This document discusses neonatal cholestasis. It defines neonatal cholestasis and provides the incidence. The causes are classified as intrahepatic or extrahepatic. Common intrahepatic etiologies include idiopathic neonatal hepatitis, genetic disorders, infections, and metabolic diseases. Extrahepatic causes include biliary atresia and choledochal cyst. Evaluation involves history, physical exam, lab tests, imaging like ultrasound and HIDA scan, and potentially liver biopsy. Treatment depends on the underlying cause but may include nutritional support, medications, surgery like Kasai procedure, or liver transplantation.

1. NEONATAL CHOLESTASISNEONATAL CHOLESTASIS
Dr Surya Kumar

2. OBJECTIVESOBJECTIVES
 To know when cholestatic liver disease should be
excluded in the diagnosis of an infant who has jaundice.
 How to evaluate a neonate with conjugated
hyperbilirubinemia.
 Know the therapeutic management of neonates with
cholestasis.
 Understand the differential diagnosis for neonatal
cholestasis.

3. DEFINITIONSDEFINITIONS
NASPGHAN Definition :
Prolonged conjugated hyperbilirubinemia that
occurs in the newborn period with conjugated
bilirubin concentration >1 mg% if the total
bilirubin <5.0mg% or >20% of the total
bilirubin if the total bilirubin >5.0mg%.
(Moyer et al J PEDIATR GASTROENTEROL NUTR 2004;39:115)

4. IAP Definition:
Neonatal cholestasis is defined as conjugated
hyperbilirubinemia > 1.5-2 mg% in a newborn/
infant with passage of high coloured urine with
or without acholic stools.
(Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851)

5. Incidence:Incidence:
Constitutes 30% of hepatobiliary disorders in
india.( Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851)
Affects one in 2500 live births.

6. ETIOLOGIESETIOLOGIES
Intrahepatic causes
Extrahepatic causes

7. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Hepatocellular causes Bile duct injury
(Neonatal hepatitis)
Idiopathic: INH
Toxic Intrahepatic bile duct
Genetic/Chromosomal hypoplasia or paucity
Infectious
Metabolic
Miscellaneous

8. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Idiopathic Neonatal Hepatitis
Toxic
◦ TPN-associated cholestasis
◦ Drug-induced cholestasis
Genetic/Chromosomal
◦ Trisomy 18
◦ Trisomy 21

9. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Infectious
◦ Bacterial sepsis (E. coli, Listeriosis, Staph.
aureus)
◦ TORCHES
◦ Hepatitis B and C
◦ Echo virus

10. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic
◦ Disorders of Carbohydrate Metabolism
 Galactosemia
 Fructosemia
 Glycogen Storage Disease Type IV
◦ Disorders of Amino Acid Metabolism
 Tyrosinemia
 Hypermethioninemia

11. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic (cont.)
◦ Disorders of Lipid Metabolism
 Niemann-Pick disease
 Gaucher disease
◦ Disorders of Bile Acid Metabolism
 3B-hydroxysteroid dehydrogenase/isomerase
 Trihydroxycoprostanic acidemia

12. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic (cont.)
◦ Peroxisomal Disorders
 Zellweger syndrome
◦ Endocrine Disorders
 Hypothyroidism
 Idiopathic hypopituitarism

13. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Metabolic (cont.)
◦ Miscellaneous Metabolic Disorders
 Alpha-1-antitrypsin deficiency
 Cystic fibrosis
 Neonatal iron storage disease

14. INTRAHEPATIC ETIOLOGIESINTRAHEPATIC ETIOLOGIES
Miscellaneous
◦ Arteriohepatic dysplasia (Alagille syndrome)
◦ Nonsyndromic paucity of intrahepatic bile
ducts
◦ Caroli’s disease
◦ Byler’s disease
◦ Congenital hepatic fibrosis

15. EXTRAHEPATIC ETIOLOGIESEXTRAHEPATIC ETIOLOGIES
Extrahepatic biliary atresia
Choledochal cyst
Bile duct stenosis
Spontaneous perforation of the bile duct
Cholelithiasis
Inspissated bile/mucus plug
Extrinsic compression of the bile duct

16. (Consensus report on neonatal cholestasis syndrome,INDIAN PEDIATRICS 2000;37:845-851)

17. CLINICAL PRESENTATIONCLINICAL PRESENTATION
Jaundice
Scleral icterus
Hepatomegaly
Acholic stools
Dark urine
Other signs and symptoms depend on specific
disease process

18. GOALS OF TIMELY EVALUATIONGOALS OF TIMELY EVALUATION
Diagnose and treat known medical and/or life-
threatening conditions.
Identify disorders amenable to surgical therapy
within an appropriate time-frame.
Avoid surgical intervention in intrahepatic
diseases.

19. APPRACH TO DIAGNOSIS- IAPAPPRACH TO DIAGNOSIS- IAP

20. Approach to diagnosis: NASPGHANApproach to diagnosis: NASPGHAN

23. History:History:

24. History (contd.)History (contd.)

25. Physical examination:Physical examination:

26. Physical exam (contd)Physical exam (contd)

27. Investigations:Investigations:
Urgent investigations:
◦ CBC with PS,
◦ LFT: Total and direct bilirubin, SGOT, SGPT,
alkaline phosphatase, GGT,PT/PTTK.
◦ Electrolytes.
◦ Blood culutre.
◦ Urine culture, routine microscopy.
◦ RBS (pre-feed).
◦ Ascitic tap (if ascitis).

28. Further tests:Further tests:
Ophthalmologic examination.
Serum/ urine bile acid levels.
DCT and coomb’s test.
Cord blood IGM.
FTA-ABS, CFT for rubella, CMV, herpes. Sweat
chloride.
HBsAG in mother and infant.
Liver biopsy:
light microscopy.
specific enzyme assay.

29. • TORCH,VDRL, Hepatitis B/C, HIV
• T4,TSH
• Serum cortisol
• Alfa -1 AT levels and phenotype
• Galactose -1 Phosphate Uridyl transferase
(to r/o galactosemia)
• Urinary succinyl acetone (to r/o
tyrosinemia)
• Cholesterol, triglycerides
• S. iron and ferritin levels (to r/o neonatal
hemachromatosis)

30. Radiological evaluationRadiological evaluation
Ultrasonography
 Excludes choledochal cyst, dilated CBD.
 Findings s/o BA:
1. GB length (<1.5cm long/small lumen)
2. GB contraction [CI<86% ± 18% (mean ± SD) in 6-week-
oldinfants and 67% ± 42% in 4-month-old infants]
3. Triangular cord sign: a triangular- or tubular-shaped
echogenic densitythat was located immediately cranial to
the portal vein bifurcation andwas 3 mm or more thick
(Kanegawa et al. AJR 2003;181:1387)

32. Sonogram illustrates method of measuring gallbladder length (long
arrow) and width (short arrow). These measurements were obtained
using maximal longitudinal image.

33. 15-day-old female neonate with unknown cause of infantile
cholestasis. Sonogram reveals tubular echogenic cord (arrows).
"Triangular cord" was 0.3–0.4 cm wide and 1.3–1.6 cm long.

34. Hepatobiliary Scintigraphy:Hepatobiliary Scintigraphy:
Tc labelled IDA dyes used.
Depends on hepatocellular function & patency
of biliary tract.
Neonatal Hepatitis: delayed uptake, n.
excretion.
Biliary Atresia: normal uptake, absent
excretion.
Sensitive (97%) not specific (80%) for EHBA.
Phenobarbitol priming (5mg/kg x 5d)

35. Gayatri devi 2.5 m/F(2000) CHOLEDOCHAL CYST

36. Invasive studiesInvasive studies
◦ Duodenal intubation
◦ Percutaneous liver biopsy
◦ Percutaneous transhepatic cholangiography
◦ ERCP
◦ MRCP
◦ Exploratory laparotomy with intraoperative
cholangiogram

38. ERCP imageERCP image

39. intra- and extrahepatic (c) biliary dilatation, as well as focal
intrahepatic biliary cystic dilatations (arrows). g = gallbladder.

40. Percutaneous transhepaticPercutaneous transhepatic
cholangiographycholangiography

41. LIVER BIOPSY:LIVER BIOPSY:
Most imp. Inv in differentiating NH and BA.
Accuracy of 83% to 97%.
Prerequisites: Normal PT & platelet count.
Complications:
Bleeding
Bile peritonitis
Pneumothorax

42. F/o neonatal hepatitis:F/o neonatal hepatitis:
Marked irregularities in size of hepatocytes.
Bile canaliculi reduced.
Kupffer cells swollen.
Extramedullary hematopoiesis.
Relative absence of bile duct proliferation.

43. f/o biliary atresia:f/o biliary atresia:
Proliferation of proximal ductules.
Bile plugs.
Portal tract lymphatics and arterioles dilated.
Secondary paucity of portal bile ducts.
Intracellular and canalicular cholestasis.

44. Indications for laparotomy-IAPIndications for laparotomy-IAP
1) Acholic stools & liver bopsy-BA
2) Biopsy equivocal but acholic stools,
intrahepatic causes r/o, non excreting HIDA.
3) Biopsy equivocal,acholic stools, baby 7 wks &
lap and peroperative cholangiogram.
4) Biopsy equivocal, acholic stools, ERCP atresia.

45. EXTRAHEPATIC BILIARY ATRESIAEXTRAHEPATIC BILIARY ATRESIA
Generally acholic stools with onset at about 2
weeks-old
Average birth weight
Hepatomegaly with firm to hard consistency
Female predominance
No well-documented familial cases

46. EXTRAHEPATIC BILIARY ATRESIAEXTRAHEPATIC BILIARY ATRESIA
Increased incidence of polysplenia syndrome
and intra-abdominal vascular anomalies
Normal uptake on radionucleotide scan with
absent excretion
Biopsy shows bile duct proliferation, bile plugs,
portal or perilobular fibrosis and edema, and
intact lobular structure

47. IDIOPATHIC NEONATAL HEPATITISIDIOPATHIC NEONATAL HEPATITIS
Generally normal stools or acholic stools with
onset at one month-old
Low birth weight
Normal liver on exam or hepatomegaly with
normal to firm consistency
Male predominance
Familial cases (15-20%)

48. IDIOPATHIC NEONATAL HEPATITISIDIOPATHIC NEONATAL HEPATITIS
Impaired uptake on radionucleotide scan with
normal excretion
Biopsy shows intralobular inflammation with
focal hepatocellular necrosis and disruption of
the hepatic architecture. No alteration of the
bile ducts. Giant cell transformation occurs
but is non-specific.

49. ALPHA-1-ANTITRYPSIN DEFICIENCYALPHA-1-ANTITRYPSIN DEFICIENCY
Alpha-1-antitrypsin makes up 90% of alpha-1-
globulin fraction
Associated with PiZZ (about 10-20% will have
liver disease) and rarely with PiSZ and PiZ-null
phenotypes
Biopsy shows hepatocellular edema, giant cell
transformation, necrosis, and pseudoacinar
transformation.

50. ALPHA-1-ANTITRYPSIN DEFICIENCYALPHA-1-ANTITRYPSIN DEFICIENCY
Biopsy also shows accumulation of PAS-
positive, diastase-resistant globules in the
cytoplasm of periportal hepatocytes.
Varying degrees of fibrosis correlate with
disease prognosis.

51. INTRAHEPATIC CHOLESTASISINTRAHEPATIC CHOLESTASIS
SYNDROMESSYNDROMES
Includes several diagnostic entities.
Biopsies show cholestasis. May show paucity
of intrahepatic bile ducts, giant cell
transformation, and/or fibrosis.

52. TREATMENTTREATMENT
Surgical
◦ Kasai procedure for biliary atresia
◦ Limited bile duct resection and re-anastomosis
◦ Choledochal cyst excision
◦ Cholecystectomy
◦ Liver transplantation

53. KASAI PROCEDUREKASAI PROCEDURE
Performed for biliary atresia that is not
surgically correctable with excision of a distal
atretic segment.
Roux-en-Y portoenterostomy
Bile flow re-established in 80-90% if performed
prior to 8 weeks-old.
Bile flow re-established in less than 20% if
performed after 12 weeks-old

54. KASAI PROCEDUREKASAI PROCEDURE
Success of the operation is dependent on the
presence and size of ductal remnants, the
extent of the intrahepatic disease, and the
experience of the surgeon.
Complications are ascending cholangitis and
reobstruction as well as failure to re-establish
bile flow.

56. TREATMENTTREATMENT
Medical management
◦ Nutritional support
◦ Treatment of pruritus
◦ Choleretics and bile acid-binders
◦ Management of portal hypertension and its
consequences

57. IMPAIRMENT MANAGEMENT
(NASPGHAN)
MANAGEMENT
IAP
Malabsorption Medium chain TGs given Medium chain TGs given,breast
feeding cont, 200 Kcal/kg/d,1-2
gm protein/kg/d
Fat soluble vit malabsorption
Vit A deficiency 10,000-15,000 IU/d AQUASOL-
A
50,000 IU i.m –diagnosis
10,000 IU monthly
Vit E deficiency 50-400 IU/d; oral alfa tocopherol 50-200 mg/d orally
Vit D deficiency 5000 -8000IU/d of D2
3-5 mcg/kg/d of 25 HCC
30,000 IU i.m –diagnosis
& monthly
Vit K deficiency 2.5 -5.0 mg alternate day as
water soluble derivative of
menadione.
5 mg/d im x3 days,5 mg wkly.
Perform PT monthly.
Microutrient deficiency Ca, P, Zn supplementation Ca, P, Zn supplementation
Water soluble Vit def. 2 times RDA supplementation 2-5 times RDA supplementation

58. TREATMENTTREATMENT
Treatment of pruritus
◦ Bile acid-binders: cholestyramine (4-8 g/day)
◦ Ursodeoxycholic acid (15-20 mg/kg/day)
◦ Phenobarbital (5mg/kg/day)
◦ Rifampicin (10 mg/day)
◦ Terfenadine (1-3 mg/kg/day)
◦ Photothearpy with UV/ Infrared rays x 3-10 min/day

59. TREATMENTTREATMENT
Management of portal hypertension and its
consequences
◦ Variceal bleeding
 Fluid rescuscitation
 Blood products
 Sclerotherapy
 Balloon tamponade
 Portovenous shunting
 Propanolol

60. TREATMENTTREATMENT
Management of portal hypertension and its
consequences (cont.)
◦ Ascites
 Sodium restriction
 Diuretics: spironolactone, furosemide
 Albumin
 Paracentesis
◦ Thrombocytopenia managed with platelet infusions
when clinically indicated

61. LIVER TRANSPLANTATIONLIVER TRANSPLANTATION
Biliary atresia is the most common indication
for transplant and may be the initial treatment
when detected late or may be used as a salvage
procedure for a failed Kasai.
Used early in cases of tyrosinemia.
Cost: In excess of 100,000 $
Only few centres in india

62. Liver transplantationLiver transplantation
Indications:
1)Decompensated liver disease(ascites and/or
encephelopathy) .
2)Failed portoenterostomy.
• 1-year survival rate- 85-90%
• 5-8 year survival rate- 75-80%
• 1/3 to 1/2patients are of Biliary Atresia.(Whitington et al SEMIN LIVER
DIS1994;14:303-317)

63. PrognosisPrognosis
Biliary Atresia:
• Age(< 8 wks): the single most important
determinant in successful management of BA.
• Of pts. Undergoing Kasai’s procedure,80%
jaundice free if done before 60 days, as against
25-35% of infants operated later on.(Mieli –Vergani et al. LANCET 1989;1:421-423)
Neonatal Hepatitis:
• No indicators to predict prognosis.

64. Long term outcomeLong term outcome
Biliary Atresia:
Mean survival in untreated pts. :19 mths(Hays et al. SURGERY 1963;54:373-375)
3-year survival : <10% (Karrer et al J PEDIATR SURG 1990;25:1076-1080)
Neonatal Hepatitis:
Upto 60% of pts.with idiopathis NH recover
completely without any specific therapy.
Upto 10% die acutely of bleeding manifetstations
or fulminant hepatic failure.
 30 % progress to liver cirrhosis and death due to
CLD.

65. Key messagesKey messages
Refer early to specialised centres.
Congenital infection is the commonest cause of
cholestatic jaundice in infants.
Percutaneous liver biopsy is safe and most
useful for diagnosis.
Surgery for BA and choledochal cyst should be
done before 2 months of age.

66. ThankYou