Review
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The overlap between IBS and IBD – what is it and what does it mean? Expert Rev. Gastroenterol. Hepatol. 8(2), 139–145 (2014)
Vladimir Stanisic and Eamonn MM Quigley* Division of Gastroenterology and Hepatology, Houston Methodist, Houston, TX, USA *Author for correspondence: [email protected]
The nature and clinical implications of irritable bowel syndrome (IBS)-type symptoms in patients with inflammatory bowel disease (IBD) who are in apparent remission have generated considerable debate. While, on the one hand, these symptoms satisfy Rome III criteria for IBS and their occurrence correlates highly with anxiety, a known trigger for IBS, on the other hand, recent studies have shown that many of these patients exhibit subtle inflammatory changes. Are these symptoms ‘true’ IBS superimposed on IBD, or an active but sub-clinical form of IBD? We propose a unifying model to explain and reconcile current knowledge on this topic, a model that could provide a conceptual framework for understanding the nature of these symptoms and point towards effective management strategies. We propose that IBS symptoms in IBD patients who are in remission be termed irritable inflammatory bowel syndrome in order to emphasize their unique presentation and etiology and to distinguish them from both IBS and IBD. KEYWORDS: calprotectin . cytokines . immune activation . inflammatory bowel disease . irritable bowel syndrome .
irritable inflammatory bowel syndrome
In this article, we examine the nature of irritable bowel syndrome (IBS) symptoms in patients with inflammatory bowel disease (IBD) and discuss arguments for classifying these symptoms as either ‘true’ IBS coincidental with IBD or ongoing subclinical IBD. More importantly, we discuss why these two approaches fail to explain current observations or to enable adequate recommendations regarding potential diagnostic and treatment options. Finally, we propose a novel approach to IBS symptoms in IBD patients, which will attempt to reconcile current data and could, ultimately, provide clearer management recommendations. Central to our approach is the idea that inflammation and altered intestinal permeability are integral to the development of IBS-like symptoms in IBD patients and that this inflammation arises from interactions between known IBS triggers and pathophysiologic mediators with those of IBD. Background
At first sight, IBS and IBD appear to be quite separate, well-defined entities. Yet, they do share some similarities. Symptom onset and clinical relapse in both IBS and IBD involve multifactorial, yet incompletely understood, triggers that likely include variable combinations of environmental, www.expert-reviews.com
10.1586/17474124.2014.876361
psychological and genetic components and, possibly, feature complex relationships with the resident microbial flora of the bowel, the gut microbiota. Furthermore, regardless of the trigger, the pathophysiology of both diseases involves immune system activation. Though evidence for immune activation in IBS is more subtle and contentious, it has been shown, in IBS, that psychological stress can lead to recruitment and activation of intestinal mast cells, leading to the release of histamine, proteases and chemokines [1–3]. IBD, on the other hand, is clearly characterized by recruitment of immune cells, particularly lymphocytes, to the intestine and subsequent release of proinflammatory cytokines [4–6]. Although each disease recruits different elements of the immune system and to quite differing degrees, they share a common consequence: compromise of the intestinal epithelial barrier, an occurrence that seems to represent a critical step in the pathogenesis of both diseases [3,4,7–11]. It must be emphasized that, in the case of IBD, the ensuing inflammatory response is far more severe and reverberates across the entire organism. The epidemiology of IBS and IBD is somewhat different. IBS affects 10–15% of the adult population in Europe and North America,
2014 Informa UK Ltd
ISSN 1747-4124
139
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
Review
Stanisic & Quigley
favors females and, in general, manifests in people under the age of 50 years (most commonly between the ages of 15 and 65 years) [2,12,13]. Though IBD can occur at any age, its incidence peaks between the ages of 15 and 30 years, is, overall, gender neutral and favors those of Caucasian and Ashkenazi Jewish origin. Symptoms of IBS and IBD show overlap in as much they may both involve abdominal pain, bloating, diarrhea and loose stools. However, in IBS, abdominal pain is by definition relieved by defecation. Also, ‘alarm features’ such as the presence of fever, nocturnal symptoms, weight and appetite loss, hemochezia, vomiting, anemia and perianal disease are absent in IBS and are common in IBD. Extracolonic symptoms in IBS include dyspepsia, heartburn and nausea, whereas IBD may affect joints, eyes, skin and liver [14]. Other risk factors for IBS include a history of functional pain in childhood, anxiety, stress and prior exposure to intestinal infection. For IBD, cigarette smoking, living in an urban environment, and, possibly, diet, use of oral contraceptives, perinatal or childhood exposure to infection and/or antibiotics or atypical mycobacterial infections may play a role [14]. Currently, the management of IBS is multimodal and often empirical, involving lifestyle modifications and the use of medications aimed at alleviating individual symptoms as no disease modifying has been established. IBD, on the other hand, involves structured top-down or bottom-up approaches based on a range of anti-inflammatory medications from 5-aminosalicylate derivatives, through corticosteroids to immunomodulators and biologicals. IBS-like symptoms in IBD: prevalence & significance
Over the last several years, much interest and debate have been generated around the interpretation of IBS-type symptoms in IBD patients who are in apparent clinical remission. Indeed, though results vary considerably, up to 59.7% of Crohn’s disease (CD) and 38.6% of ulcerative colitis (UC) patients in apparent remission complain of IBS-like symptoms [15–17]. The occurrence of such symptoms in the IBD patient represents a source of considerable stress, incurs considerable morbidity and impairs quality of life (QoL) [17]. In addition, it represents a diagnostic and therapeutic conundrum for the physician since no clear guidelines or even consensus opinion exists regarding the source of these symptoms, and the potential impact that they have on the course of IBD. The key question has been whether the occurrence of IBS symptoms in IBD patients who are in remission represents true IBS superimposed on IBD, or whether, despite the presence of remission, as defined by widely employed criteria, these same symptoms represent active, though subtle, IBD with ongoing intestinal inflammation? How one resolves this dilemma has tremendous implications for patient management. So how should we interpret IBS-like symptoms in the context of IBD? To address this question, we will examine arguments for classifying patients with IBS-like symptoms in IBD as either: . .
‘true’ IBS superimposed on IBD or, subclinical IBD.
140
Finally, we will propose a theoretical model that seeks to reconcile these observations and competing arguments into a unified conceptual framework. Arguments for IBS coincidental with IBD or ‘true IBS in IBD’
Given the high prevalence of IBS in the general adult population and the relatively high prevalence of IBD in Western nations, it should come as no surprise that IBS and IBD could coexist, purely on the basis of chance. Though this seems unlikely based on the prevalence rates of 40–60% for IBS in IBD quoted above which (four- to fivefold higher than general population rates) this is a possibility that must be considered. .
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The IBD patient population suffering from these symptoms can be clearly and reliably distinguished from asymptomatic IBD patients in remission based on Rome III (or Rome II) criteria for IBS. Indeed, several studies have been able to identify a substantial percentage of IBD patients in remission who fulfill criteria for IBS; this alone would appear, at face value, to indicate an essential commonality between this patient population and IBS, in general (‘true’ IBS) [11,15,16,18–22]. At least two studies have reported a higher prevalence of IBS-like symptoms in female than in male patients with IBD, a feature of ‘true’ IBS [20,22]. Importantly, studies have shown that IBS-like symptoms in IBD are positively correlated with anxiety, a known trigger of IBS symptoms in otherwise healthy populations [15,21,22]. A study by Aguas et al. [23] showed that IBS is more prevalent in first-degree relatives of patients with IBD suggesting a shared genetic susceptibility and, at the very least, the possibility that these IBD patients were, in fact, predisposed to develop IBS in addition to IBD. A study by Berrill et al. [20] showed that IBS symptoms in IBD patients occur regardless of IBD disease type, the nature and intensity of their IBD treatment regimens and the duration of remission, suggesting a poor correlation between IBD disease activity and IBS-like symptoms. A study by Porter et al. showed that IBS is a risk factor for the development of IBD. They showed that the incidence of IBD was 8.6-fold higher among those diagnosed with IBS compared with those who did not carry this diagnosis. [24]. In patients with a documented history of IBS symptoms prior to the diagnosis of IBD, the appearance of IBS following the induction of remission of IBD could then represent the reemergence of pre-existing IBS. Furthermore, it is statistically possible, given the high background prevalence of IBS, that some IBD patients would develop IBS de novo while in remission from IBD. Finally, it is also possible that an, as yet, unrecognized risk factor is fundamental to both disease processes, and that the coincidence of IBS and IBD represents the expression of shared genetic–environmental risk factors. At the cellular and molecular level, patients with IBS-like symptoms in IBD have been shown to exhibit increased
Expert Rev. Gastroenterol. Hepatol. 8(2), (2014)
IBS & IBD overlap
intestinal permeability, a profusion of TRPV1 pain receptor fibers [25,26], and decreased expression of the tight junction proteins zonulin-1 and alpha cathenin, phenomena that are evident in IBS, in general. Arguments for IBS symptoms in IBD representing ongoing, subclinical activity of IBD
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
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The cardinal symptoms of IBS (pain, bloating and altered bowel habit) are nonspecific, so much so that the very same Rome criteria that have been used to define ‘IBS’ or IBS-like symptoms in IBD clearly stipulate that there should be no organic explanation for the symptoms. One could argue, therefore, that as a matter of first principle, Rome criteria should not even be applied to an individual patient with known IBD regardless of disease activity. It is equally clear that the various clinical indices used to define activity in both CD and UC bear a far from perfect correlation with more direct measures of inflammatory activity such as endoscopic features, biopsy morphology or stool biomarkers. In other words, relying on the CD activity index alone will overestimate rates of true remission in CD. Several studies have shown that patients with IBS-like symptoms in IBD, in apparent remission, exhibit increased fecal levels of calprotectin – a marker of intestinal inflammation highly sensitive to disease activity in IBD and not seen in patients who are in true remission or among otherwise healthy IBS subjects [15,16]. However, recent studies by Jonefjall et al. and Berrill et al. demonstrating normal fecal calprotectin levels among some IBD patients in clinical remission, yet complaining of IBS-type symptoms, suggest that not all IBS-like symptoms, in IBD, can be explained by ongoing inflammation, at least, as detected by fecal calprotectin assays [20,22]. Vivinus-Nebot et al. reported increased levels of the proinflammatory cytokine TNF-a and higher numbers of intraepithelial lymphocytes in IBD patients in remission but with IBS-like symptoms than in those without [11]. These are features commonly present in IBD but absent in IBS. Lipopolysaccharide stimulation of biopsy samples from IBD patients in remission but with IBS-like symptoms leads to an accentuated inflammatory response [11]. However, inflammatory mediator release from cultured intestinal biopsies from IBS subjects without IBD was similar to control subjects and less than that of IBD patients [27] suggesting that, at the mucosal level, ongoing inflammatory processes are a characteristic of IBD rather than IBS [11]. This is a key issue; the well-known inflammatory process in IBD bears little or no resemblance to the subtle, variable and, in some instances, absent evidence of immune activation in IBS, in general, suggesting that IBS in IBD may be a different entity. Altered intestinal permeability is a feature of both IBS and IBD and cannot be used to differentiate IBS from IBD. Retrospective and population-based studies indicating the presence of IBS-type symptoms for many years (up to 20) before a diagnosis of IBD and CD, in particular, is made [18,28–31].
www.expert-reviews.com
Review
As we have seen from this brief summary the controversy generated by this issue and the clinical dilemmas that it can pose arise from the fact that IBS in IBD presents with nonspecific symptoms and, superficially and albeit variably, manifests pathophysiological characteristics of both IBS and IBD. An attempt has been made over the last several years to distinguish these two scenarios in a given patient by performing an assay for fecal levels of calprotectin. The goal was to differentiate ‘true’ IBS in the IBD patient from those with ongoing subclinical activity of IBD in order to guide management. In this way, true IBS patients would be spared the aggressive antiinflammatory regimens reserved for IBD, and patients with ongoing IBD would be more appropriately treated. While calprotectin has served as a reliable predictor of inflammatory activity in this population [15,16], we do not know how the detection of such activity informs therapeutic decisions or predicts therapeutic response, as this has not been directly studied. Furthermore, it is evident from the recent studies, which have routinely employed calprotectin in their assessment of disease activity, that some IBD patients will manifest IBS-like symptoms in the face of normal levels of calprotectin in the feces [20,22]. It must also be conceded that attempting to define, in each IBD patient, if their symptoms might be based on ongoing inflammation may be an ultimately futile exercise as inflammation at the cellular and molecular level may remain undetectable by currently available biomarkers. Current research goals
To date, studies of IBS-like symptoms in IBD populations have been largely descriptive and have focused on defining prevalence rates and clinical associations. In some studies, a role for ongoing IBD activity has been supported by the documentation of elevated levels of calprotectin in the stool [15,16]; others have identified these symptoms in the absence of any evidence of activity and in the face of normal fecal levels of calprotectin [20,22]. Most recently, more extensive and detailed studies have revealed indications of immune activation and epithelial barrier dysfunction in patients with no other features of overt inflammation [11]. To better understand the pathophysiology and clinical relevance of IBS symptoms in IBD, current research is focused on: .
.
.
The pathophysiology of IBS symptoms in IBD patients in apparent remission. A number of studies have been conducted to define, at a cellular and molecular level, changes that may be relevant to the genesis of these symptoms [11]. The assessment of the utility of the inflammatory marker calprotectin in patients who have IBS-like symptoms in IBD to discriminate between those who have underlying inflammation and those who may have truly had IBS devoid of significant inflammation [15,16,20,22]. The evaluation of psychological and epidemiological aspects of IBS-like symptoms in IBD. These studies aim to evaluate possible psychosocial and other environmental triggers of 141
Review
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Stanisic & Quigley
these symptoms and to describe the impact that these symptoms have on patients’ QoL. Employing the occurrence of IBS-like symptoms in IBD as a window into the pathophysiology of IBS, in general
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Irritable IBD: a unifying model of IBS symptoms in IBD patients who are in remission
There is an approach that could potentially reconcile the aforementioned observations and provide a unifying concept for the interpretation of IBS-like symptoms in IBD. It is possible that the characteristics of IBS (or more accurately an IBS-like syndrome) occurring in the IBD patient who is in remission are so influenced by the underlying IBD that they no longer completely resemble IBS seen in an otherwise healthy population. The key question that we are posing is: What would IBS look like in a person with IBD? Would it be the same as IBS in an otherwise healthy individual or would it have different features related to the presence of an underlying chronic illness? So far, it has been assumed that ‘true’ IBS in IBD would mimic IBS seen in the general population, but this may not be the case. Given that both IBS and IBD engage complementary aspects of the immune system and that they both ultimately affect intestinal function, it is not implausible to propose that IBS in IBD would involve an expanded spectrum of pathophysiological features not seen in otherwise healthy IBS patients. One analogy to this situation would be a comparison between the occurrence of pneumonia in a healthy person and in patient infected with HIV. The causative pathogen may well be the same but the severity of symptoms, as well as cellular and molecular responses, disease course, outcome and, consequently, therapeutic approach will be vastly different. Understanding IBS symptoms in the IBD patient as a form of IBS that is fundamentally transformed because of the underlying IBD would help explain the occurrence of proinflammatory features in a phenotype that otherwise clearly satisfies recognized clinical criteria for IBS. It is possible that, in these particular patients, different components of the immune system interact with the host’s neuromuscular apparatus and brain–gut axis to produce a new syndrome distinct from ‘true’ IBS, full-blown IBD or subclinically active IBD. In this way, we can simultaneously accept that IBS symptoms in IBD are not ‘simply’ superimposed or coincidental IBS, as reflected by the presence of indicators of a proinflammatory state, which are neither typical for ‘pure’ IBS nor do they inevitably represent the ongoing activity of IBD defined by every means that are currently at our disposal. One pathophysiological mechanism that could provide an overarching explanation for the occurrence of IBS-like symptoms revolves around the alteration in intestinal permeability, which can be found in both IBS and IBD. It is possible that the epithelium in IBD patients who are in remission is already ‘primed’ by a low level of inflammation related to IBD, per se. IBS-type triggers, such as stress or anxiety, then 142
lead to the release of histamine and other chemokines from mast cells [32] and, thereby, foster further recruitment of lymphocytes and the production of proinflammatory cytokines. These, in turn, result in increased intestinal permeability, histamine release and upregulation of TRPV1 pain receptors, thereby generating IBS-like symptoms. Meanwhile, their effects on an IBD primed molecular milieu would lead to activation of inflammatory pathways and production of cytokines such as TNF-a and calprotectin [25,26]. This proposal is supported by the findings of Vivinus-Nebot et al. [11] who documented features characteristic of both IBS and IBD in biopsies taken from their patient population, as well as the shared feature of increased intestinal permeability. Specifically, they found that the expressions of the tight junction proteins zonulin-1 and a-cathenin were decreased both among those with IBS, without IBD and those with IBS-like symptoms in IBD. On the other hand, they also found that patients with IBS-like symptoms in IBD had increased expression of TNF-a and increased numbers of intraepithelial leukocytes, features of IBD. In order to emphasize the distinct nature of IBS-like symptoms in IBD patients who are in remission and differentiate them clearly from both IBS in otherwise healthy individuals patients and subclinical but active IBD, and to simplify what is currently a cumbersome description, we suggest referring to this occurrence as irritable inflammatory bowel syndrome (IIBS). This name indicates the nature of the symptoms, namely, IBS like, the context occurring in an IBD patient, and finally, signifies that it is a syndrome rather than a clearly delineated disease entity. The central concept is that both IBS symptoms and intestinal inflammation are integral features of IIBD. We speculate that this particular combination of symptoms and an inflammatory background is sufficiently distinct (from both IBS and IBD) and reproducible to be recognized as a separate syndrome. Importantly, by differentiating it from both IBS and IBD, we aim to emphasize its unique role in patients with IBD and its potential to uniquely affect the clinical course of IBD. We suggest the following diagnostic criteria for IIBS based on the current literature [11,15,16,18,20–22]: .
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Patients should have a firm diagnosis of IBD and be in clinical remission as judged by recent endoscopic and imaging studies, normal levels of the systemic inflammatory markers C-reactive protein and erythrocyte sedimentation rate and a simple Crohn’s disease activity index 250 mg/g gave a sensitivity of 71.0% and a specificity of 100.0% (PPV 100.0%; NPV 47.1%) for active mucosal disease (Mayo score >0). It must be noted that JelsnessJorgensen and colleagues suggested that a cutoff of
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The overlap between IBS and IBD – what is it and what does it mean? Expert Rev. Gastroenterol. Hepatol. 8(2), 139–145 (2014)
Vladimir Stanisic and Eamonn MM Quigley* Division of Gastroenterology and Hepatology, Houston Methodist, Houston, TX, USA *Author for correspondence: [email protected]
The nature and clinical implications of irritable bowel syndrome (IBS)-type symptoms in patients with inflammatory bowel disease (IBD) who are in apparent remission have generated considerable debate. While, on the one hand, these symptoms satisfy Rome III criteria for IBS and their occurrence correlates highly with anxiety, a known trigger for IBS, on the other hand, recent studies have shown that many of these patients exhibit subtle inflammatory changes. Are these symptoms ‘true’ IBS superimposed on IBD, or an active but sub-clinical form of IBD? We propose a unifying model to explain and reconcile current knowledge on this topic, a model that could provide a conceptual framework for understanding the nature of these symptoms and point towards effective management strategies. We propose that IBS symptoms in IBD patients who are in remission be termed irritable inflammatory bowel syndrome in order to emphasize their unique presentation and etiology and to distinguish them from both IBS and IBD. KEYWORDS: calprotectin . cytokines . immune activation . inflammatory bowel disease . irritable bowel syndrome .
irritable inflammatory bowel syndrome
In this article, we examine the nature of irritable bowel syndrome (IBS) symptoms in patients with inflammatory bowel disease (IBD) and discuss arguments for classifying these symptoms as either ‘true’ IBS coincidental with IBD or ongoing subclinical IBD. More importantly, we discuss why these two approaches fail to explain current observations or to enable adequate recommendations regarding potential diagnostic and treatment options. Finally, we propose a novel approach to IBS symptoms in IBD patients, which will attempt to reconcile current data and could, ultimately, provide clearer management recommendations. Central to our approach is the idea that inflammation and altered intestinal permeability are integral to the development of IBS-like symptoms in IBD patients and that this inflammation arises from interactions between known IBS triggers and pathophysiologic mediators with those of IBD. Background
At first sight, IBS and IBD appear to be quite separate, well-defined entities. Yet, they do share some similarities. Symptom onset and clinical relapse in both IBS and IBD involve multifactorial, yet incompletely understood, triggers that likely include variable combinations of environmental, www.expert-reviews.com
10.1586/17474124.2014.876361
psychological and genetic components and, possibly, feature complex relationships with the resident microbial flora of the bowel, the gut microbiota. Furthermore, regardless of the trigger, the pathophysiology of both diseases involves immune system activation. Though evidence for immune activation in IBS is more subtle and contentious, it has been shown, in IBS, that psychological stress can lead to recruitment and activation of intestinal mast cells, leading to the release of histamine, proteases and chemokines [1–3]. IBD, on the other hand, is clearly characterized by recruitment of immune cells, particularly lymphocytes, to the intestine and subsequent release of proinflammatory cytokines [4–6]. Although each disease recruits different elements of the immune system and to quite differing degrees, they share a common consequence: compromise of the intestinal epithelial barrier, an occurrence that seems to represent a critical step in the pathogenesis of both diseases [3,4,7–11]. It must be emphasized that, in the case of IBD, the ensuing inflammatory response is far more severe and reverberates across the entire organism. The epidemiology of IBS and IBD is somewhat different. IBS affects 10–15% of the adult population in Europe and North America,
2014 Informa UK Ltd
ISSN 1747-4124
139
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
Review
Stanisic & Quigley
favors females and, in general, manifests in people under the age of 50 years (most commonly between the ages of 15 and 65 years) [2,12,13]. Though IBD can occur at any age, its incidence peaks between the ages of 15 and 30 years, is, overall, gender neutral and favors those of Caucasian and Ashkenazi Jewish origin. Symptoms of IBS and IBD show overlap in as much they may both involve abdominal pain, bloating, diarrhea and loose stools. However, in IBS, abdominal pain is by definition relieved by defecation. Also, ‘alarm features’ such as the presence of fever, nocturnal symptoms, weight and appetite loss, hemochezia, vomiting, anemia and perianal disease are absent in IBS and are common in IBD. Extracolonic symptoms in IBS include dyspepsia, heartburn and nausea, whereas IBD may affect joints, eyes, skin and liver [14]. Other risk factors for IBS include a history of functional pain in childhood, anxiety, stress and prior exposure to intestinal infection. For IBD, cigarette smoking, living in an urban environment, and, possibly, diet, use of oral contraceptives, perinatal or childhood exposure to infection and/or antibiotics or atypical mycobacterial infections may play a role [14]. Currently, the management of IBS is multimodal and often empirical, involving lifestyle modifications and the use of medications aimed at alleviating individual symptoms as no disease modifying has been established. IBD, on the other hand, involves structured top-down or bottom-up approaches based on a range of anti-inflammatory medications from 5-aminosalicylate derivatives, through corticosteroids to immunomodulators and biologicals. IBS-like symptoms in IBD: prevalence & significance
Over the last several years, much interest and debate have been generated around the interpretation of IBS-type symptoms in IBD patients who are in apparent clinical remission. Indeed, though results vary considerably, up to 59.7% of Crohn’s disease (CD) and 38.6% of ulcerative colitis (UC) patients in apparent remission complain of IBS-like symptoms [15–17]. The occurrence of such symptoms in the IBD patient represents a source of considerable stress, incurs considerable morbidity and impairs quality of life (QoL) [17]. In addition, it represents a diagnostic and therapeutic conundrum for the physician since no clear guidelines or even consensus opinion exists regarding the source of these symptoms, and the potential impact that they have on the course of IBD. The key question has been whether the occurrence of IBS symptoms in IBD patients who are in remission represents true IBS superimposed on IBD, or whether, despite the presence of remission, as defined by widely employed criteria, these same symptoms represent active, though subtle, IBD with ongoing intestinal inflammation? How one resolves this dilemma has tremendous implications for patient management. So how should we interpret IBS-like symptoms in the context of IBD? To address this question, we will examine arguments for classifying patients with IBS-like symptoms in IBD as either: . .
‘true’ IBS superimposed on IBD or, subclinical IBD.
140
Finally, we will propose a theoretical model that seeks to reconcile these observations and competing arguments into a unified conceptual framework. Arguments for IBS coincidental with IBD or ‘true IBS in IBD’
Given the high prevalence of IBS in the general adult population and the relatively high prevalence of IBD in Western nations, it should come as no surprise that IBS and IBD could coexist, purely on the basis of chance. Though this seems unlikely based on the prevalence rates of 40–60% for IBS in IBD quoted above which (four- to fivefold higher than general population rates) this is a possibility that must be considered. .
.
.
.
.
.
.
The IBD patient population suffering from these symptoms can be clearly and reliably distinguished from asymptomatic IBD patients in remission based on Rome III (or Rome II) criteria for IBS. Indeed, several studies have been able to identify a substantial percentage of IBD patients in remission who fulfill criteria for IBS; this alone would appear, at face value, to indicate an essential commonality between this patient population and IBS, in general (‘true’ IBS) [11,15,16,18–22]. At least two studies have reported a higher prevalence of IBS-like symptoms in female than in male patients with IBD, a feature of ‘true’ IBS [20,22]. Importantly, studies have shown that IBS-like symptoms in IBD are positively correlated with anxiety, a known trigger of IBS symptoms in otherwise healthy populations [15,21,22]. A study by Aguas et al. [23] showed that IBS is more prevalent in first-degree relatives of patients with IBD suggesting a shared genetic susceptibility and, at the very least, the possibility that these IBD patients were, in fact, predisposed to develop IBS in addition to IBD. A study by Berrill et al. [20] showed that IBS symptoms in IBD patients occur regardless of IBD disease type, the nature and intensity of their IBD treatment regimens and the duration of remission, suggesting a poor correlation between IBD disease activity and IBS-like symptoms. A study by Porter et al. showed that IBS is a risk factor for the development of IBD. They showed that the incidence of IBD was 8.6-fold higher among those diagnosed with IBS compared with those who did not carry this diagnosis. [24]. In patients with a documented history of IBS symptoms prior to the diagnosis of IBD, the appearance of IBS following the induction of remission of IBD could then represent the reemergence of pre-existing IBS. Furthermore, it is statistically possible, given the high background prevalence of IBS, that some IBD patients would develop IBS de novo while in remission from IBD. Finally, it is also possible that an, as yet, unrecognized risk factor is fundamental to both disease processes, and that the coincidence of IBS and IBD represents the expression of shared genetic–environmental risk factors. At the cellular and molecular level, patients with IBS-like symptoms in IBD have been shown to exhibit increased
Expert Rev. Gastroenterol. Hepatol. 8(2), (2014)
IBS & IBD overlap
intestinal permeability, a profusion of TRPV1 pain receptor fibers [25,26], and decreased expression of the tight junction proteins zonulin-1 and alpha cathenin, phenomena that are evident in IBS, in general. Arguments for IBS symptoms in IBD representing ongoing, subclinical activity of IBD
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
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. .
The cardinal symptoms of IBS (pain, bloating and altered bowel habit) are nonspecific, so much so that the very same Rome criteria that have been used to define ‘IBS’ or IBS-like symptoms in IBD clearly stipulate that there should be no organic explanation for the symptoms. One could argue, therefore, that as a matter of first principle, Rome criteria should not even be applied to an individual patient with known IBD regardless of disease activity. It is equally clear that the various clinical indices used to define activity in both CD and UC bear a far from perfect correlation with more direct measures of inflammatory activity such as endoscopic features, biopsy morphology or stool biomarkers. In other words, relying on the CD activity index alone will overestimate rates of true remission in CD. Several studies have shown that patients with IBS-like symptoms in IBD, in apparent remission, exhibit increased fecal levels of calprotectin – a marker of intestinal inflammation highly sensitive to disease activity in IBD and not seen in patients who are in true remission or among otherwise healthy IBS subjects [15,16]. However, recent studies by Jonefjall et al. and Berrill et al. demonstrating normal fecal calprotectin levels among some IBD patients in clinical remission, yet complaining of IBS-type symptoms, suggest that not all IBS-like symptoms, in IBD, can be explained by ongoing inflammation, at least, as detected by fecal calprotectin assays [20,22]. Vivinus-Nebot et al. reported increased levels of the proinflammatory cytokine TNF-a and higher numbers of intraepithelial lymphocytes in IBD patients in remission but with IBS-like symptoms than in those without [11]. These are features commonly present in IBD but absent in IBS. Lipopolysaccharide stimulation of biopsy samples from IBD patients in remission but with IBS-like symptoms leads to an accentuated inflammatory response [11]. However, inflammatory mediator release from cultured intestinal biopsies from IBS subjects without IBD was similar to control subjects and less than that of IBD patients [27] suggesting that, at the mucosal level, ongoing inflammatory processes are a characteristic of IBD rather than IBS [11]. This is a key issue; the well-known inflammatory process in IBD bears little or no resemblance to the subtle, variable and, in some instances, absent evidence of immune activation in IBS, in general, suggesting that IBS in IBD may be a different entity. Altered intestinal permeability is a feature of both IBS and IBD and cannot be used to differentiate IBS from IBD. Retrospective and population-based studies indicating the presence of IBS-type symptoms for many years (up to 20) before a diagnosis of IBD and CD, in particular, is made [18,28–31].
www.expert-reviews.com
Review
As we have seen from this brief summary the controversy generated by this issue and the clinical dilemmas that it can pose arise from the fact that IBS in IBD presents with nonspecific symptoms and, superficially and albeit variably, manifests pathophysiological characteristics of both IBS and IBD. An attempt has been made over the last several years to distinguish these two scenarios in a given patient by performing an assay for fecal levels of calprotectin. The goal was to differentiate ‘true’ IBS in the IBD patient from those with ongoing subclinical activity of IBD in order to guide management. In this way, true IBS patients would be spared the aggressive antiinflammatory regimens reserved for IBD, and patients with ongoing IBD would be more appropriately treated. While calprotectin has served as a reliable predictor of inflammatory activity in this population [15,16], we do not know how the detection of such activity informs therapeutic decisions or predicts therapeutic response, as this has not been directly studied. Furthermore, it is evident from the recent studies, which have routinely employed calprotectin in their assessment of disease activity, that some IBD patients will manifest IBS-like symptoms in the face of normal levels of calprotectin in the feces [20,22]. It must also be conceded that attempting to define, in each IBD patient, if their symptoms might be based on ongoing inflammation may be an ultimately futile exercise as inflammation at the cellular and molecular level may remain undetectable by currently available biomarkers. Current research goals
To date, studies of IBS-like symptoms in IBD populations have been largely descriptive and have focused on defining prevalence rates and clinical associations. In some studies, a role for ongoing IBD activity has been supported by the documentation of elevated levels of calprotectin in the stool [15,16]; others have identified these symptoms in the absence of any evidence of activity and in the face of normal fecal levels of calprotectin [20,22]. Most recently, more extensive and detailed studies have revealed indications of immune activation and epithelial barrier dysfunction in patients with no other features of overt inflammation [11]. To better understand the pathophysiology and clinical relevance of IBS symptoms in IBD, current research is focused on: .
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The pathophysiology of IBS symptoms in IBD patients in apparent remission. A number of studies have been conducted to define, at a cellular and molecular level, changes that may be relevant to the genesis of these symptoms [11]. The assessment of the utility of the inflammatory marker calprotectin in patients who have IBS-like symptoms in IBD to discriminate between those who have underlying inflammation and those who may have truly had IBS devoid of significant inflammation [15,16,20,22]. The evaluation of psychological and epidemiological aspects of IBS-like symptoms in IBD. These studies aim to evaluate possible psychosocial and other environmental triggers of 141
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these symptoms and to describe the impact that these symptoms have on patients’ QoL. Employing the occurrence of IBS-like symptoms in IBD as a window into the pathophysiology of IBS, in general
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Irritable IBD: a unifying model of IBS symptoms in IBD patients who are in remission
There is an approach that could potentially reconcile the aforementioned observations and provide a unifying concept for the interpretation of IBS-like symptoms in IBD. It is possible that the characteristics of IBS (or more accurately an IBS-like syndrome) occurring in the IBD patient who is in remission are so influenced by the underlying IBD that they no longer completely resemble IBS seen in an otherwise healthy population. The key question that we are posing is: What would IBS look like in a person with IBD? Would it be the same as IBS in an otherwise healthy individual or would it have different features related to the presence of an underlying chronic illness? So far, it has been assumed that ‘true’ IBS in IBD would mimic IBS seen in the general population, but this may not be the case. Given that both IBS and IBD engage complementary aspects of the immune system and that they both ultimately affect intestinal function, it is not implausible to propose that IBS in IBD would involve an expanded spectrum of pathophysiological features not seen in otherwise healthy IBS patients. One analogy to this situation would be a comparison between the occurrence of pneumonia in a healthy person and in patient infected with HIV. The causative pathogen may well be the same but the severity of symptoms, as well as cellular and molecular responses, disease course, outcome and, consequently, therapeutic approach will be vastly different. Understanding IBS symptoms in the IBD patient as a form of IBS that is fundamentally transformed because of the underlying IBD would help explain the occurrence of proinflammatory features in a phenotype that otherwise clearly satisfies recognized clinical criteria for IBS. It is possible that, in these particular patients, different components of the immune system interact with the host’s neuromuscular apparatus and brain–gut axis to produce a new syndrome distinct from ‘true’ IBS, full-blown IBD or subclinically active IBD. In this way, we can simultaneously accept that IBS symptoms in IBD are not ‘simply’ superimposed or coincidental IBS, as reflected by the presence of indicators of a proinflammatory state, which are neither typical for ‘pure’ IBS nor do they inevitably represent the ongoing activity of IBD defined by every means that are currently at our disposal. One pathophysiological mechanism that could provide an overarching explanation for the occurrence of IBS-like symptoms revolves around the alteration in intestinal permeability, which can be found in both IBS and IBD. It is possible that the epithelium in IBD patients who are in remission is already ‘primed’ by a low level of inflammation related to IBD, per se. IBS-type triggers, such as stress or anxiety, then 142
lead to the release of histamine and other chemokines from mast cells [32] and, thereby, foster further recruitment of lymphocytes and the production of proinflammatory cytokines. These, in turn, result in increased intestinal permeability, histamine release and upregulation of TRPV1 pain receptors, thereby generating IBS-like symptoms. Meanwhile, their effects on an IBD primed molecular milieu would lead to activation of inflammatory pathways and production of cytokines such as TNF-a and calprotectin [25,26]. This proposal is supported by the findings of Vivinus-Nebot et al. [11] who documented features characteristic of both IBS and IBD in biopsies taken from their patient population, as well as the shared feature of increased intestinal permeability. Specifically, they found that the expressions of the tight junction proteins zonulin-1 and a-cathenin were decreased both among those with IBS, without IBD and those with IBS-like symptoms in IBD. On the other hand, they also found that patients with IBS-like symptoms in IBD had increased expression of TNF-a and increased numbers of intraepithelial leukocytes, features of IBD. In order to emphasize the distinct nature of IBS-like symptoms in IBD patients who are in remission and differentiate them clearly from both IBS in otherwise healthy individuals patients and subclinical but active IBD, and to simplify what is currently a cumbersome description, we suggest referring to this occurrence as irritable inflammatory bowel syndrome (IIBS). This name indicates the nature of the symptoms, namely, IBS like, the context occurring in an IBD patient, and finally, signifies that it is a syndrome rather than a clearly delineated disease entity. The central concept is that both IBS symptoms and intestinal inflammation are integral features of IIBD. We speculate that this particular combination of symptoms and an inflammatory background is sufficiently distinct (from both IBS and IBD) and reproducible to be recognized as a separate syndrome. Importantly, by differentiating it from both IBS and IBD, we aim to emphasize its unique role in patients with IBD and its potential to uniquely affect the clinical course of IBD. We suggest the following diagnostic criteria for IIBS based on the current literature [11,15,16,18,20–22]: .
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Patients should have a firm diagnosis of IBD and be in clinical remission as judged by recent endoscopic and imaging studies, normal levels of the systemic inflammatory markers C-reactive protein and erythrocyte sedimentation rate and a simple Crohn’s disease activity index 250 mg/g gave a sensitivity of 71.0% and a specificity of 100.0% (PPV 100.0%; NPV 47.1%) for active mucosal disease (Mayo score >0). It must be noted that JelsnessJorgensen and colleagues suggested that a cutoff of
