Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

Authors


Dr G. Boeckxstaens, Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
E-mail: g.e.boeckxstaens@amc.uva.nl

Summary

Background:  Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear.

Aim:  To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome.

Methods:  Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves.

Results:  Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18–30) and 30 (27–45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis.

Conclusions:  Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.

Introduction

Irritable bowel syndrome (IBS) is defined as a functional bowel disorder characterized by chronic abdominal pain or discomfort, associated with altered defecation and changes in bowel habit, in the absence of any detectable organic cause.1 Because reliable biological markers are not available, the diagnosis is based on symptom-based criteria such as the Rome criteria.1

Irritable bowel syndrome is a multifactorial disorder, of which the aetiology is largely unknown. Proposed mechanisms contributing to development of IBS symptoms include abnormal motility and associated alterations in gut transit, psychological factors including mental stress, food allergens and postinfectious neuroimmune modulation of gut functions (see Camilleri for review2). At present, one of the leading hypotheses regarding the origin of symptoms in IBS is provided by the concept of visceral hypersensitivity.3, 4 In this view, hypersensitivity of the gut may lead to alterations in gut motility by altering regulatory reflex pathways and secretory functions, which in turn may lead to functional disturbances. In addition, normal, physiologic stimuli may be perceived with increased intensity or may even cause pain. The evidence that patients with IBS exhibit enhanced visceral sensitivity however is not unequivocal. By assessing the sensory responses to mechanical distension of the colon and recto-sigmoid, several studies have indeed shown that as a group, patients with IBS report pain at distension levels that are normally not perceived as painful.5–8 However, the reproducibility of these findings is still unclear.9 In addition, specific hypersensitivity to colorectal distension is far from consistent, and has only been reported in 20–80% of IBS patients across studies.10 In the remainder of patients, colorectal sensitivity appears to be normal.

It has previously been suggested that IBS patients with visceral hypersensitivity and IBS patients with normal sensitivity may represent different subpopulations with distinct pathophysiologies.3, 6, 11 These subpopulations may therefore present with different symptom patterns, related to the presence or absence of a hyperreactive gut. Moreover, these subpopulations may show differential responses to certain pharmacological interventions. In particular, drugs that are aimed to reduce visceral sensitivity may only be effective in hypersensitive individuals. In previous clinical trials these issues have not been well addressed. This is mainly due to the fact that the presence or absence of visceral hypersensitivity in individual patients can only be identified by gut distension tests, which is relatively invasive, time-consuming and often bothersome for patients. Ideally, hypersensitive patients should be distinguishable from their normosensitive counterparts on clinical parameters. A similar study in patients with functional dyspepsia (a condition with a largely overlapping pathophysiology12) indeed confirmed that the presence of hypersensitivity to gastric distension was associated with specific dyspeptic symptoms.13

The present study aimed to identify possible associations between specific IBS symptoms and the presence of hypersensitivity to rectal distension. Such associations may further support the concept that individuals with visceral hypersensitivity may represent a distinct subpopulation of IBS patients. In addition, positive associations between symptoms and visceral hypersensitivity could help to classify or select patients for large-scale evaluations of future interventions aimed at reducing visceral hypersensitivity in IBS.

Subjects and methods

Study subjects

Healthy volunteers.  In order to obtain normal values, 17 healthy volunteers [8 women (47%); age, 19–62 years; mean age, 39 ± 17 years] were recruited by public advertisement. Each healthy volunteer needed to be free of gastrointestinal symptoms, without previous gastrointestinal surgery and not taking any medication.

Patients.  The patient data in this study were obtained from 92 consecutive patients between 1999 and 2003. The Academic Medical Centre is a considered a tertiary care centre, but really serves as a combined secondary and tertiary health care facility. Ninety-two IBS patients [52 women (57%); age, 18–65 years; mean age, 39 ± 12 years] were evaluated. All patients fulfilled the Rome II criteria for IBS.1 In addition to careful history taking, all patients underwent a minimal work-up to exclude organic disease. This included a normal physical examination, a negative sigmoidoscopy or colonoscopy, normal thyroid stimulating hormone levels and blood counts and negative stool examinations. In case of longstanding refractory diarrhoea, additional work-up was performed to exclude coeliac disease, giardiasis and malabsorption and rectal biopsies were taken to rule out collagenous colitis. Patients had to be free of any concomitant disease, including overt psychiatric disorders. Concomitant medication likely to interfere with gastrointestinal tract function or visceral perception other than fibres or bulking agents was discontinued at least 7 days before the study. Patients who previously underwent abdominal surgery, except for uncomplicated appendectomy or laparoscopic cholecystectomy, were excluded.

Symptom questionnaires

Symptom scores and pain scores were assessed on the day of the barostat study, prior to the distension test.

Gastrointestinal symptoms.  The intensity of individual gastrointestinal symptoms of abdominal bloating, flatulence, decreased bowel movements, increased bowel movements, soft stools, hard stools, urgency and the feeling of incomplete evacuation was scored on a self-rated scale, derived from the validated Gastrointestinal Symptom Rating Scale (GSRS), in which the intensities of the symptoms are scored on a 7-graded Likert scale, with descriptive anchors (0 = no symptoms at all; 1 =minimal symptoms; 2 = mild symptoms; 3 = moderate symptoms; 4 = rather serious symptoms; 5 = serious symptoms and 6 = very severe symptoms).14

Abdominal pain.  A 5-point score was used to evaluate abdominal pain. Patients had to answer the following question: ‘Please consider how much abdominal pain you experienced in the past 4 weeks’. Possible answers were: 1 = none; 2 = mild; 3 = moderate; 4 = severe and 5 = very severe.15

Barostat studies

To assess the sensitivity to rectal distension, we used an electronic barostat that automatically corrected for the compressibility of air (Synetics Visceral Stimulator, Stockholm, Sweden). The polyethylene barostat bag had a capacity of 500 mL, with a maximal length of 13 cm. The bag was tightly wrapped on the distal end of a double lumen polyvinyl tube to connect it to the barostat device (Salem Sump tube 14 Ch.; Sherwood Medical, St Louis, MO, USA). Before the distension studies, subjects received a tap water enema, followed by a 60-min rest. To introduce the bag into the rectum, it was carefully folded on both sides of the catheter to ensure adequate unfolding upon inflation. The folded bag was lubricated and introduced into a transparent flexible plastic tube (inner diameter 10 mm; Tygon® Laboratory Tubing, Saint-Gobain, Paris, France). Subsequently, the tube was placed into the rectum, 15 cm beyond the anal verge, with the subject lying in the left lateral decubitus position. The introductory tube was then removed over the catheter and the bag was unfolded by inflating it with 200 mL of air. By gently pulling back the catheter, the bag was positioned in the distal rectum (5 cm from the anal verge). The catheter was secured to the buttock by tape.

Subjects were studied in the left lateral decubitus position. After a 15-min adaptation period, minimal distending pressure (MDP) was determined. This pressure level equals the intra-abdominal pressure. We defined MDP as the minimum pressure at which the corresponding intrabag volume was at least 30 mL. In practice however, once the intra-abdominal pressure had been overcome, there was a steep rise in intra-balloon volume, allowing proper recording of respiratory excursions. The distension protocol consisted of a series of phasic, semirandomly ascending isobaric distensions, of 3 mmHg increment above MDP (3, 6, 12, 9, 18, 15, 24, 21, 30 mmHg, etc.). The inflation rate was 38 mL/s and each distension step lasted 2 min, separated by 1-min intervals at baseline (MDP). Sensations were scored halfway (at 1 min) along each distension step. We used a 6-point scale with verbal descriptors (0 = no sensation; 1 = first sensation; 2 = first sense of urge; 3 = normal urge to defecate; 4 = severe urge to defecate and 5 = discomfort/pain). Sensation scores were automatically logged onto the data file at each score point. If the subject reported discomfort or pain, the bag was instantaneously deflated. In addition, the bag was automatically deflated at pressures above 60 mmHg or volumes above 500 mL.

Statistical analysis

Primary endpoints were the thresholds for first sensation (sensation score 1), normal urge to defecate (sensation score 3) and discomfort/pain (sensation score 5) during rectal distension. The discomfort/pain thresholds obtained from the healthy volunteers were used to define the normal range (between the 5th and 95th percentile) for sensitivity to rectal distension. In previous studies, hypersensitivity has been defined as a threshold below the 95% confidence interval of a normal control group.6, 7 However, this definition is largely influenced by the sample size and test distribution. Therefore, we used the lower limit of the normal range of discomfort/pain thresholds (≤5th percentile) as a cut-off to distinguish patients with hypersensitivity to rectal distension from patients with normal rectal sensitivity. The association between specific IBS symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic (A-ROC) curves.16, 17 The A-ROC curve summarizes the accuracy of a specific symptom to distinguish hypersensitive from normosensitive patients. The A-ROC curve is obtained by plotting the true positive proportion (hypersensitive patients with the symptom present, y-axis) to the false positive proportion (normosensitive patients with the symptom present, x-axis) at each possible cut-off (0–7 points or 1–5 points for symptom rating and pain scores, respectively) defining the presence of a particular symptom. The area under a ROC curve represents the probability that a random pair of patients will be correctly classified as hypersensitive or normosensitive by the concerning symptom. A value of 0.50 is obtained when the symptom does no better than chance, whereas a value of 1.0 means perfect accuracy or discrimination. Estimates of A-ROC curves for each symptom were expressed with their 95% confidence limits.18 All other data are given as mean ± s.d. Continuous data were compared using Student's t-test or the Mann–Whitney U-test when appropriate, and categorical data using Chi-square tests. Differences were considered significant at the 5% level. Statistical evaluations were performed using commercially available software (SPSS 11.0; SPSS Inc., Chicago, IL, USA).

Results

Clinical characteristics of IBS patients

No significant differences were seen between patients and healthy volunteers for age and gender. Based on their predominant bowel habit, 37 IBS patients (40%) were considered as diarrhoea predominant (IBS-D), 25 (27%) as constipation predominant IBS (IBS-C) and 30 (33%) as alternating IBS (IBS-A). The mean duration of symptoms at intake was 8 ± 8 years (range 1–30 years). Table 1 shows the prevalence and severity of individual IBS symptoms in the overall number of patients.

Table 1.  Prevalence and severity of irritable bowel syndrome (IBS) symptoms in 92 IBS patients
 AbsentPresentaSevereb
  1. Data are presented as absolute numbers and (row percentages).

  2. a Present; scores of ≥2 on a 0–6 [Gastrointestinal Symptom Rating Scale (GSRS)] or a 1–5 (Pain) scale.

  3. b Severe: scores of ≥5 or ≥4, on a 0–6 (GSRS) or a 1–5 (Pain) scale, respectively.

Abdominal bloating11 (12)81 (88)35 (38)
Flatulence6 (7)86 (93)36 (39)
Decreased bowel movements50 (54)42 (46)11 (12)
Increased bowel movements29 (31)63 (69)17 (19)
Hard stools17 (18)75 (82)22 (24)
Soft stools44 (48)48 (52)7 (8)
Urgency28 (31)64 (69)20 (22)
Incomplete evacuation11 (12)81 (88)22 (24)
Abdominal pain0 (0)92 (100)70 (76)

Sensitivity to rectal distension in healthy volunteers

In healthy volunteers, the mean MDP was 6 ± 3 mmHg. Median thresholds for first sensation, urge and discomfort/pain were 3, 12 and 30 mmHg above MDP, respectively (see Table 2 for interquartile ranges). The normal range for the threshold for discomfort/pain (between the 5th and 95th percentile) was 18–57 mmHg above MDP. Individual thresholds are shown in Figure 1.

Table 2.  Sensory thresholds (mmHg above minimal distending pressure) in irritable bowel syndrome (IBS) and IBS subpopulations compared with healthy volunteers
 Healthy volunteersIBS
AllHypersensitiveNormosensitive
  1. Data are expressed as median (interquartile range). Hypersensitive patients were defined by a threshold for discomfort/pain below the 5th percentile of healthy volunteers.

First sensation3 (3–9)3 (3–6)3 (1.5–3)3 (3–6)
Urge to defecate12 (9–15)9 (6–12)6 (6–9)9 (9–15)
Discomfort/pain30 (27–45)24 (18–30)18 (12–18)30 (24–39)
 n = 17n = 92n = 41n = 51
Figure 1.

Individual thresholds for discomfort/pain in healthy volunteers (HV) and patients with irritable bowel syndrome (IBS). Solid horizontal lines represent median values; the dotted lines represent the normal range of normal values obtained in healthy volunteers. *P = 0.001 vs. healthy volunteers (Mann–Whitney U-test).

Sensitivity to rectal distension in IBS patients

All IBS patients.  In IBS patients, MDP was 6 ± 3 mmHg. Overall, median thresholds for first sensation, urge and discomfort/pain were 3, 9 and 24 mmHg above MDP, respectively (see Table 2 for interquartile ranges). The individual thresholds at which IBS patients reported discomfort/pain are shown in Figure 1. Thresholds for urge and discomfort/pain were significantly lower than those in healthy volunteers (P = 0.011 and P = 0.001 respectively; Mann–Whitney U-test).

Hypersensitive vs. normosensitive IBS patients.  Using the 5th percentile cut-off of the normal values obtained in healthy volunteers (i.e. a threshold for discomfort/pain ≤18 mmHg above MDP) 41 patients (45%) showed hypersensitivity to rectal distension. The prevalence of hypersensitivity was significantly higher in female, compared with male patients (56 and 30%, respectively, P = 0.014). Mean age was not significantly different between the subgroups (36 ± 11 and 40 ± 13 years for hypersensitive and normosensitive patients, respectively). The sensory thresholds of hypersensitive and normosensitive IBS patients and healthy volunteers are summarized in Table 2.

Symptom prevalence in hypersensitive vs. normosensitive IBS patients

Dominant bowel habit.  Bowel habit predominance was not associated with the presence or absence of hypersensitivity to rectal distension. In total, 16 of 41 (39%) of the hypersensitive patients were considered as having IBS-D, 11 of 41 (27%) IBS-A and 14 of 41 (34%) IBS-C, vs. 21 of 51 (41%), 14 of 51 (28%) and 16 of 51 (31%) of the normosensitive patients, respectively (Figure 2). Conversely, 16 of 37 of IBS-D patients (43%), 11 of 25 of IBS-C patients (44%) and 14 of 30 of IBS-A (47%) patients were hypersensitive.

Figure 2.

Prevalence of irritable bowel syndrome (IBS) subgroups based on predominant bowel habit in normosensitive (NS) vs. hypersensitive (HS) patients. IBS-C, constipation predominant; IBS-A, alternating constipation and diarrhoea; IBS-D, diarrhoea predominant.

Individual IBS symptoms.  We evaluated the prevalence of individual IBS symptoms in normosensitive and hypersensitive patients defined by two different cut-offs, i.e. symptoms of at least mild intensity (symptom rating or pain scores of ≥2) and at least severe intensity (symptom rating of ≥5 or pain scores ≥4). Abdominal pain of at least mild intensity was present in all patients (Figure 3a). The prevalence of individual symptoms of at least mild severity was comparable between hypersensitive and normosensitive patients (Figure 3a). Likewise, with the exception of pain, the observed prevalence for individual symptoms that were rated at least severe was not statistically different between hypersensitive and normosensitive patients (Figure 3b). In contrast, severe pain scores (≥4) were more prevalent in hypersensitive, compared with normosensitive IBS patients (88% vs. 67%, P = 0.018, Chi-square).

Figure 3.

Prevalence of individual irritable bowel syndrome symptoms in normosensitive vs. hypersensitive patients. (B, bloating; F, flatulence; dBM, decreased bowel movements; iBM, increased bowel movements; LS, loose stools; HS, hard stools; U, urgency; IE, incomplete evacuation; P, pain). (a) Percentage of patients reporting at least mild symptom intensity [i.e. scores of ≥2 on a 0–6 (Gastrointestinal Symptom Rating Scale, GSRS) or a 1–5 (Pain) scale]; (b) Percentage of patients reporting at least severe symptom intensity, i.e. scores of ≥5 or ≥4, on a 0–6 (GSRS) or a 1–5 (Pain) scale, respectively. *P < 0.05 by Chi-square.

Discriminative value of specific symptoms to distinguish hypersensitive from normosensitive IBS patients

The association between specific IBS symptoms and the presence of hypersensitivity was examined using A-ROC curves. As described above, the A-ROC curve represents the accuracy of a particular symptom to correctly classify a patient as hypersensitive or normosensitive at each possible cut-off. As shown in Table 3, the A-ROC values of the individual symptoms were all close to the non-discriminative value of 0.5.

Table 3.  Accuracy of specific irritable bowel syndrome symptoms to correctly classify hypersensitive or normosensitive individuals using two different cut-offs (see text)
 A-ROC (95% confidence interval)
5th percentile of HV1st quartile vs. 4th quartile
  1. A-ROC, Area under the Receiver Operating Characteristic; HV, healthy volunteers.

  2. Interpretation: 0.5 = no better than chance; 1.0 = perfect accuracy.

Bloating0.53 (0.41–0.65)0.55 (0.38–0.73)
Flatulence0.52 (0.40–0.64)0.65 (0.48–0.81)
Decreased bowel movements0.55 (0.43–0.67)0.67 (0.51–0.83)
Increased bowel movements0.51 (0.39–0.63)0.56 (0.39–0.73)
Loose stools0.54 (0.42–0.65)0.58 (0.42–0.75)
Hard stools0.53 (0.41–0.65)0.59 (0.42–0.77)
Urgency0.53 (0.41–0.65)0.61 (0.44–0.78)
Incomplete evacuation0.57 (0.45–0.69)0.63 (0.47–0.79)
Abdominal pain0.61 (0.49–0.72)0.65 (0.48–0.81)

It is important to realize that the cut-off point that discriminates hypersensitive and normosensitive patients may be crucial for the outcome. Therefore, we performed an additional analysis and compared the group of patients within the lowest quartile (threshold <18 mmHg above MDP; n = 17) with those in the highest quartile (threshold ≥30 mmHg above MDP; n = 30). The A-ROC values obtained were comparable with the results using the 5th percentile cut-off (see Table 3).

Discussion

This study aimed to explore the possible associations between specific IBS symptoms and the presence of visceral hypersensitivity in patients with IBS. Our data confirm that hypersensitivity to painful rectal distension can be demonstrated in about one-half of patients with IBS. Visceral hypersensitivity was more prevalent in female, compared with male patients. The two subpopulations of IBS patients, defined by the presence or absence of visceral hypersensitivity, were comparable in terms of age and bowel habit predominance. Severe abdominal pain was more prevalent in hypersensitive patients, whereas the prevalence of individual gastrointestinal symptoms was similar in both groups. However, none of the specific IBS symptoms (including pain) could accurately distinguish hypersensitive from normosensitive subjects. Therefore, selection based on clinical parameters is unlikely to discriminate individual IBS patients with visceral hypersensitivity from those with normal visceral sensitivity.

Earlier studies have indeed suggested that rectal sensory characteristics may play a role in the predominant symptom patterns of patient subgroups. For example, IBS-C patients experienced decreased sensations of urge during rectal distension compared with IBS-D patients.19 However in the present study, differences in bowel habit were not associated with the presence or absence of hypersensitivity to rectal distension. In addition, hypersensitivity has been linked to certain individual IBS symptoms, such as the feeling of incomplete evacuation and urgency.6, 20, 21 Except for severe pain, we were unable to demonstrate such correlation. Severe pain was significantly more prevalent in hypersensitive patients. Similar findings have been reported in functional dyspepsia, where the presence of visceral hypersensitivity was associated with epigastric pain.13 Furthermore, it was also shown previously that patients with pain predominant IBS were more susceptible to rectal sensitization in response to repetitive sigmoid distension, compared with non-pain predominant IBS patients.22 These findings suggest that there may be an association between pain and visceral hypersensitivity. To evaluate the possible predictive value of this symptom, we performed an A-ROC curve analysis. This revealed that the rather weak association was unable to select individual IBS patients with hypersensitivity. The same was true for all other symptoms studied. Additionally, we compared the group of patients with the lowest discomfort/pain thresholds, excluding patients with intermediate sensitivity. Again, none of the symptoms could adequately distinguish hypersensitive from normosensitive patients, illustrating that IBS patients with visceral hypersensitivity cannot be identified solely based on clinical symptoms.

The discomfort/pain threshold to define hypersensitivity was ≤18 mmHg above MDP. Compared with previous studies, this cut-off is rather conservative.6–8 Because distension protocols and laboratory conditions are not necessarily comparable, we defined the range of normality based on our own sample of healthy controls, rather than using an historical cut-off. In addition, it seems unlikely that a less stringent cut-off increases the differences between the subgroups.

The fact that hypersensitive and normosensitive IBS present with comparable, heterogeneous symptom patterns does not exclude that hypersensitive patients may have a different underlying pathophysiology. In view of the hypersensitivity concept, it is possible that visceroanalgesic drugs may be only effective in those patients. Patient selection based on other criteria, such as bowel habit and gender, has already been shown to be of great importance for the outcome of clinical trials evaluating the efficacy of several contemporary compounds for IBS, for example alosetron and tegaserod.23, 24 Our study indicates that until clear criteria or alternative methods have been established to select individual hypersensitive patients, evaluation of perceptual thresholds to gut distension is still required. We perceive that such an approach would be very demanding if not impossible in large scale clinical trials. However, a ‘proof of principle’ study for the definitive foundation of the hypersensitivity concept in IBS is certainly warranted.

In conclusion, hypersensitive and normosensitive IBS patients present with comparable, heterogeneous symptom patterns. Therefore, selection based on clinical parameters is unlikely to discriminate individual IBS patients with visceral hypersensitivity from those with normal visceral sensitivity.

Acknowledgements

This study was funded by a grant from The Netherlands Digestive Diseases Foundation (MLDS), grant number WS 99-38.

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