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Heme breakdown

End product: Bilirubin


Site:
Reticulo-endothelial cells of liver,
spleen,
bone marrow
Microsome

Bilirubin
Hemoglobin
Cytochrome

Myoglobin
Catalase

90%

Peroxidase

HEME

BILIRUBIN

Hemoglobin
6gms/day

250 mg Bilirubin
(35mg/gm of Hb)

Other heme- proteins

50 mg Bilirubin

300 mg Bilirubin/ day

Biliverdin reductase

Heme oxygenase
Microsomal enzyme
Requires molecular oxygen & NADPH
Iron is released from heme as ferric ion
-methyne bridge is oxidised & CO is
released

Heme

Biliverdin (Green)

Bilirubin (Yellow)

Transport to liver
Albumin: two binding site
One tightly binding
Another loosely bound

Liver
Uptake by hepatocytes
Conjugation
Secretion into bile

Uptake by hepatocytes
Carrier mediated facilitated transport
Liver has enomerous capacity to take
up bilirubin
Ligandin & protein Y

CONJUGATION OF
BILIRUBIN
Bilirubin (Unconjugated)
UDP-Glucuronic acid
UDP Glucuronyl
transferase

UDP
Bilirubin monoglucuronide (20%)
UDP-Glucuronic acid
UDP Glucuronyl
transferase

UDP
Bilirubin diglucuronide (80%)

Secretion of bilirubin
into bile

Active transport mechanism


Rate limiting step

Transporter
MOAT (multispecific organic anion
transporter) /
MRP-2 (multi drug resistance like
protein)

Drugs like phenobarbital induce UDP


glucuronyl transferases and secretion
of bilirubin into bile

CATABOLISM OF HEME BILIRUBIN


RETICULOENDOTHELIAL
SYSTEM
RBC lysis

BLOOD

Bilirubin
(unconjugated)

LIVER

Bilirubin Albumin
complex

+
Hemoglobin

INTESTINE

Bilirubin (Conjugated)
Bacterial
enzymes

Albumin

Albumin

ENTEROHEPATIC
CIRCULATION

Bilirubin
(Unconjugated)

Globin
Bilirubin
(Unconjugated)

Heme
Iron
Heme
oxygenase
Biliverdin

Bilirubin
Albumin
complex

UDP
Glucuronyl
transferase
Bilirubin
(Conjugated)

Urobilinogen

Stercobilinogen
KIDNEY

Biliverdin
reductase
Bilirubin
(Unconjugated)

LIVER

FAECES

BILE

Urinary
Urobilinogen

What is microsome ?
What is uroporphrinogen and
urobilinogen?
What is porphobilinogen?

van den Bergh reaction


Direct positive: Conjugated bilirubin
Conjugated bilirubin + Di-azotised sulfalinic acid
Purple colour

Indirect positive: Unconjugated bilirubin


Unconjugated bilirubin + Di-azotised sulfalinic acid
colour
+
Methanol
Purple colour

Biphasic reaction: Both


Both + Di-azotised sulfalinic acid
Methanol
Purple colour intensifies

Purple colour +

No

NORMAL FINDINGS
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

0.2 1.0 mg/dL


0.0 0.2 mg/dL
0.2 0.8 mg/dL

URINE
Bilirubin
Bile salt
Urobilinogen

Absent
Absent
Present in
trace

amount
(< 4mg/day)

UNCONJUGATED
BILIRUBIN

CONJUGATED
BILIRUBIN

Indirect bilirubin

Direct bilirubin

Insoluble in water

Soluble in water

Soluble in lipids

Insoluble in lipids

Can cross blood brain barrier

Doesnot cross blood brain

when level is increased

barrier

kernicterus
Never excreted in urine even if
blood level is raised.
van den Bergh reaction
Indirect positive

Excreted in urine when blood


level is raised (not in normal)
van den Bergh reaction
Direct positive

HYPERBILIRUBINEMIA
Hyperbilirubinemia Serum bilirubin above
1.0mg/dL
Latent jaundice
2.0 mg/dL

Serum bilirubin between 1.0

Jaundice (Icterus)
Yellow discolouration of skin,
sclera
Serum bilirubin above 2 mg/dL

HYPERBILIBURINEMIA

UNCONJUGATED

CONJUGATED

HYPERBILIBURINEMIA

CONGENITAL

ACQUIRED

Congenital
hyperbilirubinemia
UNCONJUGATED
Crigler-Najjar syndrome Type I
Crigler-Najjar syndrome Type II
Gilbert syndrome
CONJUGATED
Dubin-Johnson syndrome
Rotor syndrome

Congenital
hyperbilirubinemia
All are autosomal recessive except
Gilbert syndrome (autosomal
dominant)

Crigler-Najjar type I
Congenital non-hemolytic jaundice
Severe deficiency of bilirubin-UGT enzyme
Mutations in gene encoding bilirubin-UGT enzyme in
chromosome 2.
Severe unconjugated hyperbilirubinemia (> 20 mg/ dL)
Death occurs within 15-18 months of age
Treatment:
Phototherapy helps to decrease plasma bilirubin levels.
Phenobarbital is not useful.
Liver transplantation is curative.

Crigler-Najjar type II
Less severe form
Some enzyme activity is present
Unconjugated hyperbilirubinemia
(doesnot exceed 20 mg/ dL)
Patients respond to large doses of
phenobarbital

Gilbert syndrome
30% of bilirubin-UGT enzyme activity.
Harmless condition
Asymptomatic/ mild jaundice

Dubin-Johnson syndrome
Mutation in gene encoding MOAT/ MRP-2
Conjugated bilirubin cannot be secreted
into bile.
Black liver jaundice: Black pigmentation
in centrilobular hepatocytes
Conjugated hyperbilirubinemia

Rotor syndrome
Similar to Dubin-Johnson
But liver is normal (no black
pigmentation)
Cause not known

ACQUIRED
HYPERBILIRUBINEMIA

JAUNDICE

HEMOLYTIC
Or
PRE-HEPATIC

HEPATIC

OBSTRUCTIVE
Or
POST-HEPATIC

HEMOLYTIC JAUNDICE
Causes: RBC disorders
Sickle cell anemia,
Hereditary spherocytosis
G-6-PD deficiency
Incomptiable blood transfusion
Infection malaria
Antibody mediated

PATHOGENESIS IN HEMOLYTIC JAUNDICE


RETICULOENDOTHELIAL
SYSTEM

BLOOD

RBC lysis - Increased

Bilirubin
(unconjugated)
INCREASED

Hemoglobin

LIVER

Bilirubin Albumin
complex

Albumin

Albumin

INTESTINE

ENTEROHEPATIC
CIRCULATION

Bilirubin (Conjugated)
Bacterial
enzymes

Bilirubin
(Unconjugated)

Globin
Bilirubin
(Unconjugated)

Heme
Iron
Heme
oxygenase
Biliverdin

Bilirubin
Albumin
complex

UDP
Glucuronyl
transferase
Bilirubin
(Conjugated)
INCREASED

Urobilinogen
INCREASED

Stercobilinogen
INCREASED

Biliverdin
reductase
Bilirubin
(Unconjugated) INCREASED

BILE

FAECES
DARK COLOURED

LIVER

KIDNEY

Urinary
Urobilinogen
INCREASED

FINDINGS IN HEMOLYTIC JAUNDICE


BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

Increased
Normal
Increased

URINE
Bilirubin
Bile salt
Urobilinogen
Increased

UNCONJUGATED
HYPERBILIRUBINEMIA
ACHOLURIC JAUNDICE
RETENTION JAUNDICE

Absent
Absent

FAECES
DARK COLOURED

OBSTRUCTIVE JAUNDICE

Obstruction to biliary duct


Stones cholelithiasis
Cancer head of pancreas
Cirrhosis
CHOLESTATIC JAUNDICE

PATHOGENESIS OF OBSTRUCTIVE
JAUNDICE
RETICULOENDOTHELIAL
SYSTEM
RBC lysis

BLOOD

Bilirubin
(unconjugated)

LIVER

Bilirubin Albumin
complex

+
Hemoglobin

Albumin

Albumin

INTESTINE

ENTEROHEPATIC
CIRCULATION

Bilirubin (Conjugated)
Bacterial
enzymes

DECREASED

Bilirubin
(Unconjugated)

Globin
Bilirubin
(Unconjugated)

Heme
Iron
Heme
oxygenase

Bilirubin
Albumin
complex

Biliverdin

Biliverdin
reductase
Bilirubin
(Unconjugated)

UDP
Glucuronyl
transferase
Bilirubin
(Conjugated)

Conjugated
bilirubin
regrugitates
into blood
stream
increased

Urobilinogen

LIVER

Stercobilinogen
KIDNEY

FAECES light coloured

BILE

DECREASED
Urinary
Urobilinogen

BILE SALT IN OBSTRUCTIVE


JAUNDICE
LIVER

INTESTINE

ENTERO HEPATIC
CIRCULATION

Bile salts (15-30 gms/day)


Cholesterol
7- HYDROXYLASE
Cholic acid

Emulsify fat

LIVER

Cheno deoxy cholic acid


Taurine
or
Glycine

Tauro-cholic acid
Glyco- cholic acid

98%
Absorbed by intestinal
cells

Tauro-cheno- deoxy cholic acid


Glyco-cheno- deoxy cholic acid

Na+/ K+

Na+/ K+ salts of bile acids (BILE SALTS)


Regrugitated into blood stream excreted in urine

FAECES
BULKY, GREASY
STEATORRHEA

FINDINGS IN OBSTRUCTIVE
JAUNDICE
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

Increased
Increased
Normal

URINE
Bilirubin
Bile salt
Urobilinogen

Present
Present
Absent

HIGH COLOURED URINE

Conjugated hyperbilirubinemia
Pruritis itching
Fat soluble vitamin deficiency
Choluric jaundice
Regurgitation jaundice

FAECES
PALE CLAY
COLOURED STOOLS
STEATORRHEA

HEPATIC JAUNDICE
LIVER DISEASE
Hepatitis Hep A, B, C, D, E
Alcoholism
Drugs
Toxins

PATHOPHYSIOLOGY
Destruction of hepatocytes
FINDINGS IN HEPATIC JAUNDICE
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

Increased
Increased
Increased

URINE
Bilirubin
Bile salt
Urobilinogen

Present
Absent
Decreased
or
Normal

FAECES
Normal

Both conjugated & unconjugated bilirubin raised

Neonatal physiological
jaundice
Unconjugated hyperbilirubinemia
2nd day after birth 2 weeks
Transient condition
Causes:
Increased rate of hemolysis
Immature liver (decreased bilirubin-UGT activity)
Complication: Kernicterus
Treatment: Phenobarbital & Phototherapy (blue light)

NORMAL TOTAL
BILIRUBIN
LEVELS IN NEWBORNS
DAYS ATER BIRTH TOTAL BILIRUBIN (mg/ dL)
1st day

2.0 6.0

2nd & 3rd days

6.0 10.0

4th & 5th days

4.0 8.0

Drugs like sulfa release bilirubin from


albumin can precipitate
kernicterus in newborns

bilirubin: unconjugated bilirubin


bilirubin: bilirubin monoglucuronide
bilirubin: bilirubin diglucuronide
bilirubin: in case of conjugated
hyperbilirubinemia, the conjugated
bilirubin gets covalently attached to albumin

Breast milk jaundice


Oestrogen present in breast milk
inhibits bilirubin-UGT enzyme

LIVER FUNCTION TEST

Tests based on excretory function


BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

URINE
Bile pigment
Bile salt
Urobilinogen

Tests based on enzyme levels


Tests based on synthetic function

URINE TEST
Bilirubin

Fouchets test:
Bilirubin + Ferric chloride

Green colour

Gmelins test:
Bilirubin + HNO3

Bile salt

Green fluorescence

Hays test:
Sulphur powder sinks to bottom

Urobilinogen

Ehrlichs aldehyde test:


Urobilinogen + Ehrlichs aldehyde reagent
Red/pink colour

NORMAL FINDINGS
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

0.2 1.0 mg/dL


0.1 0.4 mg/dL
0.2 0.7 mg/dL

URINE
Bilirubin
Bile salt
Urobilinogen

Absent
Absent
Present in
trace

amount
(< 4mg/day)

FINDINGS IN HEMOLYTIC JAUNDICE


BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

Increased
Normal
Increased

URINE
Bilirubin
Bile salt
Urobilinogen
Increased

UNCONJUGATED
HYPERBILIRUBINEMIA
Acholuric jaundice

Absent
Absent

FAECES
DARK COLOURED

OTHER CAUSES OF UNCONJUGATED


HYPERBILIRUBINEMIA
Neonatal physiological jaundice
Criggler Najjar Type I & II
Gilberts syndrome

FINDINGS IN OBSTRUCTIVE
JAUNDICE
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

Increased
Increased
Normal

URINE
Bilirubin
Bile salt
Urobilinogen

Present
Present
Absent

HIGH COLOURED URINE

Conjugated hyperbilirubinemia
Pruritis itching
Fat soluble vitamin deficiency
Choluric jaundice

FAECES
PALE CLAY
COLOURED STOOLS
STEATORRHEA

OTHER CAUSES OF CONJUGATED


HYPERBILIRUBINEMIA
Dubin-Johnson syndrome
Rotor syndrome

FINDINGS IN HEPATIC JAUNDICE


BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin

Increased
Increased
Increased

URINE
Bilirubin
Bile salt
Urobilinogen

Present
Absent
Decreased
or
Normal

FAECES
Normal

Both conjugated & unconjugated bilirubin raised

LIVER ENZYMES
ALT Alanine transaminase (SGPT)
AST Aspartate transaminase
(SGOT)
Alkaline phosphatase
Glutamyl transpeptidase

ALT & AST


Hepatocytic cytosolic enzymes
Increased whenever there is damage to
hepatocytes HEPATIC JAUNDICE
AST is also increased in cardiac disease
Normal levels: ALT = 15 45 IU/L
AST = 10 40 IU/L

ALP:
Present in biliary epithelium & osteoblast
Elevated in obstructive liver disease &
bone disorders
Normal values =
3 13 KA/dL
40 125 IU/L

GGT:
Present in liver, kidney, prostate
Induced by alcohol
Increased in alcoholic liver disease
Normal values = 10 30 IU/L

LIVER ENZYMES IN JAUNDICE


HEMOLYTIC

HEPATIC OBSTRUCTIVE

ALT
AST

Normal

Increased

Normal
Or Slightly increased

ALP

Normal

Normal
Or Slightly
increased

Increased

GGT

Normal

Increased in
alcoholism

Normal

OTHER TEST
Serum Albumin: Decreased
Plasma Prothrombin time: Prolonged

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