Jaundice: Jaundice (or icterus), broadly defined, refers to the accumulation of excessive amounts of bilirubin in either the circulation
or the tissues.
Normal Bilirubin Metabolism (see Figure 1)
Figure 1: Normal Bilirub in Metabolism
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Bilirubin is primarily derived from breakdown of the hemoglobin of aging red cells by the mononuclear phagocytic system (MPS).
Although the normal degradation of erythrocytes can occur in any tissue that contains phagocytes, the process is concentrated
in the organs of the MPS (particularly the spleen). The hemoglobin molecule is initially split into heme and globin. Heme
is further metabolized into biliverdin and eventually bilirubin, during which process the iron within the heme molecule is
extracted for either reuse in the production of hemoglobin or storage within tissues. Smaller amounts of bilirubin are obtained
from the degradation of other iron-containing molecules such as myoglobin and hepatic hemoproteins. Bilirubin is released
from the tissues into the blood stream, where it binds to albumin and is carried via the circulation to the liver. Albumin-bound
bilirubin (called unconjugated, indirect or free bilirubin) is fat soluble and water insoluble, and cannot pass from the renal
circulation into the urine. Unconjugated bilirubin, upon reaching the hepatic vasculature, is separated from albumin and enters
hepatocytes. The hepatic enzyme glucuronyl transferase conjugates intracellular unconjugated bilirubin to form bilirubin diglucuronide
(called conjugated or direct bilirubin). Conjugated bilirubin is then released from hepatocytes into the bile canaliculi,
and excreted via the biliary system into the duodenum. Hepatocyte release of conjugated bilirubin into bile is the rate-limiting
step of bilirubin metabolism. Hepatocytes do not normally release significant amounts of conjugated bilirubin back into the
circulation. Conjugated bilirubin is water soluble and fat insoluble, and when present in the circulation will enter the urine.
Conjugated bilirubin entering the ileum and large intestine from the duodenum is converted by bacterial enzymes into urobilinogen,
most of which is subsequently excreted the feces. Bile-derived pigments such as urobilin (oxidized urobilinogen) give feces
its characteristic color. Some intestinal urobilinogen is reabsorbed by the colon and enters the portal circulation. Although
most of this reabsorbed urobilinogen is recycled by the liver, small amounts enter the systemic circulation and spill over
into the urine.
Classification of Jaundice
Jaundice is classified as prehepatic, hepatic or posthepatic, a classification based on the phase in bilirubin metabolism
that is affected by the causative disease process.
1. Prehepatic
Prehepatic jaundice is usually caused by the release of hemoglobin associated with RBC lysis. High plasma levels of unconjugated
(free) bilirubin derived from massive hemoglobin breakdown can overwhelm hepatic bilirubin metabolism. Since the liver is
usually very effective at conjugating free bilirubin, hemolysis must be acute and severe to cause jaundice. Patients with
prehepatic jaundice are therefore invariably severely anemic. Jaundice is typically transient, since ongoing hemolysis of
sufficient magnitude to cause persistent jaundice would cause death due to anemia. Hemolytic anemia in dogs and cats is most
commonly subacute or chronic, and therefore usually does not cause detectable jaundice.
Theoretically, prehepatic jaundice should cause high unconjugated bilirubin and normal conjugated bilirubin levels. However,
the increased hepatic production of conjugated bilirubin in response to high levels of unconjugated bilirubin can overwhelm
hepatocyte excretion mechanisms, particular if liver function is impaired by hypoxia secondary to severe anemia. Prehepatic
jaundice is therefore often a mixture of unconjugated and conjugated hyperbilirubinemia.
Common Causes of Prehepatic Jaundice
Immune-mediated hemolytic anemia Zinc toxicity
Heinz-body hemolytic anemia (e.g. onion toxicity) Erythrocyte parasites
Transfusion reaction
Cats: Mycoplasma hemofelis infections Dogs: Heartworm (caval syndrome)
Feline leukemia virus-associated anemia
Hypophosphatemia-induced hemolytic anemia
Acetaminophen toxicity
Neonatal isoerythrolysis
2. Hepatic Jaundice
Hepatic jaundice is caused by dysfunction of either hepatocytes or the intrahepatic biliary tree. Hepatocyte uptake and conjugation
of free bilirubin is impaired, as is hepatocyte and biliary excretion of conjugated bilirubin. Since the healthy liver has
a large functional reserve, most normal hepatic functions (including bilirubin metabolism) are not impaired unless liver disease
is severe. Mild hepatic diseases such as steroid or diabetic hepatopathy do not typically cause jaundice. Theoretically, any
cause of severe liver dysfunction could cause hepatic jaundice. However, despite causing profound hepatic dysfunction, some
diseases (portosystemic shunts in particular) rarely cause jaundice. Since hepatocyte excretion of conjugated bilirubin is
the rate-limiting step in bilirubin metabolism, hepatic jaundice would be expected to be associated with elevated plasma levels
of conjugated bilirubin and normal unconjugated bilirubin levels. Usually, however, the intracellular build up of conjugated
bilirubin in the failing liver then causes unconjugated bilirubin to also bank up within hepatocytes, following which both
forms of bilirubin spill over into the circulation. Like prehepatic jaundice, hepatic jaundice is therefore usually a mix
of unconjugated and conjugated hyperbilirubinemia.
