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  • Understand the origins of bilirubin in the plasma, and the need to excrete this substance
    • Describe how bilirubin is transported through the body
  • Describe the pathway of bilirubin handling, and further metabolic modifications that occur
    • Describe the mechanism and consequences of bilirubin conjugation
    • Delineate the mechanism of bilirubin secretion into the bile
    • Understand how enteric bacteria modify bilirubin and the fate of the metabolic products produced
  • Explain the difference between conjugated and unconjugated hyperbilirubinemia, and diseases that can cause these conditions
    • Outline treatments that are effective in resolving the symptoms of hyperbilirubinemia
    • Explain the mechanisms that can lead to pigment gallstones

image Bilirubin is a metabolite of heme, a compound that serves to coordinate iron in various proteins. Very recently, bilirubin has been shown to possess important functions as an antioxidant, but it also serves simply as a means to excrete unwanted heme, derived from various heme-containing proteins such as hemoglobin, myoglobin, and various P450 enzymes. Bilirubin and its metabolites are also notable for the fact that they provide color to the bile and stool, as well as, to a lesser extent, the urine.

Role and Significance

image It is important for the body to be able to excrete bilirubin as it is potentially toxic. As we will discuss at the end of this chapter, certain disease states that involve excessive levels of bilirubin in the bloodstream can lead to accumulation of bilirubin in the brain due to its ability to cross the blood–brain barrier, a condition known as kernicterus (meaning “yellow-stained nucleus”). The development of this condition impairs brain function by mechanisms that are not well-understood, but it can be fatal if left untreated. Bilirubin is also notable for its yellow coloration. Accumulation of this substance in the blood is the basis for jaundice, or a yellow discoloration of the skin and eyes which is a common symptom of liver diseases. Thus, measurement of bilirubin in the plasma can be a useful marker of such conditions.

Bilirubin derives from two main sources. The majority (80%) of the bilirubin formed in the body comes from the heme released from senescent red blood cells. The remainder originates from various heme-containing proteins found in other tissues, notably the liver and muscles.

Cellular Heme Metabolism

Bilirubin is produced by a two-stage reaction that occurs in cells of the reticuloendothelial system, including phagocytes, the Kupffer cells of the liver, and cells in the spleen and bone marrow. Heme is taken up into these cells and acted on by the enzyme heme oxygenase, liberating the chelated iron from the heme structure and releasing an equimolar amount of carbon monoxide, which is excreted via the lungs. The reaction yields a green pigment known as biliverdin (Figure 13–1). Biliverdin is then acted on by the enzyme biliverdin reductase, again releasing a molecule of carbon monoxide and producing the yellow bilirubin. Although ...

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