Interesting Case Rounds July 31, 2008 Sean Caine CCFP-EM Resident

The Case 90 d F referred from urgent care for FTT and prolonged jaundice

History

History Pregnancy Delivery Mother was 23 yo Caucasian female G1P0 O neg Routine serology was normal GBS negative Nonsmoker. No EtOH Uncomplicated pregnancy (no PIH or GDM) Delivery SVD @ 39wks GA ROM x 3 hrs BW=3220 Apgar 91,95 DAT negative Newborn metabolic screen was normal Tbili at discharge =190 d/c home 24hrs postpartum Consider pointing out tbili on nomogram

History Followed by GP qweekly x 6 wks Jaundiced noted again at 6wk follow up with maternity care clinic 1 oz wt loss in past month Exclusively breast fed. Feeds well. ~6-8 BM/day. Stools are typically yellow. Recently have become more pale. ~6-8 wet diapers/day. Urine is brown. ROS otherwise unremarkable for sleep, appetite, activity, or symptoms indicative of focus for infection etc

On exam VS: 36.6 119 88/47 36 No apparent distress. Awake. Alert. Interactive and pleasant ++scleral icterus. +jaundice Firm liver edge. Palpable spleen tip. CV, Resp, CNS, Abdo exam otherwise unremarkable

Labs/Investigations

Labs/Investigations CBC LFT/enzymes Ammonia 61 H (12-47) Hb 110 (90-140) WBC 21.5 H (5-19.5) Plt 569 H (150-400) Neut 9.2 H (1-9) Lytes, Cr, Urea – NORMAL Urinalysis/R&M LARGE Leuks, SMALL blood 20-30 WBC/hpf 0-5 RBC Few bacteria LFT/enzymes Tbili 178 H (0-23) Direct bili 118 H (0-7) ALT 199 H (1-35) AST 262 H (10-65) ALP 461 H (40-390) GGT 796 H (8-35) Albumin 38 INR 1.1 PTT 40.5 H (27-36) Ammonia 61 H (12-47) Bottom line: Conjugated hyperbilirubinemia in 3 month old infant with elevated lever enzymes and urinalysis consistent with UTI

Objectives Review features of physiologic and pathologic jaundice Review approach to neonatal cholestasis Highlight some common pitfalls Return to the case to review the work up and diagnosis

Hyperbilirubinemia Has increasingly become a presenting complaint to ER due to early postpartum discharge However, still rare to encounter in Calgary ER Screened by PHN/GP in first 3-5 days postpartum Direct admit to PLC Unit 31 for assessment +/- phototherapy Very common problem. Often benign and easy to become complacent about. Thought it would be worthwhile to review as although rare to encounter in ER here, very common problem, and may be encountered more frequently outside the CHR . In particular for our FRCP residents who will be unlikely to encounter this at AC. Even though patients are sent to PLC, they typically bypass ER and are directly assessed on the floor.

Hyperbilirubinemia

Physiologic vs. Pathologic Jaundice in the Newborn

Physiologic vs. Pathologic Jaundice in the Newborn1 Unconjugated hyperbilirubinmia 60% term & >80% preterm neonates in first week Rises at rate <85 umol/L/day Appears on 2nd or 3rd day of life Typically peaks btwn days 2-4 Begins to decline on days 5-7 at rate of 34 umol/L/day Pathologic Appears <24 hrs Excessive for infant’s age (Tbili > 205 umol/L) Elevated direct bilirubin Jaundice present at or beyond 3 wks Sick infant Tbili rising >85 umol/L/day Unexplained jaundice following phototherapy Jaundice in the presence of risk factors Cover etiology of physiologic jaundice. Recognize that there is overlap. In particular with the timeline as sepsis, metabolic disorder (G6PD or PK deficiency). But they will be accompanied by story of unexplained irritability, feeding difficulties, hypotonia, lethargy, seizure, fever etc. Recent studies suggest that clinical examination is poor predictor of severity of jaundice This info is direct from the AAP guidelines. The same guidelines Dr. Jorgenson made sure to provide each family resident and all to eagerly review at 3-4 in the morning.

Ddx Conjugated vs. Unconjugated Hyperbilirubinemia Physiologic Pathologic Hepatic Infectious Sepsis Hep B, TORCH Metabolic Galactosemia Tyrosinemia Alpha-1-antitrypsin Hypothyroidism CF Drugs TPN Idiopathic neonatal Cholestasis Bile duct paucity AbN Bile acid metabolism Extra Hepatic Biliary atresia Choledocal cyst Non-hemolytic Cephalohematoma Polycythemia Sepsis Hypothyrodism Gilbert’s Crigler- Najjar Hemolytic Extrinsic Immune ABO-incompatibility Rh-incompatibility Kelly-Duffy etc Non immune Splenomegaly Sepsis AV malformation Hemolytic Intrinsic Membrane Spherocytosis Elliptocytosis Enzyme G6PD PK deficiency Hemoglobin Alpha thal

Ddx of Hyperbilirubinemia According to Time of Onset First 24 hours 24-72 hours 72-96 hours > 1 week Often pathologic Hemolysis (Rh or ABO) Sepsis (GBS, TORCH) Cephalohematoma Spherocytosis Hemorrhagic disease of the newborn Often pathologic Breast milk jaundice Prolonged Physiologic Hypothyroidism Neonatal Hepatitis Galactosemia Familial Cholestasis Biliary atresia Paucity of bile ducts Physiologic Polycythemia Dehydration Hemolysis G6PD PK def Cephalohematoma Spherocytosis Sepsis/TORCH Physiologic Dehydration Sepsis Gilbert’s Crigler-Najjar Hypoxia/resp distress/hypoG

Neonatal Cholestasis Defined as the impaired canalicular biliary flow resulting in acumulation of biliary substances (bilirubin, bile acids, and cholesterol)2 Estimated incidence of 1/2500 live births Jaundice at 2-3 weeks of age increases suspicion2 2.4-15% of newborns are jaundice at 2 weeks of age6 Estimated that 60-375 jaundiced infants at 2 weeks of age would need to be tested to detect one case of cholestasis 26

Common Pitfalls Breast feeding jaundice Breast milk jaundice Exaggeration of physiologic jaundice Day 2  7 Premature babies: can last up to 10 days Breast milk jaundice 2% of breast fed babies Starts ~ day 7, persists until week 2-3 May persist for 3-10 weeks at low levels Unconjugated Theory: glucuronidase in breast milk  increased enterohepatic bilirubin re-circulation

Neonatal Cholestasis Clinical Presentation Prolonged jaundice Pale stools Dark urine Coagulopathy Hepatomegaly Splenomegaly RUQ mass FTT Less specific suggestive of underlying metabolic, CNS, or infectious aetiology: Fever Irritability Lethargy, Seizures Poor feeding Dysmorphic features

Ddx Neonatal Cholestasis Infectious Bacterial Protozoal TORCH Echovirus Adenovirus Parvovirus B18 Obstruction Biliary Atresia Choledochol cyst Tumor Inspissated bile/plug sybdrome Gallstone Biliary Sludge Metabolic/Genetic Alagille Syndrome α-1-Antitrypsin Galactosemia Tyrisonemia Lipid metabolism disorders Bilae acid metabolism disorders Mitochondrial Disease Citrin deficiancy

Approach to Neonatal Cholestasis Initial investigations: Establish cholestasis and determine severity of disease Detailed hx, exam Fractioned serum bili Tests for liver injury (AST, ALT, ALP, GGT) LFT (Albumin, INR, PTT, serum ammonia, glucose) Detect conditions that require immediate treatment CBC, blood & urine cultures to r/o sepsis Serum T4 and TSH Metabolic Screen: lactate, ammonia, iron, ferritin, urinalysis, urine amino acids and organic acids Viral serologies, VDRL, and cultures

Approach to Neonatal Cholestasis Differentiate extrahepatic disorders from intrahepatic causes of cholestasis U/S Hepatobiliary scintigraphy Perc liver bx, Exploratory laparotomy with intraoperative Establish other specific diagnosis α-1-antitrypsin, CF, Alagille, PFIC, storage disorders

Back to the Case Initial investigation: establish cholestasis Detect conditions that require treatment Differentiate extrahepatic disorders from intrahepatic causes of cholestasis Investigate for the rare diagnosis

BiliaryAtresia Inflammation of bile ducts leading to progressive obliteration of the extrahepatic biliary tract Most common cause of cholestasis in the first few weeks of life Incidence of 1/10,000 to 1/20,000 births Cause remains unknown though various infectious (CMV, reovirus, rotavirus) and genetic causes have been proposed

Biliary Atresia Jaundice typically develops in weeks 3-6 Uncommon for jaundice to be present at birth 10-15% association with congenital malformations (polysplenia, malrotation, etc)

Biliary Atresia Diagnosis U/S can be suggestive Liver biopsy is the most useful test HIDA useful Specificity improved with phenobarb 5d before scan Duodenal aspirate Exploratory laparotomy & intraoperative cholangiogram ERC and MRC likely to have future Hepatobiliary iminodiacetic acid scan

Ultrasound Main utility is to r/o other extrahepatic causes (ie choledochol cyst) Findings suggestive of biliary atresia Absence of gallbladder Abnormal gallbladder size and shape “Triangular cord” sign Absence of a common bile duct

Ultrasound Fibrous triangular cord antrerior to portal vein

Ultrasound Abnormally small and contracted gallbladder and irregular contour and septations in the gallbladder neck. Common bile duct not visualized Consistent with biliary atresia

Biliary Atresia Treatment Primary treatment is Kasai procedure Early diagnosis and surgery is critical Narrow window for optimal short and longterm outcomes bile drainage achieved in >80% of patients <60 days of age vs. 20% of infants >90 days 4 yr survival with native liver 49% with sx <30 days of age 36% with sx at 31-90 days of age 23% with sx at >90 days of age Kasai is a portoenterostomy with roux-en-Y loop of bowel being anastomosed to the liver and portal fibrous plate

Kasai

Pearls Recognize pathologic features of jaundice Obtain fractioned serum bili level (ie total and direct) on all 2-3 week old jaundiced infants Infants with biliary atresia will often appear to be well in the first 1-2 weeks of life Neonatal cholestasis is rare, but timely diagnosis is crucial!

References Subcommittee on Hyperbilirubinemia. Management of Hyperbilirubinemia in the Newborn Infant 35 or More weeks of Gestation. Pediatrics. 2004;114:297-316. Venigalla S, Gourley GR. Neonatal Cholestasis. Seminars in Perinatology.2004;28:348-355. Suchy F. Neonatal Cholestasis. Pediatrics in Review. 2004;25:388-395. Schreiber RA, Barker CC, Roberts EA, et al. Biliary Atresia: the Canadian Experience. Journal of Pediatrics. 2007;151:659 Abrams S, Shulman R. Causes of Neonatal Cholestasis. UpToDate. Last updated June 12, 2008. Abrams S, Shulman R. Approach to Neonatal Cholestasis. UpToDate. Last updated September 26, 2006.

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