Bilirubin Toxicity to Human Erythrocytes: A More Sanguine View

Abstract

In 1962 Watson1 observed that a small fraction of the bilirubin in blood from jaundiced newborns is associated with red cells. A few years later, Cheung et al2 showed that red cells undergo time- and concentration-dependent changes in morphology and metabolism, with eventual hemolysis, when incubated with bilirubin in buffer, particularly at concentrations of >340 μM (20 mg/dL). (In retrospect, it seems highly likely that the bilirubin solutions to which the cells were exposed were supersaturated and may have contained aggregated forms of bilirubin.3–7) The bilirubin-induced morphologic changes were illustrated by striking photographs similar to those published some 30 years later, without reference to the earlier work, by others.8,9 These changes were reversible by addition of serum albumin to the incubation medium and did not occur when albumin was present in the medium from the start. Subsequently, Brito et al10 have confirmed and extended these observations and recently reviewed the toxicity of bilirubin to red cells (again without alluding to the seminal earlier work). For the neonatologist, an important question is whether bilirubin-induced hemolysis is clinically significant in neonatal jaundice or in other unconjugated hyperbilirubinemias. The review implies that it is.10 There is, however, much evidence that it is not: 1. Gunn rats and patients with severe Crigler-Najjar syndrome have lifelong unconjugated hyperbilirubinemia yet no abnormal hemolysis. In fact, the human disorder was originally described as a “nonhemolytic jaundice,”11 and patients have been described who showed no abnormal erythrocyte morphology, reticulocytosis, or other evidence of hemolysis despite prolonged exposure to high plasma bilirubin concentrations.12–14 Comparisons between nonjaundiced and jaundiced rats with congenital unconjugated bilirubinemia (Gunn rats) showed no difference in hematocrit values in male rats and only slightly lowered values in jaundiced female rats.15 No difference … Address correspondence to Antony F. McDonagh, PhD, Division of Gastroenterology and the Liver Center, Room S-357, Box 0538, University of California, 513 Parnassus Ave, San Francisco, CA 94143-0538. E-mail: tony.mcdonagh{at}ucsf.edu