chapter  11
36 Pages

Mechanisms Involved in Bile Acid-Induced Cholestasis

ByIbrahim M. Yousef, Guylaine Bouchard, Beatriz Tuchweber, Gabriel L Plaa

In cholestasis, decreased biliary secretion increases BA reflux into plasma, which can reach up to 100 times the level in controls (9). In general, serum BA appears to be in good correlation with the severity of hepatobiliary diseases {9, 12). Primary BA are classically increased. The increase, however, appears to be greater for CA than COCA in the early stages or in mild cholestasis, and the adverse phenomenon occurs in severe cholestasis (9). The percent contributions of the secondary BA deoxycholic acid (DCA) and lithocholic acid (LCA, the dehydroxylated product of the primary BA) are decreased. Another constant finding is the elevated plasma level of BA precursors such as 7-a-hydroxy-cholesterol and 3-f:J-hydroxy-5-cholenoic acid, as well as polyhydroxylated BA {3, 16, 17). The presence of 3-f:J-hydroxy-5-cholenoic acid, which is 90% sulfated or glucuronidated, is a characteristic feature of cholestasis, as this compound is absent or present in trace amounts under normal conditions ( 18). Taurineconjugated BA are increased in cholestasis. Indeed, the level of the taurine-conjugated form appears to be in good correlation with the pruritus of cholestasis (18). Higher levels of glucuronidated, glucoside, and sulfated BA are also observed, with sulfates usually exceeding glucuronides (8, 9, 19). Ostrow (9) postulated that the increased percent contribution of BA sulfate esters in many subjects with liver disease may be related to disease progression or severity. In neonatal cholestasis, sulfated LCA shows the largest relative increase compared to CA and COCA sulfates (20). However, COCA constitutes an important part of the pool of BA glucuronides (7-8% of total BA) (21 ).

While urinary BA elimination is minor under normal conditions, it becomes a major factor in BA kinetics in cholestasis. Increased plasma BA levels and conjugation appear to be direct mediators of augmented urinary BA content {8, 22). The elimination rate, however, is highly variable for various BA: Sulfated BA are excreted 15-1()() times more rapidly than free BA, and glucuronides 7-10 times more rapidly {9, 23). Furthermore, different sulfated BA show different renal clearance rates: