The Jaundiced ‹header› 9/17/03

The jaundiced infant From whence cometh ?

Martin F. Graham MD n 80% daily bilirubin prodn from the catabolism of hemoglobin Division of Pediatric Gastroenterology n heme dissociates from globin and Nutrition n heme oxygenase in RE cells, Virginia Commonwealth University/MCV macrophages, parenchymal cells

n catalyzes the cleavage of the tetrapyrrole ring at the methene bridge

n Releases biliverdin, Fe ,CO n : an increase in serum n Biliverdin reduced to bilirubin IX-a by bilirubin biliverdin reductase n Major catabolic product but…insoluble

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How to excrete bilirubin ? How to excrete bilirubin ? First solubilize it !!!

n Conjugation with glucuronic acid Let it flow in bile…. Conjugation bile secretion bile excretion n One/both propionic acid side chains n UDP-glucuronyl transferase UDP-GT1A1 hepatocyte bile flow n diglucuronide > 90% of bilirubin conjugates in normal human bile n Conjugation bile ducts n Photoisomerization n Bile Secretion OATP-2 n exposure to light 425 - 475 nm n changes the configuration of the n Bile Excretion double bonds adjacent to the outer pyrrole rings

n discovered incidentally

n phototherapy NB: once bilirubin is conjugated, it requires bile flow

for excretion into the gut Organic anion transporting polypeptide graham 9/03 graham 9/03

If you are jaundiced….stay calm - you have one of two problems: The cardinal first step in evaluation

unconjugated conjugated 1. Handling the unconjugated bilirubin

load UDP-GT1A1 hepatocyte bile flow 2. Excreting the conjugated bilirubin in bile ducts

bile OATP-2

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Unconjugated hyperbilirubinemia Unconjugated hyperbilirubinemia

unconjugated unconjugated n Increased bilirubin load n Decreased conjugation n RBC load - n Physiologic

n Hemolysis UDP-GT1A1 n UDP-GT1A1 UDP-GT1A1 n ABO, Rh OATP-2 OATP-2 n RBC membrane, pyruvate kinase n G6PD Deficiency-X linked

n Male hemi, Female homo

n Drugs n Breast milk

Organic anion transporting polypeptide

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Physiologic jaundice of infancy Physiologic jaundice of infancy -

n n Immaturity - UDP-glucuronosyl transferase (UDP-GT1A1) Action taken depends on risk factors

n 0.1% - 17-30 wks, 1 % - 30-40 wks, 100% - 14 wks post-natal n IV hydration n Induction after birth irrespective of gestational age n Common n Phototherapy n Peaks at day 3 n Bilirubin level 10 -12 n Photosomerizaion- bilirubin solubilization - n Danger - excretion n barrier n Risk n n Low birth weight

n Asphyxia neonatorum

n Septicemia

n Hypoalbuminemia, drugs n , deafness, mental retardation

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Conjugation defects - UDP-GT1A1 mutations Breast milk jaundice

n Criggler-Najjar I, II n 2 weeks of life n I - activity O%, AR, 1:1000, bil > 20, kernicterus ++, any exon n II (Arias) - activity <10%, AR/AD, 1:1000, bil 15-20, kernicterus low n Etiology unknown

n UGT 1A1 only, induceable by phenobarbitol n ? Increased enterohepatic circulation of bilirubin

variable exons promoter common exxons n Inadequate breast milk, dehydration

1A13 1A4 1A3 1A2 A (TA)6 TAA UGT 1A1 2 3 4 5 n Off breast for 48 h n Pump milk • Gilbert’s syndrome n Document drop in bilirubin - 2 points • Mild, chronic, recurrent, activity 30%, fasting, illness • 9 % of population homozygous, 47 % heterozygous n Restart breast feeding • extra TA in promoter - (TA)7 n Not a reason to discontinue • at risk for hyperbili if: co-inherited eg G6PD/other UGT, breast feeding graham 9/03 graham 9/03

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Conjugated hyperbilirubinemia How and why does bile flow

n Synthesized from cholesterol - hepatocyte n Occurs later in life - 3-4 weeks n 7, and 12 a - hydroxylation

n Serious etiologies - chronic disease n Conjugated, actively secreted into canniliculus

n Anything that impairs bile flow n Pulls water n Essential property - amphiphilic - sits n Clinical consequences result from impaired bile flow comfortably at lipid/water interface n Forms micelles with phospholipid

n “solubilizes” fat and cholesterol in water

n 95% reabsorbed in terminal ileum - recirculated

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Normally, bile salts are actively secreted into the canaliculus: this generates bile flow and Functions of bile bilirubin excretion

n Micellize dietary fat in gut lumen Anion pumps n Chylomicrons Cannilicular multispecific organic anion transporter n Lymphatic system

n Excrete cholesterol from Multi drug resistant cMOAT / MRP associated protein n Excrete bilirubin * in Dubin- Johnson syndrome

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In cholestasis, injury impairs the bile salt secretory apparatus Histologic patterns of injury

n Disruption of actin filaments A. Normal portal tract around canaliculus B. Ballooning degeneration of n Loss of villous processes hepatocytes n Interruption of transport C. Bile duct inflammation (Bactrim) pumps: MRP3 (multi drug resistent-associated protein D. Portal fibrosis, loss of bile ducts 3) (8 mos later) E. Necrosis (acetominophen)

F. Fat accumulation

Lee, NEJM 2003

Lee, NEJM 2003 graham 9/03 graham 9/03

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Injury impairs bile salt secretion into the Remember: the elevated conjugated bilirubin is canaliculus, reduces bile flow and bilirubin merely a symptom of the underlying excretion: conjugated bilirubin rises pathobiology - impaired bile flow - “cholestasis”

n Infectious n Viral

n bacterial n Toxic n Drug

n TPN n Metabolic

n Galactosemia

n Fructosemia

n Tyrosinemia n a-1 antitrypsin n Blockage

n Cystic fibrosis NB: bile salts are detergents - their accumulation in the

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Consequences of impaired bile flow - cholestasis Causes of cholestatic jaundice in infancy

n Fat malabsorption n Steatorrhea- fatty, bulky stools n Surgical n Fat soluble vitamin deficiency n Metabolic n D - rickets n K - - n Infectious n Hypercholesterolemia - n Genetic

xanthomata Feldman's GastroAtlas Xanthomata in 7 yo with n Toxic n Hyperbilirubimemia Allagille’s syndrome n Injury to liver - cirrhosis

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Surgical causes Obstructive cholangiopathies

n Sclerosing cholangiopathy n Progressive - n Choledocal cyst fibrosis, n cirrhosis Caroli’s n Caroli’s disease disease n Early n Progressive - fibrosis, cirrhosis intervention - Biliary n Early intervention - < 10 weeks can prevent cirrhosis <10 weeks can atresia n Bile plug syndrome prevent Choledocal cirrhosis n Cholelithiasis cyst

n TPN

n ECHMO

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Obstructive cholangiopathies Obstructive cholangiopathies

n Kasai n Kasai procedure procedure

n Porto- n Porto- enterostomy enterostomy

n Resection

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Obstructive cholangiopathies Obstructive cholangiopathies

n Kasai n Kasai procedure procedure

n Porto- n Porto- enterostomy enterostomy

n Resection n Resection

n Incision porta n Incision porta

n Dripping bile

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Obstructive cholangiopathies Idiopathic cause

n Kasai n Neonatal / giant cell hepatitis

procedure n 40% of cholestatic hepatitis

n Porto- n Males> female 2:1 enterostomy n Ballooning degeneration n Resection n Multinucleated giant cells n Incision porta n May resolve n Dripping bile Feldman's GastroAtlas n Roux-en-Y n May progress to cirrhosis, liver anastamosos failure

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Metabolic causes Metabolic causes

n a-1-antitrypsin deficiency n Galactosemia n Hydrolysis of lactose to glucose and n PiZZ phenotype galactose

n 1:2000 live births n Transferase deficiency

n Autosomal recessive n AR, 1:50,000 Feldman's GastroAtlas n Vomiting, diarrhea, hypoglycemia n Low serum levels of a1-antitrypsin n Cholestatic hepatitis early n Altered protein - impaired secretion RER to Golgi n Rapid cirrhosis, ascites, n Accumulation of 1-antitrypsin in hepatocyte a- n reducing sugar in urine

Feldman's GastroAtlas n Hepatocellular injury, cholestasis, cirrhosis n Neg gluc oxidase dipstick

n PAS positive diastase resistant staining on n Lactose-free formula histology

n Severity variable graham 9/03 graham 9/03

Metabolic causes Genetic causes

n Tyrosinemia n Alagille’s Syndrome n AR, n Triangular facies

n Deficieny of fumarylacetoacetate hydrolase n Bossing, pointed chin n last enzyme in the tyrosine degradation n Cholestasis pathway n Pruritis, xanthomata, cholesterol

n Intermed metabs, maleylacetoacetate, n Cardiac anomalies fumarylacetoacetate responsible for the n PPS, TOF, coarctation hepatic and renal symptoms n Bone n Hemi, butterfly vertabrae n Cholestatic hepatitis, progressive failure n Short ulna n Inc plasma tyrosine Feldman's GastroAtlas Tyrosinemia n Retinal pigment n Succinylacetone in blood or urine Feldman's GastroAtlas n Paucity of intrahepatic bile ducts n hepatocellular carcinoma by 3 yrs Micronodular cirrhosis n Chromosome 20 deletion (20p) n Rx: phylalinine/tyrosine-free formula

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Genetic causes Infectious causes

n Septicemia n Cystic fibrosis n Gram negative n Viscid mucus in bile ducts n LPS n n Cholestatic TORCHES infections syndrome in infancy Feldman's GastroAtlas n Toxoplasmosis

n Biliary cirrhosis in n rubella teens Feldman's GastroAtlas n CMV Newborn CMV hepatitis n Can be associated n Herpes intranuclear inclusion bodies with meconium in bile duct epithelium n syphilis

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Toxic causes Clinical approach to jaundiced infant

n Unconjugated n Total parenteral nutrition n Benign - Physiologic/hemolytic/breast milk n Amino acid solution and lipid n Conjugated n Dose related n Serious - must be expeditious n Low birth weight, sick, septic, n Ultrasound - fasted - feed during exam asphyxiated ?gallbladder contraction Ultrasound: choledocal cyst n Can lead to cirrhosis and liver n HIDA scan - loading dose of phenobarbitol failure n ? Excretion into gut n MRCP - MR cholangio-pancreatogram n Do not exceed Feldman's GastroAtlas n a-1-antitrypsin level n protein - 1.5 gm/kg/day TPN injury: bile plugging, rosette formation n TORCHES titers n Fat - 1 gm/kg/day n Metabolic screen - urine, serum

n Sweat test

graham 9/03 n Operative cholangiogram, liver biopsy HIDA scan: non-excretiongraham 9/03

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