Icterus is a term used to describe the clinical appearance of hyperbilirubinemia. While reference values may vary, in most
instances a serum bilrubin > 1 mg/dl is considered abnormal but clinically detectable icterus usually does not occur until
the bilirubin is > 3 mg/dl.
Bilirubin is formed from the breakdown of hemoglobin (primary source), myoglobin and other proteins containing porphyrin.
The cells of the mononuclear phagocytic system in the spleen, liver and bone marrow phagocytize damaged red blood cells.
The red blood cells are broken down and hemoglobin released. Hemoglobin is broken down into heme and globin. Globin is converted
to amino acids. Heme is broken down into iron and protoporphyrin. Protoporphyrin is converted to biliverdin and then bilirubin.
Bilirubin is released from the phagocytic cells, attached to a transport protein and transferred into the hepatocytes of the
liver through a saturable membrane transport system. Once in the hepatocyte, bilirubin binds to the protein ligandin, which
prevents efflux back into the bloodstream. This bilirubin is then conjugated and most of it excreted into the bile canaliculi
with much less moving into the bloodstream. Some of the bilirubin in the bloodstream remains unbound and passes into the
urine but some is protein bound in circulation (biliprotein, delta bilirubin). This is why both conjugated and unconjugated
bilirubin can be found in circulation. The conjugated bilirubin in the bile is excreted into the small intestine where bacteria
convert it to urobilinogen. Almost all urobilinogen is excreted into the feces as stercobilin with only a small amount reabsorbed
that either is taken up by the liver or excreted in the kidneys.
Hyperbilirubinemia can result from excessive bilirubin production (pre hepatic), impaired hepatic uptake/conjugation (hepatic)
or decreased excretion (post hepatic). Excess bilirubin production is most commonly due to hemolysis but may also occur with
extensive internal bleeding and breakdown of damaged red blood cells. With extravascular hemolysis bilirubin production occurs
as described above but with intravascular hemolysis hemoglobin is free in circulation then complexes with haptoglobin and
is removed by hepatocytes where hemoglobin breakdown occurs.
Hepatocellular dysfunction from decreased functional mass, poor perfusion or defects in uptake or conjugation can also cause
hyperbilirubinemia and icterus. This occurs with inflammatory, infiltrative and necrotic diseases of the liver.
Decreased bilirubin excretion results from impaired bile flow outside of the liver. Inflammatory, infectious, neoplastic
and obstructive diseases that affect the cystic duct, gall bladder, common bile duct, or duodenum can affect bile flow.