Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal (GI) disorder that affects 10% to 15% of the United States population and is characterized by abdominal pain and altered bowel functioning.1,2 Even though the majority of sufferers have mild symptoms and do not seek medical care, some IBS patients have substantial disability and emotional distress.3 IBS is the most common problem of patients visiting gastroenterologists and ranks among the top ten presenting complaints of patients in primary care. IBS been estimated to account annually for $1.6 billion in direct healthcare costs and $19.2 billion in indirect costs in the US.4
The causes of IBS are poorly understood. The current consensus is that IBS involves both altered gut reactivity, altered pain perception, and brain-gut dysregulation.2 A number of additional factors may be involved in susceptibility to IBS including immune changes after gut inflammation (leading to post-infectious IBS), a history of sexual abuse, childhood learning of illness behavior, high neuroticism, and life stressors.2,5
None of the individual factors contributing to IBS are found in all patients, but some, such as visceral hyperalgesia, characterize half or more of patients in some studies.6 Multiple contributing factors often co-exist in an individual patient with IBS. These observations have gradually led to a broader multi-factorial perspective on the nature of IBS.5 Frequent comorbidity of the disorder with other medical conditions and non-GI somatic symptoms also is characteristic of IBS.
In the past decade, increasing evidence indicates that IBS overlaps with a number of other health problems. There is ample evidence from more than 20 studies of high rates of psychiatric comorbidity in IBS.7 Most of these studies have found that at least half of IBS patients have a diagnosable Axis I diagnosis, predominantly depression or anxiety disorders. IBS also overlaps with other functional GI disorders, such as functional dyspepsia.1
In this article, we focus on the third type of comorbidity, namely the overlap of IBS with other chronic, functional somatic (nonpsychiatric and non-GI) disorders, and the frequency of general physical symptoms in this disorder. We will first summarize the evidence for somatic comorbidity and then discuss possible explanations and clinical implications.
Overlap with Other Syndromes
In a recent comprehensive literature review of IBS comorbidity, we found higher rates of various disorders including back pain, bronchial hyper-responsiveness, premenstrual syndrome, dysmenorrhea, dyspareunia, nonmenstrual bleeding, and interstitial cystitis documented in case reports.7–11 We also found significantly elevated rates of overlap between IBS and four specific somatic disorders — fibromyalgia, chronic fatigue syndrome (CFS), chronic pelvic pain, and temporomandibular joint disorder (TMJ) — reported in controlled studies. An update of the literature search for the 3 years since our review shows that this picture remains unaltered. As indicated in Table 1, the rates of co-occurrence of these conditions with IBS exceed the prevalence of the individual disorders in the general population.
Overlap Between IBS and Four Comorbid Somatic Disorders7
The association between IBS and other somatic conditions may be exaggerated by the nature of published research studies. Most have been conducted on patients seeking clinical care, which is likely to elevate comorbidity estimates. A person with both fibromyalgia and IBS, for example, may be more impaired and distressed than someone with IBS alone and therefore more likely to seek clinical care. The data also come primarily from subspecialty clinics, which may inflate comorbidity rates, because patients in these settings have more severe symptoms, and comorbidity is associated with greater IBS severity.12,13 The varying case definitions used for IBS and other disorders in different studies, the small patient samples, and the fact that studies of comorbidity in IBS patient samples have been far fewer than studies of IBS symptoms in the other disorders are additional reasons to exercise caution in drawing conclusions from this literature.
Nevertheless, it is clear from a large number of studies that comorbidity exists between IBS and at least the four other conditions listed in Table 1. Even when only median values are considered, one finds that 49% of people with fibromyalgia, 50% of those with pelvic pain, and 51% of patients with chronic fatigue are reported to have IBS. (Only a single estimate exists for TMJ, reporting 64% of those patients to have IBS.14) This suggests that IBS occurs four to five times more often among patients with these disorders compared with the general population.
Nonspecific Physical Symptoms in IBS
Several studies of IBS ranging in size from 88 to 606 patients have demonstrated that, aside from comorbid syndromes, many IBS patients experience nonspecific physical symptoms that are not clearly associated with particular diseases.9,15–19 As shown in Table 2 (see page 323), these symptoms (collectively referred to by gastroenterologists as “extra-colonic symptoms”) include urinary symptoms, musculoskeletal symptoms, pain symptoms, fatigue, and sleep problems.
Percentage of IBS Patients Reporting Non-GI Somatic Symptoms in Clinical Studies
Some of these symptoms are found to be elevated consistently across several studies. For example, headaches (reported by 23% to 45% of IBS patients) and back pain (28% to 81%) were both found in four studies to be more common among IBS patients than control subjects.9–15,17 In fact, Maxton et al.17 suggested that these symptoms were so frequent in IBS patients compared with patients with other GI disorders (eg, ulcerative colitis, Crohn's disease, peptic ulcers), that they could be used to discriminate IBS from competing diagnostic possibilities. However, the range of symptoms reported in IBS is perhaps even more impressive. In some studies, the majority of symptoms listed on inventories of general physical complaints are endorsed more frequently by IBS patients than by controls.9,15–19
Etiology of IBS Comorbidity
Even a superficial study of the characteristics of IBS and its four comorbid conditions — CFS, fibromyalgia, chronic pelvic pain, and TMJ — reveals an intriguing number of similarities among them. They all predominantly affect women and are associated with excess rates of affective symptoms and psychiatric diagnoses, pain sensitivity, autonomic dysfunction, evidence of abnormal immune activity, chronicity and a fluctuating course, stress, unclear or unknown etiologies, age of onset in early or middle adulthood, and poor response to standard medical interventions.
These similarities, and the fact that these conditions not only overlap with IBS but also with each other, have led to a number of hypotheses to account for the relationship between them.14,20 Some hypotheses also offer explanations for the excess of general non-GI symptoms in IBS. These hypotheses can be classified into three types, which we will describe with the relevant supporting evidence.
One view of IBS comorbidity is to consider all the overlapping disorders to be variants of the same somatic syndrome. For example, Wessely et al.21 emphasized that these syndromes have far more in common than what distinguishes them and proposed that classification into distinct diagnoses may be an artifact of different medical specialties. Where a gastroenterologist might diagnose IBS in a patient with a polysymptomatic somatic syndrome, a rheumatologist might diagnose fibromyalgia and a gynecologist diagnose chronic pelvic pain.
Another version of this idea, that somatic syndromes differ superficially but represent a single unified condition, derives from the biopsychosocial model. The key tenets of the this model, as described by Drossman22 for IBS, are that biological, psychological or social/environmental factors all contribute to the disorder, that no particular factor is necessary for the development of the disorder, and that these factors interact in different combinations.
Both the diagnostic artifact and biopsychosocial hypotheses offer plausible explanations for overlap between these disorders. However, both concepts conflict with data showing that these disorders are distinct disease entities. Most notably, Robbins et al.23 used confirmatory factor analysis to show that IBS, fibromyalgia, and CFS are represented by distinct symptom clusters and that combining them does not produce satisfactory symptom models. Nimnuan et al.24 performed a principal components analysis on symptom data from 550 medical patients and concluded that 13 functional somatic syndromes represented by the patients were related. However, a single common somatic factor explained only 30% of the variance. Whitehead et al. and Talley et al. used factor analysis to address the related issue of IBS comorbidity with GI disorders and showed that IBS consists of a symptom cluster separate from other conditions such as functional dyspepsia.25–28
In summary, the view that IBS and comorbid somatic syndromes are variants of a single super-syndrome is not supported by existing data.
In addition to the many similarities between IBS and comorbid disorders, research on these conditions also has revealed similarities in physiological findings, such as increased pain sensitivity and autonomic nervous system (ANS) abnormalities. These findings encouraged hypotheses about possible shared pathophysiological abnormalities that could account for the overlap and notable similarities.
Abnormal pain sensitivity has been identified in all five somatic disorders, but has been most extensively investigated in fibromyalgia and IBS. These data do not reveal a common type of hypersensitivity to pain. For example, the majority of IBS patients have lowered intestinal pain thresholds, while their somatic pain thresholds (such as threshold for pain stimuli on the skin of the hands) are usually found to be normal or even higher than in healthy controls.29–31
Conversely, patients with fibromyalgia show decreased somatic pain thresholds but normal visceral pain thresholds.32,33 Chang et al.32 studied IBS patients with or without comorbid fibromyalgia and found only IBS patients with fibromyalgia exhibited somatic hypersensitivity. Thus, each disorder is characterized by its own distinct pattern of hyperalgesia, rather than sharing a general pain sensitization mechanism.
Several studies have reported evidence of ANS dysfunction in IBS, CFS, and fibromyalgia. This prompted speculation that autonomic dysfunction could be the common denominator between these conditions. However, the patterns of ANS abnormalities are dissimilar.7 ANS research on IBS has provided inconsistent results, with studies reporting either increased or decreased sympathetic activity or parasympathetic activity, or specific ANS abnormalities only in specific symptom subgroups.
In CFS, the studies have similarly proved inconsistent, with some finding no difference from healthy controls, while others find elevated sympathetic activity or parasympathetic withdrawal. In fibromyalgia, the pattern is clearer, with elevated sympathetic and decreased parasympathetic activity. In all three conditions, ANS abnormalities are seen in only a minority of patients. Thus, ANS data fall short of providing a pervasive physiological mechanism plausibly linking these disorders.
Although the etiology of IBS is unknown, a subset of patients appears to develop the disorder as a consequence of gastroenteritis. IBS may develop in about 25% of people after acute gut infection.34,35 A similar etiologic mechanism has been suggested for patients with CFS based on patient surveys.36 However, post-infectious IBS is thought to occur only after GI inflammatory reactions, whereas post-infectious CFS may be related to systemic viral infections. As there is little evidence for general immunologic abnormalities in most IBS patients (although some IBS patients have evidence of low-level chronic immune activation, eg, elevated mast cell density in the bowel wall37), the general immune connection with CFS remains quite uncertain.38
Even less evidence exists for the other three conditions. Thus, there is limited support for immune changes as a unifying theme in the comorbidity of IBS and the other somatic disorders.
Most of the body's serotonin is in the GI tract, where serotonin is involved in the regulation of motility and sensation in the gut.39 In the CNS, serotonin is an important neurotransmitter, and abnormalities may play a role in mood disorders. Antidepressants that modify CNS and peripheral serotonin levels seem to benefit patients with both IBS and other chronic pain syndromes, including fibromyalgia and TMJ.40,41 Similarities in response to antidepressants are consistent with the existence of a common serotonin-related pathophysiology in IBS and comorbid disorders. For example, the effect of antidepressants on IBS bowel symptoms are independent of the effect on depression.42 Similarly, a recent study of a serotonin and norepinephrine reuptake inhibitor in patients with fibromyalgia found that symptoms improved in both depressed and nondepressed patients.43 In IBS, therapeutic doses of antidepressants for pain management are lower than doses used to treat depression, and the same is observed in management of chronic TMJ pain.44
The serotonin hypothesis appears to be promising in the quest for common pathophysiology between IBS and other somatic syndromes. However, its limitations are the absence of data linking any of these disorders except IBS to serotonin abnormalities, the fact that not all patients with any of these disorders respond to antidepressants, and the fact that serotonin abnormalities may not explain common characteristics of the disorders apart from pain sensitivity and high rates of depression.45
Disturbance in neuroendocrine mediators of the stress response, such as corticotropin-releasing factor (CRF) or cortisol, has been proposed as a possible mechanism underlying IBS, fibromyalgia, and CFS. There is some evidence for heightened neuroendocrine stress reactivity in IBS in the form of exaggerated CRF and ACTH stress activity.46 In contrast, low cortisol and reduced hypothalamus-pituitary-adrenal axis activity have been reported in fibromyalgia and CFS.47 Therefore, the evidence for neuroendocrine abnormalities in IBS is limited, ambiguous, and in a direction at odds with its comorbid conditions.
Visceral Afferent Overlap Hypothesis
Mayer et al.48 hypothesized that non-GI symptoms of IBS patients result from unique characteristics of the afferent innervation of the viscera. Most visceral afferents converge on dorsal horn cells in the spinal cord that primarily receive afferent information from somatic structures, while visceral afferent fibers from each organ diverge and spread to multiple spinal segments. These “wiring” peculiarities of visceral afferents can render the sensations associated with visceral stimulation vague and broad and lead to referral of visceral pain to other somatic organs. This hypothesis may help explain the increased experience in IBS of general non-GI symptoms but seems of little help in explaining the close relationship of IBS with other somatic syndromes.
In addition to having high rates of psychiatric disorders, IBS patients have elevated rates of a spectrum of adverse psychosocial factors known to influence health, including subjective stress and a history of sexual trauma.5 The same factors are typically over-represented among patients with the other chronic disorders listed in Table 1.14
It is unclear what role these psychological factors have in the bowel symptoms of IBS or why they are prevalent in IBS. For example, even though sexual abuse is common, it seems to be unrelated to the visceral hyperalgesia that is thought to be a key physiological dysfunction in IBS. In fact, IBS patients with a history of sexual abuse seem to have higher pain thresholds than other people with IBS.49
There is some evidence that anxiety or depression may be associated with increased risk of comorbid medical conditions in IBS.50 However, the psychological tendency of somatization seems to be a stronger correlate of comorbidity in IBS. For example, Chang et al.32 found that patients who had both IBS and fibromyalgia did not have higher psychological distress than patients with IBS only, except for higher scores on a somatization scale. Walker et al.51 found patients who had both IBS and chronic pelvic pain scored significantly higher on somatization scales than those with IBS alone, and logistical regression analysis demonstrated that the number of somatization symptoms was the best predictor of which patients had chronic pelvic pain in addition to IBS. We also found that somatization scores correlate better than anxiety or depression with the number of comorbid medical conditions of IBS patients.52 These findings suggest that somatization may be a key psychological mediating factor in IBS comorbidity.
Somatization traditionally has been viewed as a pathological psychiatric process. The most florid version of it is somatization disorder, a serious condition that involves multiple organ systems over time, with symptoms that have little or no biological derivation. However, a number of other more limited “somatoform” disorders such as functional abdominal pain are also recognized. One-fourth of IBS patients have been found to meet diagnostic criteria for somatization disorder.53 However, stringent categorizations from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV),54 seem to poorly capture the psychologically mediated tendencies of most IBS patients to experience other physical symptoms.
Another way to conceptualize somatization is to view it as a behavioral trait on a continuum from normal to abnormal, which was defined by Lipowski55 as “the propensity to experience and report somatic symptoms, to misattribute them to disease, and to seek medical attention for them.” This trait can be measured easily by simply counting the number of physical symptoms reported by patients on symptom inventories. When this approach is used in research on patients with diagnosed medical disorders, symptoms known to be associated with the disorder must be omitted and the scale scores prorated.
Somatization seems to explain non-GI symptoms in IBS because high emotional distress and sexual abuse rates are observed in IBS and are also associated with general somatization tendencies in the general population and in medical patient samples.56,57 On the other hand, the hypothesis that psychological factors explain IBS comorbidity is limited because not all patients have measurable psychological abnormalities compared with other medical patients or healthy controls. In addition, IBS, CFS, and fibromyalgia are demonstrably independent disorders, and when psychological factors such as somatization, depression, and anxiety are controlled for statistically, they fail to account for the association between IBS and other somatic disorders.9,15,16
In summary, none of the three explanations described above satisfactorily explain comorbidity in IBS. Any satisfactory model of IBS comorbidity will have to take into account that IBS and other somatic conditions are characterized by distinct clusters of symptoms, elucidate a mechanism for association between poly-symptom clusters in individuals, and accommodate the fact that, although amplified by psychological factors, the tendency toward somatic symptoms and comorbid medical conditions is partly independent of psychological variables.
Dual-Etiology Hypothesis of IBS
We recently proposed an alternative hypothesis of IBS that might clarify IBS comorbidity and could explain the paradox of simultaneous shared and distinctive features of IBS comorbid conditions.7 This hypothesis proposes that IBS is not a single disease entity but a label currently applied to at least two separate subgroups of patients who share the same cluster of GI symptoms but for different reasons. Some patients have a primarily biological basis for their IBS symptoms, whereas others have bowel symptoms primarily due to psychological or social/environmental factors.
Our hypothesis suggests that the overlap with other somatic disorders occurs specifically in the predominantly psychological IBS subgroup, through the psychological mechanism of somatization, and that the physiological subgroup will have more physiological characteristics of IBS (such as motility disturbance and visceral pain sensitivity) but lack the comorbidities and adverse psychosocial factors of the psychological subgroup. Although recognizing that the hypothesis is an over-simplification, we believe that if this dichotomy is borne out by research, it could help bring much needed clarity to IBS. For example, it could explain why every characteristic associated with IBS is found only in a subset of patients, and why only some IBS patients seem prone to somatic comorbidities.
We are conducting a large 3-year study to test this dual-etiology concept, assessing a broad range of physiological and psychological indicators in a single patient sample. However, data published previously by other investigators provide some support for the hypothesis.
A recent cluster analysis by Guthrie et al.58 examined how a variety of characteristics grouped together in the patients. They found three distinct patient groups. One group, a psychosocial subgroup, was characterized by high rates of psychiatric morbidity, low pain thresholds, and more frequent doctor visits, interpersonal problems, and sexual abuse. A second group had low pain thresholds but low sexual abuse rates and only moderate psychiatric morbidity; a third had high pain thresholds, constipation or alternating bowel habits, few doctor visits, and little sexual abuse. Similarly, Dunlop et al.59 found that a history of psychiatric diagnoses was only half as frequent in IBS of post-infectious etiology compared with IBS cases without infectious etiology.
Clinical Implications of Comorbidity in IBS
Even though the phenomenon of somatic comorbidities in IBS has a significant adverse effect on both patients and healthcare systems, it has been over-looked and rarely evaluated systematically. Implications of comorbidity can be appreciated in several areas.
Healthcare Use and Costs
Levy et al.45 have demonstrated that patients with IBS have more than twice the medical expenses of other patients. There is growing evidence that extra costs are unrelated to the bowel symptoms that define IBS. Levy et al. reported that 66% of excess costs are for non-GI indications and 78% of health care visits were for non-GI somatic complaints. Similarly, Drossman et al.60 found IBS patients make three times as many non-GI healthcare visits as control subjects. These data indicate comorbidity with other somatic syndromes and general physical symptoms account for one-third to one-half of the healthcare use and costs of IBS. A small sample of IBS patients found non-GI symptoms accounted for 28% of the variance in their healthcare visits in the previous 12 months.61
Functional Ability and Quality of Life
Two IBS patients with equivalent bowel symptoms may have very different degrees of disability, and this seems to be reflected by comorbidity. IBS patients with more comorbid medical conditions and more non-GI symptoms have significantly more work absenteeism.61,62 Studies that measure quality of life of IBS patients also find that comorbid conditions and symptoms are associated with greater quality of life impairment.62,63
IBS Disease Morbidity
IBS patients with one or more comorbid somatic disorders report greater severity of IBS symptoms.12,13 High numbers of non-GI symptoms in IBS patients also are associated with more severe and more frequent abdominal pain.61
Addressing Comorbidities in IBS
Given the serious consequences associated with somatic comorbidity in IBS, healthcare providers and the healthcare system need to target this problem to improve patient well-being, clinical outcomes, and cost effectiveness. We believe that this can be accomplished through several measures.
Routine screening for somatic comorbidities in IBS patients. Screening can be efficiently accomplished through questionnaires or review of the patient's diagnostic history. This needs to be more comprehensive than is typically accomplished in clinic visits for IBS. Such systematic identification of comorbidities is a necessary first step toward providing the extra care that these patients are likely to need.
Targeted therapies for comorbid medical conditions. Patients with multiple somatic syndromes need to have each of their major conditions addressed in order to fully respond to treatment. Concurrent treatment of IBS and fibromyalgia, for example, may result in a greater benefit than treating each individually, whereas leaving one unattended may undermine improvement in the other disorder.
Use of treatments known to specifically reduce general physical symptoms. Several treatments have been identified that can reduce general somatic symptoms. In IBS, the evidence is best for hypnosis, which significantly improves IBS bowel symptoms and simultaneously leads to reduction in general bodily symptoms.64,65 Similar but more limited evidence exists for psychodynamic and behavior therapy.66,67 Apart from IBS research, there is evidence that both anti-depressants and cognitive-behavior therapy can reduce somatic symptoms.57
Assessment and interventions for stress and affective symptoms that exacerbate somatization and comorbid conditions. Psychological distress and life stressors are associated with increased comorbid symptoms in IBS. Helping patients cope through referral to mental health professionals or by using psychotropic medications may help contain somatization and disease morbidity.
Centralized management of IBS patients with comorbidities. Patients with multiple health complaints and symptoms are at risk for receiving multiple medications and may be exposed over time to unnecessary tests and procedures with significant risk of iatrogenic harm. Careful oversight of the care of these patients is in order to minimize such risks.
It is hoped that routine attention to somatic comorbidity in IBS and interventions when warranted as described here will become a part of future standards for IBS management. Although the causes of somatic comorbidity remain unclear, significant advances have been made in practical management strategies to reduce the negative impact of comorbidity in IBS. Making the effort to address comorbidity will improve the health status and well-being of patients while simultaneously reducing the cost and burden of IBS on healthcare delivery systems.
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Overlap Between IBS and Four Comorbid Somatic Disorders7
|Comorbid disorder||Population Prevalence||% of patients who also have IBS*||% of IBS patients who also have comorbid disorder|
|Fibromyalgia||2%||28% to 65%||32% to 77%|
|Chronic fatigue syndrome||0.4%||14%+||35% to 92%|
|Chronic pelvic pain||14%||35%+||29% to 79%|
|Temporomandibular joint disorder||12% to 21%||16%+||64%+|
Percentage of IBS Patients Reporting Non-GI Somatic Symptoms in Clinical Studies
|Symptom||Whorwell et al.15 (n = 100)||Zaman et al.16 (n = 606)||Jones et al.9 (n = 88)||Maxton et al.17 (n = 107)||Nyhlin et al.18 (n = 128)||Fass et al.19 (n = 266)|
|Low back pain||37.1||88|
|Decreased sex drive||13.4||26.9|
|Shortness of breath||25|
|Muscle aches or soreness||36.3||29|
|Sensitivity to heat or cold||14|
|Incomplete bladder emptying||50|
|Bad breath/unpleasant taste in mouth||58||16.3||65|