a PPT on Neonatal Cholestasis presented by Dr Ajay in seminar hall of Dr B C Roy P G I P S Kolkata

1. Neonatal cholestasis
Dr. Ajay Kumar Chourasia
Dr. B.C .Roy Postgraduate
Institute of Peadiatric Sciences.
KOLKATA

2. Definition
• Biochemically as Prolonged elevation of conjugated
bilirubin beyond 1st 14 days of life up to 90 days.
• Serum direct bilirubin > 1mg/dl if TSB <5mg/dl
or > 20% of TSB if TSB >5mg/dl
• Any newborn with jaundice and dark yellow urine with
or without pale stools should be strongly suspected to
have NC.

3. We must evaluate for neonatal cholestasis if
jaundice :-
-Appears after 2 wks of age.
-Progress after 2 wks of age.
-Does not resolve after 2 wks of age.

4. Classification

5. Causes of neonatal Cholestasis

6. • Generalized bacterial sepsis
• Viral hepatitis
• Hepatitides A, B, C, D, E
• Cytomegalovirus
• Rubella virus
• Herpesviruses: herpes simplex,
human herpesvirus 6 and 7
• Varicella virus
• Coxsackievirus
• Echovirus
• Reovirus type 3
• Parvovirus B19
• HIV
• Adenovirus
Others
• Toxoplasmosis
• Syphilis
• Tuberculosis
• Listeriosis
• Urinary tract infection
INFECTIOUS

7. • Disorders of amino acid metabolism
• Tyrosinemia
Disorders of lipid metabolism
• Wolman disease
• Niemann-Pick disease (type C)
• Gaucher disease
Cholesterol ester storage disease
Disorders of carbohydrate metabolism
• Galactosemia
• Fructosemia
• Glycogenosis IV
Disorders of bile acid biosynthesis
Other metabolic defects
• α1-Antitrypsin deficiency
• Cystic fibrosis
• Hypopituitarism
• Hypothyroidism
• Zellweger (cerebrohepatorenal)
syndrome
• Wilson disease
• Neonatal iron storage disease
• Indian childhood cirrhosis/infantile
copper overload
• Congenital disorders of glycosylation
• Mitochondrial hepatopa
METABOLIC

8. Trisomies 17, 18, 21
• “Idiopathic” neonatal hepatitis
• Alagille syndrome
• Intrahepatic cholestasis (progressive familial intrahepatic
cholestasis
• [PFIC])
• FIC-1 deficiency
• BSEP (bile salt export pump) deficiency
• MDR3 deficiency
• Familial benign recurrent cholestasis associated with lymphedema
(Aagenaes syndrome)
• ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome
• Caroli disease (cystic dilation of intrahepatic ducts)
GENETIC OR CHROMOSOMAL
INTRAHEPATIC CHOLESTASIS SYNDROMES

9. • Biliary atresia
• Sclerosing cholangitis
• Bile duct stricture/stenosis
• Choledochal–pancreaticoductal junction anomaly
• Spontaneous perforation of the bile duct
• Choledochal cyst
• Mass (neoplasia, stone)
• Bile/mucous plug (“inspissated bile”)
EXTRAHEPATIC DISEASES

10. • Associated with enteritis
• Associated with intestinal obstruction
• Neonatal lupus erythematosus
• Myeloproliferative disease (trisomy 21)
• Hemophagocytic lymphohistiocytosis (HLH)
• COACH syndrome (coloboma, oligophrenia,
ataxia, cerebellar vermis
• Shock and hypoperfusion
• hypoplasia, hepatic fibrosis)
• Cholangiocyte cilia defects
MISCELLANEOUS

11. ETIOLOGICAL PROFILE OF NC IN INDIA

12. CLINICAL APPROACH

13. GOALS 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.

17. EXTRA HEPATIC CHOLESTASIS

18. BILLARY ATRESIA
obliterative cholangiopathy 2 major types:
cystic noncystic.
choledochal cysts fetal perinatal sclerosing cholangitis
• 85% of the cases, is obliteration of the entire extrahepatic biliary tree at
or above the porta hepatis. difficult problem in surgical management.
C/F -
-normal at birth and have a postnatal progressive obliteration of bile ducts
-embryonic or fetal-onset form manifests at birth
associated withother congenital anomalie
(situs inversus, polysplenia, intestinal malrotation, complex congenital
heart disease).

19. Management of Patients with Suspected
Biliary Atresia
• -To determine the presence and site of obstruction.
exploratory laparotomy and direct cholangiography
biliary tree is patent but of diminished caliber, suggesting that the no
biliary tract obliteration but to bile duct paucity
further dissection into the porta hepatis should be avoided.
Porta hepatis
fibrous ductal remnant
Hepatic artery
Traingular Cord sign

20. 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.

21. CHOLEDOCHAL CYSTS
• Choledochal cysts are congenital dilatations of the common
bile duct
• that can cause progressive biliary obstruction and biliary
cirrhosis..
• pathogenesis due to reflux of pancreatic enzymes into the
common bile duct, causing inflammation, localized
weakness, and dilation of the duct
• C/F-The infant typically presents with cholestatic jaundice;
severe liver dysfunction including ascites and coagulopathy
.
• Treatment of choice is primary excision of the cyst and a
Rouxen- Y choledochojejunostomy.

22. Cystic Dilation of the Intrahepatic Bile Ducts
(Caroli Disease)
Congenital saccular dilation of intrahepatic bile ducts.
associated with Choledochal cysts
Pathogenesis
dilation leads to stagnation of bile and formation of biliary sludge
and intraductal lithiasis.
Clinical features-
portal hypertensive bleeding .
Diagnosis-
• Ultrasonography-
• percutaneous transhepatic, endoscopic, or MR cholangiography.
Management-
Cholangitis and sepsis are treated with appropriate antibiotics.
Calculi can require surgery.

23. INTRAHEPATIC CHOLESTASIS

24. Proposed Subtypes of
Intrahepatic Cholestasis
• Disorders of bile acid biosynthesis and
conjugation
• Disorders of membrane transport and secretion
• Disorders of embryogenesis
• Unclassified (idiopathic “neonatal hepatitis”):

25. Bile acid biosynthesis.

27. 1
2
3

30. B. Disorders of bile acid biosynthesis
and conjugation
3β-hydroxy-5-C27-steroid dehydrogenase/isomerase
deficiency(HSD3B7)
3-oxoΔ-4-steroid 5β-reductase deficiency.(AKR1D1)
Oxysterol 7α-hydroxylase deficiency
.
Bile acid-coenzyme A (CoA) ligase deficiency
.
BAAT deficiency (familial hypercholanemia)

31. Deficiency of 3β-hydroxy-Δ5-C27-steroid oxidoreductase
(3β-HSD)
the 2nd step in bile acid biosynthesis,
causes progressive familial intrahepatic cholestasis.
C/F-
-jaundice with increased aminotransferase levels
-hepatomegaly;
-GGT levels are normal.
Histology - ranging from giant cell hepatitis to chronic
hepatitis.
Diagnosis- by mass spectrometry detection of C24 bile acids
in urine, which retain the 3β-hydroxy-Δ5 structure.
Management-Primary bile acid therapy, administered orally to
down regulate cholesterol 7α-hydroxylase activity, to limit
the production of 3β-hydroxy-Δ5 bile acids, and to facilitate
hepatic clearance, has been effective in reversing hepatic
injury
1

32. Deficiency of Δ4-3-oxosteroid-5β reductase(AKR1D1)
• The 4th step in the pathway of cholesterol degradation to the
primary bile acids,
C/F-cholestasis and liver failure developing shortly after birth, with
coagulopathy and metabolic liver injury resembling tyrosinemia.
Hepatic histology is characterized by
lobular disarray with giant cells, pseudoacinar transformation, and
canalicular bile stasis.
Diagnosis- Mass spectrometry is required to document increased
urinary bile acid excretion and the predominance of oxo-hydroxy
and oxo-dihydroxy cholenoic acids.
Treatment with
cholic acid and ursodeoxycholic acid is associated with
normalization of biochemical, histologic, and clinical features
2

33. Bile acid–CoA Ligase deficiency &
Bile acid –CoA:aminoacid N-acetyl transferase
deficiency (BAAT)
Conjugation with the amino acids glycine and taurine is the final step
in bile acid synthesis.
Two enzymes catalyze the amidation of bile acids.
• first reaction, a CoA thioester is formed by the rate-limiting
Bileacid-CoA Ligase.
• Other reaction coupling of glycine or taurine and is catalyzed by a
cytosolic Bile acid–CoA:amino acid N-acyltransferase
C/F- conjugated hyperbilirubinemia, growth failure, or fat-soluble
vitamin deficiency,
Diagnosis- identified with mutation of the bile acid–CoA ligase gene.
Management-Administration of conjugates of the primary bile acid,
glycocholic acid may be beneficial and can correct the fat-soluble
vitamin malabsorption improve growth.
3

34. Transport & Secretion of Bile acid

35. PHYSIOLOGY OF TRANSPORT
• Albumin-bound bile acids that reach the liver mainly via the
portal blood are efficiently removed by transport proteins
located at the sinusoidal membrane of hepatocytes.
In the overall process of bile acid transport from blood to bile,
canalicular secretion is the limiting step. This
• transport for mono anionic amidated bile acids, which
constitute the majority of secreted bile acids is ATPdependent
and is mainly performed by the bile salt export pump (BSEP,
gene symbol ABCB11)
• Bile acids conjugated with sulfate or glucuronic acid are
dianionic and are transported by other canalicular pumps, such
as MRP2(ABCC2 gene) and BCRP (ABCG2 gene).

37. Disorders of membrane transport and
secretion
1. Disorders of canalicular secretion
a. Bile acid transport: BSEP deficiency
• i. Persistent, progressive (PFIC type 2)
• ii. Recurrent, benign (BRIC type 2)
b. Phospholipid transport:MDR3 deficiency (PFIC type 3)
c. Ion transport: cystic fibrosis (CFTR)
2. Complex or multiorgan disorders
a. FIC1 deficiency
• i. Persistent, progressive (PFIC type 1, Byler disease)
• ii. Recurrent, benign (BRIC type 1)
b. Neonatal sclerosing cholangitis (CLDN1)
c. Arthrogryposis-renal dysfunction-cholestasis syndrome
(VPS33B)

38. Progressive familial intrahepatic cholestasis type 1
(PFIC 1) or FIC1disease
(formerly known as Byler disease)
• present with steatorrhea, pruritus,vitamin D–deficient
rickets, gradually developing cirrhosis, and low γ-glutamyl
transpeptidase (GGT) levels.
Locus chromosome 18q12 defect in the gene for F1C1 .
• F1C1 is p type ATPase that facilitating the transfer of
phosphotydyl serine(role in intestinal bile absorption).
• Defective F1C1 might a result intrahepatic cholestasis
• Nonsense,frame shift, and deletional mutations cause PFIC
type 1
• missense and split-type mutations result in BRIC type I.

39. PFIC type 2 (BSEP deficiency)
• is mapped to chromosome 2q24 and
• The disease results from defects in the
canalicular adenosine triphosphate–dependent
bile acid transporter BSEP(ABCB11).
• The progressive liver disease results from
accumulation of bile acids secondary to reduction
in canalicular bile acid secretion.
• Mutation in ABC11 is also described in another
disorder, BRIC type2, characterized by recurrent
bouts of cholestasis

40. PFIC type 3 (MDR3disease)
The disease results from defects in acanalicular
phospholipids flippase, MDR3 (ABCB4),
which results in deficient translocation of
phosphatidylcholine across the canalicular
membrane. Mothers who are heterozygous
for this gene can develop intrahepatic
cholestasis during pregnancy.

41. Familial hypercholanemia
• is characterized by elevated serum bile acid
concentration, pruritus, failure to thrive, and
coagulopathy.
• mutation of bile acid coenzyme A (CoA), amino
acid N-acyltransferase(encoded by BAAT)
• Mutation of both BAAT and TJP 2 can disrupt bile
acid transport and circulation.
• Patients with familial hypercholanemia usually
respond to the administration of ursodeoxycholic
acid.

42. DISORDERS OF EMBRYOGENESIS

43. C. Disorders of embryogenesis
. Alagille syndrome (Jagged1 defect, syndromic bile duct
paucity)
. Ductal plate malformation (ARPKD, ADPLD, Caroli disease)

44. Alagille syndrome (arteriohepatic dysplasia)
Intrahepatic bile duct paucity. often erroneously called intrahepatic
biliary atresia
Clinical manifestations -
facial characteristics (broad forehead; deep-set, widely spaced eyes;
long, straight nose; and an underdeveloped mandible).
ocular abnormalities - microcornea, optic disk drusen, shallow
anterior chamber)
cardiovascular abnormalities usually peripheral pulmonic stenosis,
sometimes tetralogy of Fallot, pulmonary atresia, VSD, ASD, aortic
coarctation),
vertebral defects (butterfly vertebrae, fused vertebrae,
spina bifida occulta, rib anomalies), and
tubulointerstitial nephropathy.
pancreatic insufficiency, and
defective spermatogenesis can reflect or produce nutritional
deficiency.

46. • The prognosis for prolonged survival is good,
but patients are likely to
have pruritus, xanthomas with markedly
elevated serum cholesterol levels, and
neurologic complications of vitamin E
deficiency if untreated.
Mutations in human Jagged 1 gene (JAG1),
which encodes a ligand for the notch receptor,
are linked to Alagille syndrome

47. Idiopathic neonatal hepatitis, is a disease of unknown
cause.
sporadic familial form
Metabolic /viral disease . Genetic /metabolic abbreation
Idiopathic Neonatal Hepatitis

48. Aagenaes syndrome
• idiopathic familial intrahepatic cholestasis
associated with lymphedema of the lower extremities.
-may be attributable to decreased hepatic lymph flow or hepatic
lymphatic hypoplasia.
- present with episodic cholestasis
-with elevation of serum aminotransferases, alkaline phosphatase,
and bile acids.
Between episodes, the patients are usually normal
• have a relatively good prognosis because more than 50% can
expect a normal life span.
• The locus for Aagenaes syndrome is mapped
chromosome 15q.

49. Zellweger syndrome
(cerebrohepatorenal)
• is a rare autosomalrecessive genetic disorder
• marked by progressive degeneration of the liver and kidneys
• the disease is usually fatal in 6-12 mo.
C/F :-
• generalized hypotonia and
• markedly impaired neurologic function with psychomotor
retardation.
• Patients have an abnormal head shape and unusual facies
• hepatomegaly , renal cortical cysts
• stippled calcifications of the patellas and greater trochanter
• ocular abnormalities.
• Hepatic cells has absence of peroxisomes

50. Four patients with Zellweger cerebrohepatorenal syndrome.
Note the high forehead, epicanthal folds, and hypoplasia of
supraorbital ridges and midface.

51. Neonatal iron storage disease (neonatal
hemochromatosis)
•
increased iron deposition
in the liver, heart, and endocrine organs with multiorgan failure
. This is an alloimmune disorder with maternal antibodies
directed against the fetal liver.
• C/F-
hypoglycemia, hyperbilirubinemia,hypoalbuminemia,
elevated ferritin and profound hypoprothrombinemia.
Diagnosis - confirmedby buccal mucosal biopsy
MRI demonstrating extrahepatic siderosis.
• The prognosis is poor;liver transplantation can be curative.
.

52. METABOLIC

53. α1-ANTITRYPSIN DEFICIENCY
Deficiency of the major serum protease inhibitor α1-
antitrypsin manifest neonatal cholestasis or later-onset
childhood cirrhosis. --
mutation in the SERPINA1 gene and it is an autosomal recessive
usually PiZZ homozygotes .
Enzyme modification and folding defect
Diagnosis- in Biopsy- polymerized α1-antitrypsin peptide,
hepatocellular necrosis, inflammatory cell infiltration, bile duct
proliferation, periportal fibrosis, or cirrhosis

55. C/F
Jaundice,
acholic stools
hepatomegaly are present in the 1st wk of life
but the jaundice usually clears in the 2nd-4th months.
persistent liver disease, or the development of cirrhosis
can Follow..
Therapy is supportive; liver transplantation has been
curative

56. INFECTION

57. CMV infection
• CMV present in saliva,urine,genital secretions,
breast milk and blood in ifected person and this is
the source of infection.
• Primary infection in asymptomatic in older infant
and children
• But infection in early gestational age carries high
risk fatal disease in new born.

58. C/F of Congenital early-
-petechie ,pupura(79%)
-Hepatosplenomegaly(74%)
-Jaundice (63%)
Diagnosis-
In Congenital infection CMV identifies in urine ,blood,saliva
within 2 wks of age
In perinatal infection negative in 1st weeks and positive in 4
wks.
CMV PCR
CMV antigen
CMV IgG & IgM
(negative IgG in both mother & baby – Exclude CMV
If Positive in baby then repeat after 4 wks- if titer decresing or absent --
it was due to transplacentally derived.)

59. Treatment
• Ganciclovir –
In congenital infection (6mg/kg/dose BD)for 1st
6wks of life .
Prophylactic with oral Valgalciclovir to mother
(900mg OD )for 90 days.

60. Management

61. 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).

62. 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.

63. • 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)

64. Radiological 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 density that was located immediately
cranial to the portal vein bifurcation and was 3 mm or
more thick (Kanegawa et al. AJR 2003;181:1387)

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

66. 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)

69. Invasive studies
– Duodenal intubation
– Percutaneous liver biopsy
– Percutaneous transhepatic cholangiography
– ERCP
– MRCP
– Exploratory laparotomy with intraoperative
cholangiogram

71. ERCP image

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

73. Percutaneous transhepatic
cholangiography

74. 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

75. 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 –at 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 –at 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

76. Hepatoportoenterostomy (Kasai) procedure
• Performed for biliary atresia that is not surgically
correctable with excision of a distal atretic segment.
• The rationale for this operation is that minute bile duct
remnants, representing residual channels, may be present
in the fibrous tissue of the porta hepatis
• Roux-en-Y portoenterostomy
• Bile flow re-established in 80-90% if performed prior to 8
weeks-old.
• If microscopic channels of patency > 150 μm in diameter
are found, postoperative establishment of bile flow is likely.
• Bile flow re-established in less than 20% if performed after
12 weeks-old

78. Liver 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)

79. 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.

80. 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.