Interest is growing in symptoms from nongastrointestinal sites. High Somatic Symptom Burdens and Functional Gastrointestinal Disorders

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5: High Somatic Symptom Burdens and Functional Gastrointestinal Disorders GREGORY S. SAYUK,* JILL E. ELWING,* PATRICK J. LUSTMAN,, and RAY E. CLOUSE*, *Division of Gastroenterology and Department of Psychiatry, Washington University School of Medicine, and Department of Veterans Affairs Medical Center, St Louis, Missouri See Vandenberghe J et al on page 1684 for companion article in the May 2007 issue of Gastroenterology. Background & Aims: Unexplained, multi-system somatic symptoms and syndromes, the hallmark features of somatization, are prevalent in patients with functional gastrointestinal disorders (FGIDs). We studied outpatients attending a gastroenterology clinic to see whether current somatic symptom burdens (a somatization state measure) or number of prior functional diagnoses (a somatization trait measure) could predict the presence of an FGID over structural gastrointestinal disease, and whether the predictive value was dependent on comorbid depression or anxiety disorders. Methods: Clinical data from 327 consecutive new referrals to an outpatient gastroenterology practice were reviewed, 187 with an FGID and 140 with a structural illness. Somatization state and trait were measured by using self-reported current symptoms and functional diagnoses recorded in the medical history, respectively. Psychiatric comorbidity (depression or anxiety disorders) was extracted from chart review. Results: FGID subjects endorsed more somatization state symptoms, had more somatization trait diagnoses, and had greater likelihood of psychiatric comorbidity (P <.001 for each). Logistic regression analysis adjusting for age and sex differences showed that each of these features independently predicted the likelihood of an FGID over structural disease (P <.05 for each). When high ratings on the somatization measures were present together with psychiatric comorbidity, the positive predictive value exceeded Conclusions: Higher burdens of either current somatic symptoms or functional diagnoses in the medical history are strong predictors of an FGID in outpatients presenting with gastrointestinal complaints. The mechanism is not solely dependent on a relationship with affective disorders, which independently predicts FGID, at least in part, through another path. Interest is growing in symptoms from nongastrointestinal sites that are present in patients with functional gastrointestinal disorders (FGIDs). Somatic symptoms and syndromes across several organ systems and unexplained by physical illness are reported by at least one fourth of patients, 1 a phenomenon called somatization.2 The biologic underpinnings of somatization remain unknown; its presence and degree are determined crudely by the clinical expression of medically unexplained symptoms. Because the FGIDs also lack a defined physical basis, it is possible that they represent a component of the somatization process, or at least that the neurophysiologic mechanisms underlying somatization have a relevant role in the development or presentation of FGIDs. 2 For research purposes, somatization has been operationalized in several fashions. 3 8 Measures can reflect the somatization state, an expression of recent medically unexplained symptoms, or the somatization trait, a background of remote functional syndromes provided by the medical history. Some evidence exists that overreporting of current symptoms provides a method of predicting FGID over structural gastrointestinal disease, supporting the importance of the somatization state. 9,10 There also is evidence that an increased burden of functional syndromes in the medical history helps define the FGID patient. 11,12 Thus, somatization state and trait features both might be pertinent to FGID pathophysiology. Whether these characteristics are fully interrelated or whether each bears independent relevance has not been explored. Addressing such concerns would help determine the relative importance of short-term and long-term processes on FGID expression. Depression and anxiety disorders also are comorbid conditions in patients with FGID, diagnosed at presentation or in the past in as much as 60% 70% of patients with irritable bowel syndrome (IBS), for example. 1,13 18 The significance of the association remains uncertain; the strongest observation against a direct relationship is the dissociated response of FGID symptoms from change in psychometric scale scores with successful treatment of the gastrointestinal symptoms Somatization might serve as a mediator of the relationship between FGID and psychiatric comordibity, considering the commingling of anxiety and depression with advanced degrees of somatization observed in small samples of IBS patients. 15 Whether somatization state features or trait features have greater bearing on this relationship is yet to be examined. We hypothesized that high somatic symptom counts and histories of abundant prior functional diagnoses would each independently predict the diagnosis of an FGID over a structural gastrointestinal disease in an outpatient population after controlling for potentially confounding factors, supporting the importance of both recent and chronic somatization toward susceptibility to FGIDs. We also hypothesized that comorbid psychiatric illness (depression or anxiety disorder) would not have independent predictive value toward an FGID diagnosis once the contributions from the somatization measures were taken into account. Thus, the previously observed relationship of psychiatric illness with FGID primarily would relate to its relationship with somatization. A retrospective review of chart data from a university-based practice was used to test these hypotheses. Abbreviations used in this paper: CI, confidence interval; FGID, functional gastrointestinal disorder; IBS, irritable bowel syndrome; OR, odds ratio by the AGA Institute /07/$32.00 doi: /j.cgh

2 May 2007 SOMATIC SYMPTOMS PREDICT FUNCTIONAL DISORDERS 557 Methods Subjects Consecutive patients identified from billing records, seen in an outpatient university-based adult gastroenterology practice either initially or in follow-up during a 2-year period from January 1, 2003 January 1, 2005 and followed for at least 3 months, provided the primary subject pool. Subjects were stratified into 3 groups on the basis of chart notations made by the treating physician: (1) an FGID group, in which a functional disorder had been considered responsible for the presenting symptoms; (2) a structural gastrointestinal disease group, in which a structural illness had been established and had been considered sufficient to explain the presenting symptoms; and (3) a group in which a structural illness had been identified but was considered insufficient to explain symptoms, according to the chart notations. The last group was excluded from the primary analyses. FGIDs are diagnosed in this outpatient office according to a criteria-based system (Rome II), 22 and the 3-month follow-up requirement was imposed to ensure stability of the functional or structural diagnosis. Review of clinical records for the purposes of this study was approved by the Washington University Human Studies Committee before study conception. Record Review Clinical features, including demographic characteristics and the diagnosis to which symptoms were attributed, were systematically extracted from the outpatient record by using an instrument prepared a priori for data extraction. All clinical notations, including records from office visits, telephone contacts, or written communications, were considered potential sources of clinical data. Although the investigators performing the record reviews were not blinded to subject diagnosis, they were unaware of the study hypotheses being tested. Two measures of somatization were extracted. Each subject had completed a self-reported review-of-systems checklist at the initial visit. This checklist is composed of 60 symptoms across 10 organ systems, and subjects had been asked to endorse only those symptoms that were currently experienced. Total numbers of endorsed symptoms and systems were recorded, as were responses to a subset of 13 symptoms that represented 13 of 15 symptoms included in a previously validated measure of somatic symptom severity (Table 1). 23 A high degree of somatization state was considered present for descriptive purposes in characterizing subject group if endorsement was at or above the median ( 6 symptoms). A second measure assessed somatization trait as the sum of all documented patient-reported or physician-determined gastrointestinal and nongastrointestinal functional disorders (symptoms or syndromes that were unexplained medically) that had been recorded in the history (eg, fibromyalgia, chronic headache). For descriptive purposes, a high degree of somatization trait was considered present if, in addition to the primary FGID, 2 functional disorders had been established in that individual. This threshold corresponded to the median value in a previously reported group of FGID patients who had been deemed candidates for antidepressant therapy. 24 Psychiatric comorbidity was considered present when a diagnosis of depression or an anxiety disorder was available in the medical record, having been made in the past or coexistent with the gastrointestinal disorder. Psychiatric diagnoses are made in this outpatient office by using criteria outlined in the Diagnostic and Table 1. Symptoms Included in the Somatization State Measure a General Lack of energy/fatigue Cardiovascular Chest pain Heart palpitations Shortness of breath Musculoskeletal Back pain Joint pain/muscle ache Gastrointestinal Belching/bloating/nausea Changes in stool form Stomach pain Neurologic Dizziness Fainting Headache Psychiatric Difficulty sleeping Modified from Kroenke et al. 45 a Excludes sexual symptoms included in the PHQ-15. Statistical Manual of Mental Disorders, Version IV, 8 but a specific interview or instrument is not used. Patient-reported diagnoses of depression or an anxiety disorder also were accepted as evidence of psychiatric illness. Only depression and anxiety disorders were included because together these constitute the most common psychiatric diagnoses encountered in patients with FGID. 11,25 Statistical Methods Measures of central tendency are reported as mean standard error of the mean for continuous variables and median values with ranges for categorical data. Group data were compared by using Student t tests for continuous data and 2 tests for binomial data. The overlapping of somatization state, somatization trait, and psychiatric illness was explored through the calculation of Pearson correlation coefficients and the generation of Venn diagrams. Positive predictive values were calculated as the proportion of true positives over the sum of true positives plus false positives. Logistic regression modeling without elimination was used to evaluate predictors of FGID over structural gastrointestinal disease. The somatization measures were used as continuous variables in the models. Statistical analyses were conducted by using SPSS v14.0 (SPSS Inc, Chicago, IL), with a P value.05 as a determinant of statistical significance in two-tailed testing. Results Demographic and Disorder Characteristics A total of 524 potential subjects were identified during the 2-year study period, 127 of whom had either incomplete or unretrievable records (n 32) or had not been followed for 3 months (n 95). Of the remaining 397 subjects, 70 fell into the third subject group, had presenting symptoms that were not fully explained by the identified structural gastrointestinal disease, and were not considered in the primary analyses. The 327 other subjects had a mean of months of clinical follow-up available for chart review. A summary of baseline demographic characteristics is provided in Table 2.

3 558 SAYUK ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 5 Table 2. Demographic Characteristics of the Subjects Characteristic All subjects (n 327) Subjects with FGID (n 187) Subjects with a structural gastrointestinal disease (n 140) P value a Age, mean SEM (y) Sex, n (%) Female 198 (60.6) 131 (70.1) 67 (47.9).001 Male 129 (39.4) 56 (29.9) 73 (52.1) Race, n (%) Non-white 6 (1.8) 4 (2.1) 2 (1.4).7 White 321 (98.2) 183 (97.9) 138 (98.6) a Comparing subjects with FGID with those with structural gastrointestinal disease. FGID had been diagnosed in 187 subjects (57.2%), the most common of which was IBS (n 49, 26.2% of the FGID subjects). Functional esophageal disorders had been identified in 25 (13.3%; chest pain, n 9; dysphagia, n 10, other functional esophageal disorders, n 6), functional gastroduodenal disorders in 60 (32.0%; functional dyspepsia, n 19; functional vomiting disorders, n 39; other functional gastroduodenal disorders, n 2), and non-ibs functional bowel disorders in an additional 53 (28.3%; functional abdominal pain, n 23; functional constipation, n 10; functional diarrhea, n 7; functional bloating, n 4; other functional bowel disorders, n 9). The FGID group had a significantly higher proportion of female subjects than the group with structural gastrointestinal disease (Table 2). Symptoms had been attributed to a structural gastrointestinal disease in 140 subjects (42.8%). Gastroesophageal reflux disease was the most common diagnosis in this group, being identified in 42 subjects (30.0% of all structural diagnoses). Additional prevalent diagnoses included ulcerative colitis (n 35, 25.0%), achalasia (n 20, 14.3%), and Crohn s disease (n 14, 10.0%). Twenty-nine subjects (20.7%) had a variety of other gastrointestinal diseases. Somatization Measures and Psychiatric Comorbidity Subjects with FGID were significantly more likely than their structural disease counterparts to have a high degree of somatization state, a high degree of somatization trait, and psychiatric comorbidity (Figure 1). With regard to current somatic symptoms at the time of presentation, subjects with FGID had endorsed more symptoms over more systems on the review-ofsystems checklist and almost twice as many specific somatic symptoms on the somatization state measure than subjects with structural gastrointestinal disease (Table 3). More functional disorders, other than the primary diagnosis, used in the somatization trait measure also were found in the histories of patients with FGID (Table 3). The most common of these additional disorders are listed in Table 3. Greater proportions of subjects in the FGID group had been given diagnoses of both depression and anxiety disorders than subjects with structural gastrointestinal disease (23.5% vs 6.4% and 20.3% vs 7.1%, respectively; P.001 for each comparison). The relationships between somatization state, somatization trait, and psychiatric comorbidity for each subject group are shown in Figure 2. In both groups the somatization state and trait measures were modestly but significantly correlated (r 0.44 and r 0.41, respectively; P.001 for each). Within the FGID group, the presence of a psychiatric diagnosis portended a higher scale score on the somatization state measure ( vs , P.01) and was associated with a greater number of functional disorders on the somatization trait measure ( vs , P.001). There were no differences in somatization scale scores by psychiatric comorbidity status in the group with structural gastrointestinal disease. The greater degree of commingling of all 3 features within the FGID group is apparent from review of Figure 2. Predictors of Functional Gastrointestinal Disorders Results from logistic regression modeling of clinical and demographic predictors of FGID are summarized in Table 4. Female sex, psychiatric comorbidity, and greater scores on the somatization measures each independently predicted the presence of an FGID over a structural gastrointestinal disease. When the same analysis was conducted including within the FGID group the 70 initially excluded subjects who had symptoms out of proportion to a structural gastrointestinal disease (ie, suspected functional symptoms concurrent with the structural disease), Figure 1. Percentage of subjects with high ratings on the somatization scales and with comorbid psychiatric illness (depression or an anxiety disorder) by subject group. Each feature was more common in subjects with FGID. *P.001 compared with subjects with structural gastrointestinal disease.

4 May 2007 SOMATIC SYMPTOMS PREDICT FUNCTIONAL DISORDERS 559 Table 3. Summary of Somatization Features Measure All subjects (n 327) Subjects with FGID (n 187) Subjects with structural gastrointestinal disease (n 140) P value a Review-of-systems checklist No. of systems endorsed, b mean SEM No. of current symptoms, c mean SEM Somatization state measure symptoms, d mean SEM Medical history review Prevalence of nongastrointestinal functional disorders, e n(%) Chronic headache 61 (18.7) 48 (25.7) 13 (9.3).001 Back pain 36 (11.0) 24 (12.8) 12 (8.6).15 Somatosensory disturbance 36 (11.0) 31 (16.6) 5 (3.6).001 Chronic pelvic pain 11 (3.4) 10 (5.3) 1 (0.7).02 Fibromyalgia 8 (2.4) 7 (3.7) 1 (0.7).08 No. of somatization trait disorders, mean SEM a Comparing subjects with FGID with those with structural gastrointestinal disease. b Out of a total of 10 possible systems. c Out of a total of 60 possible symptoms. d Out of a total of 13 possible symptoms. e In descending order; those with 10 total subjects not listed. the identical predictors were identified (female sex: odds ratio [OR], 2.43; 95% confidence interval [CI], ; psychiatric comorbidity: OR, 2.34; 95% CI, ; somatization state symptoms: OR, 1.30; 95% CI, ; somatization trait disorders: OR, 1.37; 95% CI, ). The cumulative contribution of psychiatric comorbidity and high degrees of somatization state and trait on the predictive value of an FGID was examined for each sex and for the whole subject group (Figure 3). With an increasing number of features, the likelihood of diagnosing an FGID increased linearly. Whereas subjects without psychiatric comorbidity and with low degrees of somatization had less than 50% likelihood of having an FGID, nearly 90% of subjects with any 2 features had an FGID, and more than 95% of subjects with all 3 features ultimately were diagnosed as having an FGID to explain the presenting symptoms. Discussion In this study we found an increase in the number of current somatic symptoms and previous functional disorders in outpatients with FGID at a university-based practice when compared with those having structural gastrointestinal diseases. As expected, psychiatric comorbidity (depression and anxiety disorders) also was more prevalent in the former subject group. In support of our hypotheses, each somatization measure independently predicted the presence of an FGID. The relationship of psychiatric comorbidity to FGID, however, was not completely mediated by somatization, because psychiatric comorbidity was retained as an independent predictor in the regression analysis. The same outcomes were found when subjects with symptoms out of proportion to structural disease were included. Thus, high current somatic symptom burdens, abundant past functional disorders, and psychiatric comorbidity each helped identify patients with functional gastrointestinal symptoms, whether structural gastrointestinal disease was present or not. The predictive value was pronounced in this outpatient population; the patient with high ratings on both somatization scales as well as a history of depression or an anxiety disorder had 95% likelihood of having an FGID. Nongastrointestinal somatic symptoms and syndromes, usually also functional in origin, have long been observed in patients with FGID. 11 For example, fibromyalgia is diagnosed in as many as two thirds of patients with IBS. 11,26 29 Similar data exist for chronic fatigue syndrome, temporomandibular joint disorder, 30 Table 4. Predictors of the Presence of FGID in This Outpatient Practice Predictor OR 95% CI P value Figure 2. Proportion-appropriate Venn diagrams showing the degree of overlap between somatization features and psychiatric comorbidity by subject group. A high degree of somatization state (SOM-S) overlapped with a high degree of somatization trait (SOM-T) in each group, but their degree of overlap and the amount of commingling with psychiatric comorbidity (PSYCH) were greater in the group with FGID. The numbers in the diagrams represent the percentages of subjects falling into each segment. Age Female sex Psychiatric comorbidity a Somatization state symptoms b Somatization trait disorders b a Presence of a diagnosis of depression or an anxiety disorder. b Measure used as a continuous variable.

5 560 SAYUK ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 5, No. 5 Figure 3. Positive predictive value for being diagnosed with an FGID over structural gastrointestinal disease in this study population by cumulative number of somatization and psychiatric features (high somatization state, high somatization trait, psychiatric comorbidity). Subjects without any features were equally likely to have a functional or structural disorder. Presence of all 3 features had a positive predictive value of 96% for FGID. and chronic back pain Somatic comorbidities have been considered almost at the level of curiosities and usually are examined individually, depending on the interests of the medical subspecialty conducting the research. Recently, a high collective somatic symptom burden in IBS patients 16,25,33 has been found to result in greater reported bowel symptom severity, 26,34 impact negatively on physical functioning and quality of life, 27,35 interfere with treatment adherence, 24 and lead to increased usage of heath care resources. 36 Thus, the importance of somatic comorbidities with regard to outcomes in FGID is becoming established. Their impact on the pathophysiology of these disorders and contribution toward risk of developing FGID are less appreciated or understood. Current nomenclature defines the presence of multiple medically unexplained symptoms as somatization, a poorly understood process that has been relegated to the field of psychiatry. 8 Several lines of investigation indicate that somatization is relevant to the development or expression of FGIDs, disorders that might actually be components of the process. First, the few available cross-sectional studies demonstrate high rates of somatization in FGID patient groups. At least 25% of IBS subjects attending a universitybased outpatient practice qualify for the diagnosis of somatization disorder, a particularly severe form of somatization that is rare in non-patient samples. 1,15 Linkage of somatization with FGID also was found in a community-based sample of non-patients, 37 and somatization has been associated with the level of symptom reporting. 38 Similarly, somatization predicts the symptom response to gastrointestinal stimuli in some tested FGIDs. 39,40 Second, somatization at baseline is an independent predictor of postinfectious IBS when subjects are followed longitudinally. 39,40 Finally, improvement in somatization scale scores has paralleled clinical response when antidepressants were used to treat functional esophageal symptoms in one study, 21 whereas improvements in depression or anxiety symptoms with antidepressants are not related closely to improvement in FGID symptoms. 19,41,42 Consequently, somatization appears to be the central element linking somatic comorbidity to FGID and possibly represents the diverse expression of a common neurophysiologic process responsible for all the symptoms. The high predictive values of somatization in detecting patients with FGID within our outpatient practice would add support to this hypothesis, at least in one clinical setting. In a clinical context, somatization can be measured as somatization state (current symptom reporting) or trait (previous functional disorders); each method depends on the expression of medically unexplained somatic symptoms and not measuring a mechanism per se. Psychiatric criteria largely are restricted to somatization disorder, a pronounced degree of somatization, and take into account both state and trait features in defining the disorder. 8 A dialogue is ongoing within the psychiatric literature as to which features are superior in the definition and recognition of somatization The present study demonstrates the overlapping yet independent importance of somatization state and trait features in predicting the presence of FGID, a novel observation. This finding is important, because somatization state is relatively easily measured with simple self-report instruments, whereas somatization trait typically relies on more extensive medical history taking by trained professionals and systematic record reviews. If somatization features become increasingly important in the assessment, management, or study of patients with FGID, then both types of measures might need incorporation for comprehensive evaluation. Psychiatric illness, specifically anxiety and depression, is found on average in 7 in 10 FGID patients. 14,16,25,46 In spite of repeated observation of comorbidity, the importance of the relationship remains unclear. Miller et al 1 and North et al 15 found that anxiety and depressive symptoms and disorders aggregate with somatization disorder in IBS patients, raising 2 possible explanations for the association. First, the psychiatric illnesses might increase the reporting of somatic symptoms, which, in turn, are but a manifestation of the processes linking depression and anxiety to the FGID. Somatization is a potential manifestation of depression in psychiatric samples, making this theory plausible. 47 Alternatively, the mechanisms behind somatization might increase reporting of psychiatric symptoms ( psychoform symptoms), as well as somatic symptoms. This phenomenon has been reported previously in psychiatric patients with somatization disorder. 15,48 If the above were operational in our FGID patients, either somatization or psychiatric illness should have fallen out of our multivariate models. Such was not the case, and our hypothesis that psychiatric illness was dependent on somatization in predicting FGID was not supported. Multiple paths linked to somatization and psychiatric illness result in FGID development and/or presentation, or these features mark the presence of an alternative, singular mechanism. Neuroendocrine-immune dysregulation and alterations in ascending and inhibitory pain pathways at the central nervous system level would be examples of such mechanisms. Physiologic measures that provide diagnostic insight into the FGIDs are limited. Clinical predictors thus remain the most useful means of identifying the disorders. In our study, 3 key clinical features (high degree of somatization state, high degree of somatization trait, and psychiatric comorbidity) collectively yielded a striking ability to predict the presence of an FGID. Moreover, these same factors could predict functional symptoms in the face of structural gastrointestinal disease. The predictive values of these features rival existing symptom-based criteria for FGID diag-

6 May 2007 SOMATIC SYMPTOMS PREDICT FUNCTIONAL DISORDERS 561 noses 22,58 and possibly should play at least a complementary diagnostic role. As a minimum, their absence would take on the role of a red flag disfavoring the diagnosis of an FGID, particularly in male subjects. Illustrating this point, male subjects lacking either a psychiatric diagnosis or high degrees of somatization in our study had less than 30% likelihood of having a functional explanation for presenting symptoms. The predictive values undoubtedly would differ depending on the type of sample (community, primary care, referral practice, etc), and this deserves further investigation. This study has significant limitations, primarily related to the nonvalidated measures used for data collection from chart review. The diagnoses required for psychiatric comorbidity were accepted from the medical record and were not determined systematically. Similarly, the somatization trait measure used diagnoses that were present in the record and possibly had not been recorded uniformly across subject groups. A bias favoring a link between FGID and somatization trait diagnoses or psychiatric comorbidity could have been introduced by the clinician if psychiatric and functional diagnoses had been solicited and recorded more intently in patients for whom such features would support the clinical diagnosis. Nevertheless, the strength of the associations is remarkable and begs verification in prospective trials with validated methods. The somatization state measure was based on a well-established instrument (the PHQ-15), 23 but it did not use the severity measure of the PHQ-15 and was extracted from a longer-item checklist. It is unlikely that this impaired the performance of the measure, because symptom counts alone are considered valid, longer lists of somatic symptoms form the parent instruments of many contemporary somatization scales, 23,60 65 and these inclusive lists are more robust determinants of somatoform disorders than abbreviated measures An additional limitation of the findings is the lack of generalization because a university-based referral practice served as the source of subjects; findings could be considerably different in community-based gastroenterology settings or in primary care. Despite the limitations inherent in the study methodology, our findings highlight the potential importance of somatic symptom and syndrome burden as well as psychiatric comorbidity in identifying patients with FGID. These features potentially reflect a single or several underlying neurophysiologic mechanisms influencing the development or presentation of the gastrointestinal disorders. 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Sayuk, MD, Instructor, Division of Gastroenterology, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8124, St Louis, Missouri gsayuk@im.wustl.edu; fax: (314) Supported in part by NIH grant DK from the United States Public Health Service and from the Sidney R. Baer, Jr, Foundation.