Neonatal Cholestasis

Hanifah Oswari
Hepatology Div
Dept of Child Health
Cipto Mangunkusumo Hospital
 Cholestatic cases at
IKA-FKUI/RSCM
February 1991-January 2000 ( 8 years )
N : 203
Sex : male : 129 ( 63,5 % )
female : 74 ( 36,5 %)
Age : 1 month - 19 months
< 1 month : 18 ( 8,9 % )
> 1-2 months : 64 ( 31,5% )
> 2-4 months : 77 ( 37,9% )
> 4 months : 44 ( 21,7% )
Intrahepatic :141(69%),
cirrhosis 11(7,8%)
? CMV : 46 HBV : 1
Toxoplasmosis :1 Sepsis : 1
Metabolic :2 Alagille : 2
Hemangioma :1

Extrahepatic : 62 (31%),
cirrhosis 18(29%)
biliary atresia : 35
Choledochal cyst : 12
“bile plug syndrom” : 12
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. Neonatal Hepatitis
2. Bile duct obstruction
3. Metabolic disorders
4. Cholestatic syndromes
5. Toxin / Drug induced
6. 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, Alagille’s,
Nonsyndromic paucity, congenital
hepatic fibrosis, Caroli’s
– Other
• Inspissated bile, cholelithiasis, tumours
 Aetiology 3
3. Metabolic disorders
– 1-antitrypsin deficiency
– Neonatal iron storage disease
– Endocrinopathies
• hypopituitary, hypothyroid
– Amino acid disorders
• tyrosinaemia, hypermethionaemia
– Lipid Disorders
• Niemann-Pick, Gaucher’s, Wolman’s,
CESD
– Urea Cycle disorders
• arginase deficiency
 Aetiology 4
– Carbohydrate disorders
• galactosaemia, fructosaemia, GSD IV
– Mitochondrial (respiratory chain defects)
– Peroxisomal disorders
• Zellweger’s, Infantile Refsum
– Bile Acid Synthetic defects
• 3-hydroxy5C27 steroid dehydrogenase
isomerase
• 4-3-oxosteroid 5-reductase
• oxysterol 7-hydroxylase
 Aetiology 5
4. Cholestatic syndromes
– 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)
5. Toxic
– Drugs
– TPN
– Aluminium
 Aetiology 4
6. Miscellaneous associations
– Shock /hypoperfusion
– Histiocytosis X
– Neonatal lupus
– Trisomies
– Erythrophagocytic lymphohistiocytosis
– Veno-occlusive disease
– Donahue syndrome (leprechaunism)
 Relative Frequency of Disease
Disease Cumulative f / 105 live
% births
"Idiopathic neonatal 35-40 1.25
hepatitis"

Biliary atresia 25-30 0.7

1-AT deficiency 7-10 0.25
Intrahepatic cholestasis 5-6 0.14
Inborn errors of BA 2 <0.1
synthesis

CMV, Rubella, Herpes 4-6 <0.1

Endocrine disorders 1 <0.1
Galactosemia 1 <0.1

Balistreri WF in Schiff’s 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 Alagille’s, 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
Birth Weight Normal Often low
Onset jaundice Mean 23d Mean 11d
Acholic stools 75% Maybe
Firm Hepatomegaly 87% 53%

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 Gb present

“triangular cord”
HIDA scan Normal uptake, Poor uptake, Nl .
no excretion excretion
Liver Biopsy Bd proliferation, Giant cells,
bile plugs, portal inflammation,
fibrosis 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 cholangio-
pancreatography)
– 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;10:793-
799
– 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
Alagille’s 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
Vit A 5 – 25,000
• Decreased fat iu/d
absorption due Vit D 25 OH C
to a low 3 – 5 ug/kg/d
micellar Vit K 5 – 10 mg /d
concentration
• MCT oil Vit E 50 – 400 u/d
• Fat Soluble
Vitamins Water 2 x daily dose
soluble
 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 Schiff’s Diseases of the Liver, 8th ed. 1999;1357-
1512