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ORIGINAL ARTICLES |
From the Center for Neurovisceral Sciences & Women’s Health, Departments of Medicine (M.M., L.C., L.Z.F., R.B., E.A.M.), Physiology (E.A.M.), Psychiatry & Biobehavioral Sciences (B.D.N., E.A.M.), UCLA, Los Angeles, CA; Greater Los Angeles Healthcare System, VA Medical Center (B.D.N.), Los Angeles, CA; and University of Arizona/VA Medical Center GI Division (R.F.), Tucson, AZ.
Address correspondence and reprint requests to Bruce D. Naliboff, PhD, Neuroenteric Disease Program, CURE Digestive Diseases Research Center, VA Greater Los Angeles Healthcare System, West Los Angeles, Building 115, Room 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073. E-mail: naliboff{at}ucla.edu
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ABSTRACT |
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METHODS: Sixty subjects with current heartburn symptoms were recruited by community advertisement and assessed for presence of stressful life events retrospectively over the preceding 6 months and prospectively for 4 months. Symptom severity by daily diary, quality of life, and psychological symptoms of anxiety, depression, and vital exhaustion were also measured.
RESULTS: The presence of a severe, sustained life stress during the previous 6 months significantly predicted increased heartburn symptoms during the following 4 months. In addition, symptoms showed a strong, independent correlation with vital exhaustion. Affective and subjective stress ratings were not strongly related to heartburn severity; however, anxiety showed the strongest relationship to impaired quality of life and depression to heartburn medication use.
CONCLUSIONS: As with other chronic conditions such as irritable bowel syndrome (IBS), heartburn severity appears to be most responsive to major life events and not an accumulation of more minor stressors or fluctuations in mood. In addition, vital exhaustion, which may in part result from sustained stress, may represent the psychophysiological symptom complex most closely associated with heartburn exacerbation. Potential mechanisms for these results include increased level and frequency of esophageal acid exposure, inhibition of gastric emptying of acid, or stress-induced hypersensitivity.
Key Words: vital exhaustion, • visceral sensitivity, • gastroesophageal reflux disease.
Abbreviations: ANOVA = analysis of variance;; BDI = Beck Depression Inventory;; BAI = Beck Anxiety Inventory;; EPI-N = Eysenck Personality Inventory Neuroticism Scale;; GERD = gastroesophageal reflux disease;; GI = gastrointestinal;; HIS = high-impact stressors;; IBS = irritable bowel syndrome;; LEDS = Life Events and Difficulties Schedule;; LSI = UCLA Life Stress Interview;; MQ = Maastricht Questionnaire;; NSAIDs = nonsteroidal anti-inflammatory drugs;; NUD = non-ulcer dyspepsia;; SRLE = Survey of Recent Life Experience.
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INTRODUCTION |
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Heartburn symptoms are very common, with reports of 20% to 30% of the population in Western countries having some heartburn symptoms and 20% reporting heartburn at least once per month (10,11). Although a significant number of upper gastric symptoms, including heartburn, are associated with acid reflux, nonacid-related (or functional) heartburn has often been associated with anxiety and emotional lability (12). Perception of acid events is also greater in subjects with greater anxiety, even though acid levels are within the normal range. In a recent study, Fass et al., using a dichotomous listening task, demonstrated that acute laboratory stress increased sensitivity to esophageal acid exposure in patients with both gastroesophageal reflux (GERD) and nonerosive reflux disease (8). Relaxation training, in contrast, has been shown to decrease both heartburn symptoms and acid sensitivity in GERD patients (13). These data are consistent with patient surveys and clinical experience that suggest that life stress may be a significant contributor to heartburn symptoms in patients with both GERD and functional heartburn. Substantial decrements in well-being or quality of life are common consequences of chronic heartburn, and are more frequently being used as measures of illness impact and treatment outcome and may also be related to life stress (14).
Several different methods have now been validated to study life stress in relation to medical and/or psychiatric symptoms. These include retrospective and diary self-reports of the frequency and severity of stressful life events as well as patient reports of mood or their own stress response. Two newer measures may be especially relevant for assessment of the impact of stress on heartburn. The first is the assessment of vital exhaustion. Although cumulative stress often has an impact on general mood including anxiety and depression, a more direct manifestation of the physiological consequences of chronic stress or allostatic load (15) is the syndrome of vital exhaustion. This includes a cardinal symptom of fatigue coupled with irritability and demoralization (16). Although not previously studied in functional GI disorders, vital exhaustion has been shown to have a significant association with heart disease even after controlling for other psychological symptoms such as depression and anxiety (17). A second innovation in stress measurement is assessments designed to separate out presence of stressful life events from the subjective response to such events. In order to gain a more objective measure of the amount of life stress a person has experienced, Brown and Harris (18) developed the Life Events and Difficulties Schedule (LEDS). This is a structured interview approach that defines the severity of a life event based on the context in which the event happens but independent of the subject’s reaction. Recent studies using this approach have shown clear associations between presence of major life events and exacerbations of symptoms in psychiatric disorders (19) as well as functional GI disorders such as irritable bowel syndrome (IBS) (1) and nonulcer dyspepsia (NUD) (20). The present study is aimed to test the general hypothesis that life stressors can enhance symptoms in patients with chronic heartburn. We therefore examined the relationship between several measures of life stress and symptom severity in patients with frequent heartburn. Based on the small literature linking stress with symptom exacerbation in other functional GI disorders, we hypothesized that severe, sustained life stressors, vital exhaustion, and psychological symptoms would be predictive of heartburn symptom severity and health-related quality of life over a 4-month follow-up period.
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METHODS |
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Procedure
After screening, subjects were evaluated at study entry and at 2- and 4-month follow-ups. No specific interventions were given or recommended by the study staff. Subjects were told that the purpose of the study was to examine how heartburn symptoms varied over time.
Measures
Symptoms
Symptoms and symptom impact were recorded daily on diary cards. Patients were instructed to complete the diary every day before bedtime for 2 weeks at study entry and for 2 weeks before each follow-up assessment. The diary card for each day included 11-point severity ratings (nothing to unbearable) of overall heartburn severity, other bodily pain, and stressfulness of the day as well as overall symptom impact (none to most). Also recorded were frequency of daytime and nighttime heartburn episodes, frequency of regurgitation, frequency of medication use, and total hours of symptoms.
Life Stress
UCLA Life Stress Interview (LSI): The LSI is a validated system similar to the LEDS for objective assessment of stressful life events (chronic strain and episodic life events) based on detailed structured interviews (21).
Chronic Strain
The interviewer, using established criteria, rated the degree of chronic strain during the past 6 months in 6 areas: intimate relationships, family, friends, work, finances, and health. Stressors directly related to heartburn or GERD were categorized separately and not included in the analysis. The overall ongoing stress (chronic strain) in each area was rated on a 5-point scale by the interviewer with specific criteria set for each content area. To check for interrater reliability in application of the criteria, 2 trained interviewers independently rated the interviews of 34 subjects. Reliability coefficients for the 6 areas ranged from 0.81 to 0.99, indicating excellent agreement on the amount of stress for all categories. In the present study, the chronic strain ratings for the 6 categories were averaged to give a general measure of chronic life stress.
Episodic Stressors
Subjects were also queried regarding episodic life events. Based on the method of Brown and colleagues (18), the interviewer elicited not only the occurrence of stressors, but also the surrounding circumstances in which they occur and that may modify the understanding of their impact. The severity and independence (how much the subject had some influence on the event) of each episodic event was rated by a consensus panel of 3 trained raters who had not interacted with the subject directly, and do not know the subject’s actual reaction to the stress. Thus, objective ratings of the event were based on knowledge of the event in its context and a judgment of how much impact the event would have on a typical person under identical circumstances. Severity ratings were made on a 5-point scale based on the information supplied by the interviewer and established criteria for each type of event (1 = no impact, not considered an event; 2 = mild impact; 3 = significant impact, important, but limited consequences; 4 = marked impact, very stressful, many consequences; 5 = severe). The subject also made a rating of each event on a similar scale. Consistent with previous studies (1), we initially examined both the number of episodic events (all events rated 2 or more) and the presence of high-impact stressors (HIS; those events rated 4 or 5). The total number of events was not related to any of the dependent variables, and total events are also captured in the Survey of Recent Life Experience (SRLE) scale described below. Therefore, the present analysis focused on the presence of HIS. HIS were found in 24% of the subjects by team rating, while 66% of the subjects self-rated at least 1 stressor as having high impact. Examples of team-rated HIS were death or serious illness of a spouse, primary fault in a serious motor vehicle accident, miscarriage, and divorce. Chronic strain and episodic events were assessed at intake.
Daily Stress
A measure of average daily stress was computed from the daily diary card question: "How stressful was your day?" rated on an 11-point scale.
Survey of Recent Life Experience
The SRLE (22) is a well-validated self-report measure of daily stressors (hassles). It contains 51 items describing typical daily stressful events, each rated on a 4-point scale (1 = not at all part of my life, 4 = very much part of my life). Alpha reliability of the total score = 0.91 (22). It differs from the original Hassles scale (23) in that SRLE was designed to lessen influence of subjective mood or stress responses on ratings of the presence of typical daily stressors. The mean stressor frequency was used as total score.
Affective Symptoms
Beck Depression and Anxiety Inventories
Both the Beck Depression (BDI) and the Anxiety Inventories (BAI) are reliable and validated inventories for assessment of symptoms of depression and anxiety, respectively (24,25). Total scores were used for both scales. Scale scores of 11 or greater are indicators of possible psychiatric diagnosis.
Maastricht Questionnaire
The Maastricht Questionnaire (MQ) is a 21-point scale that has been validated as a measure of vital exhaustion and shows good discriminate validity from traditional measures of depression (17) and predictive validity for increased risk of myocardial infarction and coronary artery disease (26–28).
Eysenck Personality Inventory Neuroticism Scale
The Eysenck Personality Inventory Neuroticism Scale (EPI-N) is a well-validated measure of stress vulnerability and has been linked to development of functional GI disorders (29).
Quality of Life
The GERD-specific Quality of Life scale is a 37-item inventory composed of 6 scales reflecting the impact of GERD on daily life, relationships, quality of life, worries and concerns, sleep, and eating (30,31). For the purposes of this study, the individual scales were averaged to yield a global score for quality of life.
Statistical Analysis
Descriptive data on symptoms for the sample were tabulated. Intercorrelations among the diary measures (at intake) were then examined to determine whether a single measure of symptom severity could be found for use in the prediction models. Bivariate correlations were performed to examine the relationships between GERD symptoms and measures of stress and psychological status. Multiple linear regression analyses were used to test the interdependent relationships among the predictor variables (stress and psychological status) at intake and the dependent variables of symptom severity and quality of life. Finally, an analysis of longitudinal changes in symptoms was carried out to examine whether initial life stress would predict GERD symptoms over the 4-month follow-up period. This was done using a 2-group (presence or absence of HIS) x 4 time period repeated measures analysis of variance (ANOVA).
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RESULTS |
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Quality of Life
The various life stress and psychological variables were also examined as predictors of GERD impact on quality of life. Table 2 shows the individual correlations, and the regression analysis is shown in Table 4. Although a variety of the psychological variables were related to quality of life and the overall prediction was significant (R2 = 0.50, p < .001), only anxiety was a significant independent predictor in the regression.
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Sex-Related Effects
The regression analyses described above were repeated using a hierarchical design with sex entered as a predictor on the first step and the other psychological and stress variables entered on the second step. Sex was not significantly related to severity of GERD symptoms and did not affect the prediction equation for the other variables. This indicates that there are similar overall relationships between psychological and stress variables and GERD severity in both men and women. In a similar regression prediction of quality of life, sex was related to quality of life (r = 0.33, p < .02), with men reporting significantly greater GERD impact on their quality of life (p < .01). However, sex did not significantly alter the prediction equation for the other variables.
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DISCUSSION |
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Impact of Acute Stress on Heartburn Symptoms
There are a variety of possible mechanisms that might account for the relationship between a life stressor and heartburn severity. Even though most of these mechanisms have been reported in the context of acute, experimental studies, they nevertheless provide plausible hypotheses to be tested in future studies on the impact of chronic stress on gut physiology. For example, experimental studies suggest that acute stress may increase the level and frequency of esophageal acid exposure by several mechanisms including increased gastric acid production (32), stress-induced inhibition of gastric emptying of acid (33), and impairment of the diaphragmatic component of the lower esophageal sphincter mechanism by stress-related breathing patterns (34). More recently, Fass et al. have demonstrated that the perceptual sensitivity to acid is increased under even mild acute laboratory stressors, such as dichotic listening (8). Dichotic listening has also been shown to enhance perception of colonic distension in healthy control subjects (35). Animal experimental evidence supports the concept of stress-induced visceral hyperalgesia, an increase in visceral pain perception during acute laboratory stress (36).
Relationship of Major Life Events With GI Symptom Severity
Although the physiological studies discussed above relate directly only to acute stressors, the current results are consistent with a growing literature linking chronic, high-impact stressors with symptom exacerbation in a variety of somatic conditions, including those involving the GI tract (37). In contrast, short-term stressors (those occurring over a few days to a week), or multiple less severe stressors may be less important. For example, Levenstein et al. (5) found a significant relationship between exacerbation of ulcerative colitis and long-term stress rated on the Perceived Stress Questionnaire (but not acute stress). A similar result was found in a 16-month prospective study of IBS in which symptom exacerbations were predicted by presence of a major threatening life stress but not daily stressors (1). Gwee et al. (4) also reported that the presence of a major life stress during the 12 months preceding hospitalization for gastroenteritis was significantly related to development of postinfectious IBS, and this relationship was independent of anxiety and neuroticism.
Although acute stressors are associated with transient autonomic, neuroendocrine, and pain modulatory responses of central stress circuits, severe, sustained stressors may produce persistent or even permanent alterations in stress responsiveness and therefore longer-lasting changes in symptom patterns. In addition to the mechanisms discussed above for acute stressors, mechanisms engaged by sustained stressors may include changes in central afferent processing, such as changes in attention or in affective responses (37). They may also include alteration in endogenous pain modulation systems, or the stress-induced generation of peripheral mediators, such as proinflammatory cytokines (38,39). The fact that patients in this study with a history of major life events did not report a greater frequency of heartburn episodes, but only greater symptom severity, may suggest that stress has its most powerful impact on the perceptual processes that lead to the judgment of how "bad" the symptoms are, rather than modulation of mechanisms influencing acid reflux (which should be more closely associated with increased episodes of heartburn). Consistent with the requirement for sustained high-impact stress for symptom modulation is the current observation that the number of stressors was not a significant predictor. In addition, it was the team rating of stress impact and not the more subjective assessment of stress impact by the subject that predicted symptom severity. This supports the hypothesis that significant life stressors are important predictors of illness regardless of self-perceived impact. Subjective ratings of stressors may not capture the impact of life events due to reporting bias, influence of mood, and poor insight.
Vital Exhaustion and Cognitive Factors in GI Symptoms
The data from this study linking heartburn symptoms to vital exhaustion reinforce the supposition that heartburn symptoms are related to global stress responses, particularly those that are of significant magnitude and chronicity to result in symptoms of fatigue and "burnout." Although the neurobiological mechanisms underlying the construct of vital exhaustion (fatigue, irritability, demoralization) are incompletely understood, they may be attributable to alterations in central arousal systems (including ascending noradrenergic systems), hypothalamic–pituitary–adrenal axis dysregulation, and the generation of proinflammatory cytokines (40). Development of vital exhaustion has also been linked to the "type D" (distressed) personality, which is defined as negative affectivity and the tendency to inhibit the expression of this affect in social interaction (41). The finding that vital exhaustion and presence of a HIS were independent predictors of heartburn symptoms suggests multiple pathways for stress affecting heartburn severity. Vital exhaustion is closely associated with negative affect and has high correlations in this sample with neuroticism (r = 0.71), depression (r = 0.78), and anxiety (r = 0.65). Presence of a HIS, on the other hand, is associated with symptom severity but is not strongly related to vital exhaustion or negative affect. These data therefore suggest several mechanisms by which heartburn severity may be enhanced. One mechanism involves a cognitive or physiological change resulting from the occurrence of a HIS, but perhaps due to good support, coping, or predisposition does not lead to a generalized change in mood, quality of life, or need to increase medications (or even high ratings of subjective stress). A second pathway is marked by presence of vital exhaustion and is part of a more generalized decline, including alterations in mood, quality of life, and increased subjective stress. Further research is needed to both verify these independent pathways as well as examine whether the differential mechanisms are perceptual, physiological, or both.
Subjective ratings of stress and standard measures of mood were not the strongest predictors of symptoms in the current study. Measures of anxiety and depression have also not been shown to be as strong predictors of symptoms as life stress in several previous studies (1,4); however, other subjective ratings of stress do predict symptom changes. Dancey et al. (42) found that severity of daily hassles, recorded on a daily basis, predicted symptoms over the next 4 days, but that symptoms also predicted the stress ratings. Levenstein et al. (5) found that a self-report measure of perceived stress was a better predictor of symptoms in ulcerative colitis than either life events or mood. In the current study, vital exhaustion may represent a good measure of overall stress impact and was significantly associated with symptoms independent of the other mood variables. Further research is clearly needed to pinpoint the best technique for assessment of the impact of stress, especially in terms of the quality of stress response that is most directly tied to physiological changes for a particular disorder. It is noteworthy that illness-specific quality of life was strongly associated with the affective measures and that anxiety was the only independent predictor of this measure. Thus, general illness impact is more closely associated with affective measures than specific symptom severity.
Heartburn Medication Use and Chronic Stress
Medication use is commonly used as an outcome measure in clinical trials of acid peptic-related disorders of the esophagus and stomach. Surprisingly, reported medication use did not cluster with the other variables of heartburn symptom severity. Although multiple measures of negative affect including depression, anxiety, and vital exhaustion were related to medication use, depression was the only significant independent predictor in the regression analysis. Of the life stress measures, only daily hassles showed a relationship with medication use, but this was not independent of depression. These findings are consistent with the concept that medication use is a distinct outcome variable from symptom frequency and severity, and that patients with greater negative mood, especially depression, more frequently turn to medications for relief (43).
Strengths and Limitations
The major strength of this study is the fact that it represents the first longitudinal study evaluating the impact of stressful life events on symptoms of heartburn. Other strengths are the inclusion of a validated objective measure of episodic life stress and examination of vital exhaustion in addition to the standard mood measures of anxiety and depression. Several limitations of the current study should be mentioned. One involves the subject sample. Subjects were obtained via advertisement and therefore probably represent a population in between those recruited from GI clinics and those randomly selected from the general population in terms of severity and impact of symptoms on quality of life. A second limitation is the length of the follow-up period. Although this study examines heartburn symptoms during a 4-month period, it may be that the length of the study was not sufficient to test within subject stress-symptom relationships. The natural history of heartburn is not well characterized, but our results do indicate that 6 months or longer may be required to examine individual variation in symptom patterns. In addition, many of the associations are based on a cross-sectional analysis, and therefore direction of causation should be interpreted cautiously. A final limitation is the lack of physiological measures. Future studies that include potential mediator variables such as esophageal pH or neuroendocrine variables may help clarify the mechanisms behind the results reported here.
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CONCLUSION |
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ACKNOWLEDGMENTS |
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The authors thank Britta Dickhaus, Joyce Reinholdt, Teresa Olivas, and Cathy Liu for data management and interview scoring, Constance Hammen for providing the LSI, and Teresa Olivas for her outstanding editorial assistance in the preparation of the manuscript.
Received for publication March 17, 2003.
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