Bile Salt Reabsorption Research Articles

Bilirubin cycles enterohepatically after ileal resection in the rat

BACKGROUND & AIMS: Patients with ileal disease, resection, or bypass are at increased risk of developing pigment gallstones, but the pathophysiological mechanisms are unknown. The aim of this study was to test the hypothesis that ileectomy induces enterohepatic cycling of bilirubin. METHODS: Ileectomy or sham operation was performed in adult male Sprague-Dawley rats with the following control procedures: no operation, ileal transection, proximal or distal jejunectomy, ileocolonic transposition, and ileocecectomy. Bilirubin and bile salt secretion rates were measured after bile duct cannulation performed 3- 11 days after intestinal surgery. Also measured were bilirubin and bile salt concentrations in the colon as well as indices of hemolysis in blood. RESULTS: Compared with controls, bilirubin secretion rates were increased significantly 3-5 days after ileectomy, distal jejunectomy, ileocolonic transposition, and ileocecectomy, with no hemolysis occurring. Bile salt secretion rates also increased significantly after ileectomy but decreased markedly with prevention of coprophagy, whereas bilirubin secretion rates remained elevated. By 8-11 days after surgery, intestinal adaptation normalized bile salt reabsorption, and hypersecretion of bilirubin was abolished. Colonic levels of unconjugated bilirubin and bile salts were increased fivefold and eightfold respectively in ileectomized animals, but unconjugated bilirubin levels remained normal in bile. CONCLUSIONS: These results are consistent with the hypothesis that enterohepatic cycling of bilirubin occurs with bile salt malabsorption. (Gastroenterology 1996 Jun;110(6):1945-57)

Description and Simulation of a Multiple Mixing Tank Model To Predict the Effect of Bile Séquestrants on Bile Salt Excretion

A nonlinear, multicompartment mixing tank model based on human physiologic parameters from the literature and in vitro bile salt sequestrant binding parameters was integrated numerically to simulate bile salt excretion. The model focuses on the transit of bile salts and resin, bile salt binding, and bile salt reabsorption as a means of gaining insight into the functioning of bile sequestrants in the gastrointestinal tract and the effect of reabsorption of bile salts on the sequestering process. The series of compartments through the ileal region were tested over a range of parameter values, and the results were compared with bile salt output from ileostomy patient data to validate the model without resin. In simulations incorporating resin with a reversible binding scheme, fecal bile salt output was 2.37 (±0.6) x 10˜3 mol/day compared with 2.64 (±1.1) x 10˜3 mol/day for human data. Assuming irreversible bile salt binding resulted in predictions of fecal bile salt excretion greater than three times physiologic values. The results of these simulations support the hypothesis that the lack of efficacy of bile sequestrants is due to the displacement of bound bile salts from the sequestrant as a consequence of anion competition and bile salt reabsorption. Gastric emptying effects and the timing of resin doses have also been investigated with the model.

Equilibrium and kinetic factors influencing bile sequestrant efficacy.

In vitro bile salt binding equilibria and kinetic studies were performed with cholestyramine to determine how these factors influence bile sequestrant efficacy in vivo. Chloride ion at physiologic concentrations caused more than a twofold reduction in glycocholate (GCH) binding, compared to binding in the absence of salt, over a range of GCH concentrations and was also observed to displace bound GCH. In addition, chloride ion displaced from cholestyramine as a result of bile salt binding was measured using a chloride selective electrode, and the results show that bile salt binding is due to ion exchange. Comparison of the results of the equilibrium binding experiments to human data shows that the effect of anion binding competition alone cannot account for the lack of efficacy of cholestyramine. Consideration of other effects, such as additional binding competition or poor availability for binding, based on data from the literature, shows that adequate bile salt binding potential exists and that these interferences are not major factors influencing resin efficacy. In kinetic studies, both binding uptake of GCH and displacement of GCH from cholestyramine by chloride ion were relatively rapid, indicating that cholestyramine should equilibrate rapidly with bile salts in the GI tract. Based on these findings, it is suggested that the low efficacy of cholestyramine is a result mainly of its relatively poor ability to prevent bile salt reabsorption in the ileum.

Nutritional and Gastrointestinal Complications of the Use of Bowel Segments in the Lower Urinary Tract

Almost all segments of the gastrointestinal tract have been used as urinary tract substitutes. The specific nutritional and gastrointestinal complications depend on the particular portion of bowel that is removed from the alimentary tract. The use of stomach theoretically may predispose the patient to hypergastrinemia and peptic ulcer disease, hypocalcemia, and iron deficiency or megaloblastic anemia. Resection of a large amount of jejunum causes malabsorption. Limited use of colon segments usually is well tolerated, but loss of large parts of the colon directly decreases available absorptive area, resulting in diarrhea. Resection of the ileum and ileocecal valve can lead to several disease states. One is mixed secretory-osmotic diarrhea. Decreased ileal reabsorption of bile salts results in fat malabsorption and steatorrhea. The presentation of increased amounts of bile salts and fatty acids to the colon decreases water absorption and stimulates active chloride and water secretion, producing a cholera-like high-volume secretory diarrhea. The loss of the ileocecal valve and ileum segment accelerates intestinal transit time, which does not allow for complete digestion and absorption of food. Water and electrolytes remain associated with undigested food particles and may overwhelm the absorptive capacity of the colon, resulting in an osmotic diarrhea. A second problem is vitamin B12 deficiency. Surgical reduction of sites in the terminal ileum for active and exclusive uptake of vitamin B12 might lead to hypovitaminosis. If this is unrecognized, patients may develop irreversible neurologic injury. A third problem is cholelithiasis. Derangements in bile salt metabolism can occur when as little as 10 cm of ileum is resected, and the propensity to form gallstones is increased. Pigment gallstones appear to be the predominant stone associated with ileal resections. The fourth possible problem is urolithiasis, the etiology of which is multifactorial in patients with ileal resections. With decreased availability of bile salts, fat malabsorption occurs. Fatty acids bind with calcium and magnesium to form soaps, resulting in increased levels of free oxalate available for absorption. Moreover, fatty acids directly increase colonic permeability to oxalate.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in plasma apolipoproteins A-I, A-II, and B, and lipoprotein cholesterol after jejunoileal bypass

In view of the role of the small intestine in lipoprotein synthesis and bile salt reabsorption, we have determined plasma lipid fractions and apolipoproteins A-I, A-II, and B at regular intervals in 26 patients who underwent jejunoileal bypass surgery for morbid obesity. After surgery, no change in plasma triglycerides was noted, but there was a prompt and significant fall in total plasma cholesterol and low density lipoprotein cholesterol, which persisted beyond 2 yr. Plasma apolipoprotein B levels did not fall concurrently, and hence the protein/lipid composition of low density lipoprotein was permanently altered by the surgery. Levels of high density Jipoprotein cholesterol were low before bypass surgery, decreased after surgery, and rose thereafter toward the normal range. Similar changes in apolipoprotein A-I and A-II values were noted. These postoperative alterations in plasma lipid and apoprotein levels demonstrate the importance of intestinal absorptive integrity in the regulation of lipoprotein metabolism.

Bile salt metabolism following jejunoileal bypass for morbid obesity.

Bile salt pool size and kinetics were evaluated in 8 morbidly obese women before and following jejunoileal bypass. The results indicate that following jejunoileal bypass pool sizes of both chenodeoxycholate and cholate decrease, turnover rates increase, and the rates of bile salt synthesis increase. Influenced by pool size, hepatic synthesis and the degree of malabsorption, the daily bile salt loss may actually decrease in time. Chenodeoxycholate is more efficiently absorbed than cholate in both the preoperative and postoperative states. In spite of greater cholate synthetic capabilities, in this malabsorptive state the chenodeoxycholate pool decreases less than the cholate pool. Although all patients received an identical surgical procedure, the effect on bile salt kinetics and pool sizes varied in these patients. Since some of the postoperative complications may be related to the degree of interference with bile salt metabolism, the individual patient's capacity for increased hepatic synthesis of bile salts and increased reabsorption of bile salts from the remaining small bowel may vary the clinical postoperative course.

Postprandial concentrations of free and conjugated bile acids down the length of the normal human small intestine.

Small intestinal samples were obtained by intubation from multiple sites along the small intestine in 11 subjects with no known gastrointestinal disease eating a normal diet and at laparotomy in a further three subjects. Free (unconjugated) bile acids were consistently demonstrated in ileal samples, and occasionally in lower jejunal samples, by thin-layer chromatography, supplemented in some cases by gas/liquid chromatography and by infrared spectroscopy. The free bile acid concentration, measured enzymically following thin-layer chromatography, reached a maximum (1 mM) in the lower ileum, where it represented half the total bile acid concentration. Following ampicillin, the concentration of free bile acids decreased markedly, suggesting that they resulted from bacterial deconjugation; at the same time the total bile acid concentration increased, suggesting impaired absorption due to the reduced concentration of the more rapidly absorbed free bile acids. Our results indicate that the presence of free bile acids in lower jejunal and ileal samples is a normal finding, and cannot be taken as evidence of abnormal bacterial overgrowth. They also suggest that bacterial deconjugation at these sites may be a factor contributing to the remarkable efficiency of bile salt reabsorption.

The increased rate of loss, and non-exponential excretion of bile salts in patients with tropical sprue and ileoctomy.

Summary: Cholic acid-carboxy/14C was administered to five control subjects, seven patients with tropical sprue and two patients with ileal resection and the daily excretion of the label in the faeces measured for seven to 13 days. Contrary to previous assumptions, the excretion was not always exponential. The practice of calculating decay constants from faecal excretion studies is therefore not valid. Four out of seven patients with sprue had an increased rate of excretion of the label, which in two subjects was similar to that of the patients with ileal resection. This indicates defective reabsorption of bile salts and may contribute to the pathogenesis of the steatorrhoea of tropical sprue.

Ischemic heart disease and dietary fiber

Data has been produced to support a hypothesis that high consumption of natural starchy carbohydrates, taken with their full complement of fiber, is protective against hyperlipidemia and IHD. Experiments in animals and man may be interpreted to support a suggestion that dietary fiber decreases the reabsorption of bile salts, increases fecal excretion, and reduces hyperlipidemia.

Effect of cholestyramine on endotoxin toxicity and absorption.

Since there is evidence that cholestyramine improves diarrheal states where failure of bile salt reabsorption would not appear significant, a study was undertaken to examine the effect of this resin on the toxicity and absorption of bacterial endotoxin. Both the toxicity of intraperitoneal injections of a cholestyramine-endotoxin suspension, and the absorption of the suspension through everted gut sacs was compared with a similar Dowex I-X8 suspension in rats. The results show that cholestyramine significantly reduces the toxicity of endotoxin when placed in the peritoneal cavity, and that it effectively inhibits the passage of51Cr labeled endotoxin through the intestinal wall.

Metabolism and transport of bile salts in the intestine

A specific sodium-dependent active transport system for conjugated and unconjugated bile salts is located in the distal half of the small intestine. Considerations of physical-chemical factors suggest that passive diffusion of unconjugated bile salts and possibly of glycine-conjugated bile salts also occurs throughout the small bowel and colon. Studies in animals designed to assess the extent of this passive absorption have been complicated by species variation. These considerations have prompted questions in normal man, dealing with the physiologic significance of the ileal transport system in the maintenance of enterohepatic bile salt circulation, and the relative importance of other intestinal sites and mechanisms for bile salt absorption. Hydrolysis of conjugated bile salts occurs regularly during their enterohepatic circulation in normal man, resulting in unconjugated primary and secondary bile salts that can be absorbed by passive processes in regions other than the ileum. The site and extent of intestinal absorption of unconjugated bile salts is dependent upon the presence of micoorganisms capable of deconjugating bile salts and a luminal milieu compatible with these enzymatic alterations. Present evidence indicates that such microorganisms exist chiefly in the colon and to a lesser extent in the terminal ileum of normal man. It is likely that the major increment of the daily unconjugated bile salt reabsorption occurs via passive absorption in the colon. The kinetics of this absorptive system(s) are unknown, and quantification of the daily traffic of unconjugated bile salts is quite complex. However, from investigations described in detail in the text, an approximation of 15 per cent of the daily circulating bile salt seems reasonable. Despite these uncertainties, it is clear that the major site of bile salt reabsorption in normal man is via ileal transport of conjugated bile salts. The efficiency of the intestinal bile salt transport systems in the maintenance of their enterohepatic circulation is essential to the accomplishment of several functions of bile salts in the intestinal lumen. These functions include participation in the hydrolysis of triglycerides, solubilization of the products of pancreatic lipolysis, and the well documented function of bile salts in the absorption of lipid soluble vitamins and cholesterol.

Effects of controlled interruption of the enterohepatic circulation of bile salts by biliary diversion and by ileal resection on bile salt secretion, synthesis, and pool size in the rhesus monkey.

The effects of controlled interruption of the enterohepatic circulation (EHC) of bile salts by biliary diversion on bile volume, bile salt secretion and synthesis rates, bile salt pool size, and the relationship to fecal fat excretion were studied in 16 rhesus monkeys. Bile from a chronic bile fistula was returned to the intestine through an electronic stream-splitter which, by diverting different percentages of bile to a collecting system, provided graded and controlled interruption of the EHC. The increase in hepatic bile salt synthesis in response to interruption of the EHC was limited and reached a maximum rate at 20% interruption of the EHC. Up to this level of biliary diversion, the increased hepatic synthesis compensated for bile salt loss so that bile salt secretion and pool size were maintained at normal levels. With diversion of 33% or more, there was no further increase in hepatic bile salt synthesis to compensate for external loss, and as a result there was diminished bile salt secretion, a reduction in bile salt pool size, and steatorrhea was observed. The effects of interruption of the EHC by the streamsplitter were compared with those produced by resection of the distal one-third or two-thirds of small bowel. While ileal resection appreciably reduced bile salt secretion, the EHC was by no means abolished. Bile salt reabsorption from the residual intestine was greater after one-third than after two-thirds small bowel resection. These observations suggest that jejunal reabsorption of bile salts occurs and may well contribute to the normal EHC.