Bile Cholestasis

Cholestatic. Pertaining to or characterized by suppression or stopping of the flow of bile (cholestasis), having intrahepatic or extra-hepatic causes. 

Hepatobiliary disease occurs due to bile duct obstruction from abnormal bile composition and flow. Hepatomegaly, splenomegaly, and cholecystitis may be present. Hepatic steatosis may also be present due to effects of malnutrition. The progression from cholestasis (impaired bile flow) to portal fibrosis and to focal and multilobar cirrhosis, esophageal varices, and portal hypertension takes several years. Many patients are compensated and asymptomatic but maybe susceptible to acute decompensation in the event of extrinsic hepatic insult from viruses, medications, or other factors.7... 

Cholestasis Reduced or lack of flow of bile, or obstruction of bile flow. 

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

J., Kuliak-Ublick, G. A., Meier, P. J., Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver, Gastroenterology 2000, 118, 422-430. 

Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999 117(6) 1370— 1379. 

Alkaline phosphatase levels and GGT are elevated in plasma with obstructive disorders that disrupt the flow of bile from hepatocytes to the bile ducts or from the biliary tree to the intestines in condition such as primary biliary cirrhosis, sclerosing cholangitis, drug-induced cholestasis, gallstone disease, and autoimmune cholestatic liver disease. 

Toxicologists classify hepatic toxicants according to the type of injuries they produce. Some cause accumulation of excessive and potentially dangerous amounts of lipids (fats). Others can kill liver cells they cause cell necrosis. Cholestasis, which is decreased secretion of bile leading to jaundice (accumulation of gruesome looking pigments that impart a yellowish color to the skin and eyes) can be... 

Figure 2.1 Hepatocyte basolateral bile acid transporters. Protein-bound bile acids returning in portal blood are taken up by the hepatocyte via the sodium taurocholate co-transporting polypeptide (NTCP) and organic-anion-transporting polypeptide (OATP). In cholestasis bile acids may be returned to blood by the multi-drug-resistance-associated protein 3 (MRP3).

Glutathione S transferases bind bile acids in vitro but doubt has been cast over whether this happens in vivo as these enzymes were not labelled by fluorescently labelled bile acids in experiments to identify the carrier proteins but may play a role with the raised levels in cholestasis. Liver fatty-acid-binding protein has been shown to bind bile acids by using a displacement assay with fluorescent fatty-acid ligand. This work clearly showed displacement to be directly related to hydrophobicity, such that lithocholate conjugates had the greatest effect. This may indicate a mechanism to minimise toxicity within the hepatocyte. 

A related protein, MRP3, has similar structure to this mutated MRP2 and can transport taurocholic acid but mutation of the equivalent residue, leucine 1084, with lysine-blocked transport of taurocholic acid. In cholestasis there is an induction of MRP3 mRNA suggesting that this transporter is active, at least when bile-acid concentrations are raised within the hepatocyte. This transporter function is shown in Figure 2.1. 

L. A. Thomas, T. Bathgate and M. J. Veysey, In Bile Acids and Cholestasis., eds. G. Baumgartner, A. Stiel, W. Gerok, D. Kepper, U. Leuschner, Kluwer Academic Publishers, Dordecht, Boston, London, 1999, 284. 

Inhibition of Bile Salt Efflux Protein and Drug-Induced Cholestasis... 

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. 

Sokol, RJ. et al. (2006) Let there be bile —understanding hepatic injury in cholestasis. Journal of Pediatric Gastroenterology and Nutrition, 43 (Suppl 1). S4-S9. 

Mita, S. et al. (2006) Inhibition ofbile add transport across Na + /taurocholate cotransporting polypeptide (SLClOAl) and bile salt export pump (ABCB 11)-coexpressing LLC-PKl cells by cholestasis-inducing drugs. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34 (9), 1575-1581. 

Funk, C. et al. (2001) Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export ofbile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and ihe inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate. Toxicology, 167 (1), 83-98. 

In animal models, silymarin has a dose-dependent stimulatory effect on bile flow that could be beneficial in cases of cholestasis. To date, however, there is insufficient evidence to warrant the use of milk thistle for these indications. 

Cholestasis can lead to a similar occurrence of a broad-/l-band. This results from the presence of lipoprotein X [Lp(X)], which migrates slightly closer to the application point than LDL but cannot be separated from it. Lp(X) is derived from bile lipids including free cholesterol and phospholipids that acquired apolipoproteins after they were released into the blood. However, this Lp(X)-derived broad-jS-band migrates closer to the application point than LDL and can be distinguished from the broad-/l-band of familial dysbetalipoproteinemia (type III). 

Rationally, 5/3-reduclase deficiency would not be a cause of MPH, but it seems appropriate to place this disorder adjacent to its 5a-counterpart. 5/3-Reductase (AKR1D1) is an essential bile-acid biosynthetic enzyme and patients with disabling mutations in this enzyme have a clinical phenotype associated with cholestasis and fiver failure. In addition to its importance in bile-acid synthesis, this aldoketo-reductase is responsible for reducing approximately two-thirds of the mass of synthesized androgens, corticosteroids, and aldosterone prior to their excretion, so has a vital role in steroid metabolism. 

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