Cholestasis

From Ganfyd

Jump to: navigation, search

Cholestasis is impaired secretion of bile. As it results in a multitude of toxins building up and has been difficult to treat it has been of perhaps as much interest to pharmacologists as gastroenterologists.

Contents

Bile Acid homeostasis

Primary bile acids are created from cholesterol by cholesterol 7α-hydroxylase CYP7A1 and then sterol 12α-hydrolyase CYP8B1 in bile acid biosynthesis. Bile acid transporters then secrete them into the intestine. The Bile acid transporters are:

  • Bile-salt excretory pump (BSEP)
  • Multidrug-resistance-associated protein 2(MRP2)
  • Multidrug-resistance-associated protein 3(MRP3)

Secondary bile acids are then formed by bacteria which contain enzymes which undertake 7α-hydroxylation of the primary bile acids, and these are then absorbed into the blood. Hepatocytes extract these with an active uptake mechanism using Na+-taurochlorate-cotransporting polypeptide(NTCP) and Na+-independent organic anion-transporting polypeptide 2(DATP2). These then circulate between the hepatocyte, gut and blood.

Causes

Obstruction

Genetic

Defects in

  • BSEP
  • MRP2
  • MRP3

Drugs

Feedback

  • Bile acids themselves are toxic

Investigations

One component of bile is bilirubin, a rise in which is often detected in liver function tests. Bile acids are not part of the standard liver group and often have to be requested separately.

Treatment

  1. Colestyramine
  2. Rifampicin in patients intolerant to colestyramine.
  3. Ursodeoxycholic acid
  4. Possibly fanesol X receptor activators
    • Chenodexycholic acid and some other bile acids (less strongly)
    • ? 6-α-ethylchenodeoxycholic acid (6ECDCA)(potent-investigational)
  5. Possibly Pregnane X receptor activators

References

  1. Chen J, Raymond K. Nuclear receptors, bile-acid detoxification and cholestasis. Lancet 2006;367:454-455