BILIRUBIN METABOLISM

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BILIRUBIN METABOLISM
Disturbances in Metabolism of Bilirubin
Deena Hamzawi, Lena Farhat, Yessmean Elrafih
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Outline

• What is bilirubin?

• Synthesis

• Metabolism

• What can go wrong?

• Case

• Summary

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What is bilirubin?

• Yellowish antioxidant that is the result of
  destruction of erythrocytes by macrophages

• Component of bile

• Contributes to the colour of feces, urine,
  plasma, and greenish colour of bile

• Open chain of 4 pyrole rings

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Synthesis

• Hemoglobin is catabolized in the spleen, the iron
  is removed and the heme molecule is converted to
  bilirubin

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Metabolism

• Bilirubin is bound to albumin in the blood

• Taken up by hepatocytes in the liver and
  conjugated with glucuronic acid (reaction is
  catalyzed by the enzyme UDP-glucuronide
  transferase)

• Makes its way to gut via the bile duct

• Hydrolyzed and reduced by intestinal flora to
  form urobilinogen

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Pathways of Urobilinogen

• Oxidized by gut bacteria to the dark pigment
  called stercobilin which is excreted in feces

• Some reabsorbed unchanged via the portal system
  and is recycled by liver

• Trace amounts reabsorbed and excreted by kidney
  into urine

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What can go wrong?
Jaundice

• Occurs when plasma bilirubin levels are elevated
  due to certain conditions such as
• - excessive hemolysis of erythrocytes in
  the blood
• - blockage of the bile duct
• - liver disease

• causes skin and the white of the eyes to take on
  a yellowish colour

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Unconjugated Hyperbilirubinemia

• Occurs when there is a problem upstream of
  conjugation such as
• - hemolysis
• - Gilberts syndrome

• Characteristics
• - no bilirubin in urine (remains usual
  colour)
• - more urobilinogen in urine
• - bilirubin in blood is unconjugated

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Hemolysis

• Breakdown of RBCs at a faster rate than normal

• Liver cannot keep up with the conjugation of
  excessive bilirubin so unconjugated bilirubin
  remains detectable in blood and is bound to
  albumin

• Excess conjugated bilirubin becomes excess
  urobilinogen (clear) which is absorbed in the
  plasma, filtered in the kidney and ends up in the
  urine at higher concentrations than normal

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Gilberts Syndrome

• Most common congenital cause of unconjugated
  hyperbilirubinaemia

• Defect in the livers uptake of unconjugated
  bilirubin and conjugation pathways

• Occurs in about 1 in 20 people

• Not dangerous but causes jaundice to appear
  following illness, dehydration or surgery

• Certain drugs such as Rifampicin, Rifamycin, and
  Probenecid can also affect the livers uptake in
  the same manner

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Conjugated Hyperbilirubinemia

• Occurs when there is a problem downstream of
  conjugation such as obstruction

• Characteristics
• - more than usual conjugated bilirubin
  in
• the urine (gives urine dark colour)
• - no urobilinogen in urine
• - bilirubin in blood is conjugated

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Obstruction

• Conjugated bilirubin cannot get into the gut
  (usually due to gallstones in the common bile
  duct, and pancreatic cancer in the head of the
  pancreas)

• The conjugated bilirubin spills into the
  bloodstream and can be filtered through the
  glomerulus, since it is water soluble

• Presence of bilirubin in urine gives it a dark
  colour

• Urobilinogen cannot be formed, therefore none is
  found in the urine and none is converted to
  stercobilin which means that stools will be pale

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Hepatocellular Jaundice

• Occurs when there is damage to the hepatocytes
  by hepatitis or alcoholic liver disease

• Cell death reduces the liver's ability to
  metabolise and excrete bilirubin leading to a
  buildup in the blood

• Hyperbilirubinemia at early stages can be due to
  both conjugated bilirubin or unconjugated
  bilirubin

• As the liver disease progresses, conjugated
  hyperbilirubinemia is the major factor

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Neonatal Jaundice

• Very common, usually harmless

• Is the result of
• - excess fetal destruction of red blood
  cells
• - immature uptake and conjugation pathways
  in liver
• - absence of gut flora to metabolize bile
  pigments

• Prematurity, dehydration can make Jaundice worse

• BBB in newborns is not complete, risk that the
  bilirubin can make its way into the CSF and cause
  damage

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CASE
Mr. Diab walks into the local Ah-Medicine Shoppe
looking very worried and concerned. Yo man you
gotta help me out, Im in bad shape, he
exclaims. He describes his symptoms to you as he
counts them on his fingers. I dont know whats
wrong with me. Im a looker, and I have noticed
that my urine is dark and my stool is so pale!
The upper right area of my stomach is tender and
my stomach hurts up here (points to his upper
stomach) Bottom line, I NEED HELP! I need to go
and start studying Wells section and learn all
these GPCRs. This pain is distracting me, and at
this rate I wont get my degree and that means no
money, no house, no car, and NO wife!
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CASE
What is the most probable bilirubin metabolism
disorder described in this case?

• CONJUGATED HYPERBILIRUBINEMIA
• Occurs after bilirubin is conjugated.
• Obstruction, such as gallstones in the
  gallbladder prevent bilirubin from getting into
  the gut.
• Presence of elevated amounts of conjugated
  bilirubin causes a brownish discoloration in the
  urine.
• No urobilinogen is found in the urine since it
  cannot be formed.
• Consequently, no stercobilin is formed ? stools
  appear light.

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Summary Slide

• Unconjugated hyperbilirubinemia occurs before
  conjugation
• Conjugated hyperbilirubinemia occurs after
  conjugation
• Jaundice also occurs from liver disease and
  overuse of alcohol
• Neonatal jaundice is common in newborns

What is bilirubin? Open chain of 4 pyrole rings
Where is it found? - Component of bile
Gilberts Syndrome

• Most common congenital cause of unconjugated
  hyperbilirubinaemia

• Occurs in about 1 in 20 people

• Defect in the livers uptake of unconjugated
  bilirubin and conjugation pathways

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References

• Stanfield, C., German, W., Principles of Human
  Physiology, Pearson, p. 436, 443
• http//student.bmj.com/back_issues/1098/data/1098e
  d3.htm
• http//www.webmd.com/digestive-disorders/bilirubin
  -15434
• http//media.www.jhunewsletter.com/media/storage/p
  aper932/news/2002/12/06/Science/Jhu-Study.Proves.B
  ilirubin.Can.Be.Toxic-2247807.shtml
• http//emedicine.medscape.com/article/178841-overv
  iew
• http//www.uptodate.com/patients/content/topic.do?
  topicKeyhep_dis/15344
• watcut.uwaterloo.ca/Pharma/slides/Metabolism.ppt