Neonatal

Cholestasis
Deddy S Putra

Clinical presentation
cholestatic syndrome :
jaundice
dark urine
stool: intermittently pigmented
acholic
clinical feature of disorders which
cause cholestasis
symptoms of chronic cholestasis

Definition
Presence of jaundice with a
conjugated bilirubin fraction >15% of
total bilirubin concentration (or > 1.5
mg/dl) in any infant beyond 2 weeks
old

Incidence

Incidence 1:2500 to 1:5000

Dick M & Mowat A Arch Dis Child 1985;60:512-516

Danks DM et al Arch Dis Child 1977;52:360-367

Liver disease in the neonate regardless of

aetiology, is frequently associated with
conjugated jaundice
Conjugated jaundice in infants nearly
always indicates liver or biliary disease

Classification of aetiology
1.
2.
3.
4.
5.
6.

Neonatal Hepatitis
Bile duct obstruction
Metabolic disorders
Cholestatic syndromes
Toxin / Drug induced
Miscellaneous

Aetiology 1
1.

Neonatal hepatitis

Idiopathic
Viral

CMV, Herpes (HS, HZ, HH6), EBV,

Rubella, ReoV3, Parvo B19, AdenoV,
Hep B, EnteroV, HIV

Bacterial and parasitic

sepsis, Listeria, TB, Toxoplasmosis,

Malaria

Aetiology 2
2.

Bile duct obstruction

Cholangiopathies

EHBA, Choledochal cysts, Alagilles,

Nonsyndromic paucity, congenital
hepatic fibrosis, Carolis

Other

Inspissated bile, cholelithiasis, tumours

Aetiology 3
3.

Metabolic disorders

1-antitrypsin deficiency
Neonatal iron storage disease
Endocrinopathies

Amino acid disorders

tyrosinaemia, hypermethionaemia

Lipid Disorders

hypopituitary, hypothyroid

Niemann-Pick, Gauchers, Wolmans,

CESD

Urea Cycle disorders

arginase deficiency

Aetiology 4

Carbohydrate disorders

Mitochondrial (respiratory chain defects)

Peroxisomal disorders

galactosaemia, fructosaemia, GSD IV

Zellwegers, Infantile Refsum

Bile Acid Synthetic defects

3-hydroxy5C27 steroid dehydrogenase
isomerase
4-3-oxosteroid 5-reductase
oxysterol 7-hydroxylase

Aetiology 5
Cholestatic syndromes

4.

Progressive familial intrahepatic cholestasis

Types 1 (Byler), 2 (BSEP defect), 3 (MDR3 defect)

Aagenaes (hereditary cholestasis with lymphoedema)

Nielsen (Greenland Eskimos)
Benign recurrent intrahepatic cholestasis
Neonatal Dubin-Johnson syndrome (MRP2 defic)

Toxic

5.

Drugs
TPN
Aluminium

Aetiology 4
Miscellaneous associations

6.

Shock /hypoperfusion
Histiocytosis X
Neonatal lupus
Trisomies
Erythrophagocytic lymphohistiocytosis
Veno-occlusive disease
Donahue syndrome (leprechaunism)
Down syndrome

PEMBAGIAN LAIN

CONGENITAL INFECTION
TORCH
SYPHILIS
HUMAN HERPESVIRUS 6 HERPES
ZOSTER
HEPATITIS B,C
HIV
PARVOVIRUS B19
SYNCYTIAL GIANT CELL HEPATITIS

GENETIC
TRISOMY 18, 21 CAT EYE SYNDROME
ENDOCRINE
HYPOHTIROID
HYPOPITUTARISM
STRUCTURAL
BILIARY ATRESIA
CHOLEDOCHAL CYST
NEONATAL SCLEROSINGCHOLANGITIS
HAIR LIKE BILE DUCT SYNROME
SPONTANEOUS PERFORATION CBD
INSPISSATED BILE SYNDROME

DUCT PAUCITY SYNDROMES

ALAGILES SYNDROME
NONSYNDROMIC DUCT PAUCITY
METABOLIC
AAT DEFICIENCY
CYSTIC FIBROSIS
GALACTOSEMIA
TYROSINEMIA
HEREDITARY FRUCTOSEMIA
GSD TYPE IV
NIEMANN-PICK TYPE A,C
WOLMAN DISEASE
PRIMARY DEFECTS IN BILE ACID SYNTESIS
BYLER DISESASE
ZELLWEGER SYNDROME

IMMUNE
NEONATAL LUPUS ERYTHEMATOSUS
NH WITH AUTOIMUNNE HEMOLYTIC
ANEMIA

Relative Frequency of Disease

Cumulative
%
35-40

f / 105 live
births
1.25

Biliary atresia

25-30

0.7

1-AT deficiency

7-10

0.25

5-6

0.14

<0.1

4-6

<0.1

Endocrine disorders

<0.1

Galactosemia

<0.1

Disease
"Idiopathic neonatal
hepatitis"

Intrahepatic cholestasis
Inborn errors of BA
synthesis
CMV, Rubella, Herpes

Balistreri WF in Schiffs Diseases of the Liver, 8th ed. 1999;1357-1512.

History

Well or otherwise
Primary history

pregnancy, birth weight, hypoglycaemic

episodes

Feeding and stooling (colour) history

Family history

Examination

General
well/sick, weight, sluggish behaviour, jaundice,
pallor
Facies
Dysmorphic, nystagmus/eye signs, cleft lip/palate
Cardiac
murmurs, situs inversus
Abdomen
liver size (use span) and position, spleen
penis size
Skin
Rash, birthmark, petechiae
Neurologic

Approach to cholestatic infant

Confirm cholestasis
Assess severity of liver dysfunction
Exclude potentially treatable
infectious and metabolic disorders
Aim for specific diagnosis

urgency in diagnosis of biliary atresia

(EHBA) as prognosis depends on
early (<60d) intervention

Initial Investigations

Confirm cholestasis
bilirubin total and conjugated fraction
Exclude sepsis
urine, blood other culture
Assess liver injury
ALT, AST, AP, GGT
Assess liver synthetic function
PT / INR, glucose, albumin, cholesterol
Look for rapidly treatable conditions
serum glucose, urine reducing substances

Specific Investigations

Abdominal US
1-AT level and phenotype
Serology for infection
Hep A, B, C, CMV, EBV, HSV, VDRL,
Metabolic screen
urine and serum amino and organic acids
TFTs, and cortisol/GH if suspect hypopit.
Serum iron, ferritin, transferrin saturation
Galactose-1-phosphate uridyl transferase

Very specific
investigations

Hepatobiliary scintigraphy (HIDA scans)

Liver biopsy
Also
serum and urine bile acids
fast atom bombardment spectroscopy of urinary
bile acids
genetic testing for Alagilles, PFIC
Echo, spine XR, bone marrow examination,
fibroblast cultures, X-rays of skull, long bones
Intraoperative cholangiogram, repeat biopsy

EHBA vs Neonatal Hepatitis

EHBA

NH

Family History

Rare

15-20%

Gender

F>M

M>F

Normal

Often low

Onset jaundice

Mean 23d

Mean 11d

Acholic stools

75%

Maybe

Firm Hepatomegaly

87%

53%

Birth Weight

Alagille D. Prog Liver Dis 1979;6:471-485

Investigating EHBA vs NH
Investigation

EHBA

NH

Duod. Aspirate

No bile

Bile present

Ultrasound

Gb absent/small
triangular cord
Normal uptake,
no excretion
Bd proliferation,
bile plugs, portal
fibrosis

Gb present

HIDA scan
Liver Biopsy

Poor uptake, Nl .
excretion
Giant cells,
inflammation,
focal necrosis

Suchy FJ in Liver disease in Children, 2nd ed. 2000;187-194

Assessment of imaging studies

Ultrasound
can assess gb size, stones, sludge, bile duct
dilatation, ascites, extrahepatic lesions
CT scan
similar information to US but need sedation/GA
MRCP (magnetic resonance cholangiopancreatography)
reliable in detecting CBD/ gb (pilot studies)
HIDA scans
helpful but 25-50% of NH fail to show excretion

Liver biopsy

Most important diagnostic tool

will diagnose EHBA in 90-95% cases
main potential problem is if biopsy too early,
histological changes of EHBA evolving
100% sensitive but 76% specific in detecting
EHBA
Zerbini MC et al Mod Pathol 1997;10:793799
also useful in assessing aetiology of
cholestasis as can detect viral inclusions,
abnormal storage material in cells etc

Surgical exploration

Occasionally necessary
Intraoperative cholangiogram and liver biopsy
Look for features of EHBA
coarse, fibrotic, green liver with subcapsular
telangiectasia
Experience of surgeon very important in
outcome
Prognosis will be worse if Kasai is performed on
Alagilles patients

Consequences of chronic
cholestasis

Reduced delivery of bile into small bowel

malabsorption of fat, fat soluble vitamins
Overflow of bile constituents into systemic
circulation pruritis, fatigue,
hypercholesterolemia, xanthoma formation
Hepatotoxicity from abnormally retained
substances (bile acids, cholesterol, bilirubin)
portal hypertension, cirrhosis

Medical management of
cholestasis
Aim to reduce complications:
optimise nutrition to reduce effects of
malabsorption
symptomatic treatment of itch,
hyperlipidemia
promote bile flow (reduce hepatotoxicity)
General considerations
immunizations
dental hygiene

Nutritional management

Calories
aim for 125% of RDA based in ideal body
wt
may need supplemental tube feeds
Fat
MCT better absorbed than LCT so consider
using these formulae eg. Pregestamil,
Alfare
Protein
aim for 2-3 g/kg/d unless encephalopathic
branched chain amino acid formula (eg
Generaid) improves nutritional status

Nutrition management 2

Essential Fatty Acids

linoleic, linolenic, arachidonic acids
may need supplementing with corn,
safflower, walnut oil or lipid emulsions
Fat Soluble Vitamins
vitamins A, D, E, K
may need to monitor levels
Water Soluble Vitamins
unknown whether deficient in cholestasis
recommend 1-2 x RDA

Malabsorption

Decreased fat
absorption due
to a low micellar
concentration
MCT oil
Fat Soluble
Vitamins

Vit A

5 25,000
iu/d

Vit D

25 OH C
3 5 ug/kg/d

Vit K

5 10 mg /d

Vit E

50 400 u/d

Water
soluble

2 x daily dose

Controlling pruritis

Oral bile acid binding resins

cholestyramine
colestipol
Ursodeoxycholic acid
Rifampicin
Opiod receptor antagonists (naltrexone)
Others
Phenobarbitone
Carbamazepine
Partial external biliary diversion
Liver transplantation

Hyperlipidemia and
xanthoma

Treatment aims:
increase conversion cholesterol to bile acids
reduce biliary regurgitation
enhance elimination bile acids and
cholesterol
Non absorbable ion resins
Ursodeoxycholic acid
Cholesterol synthesis-blocking agents
Others
plasmapheresis
partial ileal bypass
liver transplantation

Promoting bile flow

Ursodeoxycholic acid (UDCA)

Phenobarbitone
Glucocorticoids in short bursts
not appropriate in chronic situation but
used perioperatively after EHBA surgery

Immunisations

Recommend routine immunisations

Some delay DTP in EHBA because side
effects of immunisation may mask
cholangitis
Would also immunise against Hep B and A
Use Salk polio (inactivated) in transplant
recipients and household contacts
If child > 12 mo and may need transplant,
use MMR and Varicella > 1 mo before OLT

Dental Hygiene

Teeth discolouration may occur from

staining by bilirubin, biliverdin,
haemosiderin
poor oral hygiene
oral (acidified) iron preparations
dental caries
Stress good oral hygiene, regular dental
examination, restrict sugary medications
Permanent teeth usually OK unless
cholestatic > 8yo

Outcome of NH

Sporadic

60% recover
10% persistent fibrosis or inflammation
2% develop cirrhosis
30% die

Familial (or consanguinity)

30% recover
10% chronic liver disease or cirrhosis
60% die

Balistreri WF in Schiffs Diseases of the Liver, 8th ed. 1999;13571512

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