Lydia Hammaker

Congenital jaundice in rats, due to a defect in glucuronide formation.

It has recently been reported that bilirubin is excreted in the bile as a water-soluble glucuronide (1-3). The conjugation of bilirubin is believed to occur mainly in the liver (4, 5). In vitro, formation of bilirubin glucuronide has been demonstrated with a system containing liver microsomes as the enzyme source and uridine diphosphate glucuronic acid as the glucuronic acid donor (5, 6). Since conjugation of bilirubin appears to be essential for its excretion in the bile, a defect in the glucuronide forming mechanism would result in impaired pigment excretion and, hence, in retention of free bilirubin in the blood. In preliminary communications (7, 8), such defects in glucuronide formation have been reported in congenital nonhemolytic nonobstructive jaundice in man (9) and in hereditary nonhemolytic jaundice in rats (10). The present report is concerned with the details of the murine studies, while the human syndrome will be considered in a separate communication.

METABOLISM AND DISPOSITION OF C14-BILIRUBIN IN CONGENITAL NONHEMOLYTIC JAUNDICE*

In mammals, unconjugated bilirubin is rapidly cleared from the circulation and almost quantitatively excreted as a conjugate in the bile (2-4). The efficiency and rapidity of this process indicate that conjugation and subsequent biliary excretion represent the principal pathway of bilirubin disposition. If alternate pathways of bilirubin metabolism exist under physiologic conditions, their level of functional efficiency must be so low as to render detection difficult. When hepatic dysfunction causes interference with the efficiency of conjugation and excretion of bilirubin, however, resulting in hyperbilirubinemia, such alternate metabolic pathways may be expected to play a more important role in disposing of the accumulated pigment load (5). Moreover, when formation and hence biliary excretion of conjugated pigment is virtually abolished owing to an enzymatic defect in the hepatic conjugating apparatus, alternate pathways of bilirubin metabolism must assume the principal role in disposing of the bile pigment formed from the continuous breakdown of hemoglobin (6). Such metabolic anomalies associated with severe unconjugated hyperbilirubinemia exist as a rare congenital syndrome in man (Crigler-Najjar syndrome) (7, 8) and as a recessively inherited enzymatic defect in a mutant strain of Wistar rats (Gunn rats) (8, 9). In both instances, the level of unconjugated hyperbilirubinemia remains remarkably constant over months and years (8), indicating that a steady state has been established between pigment production and disposition. In the present investigation, a patient with congenital unconjugated hyperbilirubinemia and a group of hyperbilirubinemic Gunn rats were in-

Glucuronide formation in patients with constitutional hepatic dysfunction (Gilbert's disease).

IT has been shown that bilirubin has to be converted to its glucuronide or sulfate1 2 3 4 before it can be excreted in the bile. Retention of nonconjugated bilirubin in the plasma, associated with ...

Hereditary Absence of Muscle Phosphorylase (McArdle's Syndrome)

IN 1951 McArdle1 described a patient with a hitherto unrecognized muscle disorder in which marked weakness, cramping pain and prolonged stiffness of muscles were produced by moderate degrees of exe...

Bilirubin Metabolism in the Fœtus

IT has been shown that in fœtal liver the enzymatic mechanism for glucuronide formation is poorly developed, while a rapid increase in enzymatic activity occurs during the early neonatal period1. The transient hyperbilirubinæmia observed during the first few days of life is believed to be related to this inadequate development of the hepatic conjugating system1. Since a significant increase in serum bilirubin concentration usually occurs only after the cord is severed, it has been assumed that during gestation the placenta is responsible for the removal of fœtal bilirubin. It has not been determined, however, whether the placenta has the ability to conjugate the fœtal pigment or whether placental transfer of unconjugated bilirubin occurs from the fœtal to the maternal circulation.