Work Up of the Jaundiced Infant - American Liver Foundation

Bilirubin Metabolism• Bilirubin is soluble in highly nonpolarsolvents in adipose tissue or the brain• Bilirubin is sensitive to light and convert tomore polar forms that can be excretedwithout conjugation• Toxicity of bilirubin to inhibit RNA andprotein synthesis in the brain, inhibitsphosphorylation of cerebral lipids the finalpathway of neuronal signal transmission

Transport of Biliruibin• Plasma transport bilirubin either bound toalbumin or free• Unbound bilirubin is fat soluble anddiffuses easily through cellular membranes• Affinity of bilirubin to albumin is reducedby drugs (Sulfa, anti inflammatory), PH orcontrast media

Uptake of Bilirubin• Bilirubin transfer is bidirectional with freeexchange between plasma and intrahepatic• Bilirubin recognized by a hepatocyte plasmareceptor• Intracytoplasmic binding proteins (Y protein orligandin and Z protein) prevents the efflux ofbilirubin back into plasma• Ligandin synthesis is induced by Phenobarbital

Bilirubin Conjugation• Conjugation of bilirubin in microsomes ofsmooth endoplasmic reticulum• UDPG dehydrogenetion catalyzed by UDPG-dehydrogenase to glucuronic acid to bilirubinmono and diglucuronides• Glucuronyl transferase activity is present inmany tissues predominantly in liver increasesrapidly from birth to reach levels 1.5-2.5 timesof those of adults at 2 weeks of age

Bilirubin Secretion• Transfer of conjugated bilirubin fromhepatic cells to the bile is energydependent (carrier mechanism)• Conjugated bilirubin is transformed intourobilinogen by bacteria in TI and colonwhich is limited in the first few days of life(incomplete colonization of intestines)

Acute UnconjugatedHyperbilirubinemia In theNewborn

Hemolytic Anemia• Blood group incompatibility (direct coombstest)• Hereditary hemolytic syndromes(hereditary spherocytosis, , G6PD orpyruvate kinase deficiencies)• Neonatal infections of bacterial (sepsis,UTI, etc..) or viral (dehydration, acidosis,drugs/antibiotics)

Physiologic Jaundice of theNewborn• Red blood cell breakdown• Serum factors (release of inhibitors, glucoseconcentration, etc..)• Uptake across hepatic sinusoidal membrane• Binding (intracellular Y&Z proteins)• Conjugation (delayed maturation of UDPglucuronyl transferase activity, abnormal glucosehemeostasis/diabetic mothers)• Excretion (intracellular transport to bilecanaliculus)• Enterohepatic shunt (early feeding/colonozationcolonozation)

Physiologic Jaundice of theNewborn• Bilirubin values tend to reach in thenormal full term infant by 4 th -6 th day of life(6-12) and higher levels in prematureinfant by 5th-6 th day of life (11-15)15)• Jaundice appears in term infant on 2d-3dday and last less than one week• Urine is pale• Stool has normal color

Criteria to Differentiate Physiologicfrom Pathologic Hyperbilirubinemia• Appearance of jaundice in the first 36 thhours of life with total hyperbilirubinemiaover 12 and rising• Rising conjugated hyperbilirubinemia• Anemia• Hepatosplenomegaly• Signs of infections or digestive problems

Fasting and UnconjugatedHyperbilirubinemia• Decreases intestinal motility (delayed bothevacuation of meconium and developmentof bacterial flora)• Releasing glucagon and adrenaline whichactivate heme-oxygenase, increase serumfree fatty acids and interfere with bili-albbinding

Breast Milk Jaundice• Isomers of Pregnanediol inhibiting bilirubinconjugation has not been established• Increased free fatty acid and lipoproteinlipase (LPL) activity inhibiting bilirubinconjugation• Increased enterohepatic circulation andbeta-glucuronidaseactivity

Breast Milk Jaundice• Jaundice on the 5 th -6 th day of life andpersists as long as breast feeding iscontinued and decrease after 6-868 weeksand may last 3-434 months• Total unconjugated bilirubin rarely exeeds20• Kernicterus has not been observed

Chronic UnconjugatedHyperbilirubinemia In theNewborn

Conjugated HyperbilirubinemiaIn the Newborn

Extrahepatic Disorders• Extrahepatic biliary atresia (EHBA) 25-30%, bile duct stricture and choledochalcyst• Anomalies choledochopancreaticoductaljunction• Spontaneous perforation of BD• Inspissated bile• Mass (stone, tumor etc..)

Intrahepatic Disorders• Idiopathic neonatal hepatitis 15%• Intrahepatic cholestasis syndromes (Alagille(Alagille, , PFIC type1)20%• Alpha1 antitrypsin deficiency 7-10% 7• Bacterial sepsis 2%• CMV 3-5% 3• Rubella and herpes 1 %• Endocrine (hypothyrodisim(hypothyrodisim, panhypopittuitarism) ) 1 %• Metabolic (Galagtosemia(Galagtosemia, tyrosinemia, , or lipidmetabolism like Wolman, Gaucher or Nieman-Pick) 5%

Intrahepatic Disorders• Bile acids disorders• Toxic (TPN, fetal alcohol syndrome, drugs)• Genetic (Trisomies(18, 21 and 17)• Vascular (Budd-Chiarisyndrome, perinatalasphyxia, cardiac insufficiency )

Staged Evaluation of NeonatalCholestasis• Clinical evaluation (history, physical examand stool color)• Fractionated serum bilirubin• Tests for hepatocellular (ALT/AST) andbiliary disease (Alk(phos and GGT)• Tests for hepatic function (albumin, PT,serum glucose, amonia)

Staged Evaluation of NeonatalCholestasis• Exclude treatable and other disordersBacterial cultures, VDRL, viral serology likeTORCH/herpesA1AT level and phetotypeT4/TSHUrine metabolic screen ON feeds (urinereducing substance, urine bile and organicacids, serum amino acids and ferritin)Sweat CL test or genetic test for CF

Staged Evaluation of NeonatalCholestasis• Differentiate extrahepatic biliaryobstruction from intrahepatic disordersUltrasonography (hepatic texture, BD andGB)Hepatobiliary scintigraphy (HIDA scan) toevaluate poor uptake vs excreationLiver biopsy

Summary• Neonatal jaundice if largely benign it isimportant to timely evaluate and notdismiss the concern of jaundice• It is important to distinguish conjugatedfrom unconjugated hyperbilirubinemia• Always keep in mind the possibility ofEHBA (Trio: T. bili/direct >5, GGT > 5folds and absence of GB on ultrasound)

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