Cholestasis
From Ganfyd
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.
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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
- Gallstones
- Carcinoma head of pancreas
- Carcinoma of bile duct
- Stricture of bile duct
Genetic
Defects in
- BSEP
- MRP2
- MRP3
Drugs
- Oestrogens and tamoxifen
- Erythromycin and other macrolides
- Chlopromazine
- Co-amoxiclav, flucloxacillin and other oxypenicillins
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
- Colestyramine
- Rifampicin in patients intolerant to colestyramine.
- Ursodeoxycholic acid
- Possibly fanesol X receptor activators
- Chenodexycholic acid and some other bile acids (less strongly)
- ? 6-α-ethylchenodeoxycholic acid (6ECDCA)(potent-investigational)
- Possibly Pregnane X receptor activators
