BILIRUBIN A nd NEONATAL JAUNDVVVVICE.pptx

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1. BILIRUBIN METABOLISM AND NEONATAL JAUNDICE BY: DR AMADU JALLOH

2. BILIRUBIN METABOLISM Proceeds via 4 steps; 1. Formation 2. Plasma transport 3. Hepatic uptake & conjugation 4. Intestinal excretion

3. BILIRUBIN METABOLISM – STEP 1 Bilirubin is formed from the catabolism of haem-containing proteins in the reticuloendothelial system. 75% from red cell haemoglobin 25% from free haem, myoglobin and haem containing enzymes in the liver. Haem proteins haem oxygenase Biliverdin Biliverdin biliverdin reductase Bilirubin C arbon monoxide is a by product of this reaction

4. BILIRUBIN METABOLISM – STEP 2 Bilirubin is water insoluble Transported to liver bound to albumin & globulin Unbound bilirubin – free bilirubin can cross BBB Bilirubin may be displaced from albumin binding sites by drugs (sulphonamides, ceftriaxone etc ), free fatty acids (in hypoglycaemia, hypothermia), acidosis Albumin bound unconjugated bilirubin does not cross BBB

5. BILIRUBIN METABOLISM – STEP 3 Bilitranslocase and glutathione S-transferase aid hepatocyte uptake Protein Y and Z (ligandins) keep bilirubin in hepatocytes 80% of Bilirubin is conjugated in the smooth ER by UDPGT to mono & diglucuronide (water soluble ester) 20% conjugated to sulphates and other subs This is secreted into the biliary system by active transport – rate limiting step in bil metab

6. BILIRUBIN METABOLISM – STEP 4 Conjugated bilirubin is secreted into the gut Bilirubin is converted to urobilinogen by gut flora and then stercobilin & excreted in stool Some urobilinogen get reabsorbed into plasma and excreted in urine Deconjugated by glucuronidase activity in gut and breastmilk and reabsorbed via enterohepatic circulation

7. NEONATAL JAUNDICE (HYPERBILIRUBINEMIA) Definition : Hyperbilirubinemia refers, excessive level of bilirubin in the blood. Characterized by jaundice, a yellowish discoloration of the skin, sclera, mucous membranes and nails. Visible form of bilirubinemia Adult sclera >2mg/dl Newborn skin >5mg/dl unconjugated = Indirect bilirubin Conjugated = Direct bilirubin

8. NEONATAL JAUNDICE Jaundice more common in newborn Full term infants: at least 60%. Preterm infants: over 80%. 6 to 10% require phototherapy other therapeutic options.

9. NEONATAL JAUNDICE Jaundice is relatively more common in the newborn period than in any other period Reasons The newborn has a greater red cell mass and a shorter red cell life span shorter still in preterms . The normal term newborn produces 6 – 10 mg of bilirubin per kg/d in contrast to 3 – 4 mg/kg/d in the adult. Greater rate of production of bilirubin from other non-erythrocyte sources Liver function less mature - conjugation, active transport are reduced

10. NEONATAL JAUNDICE Meconium has 1mg/dl of bilirubin Enhanced enterohepatic circulation Reduced intake in the first few days of life Disease conditions readily limit liver function

11. NEONATAL JAUNDICE Very common neonatal emergency 30 – 80% of newborns develop some degree of jaundice in the 1 st week of life Does not merit inv or treatment in most cases Exaggerated under certain circumstances Unconjugated hyperbilirubinaemia may be ‘ beneficial ’ but at high levels, neurotoxic C onjugated hyperbilirubinaemia often indicates presence of some serious disorder

12. HYPERBILIRUBINEMIA AND CLINICAL OUTCOMES Deposits in skin and mucous membranes Unconjugated bilirubin deposits in the brain Permanent neuronal damage JAUNDICE ACUTE BILIRUBIN ENCEPHALOPATHY KERNICTERUS

13. CLINICAL SYMPTOMS Acute bilirubin encephalopathy/kernicterus : ▪ irritability, jitteriness , increased high - pitched crying. ▪ lethargy and poor feeling. ▪ back aching. ▪ apnea ▪ seizures ▪ long-term: upward gaze palsy, SN hearing loss, dental dysplasia

14. KERNICTERUS Most importantly…………… kernicterus: unconjugated bilirubin deposits in the brain(Basal ganglia, = yellow staining + degenerative lesions

15. STAGES OF KERNICTERUS 1 . Unable to suck, hypotonia , lethargy 2. Seizures, opisthotonus , spasticity. 3.Spasticity, shrill cry, apnea and seizures. 4. Athetosis , deafness, up gaze palsy, dental dysplasia and mental retardation

16. CAUSES OF JAUNDICE BASED ON AGE AT ONSET WITHIN 24 HOURS a . Hemolytic disease of new born a. Rh incompatibility b. ABO incompatibility b. Intra uterine infections a. Toxoplasmosis, CMV, Rubella c. Deficiency of red cell enzyme . a. G6PD deficiency, pyruvate kinase deficiency d. Others

17. ONSET -24 TO 72 HOURS OF LIFE Physiological jaundice can be aggravated & prolonged by a. Immaturity b. Cephalhematoma c. Birth asphyxia d. Hypothermia e. Infection

18. ONSET - AFTER 72 HOURS OF AGE Septicemia EHBA Breast milk jaundice Metabolic causes a. Galactosemia ( lack of enzyme that breaks down milk sugar which causes accumulation of galactose in the liver which may be fatal). b. Tyrosinemia (inability to break down the amino acid tyrosine which causes tyrosine build up in the organs and tissue esp. the liver) c. Hereditary fructosemia (lacks the protein to break down fruit sugars, wherein the body cannot change stored sugar to glucose. As a result dangerous substances are build up in the liver.) d. Gilbert syndrome (the liver does not process the bilirubin properly) e. Organic acidemia ( A group of metabolic disorders which disrupt normal amino acid metabolism)

19. PHYSIOLOGICAL VERSUS PATHOLOGICAL JAUNDICE Physiological jaundice • Jaundice due to physiological immaturity of neonates to handle increased bilirubin production. • Pathological jaundice • When TSB concentrations are not in physiological jaundice range.

20. PHYSIOLOGICAL VERSUS PATHOLOGICAL JAUNDICE Physiological Pathological Onset More than 24 hours Less than 24 hours Duration Term-<2 wks preterm-<3wks Term->2wks preterm->3wks Serum bilirubin concentration Raise <0.2mg/dl/ hr or <5mg/dl/day Raised > 0.2mg/dl/ hr or > 5mg/dl/day TSB <15mg/dl > 15mg/dl Involvement of palm and soles No Yes Signs of acute bilirubin encephalopathy No Yes Direct bilirubin Less than 2mg/dl More than 2mg /dl

21. CAUSES OF PATHOLOGICAL JAUNDICE Common causes : Hemolysis : Blood group incompatibility-ABO, Rh and minor enzyme deficiencies- G6PD • Decreased conjugation Prematurity • Increased enterohepatic circulation Breast feeding jaundice, GI obstruction • Extravasated blood Cephalhematoma , extensive bruising etc

22. RISK FACTORS FOR JAUNDICE JAUNDICE • J - jaundice within first 24 hrs. of life • A - a sibling who was jaundiced as neonate • U - unrecognized hemolysis • N - non - optimal sucking/nursing • D - deficiency of G6PD • I - infection • C - Cephalhematoma /bruising • E - East Asian/North Indian

23. WHERE DO YOU LOOK FOR JAUNDICE IN NEONATE 1. Forehead 2. Tip of nose 3. Chest 4. Knee 5. Palms and soles

24. CLINICAL ASSESSMENT OF JAUNDICE Visual inspection of jaundice 1. Examine the baby in bright natural light or white fluorescent light. No yellow or off white background 2. Make sure the baby is naked 3. Examine blanched skin and gums 4. Note the extent of jaundice (Kramer's rule) 5. Depth of jaundice (degree of yellowness)

25. MEASUREMENT OF TSB Indications a. Jaundice in first 24 hour b. Beyond 24 hr.: if visually assessed jaundice more than 15mg/dl c. If you are unsure about visual assessment d. During phototherapy, for monitoring progress and after phototherapy .

26. MANAGEMENT OF INDIRECT HYPERBILIRUBINEMIA Careful assessment and monitoring - Visual assessment - Blood level monitoring per hospital protocol at 24 hr. life or sooner as indicated - Interpretation of risk levels and need for treatment • phototherapy • Exchange Transfusions • Phenobarbital

27. THERAPEUTIC MANAGEMENT Purposes: reduce level of serum bilirubin and prevent bilirubin toxicity Modalities: 1. Phototherapy - Reduction of bilirubin levels 2. Exchange Transfusion - Reduction of bilirubin levels. 3. IV IG - prevent - Lysis of RBC's by blocking immune mediated antibody 4. Metalloporphyrin tin/zinc - prevent breakdown of Hb by heme oxidase 5. Phenobarbitone - Conjunction of bilirubin

28. PHOTOTHERAPY Safe and effective method for treatment of neonatal jaundice Bilirubin absorbs light maximum at 420-460nm

29. MECHANISM OF ACTION Conversion of insoluble bilirubin into soluble bilirubin 》》 Excretion of bilirubin 1. Photo - isomerisation 2. Structural isomerisation 3 . Photo- oxidation

30. PHOTO - ISOMERISATION Reversible reaction. Conversion of insoluble, toxic from z isomers 》》 non toxic polar (water soluble) E isomer 》》 diffuses into the blood 》》 excreted easily into bile

31. STRUCTURAL ISOMERISATION Irreversible reaction bilirubin 》》 lumirubin Rapidly excreted in bile and urine Main responsible for phototherapy induce decline of TSB Reduction of bilirubin directly proportional to dose of phototherapy.

32. PHOTO - OXIDATION Minor reaction photo-oxidation of bilirubin to water soluble polymers colourless by product Riboflavin - catalyze the dermal photo-oxidation

33. INDICATIONS FOR PHOTOTHERAPY TSB >18mg % in term TSB > 15mg % in preterm adjuvant to exchange transfusion Prophylactic PT - ELBW - Extreme preterm babies - Bruised babies - Babies with DCT positivity - Babies whose mother is ICT positive

34. PROCEDURE OF PHOTOTHERAPY Best is narrow spectral blue lights (425-475nm) White lamps (380-700nm) Distance from skin - 45cm Intensive PT - 15-20cm Shield eyes and genitalia Change position once in every 2-4 hrs Level to be checked every 10-12 hrs Frequent temperature monitoring & daily weight check

35. SIDE EFFECTS OF PHOTOTHERAPY Immediate : a. Loose stools b. Dehydration c. Hypo or hyperthermia d. Rashes e. Bronze baby syndrome • Late : a. Risks of skin malignancies b. Damage to intracellular DNA c. Retinal damage d. Testicular damage.

36. EXCHANGE TRANSFUSION The procedure involves the incremental removal of the patient's blood and simultaneous replacement with fresh donor blood, saline or plasma. indications - infants with Rh isoimmunisation include: a. Cord bilirubin 5mg/dl or more b. Cord Hb 10g/dl or less

37. EXCHANGE TRANSFUSION Complications • Hypocalcemia and hypomagnesaemia - citrate in CPD blood • Hypoglycaemia • Metabolic alkalosis or acidosis • Hyperkelemia • CVS: overload and arrhythmias • Infections: HBV, HIV • Haemolysis • Hypothermia, NEC.

38. PROLONGED JAUNDICE Definition: Persistence of significant jaundice for more than 2 weeks in term or • more than 3 weeks in preterm babies

39. CAUSES OF PROLONGED JAUNDICE Common : a. Inadequacy of breast feeding b. Breast milk jaundice c. Cholestasis • Rare causes : a. Hypothyroidism b. Criggler - Najjar syndrome c. GI obstruction due to mal rotation d. Gilbert syndrome

40. SUMMARY B ilirubin produced from breakdown of heme containing substances M etabolised in 4 steps T ransport to and metabolism in the liver mediated by carrier proteins and enzymes N ewborns especially in the 1st week of life are more prone to jaundice due to defects along the 4 steps U nconjugated bilirubin is a free radical scavenger but at high levels result in bilirubin encephalopathy

41. SUMMARY Hyperbilirubinemia is a common and potential serious issue in neonates Important to recognize and diagnose early in order to initiate prompt treatment when possible.

42. THANK YOU