Alterations in Colonic Motility and Relationship to Pain in Colonic Diverticulosis

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: Alterations in Colonic Motility and Relationship to Pain in Colonic Diverticulosis GABRIO BASSOTTI,* EDDA BATTAGLIA, GIUSEPPE DE ROBERTO,* ANTONIO MORELLI,* MARCELLO TONINI, and VINCENZO VILLANACCI *Gastroenterology and Hepatology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; Department of Gastroenterology, University of Torino, Torino, Italy; Pharmacology Section, Department of Physiological and Pharmacological Sciences, University of Pavia, Pavia, Italy; and the Second Pathology Department, Spedali Civili, Brescia, Italy Background & Aims: Although the pathophysiologic basis of colonic diverticular disease is understood incompletely, there is agreement that abnormal colon motility probably plays a major role. However, several different abnormalities have been reported in such patients. The purpose of this study was to assess whether patients with diverticulosis display an abnormal duration of regular colonic contractile patterns, which has been observed in other conditions characterized by spasticity of the viscus, such as the irritable bowel syndrome. Methods: Twelve patients with symptomatic uncomplicated diverticular disease entered the study and underwent 24-hour colonic manometric recordings using a standard technique. The duration of regular contractile patterns was compared with that recorded in 20 healthy volunteers. Results: Patients with diverticulosis had a significant increase of the duration of regular patterns of phasic pressure activity compared with healthy controls (31% vs. 6.4%, P <.001). In both groups, the 2- or 3-cycles-per-minute activity represented more than 80% of such activity, especially in the sigmoid colon. More than 30% of patients, but none of the controls, reported episodes of abdominal pain (cramping lower abdominal pain with characteristics similar to those experienced at home) during the occurrence of a regular colonic contractile pattern. This was significant by symptom association probability criteria. Conclusions: Patients with symptomatic uncomplicated colonic diverticulosis displayed increased duration of rhythmic, low-frequency, contractile activity, particularly in the segments bearing diverticula. These regular rhythms are associated significantly with reporting of abdominal pain. Colonic diverticular disease (diverticulosis) is a relatively common finding in Western populations. 1 This disorder has been attributed to aging and deficient dietary fiber intake. 2 Abnormal colonic motility is one factor implicated in the pathogenesis of this disease 3,4 ;it has been postulated that this abnormal colonic motility predisposes to the formation of pulsion diverticula in the segments of the viscus harboring the diverticula. 5,6 However, the evidence supporting a role for abnormal colonic motility in diverticulosis is controversial, and earlier studies showed either increased 7,8 or normal colonic pressures 9,10 with respect to controls. It is unclear if the former studies recorded motility proximal to the rectosigmoid junction. Therefore, motility in the colonic segment with diverticula may not have been recorded. Subsequent studies in which the recording devices were positioned within the colonic segments bearing diverticula showed that motor activity in these segments was increased with respect to that of the controls. 11,12 More recently, we had recorded motility for a prolonged (ie, 24 h) duration from the transverse colon to the rectum. 13 We observed that propulsive motor activity was increased in diverticular segments of patients with uncomplicated colonic diverticulosis. 14 On average, patients with diverticulosis had twice as many colonic highamplitude propagated contractions as compared with healthy patients. 14 In the current study, our aim was to assess whether uncomplicated diverticular disease is associated with changes in regular colonic contractile patterns. Our working hypothesis was that an increment of these patterns might represent an important pathophysiologic mechanism leading to hypersegmentation and favoring diverticula formation. Patients and Methods Twelve patients with symptomatic uncomplicated diverticular disease (4 men, 8 women; age range, y) were enrolled in this study. The severity of the disease was assessed according to international working team report classifications, 15,16 and was judged to be mild in each patient. All patients experienced abdominal pain and abnormal bowel hab- Abbreviation used in this paper: SAP, symptom association probability by the American Gastroenterological Association /05/$30.00 PII: /S (04)

2 March 2005 COLONIC CONTRACTILE PATTERNS IN DIVERTICULOSIS 249 its (constipation or, less frequently, alternating constipation and diarrhea) for more than 2 years. Because no patient had symptoms suggestive of Rome II criteria for irritable bowel syndrome, such as relief of abdominal pain with defecation, 17 abdominal pain was attributed to the underlying disease. No other endocrine or mechanical abnormalities were detected by appropriate tests, and no patient previously had undergone abdominal surgery. Barium enema showed left-sided diverticular disease (predominant in the sigmoid colon, although the descending colon also was involved) in all patients. No patient took drugs influencing bowel habits in the 2 weeks preceding the study. After careful explanation of the aims of the study, all patients gave written informed consent. The studies were performed in accordance with local ethical guidelines, following the recommendations of the Declaration of Helsinki (Edinburgh revision, 2000). Patients data were compared with those of 20 healthy volunteers (15 men, 5 women; age range, y). No volunteer complained of abdominal pain, abdominal distention, or disturbances in bowel habits. The average stool frequency was once per day. A careful drug history was obtained for each patient to ascertain that no patients had taken drugs known to influence gastrointestinal motility during the 2 weeks before the study. None of the healthy participants previously had undergone abdominal surgery. Methods Twenty-four hour colonic motor activity was recorded as previously described. 18,19 After an overnight fast, an 8-lumen manometric probe with side holes spaced 12 cm apart (Arndorfer Medical Specialties, Greendale, WI; outer diameter, 4.5 mm; inner diameter for each lumen,.8 mm) was introduced into the colon with a colonoscope. Before tube placement, the bowel was cleansed by asking the patients to consume a semiliquid diet for 2 days, magnesium sulfate (30 g by mouth 36 hours before colonoscopy), and tap water enemas (12 and 6 hours before the procedure). Intravenous midazolam (3 mg) was used for sedation. The probe was positioned by advancing it together with the endoscope, the tip of the probe fixed to the tip of the colonoscope by a silk thread held by biopsy forceps inside the biopsy channel of the endoscope. Once the desired portion of the viscus was reached (at least the proximal part of the transverse colon), the forceps were opened and the colonoscope was withdrawn gently, aspirating air as completely as possible. The probe then was connected to external physiologic pressure transducers (type I; Bell & Howell, Durham, NC) and to a low-compliance pneumohydraulic system (Arndorfer Medical Specialties), perfusing bubble-free distilled water at a constant rate of.2 ml/min. At this perfusion rate, distal occlusion of individual recording ports yielded an increased rate of more than 100 mm Hg/s. Intraluminal pressures were recorded by a Beckman R-611 Dynograph recorder (Sensormedics Italia, Milan, Italy) coupled to the transducers (paper speed,.5 mm/s). Patients used an event marker to record the start and end time for episodes of pain on the tracings. Figure 1. Representative manometric tracing of a patient with diverticular disease. Recording points are from the transverse (T), the descending (D), and the sigmoid (S) colon, and from the rectosigmoid junction (RS). The arrow shows a movement artifact, and the asterisk shows a regular contractile pattern occurring at 3 cycles per minute. Experimental Procedures After the probe was positioned, catheter placement was confirmed by fluoroscopy. Then patients were moved to the motility laboratory where they rested for an average of 3 hours to allow air elimination from the colon and recovery from the endoscopy procedure. Thereafter, a 24-hour recording was obtained. During the recording, two 1000-kcal mixed meals and a 450-kcal breakfast were served, as previously described. 20 At the end of the study, tube position was reconfirmed by fluoroscopy to assess for significant ( 10 cm) displacement of the probe. Data Analysis To minimize interobserver variability, all tracings were analyzed manually by one of the authors who was blinded with respect to meal times and time of day. A regular contractile pattern was defined, as previously reported, 21 as a sequence of waves occurring consecutively for at least 2 minutes at a constant frequency (Figure 1). The following variables were taken into account for calculations 22,23 : (1) the total duration of regular contractile patterns over 24 hours, irrespective of the number of cycles per minute; (2) the cumulative duration of regular contractile patterns occurring at frequencies of 2 per minute, 3 per minute, 4 per minute, and 5 per minute; frequencies of 5 or more per minute were cumulated because previous studies showed that they occur infrequently over 24 hours ; (3) the percentage of time occupied by regular contractile patterns in single colonic segments; (4) the contractile response to meals (concerning regular activity) was assessed by comparing 3-hour fasting with the 3-hour postprandial period; (5) the cyclic occurrence of regular contractile

3 250 BASSOTTI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 3 patterns (mimicking the cyclic migrating motor activity observed in the stomach and small bowel); (6) the migration (defined as sequential aboral propagation in at least 3 consecutive recording points) of contractile patterns; and (7) the relationship between report of abdominal pain and contractile activity. The symptom of pain was considered to be associated with a motor event if an episode of pain similar to that experienced at home occurred within a time window of 5 minutes from the appearance of a regular contractile pattern. Statistical Analysis Nonparametric tests were used for statistical evaluation because the data were not distributed normally. The Kruskall Wallis test, the Wilcoxon rank-sum test (2-sided), and the 2 test were applied where appropriate. Values of P.05 were chosen for rejection of the null hypothesis. Data are presented as mean SD. Symptom Association Probability The association between abdominal pain and colonic regular contractile patterns was assessed by using a modification of the symptom association probability (SAP) technique, originally developed for assessment of esophageal symptoms. 24 Because this score is believed to be the best parameter to quantify the temporal association between reflux and symptoms, it recently has been adapted to colonic motility recordings. 25 The SAP was calculated by using the following method. 25 First, the 24-hour manometry recordings were divided into consecutive 5-minute periods; then, all these periods (total, 288) were scanned for the presence of pain and regular contractile patterns and were classified as patternpositive or pattern-negative. Thereafter, a contingency table was constructed containing 4 fields: (1) one field containing the number of 5-minute periods with pain and regular contractile patterns; (2) one field containing the asymptomatic number of 5-minute periods with regular contractile patterns; (3) one field containing the symptomatic number of 5-minute periods without regular contractile patterns; and (4) one field containing the asymptomatic number of 5-minute periods without regular contractile patterns. The Fisher exact test was applied to calculate the probability (P value) that the observed association between a regular contractile pattern and pain occurred by chance, and the SAP was obtained by the following formula: (1.0 P) 100%. 24,25 Results General Considerations The tip of the probe was in the transverse colon in all controls and in 10 patients. In the remaining 2 patients, it was positioned just below the splenic flexure. No significant catheter displacement was observed at the end of the study. In the 20 controls, overall regular contractile activity comprised 1152 minutes (6.4%) out of 18,000 minutes Table 1. Regular Frequency Pattern Contractions Recorded in the Colon in Controls and in Patients With Diverticular Disease Cycles per minute Duration in controls (%) Duration in patients (%) of all colonic contractile activity over 24 hours (the remaining 10,800 minutes of recording were represented by motor quiescence). In patients with diverticular disease, overall regular contractile activity comprised a higher (P.001) percentage of regular activity (ie, 3709 minutes [31%] out of 12,000 minutes of all colonic contractile activity, the remaining 5280 minutes being quiescent over 24 hours). Overall, regular activity appeared to be more frequent during daylight hours (considered from 9 AM 9 PM), when it was detected in 65% of controls and 55% of patients (P.7). The average wave amplitude was 25 9 mm Hg for controls and mm Hg for patients (P.9). The various contraction frequencies detected in controls and patients are shown in Table 1. In both groups the 3-cycles-per-minute frequency accounted for a large part of the total regular activity (Table 1), representing 80% of such activity in controls (P.05 vs. all the other frequencies) and slightly more than 60% (P.06 vs. the 4 per minute and the 5 per minute frequencies) in patients. In patients with diverticulosis, the 2-cycles-perminute activity was significantly more prevalent (P.05) with respect to the 4-per-minute and the 5-perminute frequencies. The other frequency patterns were far less prevalent, and the 2- and 3-cycles-per-minute patterns together represented more than 85% of all the regular contractile frequencies. Regional Distribution of Contractions Table 2 shows the regional distribution of regular contractile activity. Of the colonic segments studied, regular contractile activity had the longest duration of all activity in the sigmoid colon, accounting for more than half of all contractile activity in this segment; this was associated with significant regional differences. In controls, regular contractile activity was more prevalent in the sigmoid than in the descending (P.006) and transverse (P.001) colon; moreover, it also was more frequent in the descending than in the transverse colon (P.04). In patients, regular contractile activity also was more prevalent in the sigmoid than in the descend-

4 March 2005 COLONIC CONTRACTILE PATTERNS IN DIVERTICULOSIS 251 Table 2. Percentage of Time With Regular Colonic Frequency Patterns in Controls and in Patients With Diverticular Disease Segment Duration in controls (%) Duration in patients (%) Transverse Descending Sigmoid ing (P.01) and transverse (P.001) colon; no differences were found in the descending compared with the transverse colon (P.48). Effect of Meals The comparison of contractile activity for 3 hours before and 3 hours after meals showed a significant overall postprandial increase of regular contractile activity in controls (7.2.5 vs min, P.01) but not in patients with diverticular disease ( vs min, P.09). Relationship of Contractile Sequences and Symptoms Analysis of contractile patterns over 24 hours disclosed no cyclic activity or migration of the regular contractile patterns between 3 recording sites in both groups of patients. During the recording, 4 patients (33%) reported 1 3 episodes (average, 1) of cramp-like lower-abdominal pain. Abdominal pain always was associated temporally (within a 5-minute window) with regular colonic contractile activity at a frequency of 2 and 3 cycles per minute. These episodes lasted 5 10 minutes: in 3 patients the regular contractile pattern was in the sigmoid colon, and in 1 patient it was in the descending colon. These patients had SAP scores 95% (range, 97% 99.9%), showing that the episodes of pain had a strict relationship with the contractile patterns. No episodes of pain were recorded in the remaining patients. None of the controls had episodes of pain during recording (P.05 vs. patients). Discussion Abnormal colonic motor activity seems to be a consistent feature of patients with diverticular disease. 4,5,11,12,14 It is not known whether abnormal rhythmic patterns of contractions are present in this condition. Such regular contractions have been described in slowtransit constipation 22 and in irritable bowel syndrome. 23 However, the specificity and relationship of these patterns to symptoms still is defined poorly. In the present study, we showed that patients with symptomatic uncomplicated diverticular disease of the colon had excess rhythmic contractile activity, especially in the low-frequency range (ie, 2 3 cycles/min). The duration of this rhythmic activity in specific segments was 5-fold higher in patients than that observed in controls. It is hypothesized that this type of contractile activity might lead, in a predisposed colon, to herniation and diverticula formation. It also is conceivable that persistent regular contractile activity may cause fecal stasis in the affected segments. 26 This hypothesis is supported by the fact that the abnormalities we observed were present chiefly in the segment of the viscus harboring the diverticula. Our hypothesis was that the pathologic duration of rhythmic, slow-frequency patterns might be associated with the thickening of the bowel wall muscle layers, a consistent finding in colonic diverticulosis. 27,28 An alternative explanation for these findings is that increased regular activity was recorded because the colonic lumen is more narrow in patients with diverticulosis. In healthy patients, manometry was most accurate for recording contractile activity when the lumen was more narrow. 29 However, the colonic diameter of the diverticular segments in our patients was decreased only slightly (as measured on barium enema), and we feel it is unlikely that this variable per se could affect motility, although this remains unproven. How can the findings be explained? Histopathologic observations with silver stains did not reveal morphologic abnormalities in the myenteric plexus of patients with diverticulosis. 30 More recent in vitro studies have focused on cholinergic innervation of the colon. Cholinergic stimulation induced low-frequency slow-wave activity instead of action potential bursts in diverticulosis. 31 Another study observed features of cholinergic denervation hypersensitivity in diverticular disease. This was characterized by decreased smooth muscle choline acetyltransferase activity, up-regulation of muscarinic M3 receptors, and increased sensitivity to exogenous acetylcholine. 32 Cholinergic hypersensitivity may account for the imbalance between excitatory and inhibitory innervation in colonic tissue of diverticula. 33 A case-control study observed a lower incidence of perforated colonic diverticular disease in patients who used calcium channel blockers. 34 Perhaps the favorable effect of the calcium channel blockers are explained by the fact that at least some calcium blockers decrease colonic contractility 35 and tone. A temporal correlation between abdominal pain and the occurrence of regular colonic contractile activity was found in more than 30% of patients with diverticulosis. This correlation displayed a high SAP score, showing

5 252 BASSOTTI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 3 that the appearance of abdominal pain during 2- or 3-cycles-per-minute patterns was strictly related. As previously stressed, 25 although there was a statistically significant association, this does not prove a causal relationship. The SAP provides objective information on the probability that the earlier-described relationship occurred by chance. In case of a SAP of 97% or more, the probability that the observed association occurred by chance is 3% or less. This relationship is similar to what we have described in patients with irritable bowel syndrome. 23 Indeed, some overlap in symptoms exists between diverticular disease and irritable bowel syndrome, 36 and evidence suggests that patients with the latter disorder are more likely to develop diverticula than controls. 37 In addition, patients with symptomatic uncomplicated diverticular disease display heightened visceral perception of rectosigmoid distension stimuli, and this is not considered to be caused by altered compliance of the gut wall. 38 Therefore, as in irritable bowel syndrome, it is conceivable that the occurrence of several pathophysiologic mechanisms, such as muscular dysfunction, visceral hypersensitivity, and inflammation, may be involved in symptom generation in diverticulosis A limiting factor of this study was that we did not include asymptomatic patients with diverticulosis. Therefore, we do not know whether the motor abnormalities related to regular colonic patterns in symptomatic patients also are present in asymptomatic patients. Another limiting factor was that the association between abdominal pain and rhythmic low-frequency contractile patterns was found in a minority of patients. Because most patients (and none of the healthy controls) did not display such an association, we feel that this finding needs to be appraised carefully in larger studies to determine more accurately where there is truly an association between rhythmic contractile patterns and report of pain in symptomatic diverticular disease. In conclusion, we have shown that patients with symptomatic uncomplicated colonic diverticulosis display longer durations of rhythmic low-frequency contractile activity in the segments bearing diverticula. The significance of this finding requires further investigation. References 1. Delvaux M. Diverticular disease of the colon in Europe: epidemiology, impact on citizen health and prevention. Aliment Pharmacol Ther 2003;18(suppl 3): Simpson J, Scholefield JH, Spiller RC. Pathogenesis of colonic diverticula. Br J Surg 2002;89: Bassotti G, Chistolini F, Morelli A. Pathophysiological aspects of diverticular disease of colon and role of large bowel motility. World J Gastroenterol 2003;9: Stollman N, Raskin JB. Diverticular disease of the colon. Lancet 2004;363: Painter NS. The cause of diverticular disease of the colon, its symptoms and its complications. Review and hypothesis. J R Coll Surg Edinb 1985;30: Simmang CL, Shires GT. Diverticular disease of the colon. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger & Fordtran s gastrointestinal and liver disease. 7th ed. Philadelphia: Saunders, 2002: Arfwidsson S. Pathogenesis of multiple diverticula of the sigmoid colon in diverticular disease. Acta Chir Scand 1964; 342(suppl): Painter NS, Truelove SC, Ardran GM. Segmentation and the localization of intraluminal pressures in the human colon, with special reference to the pathogenesis of colonic diverticula. Gastroenterology 1965;49: Weinreich J, Andersen D. Intraluminal pressure in the sigmoid colon. II. Patients with sigmoid diverticula and related conditions. Scand J Gastroenterol 1976;11: Weinreich J, Moller SH, Andersen D. Colonic haustral pattern in relation to pressure activity and presence of diverticula. Scand J Gastroenterol 1977;12: Trotman IF, Misiewicz JJ. Sigmoid motility in diverticular disease and the irritable bowel syndrome. Gut 1988;29: Cortesini C, Pantalone D. Usefulness of colonic motility study in identifying patients at risk for complicated diverticular disease. Dis Colon Rectum 1991;34: Bassotti G, Crowell MD. Colon and rectum: normal function and clinical disorder. In: Schuster MM, Crowell MD, Koch KL, eds. Schuster atlas of gastrointestinal motility in health and disease. 2nd ed. Hamilton: BC Decker Inc, 2002: Bassotti G, Battaglia E, Spinozzi F, et al. Twenty-four hour recordings of colonic motility in patients with diverticular disease. Evidence for abnormal motility and propulsive activity. Dis Colon Rectum 2001;44: Torsoli A, Inoue M, Manousos O, et al. Diverticular disease of the colon: data relevant to management. Gastroenterol Int 1991; 4: Kohler L, Sauerland S, Neugebauer E, for the scientific committee of the European Association for Endoscopic Surgery (EAES). Diagnosis and treatment of diverticular disease. Results of a consensus development conference. Surg Endosc 1999;13: Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(suppl 2):II43 II Bassotti G, Chistolini F, Marinozzi G, et al. Abnormal colonic propagated activity in patients with slow transit constipation and constipation-predominant irritable bowel syndrome. Digestion 2003;68: Bassotti G, Chistolini F, Sietchiping Nzepa F, et al. Colonic propulsive impairment in intractable slow-transit constipation. Arch Surg 2003;138: Bassotti G, Betti C, Imbimbo BP, et al. Colonic motor response to eating: a manometric investigation in proximal and distal portions of the viscus in man. Am J Gastroenterol 1989;84: Bassotti G, Bucaneve G, Pelli MA, et al. Contractile frequency patterns of the human colon. J Gastrointest Motil 1990;2: Bassotti G, Chistolini F, Battaglia E, et al. Are colonic regular contractile frequency patterns in slow transit constipation a relevant pathophysiological phenomenon? Dig Liver Dis 2003; 35: Bassotti G, Sietchiping-Nzepa F, de Roberto G, et al. Colonic regular contractile frequency patterns in irritable bowel syndrome: the spastic colon revisited. Eur J Gastoenterol Hepatol 2004;16: Weusten BL, Roelofs JM, Akkermans LM, et al. The symptom

6 March 2005 COLONIC CONTRACTILE PATTERNS IN DIVERTICULOSIS 253 association probability: an improved method for symptom analysis of 24-hour esophageal ph data. Gastroenterology 1994;107: Clemens CHM, Samsom M, Roelofs JMM, et al. Association between pain episodes and high amplitude propagated pressure waves in patients with irritable bowel syndrome. Am J Gastroenterol 2003;98: Connell AM. The motility of the pelvic colon. II. Paradoxical motility in diarrhoea and constipation. Gut 1962;3: Morson BC. The muscular abnormality in diverticular disease of the sigmoid colon. Br J Radiol 1963;36: Hughes LE. Postmortem survey of diverticular disease of the colon. II. The muscular abnormality of the sigmoid colon. Gut 1969;10: von der Ohe M, Hanson RB, Camilleri M. Comparison of simultaneous recordings of human colonic contractions by manometry and a barostat. Neurogastroenterol Motil 1994;6: Vuong NP, Sezeur A, Balaton A, et al. Myenteric plexuses and colonic diverticulosis: results of a histological study. Gastroenterol Clin Biol 1985;9: Huizinga JD, Waterfall WE, Stern HS. Abnormal response to cholinergic stimulation in the circular muscle layer of the human colon in diverticular disease. Scand J Gastroenterol 1999;34: Golder M, Burleigh DE, Belai A, et al. Smooth muscle cholinergic denervation hypersensitivity in diverticular disease. Lancet 2003;361: Tomita R, Fujisaki S, Tanjoh K, et al. Role of nitric oxide in the left-sided colon of patients with diverticular disease. Hepatogastroenterology 2000;47: Morris CR, Harvey IM, Stebbings WS, et al. Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? A case control study. Gut 2003;52: Narducci F, Bassotti G, Gaburri M, et al. Nifedipine reduces the colonic motor response to eating in patients with the irritable colon syndrome. Am J Gastroenterol 1985;80: Otte JJ, Larsen L, Andersen JR. Irritable bowel syndrome and symptomatic diverticular disease: different diseases? Am J Gastroenterol 1986;81: Havia T, Manner R. The irritable colon syndrome: a follow-up study with reference to the development of diverticula. Acta Chir Scand 1971;137: Clemens CHM, Samsom M, Roelofs J, et al. Colorectal visceral perception in diverticular disease. Gut 2004;53: Collins SM, Vallance B, Barbara G, et al. Putative inflammatory and immunological mechanism in functional bowel disorders. Best Pract Res Clin Gastroenterol 1999;13: Simpson J, Scholefield JH, Spiller RC. Origin of symptoms in diverticular disease. Br J Surg 2003;90: Colecchia A, Sandri L, Capodicasa S, et al. Diverticular disease of the colon: new perspectives in symptom development and treatment. World J Gastroenterol 2003;9: Address requests for reprints to: Dr. Gabrio Bassotti, Strada del Cimitero, 2/a, San Marco, Perugia, Italy. gabassot@ tin.it; fax: (39)