Studies on Kernicterus

This paper presents interesting material on three topics related to kernicterus; a study of the manifestations and pathologic anatomy of kernicterus in rats with a congenital deficiency of the enzyme for conjugating bilirubin with glucuronic acid in the liver (Gunn's strain of rats); studies of the role of sulfonamides in development of kernicterus in humans and in newborn rats; and a consideration of the various theories of the pathogenesis of kernicterus. In the first study, the pathologic anatomy of kernicterus that developes in the Gunn strain of rats is shown to be similar to that which occurs in humans. Pathologic and biochemical studies indicated that the bilirubin in the brain cells appears to be the unconjugated form, and the earliest pathologic changes are associated with the presence of bilirubin in the cells. It is concluded that the pathologic changes of kernicterus are initiated by bilirubin as a toxic agent and that the bilirubin is not present merely as a consequence of proceeding damage to the cells. In an effort to elucidate the relationship of administration of sulfonamides to an increased incidence of kernicterus in premature infants, studies were undertaken in newborn albino rats. The sulfonamide under consideration, Gantrism® (sulfisoxazole), was shown not to be toxic in itself for newborn rats. It did not produce evidence of hemolysis or damage to the liver or pancreas. When bilirubin or trypan blue was injected into newborn rats which had been treated with Gantrisin®, all the tissues except brain were stained. It was concluded that Gantrisin® does not alter the permeability of the blood brain barrier. It had been previously observed that sulfonamide treatment produced a decrease in the bilirubinemia in the Gunn strain of rat, and an increased occurrence of icterus in all tissues. Thus, it is suggested that the drug induces a shift of bilirubin from the vascular bed into other body compartments without altering capillary permeability. In the third part of this paper, the present knowledge of the pathogenesis of kernicterus and the various theories concerning its development are reviewed. The authors propose that unconjugated bilirubin is itself the toxic agent producing nerve-cell necrosis. They envisage kernicterus as being the result of a presence of a diffusable form of unconjugated bilirubin in plasma and a shift of this compound from the circulating blood to the brain and other tissues. The increase in the unconjugated bilirubin is due to deficient activity of glucuronyl transferase in the liver, and the formation of the diffusable compound is possibly related to failure of adequate protein-binding of bilirubin.