CHOLEASTASIS IN

INFANCY
INTRODUCTION
 Cholestasis is not a disease but a
symptom of many disease .
 It is an uncommon but potentially
dangerous condition which indicates
hepatobiliary dysfunction.
 Cholestasis occurs in approximately 1 in
2,500 births
 However distinguishing jaundice caused by cholestasis from
non-cholestasis is critical because cholestasis from the former is
much more likely to have a serious etiology that needs prompt
diagnosis and therapy.
Jaundice from non-cholestasis are usually characterised by
unconjugated hyperbilirubinaemia while does of cholestasis are
characterised by conjugated hyperbilirubinaemia.
Conjugated hyperbilirubinemia in the first month of life is
pathologic and may be serious or even life-threatening disease
requiring urgent evaluation
DEFINITION

Cholestasis is a decrease in bile secretion by

hepatocytes or obstruction to flow of bile through the
intrahepatic or extrahepatic bile duct.
this results:
a. in the retention or accumulation of substances
that are normally excreted in the bile within the
serum .
Examples of these substances include ; bilirubin,
bile salts, bile acids, and/or cholesterol
b. Reduction in the bile salt excreted in the
intestine.
cholestasis in infancy is therefore
characterised by prolonged conjugated
hyperbilirubinaemia more than 2 weeks.
 Conjugated hyperbilirubinemia in a
neonate is defined as a serum conjugated
bilirubin concentration greater than 1.0
mg/dL (17.1 micromol/L) if the total serum
bilirubin is <5.0 mg/dL (85.5 micromol/L) or
greater than 20 percent of the total serum
bilirubin if the total serum bilirubin is >5.0
mg/dL (85.5 micromol/L).
AETIOLOGY
The causes of cholestasis can be grouped
anatomically into
 Intrahepatic
 Extrahepatic (also known as neonatal hepatic
syndrome, NHS)
The most common causes of cholestatic
jaundice in the first months of life are biliary
atresia and neonatal hepatitis which account for
most cases.
 AETIOLOGY

INTRAHEPATIC EXTRAHEPATIC [ NHS]

 IDIOPATIC BILIARY ATRESIA
 GENETIC BILIARYHYPOPLASIA
Down syndrome BILIARY STENOSIS
 HEPATITIS CHOLEDOCHAL CYST
MASS
Vertical transmission
 METABOLIC
Abnormal met of a’a, cho
Alpha 1 antitrypsin def
 INFECTION
Torchs
CLINICAL FEATURES
Cholestasis typically is noted in the first 2 wk of
life. Infants are jaundiced and often have dark
urine (containing conjugated bilirubin), acholic
stools, and hepatomegaly. If cholestasis persists,
chronic pruritus is common, as are symptoms and
signs of fat-soluble vitamin deficiency .
Aside from the above features, the clinical
presentation of the cholestatic infant can vary
widely depending on the etiology
 Infants with cholestatic jaundice caused by bacterial sepsis,
galactosemia, hypopituitarism, or gallstone often appear acutely
ill, irritated, poor feeding, hypotonic, hypogycemic.
These disorders require early diagnosis and urgent treatment.
However, many infants with cholestatic jaundice(esp those
with biliary atresia) appear otherwise healthy and grow normally.
The benign appearance of such an infant may lull the parents or
physician into believing that the jaundice is physiologic or
caused by breast-feeding, when in fact it may be caused by
biliary atresia.
 Some infants may present with bleeding
disorder
Cholestasis as a result of a genetic
mutation may have associated physical
findings such as a heart murmur, vertebral
anomalies, typical facial features and eye
findings in Alagille syndrome (such as broad
forehead, deep set eye and pointed chin).
 Infants with congenital infection may
have growth restriction, microcephaly and
hapatomegaly.
Those with choledochal cyst have a mass
in the right upper quadrant of the abdomen.
IMAGE OF A BOY WITH ALAGILLE
SYNDROME
 CHOLESTASIS

BILE RETENTION PROGRESSIVE BILIARY CIRRHOSIS BILE IN GUT

BILE ACID PORTAL H MALASORPTION

(HEPATOTOXIC,PURITIS)
MALNUTRITION

CHOLESTEROL DIARRHOEA
(XANTHOMATOSIS) GWT RETARDATION
CA LOST
COPPER
(HEPATOTOXICITY )
FAT SOLUBLE VIT.
NIGHT BLINDNESS (A)
MET. BONE DX (D)
COAGULOPATHY(K)
NEUROMUSCULAR DEGEN (E)
DIAGNOSIS OF CHOLESTASIS IN
INFANCY
The Cholestasis Guideline Committee
recommends that any infant noted to be jaundiced at
2 weeks of age be evaluated for cholestasis with
measurement of total and direct serum bilirubin.
However, breast-fed infants who can be reliably
monitored and who have an otherwise normal history
(no dark urine or light stools) and physical
examination may be asked to return at 3 weeks of
age and, if jaundice persists, have measurement of
total and direct serum bilirubin at that time.
 A detailed history and meticulous physical
examination could provide clues to a specific
diagnosis.
Once cholestasis is established the infant
should be referred to a gastroenterologist
where further investigation is done.
The work up should be done in a step wise
manner to rule out the causes.
 conditions like sepsis, metabolic
disorders (galactosemia) and other
endocrinopathies which are life threatening
should be ruled out first.
Once they have been excluded the next
step is to rule out biliary atresia.
If this has been excluded then the causes
of intrahepatic cholestasis is next.
 DIAGNOSTIC EVALUATION FOR NEONATAL CHOLESTASIS
ETIOLOGY TEST
Hepatic dysfunction Albumin, PT/PTT, AST, ALT, GGT, bilirubin
(total and direct)

Infections Urine cultures, TORCH titers

Endocrinopathy TSH, thyroxine

Cystic fibrosis Sweat chloride test

Galactosemia Reducing substances (eg, galactose) in

urine

α 1-Antitrypsin deficiency Serum levels of α1-antitrypsin

Genetic errors in bile acid synthesis Bile acid levels in urine and serum

Inborn errors of metabolism Urine organic acids, serum ammonia,

serum electrolytes
 In biliary atresia there is elevation of alkaline
phosphatase and gamma glutaryl transfarase unlike in
neonatal hepatitis(NH)
While there is elevation of alanine aminotransferase
(ALT) and aspartate aminotransferase(AST) in NH while it
maybe near normal in BA.
Thou this liver enzymes are sensitive indicators for
hepatocellular injury , they are not of prognostic value as
this enzymes can be found in diseases of the bone and
kidney.
While in 30-40% of cases the aetiologies are unknown
 RADIOLOGICAL
INVESTIGATIONS
ABDOMINAL ULTRASOUND
This is the most useful initial imaging study in the evaluation of
neonatal cholestasis. This can assess the size and appearance
of the liver and gall bladder .This can be used to diagnose
choledochal cyst , small or absent gall bladder that suggests
biliary atresia. Ultrasound is also recommended for infants with
cholestasis of unknown etiology.
HEPATOBILIARY SCINTIGRAPHY
This is used to distinquish between biliary atresia and other
causes. It involves injecting technetium labelled iminodiacetic
acid derivative into the vein of the arm. The liver and the
intestine are scanned at intervals, if there is excretion of the
isotope into the intestine, then there is no biliary atrsia
 ENDOSCOPIC RETROGRADE
CHOLANGIOGRAPHY
This can be useful in infants with biliary obstruction.
However the need for high technical expertise and
general anesthesia for the study limits its feasibility.
DUODENAL ASPIRATE ANALYSIS
Duodenal fluid is obtained by eithe placing a tube or a
string in the duodenum and the aspirate is analyzed
for bilirubin concentration. This test has limited use
because it is highly invasive.
LIVER BIOPSY
Percutaneous liver biopsy is the most definitive
investigation in the evaluation of neonatal
cholestasis. The characteristic findings in biliary
atresia include bile duct proliferation, bile plugs and
portal tract edema and fibrosis. These should be
differentiated from those seen in idiopathic neonatal
hepatitis that include diffuse cell swelling, giant cell
transformation and focal hepatocellular necrosis.
This can also demonstrate viral inclusion bodies
suggesting CMV or HS infection.
MANAGEMENT
SUPPORTIVE TREATMENT
This consists primarily of nutritional therapy, including supplements of
vitamins
 A: 2500-5000 IU/day
 D:400-1200 IU/day
 E:15-200 mg/day
 K: 5mg/month
the vitamin supplementation should continue atleast 3months after jaundic
Puritus which is a feature of prolonged cholestasis can be treated using
drugs that decrease the level of circulating bile acids in the blood .
ursodeoxycholic acid (UDCA) is a hydrophilic bile acid and acts by altering
the bile pool by replacing the hydrophobic bile acids. It also improves bile flow.
 Rifampin acts by inhibiting hepatic uptake
of bile acid by hepatocyte and induces the
hepatic microsomal enzymes.
 Phenobarbital stimulates bile acid flow,
enhances bile acid synthesis, induces
hepatic microsomal enzymes and hence
lowers the circulating bile acid level.
 Formula fed infants should be fed with
formula that is high in medium-chain
triglycerides such as pregestimil or alimantin
because it is absorbed better in the
presence of bile salt deficiency
For those with anorexia they should be fed
with nasogastric tube.
 SPECIFIC TREATMENT
This is directed towards the etiology
Biliary atresia is progressive and, if untreated,
results in liver failure, cirrhosis with portal
hypertension by several months of age, and death
by 1 yr of age
Infants with presumed biliary atresia require
surgical exploration with an intraoperative
cholangiogram. If biliary atresia is confirmed, a
portoenterostomy (Kasai procedure) should be done.
 This surgery invovles removal of the
fibrous tissue and a Rout-en-Y anastomosis
made between the jejunum and the hilum of
the liver
IMAGE OF THE KASAI PROCEDURE
 Ideally, this procedure should be done in
the first 1 to 2 months of life. After this
period, the prognosis significantly worsens.
Over time most infants develop persistent
cholestasis , recurrent ascending
cholangitis, and failure to thrive and liver
cirrhosis leading to need for a liver
transplant .
 Cholestasis caused by infection should be
treated appropriately eg use of penicillin for
syphilis and antibiotics for bacterial
infections
Idiopathic neonatal hepatitis syndrome
usually resolves slowly, but permanent liver
damage may result and lead to death
INFANT WITH URINE THAT STAINS
DIAPER
CONCLUSION
The rapid and effective diagnosis of the cause of cho-
lestasis in an infant is challenging. The initial detection
of these infants remains in the domain of the primary
care provider and depends on the recognition of jaundice
past the age of 2 weeks or recognition of abnormal stool
or urine color. Laboratory testing for cholestasis should
include direct (conjugated) bilirubin.
REFERENCES
 Journal of paediatric gastroenterologist
and nutrition.
 Journal of the Arab Neonatology Forum
 JK journal
ANY QUESTION
 Transcutaneous bilirubin meter
 Alagille is an autosomal dorminant
genetic disorder that affects the liver heart
kidney and other system of the body
 Serum bilirubin >2mg/dl
 Alkaline phosphatase, glucoronic
transpeptidase