What is the pathophysiology of unconjugated hyperbilirubinemia?

Updated: May 21, 2019
  • Author: Hisham Nazer, MBBCh, FRCP, DTM&H; Chief Editor: BS Anand, MD  more...
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Answer

Unconjugated bilirubin is transported in the plasma bound to albumin. At the sinusoidal surface of the liver, unconjugated bilirubin detaches from albumin and is transported through the hepatocyte membrane by facilitated diffusion. Within the hepatocyte, bilirubin is bound to two major intracellular proteins: cytosolic Y protein (ie, ligandin or glutathione S-transferase B) and cytosolic Z protein (also known as fatty acid–binding protein [FABP]). The binding of bilirubin to these proteins decreases the efflux of bilirubin back into the plasma and, therefore, increases net bilirubin uptake. (See the image below.)

Enterohepatic circulation of bilirubin. Enterohepatic circulation of bilirubin.

In order for bilirubin to be excreted into bile and, therefore, eliminated from the body, it must be made more soluble. This water-soluble, or conjugated, form of bilirubin is produced when glucuronic acid enzymatically is attached to 1 or both of the propionic side chains of bilirubin IX-alpha (ZZ). Enzyme-catalyzed glucuronidation is one of the most important detoxification mechanisms of the body. Of the various isoforms of the UGT family of enzymes, only 1 of them, bilirubin-UGT1A1, is physiologically important in bilirubin glucuronidation.

UGT enzymes are normally concentrated in the lipid bilayer of the endoplasmic reticulum of the hepatocytes, intestinal cells, kidneys, and other tissues.

Attachment of glucuronic acid to bilirubin occurs through an ester linkage and, therefore, is called esterification. This esterification is catalyzed by bilirubin-UGT, which is located in the endoplasmic reticulum of the hepatocyte. This reaction leads to the production of water-soluble bilirubin monoglucuronide and bilirubin diglucuronide. Other compounds, such as xylose and glucose, also can undergo esterification with bilirubin.

Bilirubin diglucuronide is the predominant pigment in healthy adult human bile, representing over 80% of the pigment. However, in subjects with reduced bilirubin-UGT activity, the proportion of bilirubin diglucuronide decreases, and bilirubin monoglucuronide may constitute more than 30% of the conjugates excreted in bile.


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