Pathophysiology
Summary
Bilirubin metabolism begins with the breakdown of heme by splenic macrophages, generating iron and a porphyrin ring. The porphyrin ring is converted into unconjugated bilirubin, which travels in the blood bound to albumin. Phase II conjugation occurs in the liver via UDP-glucuronyltransferase, which converts it to the water-soluble conjugated bilirubin, which is excreted into bile. Intestinal flora further break conjugated bilirubin down into urobilinogen, the majority of which is oxidized into stercobilin in the intestines, some is recycled into the liver, and a small fraction is excreted in the kidneys as urobilin.
The pathologies involving bilirubin can be categorized based on their direct/total bilirubin ratio. Unconjugated hyperbilirubinemia occurs when the direct/total bilirubin is > 20%, where most elevated bilirubin is unconjugated, indicating issues in bilirubin production or uptake in the liver. Hemolysis and autosomal recessive disorders that cause dysfunction of UDP-glucuronyltransferase are associated with unconjugated hyperbilirubinemia. Inherited causes include Gilbert's syndrome, which results from decreased activity of UDP-glucuronyltransferase and presents as mild jaundice during physiological stress, and Crigler-Najjar syndrome, which lacks this enzyme and causes significantly elevated levels of unconjugated bilirubin in infants that can result in severe conditions likeencephalopathy, kernicterus, and death.
Mixed hyperbilirubinemia is characterized by a direct/total bilirubin fraction between 20-50%. Mixed disease indicates liver dysfunction, where the liver is impaired in its ability to both uptake unconjugated bilirubin and excrete it as conjugated bilirubin. Common etiologies include viral hepatitis, in which both AST and ALT are elevated (ALT>>AST), and alcoholic hepatitis, where AST and ALT are both elevated, but the AST:ALT > 2:1. Both forms of hepatitis are associated with increased gamma-glutamyl transferase (GGT).
Conjugated hyperbilirubinemia, defined by a direct/total bilirubin fraction > 50%, suggests an issue with the excretion of conjugated bilirubin. Common causes include cholestasis, where bile flow is obstructed, leading to dark urine & pale stools, as well as increased alkaline phosphatase and increased GGT. Another culprit is Dubin-Johnson syndrome, an autosomal recessive disorder of the intrahepatic bile duct that leads to a black liver due to pigment deposition. Rotor syndrome, also autosomal recessive, is similar but more mild, and presents with a histologically normal liver. In neonates, biliary atresia can cause severe cholestasis and conjugated hyperbilirubinemia; it presents with symptoms of cholestasis, as well as increased alkaline phosphatase and GGT.
Lesson Outline
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FAQs
Splenic macrophages are responsible for breaking down red blood cells. During this process, heme is converted into iron (which is subsequently recycled) and the porphyrin ring. The porphyrin ring from heme is converted into biliverdin and subsequently unconjugated bilirubin, signifying the first steps in bilirubin production.
Unconjugated hyperbilirubinemia occurs when the direct/total bilirubin fraction is > 20%. This suggests that the majority of the elevated bilirubin is in its unconjugated form, often pointing to issues in bilirubin production or uptake by the liver cells, as seen in conditions like hemolysis or Gilbert's syndrome. Mixed hyperbilirubinemia is indicated by a direct/total bilirubin fraction between 20-50%. In this case, both conjugated and unconjugated bilirubin levels are elevated, usually suggesting hepatic dysfunction where the liver is partially able to conjugate bilirubin but not sufficiently to prevent its accumulation. This could be seen in acute hepatitis or certain inherited metabolic conditions. Conjugated hyperbilirubinemia is characterized by a direct/total bilirubin fraction > 50%, suggesting an issue in excretion of conjugated bilirubin, such as in conditions affecting the biliary system like cholestasis, bile duct obstruction, or Dubin-Johnson syndrome.
Gilbert Syndrome and Crigler-Najjar syndrome are both autosomal recessive disorders that impact the proper functioning of UDP-glucuronyltransferase, an enzyme crucial for the metabolism of bilirubin. In Gilbert syndrome, there is decreased activity of this enzyme, leading to an increase in unconjugated bilirubin, while in Crigler-Najjar syndrome, there can be a complete lack of UDP-glucuronyltransferase, leading to dramatically elevated unconjugated bilirubin levels in infants. This can have severe consequences, including kernicterus and death.
Damage to the liver can alter bilirubin metabolism, leading to accumulation of both unconjugated and conjugated bilirubin due to decreased liver uptake and dysfunctional excretion into bile, and cause a mixed hyperbilirubinemia. Viral and alcoholic hepatitis are among the leading causes this type. Notably, hepatocyte damage in hepatitis can release conjugated bilirubin into the serum which is then excreted in the urine, which is always a sign of underlying pathology.
In cholestasis, blockage of bile outflow can lead to accumulation of conjugated bilirubin in the serum and excretion in urine. Furthermore, conditions like Dubin-Johnson syndrome, due to a mutation in bile duct membrane proteins, result in decreased bilirubin excretion and subsequent conjugated hyperbilirubinemia. These conditions can drastically disrupt the normal flow and metabolism of bilirubin, leading to symptoms such as jaundice, dark urine and light-colored stool.
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