Download Biliary Atresia

Infantile cholestasis
浙江大学医学院附属儿童医院
江米足
Neonatal jaundice
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Neonatal jaundice is one of the most common
conditions needing medical attention in
newborn babies.
About 60% of term and 80% of preterm
babies develop jaundice in the first week of
life, and about 10% of breast fed babies are
still jaundiced at age 1 month.
Neonatal jaundice is generally harmless, but
high concentrations of unconjugated bilirubin
may occasionally cause kernicterus
(permanent brain damage).
Physiologic jaundice
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Jaundice becomes visible on the 2nd-3rd day,
usually peaking between the 2nd and 4th
days at 5-6mg/dl and decreasing to below 2
mg/dl between the 5th and 7th days of life.
6-7% of full-term infants have indirect
bilirubin levels ≥12.9 mg/dl and less than 3%
have levels ≥ 15 mg/dl.
Indirect bilirubin levels in full-term infants
decline to adult levels (1mg/dl) by 10-14 days
of life.
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In contrast to physiological
unconjugated hyperbilirubinaemia,
which requires careful monitoring but is
common and usually benign, the
presence of significant conjugated
bilirubin always indicates pathology
Pathologic jaundice
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It appears in the 1st 24-36hr of life
Serum bilirubin is rising at a rate faster than 5
mg/dl/24hr.
Serum bilirubin is ≥ 12 mg/dl in full-term or 1014 mg/dl in preterm infants.
Jaundice persists after 10-14 days of life.
Direct-reacting bilirubin is ≥ 2 mg/dl at any
time.
Among other factors suggesting a
nonphysiologic cause of jaundice.
Cholestasis
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An alternative or concomitant response
to injury caused by extrahepatic or
intrahepatic obstruction to bile flow.
Accumulation in serum of substances
normally excreted in bile such as
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direc-reacting bilirubin
choesterol
bile acid
trace elements occurs
Neonatal cholestasis
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Neonatal cholestasis is defined a
sprolonged elevation of serum levels of
conjugated bilirubin beyond the first 14
days of life.
Jaundice that appears after 2 wk of age,
progress after this time, or does not
resolve at this time should be evaluated
and a direct bilirubin level determined.
Neonatal cholestasis
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May be due to infectious, genetic,
metabolic, or undefined abnormalities
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mechanical obstuction of bile flow
functional impairment of hepatic excretory
function and bile secretion.
May be divided into extrahepatic and
intrahepatic disease.
Neonatal cholestasis
Neonatal cholestasis
Intrahepatic disease
Hepatocyte injury
Metabolic
disease
Viral
disease
Bile duct injury
Idiophathic
neonatal
hepatitis
Intrahepatic
bile duct
hypoplasia
or paucity
Extrahepatic
disease (bile
duct injury or
obstruction)
Extrahepatic
biliary
atresia
Extrahepatic disorders
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Biliary atresia
sclerosing cholangitis
Bile duct stenosis
Choledochal cyst
Choledochal-pancreaticoductal junction
Anomaly
Spontaneous perforation of the bile duct
Mass (neoplasia, stone)
Bile/mucous plug
Intrahepatic disorders
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Intrahepatic cholestasis, persistent
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Intrahepatic cholestasis, recurrent
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“Idiopathic” neonatal hepatitis
Alagille syndrome (Arteriohepatic dysplasia)
Intrahepatic biliary hypoplasia or paucity of
intrahepatic bile ducts (nonsyndromic)
Progressive familial intrahepatic cholestasis (PFIC)
Familial benign recurrent cholestasis associated with
lymphedema (Aagenaes)
Congenital hepatic fibrosis
Caroli disease (cystic dilatation of intrahepatic
ducts)
Metabolic disorders
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Disorders of amino acid metabolism
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Disorders of lipid metabolism
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Wolman’s disease/cholesterol ester storage disease
Niemann-Pick disease
Gaucher’s disease
Disorders of carbohydrate metabolism
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Tyrosinemia
Galactosemia
Fructosemia
Glycogen storage disease, Type IV
Disorders of bile acid metabolism
Other metabolic defects
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1-antitrypsin deficiency
Cystic fibrosis
Idiopathic hypopituitarism
Hypothyroidism
Infectious
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Generalized bacterial sepsis with possible endotoxemia
Viral infection
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Cytomegalovirus (CMV)
Rubella virus
Herpes virus (HSV and HHV-6 and -7)
varicella virus
Coxsackie virus
ECHO virus
reovirus type 3
Human immunodeficiency virus (HIV)
Parvovirus B19
Hepatitis A, B, and C virus (rare)
others
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Toxoplasmosis
Syphilis
tuberculosis
Listeriosis
Genetic and Miscellaneous
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Genetic or chromosomal
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Trisomy E
Down syndrome
Donahue syndrome (leprechaunism)
Miscellaneous
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Langerhans cell histiocytosis
Shock or hypoperfusion
Associated with intestinal obstruction
Associated with enteritis
Neonatal lupus erythematosus
Differentiation of cholestasis
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The clinical features of any form of
cholestasis are similar.
In an affected neonate, the diagnosis of
certain entities, such as galactosemia, sepsis,
and hypothyroidism, is relatively simple.
In most cases, the cause of cholestasis is
more obscure.
Differentiation among biliary atresia,
idopathic neonatal hepatitis, and intrahepatic
cholestasis is particularly difficult.
Infantile cholestasis
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Alagille syndrome
PFIC
Biliary atresia
Alagille syndrome
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Description: autosomal dominant intrahepatic
cholestasis syndrome
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Organs involved:
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liver (2)
heart(1, 2)
Who is most affected:
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absence of bile ducts
associated with congenital heart disease
onset of most symptoms ≤ 1 year old(2)
males and females equally(1)
Incidence/Prevalence:
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about 1 in 70,000 births of all races worldwide(2)
Alagille syndrome
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Causes:
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autosomal dominant(1)
genetic defect on short arm of
chromosome 20 with incomplete
penetrance, variable expression
Jagged1 gene identified in 70% Alagille
syndrome patients, which encodes a ligand
for the notch receptor
Alagille syndrome
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Complications:
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cirrhosis
increased risk of hemorrhage
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based on series of 174 patients with Alagille syndrome
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38 (22%) had hemorrhagic complications
14% overall mortality due to hemorrhage
3 (1.7%) deaths from intracranial bleeding
case report of infant with acute intracranial
hemorrhage presenting with
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irritability
seizures
vomiting
Alagille syndrome
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Associated conditions:
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associated with(1)
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congenital heart disease reported in 85% of
patients with Alagille syndrome(1)
peripheral pulmonic stenosis(1)
bony defects
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growth retardation
renal impairment secondary to mesangiolipidosis
other skeletal, cardiopulmonary and ocular abnormalities
butterfly vertebra
spina bifida
unilateral cystic kidney, abdominal coarctation,
talon cusp dental anomaly
Alagille syndrome
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Most common syndrome incorporating intrahepatic
bile duct paucity.
Clinical manifestations in various and nonspecific
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Facial characteristic
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Ocular abnormalities: posterior embryotoxon
Cardiovascular abnormalities
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broad forehead, deep-set, widely spaced eyes, long and
straight nose, an underdeveloped mandible
Peripheral pulmonic stenosis, tetralogy of Fallot
Vertebral arch defects and failure of anterior vertebral arch
fusion (butterfly vertebrae)
Tubulointerstitial nephrophathy
Growth retardation and defective spermatogenesis
History of Alagille syndrome
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Chief concern (CC):
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jaundice
pruritus
History of present illness (HPI):
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5 main characteristics
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chronic cholestasis
characteristic facies: broad forehead, deep-set eyes, straight
nose, pointed chin
posterior embryotoxon (congenital opaque ring around
margin of cornea)
butterfly-like vertebral-arch defects seen on radiologic
studies
cardiopulmonary malformations
less common features(2)
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intracranial bleeding
pancreatic insufficiency
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Testing overview:
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liver biopsy
gene testing for Jagged1 mutation
echocardiography
Biopsy and pathology:
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presence of decreased intrahepatic bile
ducts on liver biopsy (defined as ratio of
interlobular bile ducts to portal tracts <
0.5)(2)
Making the diagnosis
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5 characteristic features(2)
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chronic cholestasis
characteristic facies: broad forehead, deep-set eyes, straight
nose, pointed chin
posterior embryotoxon
butterfly-like vertebral-arch defects
cardiovascular malformations
ratio of interlobular bile ducts to portal tracts <0.5 in
association with(2)
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≥ 3 characteristic features
or 2 characteristic features if patient has positive family
history
or 1 characteristic feature if patient has Jagged1 gene defect
(mutation)
Therapy
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Treatment:
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medium-chain triglycerides and intramuscular
administration of fat-soluble vitamins may be
considered
ursodeoxycholic acid and/or cholestyramine may
reduce pruritus
liver transplant may be needed for severe liver
disease
Diet:
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medium-chain triglyceride supplement may be
used
Prognosis
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The prognosis for prolonged survival is good,
which varies depending on severity of hepatic
or cardiac involvement(2),
Patients are likely to have pruritus, xanthomas
with markedly elevated serum cholesterol
levels, and neurologic complications of vitamin
E deficiency if untreated.
liver transplantation necessary in 21-31% of
cases(2)
Progressive familial
intrahepatic cholestasis (PFIC)
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Due to defects in specific transport proteins
involved in bile formation
Characterized by unique structural abnormalities
in the bile canalicular membrane.
Present with failure to thrive, steatorrhea,
pruritus, rickets, and low GGT levels.
Cirrhosis gradually develops.
Differentiation from Alagille syndrome is the
absence of bile duct paucity and extrahepatic
features.
PFIC
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PFIC type 1 (Byler disease)
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PFIC type 2,
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Low GGT, normal serum cholesterol, high serum bile acid
levels
mapped to chromosome 18q12, present in Amish family.
similar to Byler disease
has gene locus at chromosome 2q24, present in non-Amish
family (Middle Eastern Europeans)
PFIC type 3,
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High serum levels of GGT, histologically by portal bile duct
inflammation and proliferation
at chromosome 7q21
PFIC: Types, related genes, and transport defects.
Disease
Gene
Transport defect
Aminophospholipids
PFIC1
18q21-22
PFIC2
FIC1
ATP8B1
ABCB11
P type ATP ase
Phosphatidyl serine
Phosphatidyl ethanolamine
BA
BSEP
BA
2q24
PFIC3
ABCB4
PC
MDR3
PC
7q21
Hepatocyte
BA: bile acid; PC: phosphatidylcholine.
Canaliculus
Biliary atresia
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Description:
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neonatal disorder with obliteration or
discontinuity of extrahepatic biliary system and
obstruction of bile flow, leading to persistent
direct hyperbilirubinemia beyond the first two
weeks of life
Biliary atresia
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Types:
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correctable vs. noncorrectable
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20% correctable type - normal common bile duct
becomes atretic distally
80% noncorrectable - no macroscopic biliary system
in portal triad
embryonal or fetal (10%-35%) vs. progressive
post-natal (65%-90%)
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embryonal type associated with congenital
anomalies in 10%-20% cases, more severe in
embryonal type
Biliary atresia types
Figure 1 Schematic illustration of classification of biliary atresia types 1,2,3
Jane L Hartley , Mark Davenport , Deirdre A Kelly
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Organs involved:
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Who is most affected:
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liver, intrahepatic and extrahepatic biliary ducts
4 weeks to 4 months after birth
more common in girls than boys
twice as common in African American infants
compared to Caucasian infants
more common among Chinese than Japanese or
Caucasian infants
Incidence/Prevalence:
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typical estimates are 1/10,000-13,000 births
Pathogenesis
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fetal/embryonic type - congenital obliteration
of bile ducts
progressive post-natal type
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acquired inflammatory process with gradual
degeneration of epithelium of extrahepatic biliary
ducts
causes luminal obliteration, cholestasis and biliary
cirrhosis
secondary loss of intrahepatic tree from
complications of obstruction
Complication
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biliary cirrhosis
bone disease (osteoporosis, osteopenia,
rickets, fractures) reported in 5 studies
with > 100 children with biliary atresia,
rates ranged from 11% to 45%
developmental anomalies tend to occur
in heart, digestive tract or spleen
History
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Chief concern (CC):
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jaundice
History of present illness (HPI):
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jaundice for more than 2-6 weeks after birth or
remitting jaundice, otherwise apparently
healthy infant
may have light stools (acholic stools), dark
urine (choluria)
malnourishment in patients with more
progressive liver disease
physical
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General physical:
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Skin:
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jaundice
HEENT:
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infant usually has normal activity and nutrition
early in disease
scleral icterus
Abdomen:
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hepatomegaly, liver may be hard
splenomegaly
Making the diagnosis
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infant with jaundice after age 14 days
medically treatable causes of neonatal cholestasis
excluded
other structural abnormalities excluded by abdominal
ultrasound
liver biopsy shows findings of biliary atresia (cholestasis,
bile duct proliferation, bile ductular cholestasis,
extramedullary hematopoiesis, giant cell transformation
of hepatocytes)
exploratory laparotomy and intraoperative cholangiogram
demonstrates obliteration of biliary system
Differentiate diagnosis
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TORCH syndrome - congenital
infections such as toxoplasmosis other
(for example, syphilis), rubella, CMV,
herpes
alpha-1 antitrypsin (AAT) deficiency
biliary hypoplasia
paucity of bile ducts
Testing overview
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persistent direct hyperbilirubinemia beyond 2
weeks of life requires thorough work-up
blood tests
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liver panel - transaminases, alkaline phosphate,
bilirubin, gamma-glutamyl transpeptidase
coagulation studies - PT/INR, PTT
TORCH titers (toxoplasma, RPR, rubella, CMV, HSV)
serum protein electrophoresis (SPEP) for AAT
deficiency
ultrasound - right and left upper quadrants
Testing overview
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nuclear scans for biliary excretion into gastrointestinal
tract with 99m-Tc-iminodiacetic acid derivatives (HIDA,
PIPIDA, DISIDA) after pre-stimulation with phenobarbital
orally for 5 days, may be useful if ultrasound results
equivocal
endoscopic studies - yellow bilirubin pigment in duodenal
aspirate rules out biliary atresia
percutaneous liver biopsy if no hepatobiliary excretion
diagnostic laparoscopy (or laparotomy) if unable to rule
out biliary atresia
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intraoperative cholangiogram
hepatic biopsy
Blood tests
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conjugated hyperbilirubinemia with or without liver
enzyme abnormalities depending on degree of liver
damage
elevated lipoprotein-X
elevated GGT levels (> 300 units/L in 90% of patients)
combination of lipoprotein-X > 89 mg/100 mL and GGT >
194 units/L differentiated 11 Japanese infants with biliary
atresia from 13 Japanese infants with intrahepatic
cholestasis
PT/INR and PTT may be elevated secondary to vitamin K
deficiency, these children are at risk for intracranial
hemorrhage
Biliary Atresia: Evaluation
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Laboratory
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GGT/ALK Phos
ALT/AST
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Conjugated Bili
 > 20% of total
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Hepatomegaly
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Acholic Stool
Ultrasound useful
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findings in biliary atresia - 85% sensitivity,
80% specificity
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absent or small gallbladder that does not
contract upon hormonal stimuli
no biliary dilation
increased liver echogenicity
triangular cord sign (triangular or tubular
echogenic density seen immediately cranial
to the portal vein bifurcation) reliable for
diagnosing or ruling out biliary atresia
"Triangular cord" sign
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A triangular/tubular,
echogenic density seen
just cranial to the
portal vein bifurcation
in BA
Simple, noninvasive,
inexpensive,
timesaving, and
reliable
Park et al J Hepatobil Pancreat Surg 2001;8:337
Kotb et al Pediatrics 2001;108:416
Hepatobiliary scintigraphy
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may be of value to rule out biliary atresia (BA) if
ultrasound results are equivocal
findings in BA
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increased hepatic uptake during early injection
no significant bilioenteric excretion in delayed films
(that is, no isotope in intestine at 24 hours)
nuclear scan for BA has nearly 100% sensitivity
and 85%-95% specificity
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nuclear scan more sensitive than ultrasound for BA
no activity in bowel after 24 hours on technetium Tc99m mebrofenin cholescintigraphy had 100% sensitivity,
93% specificity, 80% positive predictive value and
100% negative predictive value
Endoscopic retrograde
cholangiopancreatography (ERCP)
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no visualization of biliary ducts in biliary
atresia
very expensive
can identify other diseases
may avoid laparotomy
Biopsy and pathology
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percutaneous liver biopsy - 90% sensitivity, 80%
specificity
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deferred until 6 weeks of age when portal tracts best
developed
5 most common findings in biliary atresia
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cholestasis
bile duct proliferation
bile ductular cholestasis
extramedullary hematopoiesis
giant cell transformation of hepatocytes
findings associated with poor prognosis - giant cells,
lobular necrosis, focal necrosis, bridging necrosis,
cholangitis
stain with PAS can exclude AAT deficiency
Other diagnostic testing
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diagnostic laparoscopy (or laparotomy) if
unable to rule out BA
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gallbladder - fibrotic or extremely small,
mucoid clear secretions or no fluid
liver - early subcapsular telangiectasias
intraoperative cholangiography
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if normal biliary system - wedge biopsy of liver and
close
if abnormal biliary system - explore porta hepatis for
atretic duct
Screening
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infant stool color card described as
screening method for biliary atresia
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parents asked to observe infant's stool color and
assign 1 of 7 numbers based on different color
pictures, about 65% (78,184 infants) had stool color
card returned at 1-month-old checkup, study
conducted in Taiwan
29 infants (0.037%) diagnosed with biliary atresia, of
whom 26 were identified before age 60 days with stool
color card
stool color card had 89.7% sensitivity, 99.9%
specificity and 28.6% positive predictive value
English version of the infant stool color card (first edition).
©2006 by American Academy of Pediatrics
Chen S et al. Pediatrics 2006;117:1147-1154
Treatment overview
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medical management is uniformly fatal
surgical management in infancy
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diagnostic laparoscopy (or laparotomy)
intraoperative cholangiography
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if normal biliary system - wedge biopsy of liver and
close, not BA
if abnormal biliary system - explore porta hepatis for
atretic duct
correctable type if extrahepatic duct found anastomosis to Roux-en-Y loop of jejunum
Treatment overview
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surgical management in infancy
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noncorrectable type - Kasai procedure
(hepatoportoenterostomy)
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anastomosis of loop of jejunum to liver hilus
initial therapeutic approach in most patients with
BA
50%-65% of patients who undergo Kasai
procedure ultimately require liver transplantation
consider primary liver transplant for infants
not likely to benefit from Kasai procedure
liver transplantation
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liver transplantation
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usually after Kasai procedure, but can be
done as primary surgery
10% will require early retransplantation
5% will require retransplantation later in
life due to chronic rejection
Prognosis
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universally fatal without surgery, median survival 8 months
5-year survival 52.7% to 64.5%, 69.4% to 79.5% without
or with liver transplantation.
prognosis of patients who undergo Kasai portoenterostomy
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29%-60% 5-year survival, 25%-35% 10-year survival, 8% 20-year
survival
many will require liver transplantation
survivors have long-term complications
prognosis related to age at diagnosis and surgery
prognosis related to microscopic stage of biliary tree from hilar
specimen
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good prognosis if ductules > 120 microns
very poor prognosis if ductules < 70 microns
Significant predictors of poor
outcome
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Caucasian race
operative age > 60 days
cirrhosis at initial biopsy
non-patent extrahepatic ducts
absent ducts at plane of hepatic hilar
transection
postoperative varices or ascites