RHY/CH0056 1 Biology of Disease CH0576 Hyperbilirubinaemia & Jaundice II
Dec 18, 2015
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Biology of Disease CH0576
Hyperbilirubinaemia & Jaundice II
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Hyperbilirubinaemia
• It should be apparent that this state can arise due to a number of varied mechanisms, including:- – Excessive bilirubin production– Disordered bilirubin metabolism– Disordered bilirubin transport– Disordered biliary excretion
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Hyperbilirubinaemia
• These possible areas of breakdown give rise to the usual classification of jaundice into pre-hepatic, hepatic and post-hepatic jaundice.
• A patient who has hyperbilirubinaemia is not necessarily jaundiced.
• The terms are not synonymous!
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Hyperbilirubinaemia
• Hyperbilirubinaemia refers to an increased level of bilirubin in serum of > 1.2 mg/dL.
• At serum levels of > 2 - 2.5 mg/dL, the skin, sclera and mucous membranes take up the colour of the pigment.
• Only at this stage is the patient said to be jaundiced, or icteric.
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Classification of Jaundice
• Pre-hepatic jaundice.– Also termed haemolytic jaundice.– a) Acute haemolytic jaundice– b) Chronic haemolytic jaundice.
• Hepatic jaundice.– Also termed medical jaundice, due to
the involvement of the physicians in the treatment of the condition.
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Classification of Jaundice
• Various causes of hepatic jaundice include:– A failure in conjugation– Disturbances in bilirubin transport– Diffuse hepatocellular damage or
necrosis.– Intrahepatic jaundice.
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Classification of Jaundice• Post-hepatic jaundice
– Also termed obstructive or surgical jaundice, due to the involvement of the surgeons in treatment.
• There is obstruction to the outflow from the common bile duct, usually due to:– Gall stones, neoplasia, spasms or
strictures of the bile duct.
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Pre-hepatic Jaundice
• These states are due to an increased rate of bilirubin production > capacity of the liver to conjugate it.
• Consequently, there is a build up of unconjugated bilirubin.
• Largely due to an increased rate of red blood cell breakdown – e.g. haemolytic anaemias.
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Haemolytic Anaemias• Haemolytic anaemias are classified as
being either hereditary or acquired.• The normal red marrow is able to
compensate for premature red cell destruction by increasing its production
• The patient is said to have a ‘compensated haemolytic state’.
• The marrow does have a limit to its capacity to increase red cell production.
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Haemolytic Anaemias
• If the life span of the red cells falls below about 15 days, the capacity of the bone marrow to compensate is exceeded.
• If the compensation by the marrow is not enough to maintain the circulating [Hb] the individual, by definition, develops an anaemia - a haemolytic anaemia.
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Haemolytic Anaemias
• Three important criteria must be satisfied before a diagnosis of haemolytic anaemia is made:– There must be shortened red cell
survival.– There must be anaemia (circulating
Hb)– There must be a fully functioning bone
marrow.
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Haemolytic Anaemias• Haemolytic anaemias due to intrinsic
red cell abnormalities • Hereditary:
– Abnormal erythrocyte skeleton– Red cell enzyme deficiencies– Disordered Hb synthesis
• Deficient globin synthesis (Thalassaemias)• Structurally abnormal globin synthesis.
(Haemoglobinopathies)
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Haemolytic Anaemias
• Acquired– Membrane defect e.g. PNH.
• Haemolytic anaemias due to extrinsic defects– Antibody mediated
• Isohaemagglutinins: transfusion reactions, HDN
• Autoantibodies: drug associated, SLE.
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Haemolytic Anaemias– Mechanical or physical trauma to red cells.– Infections e.g. malaria.
• In pre-hepatic jaundice the amount of bilirubin which is generated by the premature red cell destruction exceeds the liver’s capacity to conjugate and excrete it.
• The liver has a large reserve capacity!
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Haemolytic Anaemias• The excess circulating bilirubin is
obviously unconjugated and is carried complexed with albumin.
• As it is unconjugated it does not appear in the urine!
• The amount of conjugated bilirubin excreted into the intestine is increased, as more is handled by the liver!
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Haemolytic Anaemias• Around 20% of this conjugated
bilirubin is reabsorbed into the entero-hepatic circulation, in the form of urobilinogens.
• This is excreted in increased amounts by the kidneys, appearing in urine.
• Blood levels of unconjugated bilirubin in this pattern of jaundice are seldom > 100 mol/l.
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Hepatic Jaundice
• Failure in conjugation:– Physiological jaundice - a condition
seen in neonates. – The ability to conjugate and excrete
bilirubin does not normally mature until around two weeks, following birth.
– Premature infants will tend to show an increased level of jaundice.
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Hepatic Jaundice
– Almost all neonates have a mild and transient unconjugated hyperbilirubinaemia termed neonatal or physiological jaundice of the newborn (PJN)
• Breast fed infants show an increased frequency of PJN, possibly due to activity of glucuronidase in breast milk.
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Hepatic Jaundice
– Crigler-Najjar Syndrome - Type I– A rare genetic disorder in which there is
a complete lack of the conjugating enzymes ; UDP-glucuronyl transferases.
– This condition is invariably fatal, causing death within 18 months of birth.
– Associated with kernicterus - brain damage due to the toxic effects of bilirubin on CNS.
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Hepatic Jaundice– Crigler-Najjar Syndrome - Type II– A less severe and non-fatal form of the
disease, in which there is a partial deficiency of the liver conjugating enzymes.
– Gilbert Syndrome:– A relatively common, benign, inherited
disorder.– Around 7% of the ‘healthy’ population.
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Hepatic Jaundice• Gilberts Syndrome is a heterogenous
condition which presents with mild, fluctuating, unconjugated hyperbili……
• Primary cause is a decresed activity of UDP-glucuronyl transferases, although hepatic uptake may be impaired in some cases.
• Hyperbilirubinaemia may remain undiscovered for years
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Hepatic Jaundice
• Failure in transport:– Dubin-Johnson Syndrome– A hereditary defect in the transport of
glucuronides across the canalicular membrane of the hepatocyte.
– Conjugated hyperbilirubinaemia is seen
– Liver shows dark pigmentation.