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Enterohepatic Circulation of Bile Acids

Alan F. Hofmann

10.1002/cphy.cp060329

Source: Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion

Originally published: 1989

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Historical Aspects
2 General Features of Enterohepatic Circulation in Vertebrates
2.1 Anatomical Distribution
2.2 Overall Balance
2.3 Description Methods
2.4 Determinants of Composition and Distribution
2.5 Dynamic Aspects of Enterohepatic Circulation in Humans
2.6 Bile Acid Concentrations
2.7 Chemical Constituents
2.8 Bile Acid Biotransformations
2.9 Movements of Bile Acids in Enterohepatic Circulation
3 Application of General Principles in Humans
3.1 Cholic Acid and Deoxycholic Acid
3.2 Chenodeoxycholic Acid and Lithocholic Acid
4 Determinants of Steady‐State Biliary Bile Acid Composition in Humans
4.1 Steroid Moiety
4.2 Amino Acid Moiety
5 Methods For Characterizing Enterohepatic Circulation of Bile Acids
5.1 Bile Acid Pool Size
5.2 Bile Acid Biosynthesis or Input
5.3 Measurement of Bile Acid Fluxes
5.4 Regulation of Enterohepatic Circulation
6 Perturbations of Enterohepatic Circulation
6.1 Alterations in Input
6.2 Alterations in Interorgan Flow
6.3 Alterations in Transport
6.4 Alterations in Biotransformation
7 Epilogue: Comparison of Bile Acids and Conventional Drugs
Figure 1. Figure 1.

Schematic depiction of overall cholesterol metabolism in humans. Enclosed area for cholesterol indicates 2 exchangeable cholesterol pools. Cholesterols, slowly exchangeable pool. Cholesterolr, rapidly exchangeable pool. Numbers are within range of values obtained in healthy adults (g/day). Only the enteral loop of enterohepatic circulation (EHC) of bile acids is shown. In humans, excretion of cholesterol as neutral sterol exceeds acidic sterol excretion (bile acid excretion), whereas in many animals the majority of cholesterol is eliminated as bile acids rather than as cholesterol.
Figure 2. Figure 2.

Representation of EHC of bile acids as linear multicompartmental model. Arrow connecting systemic circulation (space 1) with sinusoidal circulation (space 3) corresponds to hepatic arterial blood flow; arrow connecting systemic circulation to portal circulation (space 2) corresponds to mesenteric circulation. In the pharmacokinetic model that has been developed, each space is further subdivided into 3 compartments that correspond to the glycine conjugate, the taurine conjugate, and the unconjugated species for any bile acid.

From Hofmann et al. 132, by copyright permission of the American Society for Clinical Investigation.
Figure 3. Figure 3.

Schematic depiction of EHC shown as a continuing movement of molecules into bile, then into the intestine, then as reabsorption from the intestine, with spillover past the liver into the systemic circulation. This model can be transformed to that shown in Figure 2 without difficulty; both depict EHC of bile acids as consisting of an enterohepatic circle and a circulatory circle.
Figure 4. Figure 4.

Chemical structure of 5 major bile acids present in human bile. Bile acids are present as their glycine or taurine amidates; in addition, glycine and taurine amidates of lithocholic acid are sulfated. Term chenic is used as a curtailed name for chenodeoxycholic acid (CDCA). Hexagons denote saturated 6‐membered rings of carbon atoms. Solid lines above the juncture of A and B rings and C and D rings correspond to methyl groups, whereas that at the bottom of the A‐B ring juncture indicates a 5β‐hydrogen group and that at the A and B rings are in a cis configuration. R, bile acid (minus its carboxyl group). The 14 bile acids in this figure comprise at least 95% of biliary bile acids in most individuals.
Figure 5. Figure 5.

Major pathways of bacterial bio‐transformation of cholic acid (CA) and CDCA in humans. 12‐Dehydroxylation is believed not to occur. Figure does not show dehydrogenation at the 3 position or 12 position to form 3‐oxo and 12‐oxo bile acids, respectively. Both occur, since 3‐oxo, 7‐oxo, and 12‐oxo bile acids are present in fecal bile acids 224.
Figure 6. Figure 6.

Enterohepatic circulation of steroid moiety of CA and deoxycholic acid (DCA) in humans. Only the enterohepatic circle is shown. Lower arc, unconjugated bile acid that is formed in distal intestine, absorbed, and returned to the liver for reconjugation. CA passing into the colon is completely 7‐dehydroxylated, but only a fraction of the DCA that is formed is reabsorbed from the large intestine. After its reabsorption, DCA is conjugated with glycine or taurine and conjugates then join the EHC of primary bile acids.
Figure 7. Figure 7.

Immunoreactive level of CA conjugates and CDCA conjugates (chenyl conjugates) after 3 equicaloric liquid meals in healthy volunteers. Level of CDCA conjugates rises sooner than that of CA conjugates, reflecting their earlier absorption from proximal small intestine. Delay of 2 h between meal ingestion and peak serum level of CA conjugates reflects transit time required for these bile acids to pass from the duodenum to the terminal ileum, where they are actively absorbed.
Figure 8. Figure 8.

Schematic depiction of hepatic uptake showing greater spillover of CDCA conjugates into systemic circulation as compared with CA conjugates. Unconjugated bile acids have a lower fractional hepatic extraction than their corresponding conjugates, so that systemic circulation is also enriched in unconjugated bile acids, as compared with their corresponding conjugated derivatives.
Figure 9. Figure 9.

Schematic depiction of EHC of CDCA (termed chenic) and lithocholic acid (LCA) in humans. Sulfolithocholyl conjugates are poorly absorbed from the small intestine. Figure does not show a small fraction of the amidated sulfated lithocholates that are fully hydrolyzed during colonic transit, resulting in reabsorption of a small fraction of unconjugated LCA.
Figure 10. Figure 10.

Schematic depiction of major biotransformations in humans that influence biliary bile acid composition. Ursocholic acid, although probably formed to a considerable extent in the large intestine, is so hydrophilic that its proportion in bile is extremely low and usually it is not detectable.
Figure 11. Figure 11.

Schematic depiction of EHC of 4 main bile acids present in human bile. Steady‐state composition of biliary bile acids represents relative balance between input and intestinal conservation for each bile acid.
Figure 12. Figure 12.

Atoms percent excess (unit for stable isotopes that is comparable with specific activity for radioactive isotopes) of biliary bile acids after administration of [24‐13C]chenodeoxycholic acid to a healthy volunteer. LCA and ursodeoxycholic acid (UDCA), which are formed from CDCA, slowly appear in bile in labeled form. Atoms percent excess of CDCA declines exponentially, indicating that CDCA metabolism (as that of CA and DCA) can be described by a single‐pool model.
Figure 13. Figure 13.

Use of biliary recovery marker to measure gallbladder storage and emptying in humans. Indocyanine green, a compound quantitatively secreted into bile, is infused intravenously at a constant rate. Left panel: in absence of gallbladder storage, duodenal output (Od) equals parenteral input (Ip). Center panel: when duodenal output is less than parenteral input, gallbladder storage is occurring. Right panel: when duodenal output exceeds parenteral input, gallbladder emptying is occurring.

From Berge Henegouwen and Hofmann 22
Figure 14. Figure 14.

Plasma disappearance of intravenously administered [14C]CDCA (chenic acid) and plasma appearance of orally administered [3H]CDCA in a healthy volunteer. Area under the curve after oral administration is only 40% of that after intravenous administration, permitting calculation of first‐pass clearance to be ∼60%. Figure has been confirmed by direct venous sampling 72.
Figure 15. Figure 15.

Diurnal levels in serum of conjugates of CA, as determined by radioimmunoassay on samples collected at intervals of 15 to 30 min, except during the night when samples were taken at hourly intervals. Healthy subjects and patients with bile acid (BA) malabsorption because of ileal resection 164 were studied. In patients with bile acid malabsorption, peak of postprandial level declines progressively during the day, indicating progressive depletion of bile acid pool. Increased synthesis occurs throughout the day; during interval between supper and breakfast, increased synthesis restores the pool in part, so that postprandial peak after breakfast is largest of 3 postprandial peaks.
Figure 16. Figure 16.

Comparison of EHC of natural bile acids (left) and a drug that is excreted into bile as its glucuronide (right). In the colon, hydrolysis of glucuronide conjugates can occur and reabsorption of the aglycone can occur but is not shown.


Figure 1.

Schematic depiction of overall cholesterol metabolism in humans. Enclosed area for cholesterol indicates 2 exchangeable cholesterol pools. Cholesterols, slowly exchangeable pool. Cholesterolr, rapidly exchangeable pool. Numbers are within range of values obtained in healthy adults (g/day). Only the enteral loop of enterohepatic circulation (EHC) of bile acids is shown. In humans, excretion of cholesterol as neutral sterol exceeds acidic sterol excretion (bile acid excretion), whereas in many animals the majority of cholesterol is eliminated as bile acids rather than as cholesterol.



Figure 2.

Representation of EHC of bile acids as linear multicompartmental model. Arrow connecting systemic circulation (space 1) with sinusoidal circulation (space 3) corresponds to hepatic arterial blood flow; arrow connecting systemic circulation to portal circulation (space 2) corresponds to mesenteric circulation. In the pharmacokinetic model that has been developed, each space is further subdivided into 3 compartments that correspond to the glycine conjugate, the taurine conjugate, and the unconjugated species for any bile acid.

From Hofmann et al. 132, by copyright permission of the American Society for Clinical Investigation.


Figure 3.

Schematic depiction of EHC shown as a continuing movement of molecules into bile, then into the intestine, then as reabsorption from the intestine, with spillover past the liver into the systemic circulation. This model can be transformed to that shown in Figure 2 without difficulty; both depict EHC of bile acids as consisting of an enterohepatic circle and a circulatory circle.



Figure 4.

Chemical structure of 5 major bile acids present in human bile. Bile acids are present as their glycine or taurine amidates; in addition, glycine and taurine amidates of lithocholic acid are sulfated. Term chenic is used as a curtailed name for chenodeoxycholic acid (CDCA). Hexagons denote saturated 6‐membered rings of carbon atoms. Solid lines above the juncture of A and B rings and C and D rings correspond to methyl groups, whereas that at the bottom of the A‐B ring juncture indicates a 5β‐hydrogen group and that at the A and B rings are in a cis configuration. R, bile acid (minus its carboxyl group). The 14 bile acids in this figure comprise at least 95% of biliary bile acids in most individuals.



Figure 5.

Major pathways of bacterial bio‐transformation of cholic acid (CA) and CDCA in humans. 12‐Dehydroxylation is believed not to occur. Figure does not show dehydrogenation at the 3 position or 12 position to form 3‐oxo and 12‐oxo bile acids, respectively. Both occur, since 3‐oxo, 7‐oxo, and 12‐oxo bile acids are present in fecal bile acids 224.



Figure 6.

Enterohepatic circulation of steroid moiety of CA and deoxycholic acid (DCA) in humans. Only the enterohepatic circle is shown. Lower arc, unconjugated bile acid that is formed in distal intestine, absorbed, and returned to the liver for reconjugation. CA passing into the colon is completely 7‐dehydroxylated, but only a fraction of the DCA that is formed is reabsorbed from the large intestine. After its reabsorption, DCA is conjugated with glycine or taurine and conjugates then join the EHC of primary bile acids.



Figure 7.

Immunoreactive level of CA conjugates and CDCA conjugates (chenyl conjugates) after 3 equicaloric liquid meals in healthy volunteers. Level of CDCA conjugates rises sooner than that of CA conjugates, reflecting their earlier absorption from proximal small intestine. Delay of 2 h between meal ingestion and peak serum level of CA conjugates reflects transit time required for these bile acids to pass from the duodenum to the terminal ileum, where they are actively absorbed.



Figure 8.

Schematic depiction of hepatic uptake showing greater spillover of CDCA conjugates into systemic circulation as compared with CA conjugates. Unconjugated bile acids have a lower fractional hepatic extraction than their corresponding conjugates, so that systemic circulation is also enriched in unconjugated bile acids, as compared with their corresponding conjugated derivatives.



Figure 9.

Schematic depiction of EHC of CDCA (termed chenic) and lithocholic acid (LCA) in humans. Sulfolithocholyl conjugates are poorly absorbed from the small intestine. Figure does not show a small fraction of the amidated sulfated lithocholates that are fully hydrolyzed during colonic transit, resulting in reabsorption of a small fraction of unconjugated LCA.



Figure 10.

Schematic depiction of major biotransformations in humans that influence biliary bile acid composition. Ursocholic acid, although probably formed to a considerable extent in the large intestine, is so hydrophilic that its proportion in bile is extremely low and usually it is not detectable.



Figure 11.

Schematic depiction of EHC of 4 main bile acids present in human bile. Steady‐state composition of biliary bile acids represents relative balance between input and intestinal conservation for each bile acid.



Figure 12.

Atoms percent excess (unit for stable isotopes that is comparable with specific activity for radioactive isotopes) of biliary bile acids after administration of [24‐13C]chenodeoxycholic acid to a healthy volunteer. LCA and ursodeoxycholic acid (UDCA), which are formed from CDCA, slowly appear in bile in labeled form. Atoms percent excess of CDCA declines exponentially, indicating that CDCA metabolism (as that of CA and DCA) can be described by a single‐pool model.



Figure 13.

Use of biliary recovery marker to measure gallbladder storage and emptying in humans. Indocyanine green, a compound quantitatively secreted into bile, is infused intravenously at a constant rate. Left panel: in absence of gallbladder storage, duodenal output (Od) equals parenteral input (Ip). Center panel: when duodenal output is less than parenteral input, gallbladder storage is occurring. Right panel: when duodenal output exceeds parenteral input, gallbladder emptying is occurring.

From Berge Henegouwen and Hofmann 22


Figure 14.

Plasma disappearance of intravenously administered [14C]CDCA (chenic acid) and plasma appearance of orally administered [3H]CDCA in a healthy volunteer. Area under the curve after oral administration is only 40% of that after intravenous administration, permitting calculation of first‐pass clearance to be ∼60%. Figure has been confirmed by direct venous sampling 72.



Figure 15.

Diurnal levels in serum of conjugates of CA, as determined by radioimmunoassay on samples collected at intervals of 15 to 30 min, except during the night when samples were taken at hourly intervals. Healthy subjects and patients with bile acid (BA) malabsorption because of ileal resection 164 were studied. In patients with bile acid malabsorption, peak of postprandial level declines progressively during the day, indicating progressive depletion of bile acid pool. Increased synthesis occurs throughout the day; during interval between supper and breakfast, increased synthesis restores the pool in part, so that postprandial peak after breakfast is largest of 3 postprandial peaks.



Figure 16.

Comparison of EHC of natural bile acids (left) and a drug that is excreted into bile as its glucuronide (right). In the colon, hydrolysis of glucuronide conjugates can occur and reabsorption of the aglycone can occur but is not shown.

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Article Title: Enterohepatic Circulation of Bile Acids
 

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Alan F. Hofmann. Enterohepatic Circulation of Bile Acids. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 567-596. First published in print 1989. doi: 10.1002/cphy.cp060329