Bile acids in plasma

Protein-bound bile acids in plasma are removed with high efficiency by the hepatocyte, partly due to the liver sinusoids that allow protein-bound material... 

In vivo, measuring bile acids in plasma and urine should be revived as potential biomarkers in the modern metabolomic era. Then the first-order scientific question will become whether early and time-controlled fasting-level measurement of bile acid concentration in plasma and urine can become a sensitive and specific biomarker for drug-induced cholestasis and ultimately liver injury at later time-points [117] Clinical trials should be conducted to evaluate whether such bile acid measurements can be used as part of a predictive panel to identify patients who are at increased risk of drug-induced cholestasis. 

Back P, Siovall J, Siovall (1974) Monohydroxy bile acids in plasma in intrahepatic cholestasis of pregnancy. Identification by computerized gas chromatography-mass spectrometry. Med Biol 52 31-38... 

Johnson, D.W, ten Brink, H.J., Schuit, R.C., Jakobs, C. (2001) Rapid and quantitative analysis of unconjugated C(27) bile acids in plasma and blood samples by tandem mass spectrometry. /. Lipid Res., 42(1), 9-16. 

Bootsma AH, Overmars H, van Rooj A, van Lint AE, Wanders RJ, van Gennip AH, et al. Rapid analysis of conjugated bile acids in plasma using electrospray tandem mass spectrometry application for selective screening of peroxisomal disorders. J. Inher. Metab. Dis. 1999 22(3) 307-10... 

Driscoll TR, Hamdan HH, Wang G, et al. 1992. Concentrations of individual serum or plasma bile acids in workers exposed to chlorinated aliphatic hydrocarbons. Br J Ind Med 49 700-705. 

Mechanism of Action An antihyperlipoproteinemic that binds with bile acids in the intestine, forming an insoluble complex. Binding results in partial removal of bile acid from enterohepatic circulation. Therapeutic Effect Removes LDL cholesterol from plasma. 

Yao, H. T. and Chiang, M. T. (2006). Effect of chitosan on plasma lipids, hepatic lipid and fecal bile acid in Hamsters. J. Food Drug Anal. 14,183-189. 

Bile acid sequestrates are anion-exchange resins, which sequester bile acid in the intestine. Cholestyramine and colestipol are the most commonly used in this category, which by this mechanism prevents bile acid re-absorption and causes decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acid in the liver by preventing enterohepatic recirculation. This leads to an increased expression of LDL receptors in liver and causes increased removal of LDL from blood and reduces the LDL cholesterol in the plasma. 

Therapeutic uses The bile acid binding resins are the drugs of choice (often in combination with diet or niacin) in treating Type lla and lib hyperlipidemias. [Note In those rare individuals who are homozygous for Type lla, that is, for whom functional LDL receptors are totally lacking, these drugs have little effect on plasma LDL levels.] Cholestyramine can also relieve pruritus caused by accumulation of bile acids in patients with biliary obstruction. 

Stiehl, A., Rudolph, G., Raedsch, R., Moller, B., Hopf, U., Loiterer, E., Bircher, J., Folsch, U., Klaus, J., Endele, R., Senn, M. UrsodeoxychoUc acid-induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis. Hepatology 1990 12 492-497... 

Bile acids are carried in plasma tightly bound to protein. The concentration of bile acids in the portal vein is high but, because of the efficiency of hepatic extraction, systemic blood concentrations remain low. In a single pass through the liver, the efficiency of extraction is -80% for cholic acid and -60% for chenodeoxycholic acid. Hepatic extraction efficiency is unchanged over a broad range of portal bile acid concentrations. 

Structures of bile acid sequestrants. Cholestyramine and colestipol are hydrophilic yet water-insoluble, nondigestible, and nonabsorbable synthetic resins. They bind bile acids in the intestine to increase their loss in feces and thereby decrease plasma cholesterol levels. 

Answer D. Cholestyramine and colestipol are resins that sequester bile acids in the gut, preventing their reabsorption. This leads to release of their feedback inhibition of 7-alpha hydroxylase and the diversion of cholesterol toward new synthesis of bile acids. Increase in high-affinity LDL receptors on hepatocyte membranes decreases plasma LDL. These drugs have a small but significant effect to increase plasma HDL rather than decrease it, but their ability to increase TGs precludes their clinical use in the management of hypertriglyceridemias. 

There is a large production of hepatic lymph which appears to arise by passage of fluid from the perisinusoidal space, from bile duct area and in the portal tract area (A12). It has been suggested that blood, lymph, and bile enter into an equilibrium in the portal tract (Review article, 2). The lymphatics could also act as a transport system between the liver lobule and the biliary epithelium (All). A detailed study of the relative concentrations of BSP and its metabolites in lymph, bile, and plasma indicated that the composition of lymph differs from that of bile and plasma (K20). Thus, it seems unlikely that lymphatics were the transport system for BSP from liver cells to bile. During biliary stasis there is a rapid rise in lymphatic BSP levels (B32, G12) and the relative concentrations of BSP metabolites approach those found in bile (K20). On ligation of the bile duct the level of bilirubin and bile acids in lymph also rises (G12) as does the plasma level of BSP (BIO) and rose bengal (B22). 

The interruption of enterohepatic recirculation of bile acids by the resins effectively lowers plasma cholesterol levels since cholesterol must now be diverted to de novo synthesis of bile acids. In addition, intestinal absorption of dietary cholesterol, normally facilitated by bile acids, is also reduced due to their excretion. Two significant compensatory mechanisms are called into action increased activity of hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase), which is the rate-controlling enzyme in the hepatic synthesis of cholesterol (see Fig. 11-4 and discussion to follow), and an increase in the number of LDL receptors. The latter mechanism offered the first meaningful treatment of heterozygous FH. Homozygous FH patients lacking LDL receptors, of course, do not respond. 

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