Enterohepatic circulation of bile acids

Bile acids are reabsorbed along the whole small intestine, preferentially, however, by the distal ileum. Absorption seems to take place by different 

Taurine conjugates are not absorbed in the upper intestine of human subjects (31,32), the major transport taking place in the lower ileum by both an active mechanism and passive ionic diffusion. Glycine conjugates, particularly those of dihydroxy bile acids, on the other hand, are absorbed also in the jejunum by passive ionic diffusion (33). Negligible amounts of free bile acids are normally found in the upper small intestine (23), while deconjugation is known to occur in the lumen of the terminal ileum. Absorption of free bile acids appears to take place by both ionic and nonionic diffusion, the transport for dihydroxy bile acids being particularly rapid even in the upper intestine (33). 

Reabsorption of bile acids is very effective, so that only a small percentage escapes into the cecum. The rest returns via the portal circulation as conjugates [or as unconjugated bile salts if free bile acids were present in the gut lumen (34)] into the liver, thus completing the enterohepatic circulation. Before resecretion, free bile salts are conjugated in the liver with taurine and glycine. 

It has been calculated that the human bile salt pool, amounting to about 2-4 g (35-38), circulates two to three times during each meal or five to ten times daily (7). Thus, theoretically, 10-40 g of bile acids is secreted by the liver into the intestine daily. Almost the same amount is transported by the portal blood back to the liver, yet the serum bile acid concentration is normally low, indicating that the normal liver effectively extracts bile salts from the portal blood. In view of this relatively high bile acid load to the liver, it is understandable that disturbances in liver function can lead to an augmented bile acid concentration in the systemic circulation, though under these conditions bile acid secretion into the intestine is also reduced. 

Most of the bile acids which escape from the terminal ileum into the colon undergo under normal conditions a transformation to secondary bile acids via the action of colonic bacteria (1,4). The amount of primary bile acids in feces is thus negligible, if any, the mixture of fecal bile acids consisting of compounds with a wide range of polarity (38-41). However, in contrast to neutral sterols, bile acids are not degraded to any appreciable extent into undetectable metabolites during the intestinal passage (42). 

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M. C. Carey, in Enterohepatic Circulation of Bile Acids and Sterol Metabolism, G. Paumgartner, ed., MTP Press, Lancaster, Boston, 1984. 

Grundy SM, Ahrens EH, Jr., Salen G. Interruption of the enterohepatic circulation of bile acids in man comparative ef-... 

The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

Secondly, ileal resection disrupts enterohepatic circulation of bile acids due to loss of the ileal sodium-dependent bile acid transporter (ISBT) leading to... 

Another possible mechanism involves the effect of saponins on micelle formation. Saponins are known to alter the size or shape of micelles (Oakenfull, 1986 Oakenfull and Sidhu, 1983), an observation that is consistent with decreased bile acid absorption (Stark and Madar, 1993) and increased fecal bile acid excretion (Malinow et al., 1981 Nakamura et al.,1999). Saponins may also directly bind bile acids (Oakenfull and Sidhu, 1989), which would presumably interfere with micelle formation and decrease cholesterol absorption. Other studies have found that saponins decrease the absorption of fat-soluble vitamins (Jenkins and Atwal, 1994) and triglycerides (Han et al., 2002 Okuda and Han, 2001), indicating decreased micelle formation. However, direct evidence showing impaired micelle formation in vivo is lacking. Moreover, Harwood et al. (1993) reported no change in bile acid absorption or interruption of the enterohepatic circulation of bile acids in hamsters fed tiqueside, despite significant reductions in cholesterol absorption. 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

During anesthesia intestinal motility is dramatically reduced, which secondarily might influence the intestinal absorption of the candidate compound. Bile flow is relatively constant during the first 2 to 3 hours but declined during prolonged anesthesia (Fig. 1) due to the interruption of the enterohepatic circulation of bile acids. 

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing their re-absorption. In so doing, more endogenous cholesterol is directed to the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are excreted in the faeces. 

Enterohepatic circulation of bile acids 36 12.4.2 Enzyme adaptation 54... 

Figure 47-9 Enterohepatic circulation of bile acids. A, Normal circulation B, impaired circulation.

Dawson PA. Bile secretion and the enterohepatic circulation of bile acids. In Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran s gastrointestinal and liver disease, 7th ed. Philadelphia WB Saunders, 2002 1051-64. 

Hofmann AF. Chemistry and Enterohepatic Circulation of Bile-Acids. Hepatology 1984 4 S4-S14. 

Fig 5. Diagrammatic representation of the enterohepatic circulation of bile acids. 

Nearly all bile acids are choleretic agents that is, they increase bile flow when infused intravenously into various animal species. In all vertebrtae species examined, there is a close relationship between bile flow and the hepatic excretion rate of bile acids (B24). Acute interruption of the enterohepatic circulation of bile acids in man by diversion of bile flow causes the rate of bile secretion to decrease by about 50% (TIO). Thus, the excretion of bile acids from the liver is the major determinant of bile water and solute excretion, predominantly because of the osmotic activity of bile acids in bile. Some interesting studies in dogs have been performed with the bile salt taurodehydrocholate (taurine conjugate of 3,7,12-triketo-5fl-cholan-24-oic acid), which, for stereochemical reasons, cannot form micelles and should therefore have greater osmotic activity than other bile acids. At the same... 

Although research has shown that bile acids play an important role in liver and intestinal function, and that the metabolism or enterohepatic circulation of bile acids is altered in certain diseases, tests involving bile acids are uncommon in the clinical chemistry laboratory. This is probably because bile acid tests are not absolutely necessary for the diagnosis of any important or well-known disease and they are generally regarded as too specialized for routine use (H12). Thus, at present bile acid tests tend to be confined to gastroenterology units with research interests in bile acid metabolism. However, there is currently much interest in evaluating serum bile acid levels as a liver function test (H19) and bile acid tests have been developed to assess various aspects of intestinal function, as described below. 

Thus, in the normal intestine with an intact enterohepatic circulation of bile acids, it is the product of the maximum solubility of the various lipids and their respective passive permeability coefficients that primarily dictates the rates of uptake into the intestinal mucosa. Hence, over 100 g of medium- and long-chain-length fatty acids... 

The primary bile acids are defined as those formed from cholesterol in the liver. Secondary bile acids are those formed from the primary bile acids through the action of intestinal microorganisms during the enterohepatic circulation of bile acids. The secondary bile acids may be subjected to further structural modifications by liver enzymes. The main primary bile acids in most mammalian species are cholic acid and chenodeoxycholic acid.t Other... 

The enterohepatic circulation of bile acids is characterized by a large pool of bile acids (2,15,26) which cycles many times (probably six to ten) each day. The size of the pool is determined by the efficiency of intestinal absorption and by the rate of hepatic synthesis of bile acids from cholesterol (94). The efficiency of absorption is high—in health probably greater than 98 %— and the amount of bile acids not absorbed is balanced by hepatic synthesis (Fig. 17). Bile acids are excreted only in feces, and their nucleus is considered invulnerable to bacterial attack therefore, the measurement of fecal bile acids either by chemical estimation or isotope dilution techniques indicates hepatic synthesis (94). The pool size may be estimated directly by isotope dilution, and an indirect estimate of pool size can be obtained by measuring jejunal bile acid concentration during digestion of a test meal. 

Fig. 17. Schematic depiction of the enterohepatic circulation of bile acids in man. In the steady state, fecal excretion equals hepatic synthesis, and accordingly hepatic synthesis may be estimated from fecal bile acid excretion. The pool size may be estimated only by isotope dilution techniques, which also give the hepatic synthesis rate (94). The mass of bile acid secreted into the small intestine is equal to the pool multiplied by the number of cycles per day this cannot be estimated by any simple means in intact man at present. The diagram does not show the complexity of intestinal absorption of bile acids, which involves passive absorption of the glycine dihydroxy bile acids from the jejunum and active absorption of all conjugated bile acids from the ileum, as well as passive absorption of probably predominantly unconjugated bile acids from the colon.

The enterohepatic circulation of bile acids may be interrupted by biliary obstruction or biliary fistula the events occurring in fat digestion in the absence of bile acids have been discussed. Of more interest are the disturbances in bile acid and fat metabolism occurring when the enterohepatic circulation of bile acids is interrupted by ileal disease or resection. 

Fig. 18. Schematic depiction of the enterohepatic circulation of bile acids in patients with slight impairment in bile acid absorption. Decreased absorption causes increased hepatic synthesis, which restores the bile acid pool size to normal. Fat digestion is essentially normal, and fat malabsorption is not present. The increased passage of bile acids into the colon causes sodium and water secretion, manifested by diarrhea which is responsive to cholestyramine. The figure does not show the complexity of the intestinal absorption in these patients. Since they have predominantly glycine-conjugated bile acids, jejunal absorption may be increased further, since the concentration of bile acids in colonic content is increased, passive absorption from the colon probably also is increased and contributes to the conservation of the bile acid pool. Since the increased synthesis, as well as alterations in the site of intestinal absorption, results in maintenance of the bile acid pool at essentially normal levels, such patients have been termed compensated. The syndrome has been termed 5,6 acid diarrhea or cholanorrheic diarrhea. ...

An understanding of the mechanisms by which the compensatory increase in bile acid and cholesterol synthesis takes place following interrupted enterohepatic circulation of bile acids would be important not only... 

This raises a question of whether the mechanism of stimulated bile acid production during interrupted enterohepatic circulation of bile acids is different from that found during the enhanced cholesterol production in obesity. It is reasonable to assume that in obesity the biliary secretion of both bile acids and cholesterol is augmented and that subsequent intestinal reabsorption from the expanded intraluminal pool is increased in absolute figures (probably decreased relatively). Thus the fluxes both of bile acids via the portal blood and of cholesterol via the lymphatics back to the liver are augmented. Despite these two fluxes, from which the former at least is supposed to inhibit bile salt production (and cholesterol synthesis as well), the hepatic synthesis of bile acids is actually increased, suggesting that it is an increased cholesterol synthesis which stimulates bile acid production. 

It can be expected that total fast or a low-calorie diet, which effectively inhibit cholesterol synthesis in man (11,88,139,141), would dramatically reduce the serum cholesterol level during interrupted enterohepatic circulation of bile acids. Occasionally, this has turned out to be true (139) (see Fig. 2), but frequently a moderate or even only a negligible further fall is seen (11,88)... 

Studies with radioactive glycocholate or taurocholate demonstrated a virtual absence of the enterohepatic circulation of bile acids in patients with jejunotransversocolostomy (77). The small amount of absorbed bile acids contained some deconjugated cholate and deoxycholate (which had been reconjugated in the liver), indicating a rapid bacterial action during an apparently fast intestinal passage. Under these conditions, steatorrhea is apparently not solely due to bile salt deficiency induced impairment of micelle formation, but reduced absorptive area may play an important contributory role. No direct measurement of bile acid synthesis by fecal determination has been performed in this condition. 

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