Changes in the absorption of bile acids after total colectomy in patients with an ileostomy or pouch-anal anastomosis

Bile acid absorption was investigated using⁷⁵Se Taurohomocholate (SeHCAT) in controls and patients who had undergone total colectomy with either conventional ileostomy or pouch-anal anastomosis for ulcerative colitis or adenomatous polyposis. Whole-body retention of SeHCAT after 168 hours was greater in the controls than the patients who had undergone colectomy (P<.05). Retention of SeHCAT did not differ significantly between patients with an ileostomy and patients with pouch-anal anastomosis, but patients with an ileostomy and ileal resection of more than 20 cm retained less SeHCAT than patients with a pouch-anal anastomosis (P<.01). Analysis of fecal bile acids from ileostomies and pouches showed that bacterial metabolism of primary conjugated bile acids was greater in patients with a pouch. It was concluded that bile acid absorption was not significantly impaired by construction of a pouch compared with conventional ileostomy but bacterial metabolism of bile acids was greater in the pouches. Supported by a grant from the Yorkshire Regional Health Authority and was presented in part at the St. Mark's Hospital 150th Anniversary International Conference, May 29 to 31, 1985.     

Excretion, deconjugation, and absorption of bile acids after colectomy for ulcerative colitis. Comparative studies in patients with conventional ileostomy and patients with Kock's reservoir

Bile acid metabolism was studied in 26 patients with a continent ileostomy (Kock's reservoir) and 32 patients with conventional ileostomy. All had been colectomized for ulcerative colitis. In patients with a continent ileostomy the 14C-glycocholic acid breath test showed increased pulmonary 14CO2 excretion as evidence of abnormal bacterial deconjugation of bile acids and increased faecal 14C excretion as evidence of bile acid malabsorption. Faecal bile acid excretion, determined chemically, and, by inference, bile acid synthesis were only moderately increased (median, 1.8 mmol/day). The disturbance of bile acid metabolism was similar to that found in 32 patients with conventional ileostomy, but more pronounced with higher faecal 14C. A significant difference was that no abnormal bacterial deconjugation took place in patients with conventional ileostomy, since their pulmonary 14CO2 excretion was subnormal. Stool mass was almost identical in the two groups, with median values of 665 and 663 g/day, respectively. Faecal fat excretion was normal in most in both groups. Thus bile acid metabolism is slightly more disturbed in patients with a continent ileostomy than in patients with conventional ileostomy. The resulting malabsorption was modest in both groups.     

Ileal excretion and bacterial modification of bile acids and cholesterol in patients with continent ileostomy.

Bile acid (acidic sterol) and neutral steroid excretion were determined in 15 patients, five with conventional ileostomy, five with continent ileostomy, and five with continent ileostomy and an ileal resection. Acidic sterol losses were normal in conventional ileostomy patients and not significantly increased in those with continent ileostomy alone. Bile acid excretion rates were significantly increased in patients with a continent ileostomy and an ileal resection. Neutral steroid excretion was similar in all groups and not different from normal. Deoxycholic acid was not detected in ileal effluent of patients with conventional ileostomy and less than 2% of neutral steroid excreted was in the form of bacterial metabolites of cholesterol. The same was true of six of the 10 patients with continent ileostomies; in the other four patients at least 10% of acidic or neutral steroids were excreted as secondary bile acids or as a coprostanol. Modification of steroids was not related to ileal resection. Continent ileostomy was associated with a significant increase in percentage water content and a reduction in the pH of ileal effluent.     

Fasting and postprandial ileal function in adapted ileostomates and normal subjects.

The output of 11 established ileostomies was compared with ileal flow measured by intestinal perfusion in five normal volunteers when fasting and during the ileal passage of test meals containing different proportions of medium chain triglyceride and long chain triglyceride. Oroileal transit of the meal was the same in the two groups, but ileostomy output was less than ileal flow of normal persons both fasting (16.3 +/- 10.9 vs 62.4 +/- 24.7 ml/h, p less than 0.001) and after the long chain triglyceride rich meal (35.4 27.0 vs 96.1 +/- 20.2 ml/h, p less than 0.001). After ingestion of the medium chain triglyceride rich meal, ideal flow failed to increase in normal subjects but in ileostomates the changes in flow after medium chain triglyceride and long chain triglyceride rich meals were not significantly different. The fasting ileostomy effluent composition differed from that of normal fasting ileal content in having a higher concentration of potassium (8.0 +/- 2.9 vs 4.7 +/- 0.6 mmol/1, p less than 0.04) and a higher osmolality (353 +/- 63 vs 287 +/- 5 mosm/kg, p less than 0.05). Sodium concentration tended to be lower in ileostomy effluent, but in contrast to previous reports, ileostomy effluent was of consistently alkaline pH (7.2 +/- 0.3). These concentrations were not significantly altered by either type of meal. The long chain triglyceride rich meal increased the ileal flow of bile acids in both normal subjects and ileostomates, whereas the medium chain triglyceride rich meal increased bile acid flow in ileostomates but not in normal subjects, possibly reflecting a different amount of the bile acids in the ileum of the ileostomate. In the adapted ileostomate, the low volume and high potassium concentration of fasting effluent suggest that sodium and water absorption are continuously stimulated by chronic salt depletion.     

Faecal excretion of intravenously injected 14C-cholic acid in patients with conventional ileostomy and in patients with continent ileostomy reservoir.

Bile salt absorption, as determined by the faecal excretion in i.v. injected 14C-cholic acid (FBS) was studied in 13 ileostomy patients before and after conversion to Kock's continent ileostomy reservoir. The result was compared with that obtained in 8 ileostomy patients in whom about 50 cm of the terminal ileum has also been removed. As compared with 16 healthy controls, FBS was moderately increased in the conventional ileostomy patients, but still within normal limits. After conversion to ileostomy reservoir all patients had pathological FBS, although less severe than in the ileostomy patients with ileal resection. Bacterial contamination probably contributes more than the structural mucosal changes to the bile malabsorption in the pouch, whereas reduced mucosal surface and short small-intestinal transit time are the main causes of malabsorption in ileostomy patients in whom an appreciable amount of the terminal ileum has been resected.     

Olsalazine does not increase the bile acid losses in subjects with a permanent ileostomy

Olsalazine is a novel compound presently under development for the treatment of ulcerative colitis. Olsalazine sometimes causes diarrhoea; one of the possible explanations could be an increased load of bile acids in the colon. Bile acid ileostomy output was therefore measured enzymatically and after oral administration of tauro-23-[75Se]selena-25-homocholic acid (SeHCAT) in eight subjects during intake of placebo or olsalazine. The bile acid output showed great individual variations during both treatment periods, but there was no indication that olsalazine interfered with bile acid handling in the terminal ileum.     

Bacterial contamination of the small bowel evaluated by breath tests, 75Se-labelled homocholic-tauro acid, and scanning electron microscopy

Eighty-one patients with diarrhoea due to suspected bacterial contamination of the small intestine were investigated with the bile acid breath test (BABT) and 75Se-labelled homocholic-tauro acid (SeHCAT). The impact of bile acid malabsorption due to dysfunction of the terminal ileum on BABT was evaluated. The group of patients with abnormal BABT, notably the 6-h accumulated value, showed a high frequency of reduced SeHCAT values (p less than 0.01), indicating that a reliable test for bile acid malabsorption is indispensable for interpreting the BABT in the investigation of small-intestinal bacterial overgrowth. The results of the 14C-D-xylose breath test were compared with the outcome of the combined SeHCAT-BABT in 44 patients. In contrast to previous findings no correlation between the two breath tests was found. On the contrary, a significant negative correlation was encountered (p less than 0.01) for patients in whom either breath test was abnormal. Scanning electron microscopy for demonstration of adherent microorganisms was included in the investigations. No correlations were found with the outcomes of the different breath tests. The effect of antibiotic treatment was evaluated with regard to symptoms and breath tests. The results of the investigation indicate that different tests are needed for the diagnosis of bacterial overgrowth of the small intestine, because of the different metabolic characteristics of the contaminating bacteria.     

Bile acid malabsorption in patients with an ileum reservoir with a long efferent leg to an anal anastomosis

Biliary metabolism in 11 patients with ileum reservoirs with anal anastomosis and a long efferent leg was studied. Eleven healthy persons served as controls. A significantly higher excretion of bile acids was found in the patients, but they seemed to have a normal cholic acid pool size. The bile acids excreted were cholic acid and chenodeoxycholic acid, the so-called primary bile acids, for more than 90%, whereas the normal controls mainly excreted secondary bile acids (deoxycholic acid and lithocholic acid). Fat excretion was generally not increased in the group but was above normal in two patients. Vitamin B12 absorption was subnormal in two patients and was not correlated to bile acid excretion. Bile acid excretion was not correlated to the weight of feces. The bacterial flora was more feces-like than would have been expected from a normal terminal ileum but was correlated neither to the bile acid excretion nor to the quantity of feces. We conclude that the patients showed dysfunction of the terminal ileum with regard to biliary acid absorption comparable to that found in patients with partial ileal resections.     

Comparison of 75SeHCAT retention half-life and fecal content of individual bile acids in patients with chronic diarrheal disorders

Measurement of the retention of 23-75Se-25-homotaurocholic acid (SeHCAT) has been suggested as a new test for ileal function. We investigated 31 patients with chronic diarrhea, 10 with ileal Crohn's disease and 21 with diarrhea but without ileal disease. The whole-body retention half-life of 1 mu Ci SeHCAT was determined and compared to the fecal content of total and individual bile acids. Patients with ileal disease had increased primary fecal bile acids (chenodeoxycholic acid: mean 6.95 mg/g dry weight, range 3.15-10.6 mg/g; cholic acid: mean 18.15 mg/g, range 10.3-33.9 mg/g) and a short SeHCAT retention (mean 11.9 h, range 2-24 h), whereas patients with intact ileum had normal fecal bile acids and a SeHCAT retention of 85.9 h (range 28-216 h). SeHCAT retention half-life differentiated well between patients with ileal disease and patients with normal ileum, thus indicating the SeHCAT test as a valid investigation method for detection of primary bile acid malabsorption in patients with chronic diarrhea and ileal dysfunction.     

Apparent selective bile acid malabsorption as a consequence of ileal exclusion: effects on bile acid, cholesterol, and lipoprotein metabolism.

A new model has been developed to characterise the effect of a standardised ileal exclusion on bile acid, cholesterol, and lipoprotein metabolism in humans. Twelve patients treated by colectomy and ileostomy for ulcerative colitis were studied on two occasions: firstly with a conventional ileostomy and then three months afterwards with an ileal pouch operation with an ileoanal anastomosis and a protective loop ileostomy, excluding on average 95 cm of the distal ileum. The ileostomy contents were collected during 96 hours and the excretion of bile acids and cholesterol was determined using gas chromatography-mass spectrometry. Fasting blood and duodenal bile samples were collected on two consecutive days. After the exclusion of the distal ileum, both cholic and chenodeoxycholic acid excretion in the ileostomy effluent increased four to five times without any change in cholesterol excretion. Serum concentrations of lathosterol (a marker of cholesterol biosynthesis) and 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) were increased several fold. Plasma concentrations of total VLDL triglycerides were also increased whereas the concentrations of total and LDL cholesterol, and apolipoprotein B were decreased. There were no changes in biliary lipid composition or cholesterol saturation of bile. The results show that the exclusion of about 95 cm of distal ileum causes malabsorption of bile acids but apparently not of cholesterol. The bile acid malabsorption leads to increased synthesis of both bile acids and cholesterol in the liver. It is suggested that bile acids can regulate cholesterol synthesis by a mechanism independent of the effect of bile acids on cholesterol absorption. The enhanced demand for cholesterol also leads to a decrease in plasma LDL cholesterol and apolipoprotein B concentrations. The malabsorption of bile acids did not affect biliary lipid composition or cholesterol saturations of VLDL triglycerides.     

The effect of the site of lesion and extent of resection on duodenal bile acid concentration and vitamin B12 absorption in Crohn's disease.

Duodenal bile acid concentration following a standard meal, glycine/taurine (G/T) ratio, vitamin B12 absorption, and faecal fat were determined in 79 patients with Crohn's disease. Intestinal resection had been made in 50 patients before the study, and no evidence of recurrence was present at the time of the study. Among 46 patients subjected to ileal resection of 10-180 cm, a reduced duodenal bile acid concentration and vitamin B12 malabsorption was almost invariably present when 50 cm or more of ileum had been removed. Patients with smaller resections and unoperated patients did not show a consistent pattern. Vitamin B12 absorption and duodenal bile acids were of equal value as indicators of ileal dysfunction with the exception that, in 10 ileostomy patients, duodenal bile acids were decreased in every case, but vitamin B12 absorption only when 80 cm of ileum or more had been resected. G/T-ratio was related to the extent of ileal resection-being elevated after large resections (80 cm or more)-but not to the presence of an abnormal flora. Faecal fat was much more elevated in ileostomy patients with large ileal resection (80 cm or more) than in unoperated patients and patients without an ileostomy.     

Clinical application of a selenium (75Se)-labelled bile acid for the investigation of terminal ileal function

With the introduction of a selenium bile acid SeHCAT (tauro-23-75Se-Selena-25 homocholic acid) a new and clinically valuable test for the functioning of the terminal ileum has been made available. Previous studies have shown that the test detects patients with bile acid malabsorption due to ileal disease. In this study SeHCAT retention was evaluated in nine patients with Crohn's disease and in seven healthy controls after intravenous administration of 0.15 MBq (4 muCi). A simple way of expressing the results is proposed. By using the calculated time required to eliminate 50% of the SeHCAT (WBR50), information is obtained as to the degree of terminal ileum malfunction regarding bile acid absorption. Accurate values seem to be achieved within 48 hours. As the SeHCAT is a gamma-ray emitter the dose retained could be measured by external counting. We suggest a practical design for the test using a simple scintillation spectro-photometer with a single detector in a low-background room. In patients and healthy controls the SeHCAT retention as calculated by WBR50 was 63 hrs (15-163) and 120 hrs (range 99-141), respectively. There was no overall relation between SeHCAT elimination and the intestinal transit time, although in the patient group a significant correlation was demonstrated, probably secondary to the impairment of the terminal ileum. A significant correlation was shown between the outcome of the test and the faecal excretion of total bile acids.     

New Insights into Bile Acid Malabsorption

Bile acid malabsorption occurs when there is impaired absorption of bile acids in the terminal ileum, so interrupting the normal enterohepatic circulation. The excess bile acids in the colon cause diarrhea, and treatment with bile acid sequestrants is beneficial. The condition can be diagnosed with difficulty by measuring fecal bile acids, or more easily by retention of selenohomocholyltaurine (SeHCAT), where this is available. Chronic diarrhea caused by primary bile acid diarrhea appears to be common, but is under-recognized where SeHCAT testing is not performed. Measuring excessive bile acid synthesis with 7α-hydroxy-4-cholesten-3-one may be an alternative means of diagnosis. It appears that there is no absorption defect in primary bile acid diarrhea but, instead, an overproduction of bile acids. Fibroblast growth factor 19 (FGF19) inhibits hepatic bile acid synthesis. Defective production of FGF19 from the ileum may be the cause of primary bile acid diarrhea.     

Comparison of maximal postprandial serum cholylglycine concentration with the retention of 75Se-homotaurocholic acid in ileal dysfunction

The retention of 75Se-homotaurocholic acid (75SeHCAT) was measured in 12 healthy controls and in 21 patients with Crohn's disease and compared with the maximum postprandial rise in the serum concentration of cholylglycine (CG) in order to detect bile acid malabsorption. The retention of 75SeHCAT was lowered in all patients with inflammation or resection of the terminal ileum over a length more than 20 cm. In 64% of these patients bile acid malabsorption could also be detected by the absence of a significant rise of the postprandial CG serum level but only if the loss of the ileal function exceeded 30 cm. Although less sensitive than the 75SeHCAT retention, the CG method is simpler to apply in terms of laboratory technology and does not involve exposure to radioactivity. The CG method appears to be of use to detect bile acid malabsorption in certain cases. In the case of negatively if still bile acid malabsorption is suspected more sensitive tests such as 75SeHCAT retention should be carried out to further evaluate bile acid malabsorption.     

Stagnant loop syndrome in patients with continent ileostomy (intra-abdominal ileal reservoir).

Intestinal absorption and bacteriology of the ileal contents were compared in seven patients with continent ileostomy and seven patients with conventional ileostomy. The absorption of vitamin B12 was reduced in five patients with continent ileostomy and subnormal in two patients with conventional ileostomy. Steatorrhoea was present in four patients with continent and one patient with conventional ileostomy. Increased concentrations of total anaerobic bacteria and Bacteroides were found in the ileum of the patients with continent ileostomy. After an oral dose of (1-14C) glycocholic acid there was no difference in the faecal excretion of radioactivity, whereas the 14CO2-expiration was increased in two patients with continent ileostomy. In four patients with continent ileostomy and malabsorption of B12, there was evidence of a stagnant loopsyndrome as oral lincomycin treatment resulted in increased absorption of B12 decreased excretion of faecal fat, and decreased concentrations of Bacteroides in the ileum.     

Bile acid malabsorption after intestinal bypass surgery for obesity. A comparison between jejunoileal shunt and biliointestinal bypass

Seventeen patients were operated on with intestinal shunts for morbid obesity, in eight a biliointestinal bypass (BI) was constructed and in the rest a conventional jejunoileal (JI)-shunt. The reduction in weight was similar in both groups, and so was malabsorption of fat, but the BI-group had significantly less bowel motions with less watery diarrhoea. Bile acid malabsorption was measured both chemically by estimating the total amount of faecal bile acids excreted, as well as indirectly by using a 75Se-labelled synthetic bile acid (SeHCAT). Both techniques revealed a substantial loss of bile acid after both types of operation, but patients with BI bypass surgery had significantly lower elimination time of the bile acid than those with JI-shunts. There was a significant negative correlation between SeHCAT retention and total faecal bile acids. However, some patients with low SeHCAT retention had normal or even reduced output of faecal bile acids. Estimation of faecal bile acids may display false negative results when the bile acid pool is decreased. The SeHCAT-test seems to be a better technique for measuring bile acid losses. The study suggests that BI bypass surgery for obesity seems to be advantageous over the JI shunt in reducing the postoperative loss of bile acids and choleretic diarrhoea, without influencing the weight loss.     

Direct measurement of first-pass ileal clearance of a bile acid in humans

The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%), implying a possible wide variation in recycling frequency per day.     

Ileal ecology after pouch-anal anastomosis or ileostomy. A study of mucosal morphology, fecal bacteriology, fecal volatile fatty acids, and their interrelationship

Ileal mucosal morphology, fecal bacteriology, fecal volatile fatty acids, and their interrelationships were studied in 15 patients with an ileal pouch-anal anastomosis and 14 patients with an ileostomy after proctocolectomy for ulcerative colitis. Pouch effluent, compared with ileostomy effluent, had a greater ratio of anaerobes to aerobes (p less than 0.05), and greater numbers of Bacteroides (p less than 0.01) and Bifidobacteria (p less than 0.05). Fecal volatile fatty acids, products of anaerobic bacterial fermentation, were also increased in pouch effluent compared with ileostomy effluent (propionate, p less than 0.05; butyrate, p less than 0.01). Mucosal change in the pouches showed no significant correlation with frequency of defecation, completeness of emptying, or pouch design, but the degree of villous atrophy was correlated with the number of Bacteroides (rs = 0.93, p less than 0.01) and with fecal butyrate (rs = 0.68, p less than 0.05). Fecal propionate was significantly correlated with the percentage of stool retained after defecation (rs = 0.82, p less than 0.01). These findings indicate that the bacterial ecology of ileal pouches has an important influence on the morphology of their mucosal lining.     

Kinetics for the synthetic bile acid 75selenohomocholic acid-taurine in humans: comparison with [14C]taurocholate

The "apparent" fractional turnover rate of the gamma-labeled bile acid analogue 75selenohomocholic acid-taurine (75SeHCAT) was assessed from decline in radioactivity over the gallbladder area on 4 successive days using a gamma-camera, and was compared in the same subjects with the fractional turnover rate of the corresponding natural bile acid, cholic acid-taurine, labeled with 14C ([14C]CAT) using the classical Lindstedt technique. Very similar results were obtained in 5 healthy individuals (coefficient of variation 4.8%, medians 0.35 and 0.34, respectively). By contrast, the fractional deconjugation rate assessed from zonal scanning of glycine- and taurine-conjugated bile acids on thin-layer chromatography was much less for 75SeHCAT than for [14C]CAT (0.02 and 0.13, respectively; p less than 0.05). The fractional rate for deconjugation plus dehydroxylation was also determined by zonal scanning, and gave lower values for 75SeHCAT than for [14C]CAT (0.02 and 0.12, respectively; p less than 0.05). There was a striking similarity between the fractional rate for deconjugation alone and that for deconjugation plus dehydroxylation for both bile acids in individual samples (r = 0.999, p less than 0.001), suggesting that these two processes might occur simultaneously and probably involve the same bacteria. We conclude that our scintiscanning technique provides an accurate, noninvasive method of measuring fractional turnover rate of a bile acid in humans, and that the finding that 75SeHCAT remains conjugated with taurine during enterohepatic recycling means that absorption should be specific for the ileal active transport site, thus rendering it an ideal substance for assessing ileal function.     

Idiopathic bile acid malabsorption--a review of clinical presentation, diagnosis, and response to treatment.

Between 1982 and 1989, the seven day retention of 75SeHCAT was measured in 181 patients with chronic diarrhoea that remained unexplained after full investigation. Altogether 121 of the 181 had a seven day 75SeHCAT retention greater than or equal to 15% and thus had no evidence of abnormal bile acid turnover. Twenty one had a seven day 75SeHCAT retention greater than or equal to 10% but less than 15%. Their clinical features were typical of the irritable bowel syndrome, and none of eight treated with cholestyramine showed symptomatic improvement. Sixteen patients had a seven day retention greater than or equal to 5% and less than 10%, six of whom had improved symptoms after treatment with bile acid chelating agents. The remaining 23 patients had a 75SeHCAT retention of less than 5% at seven days and responded to bile acid chelators. This group had a characteristic illness with intermittent watery diarrhoea, but no constitutional upset. It was not possible to distinguish the patients with bile acid malabsorption exclusively on the basis of the clinical symptoms and investigations, other than 75SeHCAT retention. We conclude that the measurement of 75SeHCAT retention is useful, appropriate, and necessary in patients with unexplained chronic diarrhoea.