Bilirubin
Hemoglobin
Cytochrome
Myoglobin
Catalase
90%
Peroxidase
HEME
BILIRUBIN
Hemoglobin
6gms/day
250 mg Bilirubin
(35mg/gm of Hb)
50 mg Bilirubin
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
Transporter
MOAT (multispecific organic anion
transporter) /
MRP-2 (multi drug resistance like
protein)
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?
Purple colour +
No
NORMAL FINDINGS
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
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
barrier
kernicterus
Never excreted in urine even if
blood level is raised.
van den Bergh reaction
Indirect positive
HYPERBILIRUBINEMIA
Hyperbilirubinemia Serum bilirubin above
1.0mg/dL
Latent jaundice
2.0 mg/dL
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
BLOOD
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
Increased
Normal
Increased
URINE
Bilirubin
Bile salt
Urobilinogen
Increased
UNCONJUGATED
HYPERBILIRUBINEMIA
ACHOLURIC JAUNDICE
RETENTION JAUNDICE
Absent
Absent
FAECES
DARK COLOURED
OBSTRUCTIVE 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
BILE
DECREASED
Urinary
Urobilinogen
INTESTINE
ENTERO HEPATIC
CIRCULATION
Emulsify fat
LIVER
Tauro-cholic acid
Glyco- cholic acid
98%
Absorbed by intestinal
cells
Na+/ K+
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
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
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
6.0 10.0
4.0 8.0
URINE
Bile pigment
Bile salt
Urobilinogen
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
NORMAL FINDINGS
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
URINE
Bilirubin
Bile salt
Urobilinogen
Absent
Absent
Present in
trace
amount
(< 4mg/day)
Increased
Normal
Increased
URINE
Bilirubin
Bile salt
Urobilinogen
Increased
UNCONJUGATED
HYPERBILIRUBINEMIA
Acholuric jaundice
Absent
Absent
FAECES
DARK COLOURED
FINDINGS IN OBSTRUCTIVE
JAUNDICE
BLOOD/SERUM
Total Bilirubin
Direct Bilirubin
Indirect Bilirubin
Increased
Increased
Normal
URINE
Bilirubin
Bile salt
Urobilinogen
Present
Present
Absent
Conjugated hyperbilirubinemia
Pruritis itching
Fat soluble vitamin deficiency
Choluric jaundice
FAECES
PALE CLAY
COLOURED STOOLS
STEATORRHEA
Increased
Increased
Increased
URINE
Bilirubin
Bile salt
Urobilinogen
Present
Absent
Decreased
or
Normal
FAECES
Normal
LIVER ENZYMES
ALT Alanine transaminase (SGPT)
AST Aspartate transaminase
(SGOT)
Alkaline phosphatase
Glutamyl transpeptidase
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
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