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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.