How is bilirubin metabolized?

Bilirubin metabolism involves several key steps:

1. Formation of Bilirubin:

- Bilirubin is primarily derived from the breakdown of heme, the iron-containing molecule in hemoglobin and other hemeproteins.

- Senescent red blood cells are phagocytosed by macrophages in the spleen, liver, and bone marrow.

- Within macrophages, heme oxygenase (HO) breaks down heme, releasing biliverdin, iron (Fe2+), and carbon monoxide (CO).

- Biliverdin reductase, an enzyme, further reduces biliverdin to form unconjugated bilirubin. This unconjugated bilirubin is transported to the liver by albumin.

2. Hepatic Uptake and Conjugation:

- In the liver, unconjugated bilirubin binds to specific carrier proteins in the hepatocyte membrane, facilitating its uptake into hepatocytes.

- Once inside the hepatocytes, unconjugated bilirubin is converted to conjugated bilirubin through a process known as bilirubin conjugation.

- The conjugation reaction involves the transfer of two glucuronic acid molecules to unconjugated bilirubin by the enzyme UDP-glucuronosyltransferase (UGT1A1).

- The resulting product, conjugated bilirubin (bilirubin diglucuronide), is water-soluble and nontoxic, in contrast to the hydrophobic unconjugated bilirubin.

3. Biliary Excretion:

- After conjugation, bilirubin is transported into the bile canaliculi, small channels within the liver, and subsequently excreted into the bile.

- Bile flows from the liver to the gallbladder, where it is stored and concentrated.

- During digestion, the gallbladder contracts, and bile is released into the small intestine.

4. Intestinal Metabolism and Enterohepatic Circulation:

- In the intestines, gut bacteria play a crucial role in bilirubin metabolism. Bacterial enzymes, such as beta-glucuronidases, hydrolyze the glucuronic acid conjugates, releasing unconjugated bilirubin.

- Some of the unconjugated bilirubin may be reabsorbed through the intestinal wall (enterohepatic circulation) and returned to the liver.

- The majority of unconjugated bilirubin is further metabolized by intestinal bacteria to form various breakdown products, including stercobilin and urobilin, which contribute to the color of feces.

Ultimately, bilirubin is eliminated from the body primarily through fecal excretion and, to a lesser extent, through urinary excretion of some bilirubin breakdown products.