Bilirubin metalbolism in cholestasis

Abstract

Jaundice is most commonly due to the retention of biliary bile pigments as the result of intra - or extra hepatic cholestasis. The impairment in the excretion of bilirubin conjugates seen in cholestasis is usually associated with defects in the excretion of other biliary solutes, such as bile acids and biliary lipids; the resulting plasma patterns may, however, be very different. The mechanisms underlying the reflux of bile pigments from the hepatocytes or bile ductules are still poorly understood. It has been postulated that there are structural and functional alterations in the properties of the hepatic plasma membranes, particularly the canalicular microvilli; in addition, microfilament and microtubular dysfunction may cause changes in tight junction permeability (Erlinger et al, 1986). In most types of cholestatic liver disease the pattern of serum total bilirubin concentrations follows that of serum bile acids. However, in benign recurrent intrahepatic cholestasis there is a marked dissociation between bilirubin and bile acid levels (Summerfield et al, 1981), so that whereas at the beginning of an attack serum bile acids are extremely high the serum bilirubin is only slightly raised. Subsequently the bile acid concentration falls while the serum bilirubin continues to rise and may not return to normal for several weeks (fig. 1). A discrepancy between the patterns of serum bile pigments and serum bile acids is also seen following biliary drainage (fig. 2) where the time taken for the serum bilirubin to return to normal is far greater than for serum bile acids (Summerfield et al, 1983). In this situation the fact that conjugated bilirubin binds more tightly to plasma and tissue proteins than conjugated bile acids may be significant. These examples have been included to make the point that in cholestasis these two indices of liver function do not necessarily change in a similar way. Conjugated hyperbilirubinaemia occurs in the absence of raised serum bile acids in the Dubin-Johnson (Cohen et al, 1972) and following the administration of the cholephilic drug ioglycamide (Mese et al, 1985); these observations add further support to the generally accepted postulate that the secretion of bile acids proceeds by a different pathway from that of bilirubin and other organic anions such as bromosulphthalein and indocyanine green.