This document discusses direct jaundice and neonatal cholestasis. It begins by defining direct jaundice and noting that it indicates cholestasis and hepatobiliary dysfunction. The causes of neonatal cholestasis are then outlined, including extrahepatic (e.g. biliary atresia), intrahepatic (e.g. PFIC), and hepatocellular disorders (e.g. metabolic and infections). The diagnostic evaluation, management, and specific conditions like biliary atresia and choledochal cyst are then reviewed over multiple sections.

1.  Presented by Dr Sonali Paradhi Mhatre

2. Direct Jaundice
 Defined as measure of direct reacting
bilirubin of >1mg/dl in TSB <5. OR more
than 20 % of the TSB levels.
 Also known as Conjugated
hyperbilirubinemia.
 It is a biochemical marker of cholestasis
& indicator of hepatobiliary dysfunction.
 Neonatal cholestasis : Defined as prolonged
elevation of serum levels of conjugated
bilirubin beyond the first 14 days of life.

3. Causes
Extrahepatic
Biliary
• Biliary atresia
• Choledochal cyst
• Bile duct stenosis
• Spontaneous bile
duct perforation
• Neoplasms
Intrahepatic Biliary
• Intrahepatic bile
duct paucity :
a.)PFIC
(Progressive
familial
intrahepatic
cholestasis.
b.)Syndromic
(Algille)
Hepatocellular
disorders
• Metabolic ( α1-
antitrypsin def,
galactosemia,
cystic fibrosis,
tyrosinemia,etc)
• Infections
(TORCH, EBV,
E.coli,
streptococcus)
Other causes
• Total Parenteral
nutrition
• Idiopathic
neonatal
hepatitis
• Neonatal
hemochromatosis
• ECMO

4. History
 Does the baby appear sick.
 Gestational age
 Maternal and neonatal blood groups
 Age of onset of jaundice / duration.
 Consanguity
 Feeding history
 Associated complaints : vomiting, lethargy, irritability
 H/O NICU admission .(TPN?? , weight loss??, early jaundice not responding to PT)
 Antenatal history of APH, PPROM, maternal DM, Thyroid disorders, antenatal infections.
 Colour of urine and stools. Time of meconium passage.
 Family history of Jaundice, anaemia, splenectomy, metabolic disorder.
 Previous sibling history , H/O neonatal deaths or morbidities in family.

5. Clinical assessment
 Whether the baby appears sick**
 Neurologic assessment.
 Vitals, weight assessment, general nutrition assessment. Signs of sepsis.
 Dysmorphism
 Colour of the skin ( greenish yellow??)
 Bruising, petechiae
 Hepatosplenomegaly, palpable mass in Rt abdomen (cyst?)
 Abdominal mass, distension, ?Ascitis.
 Murmur or evidence of heart failure (syndrome association)
 Diaper examination for stool and urine colour.

6. LabInvestigations
• Bilirubin
• Liver enzymes
(AST,ALT)
• GGT
• PT,PTTK, Proteins
• Ammonia
• BSL,Septic screen
• Urine reducing
substances
• TORCH titres
• UAA/PAA
Imaging
• Ultrasonography
• Hepatobiliary
scanning (HIDA)
• Endoscopic
retrograde
cholangiopancreato
graphy.
• CXRay
Others
• Percutaneous
liver biopsy
• Magnetic
resonance
cholangiopancr
eatography
Workup

7. Approach to a case of neonatal cholestasis…
Jaundice infant ( 2 to 8 wks old)
Manage acute illness
Consider UTI,
Sepsis,
Galactosemia,
Tyrosinemia,
Hypopitutarism,
Iron storage disorders,
Metabolic disorders,
Hemolysis
Direct Jaundice ?
Is pt acutely ill???
Measure serum direct
bilirubin
Cholestatic jaundice Indirect hyperbili
Evaluate and treatHistory
Physical examination
Urinanalysis
Urine culture
Findings of
specific disease ?

8. Approach to a case of neonatal cholestasis…
Findings of
specific disease ?
Screen for galactosemia,
hypothyroidism positive ?
Evaluate further
Low α1 antitrypsin? Choledochal cyst?
Manage further
accordingly
Consider GI problem
CBC, platelet
Bilirubin, AST, ALT, Alkaline
phosphatase, glucose
PT,PTTK, albumin
Urine reducing substance
USG abdomen
Antitrypsin α1
Does bili normalize
by 6 wks of age?
No
hyperbilirubinemia
Further management
Pediatric surgery
Operative cholangiogram
Consider :
Percutaneous liver biopsy
Scintiscan
Duodenal aspirate
ERCP

9. Approach to a case of neonatal cholestasis…
Consider :
Percutaneous liver biopsy
Scintiscan
Duodenal aspirate
ERCP
Is there any
evidence of
biliary
obstruction??
Consult
pediatric
surgeon.
Operative
cholangiogram
Medical evaluation :
Infection
Metabolic disorders
Genetic disorders
Others

10. Biliary Atresia
 Biliary atresia is the most common cause of
end stage liver disease in infants and is a
leading cause of liver transplantation in
pediatrics.
 Incidence is estimated to be between 1:8000
and 1:12000 per live births and has a female
preponderance.
 There is no excretion of bile from the liver
into the duodenum leading to cholestasis,
fibrosis and ultimately cirrhosis.

11. Hepatobiliary
Anatomy

12. Classification of Biliary Atresia
(based on the extent & site of fibrosis in the biliary tree)

13. Biliary atresia VS Idiopathic neonatal hepatitis
Biliary Atresia Idiopathic neonatal hepatitis
Rarely recurs in family Familial
Presentation postnatally Early presentation
Can be seen in term / preterms More common in premature, SGA babies
Persistent acholic stools Transient severe impairment in bile secretion
Palpable liver with abnormal size and consistency Rarely seen
Increased incidences of abnormalities like malrotation,
levocardia, vascular anamolies.
No associations

14. Clinical features :
 Jaundice >2 wks
 Pale stools
 Dark urine
 Occasionally, bleeding secondary to
Vit K def.
 Hepatomegaly , splenomegaly
 Ascitis

15. Diagnosis
 The GOLD standard for diagnosis is Exploratory laparotomy with
intraoperative cholangiogram.
 AAP recommends that any infants who is jaundiced at 3wks age
should have a total and direct bilirubin measurement.
 Ultrasonography helps in differentiating biliary atresia from other
causes of neonatal cholestasis.
 Hepatobiliary schintigraphy is a non invasive way for ruling out
extrahepatic biliary atresia.
 Liver biopsy is an important tool in the evaluation of an infant with
conjugated hyperbilirubinemia and should be performed preferably
within 8 wks of age.
 Endoscopic retrograde cholangiopancreatography permits visualization
of the biliary tree in young infants but is technically challenging in
newborn.

16. Hepatobiliary schintigraphy
 Hepatobiliary schintigraphy with technetium
labelled iminodiacetic acid derivatives differentiate
biliary atresia from non obstructive causes of
cholestasis.
 Test in sensitive but not specific for BA.
 In Biliary atresia , the hepatic uptake of the tracer is
normal but its excretion in the intestine is absent.
 HIDA – hepatobiliary iminodiacetic acid scan
 DISIDA- Diisopropyl iminodiacetic acid scan
 PIPIDA – Paraisopropyl iminodiacetic acid scan.
 Phenobarbitone Priming needed for 3- 5 days prior to
the procedure.

17. Hepatobiliary schintigraphy
Radioactive tracer
injected through an
accessible vein.
Uptake by liver
Stored in the gall bladder
Excreted in the
intestines.

18. Hepatobiliary schintigraphy
 In the absence of disease, Radioactive tracer
visualized within 1 hr in the gall bladder.
 Dyanamic images taken at 20min Pre and post feeds.
 Static images taken at 30min, 4 hys , 24 hrs.
 If not visualized within 4 hrs, indicates cholecystitis
or cystic duct obstruction.
 Delayed 24 hr film indicated if no tracer visualized in
intestines till then.
 If tracer excreted in intestines – BA ruled out.
 If no excretion - BA or severe neonatal hepatitis with
interlobular bile duct paucity. (Liver biopsy
indicated)

19. Treatment
 Early diagnosis of biliary atresia and surgical repair
leads to a better outcome.
 Hepatic portoenterostomy (KASAI’s Surgery) is
currently the procedure of choice .
 Kasai’s procedure has the greatest chance of
reestablishment of bile flow and long term survival of
the infant;s liver if performed before 45 – 60 days.
 Liver transplant is selectively performed for the for
those infants with progressive liver failure or those with
unsuccefull Kasai’s procedure.

20. Choledochal cyst
 Choledochal cysts are congenital anamolies of the biliary tract with
dilatations of the extrahepatic and sometimes intrahepatic biliary system.
 After BA, choledochal cyst is the most common cause of obstructive
jaundice in the newborn period.
 Etiology unknown.
 Triad of symptoms – Intermittent obstructive jaundice, Abdominal pain and
a cystic abdominal mass.
 Ultrasonography most common diagnostic tool used.
 Complications include recurrent cholangitis, biliary cirrhosis, rupture with
bile peritonitis, hepatic abscess, gallstones, and later cholangiocarcinoma
of the cyst wall.
 Complete excision of the cyst mucosa is the treatment of choice.

21. Intrahepatic Biliary causes
of Cholestasis
Non-syndromic causes :
1. PFIC (Progressive
familial intrahepatic
cholestasis)
2. Caroli disease /
syndrome.
Syndromic causes :
Allagille Syndrome

22. Progressive familial intrahepatic cholestasis
 Genetic basis
 Presents in first few months of life.
 3 types identified – PFIC-1, PFIC-2 & PFIC-3.
 Common presentations are in the form of Hsmegaly, failure to thrive, malabsorption, fatsoluble vitamin
deficiencies, coagulopathy, Intractable pruritus,
 Progression to cirrhosis is rapid without treatment.
 Biliary diversion, ileal exclusion are modalities of choice. Liver transplant is needed in many patients.

23. Allgille Syndrome

24. Infections associated with neonatal cholestasis :
Bacterial and
Parasitic
Bacterial sepsis
Syphilis
Listeriosis
Tuberculosis
Urinary tract infections
?Malaria
Toxoplasmosis
Viral
Cytomegalovirus
Herpes
Rubella
Adenovirus
Parvovirus B6
Hepatitis B /E

25. Metabolic disorders causing neonatal cholestasis :

26. Parenteral nutrition associated cholestasis
 Seen in newborns on prolonged TPN (>2 wks)
 Risk factors : Prematurity, short bowel syndrome, Functional liver
immaturity, Sepsis, lack of enteral feeds, Possible toxicity from the
components of Parenteral nutrition.
 Clinical features are similar to other cholestatic jaundice. Alternative
causes of cholestasis need to be excluded.
 Heoatocellular and canalicular cholestasis, steatosis and periportal
fibrosis are seen on liver biopsy. Evolution of biliary cirrhosis can occur
with continued use of parenteral nutrition.
 Management : trophic enteral feeds, UDCA (10-20mkd) , alternatives to
soy based lipid emulsions.
 Liver transplantation or combined liver-intestinal transplant may be the
only option in patients with end stage liver disease and extreme short
bowel syndrome.

27. Management
1.) Medical :
 Special formulas (medium chain triglycerides) : as it is absorbed better
regardless of the luminal concentration of bile acids.
Breastfed cholestatic infants should be given supplemental MCT.
 Vitamin Supplements (Vit K, E, D, A)
 Dietary restrictions (as per diagnosis)

28. Target FSV Levels and Replacement Regimens
Vitamin Target Range (Serum Level) Supplementation Strategy
A (retinol) 19–77 μg/dL retinol:RBP molar ratio
>0.8
Increments of 5000 IU (up to 25–50 000 IU/d)
orally or monthly intramuscular
administration of 50 000 IU
D (25-hydroxy vitamin D) 15–45 ng/mL Increments of 1200 to 8000 IU orally daily of
cholecalciferol or ergocalciferol; alternatively
calcitriol at 0.05 to 0.20 μg/kg per d
E (α tocopherol) 3.8–20.3 μg/mL vitamin E:total serum
lipids ratio >0.6 mg/g
Increments of 25 IU/kg of TPGS orally daily (to
100 IU/kg per d)
K (phytonadione) INR ≤ 1.2 1.2 < INR ≤ 1.5 2.5 mg vitamin K orally daily,
1.5 < INR ≤ 1.8 2.0–5.0 mg vitamin K
intramuscular and 2.5 mg vitamin K orally
daily, INR > 1.8 2.0–5.0 mg vitamin K
intramuscular and 5.0 mg vitamin K orally
daily
Efficacy of Fat-Soluble Vitamin Supplementation in Infants With Biliary Atresia
Benjamin L. Shneider et al.for the Childhood Liver Disease Research Education Network (ChiLDREN), 2012

29. Management
2.) Pharmacological :
 UDCA (Ursodeoxycholic acid) : helps cholestasis by substitution in the bile pool
for more hydrophobic bile acids & stimulation of the bile flow.
Recommended dose : 15-30mg/kg/d in divided doses.
 Phenobarbitone : Acts by inducing hepatic microsomal enzymes and increasing
bile flow.
Recommended dose : 3 – 5mg/kg/day
 Cholestyramine : Binds the bile acids in intestinal lumen , thereby decreasing the
enterohepatic circulation of bile acids, which lead to fecal excretion and increasing
hepatic synthesis of bile from cholesterol. Thus, decreasing the cholesterol levels.