Systemic regulation of bilirubin homeostasis

Abstract

Neurotoxic bilirubin is the end product of heme catabolism in mammals. Bilirubin is solely conjugated by uridine diphospho-glucuronosyltransferase 1A1, which is a membrane-bound enzyme that catalyzes the transfer of glucuronic acid. Due to low function of hepatic and intestinal uridine diphospho-glucuronosyltransferase 1A1 during the neonatal period, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage, termed kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does this most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced hyperbilirubinemia might bring certain benefits that outweigh those risks. While bilirubin is neurotoxic and cytotoxic, this compound is also a potent antioxidant. There are studies showing improved clinical conditions in patients with hyperbilirubinemia. Accumulating evidence also shows that genetic polymorphisms linked to hyperbilirubinemia are beneficial against various diseases. In this review article, we first introduce the production, metabolism, and transport of bilirubin. We then discuss the potential benefits of neonatal and adult hyperbilirubinemia. Finally, epigenetic factors as well as metabolomic information associated with hyperbilirubinemia are described. This review article advances the understanding of the physiological importance of the paradoxical compound bilirubin. (Hepatology 2018;67:1609-1619).

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

“…Bilirubin conjugation increases water solubility and reduces cytotoxicity of bilirubin. Hepatic and intestinal UGT1A1 are functionally reduced in neonatal stages, and hence, unconjugated hyperbilirubinemia is commonly found in human neonates [ 2 ]. Conjugated bilirubin, or direct bilirubin, is the major form of bilirubin in bile and is eliminated in stool.…”

“…Jaundice, a yellowish pigmentation of the skin and sclera, is caused by the disrupted excretion of bilirubin and biliverdin. Interestingly, some studies involving neonates or adults have shown that hyperbilirubinemia is protective against diseases, including metabolic syndrome and asthma, [ 2 , 3 ] suggesting that bilirubin may play a role as an antioxidant [ 4 ].…”

Effects of resuscitation with human albumin 5%, hydroxyethyl starch 130/0.4 6%, or crystalloid on kidney damage in an ovine model of septic shock

“…In clinical settings, an increase in bilirubin may indicate amongst others haemolysis, liver failure, or obstruction of the biliopancreatic system. 18 A possible explanation for the present phenomenon might be increased transport capacity of unconjugated bilirubin by increased intravascular albumin concentration. 19 The authors of the Albumin Replacement in Patients with Severe Sepsis or Septic Shock (ALBIOS) trial also detected an increase in serum bilirubin concentration in patients receiving intravenous albumin and considered relevant amounts of bilirubin in the administered albumin solutions as a potential reason.…”

Effect of UDP‐glucuronosyltransferase 1A1 activity on risk for developing Gilbert's syndrome

“…Although UGT1A1 is the sole enzyme responsible for the glucuronidation of bilirubin in humans, low UGT1A1 activity is not the sole risk factor for the development of Gilbert's syndrome . Indeed, in addition to defective bilirubin conjugation (low UGT1A1 activity), such as defective bilirubin uptake by hepatocytes (eg, polymorphisms in the organic anion transporting polypeptide 2, defective heme oxygenases, defective biliverdin reductase A, G6PD deficiency, and breast feeding) are also risk factors for the development of unconjugated hyperbilirubinemia . Those risk factors are worthy of investigation in patients suffering from hyperbilirubinemia with low to moderate UGT1A1 activity (>41% of normal).…”