RHY/CH00561 Biology of Disease CH0576 Hyperbilirubinaemia & Jaundice II

RHY/CH00562 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/CH00563 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/CH00564 Hyperbilirubinaemia Hyperbilirubinaemia refers to an increased level of bilirubin in serum of > 1.2 mg/dL. At serum levels of > 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/CH00565 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/CH00566 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/CH00567 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/CH00568 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/CH00569 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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/CH 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.