pre-hepatic metabolism (bilirubin)

Last reviewed 01/2018

Bilirubin is first formed in macrophages of the reticuloendothelial system. The initial substrate is predominantly haemoglobin, but any compound containing a haem nucleus may be a precursor e.g. catalase, myoglobin.

The source of haemoglobin is senescent erythrocytes. They are phagocytosed by the macrophage. 7.5g per day of haemoglobin are released in the healthy adult.

Within the macrophage, haemoglobin is broken down to:

• globin chains; broken down into constituent amino acids for recycling
• haem group

Then, the haem group is cleaved by the enzyme haem oxygenase to liberate:

• iron cations; stored in macrophage and recycled to cytoplasmic pool
• carbon monoxide; expired via lungs
• biliverdin

Biliverdin is converted to bilirubin by the enzyme biliverdin reductase. Up to 250mg of bilirubin is produced per day in the healthy adult.

Bilirubin is insoluble in water and so must be carried by albumin within plasma. Binding with albumin also shields it from uptake by adipose tissue with subsequently reduced toxicity. Bilirubin then circulates haematogenously before uptake by the liver.

If not taken up by the liver or if produced in excess, unconjugated bilirubin is deposited in extra-hepatic tissues. This results in pre-hepatic jaundice.