Division of Perinatology Department of Child Health Medical School University of Sumatera Utara

Bilirubin metabolism HEME + Globin BILIVERDIN BILIRUBIN Alb UCB LIVER CO (Heme Oxygenase) Conjugated bilirubin Free unconjugated bilirubin

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Rate of bilirubin production exceeds the rate of bilirubin elimination ↑ total serum bilirubin (TSB) concentration  hyperbilirubinemia (jaundice) DEFENITION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 1. Physiologic jaundice Almost every newborn infant First week of life (2 nd -3 rd day) Resolves spontaneously If develops in 1 st 24 h of life  considered pathologic until proven otherwise CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Exclution criteria: - Unconj bilirubin level >12.9 mg/dL in term - Unconj bilirubin level > 15 in preterm - Bilirubin level ↑ at rate >5 mg/dL/day - Jaundice in the 1 st 24 h of life - Conj bilirubin level >2 mg/dL - Clinical jaundice persisting >1 week in full term or >2 weeks in preterm Physiologic jaundice…… CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Mechanisms: - ↑ bil load because the larger RBC volume, the shorter life span of RBC, ↑ enterohepatic recirc of bil in newborn. - Defective uptake by the liver because ↓concentration of bil binding protein (ligandin). - Defective conjugation because ↓ glucoronyl transferase activity. - Impaired excretion into bile. - Overall impairment/immaturity of liver function. Physiologic jaundice…….. CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 2. Hemolytic anemia - RBC defects: def G6PD, def piruvat kinase, halassemia. Etc - Acquired hemolytic anemia: ABO incompatibility. 3. Polycitemia. The liver not have capacity to metabolize the ↑ bil load  ↑ blood vol CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 4. Blood extravasation 5. Defects of conjugation Congenital def of glucoronyl transferase - Cligler-Najjar syndrome type I: severe def uridine diphosphate (UDP) glucoronyl transf.  Unresposive to phenobarbital therapy. - Cligler-Najjar syndrome type II: moderate def UPD glucoronyl transf  responsive to phenobarbital therapy. - Gilbert syndrome: mild def UDP) glucoronyl transf  responsive to pheno therapy CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Glucoronil transferase inhibition: - Drugs (novobiocin) - Lucey-Driscoll syndrome: unspecified maternal gesation hormone in infant interferes with the conj of bil. Defects of conjugation…… CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 6. Breast milk jaundice (late onset) Prolongation of ↑enterohepatic circ of bil because of a factor in human milk that promote intestinal absorbtion. Higher peak (10-30 mg/dL) by days Metabolic disorders: galactosemia, hypothyroidism, maternal diabetes, ect. 8. ↑ enteohepatic recirc: pyloric stenosis, duodenal atresia, ileus, ect. CLASSIFICATION

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Unconj bil  cross blood brain barrier  brain cell  neuronal dysfunction  depress O2 consumption  death. ENCEPHALOPATHY KERNICTERUS Post mortem diagnosis Risk if bi level >25 mg/dL MORBIDITY

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Joundice at face, especially at nose, descending to the torso and lower extremities. Areas of bleeding (cephalhematoma, ptechiae) indicates blood extravasation. Hepatosplenomegaly (hemolytic disease, liver disease, or infection) Sign of prematurity, IUGR, postmaturity. Plethora (polycitemia) Pallor (hemolytic disease) Neurologic signs: lethargy, poor feeding, vomiting, hypotonia. SIGNS AND SYMPTOM

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 1. Laboratory studies Total and direct bilirubin Complete blood cell count and reticulocyte count. Blood type and Rh status in mother and infant Direct Coomb’s test Measurement of serum albumin Urine test DIAGNOSIS

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 2. Radiologis studies: intestinal obstruction 3. Transcutaneous bilirubimentry (TcB)  measures the degree of yellow color by selective wavelength reflection. 4. Expired carbon monoxide breath analyzer. DIAGNOSIS

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 1. Phototherapy TSB level 20 mg/dL ar 48 h of life maybe treated initially with phototherapy. If TSB ↓ by 1-2 mg/dL within 4-6 h, exchange transfusion maybe not necessary. Light source: blue fluorescent tubes. Distance from the light to the infant: inches MANAGEMENT

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Eye should be covered with opaque patches Termination of phototherapy: bil level is low enough to eliminate the risk of kernicterus and the infants is old enough to handle the bil load. Complication: retinal degradation, increased insensible water loss (  ↑fluid requirements by 25%), bronze baby syndrome (destruction of protoporphirin  urine and skin become bronze) MANAGEMENT

Phototherapy

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 2. Exchange transfusion TSB mg/dL (↑bil >0.5 mg/dL/h) Presence of hypoxia, acidosis, sepsis or hypoproteinemia. Albumin transfusions maybe useful if bil level >20 mg/dL and serum albumin level <3 g/dL. Infusion of 1 g of albumin 1 h before exchange transfusion may improve the yield of bil removal. MANAGEMENT

Exchange transfusion

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA 3. Pharmacology Phenobarbital - ↑ligandin in liver, ↑ production of glucoronyl transferase, and enhancing bil excretion. - Takes 3-7 day to become effective  less effective in the newborn - More useful to give pheno 1-2 week before delivery to pregnant woman whose fetus documented hemolytic disease. MANAGEMENT

UNCONJUGATED (INDIRECT) HYPERBILIRUBINEMIA Metalloporphyrins - Inhibit heme oxygenase (HO) by acting as a competitive inhibitor. Supportive management - breast feed MANAGEMENT

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA A sign of hepatobiliary dysfunction After the first week of life Direct bil level > 2.0 mg/dL or is >20% of the TSB Caused by a defect or insufficiency in bile secretion, biliary flow, or both resulting in an inability to remove conj bil from the body. DEFENITION

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA 1. Extrahepatic biliary disease Biliary atresia Choledochal cysts  dilatations of extrahepatic tree. Biliary diseases: duct stenosis, cholelithiasis, and neoplasm. CLASSIFICATION

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA 2. Intrahepatic biliary disease Intrahepatic bile duct paucity Progressive intrahepatic cholestasis Inspissated bile 3. Hepatocellular disease Metabolic and genetic defects: cystic fibrosis, Dubin-Johnson and Rotor’s Syndrome, Galactosemia, etc. CLASSIFICATION

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA Infection Total parenteral nutrition (TPN) cholestasis Idiopathic neonatal hepatitis Miscellaneous: shock or hyperperfusion Hepatocellular disease….. CLASSIFICATION

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA Jaundice Acholic stools Dark urine Hepatomegaly Splenomegaly Pruritus Failure to thrive Decrease feeding Ascites Portal hypertention CLINICAL PRESENTATION

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA Alagille’ssyndrone: peripheral pulmonal stenosis, vertebral anomalies, peculiar faces Zellweger’ssyndrome or cerebrohepatorenal syndrome: hypotonia, seizures, dysmorphic features. Congenital infection: microcephaly, intracranial calcifications, IUGR. CLINICAL PRESENTATION

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA 1. Laboratory studies Bilirubin levels (total and direct) Liver function test Prothrombin time an partial trhomboplastin time Gamma-glutamil transpeptidase, 5- nucleaotidase, serum bile aced: ↑ in cholestasis DIAGNOSIS

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA A complete blood cell count and reticulocyte count Serum cholesterol, triglycerides, and albumin levels: assessment of liver failure Ammonia levels: assessment of liver failure Serum glucose levels Urine testing TORCH DIAGNOSIS Laboratory studies……

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA Alpha-fetoprotein (AFP) Other tests: hepatitis, sepsis, metabolic disorders. 2. Radiologic studies: USG, hepatobiliary imaging. 3. Other studies: persutaneus liver biopsy, exploratory laparatomy. DIAGNOSIS

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA 1. Medical management Phenobarbital Cholestiramine: ↑fecal excretion of bile salts and ↑hepatic synthesis of bile salt from cholesterol. Actigall (ursodeoxycholic acid), sucsessfully used in conjunction with phenobarbital and cholestyramine. MANAGEMENT

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA 2. Dietary management Medium-chain triglycerida (MCT): can be absorbed without the action of bile salt. Vitamin supplementation: A,D,E, and K Dietary restriction: removal galactose, lactose,fructose, and sucrose may prevent cirrhosis. MANAGEMENT

CONJUGATED (DIRECT) HYPERBILIRUBINEMIA 3. Surgical management Laparatomy with biopsy Kasai procedure: to establish biliary drainage Liver transplantation. 4. Other treatments Infectious diseases (hepatitis, bacterial infections) TPN-induced conjugated hyperbilirubinemia: will usually resolve once TPN is stopped. MANAGEMENT