Irritable bowel syndrome is probably the most common functional gastrointestinal disorder and is characterized by abdominal pain along with altered bowel function. It is a disorder of female predominance. This article focuses on how being female influences the pathophysiology, diagnosis, management, and treatment of this common disorder and discusses the evidence and important controversies related to these areas.
Key points
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Irritable bowel syndrome (IBS) is a predominantly female disorder characterized by abdominal pain or discomfort associated with altered bowel habit (diarrhea, constipation, or both) symptoms.
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Pathophysiology of IBS is heterogeneous and includes altered motility, visceral hypersensitivity, changes in gut permeability, immune activation, brain-gut dysregulation, autonomic nervous system dysfunction, and changes in gut microbiome, all of which may be mediated by gender-related differences.
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A confident IBS diagnosis can be made based on symptom criteria, exclusion of alarm features, recognition of female predominant overlap syndromes, and thoughtful use of bowel habit–based diagnostic work-up.
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Successful management of the female patients with IBS involves understanding female gender roles as well as establishment of active listening and a caring positive clinician-patient relationship.
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Treatment approach requires an assessment of lifestyle (diet, sleep, and exercise), gut-directed pharmacotherapy, and psychological therapies as indicated by IBS disease severity.
Introduction
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain and discomfort that is associated with altered bowel function and that can involve diarrhea, constipation, or mixed bowel patterns. It is a chronic disorder with a female predominance ranging from 2:1 to 4:1 depending on the clinical setting. Worldwide the prevalence varies from 7% to 21%. Female prevalence may also vary according to geographic location. In Asia the distribution seems to be fairly equal between men and women but in the United States, Israel, and Canada the disorder is twice as prevalent in women. In veterans returning from the Gulf War, IBS is more prevalent in women than in men (3.7% vs 1.6%) and more often linked to depression, whereas men have a greater likelihood of having posttraumatic stress disorder (PTSD). Female patients have more constipation and abdominal pain and male patients complain more of diarrhea.
Although several pathophysiologic mechanisms have been put forth, including increased visceral sensation, alterations in intestinal motility and permeability, autonomic nervous system dysregulation, activation of GI immune function, brain-gut dysregulation, and alterations in the gut microbiome, sex hormones and psychosocial factors may also play a pathophysiologic role. It is also notable that many of the comorbid conditions associated with IBS also have a female predominance; for example, fibromyalgia, chronic pelvic pain, migraine headache, and chronic fatigue syndrome, as well as other functional GI disorders such as functional dyspepsia. This article focuses on how female gender influences the pathophysiology, diagnosis, management, and treatment of this common disorder and discusses the evidence and important controversies related to these areas.
Introduction
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain and discomfort that is associated with altered bowel function and that can involve diarrhea, constipation, or mixed bowel patterns. It is a chronic disorder with a female predominance ranging from 2:1 to 4:1 depending on the clinical setting. Worldwide the prevalence varies from 7% to 21%. Female prevalence may also vary according to geographic location. In Asia the distribution seems to be fairly equal between men and women but in the United States, Israel, and Canada the disorder is twice as prevalent in women. In veterans returning from the Gulf War, IBS is more prevalent in women than in men (3.7% vs 1.6%) and more often linked to depression, whereas men have a greater likelihood of having posttraumatic stress disorder (PTSD). Female patients have more constipation and abdominal pain and male patients complain more of diarrhea.
Although several pathophysiologic mechanisms have been put forth, including increased visceral sensation, alterations in intestinal motility and permeability, autonomic nervous system dysregulation, activation of GI immune function, brain-gut dysregulation, and alterations in the gut microbiome, sex hormones and psychosocial factors may also play a pathophysiologic role. It is also notable that many of the comorbid conditions associated with IBS also have a female predominance; for example, fibromyalgia, chronic pelvic pain, migraine headache, and chronic fatigue syndrome, as well as other functional GI disorders such as functional dyspepsia. This article focuses on how female gender influences the pathophysiology, diagnosis, management, and treatment of this common disorder and discusses the evidence and important controversies related to these areas.
Pathophysiology
Table 1 summarizes the proposed mechanisms of IBS and emphasizes the heterogeneity of the disorder. Diet, gut (motility, visceral hypersensitivity), psychological (somatization, anxiety, and depression), and genetic and central (eg, brain-gut signaling) factors have all been postulated to play a role in pathophysiology but may not all be present in each individual. Likely there is interplay of genetic and environmental factors that influence the development of this disorder. Recent research has emphasized immune-mediated factors, especially the effect of infection on the gut microbiome (postinfectious IBS) as well as intestinal dysbiosis (small intestinal bacterial overgrowth [SIBO]). A recent review showed that female sex, in addition to severity of infection, and psychological distress at the time of infection are strong risk factors for developing postinfectious IBS.
| Site of Defect | Proposed Problem/Defect |
|---|---|
| GI tract | Diet (food intolerance or sensitivity) |
| Changes in microbiome (possibly antibiotics, dysbiosis) | |
| Immune mediated secondary to infection | |
| Altered motility | |
| Increased intestinal permeability | |
| Increased mast cells | |
| Effects of sex hormones | |
| Genetic a | Abnormality in serotonin receptors |
| Abnormality in sodium ion channel | |
| Defect in protein in immune response | |
| Altered bile acid metabolism | |
| Psychological | Depression |
| Anxiety | |
| Stress | |
| Coping | |
| Abuse: sexual, physical, verbal, early adverse life events | |
| Somatization | |
| Posttraumatic stress disorder | |
| CNS | CNS processing of afferent gut signals |
| Visceral hypersensitivity | |
| Sex hormones |
Although these factors may be important, it ignores the research on sex hormones (estrogen, progesterone, and testosterone) and how these too may influence the pathogenesis of this disorder. Table 2 summarizes the key points about the role of hormones in the pathophysiology of IBS. Much of this research has been done in animal models and not in humans. In many human studies the effects of the menstrual cycle and menopause have not been considered. Estrogen and progesterone receptors exist in the brain and the gut and therefore influence motility, visceral sensitivity, and autonomic processing. Evidence also points to estrogen receptors modifying gut permeability, which likely influences the microbiome in ways that are not yet appreciated. A better understanding of the role of female hormones in the pathogenesis of IBS may help the approach to diagnosis as well as possibly to drug development.
| Known Effects of Ovarian Hormones | Influences of Hormones in Pathophysiology of IBS |
|---|---|
| GI Motility | |
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| Visceral Hypersensitivity | |
| — | F pt with IBS at greater risk for somatic and visceral pain conditions |
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| Stress and Ovarian Hormones | |
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| Ovarian Hormones and Gut Permeability | |
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| Hormones and Immune Activation (Limited Data) | |
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a Not all data on menstrual cycle consistent.
b Methodological problems with menstrual cycle not always considered; stress hormones measured in blood/plasma not tissue.
Diagnosis
Female Patients: Social Considerations
In the literature on diagnosis there is little discussion of social considerations. Recognition of these factors could result in more directed questioning when diagnosing and treating patients with IBS. Appreciation of gender roles may help providers take better care of female patients. Within society there are certain expectations of women that influence how they behave as patients and what they reveal in the health care setting. Toner and Akman identified several themes in women with IBS that clinicians should keep in mind when seeing patients: shame and bodily functions; bloating, physical appearance, and pleasing others; assertion and anger. Women are socialized to think that bodily functions are private and that losing control is shameful. This attitude may make them reluctant to disclose information and may necessitate more gentle probing about symptoms and response to treatment. Women are socialized to want to be thin and attractive. However, clinicians often minimize the importance of this symptom and the degree to which bloating causes psychological as well as physical distress results in hypervigilance about these symptoms. If not taken seriously, patients develop further distress and more pain from bloating, which can also result in seeking care from multiple providers. Attention to this symptom is important to both history taking and ultimately the treatment plan. In addition, in Western society women are the primary caregivers and, as such, they are trained to please others and suppress their own needs. Many female patients are concerned that being assertive or angry or asking a lot of questions is not seen as socially acceptable. In an effort to be reassuring, providers may trivialize the patient’s concerns and the patient in turn may self-silence (ie, not fully disclose her symptoms). In a study of patients with inflammatory bowel disease (IBD) compared with patients with IBS, patients with IBS were less expressive about their needs. Clinicians should be careful not to demean symptoms and take extra care to address patients’ concerns so that symptoms, and even response to treatment, are fully understood.
General Principles
The diagnosis of IBS is made when the patient shows classic symptoms and commonly occurring organic GI diseases have been ruled out. Rome III criteria outline the major diagnostic features of IBS ( Box 1 ). The cardinal feature of IBS is abdominal pain or discomfort but symptoms are also characterized by a change in bowel habits involving diarrhea, constipation, or a mixed bowel pattern. It is usual in the diagnostic work-up to identify a predominant bowel type. Table 3 suggests an approach to the diagnostic work-up using the predominant bowel habit. The Rome III criteria also rely on stool consistency to help define the predominant bowel habit because this has been shown to better correlate with bowel subtype and transit. The Bristol Stool Form Scale is a validated scale that can be easily referenced at the time of the office visit for clinicians to evaluate the predominant stool type. Other symptoms, such as belching, abdominal distention, or bloating, may be present but are also seen in patients with other functional disorders.
IBS is defined as recurrent abdominal pain/discomfort a occurring at least 3 d/mo for the last 3 months that is associated with 2 or more of the following features:
- 1.
Improvement with defecation
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Associated with a change in stool frequency
- 3.
Associated with a change in stool form
- 1.
Criteria should be documented for the last 3 months with symptom onset for at least 6 months before diagnosis.
IBS subtypes
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IBS-D: loose or watery stools greater than or equal to 25% and hard or lumpy less than 25% of the time.
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IBS-C: hard or lumpy stools greater than or equal to 25% of the time and liquid stools less than or equal to 25% of the time.
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IBS-M: hard or lumpy stools greater than or equal to 25% or the time and loose or watery stools greater than or equal to 25% of the time.
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IBS-U: unable to subtype bowel habit.
- 1.
Abbreviations: IBS-C, IBS-constipation; IBS-D, IBS-diarrhea; IBS-M, IBS-mixed.
a Discomfort; uncomfortable feeling not defined as pain.
| IBS-C | IBS-D | IBS-M | All IBS |
|---|---|---|---|
| Refractory cases: consider GI referral for work-up of pelvic floor dysfunction or slow-transit constipation |
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a ALARM FEATURES include age greater than or equal to 50 years, unintentional weight loss, blood in stools, nocturnal symptoms, change in symptoms, recent antibiotic and family history of organic GI disease (colorectal cancer, celiac disease, and IBD).
Irritable Bowel Syndrome-Constipation
In patients with IBS-constipation (IBS-C), pelvic floor dyssynergia is a particular concern, especially in female patients. Dyssynergia refers to an inability to coordinate the movement of pelvic floor muscles with the anal sphincter and abdominal wall muscles. Patients often present with similar symptoms of abdominal pain/discomfort and bloating, but may also experience feelings of incomplete evacuation and need for digital maneuvers to remove stool. Symptoms may not accurately identify all patients so, if treatment response seems refractory, referral to a motility specialist who can perform anal manometry with balloon expulsion and defecography may be warranted. Referral often facilitates performance of biofeedback, which preliminary data suggests ameliorates both bowel and abdominal symptoms to a significant degree.
Another concern, particularly in patients with IBS-C is colorectal cancer (CRC). The prospective literature, although limited, suggests that the risk of CRC in patients with IBS without alarm features is less than 1%. Although there has been a slight increase in the incidence of CRC in younger patients, this is probably of less concern for younger female patients with IBS because CRC occurs 25% more commonly in men and 20% more commonly in African Americans. A recent meta-analysis comparing constipated with nonconstipated individuals supports doing age-appropriate colon cancer screening, particularly in female patients with IBS.
Irritable Bowel Syndrome-Diarrhea
In patients with diarrhea, special consideration should be given to excluding several common disorders: celiac sprue, microscopic colitis, IBD, and bile salt diarrhea. The prevalence of celiac disease in the Western world in the white population is estimated to be about 1% with a slightly higher prevalence in female patients. Decision analysis supports screening for this disorder when the prevalence is at this level, and American College of Gastroenterology (ACG) guidelines have also supported having a low threshold for screening, particularly in patients with IBS-diarrhea (IBS-D) or IBS-mixed (IBS-M) Recommended screening consists of a tissue transglutaminase immunglobulin A (tTG-IgA) level as well as an IgA level. Two percent of the celiac population is IgA deficient so obtaining the IgA level helps to determine whether the tTG assay result is valid. For patients with IgA deficiency the recommended test is the deamidated antigliadin IgG antibody with the tTG IgG (less sensitive than tTG-IgA).
Microscopic colitis should be considered in the differential of patients with IBS-D. Certain symptoms, such as age more than 50 years, shorter duration of symptoms, presence of autoimmune disorders, introduction of new medications (nonsteroidal antiinflammatory drugs, proton-pump inhibitors, olmesartan, selective serotonin reuptake inhibitors [SSRIs]), nocturnal symptoms, and weight loss should increase the concern for this disorder. In these cases the literature supports colonoscopy with random biopsies.
Concern for Crohn disease and ulcerative colitis (IBD) also enters into the IBS diagnostic picture and patients may have overlapping symptoms. The practical question is how often IBD occurs in patients being screened for IBS. A prospective study of patients with IBS and control patients undergoing colonoscopy revealed that IBD was found in less than 1% of patients with IBS and none of the control patients. Unless there are alarm features, colonoscopy is not the place to start to distinguish these two disorders. Instead, 2 biomarkers, fecal calprotectin and C-reactive protein (CRP), have been assessed in systematic reviews with meta-analyses and have shown utility. Both are measures of inflammation. A fecal calprotectin level less than 40 μg/g or CRP level less than .5 mg/dL were associated with a less than 1% risk of IBD in patients with IBS with usual symptoms. Fecal calprotectin was also found to be a cost-effective screening test.
Bile salt diarrhea should be considered in patients who have undergone cholecystectomy. The presumed mechanism is that unabsorbed bile acids in the colon stimulate water and electrolyte secretion, thereby increasing transit. Usually a trial of a bile salt sequestrant agent (eg, cholestyramine) is tried. Although several assays are available to detect bile salt diarrhea, they have not been widely available. These tests include SeHCAT (tauroselcholic [selenium 75] acid) retention test, serum C4 measurement, and fecal bile acid measurement. Increased availability of these tests would help identify those individuals who would be most likely to respond to treatment with a bile salt sequestrant.
Although IBS-C has been reported to occur after infectious gastroenteritis, IBS-D is more common. This entity, postinfectious IBS (PI-IBS), is thought to occur because of changes in the intestinal flora, which happens in about 10% of patients who develop bacterial gastroenteritis. Some patients remember the precipitating event but others do not. Reliable biomarkers exist for celiac disease but not for IBS to date. However, a recently developed assay holds promise to help in distinguishing IBS-D from IBD. Antivinculin and anti–cytolethal distending toxin B (anti-CdtB) antibodies were recently isolated in an animal model of campylobacter-induced PI-IBS. Vinculin is a cytoplasmic actin-binding protein that is essential to the adhesional system between epithelial cells, and CdtB is a bacterial toxin that develops when cells are infected. Antivinculin and anti-CdtB levels were tested in 2375 patients from the Target 3 study for rifaximin and compared with patients with IBD (N = 142; 73 = Crohn’s, 69 = ulcerative colitis), patients with celiac (N = 121), and healthy controls (HC = 43). This assay, which recently became commercially available, had a specificity of 91.6% for anti-CdtB and 83.8% for antivinculin. The levels of these antibodies were statistically significantly higher in patients with IBS-D compared with patients with IBD. It did not perform as well in patients with celiac but a biomarker (tTG) already exists for this disorder.
Irritable Bowel Syndrome-Mixed
Patients with IBS-M may be the most challenging patients to diagnose because, without clinical detective work, it may be more difficult to ascertain whether they have mixed bowel habits or IBS-C that is responding to laxative agents. A careful history is helpful and may reveal that the patient has constipation followed by periods in which they have stools of variable consistency that are interpreted by the patient as diarrhea. A stool diary that records laxative use may also be enlightening. An abdominal radiograph can be used to show stool burden on the right or left side, which is suggestive of stool accumulation.
Overlap Syndromes in Female Patents
Overlap syndromes are more common in women. Table 4 presents a summary of the overlap conditions that most commonly occur in IBS. The most common conditions include migraine headache, temporomandibular joint syndrome, fibromyalgia, joint hypermobility syndrome, interstitial cystitis, and anxiety and depression. Other functional GI disorders, such as gastroesophageal disease and dyspepsia, are often reported in all patients with IBS. In addition, there are gynecologic conditions that commonly overlap, including endometriosis, dysmenorrhea, chronic pelvic pain, and vulvodynia.
| Neurologic | Migraine headaches |
| Musculoskeletal | Fibromyalgia Joint hypermobility syndrome Temporomandibular joint syndrome |
| GI | GERD Dyspepsia Pelvic floor dysfunction |
| Genitourinary | Bladder pain/interstitial cystitis Chronic cyclic pelvic pain Dyspareunia Dysmenorrhea Endometriosis Adenomyosis Vulvodynia |
| Psychological | Anxiety Depression |
| Other | Chronic fatigue syndrome |
A common pathogenesis for these disorders has not been elucidated but is similar to those suggested in IBS.
The presence of these disorders has implications for diagnosis and treatment and may strengthen the clinical suspicion that a patient has IBS. Lackner and colleagues showed that some patients with IBS have as many as 5 comorbid conditions. These patients usually have more severe symptoms and require a more comprehensive approach to treatment.
Between 12% and 23% of menstruating women have endometriosis. However, there is no good noninvasive screening tests so clinical suspicion is necessary to make this diagnosis. The signs and symptoms of this disorder (abdominal pain and altered bowel function) meet the clinical criteria for IBS. One study showed that women with endometriosis are 6 times more likely to be diagnosed with IBS. Symptoms that correlated with endometriosis in women who had IBS and also had laparoscopically proven endometriosis were worsening of symptoms premenstrually and having intermenstrual bleeding. On physical examination, patients more commonly had vaginal forniceal tenderness. The gold standard for diagnosis is laparoscopic examination with biopsies histologically confirming the presence of endometriosis.
Other gynecologic conditions are also seen in patients with IBS, such as chronic pelvic pain, vulvodynia, and dysmenorrhea.
Clinical management
General Principles
The variable severity of IBS must be taken into account when developing a treatment approach to patients. Although no global consensus definition of severity exists, IBS can be classified as mild, moderate, or severe depending on multiple measures, including symptoms (particularly abdominal pain), health-related quality of life (QOL), presence of comorbid health conditions and psychological distress, and health care costs. In addition, the health care setting may also influence the severity of disease that clinicians encounter; for example, there is a predominance of milder disease in the primary care setting. Although previous studies estimated that 5% of the patients seen had severe disease, newer studies have shown a prevalence as high as 19% to 34%. Women have also been described as having more severe disease. Increasingly, evidence supports that patients’ perceptions of severity are linked to their health-related QOL as well as their abdominal symptoms. The cornerstone of therapy is developing a therapeutic clinician-patient relation. Drossman outlined the core concepts of optimizing communication skills in patients with functional GI disorders. Drossman detailed many important concepts, such as active listening, empathy, setting realistic goals, educating and reassuring patients, as well as setting boundaries and dealing with time constraints. A video link showing these concepts can be found on http://www.youtube.com/watch?v=IDaG0rIR .
Successful treatment also depends on a global view. The Rome Foundation has developed an invaluable tool called the multidimensional clinical profile to assess and integrate information about the illness of a patient with IBS into a meaningful treatment plan. This profile takes into account and defines the following features: categorical diagnosis (meeting Rome Criteria of diagnosis), clinical modifiers (subtype; eg, IBS-C, PI-IBS), psychosocial factors, the impact of symptoms on daily activities, and the presence of physiologic modifiers on function and biomarkers (eg, a positive lactose breath test).
Dietary Strategies for Management of Irritable Bowel Syndrome Symptoms
Diet and irritable bowel syndrome
Exacerbation of symptoms among patients with IBS has been described to occur most commonly in relation to food ingestion, stress, and the menstrual cycle. Up to 90% of patients with IBS restrict their diets to prevent or improve their symptoms. Only recently have food-related symptoms received more attention and emerging evidence supports dietary management for patients with IBS. Ingestion of food, especially fat, stimulates the gastro-colonic motor response, which in those with IBS leads to an exaggerated physiologic response causing postprandial pain and rectal urgency. It has been suggested that tryptophan, histamine, and related compounds may modulate mood and provide an initial stimulus for persistent visceral hypersensitivity.
True food allergies are uncommon in IBS, but sensitivities are frequently reported. Only 11% to 27% of patients with IBS correctly identify the offending agent stimulating symptoms in formal, blinded food challenge studies. Immune-mediated responses to food components may play a role. Subtle structural changes were seen in the duodenal mucosa using confocal endomicroscopy when the small intestines of patients with IBS were directly exposed to certain food antigens. This finding suggests that some patients with IBS mount an immunologic response to dietary components leading to a microenteropathy related to primary or acquired food sensitivity such as can be seen PI-IBS. Patients report some food constituents as more problematic, such as wheat, fruit, and vegetables, which has led to substantial focus on the role of 2 dietary triggers: gluten and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs).
Gluten and irritable bowel syndrome
Several studies have shown that a gluten-free diet can improve IBS symptoms in a subset of patients. A 4-week, randomized controlled trial evaluating the efficacy of a gluten-free diet in patients with IBS-D and without celiac disease reported increased stool frequency, as well as altered intestinal permeability (measured by urine lactulose/rhamnose ratio) and immune activation, in the presence of gluten. Bowel movement frequency was reduced in patients randomized to a gluten-free diet compared with patients consuming gluten, and this effect was more significant in patients with either of the celiac-associated genes HLA-DQ2 or HLA-DQ8 . These genes are seen in virtually all patients with celiac disease but are present in approximately 30% of the general population. In another study, the effect of gluten was assessed by a randomized, double-blind, placebo-controlled, rechallenge trial in 34 patients with IBS with a history of nonceliac gluten sensitivity (NCGS). During 6 weeks, overall IBS symptoms were not adequately controlled in 68% of patients receiving gluten versus 40% receiving a gluten-free diet. Reintroduction of gluten to these patients with IBS was associated with worsened pain, bloating, stool consistency, and notably fatigue.
These patients may have NCGS, which is 1 or more IBS-type symptoms precipitated by ingestion of gluten-containing foods. These individuals do not satisfy the diagnostic criteria for celiac disease and have been ruled out for wheat allergy. Mechanisms that have been proposed include an effect of gluten on mucosal integrity or cellular adherence or that another component of wheat, the amylase trypsin inhibitor enzymatic family, triggers the innate immune system stimulating the release of proinflammatory cytokines in cells. In addition, it may be that fructans, a nonabsorbable carbohydrate component of wheat, may cause of symptoms. At present there are no diagnostic criteria or serologic testing available for NCGS.
Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet and irritable bowel syndrome
As suggested earlier, it may be fructans that cause IBS symptoms, as shown in a double-blind crossover trial of 37 patients with IBS with self-reported NCGS who were randomly assigned to a diet of reduced low-fermentable, poorly absorbed, short-chain carbohydrates and then placed on either a gluten or whey protein challenge. In all participants, GI complaints consistently improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey proteins. FODMAPs are found in such foods as wheat, onions, some fruits and vegetables, sorbitol, and some dairy products ( Table 5 ). These foods are not efficiently absorbed in the small intestine and therefore arrive in the colon where they produce hydrogen, methane, and hydrogen sulfide gases, which leads to increased colonic water secretion, motility, and sensation. Aside from increased flatulence, FODMAPs do not cause GI symptoms in healthy adults but may be an important trigger of meal-related symptoms in patients with IBS, possibly as a consequence of underlying abnormalities in gut physiology and visceral sensation. These theoretical concepts have been evaluated in recent clinical trials that have shown significant beneficial clinical effects on IBS symptoms through the adoption of a low-FODMAP diet.
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