The liver takes up bilirubin by binding it to albumin and transporting it through the blood. Certain drugs can displace bilirubin from albumin, allowing it to enter the central nervous system and potentially cause neural damage in infants. Once in the liver, bilirubin dissociates from albumin, enters hepatocytes through facilitated diffusion, and binds to intracellular proteins, specifically ligandin. Bilirubin solubility is increased in the hepatocyte by the addition of two molecules of glucuronic acid through conjugation. This process is catalyzed by bilirubin UDP-glucuronosyltransferase using UDP-glucuronic acid as the glucuronate donor, resulting in the formation of conjugated bilirubin. Conjugated bilirubin is actively transported against a concentration gradient into the bile canaliculi and then into the bile. Impairment in this energy-dependent, rate-limiting step can occur in liver disease. Unconjugated bilirubin is not normally secreted into bile. In the intestine, conjugated bilirubin is hydrolyzed and reduced by gut bacteria, producing urobilinogen, which is further oxidized to stercobilin. Most of the urobilinogen is converted to stercobilin, giving feces its characteristic brown color. However, some urobilinogen is reabsorbed from the gut and enters the portal blood. A portion of this urobilinogen participates in the enterohepatic urobilinogen cycle, being taken up by the liver and then resecreted into the bile. The remaining urobilinogen is transported to the kidney, where it is converted to yellow urobilin and excreted in urine, giving it its characteristic color. Jaundice, or icterus, is the yellow color of the skin, nail beds, and sclerae caused by the deposition of bilirubin due to increased levels in the blood (hyperbilirubinemia). It is typically a symptom of an underlying disorder. Jaundice can be classified into three major types, but in clinical practice, it is often more complex and can result from defects at multiple steps in bilirubin metabolism.
Bilirubin uptake by the liver: Because bilirubin is only slightly soluble in plasma, it is transported through blood to the liver by binding noncovalently to albumin. [Note: Certain anionic drugs, such as salicylates and sulfonamides, can displace bilirubin from albumin, permitting bilirubin to enter the central nervous system (CNS). This causes the potential for neural damage in infants (see p. 285).] Bilirubin dissociates from the carrier albumin molecule, enters a hepatocyte via facilitated diffusion, and binds to intracellular proteins, particularly the protein ligandin.
3.
Bilirubin diglucuronide formation: In the hepatocyte, bilirubin solubility is increased by the sequential addition of two molecules of glucuronic acid in a process called conjugation. The reactions are catalyzed by microsomal bilirubin UDP-glucuronosyltransferase (bilirubin UGT) using uridine diphosphate (UDP)-glucuronic acid as the glucuronate donor. The bilirubin diglucuronide product is referred to as conjugated bilirubin (CB). [Note: Varying degrees of deficiency of bilirubin UGT result in Crigler-Najjar I and II and Gilbert syndrome, with Crigler-Najjar I being the most severe.] 4.
Bilirubin secretion into bile: CB is actively transported against a concentration gradient into the bile canaliculi and then into the bile. This energy-dependent, rate-limiting step is susceptible to impairment in liver disease. [Note: A rare deficiency in the protein required for transport of CB out of the liver results in Dubin-Johnson syndrome.] Unconjugated bilirubin (UCB) is normally not secreted into bile.
5.
Urobilin formation in the intestine: CB is hydrolyzed and reduced by gut bacteria to yield urobilinogen, a colorless compound. Most of the urobilinogen is further oxidized by bacteria to stercobilin, which gives feces the characteristic brown color. However, some is reabsorbed from the gut and enters the portal blood. A portion of this urobilinogen participates in the enterohepatic urobilinogen cycle in which it is taken up by the liver and then resecreted into the bile. The remainder of the urobilinogen is transported by the blood to the kidney, where it is converted to yellow urobilin and excreted, giving urine its characteristic color. The metabolism of bilirubin is summarized in Figure 21.10.
E. Jaundice
Jaundice (or, icterus) refers to the yellow color of skin, nail beds, and sclerae (whites of the eyes) caused by bilirubin deposition, secondary to increased bilirubin levels in the blood (hyperbilirubinemia) as shown in Figure 21.11. Although not a disease, jaundice is usually a symptom of an underlying disorder. [Note: Blood bilirubin levels are normally ≤1 mg/dl. Jaundice is seen at 2–3 mg/dl.] 1. Types: Jaundice can be classified into three major types described below. However, in clinical practice, jaundice is often more complex than indicated in this simple classification. For example, the accumulation of bilirubin may be a result of defects at more than one step in its metabolism.