Jaundice

Bilirubin
Metabolism
Pathophysiology of
Jaundice
Oct 9, 2020 Jaundice 1
 Bilirubin Metabolism
 RBCs are broken down in RES
– Spleen, bone marrow, liver,
macrophages
 Breakdown of RBCs release Hgb
– About 8 gm of Hgb are broken down
per day
– 1 gm of Hgb releases about 35 mg of
bilirubin
Oct 9, 2020 Jaundice 2
 Bilirubin Metabolism
 Total daily out put of bilirubin
– 250 to 300 mg

Oct 9, 2020 Jaundice 3

 Bilirubin Metabolism
RBC
RES Plasma Liver
Globin
Hgb Bilirubin Bilirubin +
+ albumin Y, Z prot
Haeme
Conjugated
Biliverdin Bilirubin

Bilirubin Urobilinogen

Kidney Intestines
Conj.Bil Urobilinogen Stercobilin
Conjugated
Bilirubin

Urobilin
Urobilinogen Faeces
Oct 9, 2020 Jaundice 4
 Bilirubin Metabolism
 Hgb breakdown
– Releases globin & haeme
 Globin is broken down
– Amino acids
 Haeme is broken down to
– Release iron
– Biliverdin
 Biliverdin is further reduced
– Bilirubin

Oct 9, 2020 Jaundice 5

 Bilirubin Metabolism
 Bilirubin is then
– Released into circulation
– Combines with plasma protein
• Albumin
 Binding capacity of albumin
– >60 mg of bilirubin/dl of plasma

Oct 9, 2020 Jaundice 6

 Bilirubin Metabolism
 Certain organic anions
– Compete with bilirubin for binding
sites on albumin
• Sulphonamides, salicylates, fatty acids,
haematin
– Acidosis limit the binding of
bilirubin to albumin

Oct 9, 2020 Jaundice 7

 Bilirubin Metabolism
 These compounds
– Release bilirubin to enter into tissues
– Neonatal brain cells
• Have high affinity for bilirubin
 Basal ganglia cells
– Have  affinity for bilirubin
• Causes retention of bilirubin in brain
 Causes brain damage
– Kernicterus
Oct 9, 2020 Jaundice 8
 Bilirubin Metabolism
 The bilirubin +albumin complex
– Transported to the liver
– Taken up by liver cells
 Bilirubin is then bound to
– Y & Z transport proteins
• Prevent efflux of bilirubin into plasma

Oct 9, 2020 Jaundice 9

 Bilirubin Metabolism
 It is then conjugated to
– Glucoronic acid & sulphates
– By glucoronyl transferase
• Enzyme can be induced by
phenobarbitone & light

Oct 9, 2020 Jaundice 10

 Bilirubin Metabolism
 Conjugated bilirubin
– Actively secreted into bile canaliculi
– Some diffuse back into sinusoids
 It is then excreted into intestines
where
– Bacteria action causes
• Deconjugation into bilirubin
– It is then converted into
• Urobilinogen (stercobilinogen)

Oct 9, 2020 Jaundice 11

 Bilirubin Metabolism
 Urobilinogen
– Is excreted into faeces as
• Stercobilin
 10 to 15% of the urobilinogen is
– Reabsorbed into circulation
• Small intestines, colon
– 95% of the reabsorbed is
• Taken up by the liver
• It is re-secreted into bile ducts
Oct 9, 2020 Jaundice 12
 Bilirubin Metabolism
 5% of the reabsorbed
urobilinogen
– Is excreted by the kidney as
• Urobilinogen  Urobilin
 Daily excretion of urobilinogen
– Is less than 4 mg

Oct 9, 2020 Jaundice 13

 Bilirubin Metabolism
 Daily ecretion of urobilinogen
may  when
– Hepatic uptake & excretion is
impaired
• Hepatocellular diseases
– Production of bilirubin is greatly
increased
• Haemolysis

Oct 9, 2020 Jaundice 14

 Bilirubin Metabolism
 In extra hepatic obstruction of
bilirubin excretion
– There is marked  in urinary
excretion of urobilinogen

Oct 9, 2020 Jaundice 15

 Jaundice
 Yellow coloration
– Due to large quantity of bilirubin in
ECF
 Usually liver excretes bilirubin
rapidly
– Normal serum bilirubin
concentration
• Is 5 to 17 mol/L ( 0.3 to 1.0 mg/dL)

Oct 9, 2020 Jaundice 16

 Jaundice
 Serum bilirubin
– 90% of it is in unconjugated form
• Non polar
• Complexed to albumin
– 10% of serum albumin is conjugated
to glucoronide
• Water soluble
• Filtered & excreted by kidney

Oct 9, 2020 Jaundice 17

 Jaundice
 Bile salts enhance
– Glomerular filtration of conjugated
bilirubin
 Thus in extra-hepatic obstruction
– There is  in circulating bile salts
– And  renal excretion of conjugated
bilirubin

Oct 9, 2020 Jaundice 18

 Jaundice
 When plasma bilirubin increases
up to
– 35 mol/l jaundice can be detected
by skilled observer
– 55 to 70 mol/l jaundice is obvious
 In severe cases it can rise up to
– 250 to 350 mol/l

Oct 9, 2020 Jaundice 19

 Jaundice
 Causes of  bilirubin conc could be
– Increased destruction of RBC
• Haemolysis
– Rapid release of bilirubin in circulation
– It is of unconjugated form
– Obstruction of bile duct
• Obstructive jaundice
– Liver damage so that even the normal
amount
• Cannot be excreted

Oct 9, 2020 Jaundice 20

 Effects of
Hyperbilirubinaemia
 Bilirubin itself has
– Little pathophysiologic effects
– Not deposited in skin thus
• Does not cause itching (pruritis)
– The itching which occurs in jaundice
• Is due to bile salts
• Deposited in cutaneous tissues

Oct 9, 2020 Jaundice 21

 Effects of
Hyperbilirubinaemia
 Unconjugated bilirubin
– If not bound to plasma proteins
• Can cross the BBB
 Taken up by the brain cells
– Cause damage to brain cells
– Causing permanent impairment of
nervous functions
 Kernicterus

Oct 9, 2020 Jaundice 22

 Effects of
Hyperbilirubinaemia
 Risk of developing kernicterus is
increased by
– Conditions that favour  levels of
unconjugated bilirubin
• Haemolysis
• Hypoalbuminaemia
• Acidosis
• Compounds that compete with albumin
– FFA, drugs

Oct 9, 2020 Jaundice 23

 Effects of
Hyperbilirubinaemia
 Levels of unconjugated bilirubin
can be lowered by
– Removing the risk factors
– Facilitating biliary excretion of
unconjugated bilirubin

Oct 9, 2020 Jaundice 24

 Effects of
Hyperbilirubinaemia
 Exposure to blue light
– Causes conformation changes in
unconjugated bilirubin
• Makes it water soluble
• Without the need of conjugation
– This can prevent
• The development of kernicterus
• In neonatal jaundice

Oct 9, 2020 Jaundice 25

 Chemical Tests for Bile
Pigments
 Van de Bergh reaction
 Bilirubin pigments are exposed to
– Sulfanilic acid
– This generates diazo conjugates
– Measured calorimetrically

Oct 9, 2020 Jaundice 26

 Chemical Tests for Bile
Pigments
 When reaction is performed in
aqueous medium
– Conjugated bilirubin reacts directly
with sulfanilic acid
– Giving a positive van de Bergh
reaction

Oct 9, 2020 Jaundice 27

 Chemical Tests for Bile
Pigments
 When reaction is performed in in
methanol
– Alcohol breaks the intramolecular
hydrogen bonds of unconjugated
bilirubin
– Both conjugated & unconjugated
bilirubin
• React with sulfanilic acid

Oct 9, 2020 Jaundice 28

 Chemical Tests for Bile
Pigments
 Gives a measure of total bilirubin
levels
– This is the indirect van de Bergh
reaction
 Value for the unconjugated
bilirubin
– Obtained by subtracting values of
• Direct reaction from the indirect
reaction values
Oct 9, 2020 Jaundice 29
 Jaundice
 To determine whether the
jaundice is due to
  In levels of conjugated bilirubin or
  In levels of un-conjugated
bilirubin
 Urinalysis
– Presence of bilirubin in urine
• Indicates  levels of conjugated
bilirubin
Oct 9, 2020 Jaundice 30
 Jaundice
 Absence of bilirubin in urine
– Suggests jaundice is due to un-
conjugated bilirubin
 Estimation of total serum
bilirubin
– If 80 % to 85% of total serum
bilirubin is un-conjugated
• Patient has primary un-conjugated
hyper-bilirubinaemia

Oct 9, 2020 Jaundice 31

 Jaundice
 If > 50% of total serum bilirubin
is direct reacting bilirubin
(conjugated)
• Patient has primary conjugated hyper-
bilirubinaemia

Oct 9, 2020 Jaundice 32

 Major Causes of
Jaundice
 Jaundice with predominantly
– Un-conjugated hyper-
bilirubinaemia could be due to
• Overproduction of bilirubin
• Impaired hepatic uptake
• Impaired glucoronide conjugation

Oct 9, 2020 Jaundice 33

 Major Causes of
Jaundice
 Overproduction of bilirubin
  Break down of old RBC or
haemolysis of RBC cause
 Release of Hgb and hence
• Increase production of bilirubin

Oct 9, 2020 Jaundice 34

 Major Causes of
Jaundice
 Impaired hepatic uptake
 Bilirubin uptake by hepatocytes
require
– Dissociation of bilirubin from albumin
– Transport across cell membrane
– Binding to ligandin (transport proteins)
 Abnormalities in any of the above
steps
– Lead to  in plasma bilirubin levels

Oct 9, 2020 Jaundice 35

 Major Causes of
Jaundice
 Impaired conjugation
– Deficiency of glucoronosyl
transferase
• Acquired or genetic
– In fetus & neonates
• Transferase activity is normally low
– Likelihood of developing jaundice

Oct 9, 2020 Jaundice 36

 Major Causes of
Jaundice
 Inherited deficiency
– Gilberts syndrome
• Mild  in enzyme activity
• Mild un-conjugated
hyperbilirubinaemia
– Crigler-Najjar syndrome
• Could have total absence of enzyme
activity
– Associated with kernicterus
– Childhood mortality

Oct 9, 2020 Jaundice 37

 Major Causes of
Jaundice
 Acquired defects
– Liver diseases
– Drug induced

Oct 9, 2020 Jaundice 38

 Conjugated
Hyperbilirubinaemia
 Causes
– Impaired bilirubin excretion by
hepatic cells
– Extra-hepatic biliary obstruction

Oct 9, 2020 Jaundice 39

 Conjugated
Hyperbilirubinaemia
 Impaired bilirubin excretion
– Interference with bilirubin
excretion by hepatocytes leads to
• Efflux of bilirubin into systemic
circulation
 In conjugated bilirubin in plasma

Oct 9, 2020 Jaundice 40

 Conjugated
Hyperbilirubinaemia
 Extra-hepatic biliary obstruction
 Complete obstruction
– Leads to jaundice
• Predominantly of conjugated
hyperbilirubinaemia
  In bilirubin excretion in urine
• Bilirubinuria
– Pale stools
Oct 9, 2020 Jaundice 41