Summary
Bilirubin is the breakdown product of heme, which is the iron-containing tetrapyrrole moiety of hemoglobin, myoglobin, and several enzymes. Heme cleavage, catalyzed by microsomal heme oxygenases, gives rise to biliverdin, which is reduced to bilirubin by biliverdin reductase. As an antioxidant, bilirubin provides health benefits at low concentrations, but at very high concentrations, it can cause bilirubin-induced neurological damage (BIND). Binding to plasma albumin, rapid uptake by hepatocytes, UGT1A1-mediated conjugation with glucuronide, and ATP-dependent pumping into bile canaliculi maintain low plasma concentrations of bilirubin, preventing its tissue toxicity. A fraction of bilirubin glucuronides formed in periportal hepatocytes is pumped out into sinusoidal blood and undergoes reuptake by hepatocytes located downstream to sinusoidal blood flow. Inherited disorders causing excessive bilirubin production, reduced glucuronidation, defective canalicular excretion, or abnormal reuptake can cause hyperbilirubinemia. Newborns have transient hyperbilirubinemia that normally resolves in 1–2 weeks, but can be prolonged or exacerbated by breast-feeding, delayed UGT1A1 maturation, or several inherited disorders of bilirubin metabolism. Mutations of UGT1A1 gene that cause complete or partial loss of the enzyme activity (Crigler-Najjar syndromes, types 1 and 2, respectively) increase specifically the unconjugated fraction of plasma bilirubin. A common polymorphism of UGT1A1 promoter causes mild and harmless increase of plasma bilirubin (Gilbert syndrome). Both conjugated and unconjugated bilirubin fractions are increased in disorders of canalicular organic anion excretion (Dubin-Johnson syndrome) or reuptake of bilirubin glucuronides (Rotor syndrome). A group of monogenic disorders, termed progressive familial intrahepatic cholestasis, cause hyperbilirubinemia not by specifically perturbing the bilirubin excretory pathway, but through extensive liver injury.
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Roy-Chowdhury, N., Guha, C., Roy-Chowdhury, J. (2022). Inherited Disorders of Bilirubin Metabolism. In: Blau, N., Dionisi Vici, C., Ferreira, C.R., Vianey-Saban, C., van Karnebeek, C.D.M. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-67727-5_58
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