You are on page 1of 40

HEME DEGRADATION

AND JAUNDICE

Rizka Adi

RBCs last 120 days, degraded by


reticuloendothelial (RE) system
Under

physiologic conditions in the human


adult, 1~2108 erythrocytes are destroyed
per hour. Thus, in 1 day, a 70kg human
turns over approximately 6g of hemoglobin.
When

hemoglobin is destroyed in
the body, globin is degraded to its
constituent amino acids, which are
reused, and the iron of heme enters iron + Bile pigments
the iron pool, also for reuse.
most heme from RBCs (85%) - rest
from turnover of cytochromes, p450s,
immature erythrocytes

Amino acids

Heme

globin

iron

Bile pigments

Bile pigments
Any of several coloured compounds
derived from porphyrin that are found in
bile; principally bilirubin and biliverdin.

Bilirubin Metabolism

Bilirubin formation

Transport of bilirubin in plasma

Hepatic bilirubin transport

Hepatic uptake

Conjugation

Biliary excretion

Excrect through intestine system

Bilirubin formation

microsomal

cytosol

The iron-free porphyrin portion of heme is also


degraded, mainly in the reticuloendothelial cells of the
liver, spleen, and bone marrow.

The first step

Heme oxygenase
Heme oxygenase (HO) is an enzyme that
catalyzes the degradation of heme. This
produces biliverdin, iron, and carbon
monoxide.

Heme oxygenase
There are three known isoforms of heme oxygenase.

Heme oxygenase 1 (HO-1) is an inducible isoform in

response to stress such as oxidative stress, hypoxia, heavy


metals, cytokines, etc. Its activity is induced by its substrate
heme and by various nonheme substances.
Heme oxygenase 2 (HO-2) is a constitutive isoform which
is expressed under homeostatic conditions. Both HO-1 and
HO-2 are ubiquitously expressed and catalytically active.
A third heme oxygenase (HO-3) is not catalytically active,
but is thought to work in oxygen sensing.

In mammalian cells Heme oxygenase (HO1) has two


basic functions:
1. it recycles iron supplies within the cell to
maintain homeostasis.
2. biliverdin and biliruben (its reduced form), are
powerful antioxidants believed to aid in the prevention
of oxidative cell damage.

HOOC

CH2
CH2

M
CH

O
N
H

N
H

M -CH2
V -CH=CH2
M V

COOH
CH2
CH2 M

CH2

N
H

CH
N
H

The building of
intermolecular
hydrogen bonds by the
NH and COOH groups
is spatially hided.
Bilirubin is lipophilic
and therefore insoluble
in aqueous solution.the
solubility in water is
less.

Transport of Bilirubin in Plasma


Bilirubin on release from macrophages
circulates as unconjugated bilirubin in plasma
tightly bound to albumin.
Albumin + free Bilirubn

Why bound to albumin?

Bilirubin ~ Albumin Complex


unconjugated bilirubin

Significance:
Increase
Prevent

the solubility of whole molecule

unconjugated bilirubin freely


come into other tissue, cause damage.

Transport of Bilirubin in Plasma


H affinity binding sites
2:1

Molar
Ratio

>2:1

Bilirubin
L affinity binding sites

Plasma protein
Albumin

Bilirubin
can be replaced by

Other organic anions


PH

UB

Albumin has two binding sites for bilirubin---a high


affinity site and a low affinity site.
Albumin per 1L of plasma can bind about 342
427.5mol bilirubin, but 1.7 17.1 bilirubin per 1L .

blood

membrance

[bilirubin-albumin]
Other
antibiotics

cytosol

[bilirubin-lipids]

[albumin]

[bilirubin]

[bilirubin]

Certain drugs as sulfonamides and salicylates compete with


bilirubin for albumin binding and displace bilirubin to enter
into the brain in neonates and increase the risk of
kernicterus (a type of brain damage that can result from high
levels of bilirubin in a babys blood. It can cause athetoid
cerebral palsy and hearing loss) .

Hepatic phase
On coming in contact with the hepatocyte surface,
unconjugated bilirubin is preferentially
metabolized which involved 3 steps:
Hepatic uptake
Conjuation
Secretion in bile

Hepatic uptake of Bilirubin


Bilirubin ~ Albumin Complex
Albumin
Bilirubin
(lipid soluble)
(be) taken up by membrane of the liver

Bilirubin

carrier protein
(be) bound to

transfer
ER

ligation (Y protein, Z protein)

Conjugation of bilirubin
UDPGT Bilirubin
Bilirubin +UDP-gluconic acid
monoglucuronides + UDP
UDPGT

UDP-gluconic acid

Bilirubin diglucuronide + UDP

Conjugation occur in endoplasmic reticulum UDPglucuronosyl transferase,


Product: mono or diglucuronides.
The process of conjugation can be induced by drugs
phenobarbital.

HOOC

M V

COOH

CH2
CH2

CH
N
H

CH2
CH2 M

CH

N
H

N
H

OH

N
H

HO

M V
N
H

OH

CH

O
C
CH
O2
CH2

N
H

CO
CH2
CH M

CH2

CH

COOH
O

MV

N
H

OH
OHHOOC
O
OH

conjugated bilirubin

M V
CH

N
H

Increase the solubility of whole molecule


delete the toxicity of bilirubin.

bilirubin diglucuronides

Unconjugated bilirubin:
Bilirubin that are not conjugated with
gluconic acid , also called hemobilirubin,
indirected bilirubin.
conjugated bilirubin:
Bilirubin that are conjugated with gluconic
acid, also called hepatic bilirubin, directed
bilirubin.

Major differences between unconjugated and


conjugated bilirubin
FEATURE

Unconjugated
bilirubin

CONJUGATED
BILIRUBIN

Normal serum level

More

Less (less than


0.25mg/dl)

Water solubility

Absent

Present

Affinity to lipids (alcohol


solubilty)

Present

Absent

Serum albumin binding

High

Low

Van den Bergh reaction

Indirect (Total minus


direct)

Direct

Reanal excretion

Absent

Present

Affinity to brain tissue

Present (kernicterus)

Absent

Excretion of bilirubin into bile


Bilirubin diglucuronide is actively
transported against a concentration gradient
into bile duct.
This energy-dependent, rate limiting step
is susceptible to impairment in liver disease.
Uncojugated bilirubin is normally not
excreated.

Formation of urobilins in the intestine

Bilirubin diglucuronide is hydrolysed and reduced by


bacteria in the gut to yield urobilinogen, a colorless
compound.
Most of the urobilinogens of the feces are oxidized
by intestinal bacteria to stercobilin, which gives
stools their characteristic brown color.
Some urobilinogen is reabsorbed from the gut into
the portal blood and transported to the kidney, where
it is converted to the yellow urobilin and excreted,
giving urine its characteristic color. (bilinogen
enterohepatic circulation)
urobilin

Bilirubin diglucuronide

urobilinogen

bilin

stercobilin

Conjugated
bilirubin

blood
0.5 4mg/day
urobilin

bilinogen

prototype
Portal
vein
Sterobilin
excrection

reabsorbed
10
20%

80% 90%

bilinogen

bilinogen enterohepatic
circulation

BLOOD
CELLS

Stercobilin
excreted in feces

Urobilin
excreted in urine

Hemoglobin
Globin
Heme

O2
Heme oxygenase

Urobilinogen
formed by bacteria
INTESTINE

KIDNEY
reabsorbed
into blood

CO
Biliverdin IX

via bile duct to intestines

NADPH
Bilirubin diglucuronide
(water-soluble)

Biliverdin
reductase
NADP+
Bilirubin
(water-insoluble)
unconjugated

Catabolism of hemoglobin

2 UDP-glucuronic acid
via blood
to the liver

Bilirubin
(water-insoluble)

LIVER

Summary of bilirubin metabolism


Senescent red cells are major source of hemeproteins
Breakdown of heme to bilirubin occur in macrophage of reticuloendithelial
system ( tissue macrophages, spleen and liver).
Unconjugated bilirubin is transported through blood ( complex to albumin) to
liver.

Bilirubin is taken into liver and conjugate with glucuronic acid.

Bile is secreted into intestine where glucuronic acid is removed and the
resulting bilirubin is converted to urobilinogen.
A portion of urobilinogen is reabsorbed into blood, where it is converted to the
yellow urobilin and excreted by kidneys.
Urobilinogen is oxidized by intestinal bacteria to the brown stercobilin.

normal range of bilirubin:


1 16mol/l (0.1 1mg/dl)
4/5 are unconjugated bilirubin, others
are conjugated bilirubin.
<1mg/dl
1-2mg/dl
>2mg/ dl

normal
occult
Hyperbilirubinemia
jaundice

Hyperbilirubinemia: the concentration of blood bilirubin


are more than 1mg/dl.
Occult: the concentration of blood bilirubin are increased ,
but have no clinic sympotom, normally 1-2mg/dl.
Jaundice : ( also called icterus) refers to the yellow color of the
skin and scleare caused by deposition of bilirubin, secondry to
increased bilirubin levels in the blood.
Although not a disease itself, jaundice is usually a symptom
of an underlying disorder.

Based on pathophysiology, jaundice may result


from one or more of the following mechanism:
1. Increased bilirubin production ( excessive red cell
destruction)
2. Decreased hepatic uptake ( ligandin, drug, prolonged
starvation, and sepsis)
Decreased hepatic conjugation (enzyme,drugs, cirrhossis)
3. Decreeased excretion of bilirubin into bile ( gallstone,
tumour)

Simple Classification of jaundice

Accordingly, a simple classification of jaundice


is to divided into 3 predominant type:
Pre-hepatic (hemolytic jaundice)
Hepatic jaundice
Post hepatic cholestatic (obstructive
jaundice)

Hemolytic jaundice
massive lysis of red blood cells (for example, in patients
with sickel cell anemia or malaria) may produce bilirubin
faster than the liver can conjuagte it.
More bilirubin is excreted into the bile, the amount of the
urobilinogen entering the enterohepatic circulation is
increased, and urinary urobilinogen is increased.
Unconjugated bilirubin is elevated in blood.

Causes of hemolytic jaundice

Malaria
Side effects of certain drugs :antibiotic and anti-tuberculosis medicines,
levodopa,
Certain drugs in combination with a hereditary enzyme deficiency known as
glucose-6-phosphate dehydrogenase (G6PD)
Poisons Snake and spider venom, certain bacterial toxins, copper, and
some organic industrial chemicals directly attack the membranes of red
blood cells
Artificial heart valves
Hereditary RBC disorders sickle cell disease
Enlargement of the spleen
Diseases of the small blood vessels
Immune reactions to RBCs cancer
Transfusions
Kidney failure and other serious diseases
Erythroblastosis fetalis

Hepatocellular jaundice
Damage to liver cells( for example in patient with
cirrhosis or hepatitis) causes a decrease in both
bilirubin uptake and production of conjuagted bilirubin.
Unconjugated bilirubin occur in the blood and
increased urobilinogen in the urine.
The urine is dark in color and stool are pale, clay
color.
Plasma level of AST and ALT are elevated and the
patient experience nausea and anorexia.

Obstructive jaundice
In this instance jaundice is results from obstruction of
the bile duct.
For example, the presence of a hepatic tumor or bile
stone may block the bile ducts, preventing passage of
bilirubin into the intestine, patients with obstructive
jaundice experience GI pain, nausea and produce
stools that are a pale, clay color.

65 year-old lady presenting with obstructive jaundice

Biliary stones

Sample

Indices

Normal

Serum

Total Bil

1mg/dl

1mg/dl

Direct Bil

0
0.8mg/dl

Indirect Bil

1mg/dl

Color

normal

deep

deeper

deep

Bilirubin

Urobilinogen

a little

uncertain

Urobilin

a little

uncertain

Color

normal

Argilous
(complete
obstruction)

deeper

lighter or
normal

Urine

Stool

Obstructive Hemolytic
Jaundice
Jaundice
1mg/dl

Hepatic
Jaundice
1mg/dl

Diagnoses of Jaundice

You might also like