overview of neonatal cholestasis

1. NEONATAL CHOLESTASIS
Dr. Viruvanti Dinesh

2. OBJECTIVES
• Definition
• Etiology
• Approach to a case of NC
• Specific conditions causing NC
• Management

3. DEFINITION
Conjugated hyperbilirubinemia in a neonate:
• Direct bilirubin concentration > 1.0 mg/dl if TSB < 5.0
mg/dl.
• Direct bilirubin concentration > 20% of TSB if TSB >
5.0 mg/dl.
Neonatal Cholestasis: Conjugated hyperbilirubinemia
occurring in a newborn as a consequence of diminished
bile flow.

4. INCIDENCE
• 1 in 2500 infants in the West
• In India NC constitutes 19% to 33% of all CLDs in
children reporting to tertiary care hospitals.*
*Neonatal cholestasis: Consensus statement of the pediatric gastroenterology chapter of Indian Academy of
Pediatrics 2014.

5. ETIOLOGY
Neonatal
cholestasis
Intrahepatic
disease
*Metabolic
diseases
*Congenital
infections
Idiopathic neonatal
hepatitis
Intrahepatic bile
duct paucity
Extrahepatic
disease (bile duct
injury/obstruction)
Biliary atresia

6. ETIOLOGY (n=1008)*
DISEASE GROUP CAUSES IN EACH SUBGROUP
A. Hepatocellular 53% (n=533)
• Neonatal hepatitis 43% (n=468) • Giant cell hepatitis 64%
• TORCH infections 22%
• Sepsis 8%
• Malaria, UTI etc 6%
• Metabolic 4% (n=43) • Galactosemia 35%
• A1AT deficiency 33% ??
• TPN related 19%
• Tyrosinemia 7%
• Storage disorders 4%
• Hemochromatosis 2%
• Others 2% (n=22) • Inspissated bile plug syndrome
• Recurrent intrahepatic cholestasis
• PFIC
• Hypothyroidism
*Neonatal cholestasis: Consensus statement of the pediatric
gastroenterology chapter of Indian Academy of Pediatrics, 2014.

7. ETIOLOGY (n=1008)*
DISEASE GROUP CAUSES IN EACH SUBGROUP
B. Obstructive 38% (n=383) • Biliary atresia 34%
• Choledochal cyst 4%
C. Ductal paucity 3% (n=29) • Syndromic variety 17%
• Non-Syndromic variety 83%
D. Unknown 6% (n=63)
*Neonatal cholestasis: Consensus statement of the pediatric
gastroenterology chapter of Indian Academy of Pediatrics, 2014.

8. APPROACH TO A CASE OF
NEONATAL CHOLESTASIS

9. HISTORY
1. Gestational age: Prematurity is a risk factor for neonatal hepatitis
2. SGA: Congenital infections
3. Lethargy, decreased oral acceptance: Sepsis and Metabolic.
4. Worsening of general condition after initiation of feeds:
Galactosemia
5. Bleeding manifestation: Liver dysfunction
6. Acholic stools: Biliary obstruction
7. Peculiar odour of urine: Tyrosinemia type 1 (cabbage colored
urine)
8. Consanguinity: Metabolic disorders(AR disorders)
9. Maternal history: TORCH infections

10. PHYSICAL FINDINGS
• Assessment of general health:
Sick looking- Sepsis, Metabolic, congenital
infections
• Dysmorphic features: Alagille syndrome
• Head circumference: Microcephaly- TORCH
• Eye: Chorioretinitis- TORCH, Posterior
embryotoxon and drusen: Alagille syndrome
• Hearing loss: Congenital CMV infection
• Stool inspection: Acholic stools- Biliary
obstruction

12. INVESTIGATIONS
• The principal diagnostic concern to
differentiate hepatocellular diseases from
anatomical disorders &
• diseases which are managed medically from
those requiring surgical intervention.

13. INVESTIGATIONS
1. LFT-
• Serum Bilirubin-Total & Direct
To establish cholestasis
• Prothrombin time/ International normalized ratio (INR)-
Measure severity of liver dysfunction
• Serum Transaminases -sensitive indicators of
hepatocellular injury. lack specificity.
• Alkaline phosphatase high in biliary obstruction, low
specificity
• Gamma-glutamyl transpeptidase (GGTP) marker of biliary
obstruction
 Elevated - cholestatic disorders
 Low or normal levels - progressive familial intrahepatic
cholestasis (PFIC), disorders of bile acid synthesis

14. 2. ABDOMINAL ULTASONOGRAPHY-
- Confirms existence of other surgically treatable
conditions like choledochal cyst, inspissated bile plug
syndrome & choledocholithiasis
In BA,
- triangular cord sign,
- abnormal gallbladder morphology (not visualized or
length <1.9 cm or lack of smooth/complete echogenic
mucosal lining with an indistinct wall or
irregular/lobular contour),
- no contraction of the gallbladder after oral feeding and
non-visualized common bile duct (CBD).
Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics. 2006

15. 3. HIDA SCAN
- Radioactive tracer injected into vein in patent’s arm. Tracer
travels through bloodstream to liver , where bile producing
cells take it up
- Hepatic uptake of technetium-labeled iminodiacetic acid
derivatives is normal in the patients of biliary atresia but
excretion in intestine is absent
- But absence of flow into the intestine does not confirm
atresia – can occur in severe hepatitis also.
- Delay in liver biopsy for it is not justified

16. 4. Exploratory Laparotomy and Direct
Cholangiography
- The gold standard to determine presence & site of
obstruction
5. LIVER BIOPSY
- Early recognition of BA by liver biopsy avoids
unnecessary laparotomy

17. 6. METABOLIC-
- Galactosemia
- Urine reducing substance positive, infant on
lactose feeds
- Galactose-1 phosphate uridyl transferase (GALT)
enzyme used for confirmation
- Tyrosinemia
- measurement of urinary succinylacetone, succinyl acetoacetate
or assay of FAH gene is diagnostic
Consensus statement of the Pediatric Gastroenterology Chapter, Indian Academy of Pediatrics. Indian
Pediatr. 2013

18. 7. CONGENITAL INFECTIONS-
- In TORCH, CMV is most common
-Assay of pp65 antigen and CMV polymerase chain
reaction (PCR) are specific & reliable tests
8. Haemochromatosis
- Raised serum ferritin, uncorrected coagulopathy
confirmed by buccal mucosal biopsy

19. • Conjugated hyperbilirubinemia in a newborn
is always pathological and requires evaluation.
• Any newborn with jaundice and dark urine
staining the diaper with or without pale
stools should be strongly suspected to have
NC.

21. SPECIFIC CONDITIONS CAUSING NC

22. BILIARY ATRESIA
• Idiopathic progressive obstructive cholangiopathy of
both the intra- and extra-hepatic biliary tree.
• Leads to chronic cholestasis, progressive fibrosis and
eventually biliary cirrhosis.
• Usually manifests in the first few months of life with
Jaundice, pale stools, high colored urine and
hepatomegaly
• Fatal if left untreated in first 2 years of life
• Incidence: 1:15,000*
*McKiernan PJ et al.The frequency and outcome of biliary atresia in the UK and
Ireland.Lancet.2000

23. BILIARY ATRESIA

24. BILIARY ATRESIA
• Jaundice, high colored urine and pale stools
• Firm hepatomegaly
• Clinically not sick looking
• Raised AST and ALT
• Raised GGT
• Coagulopathy responsive to Vit-K

25. BILIARY ATRESIA
• Pale stools. (Sensitivity-89.7%, Specificity-99.9%)1
• Raised GGT (GGT > 300IU/L – specificity of 98.1%)2
• USG: GB: small or not visualized, Triangular cord sign
• Liver biopsy : Sensitivity 94-97%
Triad of 1.Bile ductular proliferation, 2.Fibrosis,
3.Widening of portal tract
• Laparotomy and intra-operative cholangiography: Gold
standard
1.Chen SM et al. Screening for biliary atresia by infant stool color card in Taiwan. Pediatrics. 2006.
2.Tang KS et al. Gamma-glutamyl transferase in the diagnosis of biliary atresia. Acta Paediatr Taiwan.2007.

27. BILIARY ATRESIA
Triangular cord sign:
• It is a triangular or tubular echogenic cord of fibrous
tissue seen in the porta hepatis at ultrasonography and
is relatively specific in the diagnosis of biliary atresia.
• This sign is useful in the evaluation of infants with
cholestatic jaundice, helping for the differential
diagnosis of biliary atresia from neonatal hepatitis.
• It is defined as more than 4 mm thickness of the
echogenic anterior wall of the right portal vein (EARPV)
measured on a longitudinal ultrasound scan

30. KASAI PORTOENTEROSTOMY
- Removal of the atretic extrahepatic tissue and a Roux-
en-Y jejunal loop anastomosis to hepatic hilum.
-Half of the patients normalize their bilirubin after
Kasai’s PE performed within six months
- 20% of patients undergoing Kasai’s during infancy
survive into adulthood with their native liver
Screening and outcomes in biliary atresia: summary of a National Institutes of
Health workshop. Hepatology. 2007

31. • Outcome of Kasai portoenterostomy(PE) is directly
related to age of surgery & expertise of treating unit
• PE when performed earlier than 60 days of age
established adequate bile flow in 64.7% of patients
compared with 31.8% when performed later
Impact of age at Kasai operation on its results in late childhood and
adolescence: a rational basis for biliary atresia screening. Pediatrics.
2009

32. IDIOPATHIC NEONATAL HEPATITIS
• AKA Giant cell hepatitis
• No cause identified
• More common in Preterms.
• Characterized by lobular disarray, ballooning of
hepatocytes, focal hepatic necrosis and Giant cell
transformation.
• Sporadic and Familial types
• Sporadic: good prognosis, 90% resolution by 1yr of
age
• Familial: relatively poor prognosis.
• Treatment: Supportive.

34. GALACTOSEMIA
• AR
• Deficiency of Galcatose-1-phosphate uridyl transferase (GALT)
• Accumulation of toxic metabolites in liver, kidney and brain
• Presentation at 1-2 wks of life, after ingestion of milk.
• Jaundice, Hepatosplenomegaly, liver dysfunction,
hypoglycemia, Renal tubular dysfunction, hypotonia, Nuclear
cataract, E.coli sepsis.
• If not treated, progressive liver damage leading to cirrhosis
and death
• Screening test: Non glucose reducing substance in the urine
• Diagnostic test: Measurement of GALT activity in RBCs
• Treatment: Lifelong restriction of galactose or lactose
containing foods

35. PFIC
• Progressive Familial Intrahepatic Cholestasis
• AR inheritence
• PFIC-1 : FIC-1 gene mutation, encodes p-type
ATPase, involved in aminophospholipid transport,
Chr18q
• PFIC-2: BSEP mutation (AKA SPGP), involved in
ATP dependent canalicular bile acid transport,
Chr2q
• PFIC-3: MDR3 mutation , encodes biliary
phospholipid transporter

36. PFIC contd..
PFIC-1: Systemic involvement- Liver, pancreas,
diarrhoea.
• Normal or Low GGT
• Liver biopsy: Paucity of interlobular bile ducts
• Supportive care
• Cirrhosis in first decade of life
• Liver transplant in second decade decade

37. PFIC contd..
PFIC-2: Liver specific involvement
• Normal or Low GGT
• Liver biopsy: Giant cell hepatitis, canalicular
and hepatocellular steatosis.
• Supportive care
• Worse prognosis
• Liver transplant in first decade of life

38. PFIC contd..
PFIC-3: Presentation in early adulthood
• H/O cholestasis of pregnancy in the mother
• Markedly elevated GGT
• Liver biopsy may mimic biliary atresia
• Supportive care, UDCA.
• Liver transplantation in UDCA unresponsive
cases.

39. CONGENITAL CMV INFECTION
• Petechiae, Hepatosplenomegaly and jaundice are the most
common presenting features (60-80% of the cases)
• Microcephaly with or without cerebral calcifications, IUGR
and prematurirty (30-50% of the cases)
• Important cause of SNHL
• CMV causes intrahepatic bile duct destruction and paucity.
• Serum IgM level: unreliable for diagnosis and should not be
used.
• PP65 antigen assay and Urinary CMV PCR are more reliable
• IV Gancyclovir @ 6mg/kg/day in 2 divided doses for 42days
Or Oral Valgancyclovir @ 16mg/kg/dose BD

40. ALAGILLE SYNDROME
• AD Inheritence
• JAG-1 gene mutation on Chr12p
• This gene encodes a ligand for Notch signalling pathway
• Chronic cholestasis, Characteristic facies( broad forehead, small
pointed chin, saddle nose with bulbous tip, hypertelorism), Cardiac
abnormalities, Ocular abnormalities (posterior embryotoxon, drusen),
Skeletal abnormalities (butterfly vertebrae, curved phalanges, short
ulna), Renal abnormalities.
• Usually present as Neonatal cholestasis.
• Characteristic facies may not be evident at the neonatal period
• Liver biopsy: bile duct paucity
• Supportive management
• 50% of the cases: Cirrhosis by the end of 1st decade, Liver transplant.

42. HEREDITARY TYROSINEMIA-1
• Mutation in the gene encoding FAA hydrolase

43. HEREDITARY TYROSINEMIA-1
• Accumulation of FAA and MAA
• FAA and MAA get converted to Succinyl acetoacetate,
which gets accumulated in liver and kidneys
• Neonatal cholestasis in 1/3rd of the cases
• Vomiting, diarrhoea, cabbage like odour,
hepatomegaly, coagulopathy, hypoglycemia
• Acute liver failure
• Cirrhosis
• 1/3rd of the cases which survive beyond 10 years
develop HCC

44. HEREDITARY TYROSINEMIA-1
• Screening : high Alpha-fetoprotein
• Confirmation: Increased urinary succinylacetone
• Treatment:
1. Dietary restriction of Phenylalanine and tyrosine
2. Nitisinone (NTBT/Orfadin): inhibitor of PHPP
Dioxygenase. Started at 1mg/kg/day PO in 2 divided
doses may be increased to 1.5mg/kg/day
3. Liver transplant: failure of pharmacotherapy or
when HCC is suspected.

45. NEONATAL HEMOCHROMATOSIS
• Newly recognized and rare syndrome
• ?? Gestational alloimmune disease
• Iron deposition in liver, acinar cells of pancreas,
minor salivary glands, proximal renal tubules,
adrenal cortex, thyroid and myocardium
• ALF/ congenital cirrhosis
• Oligohydramnios, placental oedema, IUGR
• Hyperbilirubinemia, Coagulopathy,
Hypoalbuminemia, Ascitis and Splenomegaly

46. NEONATAL HEMOCHROMATOSIS
• Low to normal transaminases
• Hypoalbuminemia, thrombocytopenia
• Screening: High ferritin, Low serum
transferrin, high transferrin saturation
• Confirmation: Lip biopsy showing Iron
deposition in minor salivary glands or MRI
pancreas showing low signal intensity on T2W

47. NEONATAL HEMOCHROMATOSIS
TREATMENT:
• IVIG
• DVET
• Antioxidant cocktail:
1. N-acetyl cysteine: 140 mg/kg PO, then 70mg/kg 4 hrly for 19 doses
2. Selenium: 2-3 mcg/kg/day IV over 24hrs
3. Alpha tocopheryl PEG succinate: 20-30U/kg/day PO
4. PGE1: 0.4-0.6 mcg/kg/hr IV for 2-3 wks
5. Desferrioxamine: 30mg/kg/day IV infused over 8hrs, until Ferritin levels < 500mcg/L
• At-risk pregnancies(previous child Neonatal
hemochromatosis) : IVIG at 1g/kg IV given weekly to the
pregnant woman starting from 18th week of gestation.
• Liver transplant if no response

48. MANAGEMENT

49. GENERAL MANAGEMENT
• Nutritional support: NC children are
underweight and will need nutritional
support. Calorie requirement is 125% of the
RDA
• Breast feeding should be encouraged and
1-2ml/kg/day MCT oil should be administered
in 2-4 divided dosed in EBM

51. • PRURITIS:
1. UDCA – 20mg/kg/day
2. Rifampicin- 5-10mg/kg/day
3. Phenobarbitone- 5-10mg/kg/day

52. THANK YOU