What is the biochemistry of bilirubin relative to unconjugated hyperbilirubinemia?

Updated: May 21, 2019
  • Author: Hisham Nazer, MBBCh, FRCP, DTM&H; Chief Editor: BS Anand, MD  more...
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Bilirubin is a potentially toxic catabolic product of heme metabolism. There are elaborate physiologic mechanisms for its detoxification and disposition. Understanding these mechanisms is necessary for interpretation of the clinical significance of high serum bilirubin concentrations. (See Pathophysiology and Prognosis.)

In adults, 250-400 mg of bilirubin is produced daily. Approximately 70-80% of daily bilirubin is derived from the degradation of the heme moiety of hemoglobin. The remaining 20-25% is derived from the hepatic turnover of heme proteins, such as myoglobin, cytochromes, and catalase. A small portion of daily bilirubin is derived from the destruction of young or developing erythroid cells.

Bilirubin is poorly soluble in water at physiologic pH because of the internal hydrogen bonding that engages all polar groups and gives the molecule an involuted structure. The fully hydrogen-bonded structure of bilirubin is designated bilirubin IX-alpha-ZZ. The intramolecular hydrogen bonding shields the hydrophilic sites of the bilirubin molecule, resulting in a hydrophobic structure. Water-insoluble, unconjugated bilirubin is associated with all the known toxic effects of bilirubin. Thus, the internal hydrogen bonding is critical in producing bilirubin toxicity and also prevents its elimination.

Conversion of bilirubin IX-alpha to a water-soluble form by disruption of the hydrogen bonds is essential for its elimination by the liver and kidney. This is achieved by glucuronic acid conjugation of the propionic acid side chains of bilirubin. Bilirubin glucuronides are water-soluble and are readily excreted in bile. Bilirubin is primarily excreted in normal human bile as diglucuronide; unconjugated bilirubin accounts for only 1-4% of pigments in normal bile. (See the images below.)

Production of bilirubin. Production of bilirubin.
Enterohepatic circulation of bilirubin. Enterohepatic circulation of bilirubin.
Conjugation of bilirubin. Conjugation of bilirubin.

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