Simultaneous measurement of gastric emptying, small bowel residence and colonic filling of a solid meal by the use of the gamma camera

A method for determining the profiles of gastric emptying, small intestinal residence, and colonic filling of a solid test meal, labelled with 250 microCi 99mTechnetium sulphur colloid has been evaluated in nine healthy volunteers and six patients with a disturbance in bowel habit. Mean small bowel transit time was determined by deconvolving the rate of colonic filling with the rate of gastric emptying. In normal subjects, the stomach appeared to empty exponentially with a half time of 1.2 +/- 0.3 hours (mean +/- SD). Food reached the colon by 2.8 +/- 1.5 hours. The mean small bowel transit time was 4.0 +/- 1.4 hours. In most normal subjects, the colon appeared to fill in a linear fashion with approximately 16% food residues entering every hour, and the profile of colonic filling in normal subjects was similar to the profile of ileal emptying observed after feeding a similar radiolabelled solid meal to 14 patients equipped with terminal ileostomies. There was a highly significant correlation between the onset of breath hydrogen excretion and the appearance of radioactivity over the caecum (r = 0.88, p less than 0.01), though in one third of subjects the increase in caecal radioactivity preceded the rise in breath hydrogen concentration by more than 20 minutes. There was also a highly significant correlation between the mean transit time and values for colonic filling but not values for gastric emptying. Patients with irritable bowel syndrome who had diarrhoea tended towards short small bowel transit and early colonic filling, whereas patients who have constipation tended towards long small bowel transit and delayed colonic filling. This method offers a novel means of assessing small bowel transit time, small bowel residence and the profile of colonic filling in man.     

Age-related decline in rectal mucosal lymphocytes and mast cells

BACKGROUND: Previous studies have shown that irritable bowel syndrome declines with age and is more common in women. Recent reports suggest that some diarrhoea predominant irritable bowel syndrome patients have low-grade inflammation with increased numbers of mucosal T lymphocytes, 5-hydroxytryptamine (5-HT) containing enteroendocrine cells and mast cells. OBJECTIVE: To determine whether there are age or gender-related changes in mucosal T lymphocytes, mast cells or enteroendocrine cells which might explain these findings. METHODS: Forty healthy volunteers (20 subjects below 55 years of age and 20 above 55 years) free from gastro-intestinal symptoms or disease answered detailed bowel symptom questionnaires and underwent sigmoidoscopy, rectal biopsy and colonic transit measurement. Biopsies were immunostained and quantified for lamina propria and intra-epithelial T lymphocytes, mast cells and 5-HT and peptide YY enteroendocrine cells. RESULTS: There was a reduction in lamina propria T lymphocyte counts (P = 0.018), crypt intra-epithelial T lymphocytes (P = 0.014) and mast cells (P = 0.02) in the > 55 year group. Enteroendocrine cell numbers did not decline with age and were not related to colonic transit. There were no gender differences between any of the cells quantified. CONCLUSIONS: Lymphocyte and mast cell numbers decline with age in normal large bowel mucosa. Reduced numbers of mucosal inflammatory cells may influence the low-grade inflammatory response to luminal antigens and contribute to the reduction of irritable bowel syndrome observed in older subjects.     

Differential measurement of small and large bowel transit times in constipation and diarrhoea: A new approach.

Differential measurements of small and large bowel transit times were performed in 13 subjects iwth a radiotelemetering pressure-sensitive capsule incorporating less than 10mugCi of 51-Cr. Six patients had constipation. The other seven patients had diarrhoea due to the irritable bowel syndrome (3), following vagotomy and pyloroplasty (3), or due to laxative abuse (1). This new method enables the gastric, small intestinal, and colonic transit times to be measured differentially in the same subject. The capsule can be localized in the gut lumen by reference to the characteristic pressure pattern and in relation to bony landmarks by the radioactive marker as frequently as desired without recourse to radiographs. The results show that gastric emptying and small intestinal transit did not differ in constipation and diarrhoea. By contrast the mean colonic transit was significantly faster (P smaller than 0.01) in diarrhoea whatever the cause (17.5 plus or minus 4.1 hours) than in constipation (118 plus or minus 4.1 hours).     

Crohn's Disease: A Review of 122 Cases

Summary: One-hundred-and-twenty-two patients with Crohn's disease were admitted to Royal Prince Alfred Hospital from 1966 to 1977. Thirty-seven had disease confined to small bowel, 37 to colon and 48 had combined small and large bowel involvement. The disease was twice as common in females as in males. Pain was the major symptom in patients with small bowel disease and was associated with diarrhoea if both small and large bowel were involved. Disease confined to the colon most commonly produced diarrhoea with bleeding. Perianal disease occurred more often in patients with colonic disease. Systemic complications were also more frequent in the group with disease confined to colon, and these complications were often multiple. Medical treatment with corticosteroids, salazopyrine or azathioprine, was generally unsuccessful. One in two patients required surgery, usually in the form of resection. Following resection, recurrence occurred in more than one half of the patients but was less frequent in those with colonic disease. Three-quarters of patients with a recurrence required a further resection, emphasising the unsatisfactory long-term results of surgery in this disease.     

Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.     

Effect of eating on motility of the pelvic colon in constipation or diarrhoea

Pelvic colonic pressures were recorded before, during, as well as after a meal in patients with non-specific diarrhoea (12) or constipation (14), who were selected according to strict clinical criteria of bowel habit. In the basal state diarrhoeal patients as a group had significantly less colonic activity than constipated patients, but the overlap was considerable. During the meal colonic activity was strikingly increased in diarrhoea, but returned to basal levels immediately after the meal; no such response was observed in constipation. It is suggested that this brief segmental response of the pelvic diarrhoeal colon may be inadequate to prevent entry of faeces into the rectum and the desire to defaecate, following a meal.     

Disposition of Mesalazine from Mesalazine-Delivering Drugs in Patients with Inflammatory Bowel Disease,with and without Diarrhoea

Rijk MCM, van Schaik A, van Tongeren JHM. Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea. Scand J Gastroenterol 1992;27:863-868.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum^®) and from the slow-release mesalazine drugs Pentasa^®, Asacol^®, and Salofalk^® was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from ail these drugs except Pentasa.     

Diagnosing small bowel malabsorption: a review

Malabsorption encompasses dysfunctions occurring during the digestion and absorption of nutrients. A small proportion of patients presents with chronic diarrhoea. A clinical history supportive of malabsorption may guide investigations toward either the small bowel or pancreas. Serological testing for coeliac disease will determine most cases without invasive investigations. In the clinical context of persisting weight loss and malnutrition, small bowel enteropathy may be investigated with small intestinal biopsies. Small bowel absorptive capacity and permeability might be measured by oral sugar-mix ingestion. Further, approaches to the investigation of malabsorption might also involve the detection in faeces of a substance that has not been absorbed. A variation of the latter is the use of breath testing which relies on the breakdown of the malabsorbed test substance by colonic flora. Measurement of protein absorption is difficult and unreliable; it is, therefore, rarely advocated in clinical settings. No single biological marker confirming a diagnosis of small bowel malabsorption or small bowel integrity is presently available in clinical practice. Plasma citrulline concentration, an amino acid not incorporated into endogenous or exogenous proteins, has been extensively used in research studies and supportive results are establishing its concentration as a reliable quantitative biomarker of enterocyte absorptive capacity.     

Probiotics and gastrointestinal diseases

There is increasing evidence indicating health benefits by consumption of foods containing microorganisms, i.e. probiotics. A number of clinical trials have been performed to evaluate the effects in the prevention and treatment of gastrointestinal diseases caused by pathogenic microorganisms or by disturbances in the normal microflora. Gastrointestinal infections caused by Helicobacter pylori, traveller's diarrhoea, rotavirus diarrhoea, antibiotic-associated diarrhoea (AAD) and Clostridium difficile-induced diarrhoea are conditions that have been studied. There are also studies performed on the preventive effect of probiotics on radiation-induced diarrhoea and diarrhoea in tube-fed patients. Inflammatory bowel disease and irritable bowel syndrome, two idiopathic conditions where alterations in the normal microflora have been implicated as responsible for initiation, are two further areas where the use of probiotics has been regarded as promising. The results from clinical studies have not been conclusive in that the effects of probiotics have been strain-dependent and different study designs have been used. Treatment of acute diarrhoea in children and prevention of AAD are the two most justified areas for the application of probiotics.     

Eicosanoids and their role in the pathogenesis of diarrhoeal diseases

Eicosanoids are unsaturated fatty acid compounds derived from 20-carbon 'essential' fatty acids, the most important being arachidonate. Both cyclooxygenase and lipoxygenase products of arachidonate are abundant in the human gut and their biological effects include modulation of fluid and electrolyte secretion, motor activity, mucosal blood flow, and cytoprotection, in addition to chemotaxis and immune response in inflammation. In health, these lipid mediators reinforce or synergize normal homeostatic mechanisms that could proceed in their absence. Receptors for control of intestinal secretion can be divided into two major classes, one of which triggers the production of cyclic AMP and another, which initiates phospholipid breakdown and arachidonate release. An intimate connection appears to exist between phospholipid metabolism, cytosolic Ca2+ levels, electrogenic anion secretion, Na+ pump rate, electroneutral Na+/H+ exchange activity, and intracellular pH. Ca2+-dependent secretagogues affect fluid and electrolyte transport in the small and the large bowel by increasing Ca2+ entry and Ca2+ mobilization through stimulation of eicosanoid formation, prostaglandins of the E type being the most important. Secretory diarrhoea may be thought of, therefore, as cellular Ca2+ intoxication. Uncontrolled formation of eicosanoids, perhaps with a changed spectrum of arachidonate metabolites, may not only be the source of diarrhoea associated with mucosal inflammation, but may also be critical for cell proliferation resulting in abnormal cell differentiation, which seems to be the link between long-standing inflammatory bowel disease and the increased risk of colonic neoplasia. A better understanding of the pathophysiological role of eicosanoids in diarrhoeal disease has allowed reinterpretation of the rationale behind current therapy.     

Simultaneous culture of saliva and jejunal aspirate in the investigation of small bowel bacterial overgrowth.

Both saliva and jejunal aspirate were cultured from 22 patients with suspected small bowel bacterial overgrowth and from eight controls. Large numbers of organisms (greater than 10(6)/ml) were recovered from the jejunal aspirate of 16 subjects, in five of whom the same organisms were present in similar relative proportions in the saliva, suggesting contamination of the sample with saliva, while in 11 the jejunal organisms differed from those in saliva. In eight of these the jejunal flora was a typical 'faecal' flora usually associated with small bowel bacterial overgrowth but, in three, the jejunal floral was superficially similar to that of saliva. Distinct subpopulations of bacteria, typically Gram-positive non-sporing rods, were, however, evident in the jejunum of these patients, and were also recovered, in smaller numbers, from the jejunum of controls, suggesting that they form a distinct jejunal microflora. Culture of saliva in addition to jejunal aspirate may be useful in the recognition of contamination of the proximal small bowel with saliva, and in the diagnosis of small bowel bacterial overgrowth.     

Smooth muscle myopathy as an underrecognized manifestation of active systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with protean manifestations. We here present a case of unexplained diarrhoea and abdominal pain in a patient with SLE. Investigations revealed dilatation of stomach, small bowel and colonic wall, biliary and pancreatic ducts, renal collecting systems and ureters as well as thoracic aorta and major pulmonary arteries, as manifestations of a smooth muscle myopathy that was responsive to immunosuppressive therapy with cyclosporin A.     

Metabolism of dietary sulphate: absorption and excretion in humans.

Dietary sulphate may affect colonic pathophysiology because sulphate availability determines in part the activity of sulphate reducing bacteria in the bowel. The main product of sulphate reducing bacterial oxidative metabolism, hydrogen sulphide, is potentially toxic. Although it is generally believed that the sulphate ion is poorly absorbed, there are no available data on how much sulphate reaches the colon nor on the relative contributions from diet and endogenous sources. To resolve these questions, balance studies were performed on six healthy ileostomists and three normal subjects chosen because they did not have detectable sulphate reducing bacteria in their faeces. The subjects were fed diets which varied in sulphate content from 1.6-16.6 mmol/day. Sulphate was measured in diets, faeces (ileal effluent in ileostomists), and urine by anion exchange chromatography with conductivity detection. Overall there was net absorption of dietary sulphate, with the absorptive capacity of the gastrointestinal tract plateauing at 5 mmol/day in the ileostomists and exceeding 16 mmol/day in the normal subjects. Endogenous secretion of sulphate in the upper gastrointestinal tract was from 0.96-2.6 mmol/day. The dietary contribution to the colonic sulphate pool ranged up to 9 mmol/day, there being linear identity between diet and upper gastrointestinal losses for intakes above 7 mmol/day. Faecal losses of sulphate were trivial (less than 0.5 mmol/day) in the normal subjects at all doses. It is concluded that diet and intestinal absorption are the principal factors affecting the amounts of sulphate reaching the colon. Endogenous secretion of sulphate by colonic mucosa may also be important in determining amounts of sulphate in the colon.     

High Intraluminal Fluid Flow Increases Intestinal IgA Output

Background: Stool IgA output in normal stool or chronic diarrhoea is a fraction of that recorded in high-output watery diarrhoea due to cholera. We hypothesized that high intestinal fluid flow leads to increased IgA output, and this is not a consequence of reduced degradation/reabsorption. Methods: Daily intestinal outputs of IgA and other secretory and non-secretory proteins were measured in stool from 14 volunteers with ileostomies and compared with the output during whole-gut lavage, a whole-gut perfusion system. Results: Output into whole-gut lavage was significantly higher for all the proteins (P = 0.02 to 0.001). Median IgA output into ileostomy effluent (IE) was 3.6 mg/kg/day compared with 26 mg/kg/day into whole-gut lavage fluid (WGLF). Thus IgA recovery in stool was only 12.7% of the amount in corresponding WGLF. Similar results were found for other proteins: specific IgA and IgM antibodies (5.4%-20.3 %), IgM (42.4%), IgG (8.9%), and albumin (9.3%). Six subjects with IE water content >92% had increased recovery of IgA compared with eight with <92% water. In vitro, experiments predict that degradation of IgA within the small bowel results in 80% remaining compared with the 12.7% measured in vivo. Conclusions: Our data show that high intraluminal fluid flow increases the intestinal output of IgA and other proteins, and this is not a consequence of reduced degradation/reabsorption in the colon or small bowel. This increased protein output may be a non-specific response in the early stages of acute diarrhoea.     

High intraluminal fluid flow increases intestinal IgA output

BACKGROUND: Stool IgA output in normal stool or chronic diarrhoea is a fraction of that recorded in high-output watery diarrhoea due to cholera. We hypothesized that high intestinal fluid flow leads to increased IgA output, and this is not a consequence of reduced degradation/reabsorption. METHODS: Daily intestinal outputs of IgA and other secretory and non-secretory proteins were measured in stool from 14 volunteers with ileostomies and compared with the output during whole-gut lavage, a whole-gut perfusion system. RESULTS: Output into whole-gut lavage was significantly higher for all the proteins (P=0.02 to 0.001). Median IgA output into ileostomy effluent (IE) was 3.6 mg/kg/day compared with 26 mg/kg/day into whole-gut lavage fluid (WGLF). Thus IgA recovery in stool was only 12.7% of the amount in corresponding WGLF. Similar results were found for other proteins: specific IgA and IgM antibodies (5.4%-20.3%), IgM (42.4%), IgG (8.9%), and albumin (9.3%). Six subjects with IE water content >92% had increased recovery of IgA compared with eight with <92% water. In vitro, experiments predict that degradation of IgA within the small bowel results in 80% remaining compared with the 12.7% measured in vivo. CONCLUSIONS: Our data show that high intraluminal fluid flow increases the intestinal output of IgA and other proteins, and this is not a consequence of reduced degradation/reabsorption in the colon or small bowel. This increased protein output may be a non-specific response in the early stages of acute diarrhoea.     

Medium term effects of a new 5HT3 antagonist, alosetron, in patients with carcinoid diarrhoea

Background—Carcinoid diarrhoea is associated withrapid small bowel and proximal colonic transit. Intravenousadministration of a serotonin type 3 receptor (5HT₃)antagonist restores postprandial colonic tone towards normal incarcinoid patients.
Aims—To evaluate the medium term effects of anoral 5HT₃ antagonist, alosetron, on symptoms, stool fat,and transit in patients with carcinoid diarrhoea.
Methods—In 27 patients with carcinoid diarrhoea,symptoms were recorded daily and gastrointestinal transit was measuredby scintigraphy in a three dose (0.1, 0.5, 2.0 mg, twice daily), randomised (1:1:1), parallel group, four week study. Placebo was givenduring the first week. Loperamide (2 mg capsules) was used as rescue medication.
Results—There were numerical improvements inmedian diarrhoea score, stool weight, loperamide use, and overallcolonic transit at four hours, but no overall significant drug effectwas shown. Alosetron reduced the proximal colon emptying rate (p<0.05in 20 evaluable comparisons), but did not significantly alter small bowel transit.
Conclusions—Alosetron retardation of proximalcolonic emptying in patients with carcinoid diarrhoea confirms thepotential role of a 5HT₃ mechanism in this disorder. Dosesof alosetron higher than 2.0 mg twice daily will be required forsymptomatic benefit in carcinoid diarrhoea.

Keywords:carcinoid diarrhoea; alosetron; serotoninergicagents; antagonist; colonic transit

     

Pathophysiological study of diarrhoea in a patient with medullary thyroid carcinoma. Evidence against a secretory mechanism and for the role of shortened colonic transit time.

Intubation techniques and scintigraphic studies were used to determine the origin and mechanism of diarrhoea in a patient with medullary thyroid carcinoma, high plasma immunoreactive calcitonin and normal circulating serotonin, substance P and prostaglandins E2 and F2 alpha. Normal function of the small intestine was found for the following: (a) absorption tests; (b) water and electrolyte absorption in the proximal jejunum; (c) 24 hour flow rate and composition of fluid entering the colon and (d) gastric emptying rate and small intestinal progression of a normal meal. By contrast, colonic function was markedly impaired in three ways: (a) water absorption was decreased by half; (b) as the main excreted solutes were organic acids, a large electrolyte gap was recorded in faecal water, and (c) colonic transit time of the meal marker was very short, and was in agreement with the rapid transit of ingested radioopaque markers. These data strongly suggest that decreased absorption in the colon secondary to a motor disturbance is the main mechanism of diarrhoea in this case of medullary thyroid carcinoma, while calcitonin induced small intestinal fluid secretion suggested earlier is either non-existent, or only of minor importance.     

Beneficial microbes: health or hazard?

Normal microbial flora support the health of the host by diverse mechanisms. When antibiotics, stress, disease or medications disrupt normal microflora, the ability to ward off infection by pathogens is compromised. The use of beneficial microbes (also known as biotherapeutic agents, probiotics, synbiotics) has been shown to be an effective therapeutic agent for some diseases. Various types of diarrhoea (antibiotic-associated diarrhoea, Clostridium difficile disease, traveller's diarrhoea) are most responsive to these beneficial microbes. Serious risks associated with these microbes are largely theoretical at this point, but the risks need to be studied as the use of these beneficial microbes increases in popularity. Beneficial microbes are living organisms used as therapeutic agents to restore the health of the host in times when normal microflora have been disturbed. The efficacy to prevent or treat diarrhoea has been documented in multiple large, placebo-controlled, blinded clinical trials with only a few of these beneficial microbes. Risks of these beneficial microbes are limited, but potential risks have not been extensively studied in large numbers of patients.     

The role of fat and bile acid malabsorption in diarrhoea of coeliac disease

The contribution of various factors to diarrhoea in coeliac disease (CD) was evaluated by measuring jejunal villous height, faecal masses, faecal fat, and faecal bile acids in 8 healthy subjects and in 37 consecutive patients before and during a gluten-free diet (GFD) and while receiving cholestyramine. Jejunal villous height was inversely correlated with faecal fat but not with faecal mass or faecal bile acids. A strong positive correlation was found between faecal fat and faecal mass and between the respective changes caused by GFD in these variables, whereas the correlations between faecal bile acids and faecal volume or between these changes caused by GFD were weak or nonsignificant. The cholestyramine treatment enhanced faecal bile acid and fat excretions and increased faecal volume without a significant effect on faecal solids or on the frequency of bowel movements, which in turn was significantly reduced by GFD. Thus, the present results show that the impaired fat absorption owing to mucosal damage of the upper small intestine markedly contributes to faecal volume and the frequency of bowel movements in CD and may be an important factor responsible for diarrhoea in coeliac patients, whereas no evidence was obtained for bile acid diarrhoea in CD.     

Gastrointestinal function in chronic radiation enteritis--effects of loperamide-N-oxide.

The effects of loperamide-N-oxide, a new peripheral opiate agonist precursor, on gastrointestinal function were evaluated in 18 patients with diarrhoea caused by chronic radiation enteritis. Each patient was given, in double-blind randomised order, loperamide-N-oxide (3 mg orally twice daily) and placebo for 14 days, separated by a washout period of 14 days. Gastrointestinal symptoms; absorption of bile acid, vitamin B12, lactose, and fat; gastric emptying; small intestinal and whole gut transit; and intestinal permeability were measured during placebo and loperamide-N-oxide phases. Data were compared with those obtained in 18 normal subjects. In the patients, in addition to an increased frequency of bowel actions (p < 0.001), there was reduced bile acid absorption, (p < 0.001) a higher prevalence of lactose malabsorption (p < 0.05) associated with a reduced dietary intake of dairy products (p < 0.02), and faster small intestinal (p < 0.001) and whole gut transit (p < 0.05) when compared with the normal subjects. There was no significant difference in gastric emptying between the two groups. Treatment with loperamide-N-oxide was associated with a reduced frequency of bowel actions (p < 0.001), slower small intestinal (p < 0.001), and total gut transit (p < 0.01), more rapid gastric emptying (p < 0.01), improved absorption of bile acid (p < 0.01), and increased permeability to 51Cr EDTA (p < 0.01). These observations indicate that: (1) diarrhoea caused by chronic radiation enteritis is associated with more rapid intestinal transit and a high prevalence of bile acid and lactose malabsorption, and (2) loperamide-N-oxide slows small intestinal transit, increases bile acid absorption, and is effective in the treatment of diarrhoea associated with chronic radiation enteritis.