Mature red cells are continuously being degraded in the macrophages of the liver and in the reticulo-endothelial system

(RES) of the spleen and bone marrow. The haeme is converted to biliverdin, which is reduced to produce bilirubin ( Fig. 23-1 ). About 10-15% of the bilirubin arises from the breakdown of immature red cells and cytochrome. Bilirubin released to the blood from these tissue macrophages is bound to albumin during its transport , so the concentration of neurotoxic, free bilirubin is normally low. Bilirubin is taken up at the hepatocyte cell membranes after dissociation from the albumin. Within the hepatocyte bilirubin is transferred to the endoplasmic reticulum, which contains a transferase that conjugates bilirubin with glucuronic acid . Conjugated bilirubin (bilirubin di- and mono-glucuronide) is water-soluble, so it diffuses easily through the cytoplasm and is actively secreted into the bile canaliculi. From here conjugated bilirubin is excreted into the intestine with the bile. Bacterial enzymes in the terminal ileum and the colon hydrolyse the large molecule. The free bilirubin is then reduced to urobilinogen . Most of the urobilinogen is excreted in the faeces; the remainder is absorbed in the terminal ileum, returned to the liver via enterohepatic blood, and again excreted as bile into the intestine (the enterohepatic bile pigment circuit). A small amount of the urobilinogen is excreted in the normal urine . Fig. 23-1 : Normal bilirubin metabolism. The free bilirubin is fat-soluble and toxic. The conjugated bilirubin is water-soluble bilirubin-glucuronide and non toxic. Part of the bilirubin is broken down to colourless substances, hepatocytes produce urobilinogen, and colonic bacteria stercobilinogen. Both substances can be oxidised to yellow urinary urobilin and brown faecal stercobilin (Fig. 23-1) . The renal excretion of urobilin and stercobilinogen is increased in cases with intrahepatic icterus (ie, hepatitis and other damages of hepatocytes).

Albumin concentration is a powerful neuro-protective agent as well as a major determinant of both bilirubin toxicity and level of unbound bilirubin in excessively jaundiced babies. The integrity of binding (below the1:1 molar ratio) is compromised in a newborn because newborn albumin has a poor binding ability compared to adult albumin. It is further compromised if a)albumin binding affinity is markedly decreased with concurrent prematurity, sickness or acidosis; b) protein bound drugs compete for albumin binding sites. It is further compromised for postnatal age < 72 hours, and if the serum albumin level is lower than expected. In severely hyperbilirubinemic but otherwise healthy newborns (TSB levels >95th percentile and over 72 hours age) the bilirubin to albumin ratio is a useful tool to define ones worry and potential risk for BIND. For practical purposes, the B: A ratio can be expressed in terms of mg of bilirubin to grams of albumin. A bilirubin to albumin ratio of 7.0 in mg to grams corresponds to a bilirubin to albumin molar ratio of 0.80. Exposure to bilirubin/albumin ratios of >7.0 (mgto gram) carry a clear risk of irreversible neurotoxicity, especially if such exposure is prolonged. Available clinical and experimental data suggests that B: A ratiosof >5.3 and <7.0 mg/g (molar ratios of bilirubin to albumin >0.63 and <0.80) are generally associated with reversible abnormalities of auditory brainstem responses.41-45 In a term newborn with subtle signs of BIND these B: A ratio values can be reassuring as long as the bilirubin load is vigorously reduced and signs of progression are closely monitored. Acute Bilirubin Encephalopathy 1st phase: hypotonia, poor suck-present in the first few days 2nd phase: Hypertonia (retrocollis and opisthotonos), fever 3rd phase: Gradual disappearance of the hypertonia-Up to years after the first week Chronic Encephalopathy: (Perlsteins Tetrad: Extrapyramidal Abnormalities, Hearing Loss, Gaze abnormality, and Dental Dysplasia) Extrapyramidal abnormalities: Facial grimacing, drooling, dysarthria, and athetosis--may develop by 18mo or delayed to 8or9 years. Hearing loss is usually due to injury of the cochlear nuclei in the brainstem. It may be the only manifestation Gaze abnormalities: Limitation of upward gaze, palsies Cerebral cortex is relatively spared, so intelligence is often close to normal. A form of athetonia, which is marked by slow, writhing involuntary muscle movement. A mixed muscle tone where some are too high and others too low Damage to the basal ganglia, located in the midbrain 25 percent of cerebral palsy patients are affected by athetoid cerebral palsy.