[7][8] Most often, the free and water-insoluble unconjugated bilirubin which has an internal hydrodren[clarification needed] bonding[9] will bind to albumin and, to a much lesser extent, high density lipoprotein in order to decrease its hydrophobicity and to limit the probability of unnecessary contact with other tissues[1][9] and keep bilirubin in the vascular space from traversing to extravascular space including brain, and from ending up increasing glomerular filtration.

[23][24][5] In greater detail about this reaction, a glucuronosyl moiety is conjugated to one of the propionic acid side chains, located on the C8 and C12 carbons of the two central pyrrole rings of bilirubin.

[25] When the first step is completely done, the substrate bilirubin glucuronide (also known as mono-glucuronide[26]) is born at this stage and is water-soluble and readily excreted in bile.

[1] Nonetheless, in the setting of severe liver disease, a significantly greater number of conjugated bilirubin will leak into circulation and then dissolve into the blood[note 2] and thereby filtered by the kidney, and only a part of the leaked conjugated bilirubin will be re-absorbed in the renal tubules, the remainder will be present in the urine making it dark-colored.

[3] In Dubin–Johnson syndrome, impaired biliary excretion of bilirubin glucuronide is due to a mutation in the canalicular multiple drug-resistance protein 2 (MRP2).

[3] In case of hyperbilirubinemia due to intrahepatic or extrahepatic bile ducts blockage, e.g. gallstone, the name is given as Post-hepatic (or obstructive) jaundice.

[36] In Crigler Najjar disease, there is an inherited deficiency of glucuronyl transferase resulting in high concentrations of unconjugated bilirubin appear in the plasma.

[3] In Gilbert's syndrome, glucuronyl transferase activity is reduced by approximately 70%, leading to mild accumulation of unconjugated bilirubin in the plasma.