Management of the persistently jaundiced neonate

Transcription

1 Management of the persistently jaundiced neonate Saul J. Karpen, M.D., Ph.D. Raymond F. Schinazi Distinguished Biomedical Chair Professor of Pediatrics Emory University School of Medicine/CHOA Emory Neonatal Conference May 1, 2015 No disclosures

2 Topics Liver biology & pathobiology Pre-discharge jaundice: 1969 & bilirubin geography New information about bilirubin metabolism Neonatal cholestasis and biliary atresia Not discussed: transcutaneous bilirubin measurement devices when to start/stop phototherapy alternative/experimental treatments

3 Burden of pediatric liver disease Incidence of liver disease in newborns 1:2,500 Mainly cholestatic & metabolic liver diseases No effective medical treatments for cholestasis ~ 10% of adults have liver disease starts during childhood Genetic predisposition & contribution from obesity Biliary atresia 1:10,000 newborns Early recognition is key ~ 60% will require liver transplantation; average age ~ 2½ y Donor shortage Arya & Balistreri, J GI & Hepatology, 2002

4 Liver: Master Integrator of Metabolism & Inflammation The liver receives all substances from the gut Over 5000 functions Largest organ of the body Sophisticated 3-D structure Metabolic Integrator from the Diet Fat Cholesterol Nitrogen & amino acids Carbohydrate (Glucose) Source of most serum proteins Albumin, Complement Clotting Factors Bile Ducts & Gall Bladder Essential for digestion Bile acids are detergents Elimination of toxins (Bilirubin) C Bile: intestines for elimination Bile formation (~ ½-1 liter daily) Drug & toxin metabolism/excretion Cytochrome P450 system Gut bacterial products

5 Cholestasis impaired bile flow Liver Intestine fat absorption diarrhea malnutrition Bile Acid Retention apoptosis & fibrosis cirrhosis vitamin absorption A, D, E, K deficiencies

6 Bilirubin RBCs + muscle + liver Become old or damaged Hemoglobin heme Heme unconj. bilirubin in the spleen Unconjugated bilirubin Erica Smearman, Emory Med Student

7 Bilirubin Conjugation: UGT1A1 N N N N O O HOOC COOH Glucuronide UGT1A1 N N N N O O HOOC COOH & N N N N O O HOOC COOH Unconjugated Bilirubin Not Water Soluble Mono-glucuronidated Bilirubin Di-glucuronidated Bilirubin Conjugated Bilirubin Excellent Water Solubility

8 Disorders of Bilirubin Transport & Metabolism 7% of pop I & II: ~ 1:1,000,000 ~ 1:??? (1:1300 Iranian Jews) ~ 1:?? (50 cases ) van de Steeg et al, J Clin Invest Feb 1;122(2): Erlinger S, Arias IM, Dhumeaux D. Gastroenterology Jun;146(7): Orphanet, GeneReviews

9 O HOOC COOH N N N N O O HOOC COOH N N N N O Distinct Mechanisms for Bilirubin & Bile Acid Transport Blood Bile Bile acids NTCP Na + Bile acids BSEP (ABCB11) PFIC2?Prolonged bili Rotor Organic anions OATPs (SLCO1B1/3) MRP2 (ABCC2) UGT1A1 Conjugated Bilirubin & other conjugates Dubin-Johnson HOOC COOH O N N N N Albumin O Gilbert Disease Crigler Najjar I Crigler Najjar II Rotor Adapted from Karpen, in Liver Diseases in Children, 2012

10 Stress Gilbert s presentation Fasting Illness Sleep On-call

11 UGT1A1 Promoter & Irinotecan toxicity Iyer Pharmacogenomics J 2002

12 AAP guidelines 2004

13 AAP: Risk Factors for Hyperbilirubinemia Missing Neonatal Liver Disease Dennery NEJM 2001 AAP Pediatrics 2004 Gourley JPGN 2005

14 Pediatrics, >15 85 healthy newborns 18 ABO incompatability 5 Rh Disease

15 122 ~ 2 days of life Observer B Estimate Actual Bilirubin Observer A Estimate Estimated Bilirubin Poor Inter-observer correlation Poor bilirubin guess-timates

16 Pediatrics, 1969 The dermal zone method of estimating serum bilirubin concentration described in this report is not meant to replace laboratory determinations of serum bilirubin.

17 Google search WSJ May Studies of jaundice do not accurately reflect current US birth diversity

18 Take home point Reliance on cephalocaudal zonation of jaundice ( bilirubin geography ) as a marker of serum bilirubin levels is problematic.

19 Pediatrics 2004

20 Q: What is in breast milk that leads to jaundice?

21 Brest milk jaundice: How long is too long? Winfield & Macfaul 893 infants (Aldershot, England) 55% BF 12 were jaundiced > 3 weeks ( ~ 2 %)

22 JCI 1964

23 Arias & Gartner Nature 1964

24 Think anatomic Intrahepatic bile ducts Extrahepatic bile ducts & Gall Bladder Hepatocytes

25 Causes of Neonatal Cholestasis: 82 Infants in Essen Germany BA 41% Hoerning A, et al Front Pediatr. 2014;2:65.

26 Neonatal Cholestasis Extrahepatic Bile Duct Intrahepatic Bile Duct Hepatocytes Biliary atresia Choledochal cyst Bile duct hypoplasia Bile duct duplication Agenesis of the extrahep. ducts Choledocholithiasis Inspissated bile syndrome Bile duct paucity: Alagille Syndrome (JAG1 & Notch2) Non-syndromic Ductal Plate Malformation: Congenital Hepatic Fibrosis Caroli disease ARPKD & ADPKD von Meyenburg complexes Cystic More FibrosisGenes Neonatal sclerosing cholangitis Coming in the Miscellaneous: Endocrine: panhypopituitarism, hypothyroidism Neonatal hemochromatosis TPN-associated cholestasis Near Future Indeterminant ( Neonatal Hepatitis ) Viral Infection: CMV, HSV Parvovirus B19 HAV, HBV, Adenovirus, Enterovirus Bacterial/Parasitic Infection: Gram negative sepsis Syphillis, TB, Listeria Transporter & other genes: PFIC1 (ATPB1) TJP2 PFIC2 (ABCB11) BAAT PFIC3 (ABCB4) Metabolic/Storage diseases: Lipid metabolism Niemann-Pick aa metabolism tyrosinemia CHO metabolism galactosemia Bile acid synthesis Peroxisomal Zellweger's Mitochondrial enzymopathies Urea cycle OTC deficiency 1 -antitrypsin deficiency Drug toxicity

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28 Bile Formation & Adaptation 2015 Sinusoidal Membrane Hepatocyte 2014: TJP2 Bile duct Bile acids Na + Organic anions Bile acids NTCP OATP s SLCO s Rotor Syndrome OST SLC10A1 Hypercholanemia SLC51A/B Bile acids MRP3 & MRP4 Bile acids Various conjugates ABCC3 & ABCC4 PL Flippase Bile acids Sterols PL Floppase Conjugated Bilirubin & other conjugates Transporter gene variants Solute composition of human bile Altered susceptibilities to cholestasis FIC1 BSEP STEROLIN MDR3 MRP2 Canalicular Membrane PFIC1/BRIC1 ATP8B1 PFIC2/BRIC2 ABCB11 Sitosterolemia ABCG5/G8 PFIC3 ABCB4 Dubin-Johnson ABCC2 7 mm Phospholipids 17% Bilirubin 1% Bile acids 41% 30 mm CFLD ABCC7 ASBT SLC10A2 CFTR 3 mm Cholesterol 3% Cl -- Bile acids Na + OST Bile acids SLC51A/B Proteins 7% Electrolytes 31%

29 The Emory Cholestasis 56 gene Panel Many more to come, including whole exome sequencing

30 Impaired gene responsible for a key metabolic function + No work-around pathway Metabolic Disease

31 The request for ritual bloodletting by a Consultant is a relic of the not so distant past.

32 Red Flags for Metabolic Disease History: FTT Poor feeding, lethargy Prolonged neonatal jaundice Exam: Poor tone Hepato(spleno)megaly Labs: Elevated ALT +/ CPK Direct Hyperbilirubinemia Hypoglycemia (esp. with absent urinary ketones) Hyperammonemia

33 Planning Your Workup One size does not necessarily fit all Babies: new to the world, so cast a broad DDX Is it liver specific or not? Overlapping presentation with sepsis Imaging (Liver, Brain, Heart ) Urgency

34 Tools Blood Metabolites e.g., Amino acids, Lipids, Bile acids Biochemical hallmarks Ammonia Gene Tests Urine Metabolites (e.g. succinylacetone) Textbooks & Internet Resources Liver Biopsy

35 Next Step Diagnostic Choices Wait & see TORCH & other titers Autoimmune markers Viral PCRs (HSV, CMV, Adeno, Entero ) Ceruloplasmin, Copper, Iron Panel Serum amino acids, carnitine profile Urine Organic acids, Polyols Genetics & Surgical consultations Wedge liver biopsy +/ muscle biopsy Percutaneous Liver Biopsy

36 The Role of a Liver Biopsy Reduces Blood sample volume Costs of non directed screening Time of non directed screening Advantages Directs a focused workup May provide a diagnosis Allows for use of specific histological stains Electron microscopy Overnight turnaround

37 THE LIVER BIOPSY Readily available One day turn-around Can identify many other etiologies 76% Specific 100% Sensitive Milton Finegold, MD Zerbini Mod Pathol 1997

38 Biliary Atresia Fibro-obliterative cholangiopathy with obstruction of the common bile duct as a central component. No clear genetics monozygotic twins are usually discordant Laterality defects in 5-10% Asplenia/polysplenia Cardiac defects Situs abnormalities 2 Questions: Etiology? Differential outcomes post-kasai Cameron & Bunton Brit Med J 1960 Fallon et al J Ped GI & Nutr, 2012 Davenport et al J Pediatrics, 2006

39 Best means to diagnose BA Modality Sens. Spec. PPV NPV Diagnostic Accuracy Liver Biopsy 34/34 100% 33/35 94% 34/36 94% 33/33 100% 97% Hepatobiliary Scintigraphy 30/34 88% 16/35 45% 30/49 61% 16/20 80% 66% Ultrasound 17/34 50% 29/35 82% 17/23 74% 29/46 63% 65% MRCP 29/34 85% 20/35 57% 29/44 66% 20/25 80% 71% Yang Clinical Imaging 2009

40 Entry criteria: Design set: Direct hyperbilirubinemia: ALL subjects underwent Liver bx 60 Infants: (~ 65 dol) Category Parameter BA (30) Non-BA (30) P value Significant Clinical Acholic stools 28 (93%) 13 (43%) < Lab GGT 411 +/ /- 270 < U/S Flow Liver bx Triangular Cord GB Length (mm) GB Contractility Subcapsular Flow HA Diameter Duct Proliferation Duct Plugs Multi-nucleated cells 19 (63) 21 +/ (5) 29 (96) 2.5 +/ (96) 29 (96) 8 (26) Not significant Exam: Liver or Spleen Enlargement Labs: ALT & AST, AP, WBC, Hgb Total & Direct Bili (10/6) U/S: Abnormal GB Biopsy: Grade of Fibrosis 4 (13) 33 +/ (53) 1 (3) 1.9 +/-.6 4 (13) 11 (36) 26 (86) < < < < <0.001 < < < J Hepatol Jul;61(1):

41 High utility of: Stool pigment visualization U/S, esp. Flow parameters Liver biopsy No evaluation of: Take home points HIDA, MRCP, ERCP, DNA Tool for BA: 100 % sensitivity, 97% Specificity, Diagnostic accuracy 98% J Hepatol Jul;61(1):

42 Q: When does BA start?

43 Direct Bili in ALL BA subjects within h of life early cholestasis is a cardinal feature of BA Opportunity for Newborn Screening?

44 The Kasai Hepatoportoenterostomy Successful Kasai (n=50) ~ 50:50 split Why? Failed Kasai (n=41) Cameron & Bunton Brit Med J 1960 McKiernan JPGN 2008 Maksoud J Ped Surgery 1998 Success: Total bilirubin < 20 M at any time

45 Age at Kasai & Survival with Native Liver % 5 y SNL Age at Kasai (Days) N = Chardot et al, J Hepatol Jun;58(6): Maksoud J Ped Surgery 1998 Saul J. Karpen AASLD STC June 2013

46 No role for steroids post-kasai Survival with Native Liver Bezerra JA, et al. (2014). Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA, 311(17),

47 BA in Japan: 20 year survival with native liver Era. Shinkai JPGN 2009

48 BY PRIMARY DIAGNOSIS PERCENT SURVIVAL Biliary Atresia Other Chole. or Metabolic Fulminant Liver Failure Cirrhosis Other MONTHS J Pediatr. 2012;160:820 6.e3. N=632

49 Hepatology, 2008 All newborns screened in 2004 & 2005 Total of 422,273 infants Mothers sent home with stool color card Outcome: 279 cards returned mean age of 27 days 75 diagnosed with BA (1:5600) Detected with the card < 60 days 2004: 29/40 (72 %) 2005: 34/35 (97 %) Kasai operation performed < 60 days: % % %

50 Mechanism of low GGT cholestasis Retention of bile acids within hepatocytes + GGT at apical membrane Absence of bile acids within bile ducts Geier Nature Clin GI & Hep 2006

51 Mechanism of high GGT cholestasis Retention of bile acids within hepatocytes + GGT released from apical membrane into serum Presence of bile acids within bile ducts Geier Nature Clin GI & Hep 2006

52 PFIC2 (ABCB11): A Deficiency of Bile Acid Transport PL Flippase ATP8B1 PFIC1 Solute composition of human bile Bile acids Sterols ABCB11 ABCG5/G8 PFIC2 Sitosterolemia Bilirubin 1% 7 mm Phospholipids 17% 3 mm Cholesterol 3% Proteins 7% ABCB4 PFIC3 Electrolytes 31% PL Floppase ABCC2 Dubin-Johnson Bile acids 41% 30 mm Conjugated Bilirubin & other conjugates Low GGT

53 PFIC3 (ABCB4): A Deficiency of Phospholipid Transport PL Flippase ATP8B1 PFIC1 Solute composition of human bile Bile acids Sterols ABCB11 ABCG5/G8 PFIC2 Sitosterolemia Bilirubin 1% 7 mm Phospholipids 17% 3 mm Cholesterol 3% Proteins 7% ABCB4 PFIC3 Electrolytes 31% PL Floppase ABCC2 Dubin-Johnson Bile acids 41% 30 mm Conjugated Bilirubin & other conjugates High GGT

54 San Francisco ChiLDReN Childhood Liver Disease Research & Education Network SeattleBiliary Atresia Alagille Syndrome PFIC Alpha-1-Antitrypsin Mitochondrial Cystic Fibrosis (Liver) Unknown Cholestatic Disease Salt Lake Denver Chicago U Mich. (DCC) Indianapolis Toronto Pittsburgh Los Angeles Cincinnati Philadelphia Atlanta Houston

55 Take home points: Prolonged Neonatal Jaundice Jaundice in the first few days & > 2 weeks obtain fractionated bilirubin Any Direct Bilirubin level > 1.0 mg/dl is abnormal referral to hepatologist Biliary atresia: Early intervention works check stool pigment yourself The ocular bilirubinometer is problematic New easier, comprehensive, cost effective ways to make diagnoses involving genetic panels/exomes.