Bilirubin
Bilirubin is a breakdown product of the heme component of the hemoglobin molecule and to a lesser extent of the breakdown of other porphyrin-containing compounds (e.g., myoglobulin, cytochrome P450, peroxidase, catalase).
Bilirubin exists in the serum in three forms (unconjugated bilirubin, conjugated bilirubin α, and bilirubin δ) and is responsible for the yellow color known as icterus, or jaundice, of the mucous membranes. Unconjugated, prehepatic, albumin-bound bilirubin is also known as indirect-reacting bilirubin, which used to be determined by the van den Bergh reaction; currently total bilirubin is measured by the 2,5-dichlorophenyldiazonium (DPD) method, and direct bilirubin is determined by the method of Jendrassik and Grof.62 Indirect-reacting bilirubin must be taken up by the liver cells, where it is conjugated and then excreted in the bile. Conjugated bilirubin is known as direct-reacting bilirubin, as determined by the van den Bergh reaction. Horses normally have a much higher serum bilirubin level than ruminants, and hot-blooded horses have a higher bilirubin level than coldblooded horses of the pony and draft breeds. The horse also differs from ruminants in that horses often develop moderate icterus in response to fasting or anorexia associated with many systemic diseases. The increase in the bilirubin concentration in these horses is caused almost entirely by an increase in unconjugated (indirect-reacting) bilirubin, and within a few days the bilirubin can increase from the normal range up to 6 to 8 mg/dL (103 to 137 μmol∕L). Therefore the total serum bilirubin concentration is of little diagnostic value in the ill horse unless both the direct- and indirect-reacting bilirubin values are determined. However, in general terms unconjugated hyperbilirubinemia occurs when there is increased production of bilirubin or when either hepatic uptake or conjugation of bilirubin is diminished. Conjugated hyperbilirubinemia is caused by either intrahepatic cholestasis or extrahepatic bile duct obstruction.Total serum bilirubin is elevated in animals with hemolytic anemia, and this increase is caused largely by an increase in indirect-reacting bilirubin (Box 22.18). The degree to which bilirubin is elevated in hemolytic anemia is a function of the rate of RBC destruction and the capacity of the liver to excrete the newly formed bilirubin. The total bilirubin rarely exceeds 10 mg/dL (170 μmol∕L) in hemolytic anemia. An exception is the hemolytic anemia of neonatal isoerythrolysis in newborn
■ BOX 22.18
Causes of Elevated Serum Bilirubin
Elevation of Total Serum Bilirubin
Common Causes
Hemolytic anemia Liver failure
Secondary to systemic disease or anorexia in horses
Uncommon Cause
Chronic liver failure in cattle
Elevation of Indirect-Reacting Bilirubin
Common Causes
Secondary to systemic disease or anorexia in horses Liver failure
Hemolytic anemia
Uncommon Cause
Chronic liver failure in cattle
Elevation of Direct-Reacting Bilirubin
Common Causes
Liver failure
Cholelithiasis Cholangiohepatitis
Neonatal isoerythrolysis
Uncommon Cause
Hemolytic anemia
foals, which is often associated with marked clinical icterus. In these foals the serum bilirubin may exceed 25 mg/dL (428 μmol∕L), a variable but substantial proportion of which (40% to 60%) is likely to be direct-reacting bilirubin causing kernicterus in some cases.
The second major cause of clinical icterus and increased serum bilirubin is liver failure. Liver failure results in impaired uptake and excretion of bilirubin. Acute liver failure caused by hepatic necrosis results in marked to moderate increases in both direct- and indirect-reacting bilirubin. In horses with acute liver failure, bilirubin often exceeds 10 mg/dL (170 μmol∕L), and this increase is caused primarily by increases in indirect-reacting bilirubin. Direct-reacting bilirubin rarely exceeds 25% of the total bilirubin in the horse, and increases of this magnitude suggest an intrahepatic or extrahepatic biliary obstruction. With chronic liver failure, icterus is more variable and total bilirubin rarely exceeds 10 mg/dL (170 μmol∕L). Liver failure in ruminants, particularly chronic liver failure, is associated with a much less striking elevation in serum bilirubin than occurs in horses. In the absence of hemolytic anemia, a bilirubin value above 2 mg/dL (34 μmolTL) indicates impaired hepatic function in ruminants. Hyperbilirubinemia without clinical icterus may be observed in cattle and in sheep with fatty liver associated with ketosis/acetonemia; in such cases, the predominant pigment is unconjugated bilirubin. In horses, unconjugated hyperbilirubinemia can occur a few days after prolonged halothane anesthesia.63