lecture note billy's

Bilirubin MetabolismBilirubin Metabolism

Harliansyah, Ph.DHarliansyah, Ph.DDept of Biochemistry, FKUYDept of Biochemistry, FKUY

2011, May2011, May

What Is Bilirubin?What Is Bilirubin?Bilirubin is the by product of the breakdown of Bilirubin is the by product of the breakdown of heme which is found in red blood cells. which is found in red blood cells.

Normal red blood cell destruction accounts for Normal red blood cell destruction accounts for 80% of daily bilirubin produced in the newborn. 80% of daily bilirubin produced in the newborn.

Infants produce twice as much bilirubin per day Infants produce twice as much bilirubin per day than as an adult.than as an adult.

There are two types of bilirubin - unconjugated There are two types of bilirubin - unconjugated (indirect) bilirubin and conjugated (direct) (indirect) bilirubin and conjugated (direct) bilirubin.bilirubin.

Bilirubin complexed to albumin Bilirubin complexed to albumin ((Unconjugated BilirubinUnconjugated Bilirubin) is transported to ) is transported to liver, where it is processed into liver, where it is processed into Conjugated BilirubinConjugated Bilirubin, by the liver cells., by the liver cells.

In this form Bilirubin enters the bile fluids In this form Bilirubin enters the bile fluids for transport to the small intestine for transport to the small intestine ((Conjugated Bilirubin Conjugated Bilirubin is converted to is converted to UrobilinogenUrobilinogen).).

Unconjugated BilirubinUnconjugated BilirubinUnconjugated (indirect) bilirubinUnconjugated (indirect) bilirubin– Fat-solubleFat-soluble– Not yet Not yet metabolized by by the liver by by the liver– Is not easily excretedIs not easily excreted– Is the biggest concern for newborn jaundiceIs the biggest concern for newborn jaundice– If it is not converted it can be deposited into If it is not converted it can be deposited into

the skin which causes the yellowing of the the skin which causes the yellowing of the skin or into the brain which can lead to skin or into the brain which can lead to kernicterus..

Conjugated BilirubinConjugated Bilirubin

Conjugated (direct) bilirubin Conjugated (direct) bilirubin – Water solubleWater soluble– It is It is metabolized by the liver by the liver– It is mostly excreted in stool and some in the It is mostly excreted in stool and some in the

urineurine

Bilirubin Metabolism- 1Bilirubin Metabolism- 1

Red blood cells are broken down in the Reticuloendothelial System

Red blood cells break down to hemoglobin which is further broken down to iron, globin, and heme

Iron

Globin

Heme

Biliverdin

Unconjugated bilirubin

HemoglobinRed blood cells

Liver

Conjugated bilirubin

Urobilinogen

Stercobilin

Reticuloendothelial System

Bilirubin albumin complex

Bilirubin Metabolism- 2Bilirubin Metabolism- 2Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin


Unconjugated bilirubin is then carried to the

liver by albumin

Heme is further broken down to biliverdin then to unconjugated bilirubin by the enzyme biliverdin reductase



Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin


The liver then The liver then converts converts unconjugated unconjugated bilirubin to bilirubin to conjugated conjugated bilirubin where it bilirubin where it is excreted in the is excreted in the intestines intestines The intestines

then convert the conjugated bilirubin into urobilinogen and then stercobilin



Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin


Urobilinogen is excreted in the urine

Stercobilin is excreted in the stool


Mechanism of Bilirubin FormationMechanism of Bilirubin Formation

Enzyme-catalysed degradation of haem. Haem degradation begins by haem oxygenase-catalysed oxidation of the a-bridge carbon of haem, which is converted to CO, leading to opening of the tetrapyrrole ring and release of the iron molecule. The resulting biliverdin molecule is subsequently reduced to bilirubin by cytosolic biliverdin reductase.

What Is Physiologic Jaundice What Is Physiologic Jaundice

Physiologic jaundice is an exaggerated jaundice is an exaggerated normal process seen in 60% of term normal process seen in 60% of term infants, and 80% of infants, and 80% of premature infants infants It normally occurs during the first week of It normally occurs during the first week of lifelifeIt is normally benign and self-limitingIt is normally benign and self-limitingAssociated with a bilirubin level greater Associated with a bilirubin level greater than 5-7mg/dLthan 5-7mg/dL

Factors That Contribute To Physiologic Factors That Contribute To Physiologic JaundiceJaundice

PrematurityPrematurityPolycythemiaPolycythemia

Prematurity & HyperbilirubinemiaPrematurity & Hyperbilirubinemia

Premature infants are more susceptible to infants are more susceptible to hyperbilirubinemia due to: hyperbilirubinemia due to:

Immature Immature hepatic system systemDelayed Delayed enteral feedingsfeedingsDecrease in serum Decrease in serum albumin levels levels

Prematurity & HyperbilirubinemiaPrematurity & HyperbilirubinemiaImmature Immature hepatic system - system - leads to decreased elimination of leads to decreased elimination of bilirubin from the system; therefore, higher levels of indirect bilirubin from the system; therefore, higher levels of indirect bilirubin are in the blood which leads to hyperbilirubinemiabilirubin are in the blood which leads to hyperbilirubinemia

Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin



Prematurity & Prematurity & HyperbilirubinemiaHyperbilirubinemia

Delayed Delayed enteral feedings - feedings - if feedings are delayed it if feedings are delayed it decreases intestinal motility and removal of decreases intestinal motility and removal of meconium, which , which leads to reabsorption of direct bilirubin, which is converted back to leads to reabsorption of direct bilirubin, which is converted back to indirect bilirubin. Which means bilirubin increases in the blood indirect bilirubin. Which means bilirubin increases in the blood and leads to hyperbilirubinemia and leads to hyperbilirubinemia

Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin



Prematurity & HyperbilirubinemiaPrematurity & HyperbilirubinemiaDecrease in serum Decrease in serum albuminalbumin levels levels - if there is a - if there is a decrease in the amount of albumin receptors available, decrease in the amount of albumin receptors available, bilirubin does not bind to the albumin; therefore, is bilirubin does not bind to the albumin; therefore, is considered “free” bilirubin. Which means bilirubin considered “free” bilirubin. Which means bilirubin increases in the blood and leads to hyperbilirubinemia increases in the blood and leads to hyperbilirubinemia

Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin



Polycythemia & Polycythemia & HyperbilirubinemiaHyperbilirubinemia

Polycythemia is an increased level of red blood Polycythemia is an increased level of red blood cells (RBCs) in the cells (RBCs) in the circulatory systemcirculatory system

A infant has more RBCs than an adult, and the A infant has more RBCs than an adult, and the lifespan of an RBC is shorter in neonates lifespan of an RBC is shorter in neonates

Increased RBCs and a shorter lifespan leads to Increased RBCs and a shorter lifespan leads to increased destruction of RBCs, which leads to increased destruction of RBCs, which leads to more bilirubin in the blood, which leads to more bilirubin in the blood, which leads to hyperbilirubinemiahyperbilirubinemia

Factors That Contribute To Factors That Contribute To Pathologic JaundicePathologic Jaundice

Hemolytic anemia Hemolytic anemia Rh incompatibility Rh incompatibility ABO incompatibilityABO incompatibility

G6PD (glucose-6-phosphate deficiency) G6PD (glucose-6-phosphate deficiency) deficiencydeficiency

Genetics & Genetics & HyperbilirubinemiaHyperbilirubinemia

The study was conducted in TaiwanThe study was conducted in TaiwanThe reason for this is because the Asian The reason for this is because the Asian population has twice the incidence of population has twice the incidence of hyperbilirubinemia than the Caucasian hyperbilirubinemia than the Caucasian population. population. They were looking to identify potential genetic They were looking to identify potential genetic defects that contribute to the higher incidence defects that contribute to the higher incidence of hyperbilirubinemia of hyperbilirubinemia

Genetics & Genetics & HyperbilirubinemiaHyperbilirubinemia

The three enzymes are: The three enzymes are: G6PD - glucose-6-phosphate G6PD - glucose-6-phosphate dehydrogenase dehydrogenaseOTAP 2 - organic anion OTAP 2 - organic anion transporter 2 transporter 2UGT1A1 - UDP- UGT1A1 - UDP-

glucuronsyltransferase 1A1 glucuronsyltransferase 1A1

G6PDG6PD

The G6PD enzyme is responsible for reducing NADP+(nicotinamide adenine dinucleotide phosphate) to NADPH (reduced nicotinamide adenine dinucleotide phosphate)

Pentose Phosphate Pathway

G6PDG6PDWithout adequate levels of NADPH, red blood Without adequate levels of NADPH, red blood cells are more prone to stress and oxidation, cells are more prone to stress and oxidation, which leads to which leads to hemolysishemolysis of red blood cells of red blood cells If there is a G6PD deficiency there will not be If there is a G6PD deficiency there will not be adequate levels of NADPH; therefore, leading to adequate levels of NADPH; therefore, leading to increased hemolysis of red blood cellsincreased hemolysis of red blood cellsIncreased hemolysis of red blood cells leads to Increased hemolysis of red blood cells leads to increased levels of bilirubin, which then leads to increased levels of bilirubin, which then leads to hyperbilirubinemiahyperbilirubinemia

Organic Anion Transporter 2 OATP 2Organic Anion Transporter 2 OATP 2 The function of the OATP 2 enzyme is The function of the OATP 2 enzyme is involved in the involved in the hepatichepatic uptake of uptake of unconjugated bilirubinunconjugated bilirubin

Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin



Organic Anion Transporter 2 Organic Anion Transporter 2 OATP 2OATP 2

In the study done, the identified In the study done, the identified polymorphismspolymorphisms in the OATP 2 enzyme, which led to increased in the OATP 2 enzyme, which led to increased risk for hyperbilirubinemia in the Asian risk for hyperbilirubinemia in the Asian population population If the enzyme activity is delayed there will be If the enzyme activity is delayed there will be increased levels of unconjugated bilirubin in the increased levels of unconjugated bilirubin in the blood, therefore leading to hyperbilirubinemiablood, therefore leading to hyperbilirubinemia

UDP - Glucuronsyltransferase 1A1 (UGT1A1)UDP - Glucuronsyltransferase 1A1 (UGT1A1)

The function of UGT1A1 is to convert The function of UGT1A1 is to convert unconjugated or indirect bilirubin to unconjugated or indirect bilirubin to conjugated or direct bilirubinconjugated or direct bilirubin

Iron

Globin

Heme

Biliverdin



Liver


Urobilinogen

Stercobilin



UDP - Glucuronsyltransferase 1A1 UDP - Glucuronsyltransferase 1A1 UGT1A1UGT1A1

In the study done, the authors identified In the study done, the authors identified polymorphismspolymorphisms in the UGT1A1 enzyme in the UGT1A1 enzyme which, led to increased risk for which, led to increased risk for hyperbilirubinemia in the Asian population hyperbilirubinemia in the Asian population If the enzyme activity is delayed there will If the enzyme activity is delayed there will be increased bilirubin in the blood, be increased bilirubin in the blood, therefore leading to hyperbilirubinemiatherefore leading to hyperbilirubinemia

PhysiologicPhysiologicOccurs 24 hours after Occurs 24 hours after birthbirth

PrematurityPrematurity

PolycythemiaPolycythemia

PathologicPathologicOccurs less than 24 Occurs less than 24 hours after birthhours after birth

Hemolytic anemiaHemolytic anemia

G6PD deficiencyG6PD deficiency

Physiologic JaundicePhysiologic Jaundiceversusversus

Pathologic JaundicePathologic Jaundice

KernicterusKernicterusKernicterusKernicterus is used to describe the yellow staining of the brain is used to describe the yellow staining of the brain nuclei as seen on autopsy (kern means nuclear region of the brain; nuclei as seen on autopsy (kern means nuclear region of the brain; icterus means jaundice).icterus means jaundice).

KernicterusKernicterus is a rare, irreversible complication of is a rare, irreversible complication of hyperbilirubinemiahyperbilirubinemia

If bilirubin levels become markedly elevated, the unconjugated If bilirubin levels become markedly elevated, the unconjugated bilirubin may cross into the bilirubin may cross into the blood brain barrierblood brain barrier and stain the brain and stain the brain tissuestissues

If staining of the brain tissues occurs there is permanent injury If staining of the brain tissues occurs there is permanent injury sustained to areas of the brain which leads to neurological sustained to areas of the brain which leads to neurological damage damage

Picture Of A Brain With KernicterusPicture Of A Brain With Kernicterus

Yellow staining in the brain due to

increased unconjugated

bilirubin passing through the blood

brain barrier

Retrieved April 30, 2006, from

http://www.urmc.rochester.edu/neuroslides/slide156.html

Used with permission (9)

DiagnosticDiagnosticIn term infants a normal bilirubin level is between In term infants a normal bilirubin level is between 1.0 - 10.0 mg/dL1.0 - 10.0 mg/dLIf an infant has a If an infant has a hematocrithematocrit greater than 65% greater than 65% this places that infant at risk for this places that infant at risk for hyperbilirubinemiahyperbilirubinemiaIf the reticulocyte count is greater than 5% in the If the reticulocyte count is greater than 5% in the first week of life, this identifies the infant as first week of life, this identifies the infant as trying to replace destroyed red blood cellstrying to replace destroyed red blood cellsA normal albumin level in a term infant is A normal albumin level in a term infant is between 2.6 - 3.6 g/dLbetween 2.6 - 3.6 g/dL

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