Bilirubin Physiology

Bilirubin Metabolism

Degradation product of heme
70-90% is derived from hemoglobin of erythrocytes, which are destroyed in the RES. The remainder are from non-hemoglobin hemoproteins like myoglobin, CYP, and from premature destruction

Unconjugated bilirubin is tightly but reversibly bound to albumin in the blood due to insolubility
- Can be displaced by salicylates, sulfonamides, lasix, contrast, ceftriaxone
- This displacement is important in neonates due to the risk of kernicterus from unconjugated bilirubinemia

Unconjugated bilirubin is conjugated by UGT1 and then transported out of the cell
Conjugated greatly increases the aqeuous solubility of bilirubin
- Enhances elimination from the body
- Reduces ability to diffuse across biologic membranes including the BBB

Normal bile is mostly conjugated bilirubin
In the GI tract, most conjugated bilirubin is converted to urobilinogen by bacteria in the ileum and colon, where it Is reabsorbed and returns to the liver via the portal circulation, and then re-excreted into bile. This is enterohepatic recirculation.
Excess urobilinogen reaches the systemic circulation where it is cleared by the kidneys.
- Increased in states of increased bilirubin reaching the gut or decreased liver function
  - Hemolysis
  - Liver disease
- Decreased in states of:
  - Severe cholestasis
  - Bile duct obstruction
  - Elimination of bacterial conversion to urobilinogen
Unconjugated bilirubin normally does not reach the gut, except in the following. When it does it is reabsorbed and contributes to hyperiblirubinemia.
- Neonates
- Crigler-Najjar syndrome

Normal plasma contains mostly unconjugated bilirubin with only trace conjugated bilirubin.
Modern labs quantify "direct" versus "indirect" bilirubin; the "direct" reacts rapidly to diazo reagents and the "indirect" reacts slowly and therefore needs an accelerator like ethanol due to protection of the vulnerable bond from internal H-bonds.
Classically, "direct" = conjugated, although this is inaccurate and just an approximation. About 10-20% of bilirubin gives a "direct" reaction although only <5% of bilirubin is normally conjugated.
Therefore, consider <15% direct as essentially all unconjugated. When >15%, a dipstick for bilirubinuria can clarify the situation as unconjugated bilirubin is not excreted in urine due to tight binding to albumin.
Conjugated bilirubin is easily excreted; bilirubinuria is ALWAYS pathologic.
Prolonged conjugated hyperbilirubinemia can lead to delta-bilirubin formaiton which is covalent bonding to albumin, which has a half-life of 14 to 12 days. This can cause extended mixed/pure conjugated hyperbilirubinemia although the bilirubinuria or underlying cause has resolved.