Albumin administration prevents neurological damage and death in a mouse model of severe neonatal hyperbilirubinemia

Abstract

Therapies to prevent severe neonatal unconjugated hyperbilirubinemia and kernicterus are phototherapy and, in unresponsive cases, exchange transfusion, which has significant morbidity and mortality risks. Neurotoxicity is caused by the fraction of unconjugated bilirubin not bound to albumin (free bilirubin, Bf). Human serum albumin (HSA) administration was suggested to increase plasma bilirubin-binding capacity. However, its clinical use is infrequent due to difficulties to address its potential preventive and curative benefits, and to the absence of reliable markers to monitor bilirubin neurotoxicity risk. We used a genetic mouse model of unconjugated hyperbilirubinemia showing severe neurological impairment and neonatal lethality. We treated mutant pups with repeated HSA administration since birth, without phototherapy application. Daily intraperitoneal HSA administration completely rescued neurological damage and lethality, depending on dosage and administration frequency. Albumin infusion increased plasma bilirubin-binding capacity, mobilizing bilirubin from tissues to plasma. This resulted in reduced plasma Bf, forebrain and cerebellum bilirubin levels. We showed that, in our experimental model, Bf is the best marker to determine the risk of developing neurological damage. These results support the potential use of albumin administration in severe acute hyperbilirubinemia conditions to prevent or treat bilirubin neurotoxicity in situations in which exchange transfusion may be required.

Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases

“…Blood was obtained from anesthetized mice by facial vein bleeding. Bilirubin and albumin were determined in plasma as described previously (29,60).…”

Role of the kidneys in the redistribution of heme-derived iron during neonatal hemolysis in mice

“…Most studies on mouse neonatal jaundice have been performed on genetically modified animals showing impaired bilirubin conjugation and hyperbilirubinemia, which consequently experience early neonatal lethality due to bilirubin toxicity 15 . Here, our aim was to explore the role of the kidneys in iron handling during naturally occurring neonatal jaundice in mice.…”

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

“…It has been shown that the free fraction of unbound bilirubin (Bf) causes neurotoxicity in vivo, and that the decrease of Bf by albumin supplementation increases neuro-protection and survival of the mutant mice and rats [9, 10]. …”