Liver Function Tests
Bilirubin Metabolism
a. Bilirubin is a pigment that is produced by the degradation of the heme portion of hemoglobin and myoglobin and, to a smaller extent, non-heme porphyrins.
b. Most bilirubin is produced in mononuclear phagocytes.
c. Birds lack biliverdin reductase and do not form significant quantities of bilirubin.
d. Bilirubin is metabolized to urobilinogen by bacteria in the intestine. This can be reabsorbed and excreted in urine. Urine urobilinogen may be increased with increased bilirubin delivery to the GI tract (hemolytic disease) or decreased
absent in patients with biliary obstruction orintestinal malabsorption.
Types of bilirubin
a. Unconjugated bilirubin
(1) Unconjugated bilirubin is not water soluble.
(2) It is transported in the blood bound to albumin by an ionic bond.
b. Conjugated bilirubin
(1) Unconjugated bilirubin is dissociated from albumin at the hepatocyte cell membrane and taken into the hepatocyte by plasma membrane transporters.
(2) Conjugated bilirubin is formed in the hepatocyte by glucuronidation, which renders the molecule water soluble.
Conjugated vs. unconjugated bilirubin concentrations in interpretation of hyperbilirubinemia
a. Comparison of relative concentrations of unconjugated and
conjugated bilirubin can be used to attempt to characterize the cause of hyperbilirubinemia
b. Unconjugated bilirubin should theoretically predominate in pre- hepatic or hepatic hyperbilirubinemia, and conjugated bilirubin should predominate in post-hepatic hyperbilirubinemia.
Pre-hepatic hyperbilirubinemia
Hyperbilirubinemia is an increased serum concentration of bilirubin.
Increased bilirubin production.
(1) Increased erythrocyte breakdown with hemolytic disease or
following internal hemorrhage causes increased bilirubin production.
(2) The resulting increase in bilirubin concentration overwhelms hepatic uptake, conjugation, and/or secretion capacities.
Hepatic hyperbilirubinemia
Decreased hepatic uptake or conjugation
(1) Loss of hepatic function results in decreased capacity for bilirubin uptake and conjugation.
(2) Anorexia or fasting in horses decreases bilirubin uptake by
hepatocytes. Total bilirubin concentration may reach 10 mg/dL in otherwise healthy horses.
(3) Sepsis may decrease bilirubin uptake.
Post-hepatic hyperbilirubinemia.
Cholestasis
(1) Decreased secretion of bilirubin into bile.
(2) Physical obstruction of bile flow may occur intraheptically with neoplastic disease, hepatocyte swelling in hepatic lipidosis, or
corticosteroid hepatopathy.
(3) Extrahepatic cholestasis may occur with cholangitis, cholelithiasis, cholecystitis, and pancreatitis
Bilirubinuria
a. Conjugated bilirubin passes through the glomerular filter into the urine.
b. Unconjugated bilirubin and biliprotein are albumin bound. This
molecular complex is too large to pass through the normal glomerular filter
Bile acids
1. Bile acids (also known as bile salts) are synthesized in the liver from cholesterol. They are conjugated and secreted into bile, where they function to solubilize lipids and aid in fat digestion in the intestine.
2. Most of the bile acids excreted in bile are resorbed in the portal circulation and recycled. This process is termed enterohepatic
circulation. Bile acids are efficiently removed from portal blood by cellular transporters on the sinusoidal membrane of hepatocytes.
3. Bile acids may contribute to hepatocellular membrane damage in cholestasis through a detergent action.
Increased bile acid concentration
a. Portosystemic shunts typically cause increased bile acid concentration.
(1) Portal blood (with its high concentration of bile acids) bypasses the liver and enters the systemic circulation. Bile acid uptake from systemic blood is less efficient than from portal blood.
(2) Hepatic atrophy resulting from a chronic shunt produces a loss of hepatic functional mass, resulting in decreased ability to remove bile acids from blood.
Increased bile acid concentration
In some animals with portosystemic shunts, baseline bile acid
concentration may be within the reference interval while postprandial bile acid concentration is increased.
c. In liver failure, a loss of functional hepatic mass results in increased bile acid concentration due to decreased bile acid recycling.
d. Cholestasis causes reflux of bile acids into the bloodstream, increasing bile acid concentrations.
e. Inappropriate contraction of the gallbladder may cause an elevated fasting bile acid concentration.
Decreased bile acid concentration
a. Small intestinal disease (ileal malabsorption) may cause decreased bile acid resorption. This may complicate the assessment of concurrent hepatic disease.
b. Although bile acids are synthesized by the liver, decreased bile acid concentration usually is not observed in hepatic failure. This may be explained by the recirculation and reutilization of bile acids, as well as the low reference intervals for serum bile acid values.
