Disturbances in Bilirubin Metabolism

Krista ChauWalter Gao

Sarah SonKin Wong

PHM142 Fall 2014 Instructor: Dr. Jeffrey Henderson

What is Bilirubin?

Yellow waste product from metabolism of heme

Open chain of tetrapyrrole

Known as bile pigment

Where Bilirubin is Made

80% degradation of heme in hemoglobin

20% myoglobin, cytochrome, catalase

How Bilirubin is Made

Oxidative cleavage by heme oxygenase, resulting in bilverdin

Reduction by biliverdin reductase, resulting in unconjugated bilirubin

Conjugation

Conjugated bilirubin enters bile and is secreted into the small intestines

Some urobilinogen is reabsorbed into the liver

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

Hypobilirubinemia

Downregulation or inhibition of heme oxygenase and biliverdin reductase

Unconjugated Hyperbilirubinemia

Increased production of bilirubin

◦Acute hemolytic crises causes greater breakdown of heme

Erythropoiesis

Oh no! I’m lacking UDP-glucoronosyltransferase (UGT)!

Oh no! I’m missing transporters to uptake bilirubin!

Impaired Conjugation• Crigler-Najjar Syndrome• Gilbert’s Syndrome

Impaired hepatic uptake

How can we treat Jake the liver?

Liver or hepatocyte transplants

Cytochrome P450 inducers

◦Phenobarbital

Phototherapy

◦Wavelengths of 400-500 nm

Conjugated Hyperbilirubinemia

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/bilirubin-

metabolism-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.

References

Summary 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.