1

RED AND WHITE BLOOD CELLS

WBC (leucocytes) : Granulocytes (PMN) neutrophils
basophils
eosinophils

Monocytes macrophage

Lymphocytes L.B. antibodies
L.T. cellular immune
mechanism

Sadiah Achmad
2
Neutrophils : - phagocytose bacteria
- role in acute inflammation
Basophils : - contain histamin & heparin
- role in immunologic hypersensitivity reactions
Eosinophils : - allergic reactions
- parasitic infections
Monocytes : - precursor of macrophages
- phagocytosis
Lymphocytes : role in chronic inflammation
Neutrophils & lymphocytes : quantitatively major classes in
normal blood

Sadiah Achmad
3
RBC (Erythrocytes)
Function : delivering O
2
from lung to the tissue and helping
disposal of CO
2
& proton from the tissue
Structure : - simple, composed of concentrated solution of Hb
(95% of intracell protein)
- no intracellular organelles
- non nucleated
- biconcave shape (discoid) increase surface-
volume ratio fascilitating gas exchange
- contains cytoskeletal components determine
shape
Sadiah Achmad
4
RBC count: - men : 4.6 - 6.2 million / L ~ 14 18 g/dL Hb
- women: 4.2 - 5.4 million / L ~ 12 16 g/dL Hb
Total number in circulation : 2.5 x 10
13

Hematocrit (packed cell volume / PCV) : - men : 42 - 52%
- women : 37 - 47%
Life span : 120 days

Reticulocytes ( 1% of total RBC count ) :
- contain ribosome & endoplasmic reticulum active in protein
synthesis.
- in hemolytic anemias : - life span RBC : shortened
- reticulocytes
Sadiah Achmad
5
METABOLISM OF RBC
Glycolysis
Glucose
Pentose-P pathway NADPH

Glycolysis : - lactate
- ATP
- 2,3 Bis-P glycerate (BPG/DPG)
- NADH

1. ATP: - maintain biconcave shape
- regulation of ion transport :
- Na
+
- K
+
- ATPase. Ca
2+
-ATPase
- anion exchange protein
- water in and out of the cell
Sadiah Achmad
6


2. 2,3 BPG : modulating O
2
affinity of Hb


Glycolysis
1,3 Bis-P-glycerate Glucose

ADP B-P-glycerate
mutase

2,3 Bis-P-glycerate
ATP
Pi

3-P-glycerate 2,3 Bis-P-glycerate
phosphatase


Pyruvate
Sadiah Achmad
7
3. NADH:
RBC posses a system:
NADH-cytochrome b5 met Hb-reductase system reduced
Fe
3
+
Fe
2
+


Hb Fe
3
+
Cyt.b5 red NAD
Met Hb


Hb Fe
2
+
Cyt.b5 ox NADH
Cyt b5 reductase
(met Hb reductase)

Sadiah Achmad
8
* Entry of glucose into RBC : facilitated diffusion by means
of glucose transporter (glucose permease) : GLUT I :
- 2% of protein RBC membrane
- specific for D glucose & related D hexose
- affinity for D glucose is highest
- inhibited by glucose analog (phloretin)
- not insulin dependent
- contain 12 transmembrane (hydrophobic) helical
segment
- function by generating a gated pore in the
membrane ( conformationally dependent on the
presence of glucose)

Sadiah Achmad
9
* During metab. RBC generates oxidants oxidative stress
& damage : - superoxide (O
2

), peroxide (H
2
O
2
)

- peroxyl radicals : ROO*
- hydroxyl radicals : OH* (reactive), react with
proteins, nucleic acids, lipids & other mol alter
structure tissue damage

RBC contains cytosolic enzymes to protect from oxidative
stress : - superoxide dismutase
- catalase
- glutathion peroxidase
Sadiah Achmad
10


* Anti-oxidants : compounds & reactions disposing toxic
oxygen species, scavenging, suppressing their formation or
opposing their actions (include : NADPH, GSH, vit C, vit E)


Shifted toward pro-oxidant :
- production of oxygen species (chemicals, drugs)
- antioxidants level (inactivation of enzymes)
oxidative stress cell damage


Sadiah Achmad
11
* Def. G6PD (mutation: > 300 genetic variants) hemolytic. An.
- consumpsion of beans : Vicia faba (contains oxidants)
- drugs : sulfonamides, primaquine
- chemicals : naphthalene

* RBC with def.G6PD : cannot regenerate GSH
impair the ability to dispose H
2
O
2
& O
2
radicals
- oxidation of SH groups in protein
- peroxidation of lipid membranes lysis of RBC membr.
- oxidation of-SH group of Hb precipitates inside RBC
Heinz Bodies


Sadiah Achmad
12
Fig. 60.2 Harver hal 768)
Hemolytic anemia due to deficiency of G6PD
Sadiah Achmad
13
*Normal blood: very small amount of met Hb

* Methemoglobinemia : - inherited
- acquired : ingestion of certain drugs
(sulfonamides), chemicals (aniline)
Inherited : - def. Met Hb reductase:
- abnormal Hb (Hb M) : mutation changes A.A
residue to which heme is attached altering
affinity for O
2
favoring oxidation
* Cyanosis : bluish discoloration of skin & mucous membrane
- deoxy Hb in arterial blood
- met. Hb (>10%)
Treatment : - mild met Hb (def.enz) : ingest methylene blue or
ascorbic acid ( reducing agents)
- acute massive met Hb (ingest chemicals)
methylene blue I.V.
Sadiah Achmad
14
ANEMIA
- Blood contain fewer erythrocytes / decreased Hb content
- Caused by many factors
decreased O
2
carrying capacity impaired O
2
delivery to
the tissue
symptoms : - fatigue
- faintness
- headache
- lack of concentration
Sadiah Achmad
15
The causes are varies 3 broad categories :
1. Decreased number of RBC due to shortened life span
- abn. Hb : HbS, HbC, thalassemia
- abn. membr. prot. defect cell shape : spherocytosis
- abn. enzyme : G6PD def.
- infection : malaria
- immun. desorders : hemolytic disease of the
newborn
2. Decreased production of RBC
- impaired Hb synthesis : Fe Def.
- defect in stem cell maturation : Vit. B
12
def.
3. Abnormal red cell

Sadiah Achmad
16
The body has compensatory mechanism delaying the
onset of anemia
Impaired O
2
delivery
* Increasing 2,3 DPG synthesis modulates O
2
affinity of
Hb O
2
dissociates more readily at low O
2
tension in the
tissues Hb function more efficient
* Releasing erithropoietin accelerates RBC maturation in
bone marrow
* In hemolytic anemia bone marrow produces more cells &
sometimes are released prematurely reticulocytes in
circulation
Sadiah Achmad
17
Hemolytic anemia
- Increased rate of RBC destruction
- Jaundice
- Hb in urine dark colour (black water fever)

* Inherited hemolytic anemia
1. RBC membr. defects
spherocytosis - spherocytes
- defect in spectrin - actin network
- membr. is leaky to Na
+
activity of
Na
+
- K
+
- ATP ase demand for
ATP ( high glycolytic rate)

Sadiah Achmad
18
2. Abnormal Hb :
Hb S sickle cell anemia
Hb C, Hb D, Hb E
decreased solubility in deoxy- form

3. Thalassemia : synthesis of globin chains are depressed
- | - thal
- o - thal
Sadiah Achmad
19

4. Abnormal enzyme
- G6Pd def.
G6PD gene : on x - chromosome
- all RBC are affected in males & homozygous females
- heterozygous females : part of RBC with full enzyme
activity & the remainder with
no G6PD activity
- Pyruvate kinase def.
- Met Hb reductase def.
Sadiah Achmad
20
- Acquired Hem. An
- malaria
- bacterium : clostridium welchii
- snake venoms, spider
- mismatched blood transfusion
- hemolytic disease of the newborn
releases P lipase
lysis cell membr.
Sadiah Achmad
21
HEMOGLOBIN
Function : - transport O
2
from respiratory organ to peripheral
tissue
- transport CO
2
& protons from peripheral tissue to
the respiratory organ
- carry and release nitric oxide (NO) : a potent
vasodilator & inhibitor of platelet aggregation
Hb : - globular protein
- consist of pairs of 2 different polypeptides globin
each chain contains a prosthetic group heme
Major form of human adult Hb : HbA
1
(90%), consist of
2 o chains & 2 | chains (o
2
|
2
)
- o polypeptide : 141 amino acids
- | polypeptide : 146 amino acids

Sadiah Achmad
22
Hb variants :
Besides o

& | - globin chains, there are 4 genetically distinct
globin chains, produced at different stages of development
- chains o chains
- c chains chains | chains
Hb F (o
2

2
) : predominate in fetal blood ( in adult Hb < 1%)
Hb gower I :
2
c
2
Hb gower II : o
2
c
2

Hb portland :
2

2

- o chains Hb A
2
(o
2
o
2
) : minor form of adult Hb (2-3%)


in early embryonic blood
Sadiah Achmad
23
50
40
30
20
10
6 12 18 24 30 36 1 6 12 18 24 30 36 42 48
o



|
o

|








Postconceptual age
(weeks)
Postnatal age
(weeks)
Birth
% of
Total
globin
synthe-
sis
Changes in globin chain production during development
c
o

Sadiah Achmad
24
Abnormal genetic variants of Hb
Inherited abnormalities of Hb synthesis : 2 groups.
1. Hemoglobinopathy : structurally abnormal Hb variants.
2. Thalassemia : reduced rate synthesis of one or more
normal polypeptide chains of Hb.

Hemoglobinopathies :
classified on the basis of - functional characteristics
- structural abnormalities


Sadiah Achmad
25
HbS sickle cell anemia
- a variant form of Hb A
1
in which substitution of Glu Val
occurs in the 6
th
position of | - globin chain
- point mutation ( missense mutation) incorporation
of different amino acids in the encoded protein : A U
In m-RNA : GAA / GAG (codon for Glu) GUA / GUG
(codon for Val).
- polar side chain group is replaced with nonpolar
(hydrophobic) side chain Hb S polymerizes ( in its
deoxy-form) forming long fibers precipitation of Hb
within RBC sickle shape
sickling of RBC hemolysis
low O
2
tension exacerbates sickling
Sadiah Achmad
26
Homozygous Hb S (o o, |
s
|
s
)

severe form of disease :
sickle cell anemia
- 10 - 15% of homozygous children do not survive
beyond 2 years of age
- electroph. analysis : - 80% Hb S
- 20% Hb F

Heterozygous Hb S (o, o, |, |
s
)

:
- carrier (sickle cell trait) no clinical problems
- do not exhibit symptoms, except under extreme
hypoxia
- 50% Hb S & 50% Hb A
- het. individuals : resistence to malaria parasite
Sadiah Achmad
27
Sickle cell an : is diagnosed by recombinant DNA technique
from fetal DNA, obtained by amniocentesis.
Therapy : hydroxy urea stimulate synthesis of - chain
HbF decreases sickling when O
2
tension
decreases

Hb C Hb C disease
- Glu Lys. in the 6
th
position of | - chain
- genetic alteration : G A
GAA / GAG (codon for Glu) AAA / AAG (codon for
Lys)
- Hb C can not be separated from Hb A
2
by electroph
separated by column chromatography
- |
c
gene can be identified in fetal DNA


Sadiah Achmad
28
Homozygous Hb C Hb C disease (Hb CC)
- mild anemia moderate
- major fraction : Hb C
no Hb A, Hb F slightly increased
Heterozygous Hb C : Hb C trait (Hb AC)
- clinically sillent : - no symptoms
- hematuria
- electroph. anal : - 30 40% Hb C
- 50 60% Hb A
1

Hb A
2
slightly increased
(separated by chromatography)

Hb E : - |
26
Glu Lys
- Hb E syndrome : microcytosis & hypochromia
- doubly heterozygous state for Hb E & | - thal
clinically thal major.

Sadiah Achmad
29
Hb E trait (Hb AE)
- heterozygous, clinically silent
- microcytosis
- no anemia or reticulocytes
- Hb electroph : 20 - 35% Hb E

Hb E disease (Hb EE)
- prominent microcytosis, little or no anemia
- slight splenomegaly
- Hb E : 92 98% of Hb
Hb F : normal / slightly increased
- osmotic fragility
- significant morphologic alterations
Sadiah Achmad
30
Thalassemia
Genetic defect in the coordinated synthesis of o & | - globin
chains
Def. of | - chains | - thalassemia
Def. of o - chains o - thalassemia
Anemia at about 6 months of age - Hb F synthesis ceases
- Hb A synthesis predominant
The severity of symptons - thal. major
- thal. minor
- intermediate form
Therapy : frequent transfusion complications : iron -
overload hemosiderosis
Carrier : - thal. minor mild anemia
- protect from malaria

Sadiah Achmad
31


o - Thalassemia : mutations in o - globin genes,
- mainly : - unequal crossing over loss of 1 or more loci
- deletion
- nonsense & frameshift mutations
o- globin locus is duplicated normal individual has 4 o-genes
* Deletion of all 4 genes : homozygous
- hydrops fetalis
- fatal, fetus dies in utero, severe anemia
- Hb barts (
4
)
,
80 90%
- Hb H ( |
4
), Hb portland (
2 ,

2
)

* Deletion of 3 genes 1 functional gene
- most Hb has 4 | - chain Hb H ( |
4
) : unstable
precipitates in RBC chronic hemolytic anemia
- Hb Barts
* The presence of 2 or 3 globin genes normally no anemia
Sadiah Achmad
32
| - Thalassemia
- A wide variety of mutation in | - globin gene, including deletion,
nonsense, frameshift mutations
- Affecting biosynthesis of | - globin m RNA :
- affect. promoter inefficient transcription
- premature termination
- during splicing
- during polyadenylation
Thal. major : Cooleys anemia / disease
- severe anemia
- splenomegaly
- bony deformities
- complications of iron overload
Sadiah Achmad
33
Homozygous |
o
Thal. : - predominant Hb F
- no Hb A
- variable amounts of Hb A
2
Homozygous |
+
Thal. : - Hb A variable
- Hb F & Hb A
2
increased
Thal. minor : heterozygous
- asymptomatic
- little or no anemia
- Hb electroph : - predominant Hb A
- increased Hb A
2
- normal or minimally increased
Hb F
Sadiah Achmad
34
Synthesis of Hb
Hb : iron containing heme proteins (hemoproteins)
Important hemoproteins :
- hemoglobin
- myoglobin
- cytochrom c.
- cytochrom P
450

- catalase
- tryptophan pyrrolase
Heme : Fe
2+
- protoporphyrin IX, a cyclic tetrapyrrole

Heme biosynthesis : - occurs in mitochondria & cytosol via 8
enzymatic steps
- 85% occurs in bone marrow, the
remainder in hepatocytes

Sadiah Achmad
35
Biosynthesis of porphobilinogen

A. ALA synthase occurs in mithochondria
B. ALA dehydratase is present in the cytosol

A:
COOH
|
CH
2
|
CH
2

|
C = O
|
S CoA
+
H
|
H C NH
2
|
COOH
COOH
|
CH
2
|
CH
2

|
C = O
|
H C NH
2
|

COOH
|
CH
2
|
CH
2

|
C = O
|
H C NH
2
|
H
COOH
CoA SH CO
2
ALA
SYNTHASE
ALA
SYNTHASE
Pyridoxal
phosphate
Succinyl-
CoA
Glycine
o-Amino-|-ketoadipate o-Aminolevulinate
(ALA)
Sadiah Achmad
drugs
36
B:

COOH
|
CH
2
|
C H
2

|
C = O
/
CH
2
|
NH
2
H

NH
2
COOH
|
CH
2
|
CH
2

|
O = C
|
H C N


COOH
|
C H
2

|
C
||
C

CH
2
N
| H
NH
2
COOH
|
CH
2
|
CH
2

|
C
||
CH
2H
2
O
Ala
Dehydratase
Two molecules of Porphobilinogen:PBG
o-aminolevulinate (first precursor pyrrole)
Pb

Sadiah Achmad
37
Conversion of porphobilinogen to uroporphyrinogens
HOOC
|
H
2
C


|
C
||
C

H
2
C

N
| H


COOH
|
CH
2
|
CH
2

|
C
||
CH
NH
2
UROPORPHYRINOGEN I
SYNTHASE (PBG DEAMINASE)
NH
3
4
A

P

Hydroxymethylbilane
(linear tetrapyrrole)
4 molecules of
porphobilinogen
Sadiah Achmad
38
Uroporphyrinogen III
Hydroxymethylbilane
(linear tetrapyrrole)
N
H
H
N
NH HN
A P
P A
A



P
A



P
N
H
H
N
NH HN
A P
P A
A



P
P



A
Uroporphyrinogen I
UROPORPHYRINOGEN III
(Co)SYNTHASE
SPONTANEOUS
CYCLIZATION
Sadiah Achmad
39
P

P



P

P
I

IV II

III
A
A
A
A
P

P



P

P
M
M
M
M
P





P

P
A
A
A
P
P





P

P
M
M
M
P
M A
Uroporphyrinogen I
Uroporphyrinogen III
Uroporphyrinogen
Decarboxylase
Coproporphyrinogen I
Coproporphyrinogen III
I

IV II

III
I

IV II

III
I

IV II

III
4CO
2
4CO
2
Decarboxylation of uroporphyrinogens
to coproporphyrinogens in cytosol
Uroporphyrinogen
Decarboxylase
Sadiah Achmad
40


Coproporphyrinogen III




Protoporphyrinogen III




Protoporphyrin III





Heme


Steps in the biosynthesis
of the porphyrin derivatives
from porphobilinogen

6H
Coproporphyrin
III
Ferrochelatase
Coproporphyrinogen
Oxidase
Protoporphyrinogen
Oxidase
Light
6H



Fe
2+
Pb

Or light in vitro

4CO
2
Uroporphyrinogen III Uroporphyrin III

6H
Uroporphyrinogen III
(Co) Synthase
Uroporphyrinogen I Synthase
(PBS Deaminase)
Porphobilinogen


Hydroxymethylbilane

Uroporphyrinogen I
Coproporphyrinogen I
Uroporphyrinogen
Decarboxylase
4CO
2
6H
6H
SPONTANEOUS
Copropor -
phyrin I
Uroporphyrin
I
Light
Light
Light
M
I
T
O
C
H
O
N
D
R
I
A




















C
Y
T
O
S
O
L

Sadiah Achmad
41
CH
2
I
CH
2
I
COOH
HOOC CH
2
CH
2
CH
3
CH
3
CH
2
II
CH
CH
3

CH = CH
2
N
N
N
N
Fe
2+
CH
3
Structure of heme
Sadiah Achmad
42
Regulation of heme biosynthesis
* Ala synthase is the key regulatory enzyme of heme
biosynthesis by repression & derepression (induction)
mediated by heme.
The rate of synthesis of ALA synthase increases in the
absence of heme & is diminished in its presence
* Drugs (barbiturates, griseofulvin) : induce the enzyme ( by
inducing cytochrom P
450
) derepression of ALA synthase
Sadiah Achmad
43
Hemoproteins

Heme

Protoporphyrin III

Protoporphyrinogen III

Coproporphyrinogen III

Uroporphyrinogen III

Hydroxymethylbilane

Porphobilinogen

ALA

Succinyl-CoA + Glycine


Proteins


Fe
2+
7. Protoporphyrinogen oxidase
6. Coproporphyrinogen oxidase
5. Uroporphyrinogen decarboxylase
4. Uroporphyrinogen iii synthase
3. Uroporphyrinogen i synthase
2. Ala dehydratase
1. Ala synthase
Aporepressor
8. Ferrochelatase
Regulation of
heme synthesis
Sadiah Achmad
44
Porphyria
Group of disorders due to abnormalities in heme biosynthesis
- genetic
- acquired
- 6 major types resulting from depression in the activities of
enzyme
Clinical symptoms / signs result from :
- def. of metab. products beyond the enzymatic block
- accumulation of metabolites behind the block

Sadiah Achmad
45
Mutations in DNA
Abnormalities of the
enzymes of heme synthesis
Accumulation of
ALA and PBG and/or
decrease in heme in
cells and body fluids
Neuropsychiatric signs
and symptoms
Accumulation of
porphyrinogens in skin
and tissues
Spontaneous oxidation
of porphyrinogens to
porphyrins
Photosensitivity
Biochemical causes of the major
signs and symptoms of the porphyrias
Sadiah Achmad
46
Classification of porphyrias : base on the organs / cells that are
most affected ( active heme synthesis )
- erythropoietic : active Hb synthesis in bone marrow
- hepatic : active synthesis of cytochrom P
450
in liver

Therapy : - symtomatic
- avoid anesthetics, drugs, alcohol
( induction of cyt. P
450
).
- ingestion of food rich in carbohydrates (glucose
loading) or administration of hematin ALA
synthase production of heme precursor
- photosensitivity : - administration of |-carotene
production of free radicals
- sunscreen

Sadiah Achmad
47
Catabolism of Heme
Hb Heme Biliverdin Bilirubin
O
2
CO Fe
3+
Pool Reuse

Globin


Amino
Acids


Reuse
NADPH NADP NADPH NADP
Microsomal
Heme oxyge-
nase syst.
Bil. reductase
Sadiah Achmad
48
1 gram Hb 35 mg bilirubin
Dailly bilirubin formation in adults : 250 - 350 mg, deriving
from : - mainly Hb
- other hemoprotein

Bilirubin formed in RES is transported to the liver by :
plasma albumin : - uptake of bil. by liver cells
- conjugation of bil. in SER.
- secretion of conjugated - bil. into bile
Sadiah Achmad
49
* In the liver :
- bil. is taken up at sinusoidal surface of hepatocytes by
facilitated transport syst. not rate limiting
- bil. is bound to cytosolic proteins : ligandin, Y protein
- bil. is conjugated with glucuronic acid bil. diglucuronide

Bilirubin
+
UDP - glucuronic
acid




Bil. monogluc.
+
UDP. gluc acid
UDP - glucuronosyl
transferase I






UDP - gluc.
transferase II
Bil. monoglucuronide
+ UDP





Bil. diglucuronide
+ UDP
Sadiah Achmad
50
- UDP gluc. acid : formed from UDP glucose


UDP glucose UDP glucuronic acid


- 2 isoforms of UDP - glucuronosyltransferase
- UDP - gluc.trans. can be induced by drugs e.g phenobarbital

* Conj. bilirubin is secreted into bile by an active transport
mechanism rate - limiting
Hepatic transport of conj. bilirubin is inducible by phenobarbital
After phototherapy : significant quantities of unconjugated
bilirubin is found in bile
UDP glucose
dehydrogenase
2NAD
+
2NADH + 2H
+
Sadiah Achmad
51
Hyperbilirubinemia
Normal : bilirubin in blood : < 1 mg/dl (< 17,1 mol /L)
Hyperbilirunemia : bil. in blood > 1 mg /dl
Due to : - production of bil > normal liver can excrete
prehepatic jaundice
- failure of damaged liver to excrete bil. produced in
normal amount hepatic jaundice
- obstruction to the excretory ducts of the liver
prevent the excretion of bile post hepatic
jaundice

Bil. accumulates in blood concentration of 2 2,5 ml/dl
Diffuses into the tissues jaundice / icterus

Sadiah Achmad
52
* Unconjugated hyperbilirubinemia
1. hemolytic anemias
- important causes of unconjugated hyperbil.
- capacity of the liver for handling of bil. slight
increase of unconj. bil. ( < 4 mg/dl, < 68, 4 mol/ L)
even in extensive hemolysis
- defect in handling bil. (inherited or aquired) unconj.
hyperbil.
2. Neonatal physiologic jaundice
- most common cause
- results from :
* accelerated hemolysis and
* immature hepatic system for uptake, conjugation
& secretion of bil. :
- reduced UDP - glucuronosyl transferase activity
- reduced synthesis of UDP - gluc. acid.
Sadiah Achmad
53
- penetrating blood brain barrier when concentration in
plasma 20 - 25 mg/dl toxic encephalopathy :
kernicterus mental retard
- therapy : - administration of phenobarbital
- phototherapy promotes hepatic excre -
tion of unconj. bil.

3. Crigler - Najjar syndrome type I :
Congenital Nonhemolytic Jaundice
- primary metabolic defect in conjugation of bil.
absence of UDP. gluc. trans. activity in hepatic tissue
- fatal within the first 15 months of life
- phototherapy : some reduction in plasma bil. levels
- phenobarb. : no effect
- when untreated : serum bil. exceeds 20 mg / dl
Sadiah Achmad
54
4. Crigler Najjar syndrome type II
- milder defect in bil. conjugating system
- more benign
- serum bil. levels do not exceed 20 mg/dl
- bile contains bil. monogluc. genetic defect involved
hepatic UDP - gluc. transf. II
- respond to large doses of phenobarb.

5. Gilbert syndrome
- heterogenous group of disorders
- due to compensated hemolysis associated with unconj.
hyperbil.
- expanded nucleotide repeats in promoter region of gene
encoding UDP gluc.transf. I decreased level of
enzyme
- harmless
Sadiah Achmad
55
6. Toxic hyperbilirubinemia
- aquired disorders
- result from toxin induced liver dysfunction, caused by :
chloroform, CCl
4
, acetaminophen, hepatitis virus,
cirrosis, amanita mushroom poisoning
hepatic parenchym cell damage
impairs conjugation
- frequently there is obstruction of biliary tree within the
liver conj. hyperbil.
Sadiah Achmad
56
* Conjugated hyperbilirubinemia
1. Obstruction of biliary tree
- obstruction of hepatic or common bile ducts
- bil digluc. cannot be excreted regurgitates into
hepatic veins & lymphatics conj. bil. in blood
stream & urine (choluric jaundice)

Acholuric J. : occurs in retention hyperbil.
Cholestatic J. : - include all cases of extrahepatic obstr.j.
- micro obstr. of intrahepatic biliary
ductules by swollen damaged
hepatocytes (infectious hepatitis)
Sadiah Achmad
57
2. Chronic idiopathic jaundice (Dubin Johnson Syndrome)
- in childhood or adult
- defect in hepatic secretion of conj. bil. into bile
- involves secretion of conj. estrogens & test compound
sulfobromophthalein.
- hepatocytes in the centrilobular area contain abnormal
black pigment

3. Rotor Syndrome
- rare, benign
- chronic conj. hyperbil
- normal liver histology
- defect in transport by hepatocytes of organic anions
including bilirubin.
Sadiah Achmad
58
Laboratory results in normal patients and patients with three different
causes of jaundice
40-280 mg/
24 h

increased


decreased



trace to
absent

absent


absent


present if micro-
obstruction
occurs

present
0-4 mg / 24h


increased


decreased if
microobstruction
is present

absent
direct: 0.1-0.4
indirect: 0.2-0.7

Indirect


direct
and indirect



direct

normal


hemolytic anemia


hepatitis




obstructive
jaundice

Fecal
Urobilinogen
Urine Bilirubin Urine
Urobilinogen
Serum Bilirubin
(mg/dL)
Condition
Sadiah Achmad