1) Hemoglobin is broken down in red blood cells, producing bilirubin at a rate of approximately 250-350 mg per day. 2) Bilirubin binds to albumin and is transported to the liver, where it is conjugated and secreted into bile ducts. 3) Jaundice occurs when there is excessive bilirubin that cannot be processed by the liver, resulting in a buildup that discolors the skin and eyes. It can be caused by hemolytic anemia, liver disease, or bile duct obstruction.

1. Heme catabolism &
Jaundice
Dr. N. Sivaranjani
Asst. Prof.

2. Degradation of Hb
 6g of Hb is broken per day
 1g of Hb = 35 mg of bilirubin
 Approx. 250-350 mg of bilirubin is formed per day
 85% - old RBCs (120 days) degraded per day
 15% - immature RBCs & other heme containing proteins.
dr. N. Sivaranjani 2

3. HemoglobinHeme globin
Amino acids
Reutilized
NADPH + H+
NADP+
Heme oxygenase
Fe3+
Hemoproteins
Hb - 80%
Myoglobin, Cytochromes – 20%
Reticuloendothelial cells- Liver,
Spleen, Bone marrow.
V
M
M M
V
M
PP
Fe++
CO
O2
P M
N
PM
N
VM
N
VM
N OO
IIVIIIII
I
IV
II
MICROSOMAL
Biliverdin
Linear Tetrapyrrole compoundH H H
Cleavage of the alpha
methenyl bridge b/w
pyrrole rings I and II.
dr. N. Sivaranjani 3

4. P M
N
PM
N
VM
N
VM
N OO
IIVIIIII
Biliverdin
Biliverdin reductase
H H H
NNN N OO
IIVIIIII
H H H
NADPH + H+
NADP+
H H H
Bilirubindr. N. Sivaranjani 4

5. Unconj.BILIRUBIN - ALBUMIN
Endoplasmic reticulum
Conjugated Bilirubin
Unconj.Bilirubin
UDP-Glucuronate
UDP
UDP-glucuronyl transferase
Bilirubin monoglucuronide
UDP-Glucuronate
UDP
UDP-glucuronyl transferase
Bilirubin diglucuronide
UDP
PMVM
N N
OO
IIVIIIII
H H H
H2
H
NN
P M VM
Glucuronic acid Glucuronic acid
Active process - Rate limiting step
Uptake by LIVER
Conjugation is induced
by Phenobarbitone
dr. N. Sivaranjani 5

6. Albumin – 1 high affinity binding site and 1 low affinity
binding site for bilirubin
In 100 ml plasma- 25 mg of bilirubin bind to high affinity
binding site
 Drugs – Aspirin, Sulpha antibiotic , Salicylates
Displace bilirubin from Albumin.
 So bilirubin cross BBB , enter brain & cause injury – drugs
are avoided in New born.
dr. N. Sivaranjani 6

7. Uptake of bilirubin by Liver -Ligandin
Conjugation of bilirubin – disrupts the internal H
bonding which limits the aqueous solubility of
bilirubin.C1 of Glucuronic acid condenses with carboxyl gr of
Propionic acid.
Secretion of conj. bilirubin into bile –
Active process - RATE LIMING STEP
MOAT – Multispecific Organic Anion Transport.
3 process
dr. N. Sivaranjani 7

8. Bilirubin diglucuronide
Bilirubin diglucuronide
Enterohepatic
circulation
Bilirubin
Urobilinogen
Stercobilinogen
Excreted - BROWN color of FecesStercobilin
Glucuronidase
Urobilinogen
Urobilin
Excreted in Urine
4 mg/day
100-200 mg/day
Systemic
Circulation
Bacterial
enzymes
20%
Oxidised
Oxidised
Deconjugation
dr. N. Sivaranjani 8

9. Reduced form of Bilirubin
– Colorless tetrapyrroles
Urobilinogen
Mesobilinogen
Stercobilinogen
Oxidized form
of Bilirubin
UROBILIN
STERCOBILIN
MESOBILIN
On exposure to atmospheric air, these are oxidized to colored product.
dr. N. Sivaranjani 9

10. Jaundice is a symptom of underlying
disease , NOT a disease itself.
• Jaundice is yellowish discoloration of the Sclera, Skin and mucous
membranes due to hyper-bilirubinemia and deposition of bile
pigments.

11. Bilirubin
• The normal conc. of serum bilirubin is
 Total bilirubin - 0.1 to 1.0 mg/dl
 Conjugated (direct) - 0.1 to 0.4 mg/dl
 Unconjugated (indirect) - 0.2 to 0.7 mg/dl
 1-2 mg/dl – Subclinical JAUNDICE
 >3 mg/dl – ICTERUS – Clinical JAUNDICE.
dr. N. Sivaranjani 11

12. JAUNDICE
Failure of disease
LIVER to excrete
bilirubin produced in
NORMAL amounts
Production of more
bilirubin than LIVER
can conjugate -
Increased haemolysis
Mechanical obstruction
of BILE DUCT –bilirubin
cannot enter intestine
dr. N. Sivaranjani 12

13. Intrinsic
Extrinsic
Hemoglobinopathies -
 Hereditary Spherocytosis
 G6PDH deficiency , PK deficiency
 Sickle cell anemia , α-thalassemia .
 Incompatible blood transfusion
 Autoimmune hemolytic anemia
 Malaria
Increased hemolysis of RBCs
dr. N. Sivaranjani 13

14. • Main Clinical features of hemolytic jaundice
 Icterus
 Anemia
 Splenomegaly
Other investigations :
 Hb – dec.
 Reticulocytes – inc.
 Bone marrow – Hyperplasia
dr. N. Sivaranjani 14

15. Infection
Congenital
Toxic
Tumour
 Chronic & Acute Hepatitis – VIRAL
Hepatitis
 Galactosemia
 Alcoholic hepatitis – CIRRHOSIS of liver
 Chloroform, Carbon tetrachloride,
phosphorus
 Drugs
Parenchymal Liver disease
dr. N. Sivaranjani 15

16. • Hepatic jaundice
 Caused by impaired uptake of bilirubin by LIVER
 Drugs – Rifampicin – dec uptake of bilirubin
- Novobiocin ,Primaquine – affects conjugation
 Hepatotoxic drugs – Tetracycline, Paracetamol , Alcohol
 Congenital – Gilberts ,Crigler Najjar synd.
 Caused by infective hepatitis – varying degree of liver necrosis
 Damaged liver – uptake & conjugation affected- unconj. Bilirubin inc.
 Intrahepatic cholestasis –due to block of bile canaliculi by swelling
of liver cell or bile thrombi – regurgitate of conj. Bilirubin to blood-
conj. Bilirubin inc.
dr. N. Sivaranjani 16

17. • Clinical presentation of viral hepatitis
4-10 days
Bilirubin starts to rise
Nausea, vomiting,
Anorexia, Abdominal
discomfort, Arthalgia
1-4 days
Jaundice appears
Hepatomegaly,
Occasionally
splenomegaly,
Sr. Bilirubin dec &
returns to normal
Pre icteric phase
dr. N. Sivaranjani 17

18. Infection
Obstruction
Tumour
 Cholecystitis
 Biliary cirrhosis
 Gall stones
 Bile duct obstruction / biliary atresia
 Post infective strictures
 Ca head of pancreas
 Ca gallbladder
 Ca of CBD
Obstruction in Bile duct - Prevents the
passage of bile into the intestine
dr. N. Sivaranjani 18

19. • Cholestatic jaundice / Surgical jaundice clinical features
 Icterus
 Pruritis – retention of Bile salts
 Hepatomegaly
 Purpura – Impaired Vit.K absorption
 Extrahepatic cholestasis –
 Gall stones in CBD
 Tumor of bile duct
 Atresia of main bile duct
 Bile duct stricture
 Ca head of pancreas
 Intrahepatic cholestasis –
Congenital – D-J synd., Rotor synd.
Primary biliary cirrhosis
Intra hepatic atresia
Sclerosing cholangitis
Bile duct ca
dr. N. Sivaranjani 19

20. Van den Bergh test - Bilirubin reacts with diazo reagent (diazotized
sulphanilic acid) to produce colored azo pigment - Purple color
Bilirubin Van den Bergh test
Conjugated bilirubin Colour develops immediately ,response
is direct positive.
Unconjugated
bilirubin
Colour obtained only when alcohol is
added, this response is indirect
positive.
Both unconjugated
and conjugated
bilirubin
Colour develops immediately and it gets
intensified on adding alcohol, response
is Biphasic.
EHRLICH'S test – UROBLINOGEN
dr. N. Sivaranjani 20

21. Types of jaundice Pre hepatic Hepatic Post hepatic
Type of bilirubin
elevated
unconjugated
bilirubin
Both conjugated &
unconjugated bilirubin
conjugated
bilirubin
Serum bilirubin -
Van den Bergh test
Indirect positive Biphasic Direct positive
Urine
 Conj.Bilirubin
 Urobilinogen
 Bile salt
Absent
+++
Absent
++
+ early, obst.-dec.
+
+++
Absent
++
Urine color Normal-Acholuric Dark – Choluric Dark – Choluric
Stool color Dark brown colour N /decreased Clay colored stools
AST & ALT Normal Very high inc.
ALP Levels Normal 2-3 times increased 10-12 times inc.dr. N. Sivaranjani 21

22.  Unconj. Bilirubin inc in serum
 UBG inc. in urine
 Urine normal color
 Dark color stool
 Unconj. & Conj. Bilirubin inc.
 UBG is slightly inc & dec in case
of obstructive phase in urine
 Urine dark color
 Normal color stool
 Conj. Bilirubin inc in serum
 UBG dec. in urine
 Urine dark color
 Clay color stooldr. N. Sivaranjani 22

23. Neonatal Physiological jaundice
• Most common and harmless
• it presents 2nd days of birth & disappears by 2 weeks (appro.10 day)
 Reason for inc.unconjugated bilirubin (not more than 5 mg/dl) :-
 Liver is immature for uptake, conjugation (low E) & secretion of
bilirubin
 Shorter life span of fetal RBCs of 80 - 90 days – inc. Hemolysis
 Low conversion of bilirubin to Urobilinogen by the intestinal flora.
dr. N. Sivaranjani 23

24. Pathological Jaundice – appears in the first 24 hours of life.
>19 mg/dl – unconjugated hyperbilirubinemia.
Causes :- blood incompatibilities, blood diseases, genetic syndromes,
hepatitis, cirrhosis, bile duct blockage, other liver diseases, infections,
or medications. in addition, it applies to newborns with jaundice
exaggerated by dehydration, prematurity.
Breast milk jaundice
 Occurs in breast fed infants
 Usually appears at 1st week of life
 High level of Estrogen derivative in maternal blood, which is
excreted through the milk- Inhibits UDP GT enzyme
 Harmless and resolves spontaneously
dr. N. Sivaranjani 24

25. BILIRUBIN is – NEUROTOXIC - Inc. Bilirubin
(>20 mg/dl) cross BBB – deposits in Basal ganglia,
Cerebellum etc.
 PREMATURE infants are at RISK.
 Cause IRREVERSIBLE brain damage
 Leads to KERNICTERUS - FATAL
 Permanent Neurological deficit
POOR FEEDING
LETHARGY
FITS
SPASTICITY
MENTAL RETARDATION
dr. N. Sivaranjani 25

26. Rx
• Phototherapy : uses Blue light
(420-470 nm).
Bilirubin absorbs blue light maximally.
Photoisomerization – Unconjugated bilirubin converted into a
non-toxic isomer lumirubin, which is excreted.
• Phenobarbital - induce UDP GT enzymes
• Blood transfusion – to prevents brain damage.
dr. N. Sivaranjani 26

27. Crigler-Najjar
syndrome
• AR
• Type I- total
absence of UDP
glucuronyl transf.
• Type II– partial
def. of UDP GT.
• Unconj. Bilirubin
>20mg/dl
• Kernicterus
• Death – 1yr of life
Gilbert’s
syndrome
• AD inheritance
• Males
• defective uptake
of bilirubin by
the liver
• Unconj. Bilirubin -
3 mg/dl
• harmless , no Rx
Dubin –Johnson
syndrome
• AR
• Defective
excretion of conj.
Bilirubin into
BILE
• Mutation in gene
encoding MOAT
protein
• Black liver
jaundice
Rotor
syndrome
• AR
• Exact
cause??
• Abnormal
excretion
• Harmless,
No Rx
Congenital hyperbilirubinemias:
Due to abnormal uptake/ abnormal conjugation /abnormal excretion of
bilirubin.
dr. N. Sivaranjani 27

28. Hemoglobin
(120 days )
Heme
Globin
Fe2+
CO
Amino acids - reused
Lung – Exhalation
Bone marrow – recycled
Porphyrin ring – BILIRUBIN
Summary
dr. N. Sivaranjani 28

29. Deconjugated
& reduced to
Stercobilinogen
excreted in
feces
• Bilirubin –
Albumin
complex
Conjugation
of bilirubin
Secretion of
conj. Bilirubin
into bile
Excreted as
Urobilinogen
in urine
dr. N. Sivaranjani 29

30. JAUNDICE
Unconjugated bilirubin Conjugated bilirubin
Hepatic Post-Hepatic
Physiological
Jaundice
Pathological
Hemolytic Non Hemolytic
Congenital jaundice
Crigler-Najjar syndrome
Gilbert’s syndrome
Congenital jaundice
Dubin-Johnson syndrome
Rotor’s syndrome
Unconj. &
Conjug. bilirubin
dr. N. Sivaranjani 30