Biology of Disease CH0576

1. Biology of Disease CH0576 Hyperbilirubinaemia & Jaundice II RHY/CH0056

2. 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 RHY/CH0056

3. 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! RHY/CH0056

4. 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. RHY/CH0056

5. 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. RHY/CH0056

6. Classification of Jaundice • Various causes of hepatic jaundice include: • A failure in conjugation • Disturbances in bilirubin transport • Diffuse hepatocellular damage or necrosis. • Intrahepatic jaundice. RHY/CH0056

7. 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. RHY/CH0056

8. 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. RHY/CH0056

9. 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. RHY/CH0056

10. 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. RHY/CH0056

11. 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. RHY/CH0056

12. 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) RHY/CH0056

13. Haemolytic Anaemias • Acquired • Membrane defect e.g. PNH. • Haemolytic anaemias due to extrinsic defects • Antibody mediated • Isohaemagglutinins: transfusion reactions, HDN • Autoantibodies: drug associated, SLE. RHY/CH0056

14. 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! RHY/CH0056

15. 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! RHY/CH0056

16. 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. RHY/CH0056

17. 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. RHY/CH0056

18. 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. RHY/CH0056

19. 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. RHY/CH0056

20. 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. RHY/CH0056

21. 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 RHY/CH0056

22. 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. RHY/CH0056