Bilirubin and Urobilinogen Formation

Jaudice is the visibly evident symptom of amber coloration of the skin and sclera from increased circulating concentration of the pigment bilirubin, a heme degradation product. Senescent and/or damaged red cells are phagocytized in the reticuloendothelial system, where hemoglobin degradation results in the formation of bilirubin. Newly formed bilirubin is transported in the circulation tightly bound to albumin and is taken up by the liver, where it is conjugated with glucuronic acid and actively secreted into the bile canaliculi. A small portion of water soluble, conjugated bilirubin diffuses from hepatoctes into plasma. Being water soluble, conjugated bilirubin is not bound to albumin and is freely filtered by the glomeruli, in contrast to unconjugated bilirubin.
Urobilinogen is formed from bilirubin by the action of intestinal microorganisms and a small portion is absorbed into the portal circulation. A portion of urobilinogen in the portal circulation escapes hepatic uptake, and consequent biliary excretion. Circulating, water soluble urobilinogen is filtered by the glomeruli and excreted into urine.

Laboratory Determinations

Analytic methods allow determination of total bilirubin and a "direct" fraction that is equivalent to conjugated bilirubin. "Indirect" bilirubin is the difference between total and direct and represents the unconjugated fraction.
Urine bilirubin and urobilinogen is determined semiquantitatively in urine specimens as a component of dipstick analysis in the routine urinalysis.

Normal ranges are:
total bilirubin   <  1.4 mg/dl
direct bilirubin   <   0.4 mg/dl
urine bilirubin undetectable
urine urobilinogen undetectable

Pathophysiology of Jaundice

The circulating concentration of bilirubin may become elevated as a consequence of

- increased rate of hemolysis, and/or - deficient hepatic uptake, conjugation, or secretion
- biliary obstruction

The normal liver has considerable excess capacity to take up, conjugate and secrete bilirubin. Hemolysis must be fairly significant in order for bilirubin production rate to exceed the liver's capacity to handle the increased load of unconjugated bilirubin. Jaundice from hemolytic disease, therefor, is usually relatively mild. Serum bilirubin concentraton must be greater than 2 - 3 mg/dl for jaundice to be readily noticeable. Jaundice is often not evident in hemolytic disease. Urine urobilinogen responds in a more sensitive manner to hemolysis than does serum bilirubin. Urine bilirubin is negative in hemolytic disease because the unconjugated, albumin bound fraction is elevated. Jaundice, with negative urine bilirubin, is referred to as "acholuric" jaundice and is an important sign of hemolysis.

Conjugated bilirubin predominates in jaundice from biliary obstruction, and in cases of hepatocellular liver disease as well. (The conjugated fraction predominates in hepatocellular liver disease because active biliary secretion is the rate limiting step of the process and most affected by cell injury.) Urine bilirubin is positive and urine urobilinogen is negative. Cases of biliary obstruction present with marked jaundice only when the common duct is obstructed; unaffected regions readily handle that which is regurgitated from obstructed regions. Jaundice from complete biliary obstruction is accompanied by "clay-colored" or colorless, "chalky" stools. Results from the liver enzymes AST, ALT, alkaline phosphatase and gGT are useful for distinguishing between hepatocullar and obstructive disease and in detecting partial obstruction. The transaminases are elevated to a greater extent in cases of hepatocellular disease; alk. phos. and gGT are elevated to a greater extent in obstruction. Alk. phos. and gGT are elevated in cases of partial obstruction, eventhough jaundice may be absent. Reduced biliary excretion of cholesterol also leads to hypercholesterolemia in obstructive liver disease. The differential diagnosis of jaundice from laboratory test results is summarized below.
*D/T is not typically reported, but is included here to emphasize that direct bilirubin is the predominant fraction in both hepatocellular and obstructive liver disease.

Cirrhosis refers to chronic, advanced liver disease with replacement of hepatocytes with fibrous tissue and insiduous loss of function.
The enzyme, glucuronyl transferase is often deficient in neonates and unconjugated bilirubin accumulates, usually only to a mild degree. In extreme cases, the albumin binding capacity may be exceeded (~ 20 mg/dl) and unconjugated bilirubin deposits in fatty tissue, including the central nervous system. Kernicterus refers to staining of basal ganglia and other CNS structures and consequent permanent neural damage. Kernicterus is thought to be restricted to neonates because of the immature blood-brain barrier.