The Clinical Importance of a Protein-Bound Fraction of Serum Bilirubin in Patients with Hyperbilirubinemia

Abstract

A directly reacting fraction of bilirubin that is probably covalently bound to albumin (albumin-bound bilirubin) has recently been described. To determine its clinical importance we used a new high-performance liquid-chromatography technique to measure it in the serum of 200 patients with hyperbilirubinemia from various causes. Albumin-bound bilirubin was an important fraction (8 to 90 per cent) of total bilirubin in patients with hepatocellular and cholestatic jaundice as well as in patients with the Dubin-Johnson syndrome. It was not detected in normal volunteers, neonates with physiologic jaundice, or patients with Gilbert's disease or hemolysis. Thus, albumin-bound bilirubin appears in serum when hepatic excretion of conjugated bilirubin is impaired. It becomes a larger component of serum bilirubin as jaundice subsides, delaying resolution of this disorder and causing bilirubin to persist in plasma after it has disappeared from the urine.

Origin of mammalian biliprotein and rearrangement of bilirubin glucuronides in vivo in the rat.

“…Its proportion in serum tended to be low during the early phase of obstructive jaundice but increased as jaundice receded and bilirubinemia and bilirubinuria diminished (21,24,25). Later, evidence for the occurrence of an undissociable bilirubinprotein complex in pathologic sera was obtained by reversedphase chromatography (9)(10)(11)(12)(13), and recent studies suggest strongly that the complex contains a bilirubinoid species bonded covalently to albumin (11 (13,27). (Fig.…”

“…Of the chromatographic methods currently available for distinguishing unconjugated from conjugated hyperbilirubinemia, system A is the most rapid. It is not yet known whether measuring the relative proportions of isomeric bilirubin esters in serum would be diagnostically or clinically more useful than measuring the proportion of biliprotein (13 …”

“…Consequently, icteric blood plasma may contain not only f-l-O-acyl glucuronides of bilirubin, but isomers of these (3)(4)(5). Second, there is longstanding evidence that proteins containing irreversibly bound bile pigment occur in some jaundiced sera (8)(9)(10)(11)(12)(13). Such biliproteins are not only of interest apropos of liver disease, but also with respect to the structure and biosynthesis of nonmammalian biliproteins, which are widely distributed in nature.…”

Irreversible binding of zomepirac to plasma protein in vitro and in vivo.

“…Although the amount of covalently bound drug detected in the present studies represented only a small fraction of the single dose administered, it seems likely that upon repeated, multiple doses, bound drug would accumulate to a greater extent and eventually represent a larger fraction of the drug in the body or in a particular organ. Furthermore, it might be expected that disease states or advanced age, which compromise the excretion of ZG, would lead to increased ZG levels and increased adduct formation, as with bilirubin (15). Irreversible 2) or the individual purified components (Fig.…”

“…In cholestatic liver disease, bilirubin becomes irreversibly (probably covalently) bound to albumin (10)(11)(12)(13)(14)(15), and recent studies have shown that this reaction occurs via acyl glucuronide metabolites of bilirubin (16,17). Although bilirubin glucuronides accumulate in human plasma only during liver disease (15), the glucuronide of zomepirac (ZG) reaches a plasma level similar to that of Z after administration of a single oral dose of Z to healthy subjects (3,18). Since both bilirubin and Z yield similar reactive and unstable acyl glucuronide metabolites (9), it seemed possible to us that covalent binding of Z to protein might occur in vivo via the Z glucuronide metabolite.…”