1) Neonatal cholestasis is defined as conjugated hyperbilirubinemia in newborns caused by diminished bile flow. The document discusses the definition, epidemiology, etiologies, clinical presentation, investigations and management of neonatal cholestasis. 2) The causes of neonatal cholestasis include intrahepatic causes like infections, metabolic disorders, and extrahepatic causes like biliary atresia and choledochal cysts. The most common causes of cholestasis in the first month are biliary atresia and neonatal hepatitis. 3) Evaluation involves history, physical exam, initial lab tests and further tests depending on the findings. Imaging like ultrasound

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 1st 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

10. 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

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

12. HISTORY

13. PHYSICAL
FINDINGS

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

15. 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%

16. INVESTIGATIONS
• Urgent Investigations:
1. CBC with PS, CRP
2. 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
1. Electrolytes
2. Blood culture
3. Urine R/E M/E & C/S
4. RBS (pre-feed)
5. CXR PA

17. 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

18.  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

19.  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

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

21. 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

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

23. LARGE CHOLEDOCOCELE - USG

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. 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

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

30. 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 %.

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

32. 7 POINT SCORING
SYSTEM USED BY
HISTOPATHOLOGISTS

33. 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

34. BACK
IN
2000

35. 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 2nd/ 3rd 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