1. DIRECT HYPERBILIRUBINEMIA
IN NEONATES
(NEONATAL CHOLESTASIS)
By: Dr Naved Akhter
JUNE 6, 2014

2. DIRECT HYPERBILIRUBINEMIA
• Conjugated hyperbilirubinemia in a neonate is defined as a serum
direct/conjugated bilirubin concentrationt greater than 1.0 mg/dl,if the TSB is
<5.0mg/dl. or
Greater than 20 % of TSB if the TSB is >5.0mg/dl.
(ref. IAP,INDIAN PEDIATRICS VOLUME 51__MARCH 15, 2014 & CLOHARTY)
• Conjugated hyperbilirubinemia is defined biochemically as a conjugated
bilirubin level of >2mg/dL and >20% of the total bilirubin.
(REF DOI: 10.1542/pir.33-7-29Pediatrics in Review 2012;33;29 1,AAP)
NEONATAL CHOLESTASIS
• Neonatal cholestasis is defined as conjugated hyperbilirubinemia occuring in
the newborn as a consequence of diminished bile flow, with the passage of
high coloured urine with or without acholic stools.
( REF.INDIAN PEDIATRICS VOLUME 51__MARCH 15, 2014 )

3. Incidence
• In India it constitutes 19%-33% of all chronic liver disease in children
reporting to tertiary care hospitals.
• Affects 1 in 2500 live births.
( REF.INDIAN PEDIATRICS VOLUME 51__MARCH 15, 2014 )

4. ETIOLOGIES
• Intrahepatic causes
• Extrahepatic causes

5. Biliary drainage

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

8. Intrahepatic disorders
• Idiopathic
Idiopathic Neonatal Hepatitis.
• Intrahepatic cholestasis,persistent
Severe intrahepatic cholestasis with progressive hepatocellular
disease.
Alagille syndrome(syndromic paucity of the intrahepatic bile
ducts,arteriohepatic dysplasia)
Nonsyndromic paucity of the intrahepatic bile ducts.
• Intrahepatic cholestasis,recurrent
BRIC Benign recurrent intrahepatic cholestasis.
Hereditary cholestasis with lymhedema(Aagenaes syndrome)
• Anatomic
Congenital hepatic fibrosis or infantile polycystic disease(liver &
kidney)
Caroli disease

9. • Toxic
– TPN-associated cholestasis(>2 weeks) generally in LBW infants.
It occurs due to parenteral use of lipids.Sepsis & ischemic necrosis may also
cause cholestasis.
– Drug-induced cholestasis
• Genetic/Chromosomal
– Trisomy 18,Trisomy 21
• Infectious
– Bacterial sepsis (E. coli,Staph. Aureus,listeria,tuberculosis,group B beta
hemolytic streptococcus,syphillis,HIV)
– Hepatitis B and C,rubella,herpes,EBV,coxsackie
virus,adenovirus,echoviruses 14 & 19
• Parasitic : toxoplasma

10. • Metabolic
– Disorders of Carbohydrate Metabolism
• Galactosemia
• Fructosemia
• Glycogen Storage Disease Type IV
– Disorders of Amino Acid Metabolism
• Tyrosinemia
• Hypermethioninemia
– Disorders of Lipid Metabolism
• Niemann-Pick disease
• Gaucher disease
– Disorders of Bile Acid Metabolism
• 3B-hydroxysteroid dehydrogenase/isomerase
• Trihydroxycoprostanic acidemia

11. Peroxisomal Disorders
• Zellweger syndrom
Disorders of bile acid transport.
• Rotor syndrome
• Dubin johnson syndrome
• Mitochondrial hepatopathie
Endocrine Disorders
• Hypothyroidism
• Idiopathic Hypopituitarism.
Systemic disorders
• Shock
• Heart failure
• Neonatal lupus erythematosus.

12. Miscellaneous
• Haemophagocytic lymphohistiocytosis
• Neonatal leukemia
• Erythroblastosis foetalis.
• Intestinal obstruction.
• ARC syndrome(arthrogryposis,renal tubular dysfunction and
cholestasis)
• GENETIC : PFIC (Progressive familial intrahepatic cholestasis)
• PFIC type1(Byler’s disease),type 2 and type 3.

13. EXTRAHEPATIC CAUSES
• Biliary atresia: accounting for 40% to 50% of all cases.
(ref. DOI: 10.1542/pir.33-7-291Pediatrics in Review 2012;33;291AAP)
• Choledochal cyst
• Bile duct stenosis
• Spontaneous perforation of the bile duct
• Cholelithiasis
• Inspissated bile/mucus plug
• Extrinsic compression of the bile duct.
• Neonatal sclerosing cholangitis.

14. Events that leads to cholestasis

15. • The pathophysiology of acquired BA is that of a brisk inflammatory response
involving both the intra and extrahepatic bile ducts.
• The ducts are destroyed gradually and replaced with fibrous scar tissue.
• The lumen of the bile duct is eventually obliterated and normal bile flow is
impaired,leading to cholestasis

16. CONSEQUENCES OF PROLONGED CHOLESTASIS

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

18. History

20. Physical examination

23. Investigations
Urgent investigations:
– CBC with PS.
– LFT ( to know the hepatic dysfunction)
Total Bilirubin(0.2 -1mg%) and direct bilirubin(0.0-0.4mg%),ALT(5-35U/L),
AST(5-40U/L), alkaline phosphatase(25-250U/L).
– GGT (elevated level demonstrate bile duct damage and BA)(8-78U/L)
– PT/PTT/INR(demonstrate the hepatic biosynthesis capacity)
– Electrolytes.
– Blood culutre.
– Urine culture, routine microscopy.
– RBS (pre-feed).
– Ascitic tap (if ascitis).

24. Further test
• Ophthalmologic examination.
• Serum/ urine bile acid levels
• DCT and coomb’s test.
• Cord blood IgM.
• Sweat chloride.(cystic fibrosis)
• HBsAG in mother and infant.
• Liver biopsy:
• light microscopy.
• specific enzyme assay.

25. • TORCH, VDRL, Hepatitis B/C, HIV,FTA-ABS, CFT for rubella, CMV, herpes.(t/r/o
infection)
• T4, TSH
• Serum cortisol
• Alfa -1 AT levels and phenotype
• Galactose -1 Phosphate Uridyl transferase
(to r/o galactosemia) & urine reducing substance(elevated in galactocemia).
• Urinary succinyl acetone (to r/o tyrosinemia)
• Cholesterol, triglycerides(elevated in alagille syndrome)
• S. iron and ferritin levels (to r/o neonatal hemachromatosis)

26. Algorithmic approach to differentiate EHBA from NH
(<60 days)

27. Approach to late presentation of EHBA
(>60 days of life)

28. GOALS OF TIMELY EVALUATION

29. Diagnostic algorithm for Mx of Neonatal Cholestasis

30. Dx algorithm to help in the Mx of Neonatal Cholestasis

31. Approach to diagnosis: NASPGHAN

34. Radiological evaluation
Ultrasonography
 Excludes choledochal cyst, dilated CBD.
 Findings s/o BA:
1. GB length (<1.5cm long/small lumen)
2. GB contraction .
3. Triangular cord sign: a triangular- or tubular-shaped echogenic
density that was located immediately cranial to the portal vein
bifurcation and is 3mm or more thick.

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

36. 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.

37. Hepatobiliary Scintigraphy
• Technetium ,99Tc –disopropylliminodiacetic acid(DISIDA)dyes used.
• If Tc not available,I -131 rose bengal fecal excretion test may be used.
• A nasoduodenal tube can be passed and fluid collected in 2-hrs aliquots for 24
hrs.
• If there is no bile treat with phenobarbital,5mg/kg/day for 7 days( to enhance
the isotope excretion)and repeat the duodenal fluid collection.
• Depends on hepatocellular function & patency of biliary tract.
• Neonatal Hepatitis: delayed uptake, normal excretion.
• Biliary Atresia: normal uptake, absent excretion.
• Sensitive (97%) not specific (80%) for EHBA.

38. • If no extrahepatic obstruction,the child may be observed with careful
follow up.
• If extrahepatic obstruction,the baby will need an exploratory
laparotomy,cholangiogram and liver biopsy.

39. Invasive studies
– Duodenal intubation
– Percutaneous liver biopsy
– Percutaneous transhepatic cholangiography or intraoperative
cholangiogram: GOLD standard in the dx of Biliary atresia,a KASAI
procedure is indicated if contrast is unable to fill the biliary tract or reach
the intestine.
– ERCP: Endoscopic Retrograde Cholangiopancreatography.
– MRCP:Magnetic Resonance Cholangiopancreatography.

40. Indications 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.

41. ERCP image

42. 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
• EHBA is characterized by presence of proliferation of
interlobular ducts, plugged with bile casts and portal tracts
show fibrosis.
• The liver parenchyma may be normal, or may show
intrahepatocytic or canalicular cholestasis.

43. • But in advanced cases after 2 months of life there may be full-fledged
changes of secondary biliary cirrhosis.
• In neonatal hepatitis there is marked parenchymal injury suggesting
focal necrosis, ballooning degeneration,giant cell transformation ,
inflammatory infiltrate, pseudoacinar formation and portal tract may
show mild portal triaditis.
There is no fibrosis until the disease is chronic
• Diagnosis of PIBD can be made on histology if the ratio of presence of
bile ducts to portal tracts is less than 0.4 to 0.6. But liver biopsy should
contain minimum
• 5 portal tracts to make the diagnosis of PIBD in a biopsy specimen.

44. F/O Neonatal hepatitis
• Marked irregularities in size of hepatocytes.
• Bile canaliculi reduced.
• Kupffer cells swollen.
• Extramedullary hematopoiesis.
• Relative absence of bile duct proliferation.

45. 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.

46. EXTRAHEPATIC 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.
• 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 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%).
• FINDINGS
• 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.

48. ALPHA-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.
• Biopsy also shows accumulation of PAS-positive, diastase-resistant
globules in the cytoplasm of periportal hepatocytes.
• Varying degrees of fibrosis correlate with disease prognosis.

49. INTRAHEPATIC CHOLESTASIS SYNDROMES
• Includes several diagnostic entities.
• Biopsies show cholestasis.
• May show paucity of intrahepatic bile ducts, giant cell
transformation, and/or fibrosis.

50. MANAGEMENT OF NEONATAL CHOLESTASIS
• Medical management.
• Surgical management.
• First goal in managing children with cholestasis is the recognition of
diseases amenable to specific medical therapy
(eg.galactosemia,tyrosenemia,hypothyroidism) or early surgical
intervention(biliary atresia,choledochal cyst).

51. TREATMENT
• Medical management
– Nutritional support.
– Treatment of pruritus.
– Choleretics and bile acid-binders.
– Management of portal hypertension and its consequences.

52. 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 50,000 IU i.m or
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
Or 400-1200 IU/day
Vit K deficiency 2.5 -5.0 mg alternate day. 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

53. OTHER VITAMIN AND MINERAL
REQUIREMENTS IN INFANTS WITH CHOLESTASIS
• Water soluble vitamins Oral 1-2 times the RDA
• Calcium** Oral 20-100 mg/kg/d
• Phosphorus Oral 25-50 mg/kg/d
• Zinc Oral 1 mg/kg/d
• Magnesium Oral 1-2 mEq/kg/d
Intravenous 0.3-0.5 mEq/ kg over3 hours of
50% solution
• Elemental iron Oral 5-6 mg/kg/d

54. TREATMENT
• 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

55. TREATMENT
• Management of portal hypertension and its consequences
– Variceal bleeding
• Fluid rescuscitation
• Blood products
• Sclerotherapy
• Balloon tamponade
• Portovenous shunting
– Ascites
• Sodium restriction
• Diuretics: spironolactone, furosemide
• Albumin
• Paracentesis
– Thrombocytopenia managed with platelet infusions when clinically
indicated

56. TREATMENT
• Surgical
– Kasai procedure for biliary atresia
– Limited bile duct resection and re-anastomosis
– Choledochal cyst excision
– Cholecystectomy
– Liver transplantation

57. KASAI 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.

58. • 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 re obstruction
as well as failure to re-establish
bile flow.

59. LIVER 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 Rs 15,00,000 to Rs 20,00,000
• Only few centres in india.
Indications:
• Decompensated liver disease(ascites and/or encephelopathy) .
• 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)

60. Prognosis
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.

61. Long 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.

62. Key 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.

63. Thank You