Chemistry, synthesis and catabolism of porphyrins

1. R. C. Gupta
M.D. (Biochemistry)
Jaipur (Rajasthan), India

2. Porphyrins are formed by the union of four
pyrrole rings through methenyl bridges
They usually contain a metal ion linked to
the nitrogen atoms of the pyrrole rings
Biologically important porphyrins are
usually present as conjugated proteins

3. Some important porphyrin-
containing compounds are:
Haemoglobin
Myoglobin
Cytochromes
Catalase
Peroxidase
Tryptophan pyrrolase

4. Haemoglobin
Haemoglobin is a conjugated protein made
up of four subunits
Each subunit contains a haem group and a
polypeptide chain
The haem group is made up of porphyrin
and a ferrous ion
Haemoglobin can reversibly combine with
oxygen, and transports oxygen in the body

5. Myoglobin
Structure is similar to that of haemoglobin
The difference is that it is a monomer
Myoglobin is present in muscles
It can reversibly combine with oxygen

6. Contain iron-porphyrin conjugated to
proteins
Iron-porphyrin portion similar to that of
haemoglobin
Components of respiratory chain in
mitochondria; transport electrons
Some cytochromes perform other functions
as well e.g. microsomal hydroxylation
Cytochromes

7. An iron-porphyrin containing enzyme that
is present mainly in animals
Acts on, and detoxifies, hydrogen peroxide
Catalase

8. Another iron-porphyrin containing enzyme
that acts on hydrogen peroxide
It occurs mainly in plants
Peroxidase

9. Iron-porphyrin containing enzyme
Acts on tryptophan
Tryptophan pyrrolase

13. Carbon atom numbers 1 to 8 have
different substituents attached to them
The substituents may be acetate (A),
propionate (P), methyl (M) and vinyl (V)
There are two types of porphyrins −
porphyrin I and porphyrin III

16. Type III porphyrins are found more
commonly than type I
Uro-
porphyrins
Copro-
porphyrins
Proto-
porphyrins
The important porphyrins in human
beings are:

17. Uroporphyrins are found in urine
Coproporphyrins are found in faeces
Protoporphyrins are found in blood and
tissues

19. Synthesis of porphyrins begins with the
condensation of succinyl CoA with glycine
Succinyl CoA is an intermediate of citric
acid cycle
This reaction is catalysed by d-amino-
levulinic acid synthetase (ALA synthetase)
Synthesis

21. a-Amino-b-ketoadipic acid is decarbo-
xylated to d-aminolevulinic acid (ALA)
The reaction is catalysed by ALA synthetase
Pyridoxal phosphate (PLP) is required as a
coenzyme

23. Two ALA molecules are condensed to
form the first pyrrole compound, porpho-
bilinogen
This reaction is catalysed by ALA
dehydrase

25. Different porphyrins are formed from
porphobilinogen
The exact reactions leading to the
synthesis of porphyrins are not fully
understood

26. Four porphobilinogen molecules react to
form hydroxymethylbilane
The reaction is catalysed by uropor-
phyrinogen I synthetase

27. Hydroxymethylbilane can spontaneously
cyclize to form uroporphyrinogen I
It can be enzymatically cyclized to uro-
porphyrinogen III
The enzymatic reaction is catalysed by
uroporphyrinogen I synthetase and uro-
porphyrinogen III cosynthetase

28. Uroporphyrinogens can be converted
into coproporphyrinogens
Coproporphyrinogens can be
converted into protoporphyrinogens

31. Protoporphyrin III is the most abundant
porphyrin
Haem is synthesized from protopor-
phyrin III
It is also the most important porphyrin

32. Haem synthesis is catalysed by haem
synthetase (ferro-chelatase)
Haem can combine with different poly-
peptides to form various haemoproteins
Protoporphyrin III + Fe++ Haem synthetase
Haem

33. The major purpose of porphyrin synthesis
is to form haem
The regulatory enzyme in the pathway is
ALA synthetase
The regulator is haem itself
Regulation occurs by repression and
derepression
Regulation

34. When haem is not being utilized, its
concentration increases
It combines with an aporepressor to form
the repressor
Repressor acts on ALA synthetase gene
and represses synthesis of ALA synthetase
This decreases the synthesis of porphyrins

35. When haem begins to be utilized, its
concentration decreases
The synthesis of ALA synthetase is
derepressed
The enzyme concentration increases
and so does the porphyrin synthesis

36. Haemoglobin (Hb) is the most abundant
porphyrin-containing compound
It is a tetramer made up of four subunits
Each subunit contains a haem group and a
polypeptide chain
Haemoglobin

38. The polypeptide chains are of five types
viz. a, b, g, d and e
The a chain is made up of 141 amino acids
The b , g, d and e chains are made up
of 146 amino acids each

39. The genes for polypeptide chains of
haemoglobin are called globin genes
The globin genes are present in two
clusters on two different chromosomes
The a cluster is present on chromosome
16 and the b cluster on chromosome 11

40. The a cluster contains a and z genes
The a gene locus has two genes, a1 and
a2
The a1 and a2 genes are nearly identical

41. The b cluster contains b, d, e and g genes
There are two g genes – Ag and Gg
The Ag and Gg are nearly identical

42. Haemoglobin synthesis occurs in red blood
cell precursors
It begins in pro-erythroblasts
About 65% synthesis is completed by
erythroblast stage
The remaining 35% is completed by
reticulocyte stage

43. Part of haem synthesis occurs in
mitochondria
The synthesis stops when mitochondria
disappear from red blood cells
Globin is synthesized on ribosomes in
cytosol
Synthesis of haem and globin is
synchronous

44. Expression of globin genes is
developmentally regulated
Haemoglobin synthesis begins at three
weeks of gestation
The a gene is expressed throughout life

45. The e and z genes are expressed until
about eighth week of gestation
The predominant haemoglobin at this
stage is a2e2, with some a2z2

46. After eighth week, the expression of e and
z genes declines
Expression of g gene begins and
predominates until birth
The major haemoglobin at this stage is
a2g2

47. After birth, the expression of g gene
declines, and that of b gene increases
The major haemoglobin after birth and
throughout life is a2b2, with some a2d2

48. The a2b2 haemoglobin is the normal adult
haemoglobin (HbA)
It accounts for 95-98% of the total
haemoglobin in adults
A small amount of a2d2 haemoglobin
(HbA2) is also found in adults

49. The a2e2 (and a2z2) form of Hb is known as
embryonic haemoglobin
The a2g2 form is foetal haemoglobin (HbF)
which is the predominant form in foetal life
HbF may also be present in adults in very
small amount

50. The major secondary structure in the
globin chains is a-helix
In b, g, d and e chains, there are eight a-
helical regions named A through H
There are seven helices in a chain (the
helix D is missing)
Structure of haemoglobin

51. Helices in globin chain

52. A ferrous ion is present at the centre of
each haem group
It has six electrons in its outermost orbit
Four of these link iron to the four nitrogen
atoms of haem

53. One electron of iron links it to a histidine
residue of the polypeptide chain
This is His87 in the a chain and His92 in b
and other non-a chains
These histidine residues are present in the
helix F
The bond between iron and His87/His92 is
known as the proximal iron-histidine bond

54. Helix F
Proximal histidine
Haem

55. One other histidine residue in helix E is on
the opposite co-ordination position
This is His58 in the a chain and His63 in the
non-a chains
His58/His63 is known as the distal histidine
residue

56. Distal histidine residue prevents oxidation of
Fe+2 by any oxidizing agent in the vicinity
On exposure to high oxygen tension,
oxygen enters the space between the distal
histidine residue and Fe+2
Oxygen binds loosely to Fe+2, which is
known as oxygenation of haemoglobin

57. Haemoglobin can exist in two thermo-
dynamic conformations
The conformations are known as Tense (T)
and Relaxed (R)
Binding of oxygen changes the thermo-
dynamic state of haemoglobin from T to R

58. During T→R transition, one pair of a and b
subunits rotates by 15° relative to the other
pair
The gap between the two b polypeptide
chains becomes narrower when oxygen
attaches to iron

59. 2,3-Biphosphoglycerate (2,3-BPG) is an
important regulator of oxygenation and
deoxygenation of haemoglobin
It is formed in erythrocytes from 1,3-bi-
phosphoglycerate (1,3-BPG) which is an
intermediate of the glycolytic pathway

60. Central cavity
There is a central cavity in the Hb molecule
surrounded by the four polypeptide chains

61. 2,3-BPG enters the central cavity when its
concentration is high
2,3-BPG

62. 2,3-BPG binds to the two b chains by
salt bonds
2,3-BPG
b1 - Chain
b2 - Chain

63. Low availability of O2 in tissues increases
the conversion of 1,3-BPG into 2,3-BPG
Binding of 2,3-BPG to haemoglobin
changes the R form into T form
This results in release of oxygen from
haemoglobin

64. The reverse happens in lungs where the
availability of oxygen is high
Oxygen binding changes the T form into
the R form
This narrows the central cavity, leaving no
space for 2,3-BPG

65. Each subunit of Hb can bind one oxygen
molecule
There are four subunits in a molecule of
Hb
So, one Hb molecule can bind four oxygen
molecules
Co-operative binding

67. Binding of one O2 molecule to haemo-
globin facilitates the binding of other O2
molecules
This is known as co-operative binding and
is responsible for the sigmoidal oxygen
dissociation/saturation curve

68. Co-operative binding is not shown by
myoglobin which is a monomer
Oxygenated myoglobin releases oxygen
only when oxygen tension is very low

69. Oxygen
saturation
(%)
pO2 (mmHg)
Haemoglobin
Myoglobin

70. Derivatives of haemoglobin
Haemoglobin can form
the following derivatives:
Oxyhaemoglobin
Carboxyhaemoglobin
Methaemoglobin
Sulphaemoglobin
EMB-RCG

71. Oxyhaemoglobin
This is the oxygenated form of haemo-
globin
It is bright red in colour
Oxygen is transported to tissues in the
form of oxyhaemoglobin

72. Carboxyhaemoglobin
Haemoglobin combines with carbon
monoxide to form carboxyhaemoglobin
Affinity of haemoglobin for carbon
monoxide is 200 times that for oxygen
Carboxyhaemoglogin is cherry red in
colour

73. Carboxyhaemoglobin is much more stable
as compared to oxyhaemoglobin
Once it is formed, oxygen cannot displace
carbon monoxide from haemoglobin
Formation of carboxyHb decreases the O2
carrying capacity of the blood

74. Methaemoglobin
Some drugs and chemicals can oxidize
the ferrous ion of Hb to ferric ion
These include sulphonamides, antipyrine,
nitrites, nitrobenzene etc
Hb is converted into methaemoglobin,
which is brownish red in colour

75. Some methaemoglobin is formed normally
by endogenous oxidizing agents
However, RBCs possess methaemoglobin
reductase and glutathione
These two continuously reduce met-
haemoglobin to haemoglobin

76. Methaemoglobin cannot combine with
oxygen
But methaemoglobin can combine with
cyanide to form cyanmethaemoglobin
This property is used in the treatment of
cyanide poisoning

77. The patient is given sodium nitrite and
sodium thiosulphate
Sodium nitrite converts haemoglobin into
methaemoglobin
Methaemoglobin combines with cyanide
to form non-toxic cyanmethaemoglobin
Sodium thiosulphate reacts with cyanide
to form non-toxic sodium thiocyanate

78. Sulphaemoglobin
Sulphonamides and H2S can convert
haemoglobin into sulphaemoglobin
It is dirty brown in colour, and cannot
combine with oxygen
It persists in red blood cells throughout
their remaining life span

79. Several abnormal haemoglobins result from
mutations in the globin genes
Often, a single amino acid is substituted
Hundreds of mutant haemoglobins have
been discovered
Abnormal haemoglobins

80. Most of mutant haemoglobins are capable
of normal or near-normal functioning
Such mutants are known as haemoglobin
variants

81. In some mutants, amino acid substitution
occurs in a critical region of the molecule
This impairs the functioning of haemoglobin
Such haemoglobins are known as
abnormal haemoglobins
Diseases resulting from abnormal haemo-
globins are called haemoglobinopathies

82. Some examples of abnormal
haemoglobins and the diseases
resulting from them are:
Haemoglobin S
Haemoglobin M
Thalassaemia

83. HbS is formed when the glutamate
residue at position 6 in the b chain is
replaced by valine
This amino acid residue is present on the
surface of the haemoglobin molecule
Glutamate has a polar side chain while
valine has a non-polar side chain
Haemoglobin S

84. Replacement of a polar residue by a non-
polar residue alters the surface properties
Non-polar valine residue of one molecule
attracts the non-polar residue of another
This starts a chain reaction causing
aggregation of several Hb molecules

85. Aggregated haemoglobin molecules

86. Aggregation results in the formation of a
fibrous structure
This distorts the erythrocyte into a sickle-
shaped cell

87. Aggregated haemoglobin
molecules distort RBC

88. Normal
RBC
Sickled
RBC

89. Oxygenated haemoglobin exists in the R
state
The non-polar valine residues are not
exposed on the surface in R state
Therefore, there is no aggregation of
haemoglobin molecules

90. Deoxygenated haemoglobin exists in the
T state
In T state, the non-polar valine residues
are exposed on the surface
Therefore, deoxygenated haemoglobin S
gets aggregated

91. Haemoglobin is present in deoxygenated
form when oxygen tension is low
There is aggregation of haemoglobin S
molecules and sickling of RBCs at low
oxygen tension

93. Sickled erythrocytes are susceptible to
premature destruction
Rapid destruction of erythrocytes causes
haemolytic anaemia

94. Inheritance of sickle cell anaemia is
autosomal recessive
If the defect is inherited from one parent
only, it results in sickle cell trait
Sickle cell trait doesn’t cause any clinical
abnormality

95. If the defect is inherited from both the
parents, it results in sickle cell disease
Sickle cell disease causes severe
haemolytic anaemia

96. Presence of haemoglobin S gives some
protection against malaria
The malarial parasite inhabiting RBCs gets
killed when the RBCs are sickled
Prevalence of HbS has been found to be
higher where malaria is endemic

97. Formed by replacement of His58 in the a
chain by tyrosine due to a point mutation
Phenol group of tyrosine is bonded with
iron
This converts Fe+2 into Fe+3 (forming
methaemoglobin)
Methaemoglobin cannot combine with
oxygen
Haemoglobin MBoston

98. Thalassaemia results from a decrease in,
or lack of, synthesis of either a chains or b
chains
Defective synthesis of a chains leads to a-
thalassaemia and that of b chains leads to
b-thalassaemia
Thalassaemia

99. A variety of genetic defects can
cause thalassaemia such as:
Deletion of a part or
whole of a gene
Defective processing of
the primary transcript
Defective transport or
translation of mRNA
Premature termination

100. Decreased synthesis or lack of synthesis
of one type of chain leads to an over-
production of the unaffected chain
This results in the formation of a
haemoglobin having only a chains or only
b chains

101. When the defect is transmitted by only one
parent, it results in thalassaemia minor
which is symptomless
When the defect is transmitted by both the
parents, it results in thalassaemia major
which is associated with severe anaemia

102. Porphyria is a group of disorders
Large quantities of porphyrins and/or their
precursors are excreted in urine
Excessive excretion occurs due to a defect
in the synthetic pathway
Porphyria

103. An enzyme in the synthetic pathway is
absent or deficient in porphyria
This leads to accumulation of inter-
mediates proximal to the block

104. The urine is normal in colour when fresh but
becomes pink on exposure to light
The change in colour occurs due to oxidation
of porphyrinogens
Skin photosensitivity is common in porphyria

105. Early intermediates bind to nervous tissue,
and produce neuropsychiatric abnormalities
Thus, a defect early in the pathway is more
harmful than a defect in the later steps

106. The defective gene is present in all the
tissues but the expression is usually
confined to a particular tissue
Depending upon the site of expression of
genetic defect, porphyrias may be divided
into:
Erythropoietic
porphyrias
Hepatic
porphyrias

107. Hepatic porphyrias include:
Acute intermittent porphyria
Porphyria cutanea tarda
Hereditary coproporphyria
Variegate porphyria

108. Erythropoietic porphyrias
include:
Congenital erythropoietic
porphyria
Protoporphyria

109. Acute intermittent porphyria
Mode of
inheritance
Affected
enzyme
Site of
expression
Autosomal
dominant
Uropor-
phyriogen I
synthetase
Liver cells

110. Porphyria cutanea tarda
Mode of
inheritance
Affected
enzyme
Site of
expression
Autosomal
dominant
Uropor-
phyriogen
decarboxylase
Liver cells

111. Hereditary coproporphyria
Mode of
inheritance
Affected
enzyme
Site of
expression
Autosomal
dominant
Copropor-
phyriogen
oxidase
Liver cells

112. Variegate coproporphyria
Mode of
inheritance
Affected
enzyme
Site of
expression
Autosomal
dominant
Protopor-
phyriogen
oxidase
Liver cells

113. Congenital erythropoietic porphyria
Mode of
inheritance
Affected
enzyme
Site of
expression
Autosomal
recessive
Uropor-
phyriogen III
cosynthetase
Erythroid
cells

114. Protoporphyria
Mode of
inheritance
Affected
enzyme
Site of
expression
Autosomal
dominant
Ferro-
chelatase
Liver cells

115. The clinical abnormalities are mainly
neuro-visceral in hepatic porphyrias and
cutaneous in erythropoietic porphyrias
However, some overlapping of signs and
symptoms is not uncommon

116. Acute attacks of abdominal pain, nausea
and vomiting occur in hepatic porphyrias
Over-active sympathetic nervous system
causes tachycardia, tremors and
hypertension
Hepatic porphyrias

117. Anxiety, insomnia, disorientation and
depression are also common
Motor neuropathy may cause progressive
muscular weakness
Seizures can also occur

118. Cutaneous photosensitivity is an
additional feature in:
Hereditary
copro-
porphyria
Variegate
porphyria
Porphyria
cutanea
tarda

119. Severe cutaneous photosensitivity is
present from a very early age
Porphyrin precursors are present in skin,
and damage skin on exposure to sunlight
Multiple vesicles erupt on the skin
The skin is pigmented and fragile
Erythropoietic porphyrias

120. Denuded areas on skin are prone to
infections
Bones and teeth may be pigmented due to
deposition of porphyrin precursors
Haemolysis may occur due to binding of
porphyrin precursors to haemoglobin
In protoporphyria, liver damage also occurs
in some patients

121. Cutaneous manifestations are produced by
exposure to sunlight
Neuro-visceral symptoms are precipitated
by steroids, alcohol and some drugs
The drugs include barbiturates, mepro-
bamate, carbamazepine, mephenytoin,
sulphonamides, griseofulvin etc

122. When life-span of RBCs is over, they are
broken down in reticulo-endothelial system
Haem and globin are separated
Globin is broken down into amino acids
Catabolism of haemoglobin

123. Methenyl bridge between ring I and ring II
of haem is broken by haem oxygenase
This releases iron and converts haem into
biliverdin
Biliverdin is a green pigment

125. Biliverdin is reduced to bilirubin by
biliverdin reductase
Bilirubin is yellow in colour
This is the major bile pigment in human
beings

127. Bilirubin formed from haem is insoluble in
water
It is known as unconjugated bilirubin
It has to be made water-soluble for its
excretion
Conjugation with glucuronic acid makes
bilirubin water-soluble

128. Conjugation of bilirubin occurs in liver
Bilirubin, released from reticulo-endothelial
cells, has to be transported to liver
Being water-insoluble, it is transported in
association with albumin

129. Albumin has two bilirubin-binding sites ̶ a
high-affinity site and a low-affinity site
Bilirubin is first bound to the high-affinity
site
If high-affinity sites on all the albumin
molecules are saturated, bilirubin is bound
to low-affinity site

130. The normal plasma albumin concentration is
3.5-5.5 gm/dl
This is sufficient for binding of 20-25 mg of
bilirubin on the high-affinity sites of albumin
If unconjugated bilirubin level exceeds 20-
25 mg/dl, it begins to bind to low-affinity site

131. Bilirubin is taken up by liver cells from the
circulating albumin
The uptake occurs with the help of a
carrier-mediated active transport system
In hepatocytes, bilirubin is conjugated with
glucuronic acid to make it water-soluble

132. Glucuronic acid is conjugated with the
propionate group
Since there are two propionate groups,
two glucuronate moieties can be added
The conjugation reaction occurs in two
steps

133. Bilirubin
Bilirubin monoglucuronide
Bilirubin diglucuronide
UDP-glucuronic acid
UDP
UDP
UDP-glucuronic acid
Bilirubin UDP-glucuronyl
transferase
Bilirubin UDP-glucuronyl
transferase

134. Bilirubin diglucuronide may also be formed
by a trans-esterification reaction
The reaction occurs between two bilirubin
monoglucuronide molecules
It is catalysed by bilirubin-glucuronide
glucuronosyl transferase (dismutase)

135. Bilirubin
mono-
glucuronide
Bilirubin
Bilirubin
diglucuronide
Bilirubin
glucuronide
glucuronosyl
transferase
Bilirubin
mono-
glucuronide

136. Bilirubin diglucuronide is also known as
conjugated bilirubin
It is excreted by liver into the intestine
through bile
Excretion takes place through an active
transport mechanism

137. Bilirubin is freed from glucuronic acid in the
large intestine
It is reduced by the enzymes of intestinal
bacteria to urobilinogen
Most of the urobilinogen is excreted in the
faeces

138. A small portion of urobilinogen is absorbed
into portal circulation and is taken to liver
Liver excretes most of it into the intestine
(entero-hepatic circulation of urobilinogen)
A fraction enters the systemic circulation,
and is excreted by the kidneys in urine

139. Haem
oxygenase
Biliverdin
reductase
Haem
Bilirubin UDP-gluc-
uronyl transferaseBlood
vessel

140. Serum bilirubin ranges from 0.2-1.0 mg/dl
in concentration
Jaundice
Unconjugated
bilirubin
Conjugated
bilirubin
This is total bilirubin which includes:

141. Concentration of unconjugated bilirubin in
serum is 0.1-0.6 mg/dl
It is water-insoluble
It is also known as indirect reacting bilirubin
It reacts with Ehrlich’s diazo reagent only
after addition of methanol or ethanol

142. Concentration of conjugated bilirubin in
serum is 0.1-0.4 mg/dl
It is water-soluble
It is also known as direct reacting bilirubin
It can react with Ehrlich’s diazo reagent
without the addition of an organic solvent

143. A rise in serum bilirubin concentration is
known as hyperbilirubinaemia
When the level rises above 2 mg/dl,
bilirubin gets deposited in tissues
The tissues are stained yellow
This is known as jaundice

144. The yellow staining can be seen in skin
and mucous membranes
But is most clearly visible in the sclera

145. Jaundice can occur in a number of
diseases
Post-hepatic
jaundice
Hepatic
jaundice
Pre-hepatic
jaundice
Depending upon the site of the defect,
jaundice can be divided into:

146. This is also known as haemolytic jaundice
It is due to an increased rate of haemolysis
Breakdown of haemoglobin is increased
Bilirubin is formed in large quantities
Pre-hepatic jaundice

147. Capacity of the liver cells to take up,
conjugate and excrete bilirubin is exceeded
Concentration of unconjugated bilirubin in
serum rises resulting in jaundice
Unconjugated bilirubin cannot be excreted
by the kidneys
Therefore, urine doesn’t contain bilirubin

148. As the rate of formation of bilirubin
increases, so does the rate of formation of
urobilinogen
Therefore, urinary excretion of urobilinogen
is increased

149. The laboratory findings in
haemolytic jaundice are:
• Rise in unconjugated bilirubin in serum
• Absence of bilirubin from urine
• Increase in urobilinogen in urine

150. Haemolytic jaundice can occur in:
• Thalassaemia
• Sickle cell crisis
• Spherocytosis
• Glucose-6-phosphate
dehydrogenase deficiency etc

151. A common cause of haemolytic jaundice is
“physiological jaundice of neonates”
This occurs in some neonates between the
third and tenth days of life
Erythrocytes formed during foetal life
contain HbF
These are rapidly destroyed after birth to
be replaced by erythrocytes containing HbA

152. Rate of formation of bilirubin is increased
The hepatic conjugating system is not fully
developed in the first two weeks of life
There is accumulation of unconjugated
bilirubin in blood causing jaundice
This is a transient and benign condition

153. A serious cause of haemolytic jaundice is
erythroblastosis foetalis
It is also known as haemolytic disease of
the newborns
This occurs when an Rh-negative mother
conceives an Rh-positive baby

154. The Rh-antigen can be transferred across
the placenta from the foetus to the mother
Maternal immune system starts forming
Rh-antibodies
The antibodies are transferred across the
placenta to the foetus

155. The resulting Rh-incompatibility causes
severe haemolysis in the foetus
Excessive haemolysis increases the level
of unconjugated bilirubin in serum
The baby is born with jaundice

156. The condition becomes serious if unconju-
gated serum bilirubin exceeds 20-25 mg/dl
The excess bilirubin binds to low-affinity
site of albumin
This is off-loaded in the central nervous
system which is rich in lipids
The lipids easily take up non-polar bilirubin
from the low-affinity site of albumin

157. Bilirubin is attached to basal ganglia,
hippocampus, cerebellum, medulla etc
Nervous tissue is stained yellow (known
as kernicterus)
Kernicterus is fatal or causes permanent
neurological damage if the baby survives

158. Hepatic or hepatocellular jaundice is due to
rapid destruction of liver cells
This can be caused by hepatitis (viral or
alcoholic), hepatotoxic drugs/chemicals,
advanced cirrhosis and some inborn errors
Hepatic jaundice

159. Due to destruction of liver cells, capacity of
liver to take up and conjugate bilirubin is
decreased
Concentration of unconjugated bilirubin in
serum increases even though the rate of
formation of bilirubin is normal

160. In viral hepatitis, the surviving liver cells are
inflammed and swollen, and compress the
biliary canaliculi
This results in intra-heptatic biliary
obstruction
Due to obstruction, conjugated bilirubin
regurgitates into systemic circulation

161. Hence, serum level of conjugated bilirubin
is also raised in viral hepatitis
As conjugated bilirubin is water-soluble, it
is excreted in urine
Therefore, urine contains bile pigments

162. The laboratory findings in viral
hepatitis are:
• Unconjugated bilirubin is raised in
serum
• Conjugated bilirubin is raised in serum
• Bilirubin is present in urine
• Urinary urobilinogen is usually normal

163. This is also known as obstructive jaundice
as it is due to an obstruction to the flow of
bile
The obstruction may be intra-hepatic or
extra-hepatic
The commonest cause of biliary obstruction
is presence of gall stones in the bile duct
Post-hepatic jaundice

164. The other causes of obstruction are:
• Cancer of pancreas
• Cancer of gall bladder/bile duct
• Stricture of bile duct
• Congenital atresia of bile duct
• Cholangitis

165. Conjugated bilirubin is regurgitated into
circulation
As it is water-soluble, it is excreted in urine
Due to biliary obstruction, bilirubin conju-
gated in liver

166. As bilirubin doesn’t reach the intestine,
urobilinogen cannot be formed
Therefore, urobilinogen is absent from
urine

167. The laboratory findings in
obstructive jaundice are:
• Rise in conjugated bilirubin in serum
• Presence of bilirubin in urine
• Absence of urobilinogen from urine

168. Jaundice also occurs in the
following inherited disorders of
bilirubin metabolism:
• Gilbert’s syndrome
• Crigler-Najjar syndrome
• Lucey-Driscoll syndrome
• Rotor’s syndrome
• Dubin-Johnson syndrome

169. The active transport system for hepatic
uptake of bilirubin is defective
Bilirubin UDP-glucuronyl transferase
activity in liver cells is also sub-normal
The concentration of unconjugated biliburin
is raised in serum
Gilbert’s syndrome

170. Inheritance of Gilbert’s syndrome is
autosomal dominant
A mutation occurs in the promoter
region of the gene for bilirubin UDP-
glucuronyl transferase
Expression of the gene is decreased
though the enzyme is normal in function

171. Concentration of unconjugated bilirubin in
serum is mildly raised
There is no clinical abnormality other than
the permanent yellow discoloration
No treatment is required

172. Crigler-Najjar syndrome
This is an autosomal recessive disorder
Two types have been recognized:
Crigler-Najjar
syndrome, type I
Crigler-Najjar
syndrome, type II

173. In type I, a variety of mutations occur in
the gene for bilirubin UDP-glucuronyl
transferase
The mutations may be deletions,
insertions, mis-sense mutations and
premature stop codons
The result is a totally non-functional
enzyme

174. Concentration of unconjugated bilirubin
is greatly elevated in serum
Kernicterus is common
Phototherapy and repeated plasma-
pheresis can prevent kernicterus up to
puberty but not later

175. In type II, there is a point mutation in
one allele of the gene
Bilirubin UDP-glucuronyl transferase
activity is sub-normal but not absent
Concentration of unconjugated bilirubin
in serum is moderately increased
Prognosis is much better

176. This rare disorder is believed to be due
to an inhibitor of bilirubin UDP-
glucuronyl transferase
The inhibitor is present in maternal
blood for a short period only
Lucey-Driscoll syndrome

177. Severe unconjugated hyperbilirubinaemia
develops in the newborn
The condition is transient
Phototherapy and, sometimes, exchange
transfusion may be required in the first
four days of life

178. The active transport system for excretion of
conjugated bilirubin is defective
This leads to a moderate rise in conjugated
bilirubin in serum
The inheritance is autosomal recessive
Rotor’s syndrome

179. The inheritance is autosomal recessive
The nature of the defect is similar to that in
Rotor’s syndrome
In addition, porphyrins are deposited in
liver giving it a black appearance
Dubin-Johnson syndrome

180. Concentration of conjugated bilirubin in
plasma is raised
Apart from visible jaundice, there is no
sign and symptom
No treatment is required