Crigler-Najjar syndrome is (an autosomal recessive trait) a genetic disease, the main characteristics of this disease being accumulation of high levels of free or unconjugated bilirubin in blood also called hyperbilirubinemia. During the process of normal turnover of the red blood cells (RBC), hemoglobin is broken and the waste product that is generated is bilirubin. It is produced from the reticuloendothelial cells (macrophages) when they take aged erythrocytes and degrade the heme moiety present in hemoglobin. Bilirubin is insoluble in water and before excretion in the bile it must be conjugated with a substance called UDP-glucuronic acid. This process takes place in the hepatocytes where, the bilirubin-uridine diphosphoglucuronate glucuronosyltransferase (B-UDPGT) also known as UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme which is expressed in human liver helps in the conjugation of bilirubin with UDP-glucuronic acid. To understand this process let us go through the metabolism of hemoglobin and glucuronidation reaction (Figure 27.1).

1. RBC has a mean life of 120 days. On completion of this duration it undergoes senescence releasing heme protein.

2. Breakdown of heme to bilirubin takes place in the macrophages of reticuloendothelial system (tissue macrophages, spleen and liver). First, heme is oxidized in the presence of heme oxygenase to biliverdin which is then reduced in the presence of biliverdin reductase to bilirubin.

3. Unconjugated or free bilirubin is complexed or bound with albumin and transported through blood to the liver. Unconjugated or free bilirubin which is not bound to albumin is fat soluble and travels to the brain.

4. Bilirubin is taken up by the hepatocytes through facilitated diffusion. One molecule of bilirubin is conjugated with 2 molecules of UDP-glucuronic acid by the process called “glucuronidation” and is one of the methods used by the cells for detoxification.

Some facts: DP-glucuronic acid is synthesized in the cytosol by the UDP-glucuronic acid synthetic pathway in the presence of UDP-glucose dehydrogenase.