Transcript Disturbances in Bilirubin Metabolism

Krista Chau
Walter Gao
Sarah Son
Kin Wong
PHM142 Fall 2014
Instructor: Dr. Jeffrey Henderson
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Yellow waste product from metabolism of heme
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Open chain of tetrapyrrole
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Known as bile pigment
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80% degradation of heme
in hemoglobin
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20% myoglobin,
cytochrome, catalase
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Oxidative cleavage by
heme oxygenase,
resulting in bilverdin
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Reduction by biliverdin
reductase, resulting in
unconjugated bilirubin
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Conjugated bilirubin
enters bile and is
secreted into the small
intestines
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Some urobilinogen is
reabsorbed into the
liver
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Urobilinogen is converted
to uribilin and excreted
with urine
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Most of the urobilinogen
in the intestine is
converted to stercobilin
and excreted in feces
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Downregulation or
inhibition of heme
oxygenase and biliverdin
reductase
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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)!
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Impaired Conjugation
• Crigler-Najjar Syndrome
• Gilbert’s Syndrome
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Impaired hepatic uptake
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Liver or hepatocyte transplants
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Cytochrome P450 inducers
◦ Phenobarbital
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Phototherapy
◦ Wavelengths of 400-500 nm
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Rate of secretion or flow of bile is obstructed
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Hepatitis or biliary obstructions
◦ Invasive treatments are preferred
BILE
BILE
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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.
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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.