Disturbances in Bilirubin Metabolism

1. Disturbances in Bilirubin Metabolism Krista Chau Walter Gao Sarah Son Kin Wong PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

2. What is Bilirubin? • Yellow waste product from metabolism of heme • Open chain of tetrapyrrole • Known as bile pigment

3. Where Bilirubin is Made • 80% degradation of heme in hemoglobin • 20% myoglobin, cytochrome, catalase

4. How Bilirubin is Made • Oxidative cleavage by heme oxygenase, resulting in bilverdin • Reduction by biliverdinreductase, resulting in unconjugated bilirubin

5. Conjugation • Conjugated bilirubin enters bile and is secreted into the small intestines • Some urobilinogen is reabsorbed into the liver

6. Excretion • Urobilinogen is converted to uribilin and excreted with urine • Most of the urobilinogen in the intestine is converted to stercobilin and excreted in feces

8. Hypobilirubinemia • Downregulation or inhibition of heme oxygenase and biliverdinreductase

9. UnconjugatedHyperbilirubinemia • Increased production of bilirubin • Acute hemolytic crises causes greater breakdown of heme • Erythropoiesis

10. Oh no! I’m missing transporters to uptake bilirubin! Oh no! I’m lacking UDP-glucoronosyltransferase (UGT)! • Impaired Conjugation • Crigler-Najjar Syndrome • Gilbert’s Syndrome • Impaired hepatic uptake

11. How can we treat Jake the liver? • Liver or hepatocyte transplants • Cytochrome P450 inducers • Phenobarbital • Phototherapy • Wavelengths of 400-500 nm

12. Conjugated Hyperbilirubinemia • Rate of secretion or flow of bile is obstructed • Hepatitis or biliary obstructions • Invasive treatments are preferred BILE BILE

13. References • Fox, S. “Human Physiology.” 12e. 2011. • Kapitulnik, J. “Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties.” Molecular Pharmacology. 2004. http://molpharm.aspetjournals.org/content/66/4/773 • Leach, T. “Bilirubin Metabolism and Jaundice.” AlmostADoctor. 2014. http://almostadoctor.co.uk/content/systems/-gastrointestinal-tract/liver/bilirubin- metabolism-and-jaundice. • Nazer, H. and J. Katz. “UnconjugatedHyperbilirubinemia.” Medscape. 2013. http://emedicine.medscape.com/article/178841-overview. • Nelson, D.L., and M.M. Cox. “Principles of Biochemistry.” 5e. 2008. • Ophardt, C. “Hemoglobin Catabolism and Bilirubin.” Virtual Chembook. 2003. http://www.elmhurst.edu/~chm/vchembook/634bilirubin.html. • Weisiger, R.A., and J. Katz. “ConjguatedHyperbilirubinemia.” Medscape. 2013. http://emedicine.medscape.com/article/178757-overview. • Voet, D., J.G. Voet, and C.W. Pratt. “Fundamentals of Biochemistry: Life at the Molecular Level.” 4e. 1999.

14. Summary • Bilirubin is a waste product formed from the catabolism of heme, using the enzymes heme oxygenase and biliverdinreductase. • In the liver, unconjugated bilirubin which is insoluble in water is conjugated with glucuronic acid by the enzyme UGT to form the soluble (conjugated) bilirubin. • Bilirubin is converted to microbial enzymes into urobilinogen and oxidized to stercobilin to be excreted in feces. • Urobilinogen can also be reabsorbed from intestines and converted to urobilin to be excreted in urine • Unconjugatedhyperbilirubinemia is caused by increased production of bilirubin, impaired conjugation or impaired hepatic uptake • Conjugated hyperbilirubinemia is caused by hepatic or biliary obstructions • Gilbert's syndrome is the most common hereditary cause of hyperbilirubinemia, and is found in up to 5% of the population. It is caused by elevated levels of unconjugated bilirubin in the bloodstream as • a result of reductions in glucuronyltransferase.