol

J Psychosom Res

Lancet

Am J Gastroenterol

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Review article: Helicobacter pylori-negative duodenal ulcer disease

Aliment Pharmacol Ther

Stress and peptic ulcer: life beyond Helicobacter

Br Med J

The very model of a modern etiology: a biopsychosocial view of peptic ulcer

Psychosom Med

Peptic ulcer disease: genetic, environmental, and psychological risk factors and pathogenesis

Risk factors for peptic ulcer disease: a population based prospective cohort study comprising 2416 Danish adults

Gut

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

The Danish National Patient Register

Scand J Public Health

Mental vulnerability as a predictor of early mortality

Epidemiology

The mental vulnerability questionnaire: a psychometric evaluation

Scand J Psychol

Sociodemographic characteristics, life stressors, and peptic ulcer: a prospective study

J Clin Gastroenterol

Isolation and preliminary evaluation of a low molecular (LMW) antigen preparation for improved detection of Helicobacter pylori IgG antibodies

Clin Diagnostic Lab Immunol

Psychological predictors of peptic ulcer incidence in the Alameda County Study

J Clin Gastroenterol

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