2. Cholestasis
Defined as an impairment in the excretion of bile, which can be caused by
Defects in intrahepatic production of bile,
Transmembrane transport of bile, or
Mechanical obstruction to bile flow.
3. Neonatal cholestasis
Neonatal cholestasis is defined biochemically as prolonged elevation of the serum levels of
conjugated bilirubin beyond the 1st 14 days of life.
Conjugated hyperbilirubinemia – serum conjugated bilirubin concentration greater than
1.0 mg/dL if the total bilirubin is <5.0 mg/dL or greater than 20 percent of the total bilirubin if
the total bilirubin is >5.0mg/dL.
6. Clinical presentation
Jaundice
High colored urine
Pale color stool
Steatorrhea
Pruritus
Ascites
Bleeding manifestations
Failure to thrive
7. Evaluation
History of
Consanguinity (autosomal recessive PFIC)
Congenital infection (CMV, Toxoplasma, Herpes, Syphilis)
Ultrasound during antenatal period (Choledochal cyst, bowel anomalies)
Neonatal infection (Urinary tract infection)
ABO incompatibility
Weight gain(failure to thrive in metabolic disease, ascites)
Recurrent vomiting (metabolic disease, pyloric stenosis)
Stool pattern (cystic fibrosis – delayed passage of meconium, hypothyroidism, loose
stool – infection, metabolic causes)
High colored urine
Excessive bleeding (vitamin k deficiency)
Edema (protein synthesis by liver)
Irritability (sepsis, metabolic causes)
8. Examination
Sick/Well looking
Icterus
Weight, length (failure to thrive)
Syndromic appearance (Alagille syndrome – broad nasal bridge, triangular
facies, deep set eyes)
Bleeding manifestation
Abdomen – liver and spleen size, position and consistency, ascites, mass
Direct stool and urine examination
9. Neonatal cholestasis
Sick Not sick
Treat sepsis
(Galactosemia
needs to be
excluded by urine
reducing sugar by
Benedict’s test as
sepsis can be
associated with
Galactosemia)
surgery
Fasting USG
(If the USG show a
Choledochal cyst,
the child needs to be
referred for
surgery), Metabolic
tests, Genetic tests,
Liver Biopsy
Biliary atresia to
be excluded
Test for CMV, HSV,
Urinary
Succinylacetone,
Ferritin,
GALT if urine
reducing sugar
is positive
Pigmented stools
Absent GB
Septic screen
positive
Pale color stools
Liver biopsy
Normal GB Small GB
Fasting USG (see
for contractility
post-feed)
Septic screen
negative
Choledochal
cyst
Specific
treatment
10. LABORATORY STUDIES
Total & conjugated bilirubin, prothrombin time (PT), International normalized ratio (INR) and
partial thromboplastin time (PTT), total protein and albumin.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) – To assess liver
cell injury.
Serum alkaline phosphatase and gamma - glutamyl trans peptidase (GGTP) – biliary
obstruction.
GGTP is typically elevated in biliary atresia and Alagille syndrome, while a normal to low GGTP
is seen in most forms of progressive familial intrahepatic cholestasis (PFIC), bile acid synthetic
disorders, and arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.
Electrolytes, bicarbonate, and glucose, as an initial screen for metabolic disease.
Complete blood count with differential.
11. A1AT level and an abnormal protease inhibitor phenotype (PIZZ and PISZ) – A1AT deficiency.
Urinary-reducing substances or red blood cell galactose-1-phosphate uridyl transferase drawn before any
blood transfusions (for galactosemia)
Urine Succinylacetone – hereditary tyrosinemia
Sweat test – cystic fibrosis
thyroid-stimulating hormone and thyroxine – hypothyroidism
total serum bile acid level and urine bile acid profile – disorders of bile acid synthesis
Serum amino acids and urine organic and amino acids – citrin deficiency, fatty acid oxidation defects, and
other metabolic diseases
Very long chain fatty acid levels – peroxisomal disorders and
Infectious agent serologies as indicated
Genetic testing for Alagille syndrome, cystic fibrosis, A1AT deficiency, three distinct forms of PFIC, and
peroxisomal defects are commercially available. In the near future, next-generation DNA sequencing will
allow for multiple genetic tests on small amounts of blood at a relatively low cost
12. Ultrasonography
Exclude gall stones, neoplastic lesion and other anatomic causes of cholestasis (ie,
Choledochal cyst).
Absent (or nonvisualized) gallbladder and the presence of the triangular cord sign (triangular
or band like periportal echogenic density >3 mm in thickness).
Ultrasound may also identify situs abnormalities, polysplenia, or vascular anomalies that could
be associated with biliary atresia.
13. Scintigraphy
False positive results and occasional false negative results.
A technetium-labeled iminodiacetic acid analog administered intravenously, then
uptake by the liver and subsequent excretion into the biliary tree and intestine is
monitored.
Biliary atresia – normal uptake of the isotope but absent excretion into the bile and
intestine
Neonatal hepatitis typically have delayed uptake but appropriate excretion.
14. Nonvisualization of the gallbladder or lack of excretion can occur in patients
without biliary atresia.
Five days with phenobarbital (5 mg/kg per day) increases the accuracy of this test
by enhancing isotope excretion.
The sensitivity scintigraphy in detecting biliary obstruction is approximately 99
percent, and the specificity ranges from 69 to 72 percent.
15.
16. Liver biopsy
Early diagnosis of biliary atresia and preclude unnecessary surgical exploration
Biliary atresia - Bile ductular proliferation, the presence of bile plugs, and portal or perilobular
edema and fibrosis, with the basic hepatic lobular architecture
intact
Neonatal hepatitis - Severe, diffuse hepatocellular disease, with distortion of lobular
architecture, marked infiltration with inflammatory cells, and focal hepatocellular necrosis; the
bile ductules show little alteration
Alpha 1 antitrypsin, galactosemia and various forms of intra hepatic cholestasis
If the results are equivocal and biopsy was performed when the infant was <6 weeks of age,
repeat biopsy may be necessary.
17. Endoscopic retrograde
cholangiopancreatography (ERCP)
Its utility in neonates is limited by the availability of appropriately sized
endoscopes, the need for deep sedation or general anesthesia in most cases, and
the lack of validation.
18. Cholangiogram
Open Cholangiogram — Intraoperative cholangiogram, which is the gold
standard in the diagnosis of biliary atresia.
If the intraoperative cholangiogram demonstrates biliary obstruction (ie, if
the contrast does not fill the biliary tree or reach the intestine), then
perform a hepatoportoenterostomy (Kasai procedure).
19. Biliary atresia
Most common cause of cholestasis (30%)
Early diagnosis (<8 weeks of age better prognosis)
Two types on time of onset – perinatal and embryonic
Perinatal have symptoms 2 to 4 weeks of age
Embryonic present with symptoms at birth associated with congenital
anomalies (polysplenia, malrotation)
20.
21. Type 1: Atresia of the common bile duct with patent proximal ducts
Type 2: Atresia involving the hepatic duct but with patent proximal ducts
Type 3: Atresia involving the right and left hepatic ducts at the porta
hepatis
22. Biliary atresia to be
excluded
(Baby not sick, pale stools, small or
absent gall bladder on
fasting ultrasound)
HIDA scan after
priming
(5mg/kg/day)
Liver biopsy
Age <6 weeks
Refer to
transplant center
Intra operative
Cholangiogram and
KASAI procedure
Specific
treatment
Excretion
Age >6 weeks Age >90 days
with ascites
Age 120 days
No
excretion
Inconclusive
Biliary atresia
23. Sl.no. Features Neonatal hepatitis Biliary atresia
1 Onset Anytime in neonatal period End of first week usually
2 Sex More in males More in females
3 Gestation Preterm / IUGR Term
4 Family history 15% Nil
5 Cataract May be present Absent
6 Stools Pale / normal Clay colored
7 Condition at birth Looks sick Looks healthy initially
8 Hepatosplenomega
ly
Early Late
9 Urine UBG Increased Absent
10 Transaminases Very high High
24. Sl.no. Features Neonatal hepatitis Biliary atresia
11 Alkaline phosphatase High Very high
12 TORCH screen May be positive Negative
13 Serum lipoprotein X High High
14 Cholestyramine Decreases lipoprotein Same as high
15 Alpha fetoprotein High Normal
16 USG GB seen Absent GB
17 Liver biopsy Severe, diffuse hepatocellular
disease, with distortion of lobular
architecture, marked infiltration
with inflammatory cells, and focal
hepatocellular necrosis; the bile
ductules show little alteration
Bile ductular proliferation, the presence of
bile plugs, and portal or perilobular
edema and fibrosis, with the basic hepatic
lobular architecture
intact
18 HIDA scan Radioactivity in gut No radio activity in gut
19 Cholangiogram Normal Block may be viualized
20 Prognosis Better Poor
25. Management of biliary atresia
In the Kasai portoenterostomy, an anastomosis
between the porta hepatis and a retrocolic Roux-en-Y
loop of jejunum is fashioned.
Two thirds of infants will have successful drainage, but
despite this, two thirds of those with bile drainage will
require liver transplantation at some stage in their
lives.
Diameter above 150 μm having increased chance of
good bile flow.
There was markedly improved survival in children with
total bilirubin level <2 mg/dL at 3 months after HPE.
Postoperatively, infants are typically maintained on a
formula containing high levels of medium-chain
triglycerides, supplemented with fat-soluble vitamins,
and Ursodeoxycholic acid to stimulate bile flow.
26. Indications for liver transplantation in BA
Failed Kasai hepatoportoenterostomy
Increasing cholestasis
Pruritus, and/or
Failure to thrive
Recurrent cholangitis with bile lakes in the liver on imaging studies
27. Management of child with persistent cholestasis
CLINICAL IMPAIRMENT MANAGEMENT
Malnutrition resulting from malabsorption of
dietary long-chain
triglycerides
Replace with dietary formula or supplements
containing medium chain triglycerides (1-2
mL/kg/d in 2-4 divided
doses in expressed breast milk )
Vitamin A deficiency (night blindness, thick skin) Replace with 10,000-15,000 IU/day as Aquasol A
Vitamin E deficiency (neuromuscular
degeneration)
Replace with 50-400 IU/day as oral α-
or TPGS
Vitamin D deficiency (metabolic bone disease) Replace with 5,000-8,000 IU/day of D2 or 3-5
µg/kg/day of
25-hydroxycholecalciferol
Vitamin K deficiency (hypoprothrombinemia) Replace with 2.5-5.0 mg every other day as
soluble derivative of
menadione
Micronutrient deficiency Calcium, phosphate, or zinc supplementation
28. CLINICAL IMPAIRMENT MANAGEMENT
Deficiency of water-soluble vitamins Supplement with twice the
daily allowance
Retention of biliary constituents such as
cholesterol (itch or
xanthomas)
Administer choleretic bile acids
Ursodeoxycholic acid (UDCA) (20
mg/kg/d), rifampicin
(5-10 mg/kg/d), and Phenobarbitone (5–
10 mg/kg/d)
Progressive liver disease; portal
hypertension (variceal bleeding,
ascites, hypersplenism)
Interim management (control bleeding;
salt restriction; spironolactone)
End-stage liver disease (liver failure) Transplantation
29. Summary and recommendations
Any infant who is noted to be jaundiced at two weeks of age should be evaluated for cholestasis by
measuring total serum bilirubin and conjugated (direct) bilirubin. The laboratory evaluation of breastfed
infants who have a normal physical examination, normally colored stools and urine, and can be closely
monitored may be delayed until they are three weeks of age.
Conjugated hyperbilirubinemia is defined as conjugated bilirubin concentration greater than 1.0 mg/dL if
the total bilirubin is <5.0 mg/dL or more than 20 percent of the total bilirubin if the total bilirubin is
>5.0 mg/dL.
Causes of cholestasis in neonates and young infants include several types of biliary obstruction, hepatic or
systemic infection, metabolic diseases, and toxic or alloimmune insults. Biliary atresia and neonatal
hepatitis account for most cases of cholestasis in term infants. In premature infants, cholestasis more
frequently results from total parenteral nutrition (TPN) or sepsis.
30. The evaluation of cholestatic jaundice in infants after two weeks of age should be undertaken
in a staged approach, guided by a focused history, physical examination, and laboratory
evaluation.
The initial step is rapid diagnosis and early initiation of therapy of treatable disorders (eg,
sepsis, hypothyroidism, inborn errors of metabolism).
The next step is to distinguish biliary atresia from other causes of neonatal cholestasis
because early surgical intervention for biliary atresia before 60 days of age results in improved
outcome. Key steps are ultrasonography and liver biopsy.
Additional testing is directed at the diagnosis of specific conditions and evaluation of
associated complications (eg, coagulopathy).
31. If jaundice fails to resolve in an infant in whom a treatable condition is diagnosed (eg, urinary
tract infection or galactosemia) and treated, further evaluation should be performed.
In the evaluation of an infant with cholestasis of unknown etiology, ultrasonography of the
liver is almost always included and liver biopsy is often indicated.
Hepatobiliary scintigraphy provides supportive information about biliary obstruction and can
be performed if the test is readily available and does not delay subsequent diagnostic steps.
However, the test is associated with substantial numbers of both false positive and false
negative results, so it should not be used solely to either confirm or exclude the diagnosis of
biliary atresia.
Endoscopic retrograde cholangiopancreatography (ERCP) is not routinely recommended.
However, if expertise in neonatal ERCP is available, this procedure can be used to detect
Extrahepatic obstruction, including biliary atresia or cholelithiasis.
