Transcript Altered & Disordered Physiology - CH 056

Biology of Disease - CH 0576
Hyperbilirubinaemia & Jaundice
Introduction
• Jaundice is not a disease state in itself
• It is a non-specific symptom which is a
feature of a range of disease states
• The clinical approach to jaundice must
be based on a clear understanding of
the metabolism of bilirubin and an
appreciation of the potential blocks
which can occur in the pathways.
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Bilirubin Metabolism
• Several factors lead to the removal
of aged red cells from the circulation:
–
–
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They have lost their ability to deform
They have lost enzyme activities
They have compromised their ATP levels
They are unable to staunch the flow of
Ca2+ ions into the cell, across the plasma
membrane
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Bilirubin Metabolism
• The aged red cells are removed from
the circulation by the RES cells of
the spleen and the bone marrow.
• The aged cells are unable to negotiate
the torturous route through the red
pulp of the spleen.
• Following phagocytosis, the bulk of
the red cell constituents are recycled
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Bilirubin Metabolism
• Recycling includes;
– Fe transported on transferrin
– Amino acids enter the plasma pool
– Lipids from membranes enter the plasma
pool
• The only part of the haemoglobin
molecule which is not reutilised is the
tetra-pyrolle ring from HAEM.
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Bilirubin Metabolism
• Haem is the portion of the Hb
molecule which is catabolised to form
bilirubin.
• Bilirubin is then handled by the liver
prior to its excretion in urine and in
faeces.
• Haem also forms the prosthetic group
in molecules other than haemoglobin.
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Bilirubin Metabolism
• Molecules, other than Hb, containing
haem as a prosthetic group include:
– Cytochromes
– Myoglobin
– Peroxidases
• These all contribute to bilirubin
production, via haem breakdown.
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Bilirubin Metabolism
• Daily bilirubin production in Man
averages between 250 - 350 mg.
• 85% of this amount is the result of
the breakdown of Hb from aged red
cells.
• The remaining 15% from other
sources includes the destruction of
red cell precursors in the marrow.
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Bilirubin Metabolism
• Initial stage in the degredation of haem is
under the control of the microsomal
enzyme, haem oxygenase, acting along
with NADPH-cytochrome c reductase.
• This reaction involves the cleavage of the
tetra-pyrolle ring at the  methene
bridge.
• During this step, iron is liberated.
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Bilirubin Metabolism
• The iron passes out of the RES cell
and is bound onto the transport
protein, transferrin, for passage back
to the red marrow.
• The  carbon atom from haem is
excreted at the lungs in the form of
carbon monoxide.
• Assessment of CO indicates level of
red cell breakdown.
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Bilirubin Metabolism
• The product of this initial stage in
bilirubin production is a colourless,
non-toxic molecule : biliverdin.
• This is the main excretory product in
the lower animal phyla.
• Mammals then undertake an apparent
retrograde step, by converting this
into a toxic molecule : bilirubin.
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Bilirubin Metabolism
• This conversion step must have some
evolutionary advantage:
– bilirubin crosses the placenta, whereas
biliverdin doesn’t.
• The conversion of bilverdin involves
the action of a cytoplasmic enzyme in
the RES cell : biliverdin reductase.
• Bilirubin is transported from the RES
cell to the liver for processing.
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Bilirubin Metabolism
• Bilirubin is transported, in the plasma,
bound onto the protein albumin.
• Albumin has two binding sites for
bilirubin, of greatly varying affinities.
• Bilirubin is displaced from the lower
affinity binding site by certain drugs
including:
– barbiturates, sulphonamides, salicylates.
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Bilirubin Metabolism
• Bilirubin displaced from albumin has a
very high affinity for lipid-rich
tissues, and it tends to be taken up
by the brain.
• Bilirubin is very toxic to the CNS and
causes enlargement and oedema of
the brain.
– KERNICTERUS.
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Bilirubin Metabolism
• This is a potential very serious problem in
neonates, which often have a mild
‘physiological jaundice’.
• It is a potentially very damaging side
effect in HDN.
• Adults are protected from this problem
by a fully functioning blood-brain barrier.
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Unconjugated Bilirubin
• Bilirubin, bound onto albumin, prior to
processing in the liver is often referred
to as ‘unconjugated’.
• Unconjugated bilirubin, bound onto
albumin, is non-toxic and remains in
solution for its transportation, in the
blood, to the liver for processing.
• A small amount, 20g/L is free in plasma.
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Liver Handling of Bilirubin
• On arrival at the liver the bilirubin is
dissociated from the albumin and is
actively transported across the
sinusoidal membranes into the
hepatocyte.
• This is a carrier mediated process.
• In the liver cell the unconjugated
bilirubin is bound onto two soluble
cytoplasmic binding proteins.
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Liver Handling of Bilirubin
• The two proteins are:
– Z-protein
– Ligandin.
• This binding greatly increases the
solubility of the bilirubin, allowing it
to be transported across the aqueous
cytoplasm, to the ER of the liver cell.
• The next stage is CONJUGATION.
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Liver Handling of Bilirubin
• Within the ER of the hepatocytes the
bilirubin is conjugated with UDPglucuronic acid to form glucuronides.
• This process is under the control of
two ER enzymes termed the glucuronyl
transferases.
• Di- and monoglucuronides are produced
under various circumstances.
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Liver Handling of Bilirubin
• Conjugated bilirubin (mono- or di-) is
actively transported across the
canalicular membrane, forming part of
the secretion, bile.
• Conjugated bilirubin is non-toxic.
• Bile passes down the bile ductules and
into the common hepatic duct, and, if
required, into the intestine.
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Bilirubin Metabolism
• Once within the small intestine the
glucuronides are acted upon by the
bacterial flora of the gut.
• Bacterial -glucuronidases hydrolyse
the glucuronides into free bilirubin
and glucuronic acid.
• Further bacterial action leads to the
conversion of bilirubin into a range of
products : urobilinogens.
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Bilirubin Metabolism
• The majority , about 80% of these are
excreted in faeces, following conversion
to stercobilinogens.
• The remaining 20% of the urobilinogens
are reabsorbed into the entero-hepatic
circulation.
• The majority of these are re-exreted by
the liver in bile.
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Bilirubin Metabolism
• Between 2% and 5% of the reabsorbed
urobilinogens enter the general
circulation and are excreted via the
kidneys, in urine.
• Around 1 - 2 mg of bile pigments are
excreted in the urine daily, with about
250 - 350 mg excreted in faeces daily.
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