Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial. The British-Italian Gallstone Study group.

BACKGROUND: Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization. AIM: To compare the clinical efficacy of combination therapy with ursodeoxycholic acid monotherapy. PATIENTS AND METHODS: A total of 154 symptomatic patients with radiolucent stones (< or = 15 mm) in functioning gallbladders were enrolled from six centres in England and Italy. They were randomized to either a combination of chenodeoxycholic acid plus ursodeoxycholic acid (5 mg.day/kg each) or to ursodeoxycholic acid alone (10 mg.day/kg). Dissolution was assessed by 6-monthly oral cholecystography and ultrasonography for up to 24 months. RESULTS: Both regimens reduced the frequency of biliary pain and there was no significant difference between them in terms of side-effects or dropout rate. Complete gallstone dissolution on an intention-to-treat basis was similar at all time intervals. At 24 months this was 28% with ursodeoxycholic acid alone and 30% with combination therapy. The mean dissolution rates at 6 and 12 months were 47% and 59% with ursodeoxycholic acid, and 44% and 59% with combination therapy, respectively. CONCLUSION: There is no substantial difference in the efficacy of combined ursodeoxycholic acid and chenodeoxycholic acid and that of ursodeoxycholic acid alone in terms of gallstone dissolution rate, complete gallstone dissolution, or relief of biliary pain.

Risk factors for the development of gallstone recurrence following medical dissolution. The British-Italian Gallstone Study Group.

OBJECTIVE: To assess risk factors for gallstone recurrence following non-surgical treatment. DESIGN: A prospective follow-up of a multicentre cohort of post-dissolution gallstone patients. SETTING: Six gastroenterology units in the UK and Italy. PARTICIPANTS: One hundred and sixty-three patients with confirmed gallstone dissolution following non-surgical therapy (bile acids or lithotripsy plus bile acids), followed up by ultrasound scan and clinical assessment at 6-monthly intervals for up to 6 years (median, 25 months; range, 6-70 months). OUTCOME MEASURES: Subject-related variables (sex, age, height, weight, body mass index), gallstone-related variables (number, diameter, presence of symptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporeal shock wave lithotripsy) and follow-up related variables (weight change, use of non-steroidal anti-inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariate and multivariate analysis as putative risk factors for gallstone recurrence. RESULTS: Forty-five gallstone recurrences were observed during the follow-up period. Multiple primary gallstones and length of time to achieve gallstone dissolution were the only variables associated with a significant increase in the recurrence rate. Appearance of biliary sludge during follow-up was also significantly related to development of gallstone recurrence. Use of statins or non-steroidal anti-inflammatory agents did not confer protection against recurrence. CONCLUSIONS: Patients with primary single stones are the best candidates for non-surgical treatment of gallstones, because of a low risk of gallstone recurrence. The positive association of recurrence with biliary sludge formation and time to dissolution of primary stones may provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of this condition.

Review article: epidemiology of gall-bladder disease--role of intestinal transit.

Recent epidemiological studies have suggested that hyperinsulinaemia may be a central factor in the pathogenesis of cholesterol gallstones, explaining a probable link with physical inactivity as well as abdominal adiposity. There is also increasing evidence for the hypothesis that enrichment of bile with DCA. 'the colonic bile acid', leads to enrichment of bile with cholesterol. Biliary DCA can be raised and lowered by slowing down and speeding up colonic transit, respectively. Slow transit is characteristic of non-obese British women with gallstones and of non-obese peasants in a gallstone-prone mountain community. High biliary DCA predicts recurrence of gallstones and so does laxative usage, a pointer to constipation and therefore to slow transit. In some studies, at least, a high fibre intake is protective against gallstones. Much else besides fibre influences colonic function. Future studies of gallstone aetiology should include measurements of colonic function. Measures that speed up colonic transit should be tested for their ability to prevent gallstone formation in high-risk individuals.

Irritable bowel syndrome in general practice: prevalence, characteristics, and referral.

BACKGROUND AND AIMS: Little is known about the prevalence, symptoms, diagnosis, attitude, and referral to specialists of patients with irritable bowel syndrome (IBS) in general practice. This study aimed to determine these characteristics. METHODS: 3111 patients attending 36 general practitioners (GPs) at six varied locations in and near Bristol, UK, were screened to identify those with a gastrointestinal problem. These patients (n=255) and their doctors were given questionnaires. Six months later the case notes were examined to reach criteria based diagnoses of functional bowel disorders. RESULTS: Of 255 patients with a gastrointestinal complaint, 30% were judged to have IBS and 14% other functional disorders. Compared with 100 patients with an "organic" diagnoses, those with IBS were more often women and more often judged by their GP to be polysymptomatic and to have unexplained symptoms. The majority of patients with IBS (58%) were diagnosed as such by the GP; 22% had other functional diagnoses. Conversely, among 54 patients diagnosed as having IBS by the GPs, the criteria based diagnosis was indeed functional in 91%; only one patient had organic disease (proctitis). More patients with IBS than those with organic disease feared cancer. In most some fear remained after the visit to the doctor. On logistic regression analysis, predictors of referral to a specialist (29% referred) were denial of a role for stress, multiple tests, and frequent bowel movements. CONCLUSIONS: Half the patients with gut complaints seen by GPs have functional disorders. These are usually recognised, and few patients are referred. In IBS, cancer fears often remain, suggesting unconfident diagnosis or inadequate explanation.

Effect of cholecystectomy on bowel function: a prospective, controlled study.

BACKGROUND: Published estimates of the prevalence of postcholecystectomy diarrhoea derive from retrospective or uncontrolled data. They ignore functional bowel syndromes and possible changes in diet and drug use. AIMS: To determine prospectively whether and how often cholecystectomy leads to changes in bowel function and bowel symptoms, especially to liquid stools, over and above any non-specific effect of laparoscopic surgery. PATIENTS: 106 adults undergoing laparoscopic cholecystectomy (85 women, 21 men). CONTROLS: 37 women undergoing laparoscopic sterilisation. METHODS: Before and 2-6 months after surgery patients were administered questionnaires about bowel frequency, bowel symptoms, diet, and drugs, and kept records of five consecutive defecations with assessment of stool form or appearance on a seven point scale. RESULTS: In cholecystectomised women, stated bowel frequency increased, on average by one movement a week, and fewer subjects felt that they became constipated. However, records showed no consistent change in bowel frequency, stool form, or defecatory symptoms. Six women reported diarrhoea after the operation but in only one was it clearly new and in her it was mild. Change in dietary fibre intake did not associate with change in bowel function but stopping constipating drugs did in a minority. In women being sterilised there was no consistent change in bowel function. In men having cholecystectomy no consistent changes were observed. CONCLUSIONS: In women, cholecystectomy leads to the perception of less constipation and slightly more frequent defecations but short term recordings show no consistent change in bowel function. Clinical diarrhoea develops rarely and is not severe.

Functional bowel disorders and functional abdominal pain.

The Rome diagnostic criteria for the functional bowel disorders and functional abdominal pain are used widely in research and practice. A committee consensus approach, including criticism from multinational expert reviewers, was used to revise the diagnostic criteria and update diagnosis and treatment recommendations, based on research results. The terminology was clarified and the diagnostic criteria and management recommendations were revised. A functional bowel disorder (FBD) is diagnosed by characteristic symptoms for at least 12 weeks during the preceding 12 months in the absence of a structural or biochemical explanation. The irritable bowel syndrome, functional abdominal bloating, functional constipation, and functional diarrhea are distinguished by symptom-based diagnostic criteria. Unspecified FBD lacks criteria for the other FBDs. Diagnostic testing is individualized, depending on patient age, primary symptom characteristics, and other clinical and laboratory features. Functional abdominal pain (FAP) is defined as either the FAP syndrome, which requires at least six months of pain with poor relation to gut function and loss of daily activities, or unspecified FAP, which lacks criteria for the FAP syndrome. An organic cause for the pain must be excluded, but aspects of the patient's pain behavior are of primary importance. Treatment of the FBDs relies upon confident diagnosis, explanation, and reassurance. Diet alteration, drug treatment, and psychotherapy may be beneficial, depending on the symptoms and psychological features.

The metabolic consequences of slow colonic transit.

Intestinal transit has a substantial influence on the enterohepatic circulation of bile acids and steroid hormones, on colonic pH, and on short chain fatty acid concentrations in the distal colon. Slow transit is likely to favor disease processes that are related to over-efficient enterohepatic recirculation and to lack of short chain fatty acid in the distal colon. These include gallstones, large bowel cancer, and possibly breast cancer. The best-documented influence of slow colonic transit is on bile acid metabolism. Slowing colonic transit increases deoxycholate and raises cholesterol saturation of bile, making gallstone formation more likely. In this review, we also examine the evidence that slow colonic transit may be important in the etiology of large bowel and breast cancer. There is a lack of data pertaining to the relationship between colonic transit and diseases such as colon and breast cancer. Should slow colonic transit prove to be a significant factor in the etiology of such diseases, then the health of the population might benefit from dietary and lifestyle changes that speed up intestinal transit.

Roughage revisited: the effect on intestinal function of inert plastic particles of different sizes and shape.

The mechanisms by which dietary fiber exerts its laxative action are not fully understood. Finely grinding wheat bran reduces its effect. Inert plastic particles are equipotent to bran if they consist of flakes or sliced tubing. It is not known whether altering the size or shape of inert particles alters their effect on intestinal function. In a randomized crossover study, 18 volunteers swallowed 24 g/day of plastic as branlike flakes or as small granules for 10-12 days with a two-week washout period between interventions. Whole-gut transit time (WGTT), orocecal transit time (OCTT), defecation frequency, stool form, stool water content, stool pH, and dietary intake were assessed. The plastic flakes caused a 24% (P < 0.001) reduction in WGTT and a 19% (P = 0.002) fall in OCTT. Resultant and appropriate changes in stool form, interdefecatory intervals (IDI), and stool weight were seen. The small granules did not cause any significant change in WGTT or OCTT, although IDI did decrease and stool output and stool form score increased. The stimulant effect of solid particles in the intestinal lumen upon transit time is influenced by the morphology of the particles.

Intestinal absorption of oestrogen: the effect of altering transit-time.

OBJECTIVE: The mechanism by which a high fibre diet may reduce serum oestrogens is unknown. We hypothesized that time is a rate-limiting factor in oestrogen absorption from the colon so that changes in colonic transit-rate affect the proportion of oestrogen that is deconjugated and/or absorbed. AIM: To determine if alteration of intestinal transit rate would influence the absorption of an oral dose of oestradiol glucuronide. PARTICIPANTS: Twenty healthy postmenopausal women recruited by advertisement. SETTING: Department of Medicine, Bristol Royal Infirmary. METHODS: Volunteers consumed, in turn, wheat bran, senna, loperamide and bran shaped plastic flakes, each for 10 days with a minimum 2 week washout period between study periods, dietary intake being unchanged. Before and in the last 4 days of each intervention whole-gut transit-time, defecation frequency, stool form, stool beta-glucuronidase activity, stool pH and the absorption of a 1.5 mg dose of oestradiol glucuronide were measured. RESULTS: Wheat bran, senna and plastic flakes led to the intended reduction in whole-gut transit-time, increase in defecatory frequency and increase in stool form score. Loperamide caused the opposite effect. The length of time the absorbed oestrogen was detectable in the serum fell with wheat bran and senna, although this was only significant for oestradiol. Oestrone, but not oestradiol, was detectable for a longer time with loperamide. Plastic flakes had no effect on either oestrogen. Areas under the curve did not change significantly but tended to fall with the three transit-accelerating agents and to rise with loperamide. CONCLUSION: Our data indicate there is likely to be an effect of intestinal transit on the absorption of oestrogens but more refined techniques are needed to characterize this properly.

Stool form scale as a useful guide to intestinal transit time.

BACKGROUND: Stool form scales are a simple method of assessing intestinal transit rate but are not widely used in clinical practice or research, possibly because of the lack of evidence that they are responsive to changes in transit time. We set out to assess the responsiveness of the Bristol stool form scale to change in transit time. METHODS: Sixty-six volunteers had their whole-gut transit time (WGTT) measured with radiopaque marker pellets and their stools weighed, and they kept a diary of their stool form on a 7-point scale and of their defecatory frequency. WGTT was then altered with senna and loperamide, and the measurements were repeated. RESULTS: The base-line WGTT measurements correlated with defecatory frequency (r = 0.35, P = 0.005) and with stool output (r = -0.41, P = 0.001) but best with stool form (r = -0.54, P < 0.001). When the volunteers took senna (n = 44), the WGTT decreased, whereas defecatory frequency, stool form score, and stool output increased (all, P < 0.001). With loperamide (n = 43) all measurements changed in the opposite direction. Change in WGTT from base line correlated with change in defecatory frequency (r = 0.41, P < 0.001) and with change in stool output (n = -0.54, P < 0.001) but best with change in stool form (r = -0.65, P < 0.001). CONCLUSIONS: This study has shown that a stool form scale can be used to monitor change in intestinal function. Such scales have utility in both clinical practice and research.

Increasing butyrate concentration in the distal colon by accelerating intestinal transit.

BACKGROUND: Populations at low risk of colonic cancer consume large amounts of fibre and starch and pass acid, bulky stools. One short chain fatty acid (SCFA), butyrate, is the colon's main energy source and inhibits malignant transformation in vitro. AIM: To test the hypothesis that altering colonic transit rate alters colonic pH and the SCFA content of the stools. PATIENTS: Thirteen healthy adults recruited by advertisement. METHODS: Volunteers consumed, in turn, wheat bran, senna and loperamide, each for nine days with a two week washout period between study periods, dietary intake being unchanged. Before, and in the last four days of each intervention, whole gut transit time (WGTT), defaecation frequency, stool form, stool beta-glucuronidase activity, stool pH, stool SCFA concentrations and intracolonic pH (using a radiotelemetry capsule for continuous monitoring) were assessed. RESULTS: WGTT decreased, stool, output and frequency increased with wheat bran and senna, vice versa with loperamide. The pH was similar in the distal colon and stool. Distal colonic pH fell with wheat bran and senna and tended to increase with loperamide. Faecal SCFA concentrations, including butyrate, increased with senna and fell with loperamide. With wheat bran the changes were non-significant, possibly because of the short duration of the study. Baseline WGTT correlated with faecal SCFA concentration (r = -0.511, p = 0.001), with faecal butyrate (r = -0.577, p < 0.001) and with distal colonic pH (r = 0.359, p = 0.029). CONCLUSION: Bowel transit rate is a determinant of stool SCFA concentration including butyrate and distal colonic pH. This may explain the inter-relations between colonic cancer, dietary fibre intake, stool output, and stool pH.

Irritable bowel syndrome: the view from general practice.

OBJECTIVE: To determine the attributes of the irritable bowel syndrome (IBS) in general practice as perceived by the doctors. SUBJECTS AND METHODS: We administered a 93-item questionnaire about the terminology, diagnosis and treatment of the irritable bowel to 43 of 55 randomly selected general practitioners (28 men, 15 women). RESULTS: General practitioners were unfamiliar with the Manning criteria for the irritable bowel syndrome. Nevertheless, most of them diagnosed the irritable bowel with reasonable confidence and it is less troublesome to them than pelvic pain, headache or backache. Their main concern was excluding organic disease (63%) and 65% believed their patients shared this concern. Nevertheless, they ordered few tests and were often (72%) prepared to make the diagnosis on the initial visit. They estimated that they referred only 14% of IBS patients to specialists, in most cases (56%) because of an unsatisfied patient and in 35% because of an uncertain diagnosis. For treatment, most (77%) chose 'explanation and reassurance'. Virtually all employed drugs, usually several. CONCLUSION: General practitioners say they diagnose the irritable bowel syndrome with less difficulty than other common, painful disorders, but it would be helpful to find out exactly how they do so. Their confidence could be increased by use of diagnostic criteria. Patients referred to specialists are likely to be a minority of hard-to-satisfy people. The optimal approach to such patients should be developed by general practitioners and specialists together. Specialists should strive to satisfy the patient and confirm the diagnosis in the few that are referred. Drug usuage in the irritable bowel syndrome is more than is justified and should, in our view, be minimized.

The intestinal effects of bran-like plastic particles: is the concept of 'roughage' valid after all?

OBJECTIVE: The mechanisms by which dietary fibre exerts is laxative action are not fully understood. Studies using sliced plastic tubing as a fibre substitute showed a decrease in both small and large bowel transit time. The significance of these studies is hard to interpret. We set out to compare the effects on intestinal function of wheat bran with plastic flakes similar in size and flaky shape to wheat bran (and devoid of plasticizers). DESIGN AND METHODS: Volunteers consumed coarse wheat bran then, after a washout period, plastic flakes of the same size and shape as the bran. Before and after each intervention whole-gut transit time (WGTT), defecation frequency, stool form, stool water content, stool beta-glucuronidase activity and dietary intake were assessed. RESULTS: Twenty-nine volunteers consumed a mean of 27.1 g of raw wheat bran and 24 g of plastic flakes a day. Baseline WGTT, interdefecatory intervals (IDI), stool form, weight, output, water content, and beta-glucuronidase were similar before both interventions. Both led to a decrease in mean faecal beta-glucuronidase activity, median WGTT (bran 25.8%, plastic 28.6%) and IDI (bran 23.3% plastic 25.0%). Both also increased stool form score (bran 28.6%, plastic 21.2%) and stool output (bran 67.1%, plastic 79.0%). Stool water content only rose with wheat bran (72%-75%, P = 0.014). CONCLUSION: Overall, plastic 'pseudobran' was as effective at altering colonic function as wheat bran at a similar dosage but with fewer particles. The mechanism is not by increased faecal water. Reduction in enzyme activity with plastic flakes suggests that the plastic led to qualitative and, probably, beneficial changes in the bacterial flora or their metabolic processes. The concept of roughage deserves to be revived.