R. H. Dowling

Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly

Small bowel bacterial overgrowth secondary to drug‐induced hypochlorhydria may be of particular importance in the elderly, in whom anti‐ulcer drugs are commonly prescribed and the consequences of malabsorption may be severe.

Review: pathogenesis of gallstones

The aim of this article is to review selected aspects of the pathogenesis of cholesterol‐rich, gall‐bladder stones (GBS) – with emphasis on recent developments in biliary cholesterol saturation, cholesterol microcrystal nucleation, statis within the gall‐bladder and, particularly, on the roles of intestinal transit and altered deoxycholic acid (DCA) metabolism, in GBS development.

Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones

BACKGROUND Treatment of acromegaly with octreotide increases the proportion of deoxycholic acid in, and the cholesterol saturation of, bile and induces the formation of gallstones. Prolongation of intestinal transit has been proposed as the mechanism for the increase in the proportion of deoxycholic acid in bile. AIMS To study the effects of octreotide on intestinal transit in acromegalic patients during octreotide treatment, and to examine the relation between intestinal transit and bile acid composition in fasting serum. METHODS Mouth to caecum and large bowel transit times, and the proportion of deoxycholic acid in fasting serum were measured in non-acromegalic controls, acromegalic patients untreated with octreotide, acromegalics on long term octreotide, and patients with simple constipation. Intestinal transit and the proportion of deoxycholic acid were compared in acromegalic patients before and during octreotide. RESULTS Acromegalics untreated with octreotide had longer mouth to caecum and large bowel transit times than controls. Intestinal transit was further prolonged by chronic octreotide treatment. There were significant linear relations between large bowel transit time and the proportion of deoxycholic acid in the total, conjugated, and unconjugated fractions of fasting serum. CONCLUSIONS These data support the hypothesis that, by prolonging large bowel transit, octreotide increases the proportion of deoxycholic acid in fasting serum (and, by implication, in bile) and thereby the risk of gallstone formation.

Bile acid metabolism by fresh human colonic contents: a comparison of caecal versus faecal samples

BACKGROUND Deoxycholic acid (DCA), implicated in the pathogenesis of gall stones and colorectal cancer, is mainly formed by bacterial deconjugation (cholylglycine hydrolase (CGH)) and 7α-dehydroxylation (7α-dehydroxylase (7α-DH)) of conjugated cholic acid (CA) in the caecum/proximal colon. Despite this, most previous studies of CGH and 7α-DH have been in faeces rather than in caecal contents. In bacteria, CA increases 7α-DH activity by substrate-enzyme induction but little is known about CA concentrations or CA/7α-DH induction in the human colon. AIMS AND METHODS Therefore, in fresh “faeces”, and in caecal aspirates obtained during colonoscopy from 20 patients, we: (i) compared the activities of CGH and 7α-DH, (ii) measured 7α-DH in patients with “low” and “high” percentages of DCA in fasting serum (less than and greater than the median), (iii) studied CA concentrations in the right and left halves of the colon, and examined the relationships between (iv) 7α-DH activity and CA concentration in caecal samples (evidence of substrate-enzyme induction), and (v) 7α-DH and per cent DCA in serum. RESULTS Although mean CGH activity in the proximal colon (18.3 (SEM 4.40) ×10−2 U/mg protein) was comparable with that in “faeces” (16.0 (4.10) ×10− 2 U/mg protein) , mean 7α-DH in the caecum (8.54 (1.08) ×10-4 U/mg protein) was higher (p<0.05) than that in the left colon (5.72 (0.85) ×10-4 U/mg protein). At both sites, 7α-DH was significantly greater in the “high” than in the “low” serum DCA subgroups. CA concentrations in the right colon (0.94 (0.08) μmol/ml) were higher than those in the left (0.09 (0.03) μmol/ml; p<0.001) while in the caecum (but not in the faeces) there was a weak (r=0.58) but significant (p<0.005) linear relationship between 7α-DH and CA concentration. At both sites, 7α-DH was linearly related (p<0.005) to per cent DCA in serum. INTERPRETATION/SUMMARY These results: (i) confirm that there are marked regional differences in bile acid metabolism between the right and left halves of the colon, (ii) suggest that caecal and faecal 7α-DH influence per cent DCA in serum (and, by inference, in bile), and (iii) show that the substrate CA induces the enzyme 7α-DH in the caecum.

Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones.

BACKGROUND--Octreotide treatment of acromegalic patients increases the % deoxycholic acid conjugates and the cholesterol saturation of gall bladder bile, and induces gall stone formation. AIMS--To study the roles of gall bladder emptying and intestinal transit in these phenomena. METHODS AND PATIENTS--Gall bladder emptying and mouth to caecum transit was measured in (a) control subjects and acromegalic patients given saline or 50 micrograms of octreotide, and (b) acromegalic patients taking long term octreotide. In the second group, large bowel transit was also measured. RESULTS--A single dose of octreotide inhibited meal stimulated gall bladder emptying, the ejection fraction falling from mean (SEM) 66.0 (2.3)% to 7.0 (5.3)% in controls (p < 0.001); from 72.5 (2.1) to 16.6 (5.1)% in untreated acromegalic patients (p < 0.001), and to 30.4 (9.5)% in acromegalic patients taking long term octreotide (p < 0.001 v untreated acromegalic group). Octreotide prolonged mouth to caecum transit time, from 112 (15) min to 237 (13) min in controls (p < 0.001), from 170 (13) min to 282 (11) min in untreated acromegalic patients (p < 0.001), and to 247 (10) min in acromegalic patients taking long term octreotide (p < 0.001 v untreated acromegalic patients). The mean large bowel transit in octreotide untreated compared with treated acromegalic patients remained unchanged (40 (6) h v 47 (6) h). CONCLUSIONS--Prolongation of intestinal transit and impaired gall bladder emptying may contribute to lithogenic changes in bile composition and gall stone formation in patients receiving long term octreotide.

Bile composition in inflammatory bowel disease: ileal disease and colectomy, but not colitis, induce lithogenic bile

Background : Inflammatory bowel disease is a risk factor for gall‐bladder stones, but there is controversy about the composition of these stones and whether such patients develop lithogenic bile.

Gall stone recurrence and its prevention: the British/Belgian Gall Stone Study Group's post-dissolution trial.

The British/Belgian Gall Stone Study Group (BBGSG) post-dissolution trial was a prospective, multicentre, randomised, double blind trial of: (i) low dose ursodeoxycholic acid, (ii) placebo, and (iii) a high fibre, low refined carbohydrate diet in the prevention of gall stone recurrence in patients with complete gall stone dissolution. Further aims included establishing the timing and frequency of recurrence and its association with biliary symptoms, a comparison of the sensitivity of ultrasonography v oral cholecystectography in detecting recurrent stones, and a search for risk factors predicting recurrence. Ninety three patients entered the study, and 82 were followed up for up to five years (mean (SEM) 28 (1.5) months) with six monthly ultrasonography and yearly oral cholecystectography. There were 21 recurrences (26 by oral cholecystectography or ultrasonography, or both), only two of which were symptomatic, which were detected between 12 and 42 months after trial entry. This corresponded to an actuarial recurrence rate of 33.9 (7.0%) by lifetable analysis at 42 months and subsequently. There were four recurrences in the ursodeoxycholic acid, six in the placebo, and 11 in the diet groups, corresponding to 21.9 (9.9)%, 27.4 (10.1)%, and 45.8 (12.4)% respectively at 42 months by lifetable analysis (NS). Variables including age, obesity, menopausal state, pregnancy, and oestrogen containing drugs were not shown to affect recurrence rate. Men had more frequent recurrence than women (NS). Patients who had had multiple stones experienced more recurrences than did those with single stones (NS). Recurrence did not occur in patients who took non-steroidal anti-inflammatory drugs (NSAIDs) (p < 0.02). The stone free interval between stone dissolution and trial entry proved to be important--those stone free > nine months had a recurrence rate of only 12.7 (6.0)% at 42 months compared with 55.4 (12.5)% in those stone free < nine months (p < 0.01). There was imbalance between the ursodeoxycholic acid and placebo groups for this factor, and after applying a statistical correction, the adjusted recurrence rate in the ursodeoxycholic acid group was 15% compared with 30% in both placebo and diet groups (NS). These data suggest that after medical dissolution, the risk of gall stone recurrence is not reduced by a high fibre, low refined carbohydrate diet: it may be lowered, but not abolished, by low dose ursodeoxycholic acid.

Role of intestinal transit in the pathogenesis of gallbladder stones

Increasing evidence implicates prolonged intestinal transit (slow transit constipation) in the pathogenesis of conventional gallbladder stones (GBS), and that of gallstones induced by long term octreotide (OT) treatment. Both groups of GBS patients have multiple abnormalities in the lipid composition and physical chemistry of their gallbladder bile-associated with, and possibly due to, an increased proportion of deoxycholic acid (DCA) (percentage of total bile acids). In turn, this increase in the percentage of DCA seems to be a consequence of prolonged colonic transit. Thus, in acromegalic patients OT treatment significantly prolongs large bowel transit time (LBTT) and leads to an associated increase of the percentage of DCA in fasting serum (and, by implication, in gallbladder bile). LBTT is linearly related to the percentage of DCA in fasting serum and correlates significantly with DCA input (into the enterohepatic circulation) and DCA pool size. However, these adverse effects of OT can be overcome by the concomitant use of the prokinetic drug cisapride, which normalizes LBTT and prevents the rise in the percentage of serum DCA. Therefore, in OT-treated patients and other groups at high risk of developing stones, it may be possible to prevent GBS formation with the use of intestinal prokinetic drugs.

Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly

Background: Acromegalic patients have slow colonic transit, increased rates of deoxycholic acid formation, and an increased prevalence of cholesterol gall stones, especially during long term octreotide treatment. However, the effects of this prolonged large bowel transit time on the numbers of faecal anaerobes and the activities of the enzyme systems which biotransform conjugated cholic acid into unconjugated deoxycholic acid (cholylglycine hydrolase and 7α-dehydroxylase) are unknown. Methods: Therefore, in 10 non-acromegalic controls, 11 acromegalic patients not treated with octreotide, and 11 acromegalics on long term (8–48 months) octreotide (100–200 μg three times daily subcutaneously), we measured large bowel transit time and, in freshly voided faeces, the activities of the two bile acid metabolising enzymes, and related the results to the proportion of deoxycholic acid in fasting serum. Moreover, in patients with acromegaly, we measured quantitative bacteriology in faeces. Results: Mean large bowel transit time in acromegalics not treated with octreotide (35 (SEM 6.5) hours) was 66% longer than that in non-acromegalic controls (21 (3.1) hours; NS) and became further prolonged during octreotide treatment (48 (6.6) hours; p<0.001). These octreotide induced changes in transit were associated, in acromegalic patients, with more total (15.0 (2.5) v 6.3 (1.3)×109 colony forming units (cfu)/g; p<0.05) and Gram positive (6.3 (2.3) v 3.2 (1.0)×109 cfu/g; p<0.05) faecal anaerobes. Mean faecal cholylglycine hydrolase activity in the long term octreotide group (22.0 (6.0)×10−2 U/mg protein) was 138% greater than that in non-acromegalic controls (12.0 (6.0)×10−2; p<0.01). Similarly, mean 7α-dehydroxylase activity in octreotide treated acromegalics (11.1 (1.18)×10−4 U/mg protein) was 78% greater than that in patients not receiving long term octreotide (6.3 (0.5)×10−4; p<0.001). The mean proportion of deoxycholic acid in fasting serum also increased from 18.0 (2.88)% in the untreated group to 29.6 (2.3)% during long term octreotide (p<0.05). There were significant linear relationships between large bowel transit time and: (i) faecal 7α-dehydroxylase activity; and (ii) the proportion of deoxycholic acid in fasting serum and between 7α-dehydroxylase activity and the proportion of deoxycholic acid in serum. Summary/interpretation: These data suggest that increased deoxycholic acid formation seen in acromegalics during octreotide treatment is due not only to the greater numbers of faecal anaerobes but also to increased activity of the rate limiting enzyme pathway (7α-dehydroxylation) converting cholic acid to deoxycholic acid.

Longterm pancreaticobiliary diversion stimulates hyperplastic and adenomatous nodules in the rat pancreas: a new model for spontaneous tumour formation.

A model for spontaneous tumour formation in the rat pancreas is described that requires neither cocarcinogens nor dietary manipulation. Short term hypercholecystokininaemia, when induced by raw soya flour feeding, induces benign and malignant tumours of the rat pancreas. Pancreaticobiliary diversion (PBD) results in hypercholecystokininaemia and in the short term, pancreatic hyperplasia. Longterm PBD was done to establish whether hypercholecystokininaemia thus produced would also lead to pancreatic neoplasia. After a period of 16-21 months hyperplastic and adenomatous nodules, one of the latter showing carcinoma in situ, were found in PBD rats but not in sham operated control rats.