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Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry

Patients with cholestatic liver disease are likely to inappropriately conserve bile acids. Ursodiol corrects the defect, but is this enough?

Conjugated bile acids are water soluble amphipathic end products of cholesterol metabolism that promote lipid transport in the biliary tract and small intestine by forming mixed micelles.1 Bile acids are formed in pericentral hepatocytes by a complex multienzyme process whose details have at last been largely elucidated.2 After formation, their acidic group is linked (“conjugated”) with the amino group of glycine or taurine in an amide bond that is resistant to the proteolytic enzymes present in pancreatic secretion and on the surface of the enterocyte brush border. Conjugated bile acids differ from unconjugated bile acids in being membrane impermeable and water soluble at the pH conditions prevailing in the biliary tract and small intestine.

Efficient ileal conservation of bile acids results in the accumulation of a mass of bile acids termed the bile acid “pool”. Between meals, most of the pool is stored in the gall bladder; with meals, the gall bladder discharges bile into the small intestine where bile acids promote lipid absorption. Both bile acid synthesis and ileal conservation continue after a meal but the gall bladder does not increase in volume in proportion to the amount of bile acids it contains because of its continuous concentration of bile. The gall bladder appears early in vertebrate evolution and genes for gall bladder development appear to have evolved at the same time as genes for bile acid synthesis and intestinal conservation. Development of the enterohepatic circulation and gall bladder storage resulted in far more bile acids being available for digestion than those recently synthesised. Each bile acid molecule is used multiple times before it is lost to the large intestine.3

Feedback inhibition of bile acid biosynthesis …