1. METABOLISME BILIRUBIN
dr I NJOMAN WIDAJADNJA, M.KES

2. Is a product of heme metabolism
What is Bilirubin? (indirect= cunjugated . direct = unconjugated = free)
Is a bile pigment
Is lipid soluble
Is a product of heme metabolism

3. Bilirubin bebas = bilirubin yang terlarut dalam albumin plasma darah (unconjugated)
Dalam hepar bilirubin ini dilepaskan dari albuminnya, tapi diikatkan dg glukoronida / sulfat = bilirubin terkonyugasi(conjugated)
Bentuk bilirubin yg terkonyugasi ini diekskresikan ke dalam kantong empedu usus, dan oleh bakteri usus  menjadi Urobilinogen (mudah larut)

4. Macrophage of the reticuloendothelial system at spleen
Metabolisme Heme
Fe3+ + CO
NADP+
Hemoglobin – 80%
Myoglobin
Cytochrome P450s
Hemoproteins O2
NADPH + H+
Heme
Biliverdin
Bilirubin
Heme Oxygenase
Biliverdin Reductase
Hepar
Macrophage of the reticuloendothelial system at spleen
Blood
Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).

5. HANCURNYA SEL DARAH MERAH (FATE OF RBCs)
 Life span dlm aliran darah: days
 kematian RBCs : phagocytosis and/or lysis
Normalnya: lysis terjadi sec. extravascular di dlm RE system (spleen)  RBC phagocytosis
Lysis juga terjadi sec. intravascularly (in blood stream)

6. The Fate of Bilirubin… ? Alb B B B CB B + GST MRP2 :GST sER Plasma
Hepatic Cell
Bile
Alb B ? B
+ GST
MRP2 B CB
+ UDPGA
:GST B
UGT1A1
sER
Alb = albumin B = bilirubin GST = glutathione-S-transferase
UDPGA = uridine diphosphoglucuronic acid; CB = conjugated bilirubin
UGT1A1 = UDP-glucuronosyltransferase 1A1
MRP2 = Multi-drug Resistance Protein 2
Adapted from Harrison’s 15th Ed. “Principles of Internal Medicine”, 2001.

7. Bilirubin Excretion B CB B CB Liver Enterohepatic circulation Bile
B-glucoronidase
Bacteria B ox
Urobilinogen
Urobilin CB
Stercobilinogen
Stercobilin
Bacteria usus
Intestines
feces

8. Bilirubin Excretion B CB B CB Liver Urobilin Kidney ox Urobilinogen
Urine
Enterohepatic circulation
Bile
B-glucoronidase
bacteria B CB ox
Urobilin
Urobilinogen
Stercobilin
Stercobilingogen
bacteria
Intestines
feces

9. NORMAL BILIRUBIN METABOLISM
Uptake of bilirubin by the liver is mediated by a carrier protein (receptor)
Uptake may be competitively inhibited by other organic anions
On the smooth ER, bilirubin is conjugated with glucoronic acid, xylose, or ribose
Glucoronic acid is the major conjugate - catalyzed by UDP glucuronyl tranferase
“Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi
Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut
Oxidized to stercobilin which is colored
Excreted in feces
Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney

10. Hyperbilirubinemia
Interferences at any one of the points of bilirubin processing described above can lead to a condition known as HYPERBILIRUBINEMIA.
As the name implies this disease is characterized by abnormally elevated levels of bilirubin in the blood.

11. HYPERBILIRUBINEMIA
Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when
there is an imbalance between its production and excretion
Recognized clinically as jaundice

12. Prehepatic (hemolytic) jaundice
Results from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysis
Excess RBC lysis is commonly the result of autoimmune disease; hemolytic disease of the newborn (Rh- or ABO- incompatibility); structurally abnormal RBCs (Sickle cell disease); or breakdown of extravasated blood
High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

13. Intrahepatic jaundice
Impaired uptake, conjugation, or secretion of bilirubin
Reflects a generalized liver (hepatocyte) dysfunction
In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

14. Posthepatic jaundice Caused by an obstruction of the biliary tree
Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma
Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin)
In a complete obstruction, urobilin is absent from the urine

15. Diagnoses of Jaundice

16. Neonatal Jaundice Common, particularly in premature infants
Transient (resolves in the first 10 days)
Due to immaturity of the enzymes involved in bilirubin conjugation
High levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus

17. Neonatal Jaundice
If bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form
If necessary, exchange blood transfusion is used to remove excess bilirubin
Phenobarbital is oftentimes administered to Mom prior to an induced labor of a premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl transferase
Jaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is usually pathological and needs to be further investigated

18. Causes of Hyperbilirubinemia

19. SYMPTOMS
Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice)
Detectable when total plasma bilirubin levels exceed 2-3mg/100mL
AHHH!!! I have symptoms of hyperbilirubinemia!!!

20. Causes: Increased bilirubin production
Reduced bilirubin uptake by hepatic cells
Disrupted intracellular conjugation
Disrupted secretion of bilirubin into bile canaliculi
Intra/extra-hepatic bile duct obstruction
Lead to increases in free (unconj.) bilirubin
Result in rise in conj. bilirubin levels

21. INCREASED BILIRUBIN PRODUCTION (unconj. Hyperbilirubinemia)
Hemolysis
Increased destruction of RBCs
eg sickle cell anemia, thalassemia
Drastic increase in the amount of bilirubin produced
Unconj. bilirubin levels rise due to liver’s inability to catch up to the increased rate of RBC destruction
Prolonged hemolysis may lead to precipitation of bilirubin salts in the gall bladder and biliary network
result in formation of gallstones and conditions such as cholecystitis and biliary obstruction
Other
Degradation of Hb originating from areas of tissue infarctions and hematomas
Ineffective erythropoiesis

22. DECREASED HEPATIC UPTAKE (unconj. Hyperbilirubinemia)
Several drugs have been reported to inhibit bilirubin uptake by the liver
e.g. novobiocin, flavopiridol
Bile
MRP2 B
+ GST CB
Plasma
Hepatic cell
Alb
:GST
sER
+ UDPGA
UGT1A1