Disturbances in Bilirubin Metabolism
Krista Chau Walter Gao Sarah Son Kin Wong PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson Yellow waste product from metabolism of heme Open chain of tetrapyrrole Known as bile pigment 80% degradation of heme in hemoglobin 20% myoglobin, cytochrome, catalase Oxidative cleavage by heme oxygenase, resulting in bilverdin Reduction by biliverdin reductase, resulting in unconjugated bilirubin Conjugated bilirubin enters bile and is secreted into the small intestines Some urobilinogen is reabsorbed into the liver Urobilinogen is converted to uribilin and excreted with urine Most of the urobilinogen in the intestine is converted to stercobilin and excreted in feces Downregulation or inhibition of heme oxygenase and biliverdin reductase Increased production of bilirubin ◦ Acute hemolytic crises causes greater breakdown of heme Erythropoiesis Oh no! I’m missing transporters to uptake bilirubin! Oh no! I’m lacking UDPglucoronosyltransferase (UGT)! Impaired Conjugation • Crigler-Najjar Syndrome • Gilbert’s Syndrome Impaired hepatic uptake Liver or hepatocyte transplants Cytochrome P450 inducers ◦ Phenobarbital Phototherapy ◦ Wavelengths of 400-500 nm Rate of secretion or flow of bile is obstructed Hepatitis or biliary obstructions ◦ Invasive treatments are preferred BILE BILE 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/bilirubinmetabolism-and-jaundice. Nazer, H. and J. Katz. “Unconjugated Hyperbilirubinemia.” 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. “Conjguated Hyperbilirubinemia.” 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. Bilirubin is a waste product formed from the catabolism of heme, using the enzymes heme oxygenase and biliverdin reductase. 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 Unconjugated hyperbilirubinemia 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.
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