Mechanisms of bilirubin toxicity: clinical implications

Jaundice is common in newborn infants. It results from the co-occurrence of two phenomena: (1) increased production of bilirubin caused by the breakdown of fetal red cells, and (2) low hepatic clearance caused by low concentrations of the binding protein ligandin in hepatocytes and low activity of bilirubin glucuronyl transferase, the enzyme responsible for conjugating bilirubin with glucuronic acid, and, thus enabling excretion in bile [1]. In the vast majority of infants jaundice is an innocuous event with no long lasting sequelae. In some infants the neurotoxic effects of bilirubin may cause drowsiness/lethargy, anorexia, and altered cry characteristics [2,3], and may be measurable in the form of changes in the auditory brainstem response and other neurophysiologic parameters [4]. In the majority of these infants, however, the bilirubin-induced changes seem to be reversible after the serum bilirubin level is lowered [5], although recent evidence raises questions about whether this is a consistent finding [6]. In a small minority of severely jaundiced infants, bilirubin toxicity may result in neonatal death, or survival with permanent sequelae in the form of choreoathetosis, gaze paresis, deafness, and occasionally, mental retardation [7]. The pathological correlate of this condition consists of yellow staining of the basal ganglia, and is commonly referred to by its German name, "kernicterus" [8]. Kernicterus was typically seen in infants with Rh-immunization; following the introduction of exchange transfusion and later, phototherapy, it was thought to be rare in the industrialized world [9,10]. Recent reports have suggested a resurgence of this problem [9,10]. This observation rekindled interest concerning the basic mechanisms of bilirubin neurotoxicity. The article focuses on the potential mechanisms of neurotoxicity and the implications for clinical practice.