Chronic unconjugated hyperbilirubinemia without overt signs of hemolysis in adolescents and adults.

The syndrome of chronic unconj ugated hyperbilirubinemia without overt signs of hemolysis in adolescents and adults has been variously termed cholemie simple familiale (Gilbert's disease) (1), icterus intermittens juvenilis (2), hereditary nonhemolytic bilirubinemia (3), familial nonhemolytic jaundice (4), physiologic hyperbilirubinemia (5), and constitutional hepatic dysfunction (6). These terms neither adequately describe the pathophysiology nor indicate the heterogeneity of cases with chronic jaundice of this type. The present report is a study of 23 adolescent and adult patients with chronic unconjugated hyperbilirubinemia without overt signs of hemolysis, and of their families. The object of the study was to determine the pathogenesis of chronic jaundice of this type. The metabolism of bilirubin by the liver, reviewed elsewhere (7), involves three major processes: 1) the transfer of bilirubin from plasma into the liver cell, 2) the intracellular formation of bilirubin conjugates, and 3) the excretion of the water-soluble bilirubin conjugates into the bile. Very little is known about the mechanism and regulation of the first and third of these processes. The conjugation of bilirubin, primarily with glucuronic acid, but also with sulfate and other as yet unidentified substances, converts bilirubin to more water-soluble bilirubin conjugates (8-11). In the formation of glucuronides, the transfer of glucuronic acid from uridilie diphosphate glucuronic acid (UDPGA) to suitable receptors such as bilirubin, phenols, acids, various steroids, and alcohols is catalyzed by glucuronyl transferase, an enzyme associated with the microsomal fraction of homogenates of mammalian liver (12-16). Con-