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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 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 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 Hb 110 (90-140) WBC 21.5 H (5-19.5) Plt 569 H (150-400) Neut 9.2 H (1-9) LFT/enzymes Lytes, Cr, Urea – NORMAL Urinalysis/R&M LARGE Leuks, SMALL blood 20-30 WBC/hpf 0-5 RBC Few bacteria 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) 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 Hyperbilirubinemia Physiologic vs. Pathologic Jaundice in the Newborn Physiologic vs. Pathologic Jaundice in the Newborn1 Physiologic Pathologic Unconjugated hyperbilirubinmia Appears <24 hrs 60% term & >80% preterm neonates in first week Excessive for infant’s age (Tbili > 205 umol/L) Rises at rate <85 umol/L/day Elevated direct bilirubin Appears on 2nd or 3rd day of life Jaundice present at or beyond 3 wks Typically peaks btwn days 2-4 Sick infant Begins to decline on days 5-7 at rate of 34 umol/L/day Tbili rising >85 umol/L/day Unexplained jaundice following phototherapy Jaundice in the presence of risk factors Ddx Conjugated vs. Unconjugated Hyperbilirubinemia UNCONJUGATED Physiologic CONJUGATED Pathologic Hepatic Non-hemolytic Cephalohematoma Polycythemia Sepsis Hypothyrodism Gilbert’s Crigler- Najjar Hemolytic Extrinsic Hemolytic Intrinsic Membrane Spherocytosis Elliptocytosis Enzyme G6PD PK deficiency Hemoglobin Alpha thal Immune ABO-incompatibility Rh-incompatibility Kelly-Duffy etc Non immune Splenomegaly Sepsis AV malformation 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 Ddx of Hyperbilirubinemia According to Time of Onset First 24 hours 24-72 hours 72-96 hours Often pathologic •Hemolysis (Rh or ABO) •Physiologic •Physiologic •Sepsis (GBS, TORCH) •Cephalohematoma •Spherocytosis •Hemorrhagic disease of the newborn > 1 week Often pathologic •Breast milk jaundice •Polycythemia •Dehydration •Dehydration •Sepsis •Prolonged Physiologic •Hemolysis •G6PD •PK def •Gilbert’s •Hypothyroidism •Crigler-Najjar •Neonatal Hepatitis •Cephalohematoma •Hypoxia/resp distress/hypoG •Galactosemia •Spherocytosis •Sepsis/TORCH •Familial Cholestasis •Biliary atresia •Paucity of bile ducts 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 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 Less specific suggestive of underlying metabolic, CNS, or infectious aetiology: Dark urine Coagulopathy Hepatomegaly Splenomegaly RUQ mass FTT Fever Irritability Lethargy, Seizures Poor feeding Dysmorphic features Ddx Neonatal Cholestasis Obstruction Infectious Metabolic/Genetic Biliary Atresia Bacterial Alagille Syndrome α-1-Antitrypsin Choledochol cyst Protozoal Galactosemia Tumor TORCH Inspissated bile/plug sybdrome Tyrisonemia Echovirus Lipid metabolism disorders Adenovirus Bilae acid metabolism disorders Parvovirus B18 Mitochondrial Disease Gallstone Biliary Sludge Citrin deficiancy Approach to Neonatal Cholestasis 1. Initial investigations: Establish cholestasis and determine severity of disease 2. 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 3. Differentiate extrahepatic disorders from intrahepatic causes of cholestasis 4. 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 1. Initial investigation: establish cholestasis 2. Detect conditions that require treatment 3. Differentiate extrahepatic disorders from intrahepatic causes of cholestasis 4. 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 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 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 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 1. Subcommittee on Hyperbilirubinemia. Management of Hyperbilirubinemia in the Newborn Infant 35 or More weeks of Gestation. Pediatrics. 2004;114:297-316. 2. Venigalla S, Gourley GR. Neonatal Cholestasis. Seminars in Perinatology.2004;28:348355. 3. Suchy F. Neonatal Cholestasis. Pediatrics in Review. 2004;25:388-395. 4. Schreiber RA, Barker CC, Roberts EA, et al. Biliary Atresia: the Canadian Experience. Journal of Pediatrics. 2007;151:659 5. Abrams S, Shulman R. Causes of Neonatal Cholestasis. UpToDate. Last updated June 12, 2008. 6. Abrams S, Shulman R. Approach to Neonatal Cholestasis. UpToDate. Last updated September 26, 2006. The End