METABOLISME BILIRUBIN

dr I NJOMAN WIDAJADNJA, M.KES

What is Bilirubin?

(indirect= cunjugated . direct = unconjugated = free)

Is a bile pigment
Is lipid soluble
Is a product of heme metabolism

 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)

Metabolisme Heme

Hemoglobin 80%

O2

Myoglobin
Cytochrome P450s
Hemoproteins

Heme

Fe3+ + CO

Heme
Oxygenase

NADP+
NADPH + H+

Biliverdin

Macrophage of the
reticuloendothelial system at
spleen
Modified from Ganon, W.F. Review of Medical Physiology, (6th ed.).

Biliverdin
Reductase

Bilirubin

Hepa
r
Blood

HANCURNYA SEL DARAH MERAH (FATE OF RBCs)

Life span dlm aliran darah: 60-120 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)

The Fate of Bilirubin

Plasma

Hepatic Cell

Bile

Alb
B

?
Alb

B + GST
B :GST

B + UDPGA

UGT1A1

CB

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 Harrisons 15th Ed. Principles of Internal Medicine, 2001.

MRP2

Bilirubin Excretion

Liver

Enterohepatic
circulation

CB
Bile

CB

B-glucoronidase

Bacteria usus
Intestines

Bacteria

Urobilinogen ox
Stercobilinogen

Urobili
n
Stercobilin
feces

Bilirubin Excretion

Liver

CB

Kidney

Enterohepatic
circulation

Bile
B-glucoronidase

CB

Urobilinogen

bacteria

bacteria

Urobilinogen

ox

Urobili
n

Urine

ox

Urobilin

Stercobilingogen Stercobilin

Intestines
feces

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

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.

HYPERBILIRUBINEMIA

Increased plasma concentrations of bilirubin (> 3 mg/dL) occurs when

there is an imbalance between its production and excretion
Recognized clinically as jaundice

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 ABOincompatibility); structurally
abnormal RBCs (Sickle cell
disease); or breakdown of
extravasated blood

High plasma concentrations of

unconjugated bilirubin (normal
concentration ~0.5 mg/dL)

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

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

Diagnoses of Jaundice

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

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

Causes of Hyperbilirubinemia

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

Causes:
1.
2.
3.
4.
5.

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

1)

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 livers 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

2)

DECREASED HEPATIC UPTAKE

(unconj. Hyperbilirubinemia)

Several drugs have been reported to inhibit bilirubin

uptake by the liver

e.g. novobiocin, flavopiridol

Hepatic cell

Plasma
Alb

Bile

B
B + GST

Alb

B :GST

B + UDPGA

CB
UGT1A1

sER

MRP2