Bilirubin is a breakdown product of heme (ferroprotoporphyrin IX). About 4 mg/kg body weight of bilirubin is produced each day, nearly 80% from the breakdown of hemoglobin in senescent red blood cells and prematurely destroyed erythroid cells in the bone marrow and the remainder from the turnover of hemoproteins such as myoglobin and cytochromes distributed throughout the body.
The initial steps of bilirubin metabolism occur in reticuloendothelial cells, predominantly in the spleen. Heme is converted to biliverdin by the microsomal enzyme heme oxygenase. Biliverdin is then converted to bilirubin by the cytosolic enzyme biliverdin reductase.
Bilirubin formed in the reticuloendothelium is lipid soluble and virtually insoluble in water. In order to be transported in blood, this unconjugated bilirubin must be solubilized. The process is initiated by reversible, noncovalent binding to albumin, which has both high-affinity and lower-affinity binding sites for unconjugated bilirubin. The unconjugated bilirubin-albumin complex readily passes through the fenestrations in the endothelium lining the hepatic sinusoids into the space of Disse, where the bilirubin dissociates from albumin and is taken up by the hepatocytes via a protein-mediated, facilitated process, possibly mediated by a liver-specific organic anion transport protein.
After entering the hepatocyte, unconjugated bilirubin is bound in the cytosol to a number of proteins, including proteins in the glutathione S-transferase superfamily. These proteins serve to reduce efflux of bilirubin back into the serum and present the bilirubin for conjugation. The enzyme uridine-5'-diphosphate (UDP) glucuronyl transfer-ase found in the endoplasmic reticulum solubilizes bilirubin by conjugating it to glucuronic acid to produce bilirubin monoglucuronide and diglucuronide. The now hydrophilic bilirubin diffuses to the canalicular membrane for excretion into the bile canaliculi.
Conjugated bilirubin is transported across the canalicular membrane by the multiple drug resistance-associated protein 2 (MRP2) via an adenosine triphosphate (ATP)-dependent process. This is the only energy-dependent step in bilirubin metabolism and explains why even patients with fulminant hepatic failure have a predominantly conjugated hyperbilirubinemia. Once in the bile, conjugated bilirubin passes undisturbed until it reaches the distal ileum and colon, where bacteria containing β-glucuronidases hydrolyze conjugated bilirubin to unconjugated bilirubin, which is further reduced by bacteria to colorless urobilinogen.
The urobilinogen is either excreted unchanged, oxidized and excreted as urobilin, which has an orange color, or absorbed passively by the intestine into the portal system as urobilinogen. The majority of the absorbed urobilinogen is re-excreted by the liver. A small percentage filters across the renal glomerulus and is excreted in urine.
Unconjugated bilirubin is never found in urine because in the serum it is bound to albumin and not filtered by the glomerulus. The presence of bilirubin in urine indicates a conjugated hyperbilirubinemia and hepatobiliary disease.
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