Neonatal Cholestasis

Especially for postgraduate students

1. Approach to Neonatal Cholestasis ANIRUDDHA GHOSH, PGT INSTITUTE OF CHILD HEALTH, KOLKATA

2. DEFINITION Neonatal cholestasis is defined as conjugated hyperbilirubinemia occurring in the newborn as a consequence of diminished bile flow . conjugated hyperbilirubinemia in a neonate is defined as serum direct/conjugated bil. Conc. > 1.0 mg/dL if the total serum bilirubin (TSB) is <5.0 mg/dL OR greater than 20% of TSB if the TSB is >5.0 mg/dL . Davis AR, Rosenthal P, Escobar GJ, Newman TB. Interpreting conjugated bilirubin levels in newborns. J Pediatr. 2011; 158: 562-5

3. EPIDEMIOLOGY Incidence : approx. 1 in every 2500 infants in the West . In India constitutes 19% to 33% of all chronic liver disease in children reporting to tertiary centres. Hepatocellular causes : 45-69% Obstructive causes : 19-55% Most common causes in 1 st month : - Biliary atresia - Neonatal hepatitis

4. THE INDIAN SCENARIO

5. ETIOLOGIES INTRAHEPATIC CAUSES EXTRAHEPATIC CAUSES

6. INTRAHEPATIC CAUSES Idiopathic Neonatal Hepatitis Sepsis : Bacterial: E.coli , Listeria , Staph. aureus TORCHES , Hep B/C, Echo virus Toxic TPN induced Drug induced Chromosomal : trisomy 21, 18. Endocrinal : Hypothyroidism Idiopathic hypopituitarism

7. METABOLIC: INTRAHEPATIC CAUSES Disorders of CARBOHYDRATE Metabolism : Galactosemia Hereditary fructose intolerance GSD type IV Disorders of AMINO ACID Metabolism : Tyrosinemia Disorders of LIPID Metabolism : Niemann -Pick disease PEROXISOMAL Disorder : Zellweger syndrome ZELLWEGER SYNDROME : MRI

8. OTHER INTRAHEPATIC CAUSES Alpha-I-antitrypsin deficiency Cystic fibrosis Neonatal iron storage disease Arteriohepatic dysplasia ( Alagille Syndrome ) Progressive Familial Intrahepatic cholestasis(PFIC) ALAGILLE SYNDROME

9. EXTRAHEPATIC CAUSES Extrahepatic biliary atresia (EHBA) Choledochal cyst Bile duct stenosis Choledocholithiasis Inspissated bile plug Spontaneous perforation of bile duct Extrinsic compression of bile duct

10. CLINICAL PRESENTATION Jaundice Hepatomegaly Acholic stools Dark urine Other signs & symptoms depend upon specific disease process Pale Stool Dark Urine

11. HISTORY

12. PHYSICAL FINDINGS

13. Never Forget To Look INTO THE NAPPY...

14. CONCEPT OF STOOL COLOUR CARD STARTED IN TAIWAN AND NOW IAP HAS PROPOSED THAT A SAME KIND OF CARD SHOULD BE INCORPORATED INTO WELL BABY CARDS OF IAP & GOVT. OF INDIA Sensitivity 89.7%, Specificity 99.9%, PPV 28.9%

15. INVESTIGATIONS Urgent Investigations: CBC with PS, CRP LFT : Total and Direct bilirubin - by diazo/van den Bergh OR Ektachem system (specific) ALT, AST- sensitive but lack specificity & prognostic value alkaline phosphatase –high in obstructions , low specificity GGT - marker/o obstruction, paradoxically low/normal in PFIC/Bile acid synth. dis . PT/APTT/INR, serum albumin – severity of hepatic dysfunction Electrolytes Blood culture Urine R/E M/E & C/S RBS (pre-feed) CXR PA

16. Further Tests.... Ophthalmological examination Blood group, DCT TORCH screening - CMV ( most common ) serum IgM not reliable pp65 antigen assay & CMV PCR more reliable & specific VDRL, Hep B/C, HIV, HSV Urine & serum bile acid assay – confirms cholestasis Might indicate inborn error of bile acid biosynthesis

17. TSH & Thyroxine levels – Hypothyroidism Serum cortisol level - Hypopituitarism Sweat chloride test & mutation analysis – Cystic Fibrosis Alpha1 antitrypsin – Assay of levels often wrong before 3 months Phenotyping of Pi is important After 3 months PAS positivity in liver biopsy sample Urine reducing substance & GALT assay – Galactosemia

18. Urinary succinylacetone & succinyl acetoacetate , assay of FAH gene – Tyrosinemia Markedly raised serum ferritin , uncorrected coagulopathy – HEMOCHROMATOSIS/ Neoatal Iron storage disease (confirmed by buccal mucosa biopsy ) Aldolase B assay in biopsy sample – Hereditary Fructose Intolerance METABOLIC SCREENING : to be done , even can be repeated/reviewed if done elsewhere and clinical suspicion persists

19. IMAGING & LIVER BIOPSY : OPTIONS AND RECOMMENDATIONS NASPGHN, 2004

20. ABDOMINAL ULTRASONOGRAPHY Advised to perform after 4 hours after fasting Give suggestive findings about surgical causes Choledochal cyst Inspissated bile plug syndrome Choledocholithiasis BILIARY ATRESIA : USG sensitivity as low as 73 % , so can’t exclude . TRIANGULAR CORD sign ( high sensitivity, specificity, but seldom seen ) Non visualisation of GB or CBD GB length < 1.9 cm Lack of smooth/complete echogenic mucosal lining with an indistinct wall Irregular/lobular contour No contraction of GB after oral feeding

21. TRIANGULAR CORD SIGN – fibrotic cyllindrical segment cranial to bifurcation of portal vein

22. LARGE CHOLEDOCOCELE - USG

23. CHOLEDOCOCELE – USG WITH COLOUR DOPPLER

24. CENTRAL DOT SIGN CAROLI’S DISEASE – CENTRAL DOT SIGN , USG with Doppler (also seen in CT scan)

25. DUODENAL ASPIRATE Sensitivity similar to scintigraphic scan Positive test : bil. Conc. of aspirate no greater than serum conc. Useful when other tests to detect biliary obstruction not available Not even mentioned in IAP 2014 guidelines

26. SCINTIGRAPHY – Mebrofenin/HIDA SCAN Nonvisualisation of radioactive dye within intestine even after 24 hrs Misses incomplete obstruction in early BA Time consuming , expensive , significant false-positive & false-negative results High sensitivity, low specificity “ generally adds little to the routine evaluation of cholestatic infant but may be of value if other means for excluding biliary obstruction are not available ” [ NASPGHN 2004 ] Priming loses valuable time hence, diagnosis is delayed “ performing a HIDA scan is optional and one may go for a liver biopsy straightaway ” [ IAP 2014 ] Useful in diagnosis of unusual causes like spontaneous perforation of bile duct.

27. NORMAL HIDA SCAN – VISUALISATION OF RADIOACTIVE MATERIAL IN DUODENAL LOOPS

28. SUSPECTED BA – NONVISUALISATION OF RADIOACTIVE MATERIAL IN GUT IS IT REALLY BILIARY ATRESIA ????

29. LIVER BIOPSY Most imp. Inv in differentiating NH & BA Accuracy of 60% to 95% Prerequisites : normal PT and platelet count Complications : - bleeding - pneumothorax - bile peritonitis

30. Neonatal Hepatitis markedly irregular size of hepatocytes Bile canaliculi reduced Kupffer cells swollen Remarkable giant cell formation Relative absence of bile duct proliferation

31. Biliary Atresia Proliferation of proximal ductules Bile plugs/lakes Extensive fibrosis Secondary paucity of portal bile ducts Intracellular and canalicular cholestasis Sensitivity : 99%. Specificity: 82-98 %.

32. ALPHA-1 ANTITRYPSIN DEFICIENCY Hepatocellular edema Giant cell transformation Necrosis Pseudoacinar rosette transformation PAS positive , diastase resistant globules in cytoplasm of periportal hepatocytes

33. 7 POINT SCORING SYSTEM USED BY HISTOPATHOLOGISTS

34. OTHER INVASIVE STUDIES Exploratory Laparotomy with Intraoperative cholangiogram (IOC) – “ remains the gold standard for diagnosis of biliary atresia ” [ IAP guidelines,2014 ] Percutaneous transhepatic cholangiography ERCP MRCP

35. THE INDIAN ALGORITHM

36. BACK IN 2000

37. 2014, IAP Guidelines On Approach To Neonatal Cholestasis

38. TREATMENT: SEVERAL ASPECTS

39. NUTRITION Continue breastfeeding Supplement MCT based feeds In older children : High energy diet : 200kcal/kg/day Carbohydrate : glucose polymers Protein: 1-2 gm/kg/day from vegetable sources 2-3% calories from essential fatty acids NG tube feeding in anorexic babies Vitamin supplementation should be continued till 3 months after resolution of jaundice

40. IAP GUIDELINES, 2014

41. For PRURITUS: 1. Ursodeoxycholic acid (UDCA): 20mg/kg/day 2. Rifampicin : 5-10 mg/kg/day 3.Phenobarbitone: 5-10 mg/kg/day Symptom chart should be maintained and followed while adding 2 nd/ 3 rd drug

42. SPECIFIC TREATMENT Special infant formula for galactosemia, fructosemia, tyrosinemia Nitisinone – 1 mg/kg/day : for Tyrosinemia Specific therapy for CMV (associated neurological involvement), herpes, toxoplasma related cholestasis Peritonitis- IV cefotaxime Septicemia – cefotaxime + amikacin/gentamicin No role of steroid in Idiopathic neonatal hepatitis Management of acute liver failure

43. SURGICAL TREATMENTS Kasai procedure for BA External & internal biliary diversion for PFIC without decompensated cirrhosis Choledochal cyst excision Cholecystectomy Liver transplantation

44. KASAI-SUZUKI OPERATION Centres where min. 6 portoenterostomies/yr done For BA not surgically correctible : Excision of atretic segment , Roux-en-Y portoenterostomy Prior to 8wks : bile flow re-established in 80-90% After 12wks : in <20% NO CUT-OFF for late referral Successful : serum bil. returns to normal “75-100 % cases had cirrhosis at laparotomy in India as avg. Age @ which medical attention is sought is 4.5 wks & arrival at specialised centre is 3.5 months”

45. LIVER TRANSPLANTATION Bil level >6mg/dL after 3 months of Kasai PE BA with hepatic decompensation (low albumin, prolonged INR, ascites) Of the 355 transplants in children performed in India till till till 2012, 30% was for BA Survival: 5-yr : 98% 10-yr: 90% LIVING DONOR TRANSPLANT

46. Key Points Promptly refer newborns with persistent jaundice >14 days with dark urine with/without pale stool for proper investigations & treatment. Consider BA as diagnosis in apparently healthy babies passing pale stools. Liver biopsy in suspected cases of BA is an emergency and it should be done & reported on urgent basis. Surgery for BA & choledochal cyst should be done before 8 wks. Diet rich in calorie, MCT and adequate protein, supplementation with fat & water soluble vitamins is mandatory.

47. Thank You & Have A Nice Day