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Jaundice at 14 days of age: Exclude biliary atresia

Authors:
Transoesophageal
echocardiography:
a
new
diagnostic
method
in
paediatric
cardiology
1177
Indications
for
transoesophageal
studies
in
children
(1)
Primary
diagnosis:
Atrial
pathology
Anomalous
venous
connections
Atrial
septal
defects
Atrioventricular
junction
abnormalities
Left
ventricular
outflow
obstruction
(2)
Monitoring:
Perioperative
Atrial
lesions
Atrioventricular
valve
repair/replacement
Mustard/Senning
procedure
Fontan
procedures
Continuous
monitoring
Early
postoperative
complications
Interventional
cardiac
catheterisation
Balloon
valvuloplasties
Balloon
angioplasties
Atrial
septostomies
Venous
pathway
dilatations
Coil
embolisations
Atrial
septal
defect
occlusion
Ventricular
septal
defect
occlusion
(3)
Follov
up:
Venous
pathway
reconstructions
Atrioventricular
valve
repair/replacement
Mustard/Senning
procedures
Fontan
procedures
lesions.
After
the
Mustard
or
Senning
procedure
for
complete
transposition,
transoesophageal
studies
allow
a
complete
evaluation
of
atrial
baffle
function,'2
and
thus
largely
influence
the
need
for
follow
up
cardiac
catheterisa-
tion.
After
the
various
modifications
of
the
Fontan
proce-
dure,
which
is
used
for
palliation
of
a
range
of
complex
congenital
cardiac
lesions,
the
transoesophageal
ultrasound
approach
provides
a
most
sensitive
tool
in
the
definition
of
residual
or
acquired
haemodynamic
lesions
and
yields
new
insights
into
the
patterns
of
the
pulmonary
circulation.'3
Limitations
Paediatric
transoesophageal
echocardiography
is
a
semi-
invasive
technique
that
requires
either
general
anaesthesia
or
heavy
sedation.
Thus
appropriate
patient
selection
is
mandatory
(table).
With
the
currently
available
dedicated
paediatric
scanning
equipment
studies
in
children
below
4
kg
in
weight
should
be
performed
only
if
the
information
likely
to
be
obtained
is
of
importance
for
appropriate
patient
management.
The
present
probe
technology
allows
for
only
single
plane
imaging
of
the
heart,
thus
making
transoeso-
phageal
scanning
a
strictly
totnographic
technique.
However,
it
is
likely
that
biplane'4
'5
or
multiplane
paediat-
ric
transoesophageal
probes
will
be
designed
in
the
near
future
and
will
further
increase
the
range
of
diagnostic
insights
to
be
obtained.
Conclusion
Transoesophageal
echocardiography
is
a
relatively
new
adjunct
to
the
ultrasound
evaluation
of
congenital
cardiac
lesions.
It
is
a
safe,
albeit
semi-invasive,
technique
that
rapidly
has
gained
a
well
defined
place
in
the
diagnostic
armamentarium
of
the
paediatric
cardiologist.
OLIVER
STUMPER
Department
of
Paediatric
Cardiology,
Royal
Hospital
for
Sick
Children,
Sciennes
Road,
Edinburgh
EH9
ILF
1
Gussenhoven
EJ,
Taams
MA,
Roelandt
JRTC,
et
al.
Transoesophageal two-
dimensional
echocardiography:
its
role
in
solving
clinical
problems.
J
Am
Coll
Cardiol
1986;8:975-9.
2
Kyo
S,
Koike
K,
Takanawa
E,
et
al.
Impact
of
transoesophageal
Doppler
echocardiography
on
pediatric
cardiac
surgery.
Int
Card
Imaging
1989;4:
41-2.
3
Ritter
Sb,
Hillel
Z,
Narang
J,
Lewis
D, Thys
D.
Transesophageal
real
time
Doppler
flow
imaging
in
congenital
heart
disease:
experience
with
the
new
pediatric
transducer
probe.
Dynamic
Cardiovascular
Imaging
1989;2:92-6.
4
Stumper
0,
Elzenga
NJ,
Hess
J,
Sutherland
GR.
Transesophageal
echocar-
diography
in
children
with
congenital
heart
disease-an
initial
experience.
J
Am
Coll
Cardiol
1990;16:433-41.
5
Stumper
0,
Sreeram
N,
Elzenga
NJ,
Sutherland
GR.
The
diagnosis
of
atrial
situs
by
transoesophageal
echocardiography.
J
Am
Coll
Cardiol
1990;16:
442-6.
6
Stumper
0,
Rijlaarsdam
M,
Vargas-Barron
J,
Romero
A,
Hess
J,
Sutherland
GR.
The
assessment
of
juxtaposed
atrial
appendages
by
transoesophageal
echocardiography.
Intl
Cardiol
1990;29:365-71.
7
Stumper
0,
Vargas-Barron
J,
Rijlaarsdam
M,
et
al.
The
assessment
of
anomalous
systemic
and
pulmonary
venous
connections
by
paediatric
transesophageal
echocardiography.
J
Am
Coll
Cardiol
1991;17:256A.
8
Sreeram
N,
Stumper
0,
Kaulitz
R,
et
al.
The
comparative
value
of
surface
and
transesophageal
ultrasound
in
the
assessment
of
congenital
abnorma-
lities
of
the
atrioventricular
junction.
J
Am
Coll
Cardiol
1990;16:1205-14.
9
Roberson
D,
Muhiudeen
I,
Silverman
N,
Turley
K,
Cahalan
M.
Intraopera-
tive
transoesophageal
echocardiography
in
infants
and
children
with
cardiac
shunt
lesions.
JAm
Soc
Echocardiogr
1990;3:213.
10
Stumper
0,
Kaulitz
R,
Sreeram
N,
et
al.
Intraoperative
transesophageal
versus
epicardial
ultrasound
in
surgery
for
congenital
heart
disease.
J
Am
Soc
Echocardiogr
1990;3:392-401.
11
Hellenbrand
WE,
Fahey
JT,
McGowan
FX,
Weltin
GG,
Kleinman
CS.
Transoesophageal
echocardiographic
guidance
of
transcatheter
closure
of
atrial
septal
defect.
AmJ
Cardiol
1990;66:207-13.
12
Kaulitz
R,
Stumper
0,
Geuskens
R,
et
al.
The
comparative
values
of
the
pre-
cordial
and
transoesophageal
approaches
in
the
ultrasound
evaluation
of
atrial
baffle
function
following
an
atrial
correction
procedure.
J
Am
Coll
Cardiol
1990;16:686-94.
13
Stumper
0,
Sutherland
GR,
Geuskens
R,
Roelandt
JRTC,
Bos
E,
Hess
J.
Transoesophageal
echocardiography
in
evaluation
and
management
of
the
Fontan
circulation.
J
Am
Coll
Cardiol
1991;17:1152-60.
14
Omoto
R,
Kyo
S,
Matsumura
M,
et
al.
Biplane
color
transoesophageal
Doppler
echocardiography
(color
TEE):
its
advantages
and
limitations.
Int
J
Card
Imaging
1989;4:57-8.
15
Stumper
0,
Fraser
AG,
Ho
SY,
et
al.
Transoesophageal
echocardiography
in
the
longitudinal
axis:
correlation
between
anatomy
and
images
and
its
clinical
implications.
BrHeartJ
1990;64:282-8.
Jaundice
at
14
days
of
age:
exclude
biliary
atresia
The
majority
of
infants
with
biliary
atresia
in
the
UK
are
still
being
referred
too
late
to
get
optimal
benefit
from
the
operation
of
portoenterostomy.
It
is
now
14
years
since
we
first
reported
the
importance
of
early
referral
in
this
journal.1
The
success
of
early
surgery
has
been
reported
repeatedly
since
then.
Over
80%
of
infants
with
biliary
atresia
who
underwent
surgery
before
60
days
of
age
have
become
jaundice
free,
compared
with
20-35%
for
those
with
later
surgery.2
Results
of
surgery
are
less
satisfactory
in
centres
operating
on
few
cases.3
It
was
clear
even
14
years
ago
that
infants
who
cleared
their
jaundice
had
a
good
prospect
of
long
term
survival
with
a
good
quality
of
life.'
This
has
been
confirmed
in
the
last
few
years
from
Japan
and
Europe.4
A
15
year
survival
of
87%
has
been
reported
in
infants
who
become
jaundice
free.5
The
age
at
portoentero-
stomy
dictates
the
frequency
of
survival
beyond
10
years
of
age.
For
example
in
one
series
17
of
26
(73%)
infants
operated
by
60
days
of
age
survived
to
10
years
as
compared
with
only
eight
of
71
(11%)
operated
after
90
days
of
age.
Thirty
of
48
aged
from
10
to
33
years
have
had
a
completely
uncomplicated
course
while
37
are
leading
normal
lives
with
no
current
medical
or
surgical
problems.6
Reports
from
France
are
similar
with
the
most
satisfactory
outcome
in
those
operated
on by
45
days
of
age.7
Preliminary
analysis
of
patients
treated
since
1973
at
King's
College
Hospital
suggest
a
similar
outcome
but
few
were
treated
before
45
days.
These
observations
on
the
outcome
of
early
surgery
are
in
keeping
with
what
is
known
of
the
pathology
of
biliary
atresia.8
In
the
extrahepatic
biliary
tract
there
is
a
pro-
group.bmj.com on July 10, 2011 - Published by adc.bmj.comDownloaded from
Huessein,
Howard,
Mowat
gressive
destructive
sclerosing
inflammatory
process.
The
intrahepatic
bile
ducts
are
also
involved
leading
rapidly
to
a
biliary
cirrhosis
with
a
mean
age
of
death
of
11
months.
Excision
of
the
extrahepatic
ducts
at
a
stage
when
there
are
still
patent
biliary
channels
in
the
porta
hepatitis
allows
the
liver
to
recover
sufficiently
for
normal
growth
and
develop-
ment
even
if
the
liver
is
fibrotic
and
the
intrahepatic
bile
ducts
are
abnormal.
Portal
hypertension,
present
in
all
cases
at
the
time
of
surgery,
can
remit
but
may
still
cause
alimentary
bleeding
in
10-15%.'
Further
liver
injury
may
be
caused
by
cholangitis,10
but
this
may
be
less
damaging
if
it
occurs
more
than
five
years
after
surgery."
For
the
child
who
does
not
have
a
successful
portoenter-
ostomy
liver
transplantation
is
the
other
mode
of
manage-
ment.
The
results
of
liver
transplantation
are
steadily
improving
with
a
one
year
survival
rate
after
one
or
more
transplantation
procedures
of
over
80%.12
A
five
year
survival
of
more
than
60%
has
been
reported
in
older
children
but
less
than
40%
in
infants.'3
14
Liver
transplantation
requires
many
more
resources
than
portoenterostomy.
The
patient
requires
lifelong
immuno-
suppression
with
close
supervision
for
both
medical
and
surgical
complication
and
the
longer
term
prognosis
is
unknown.
Although
an
important
mode
of
management
for
end
stage
liver
disease
and
metabolic
disorders,
the
role
of
liver
transplantation
in
biliary
atresia
is
secondary
to
that
of
portoenterostomy.
l5
Despite
several
publications
in
this
journal,
and
else-
where,
we
find
no
evidence
that
infants
born
with
biliary
atresia in
the
UK
are
being
referred
earlier.
In
1989
the
Lancet
published
the
findings
of
a
detailed
study
of
the
factors
that
might
influence
the
outcome
of
surgery
and
cause
delayed
referral.2
All
50
UK
born
infants
treated
for
biliary
atresia
at
King's
College
Hospital
in
1985-7
were
analysed.
Only
the
age
at
surgery
predicted
the
outcome.
In
the
three
years
covered
by
the
study
81%,
54%,
and
73%
were
referred
after
6
weeks
of
age
and
46%,
31%,
and
35%
after
8
weeks
of
age.
All
had
been
jaundiced
with
persistently
yellow
urine
from
the
first
week
of
life.
One
third
of
families
had
been
reassured
repeatedly
by
midwives,
health
visitors,
or
family
doctors
that
the
jaundice
was
physiological.
In
these
instances
referral
was
often
initiated
at
the
well
baby
review
at
6
weeks
of
age.
In
60%
of
cases
inappropriate
management
by
hospital
paediatric
staff
contributed
to
the
delay
in
referral.
For
example,
no
investigations
to
exclude
underlying
hepatobiliary
disease
were
performed
in
seven
infants
with
jaundice
after
2
weeks
of
age
or
in
four
with
jaundice
and
vitamin
K
responsive
haemorrhagic
diathesis.
In
five
instances
a
diagnosis
of
breast
milk
jaundice
was
made,
although
this
form
of
jaundice
produces
an
unconjugated
hyperbilirubinaemia
with
no
clinical
or
biochemical
evidence
of
liver
disease.
In
seven
instances
the
clinician
was
mislead
by
a
fall
in
the
serum
bilirubin
concentration
of
up
to
40
[tmol/l.
A
leading
article
in
the
British
Medical
Journal'6
and
letters
in
the
correspondence
columns
of
both
the
British
Medical
Journal
and
the
Lancet
have
stressed
the
measures
necessary
for
the
recognition
of
suspected
cases
of
biliary
atresia
by
6
weeks
of
age.
Of
25
infants
born
in
the
UK
in
1990
whom
we
have
treated
for
biliary
atresia,
63%
were
referred
after
6
weeks
of
age
and
33%
after
8
weeks
of
age,
that
is,
no
younger
than
the
age
of
referral
in
1985-7.
Although
70%
have
had
a
significant
drop
in
their
serum
bilirubin
concentrations
after
surgery,
as
yet
it
is
normal
in
only
50%.
We
have
no
reason
to
suspect
that
the
reasons
for
delayed
referral
in
the
1990
cohort
are
in
any
way
different
to
those
in
earlier
years.
At
least
two
were
considered
to
have
breast
milk
jaundice.
Parents
are
angry
when
they
learn
that
the
outcome
of
surgery
may
be
jeopardised
by
the
time
of
referral.
It
is
embarrassing
and
possibly
imprudent
in
these
days
of
litigation
to
delve
into
reasons
for
delayed
referral.
The
introduction
of
new
techniques'7
18
and
the
twice
weekly
performance
of
ctl-antitrypsin
phenotyping
have
excluded
genetic,
infective,
and
endocrine
disorders
more
rapidly,
reducing
the
median
time
between
referral
and
surgery
from
14
to
eight
days.
It
is
difficult
to
see
how
the
interval
can
be
reduced
further
if
unnecessary
laparotomy,
with
its
risks,'9
is
to
be
avoided.
What
is
required
to
ensure
earlier
referral
of
infants
with
biliary
atresia
in
the
UK?
(1)
The
urine
of
jaundiced
infants
must
be
tested
for
bilirubin
and
the
direct
or
conjugated
bilirubin
measured
The
vast
majority
of
infants
with
biliary atresia
are
entirely
well
during
the
first
four
to
eight
weeks
of
life
apart
from
mild
jaundice.
The
serious
nature
of
the
jaundice
will
be
appreciated
only
if
conjugated
hyperbilirubinaemia
is
found.
It
is
always
pathological.
It
must
be
suspected
in
any
jaundiced
infant
in
whom
the
urine
is
yellow
as
opposed
to
colourless
or
clear.
All
infants
with
conjugated
hyperbili-
rubinaemia
require
early
identification
to
minimise
the
risk
of
bleeding
from
vitamin
K
malabsorption
and
so
that
appropriate
investigations
can
immediately
be
undertaken
to
identify
disorders
for
which
specific
medical
or
surgical
treatment
is
available.
It
may
be
the
first
indication
of
gene-
tically
determined
disorders,
the
identification
of
which
is
of
considerable
importance
for
the
family.20
(2)
The
stool
must
be
seen,
by
the
clinician,
to
determine
whether
it
is
yellow
or
green
in
colour
If
consecutive
stools
over
a
course
of
two
to
three
days
contain
no
green
or
yellow
pigment
biliary
atresia
is
likely.
The
infant
should
be
referred
to
a
specialised
liver
centre
with
the
resources
to
exclude
rapidly
other
causes
of
complete
cholestasis
and
the
surgical
expertise
to
correct
biliary
atresia
effectively.
It
should
be
noted
that
in
a
minority
of
patients
with
biliary
atresia
the
parents
give
a
clear
history
of
the
infant
passing
green
or
yellow
stools
before
the
development
of
complete
cholestasis.
(3)
Systematic
screening
for
hepatobiliary
disorders
Professional
education
has
clearly
not
succeeded
in
getting
medical
staff
to
perform
the
two
measures
that
would
optimise
the
management
of
biliary
atresia.
Has
the
time
not
come
to
institute
systematic
screening
for
hepatobiliary
disorders
as
is
done
for
other
relatively
rare
conditions
such
as
hyperphenylalaninaemia
with
an
instance
of
approxi-
mately
1:4000
live
births
or
congenital
hypothyroidism
which
has
a
similar
incidence?2'
22
The
estimated
incidence
of
biliary
atresia
ranges
from
1:14
000
to
1:21
000
live
births.3
The
incidence
of
hepatobiliary
disease
in
early
infancy
requiring
equally
early
recognition
for
optimum
treatment
of
infective,
metabolic,
or
endocrine
causes
is
at
least
five
times
higher.23
We
would
propose
that
in
all
infants
who
remain
jaundiced
after
14
days
of
age
the
urine
should
be
tested
for
bilirubin
and
the
direct
or
conjugated
bilirubin
measured.
This
could
be
initiated
by
the
midwife
or
family
doctor.
Physiological
jaundice
almost
invariably
clears
by
14
days
of
age
except
in
a
small
proportion
of
breast
fed
infants.24
The
number
of
negative
tests
would
be
relatively
infrequent.
If
bile
is
present
in
the
urine
or
the
conjugated
bilirubin
is
raised
the
patient
should
be
referred
immediately
to
a
paediatrician.
If
the
stools
do
not
contain
green
or
yellow
pigment
over
the
course
of
two
to
three
days
the
patient
1178
group.bmj.com on July 10, 2011 - Published by adc.bmj.comDownloaded from
Jaundice
at
14
days
of
age:
exclude
biliary
atresia
1179
should
be
referred
to
a
specialist
liver
centre
able
to
perform
portoenterostomy.
This
change
in
management
could
be
facilitated
with
posters
emphasising
the
importance
of
prolonged
jaundice,
yellow
urine,
and
the
stool
colour
as
early
signs
of
treatable
hepatobiliary
disease
in
antenatal,
postnatal,
and
welfare
baby
clinics
or
family
practitioner
centres
in
which
mothers
and
babies
are
seen.
(4)
Changing
the
age
of
well
baby
review
from
6
to
4
weeks
of
age
Consideration
should
also
be
given
to
changing
the
age
at
well
baby
review
from
the
present
6
weeks
to
4
weeks.
As
well
as
identifying
infants
with
hepatobiliary
disorders
it
would
allow
earlier
detection
of
some
congenital
heart
defects,
particularly
left
to
right
shunts
and
of
subluxation
of
the
hips
which
may
be
difficult
to
detect
in
the
neonatal
period.
Disturbances
in
mother-child
relationships
might
be
more
easily
remedied
if
observed
at
4
rather
than
6
weeks
of
age.
Since
these
last
two
measures
have
been
introduced
in
Japan
the
age
of
infants
presenting
for
surgical
correction
of
biliary
atresia
has
gradually
fallen
and
the
outcome
has
steadily
improved.25
Until
such
measures
are
instituted
in
the
UK
it
is
essential
that
paediatricians
ensure
that
the
direct
bilirubin
be
measured
in
all
neonates
passing
through
their
care,
particularly
those
in
whom
jaundice
is
still
detectable
at
14
days
of
age.
It
would
not
be
necessary
to
screen
all
well
babies,
only
those
who
remain
jaundiced
after
14
days
of
age.
Physiological
jaundice
almost
invariably
clears
by
then
except
in
a
small
proportion
of
breast
fed
infants.24
The
urine
should
be
tested
for
bilirubin
and
the
direct
or
conjugated
bilirubin
concentration
mea-
sured.
This
could
be
initiated
by
the
midwife
or
family
doctor.
M
HUSSEIN
E
R
HOWARD
G
MIELI-VERGANI
ALEX
P
MOWAT
Departments
of
Child
Health
and
Surgery,
King's
College
Hospital,
Denmark
Hill,
London
SE5
9RS
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1977;52:825-7.
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Lancet
1989;i:
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9
Stringer
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J
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10
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Prognosis
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hepatic
biliary
atresia.
Arch
Dis
Child
1989;64:214-8.
11
Gottrand
F,
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0,
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F,
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Late
cholangitis
after
successful
surgical
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Am
J
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12
Sokal
EM,
Veyckemans
F,
de
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Liver
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J
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13
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N
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14
Starzl
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Demetris
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transplantation.
N
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15
Alagille
D,
Laurent
J,
Roy
CC.
Is
there
still
a
place
for
the
Kasai
procedure
in
the
treatment
of
biliary
atresia?J7
Pediatr
Gastroenterol
Nutr
1989;9:405-6.
16
Nelson
R.
Managing
biliary
atresia.
Referral
before
6
weeks
is
vital.
BMJ
1989;298:1471.
17
El
Tumi
MA,
Clarke
MB,
Barrett
JJ,
Mowat
AP.
Ten
minute
radiopharma-
ceutical
test
in
biliary
atresia.
Arch
Dis
Child
1987;62:180-1.
18
Wilkinson
ML,
Mieli-Vergani
G,
Ball
C,
Portmann
B,
Mowat
AP.
Endoscopic
retrograde
cholangiopancreatography
in
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cholestasis.
Arch
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1991
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19
Markowitz
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Daum
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Kahn
EI,
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Hepatology
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20
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AP.
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2nd
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21
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group.bmj.com on July 10, 2011 - Published by adc.bmj.comDownloaded from
doi: 10.1136/adc.66.10.1177
1991 66: 1177-1179Arch Dis Child
M Hussein, E R Howard, G Mieli-Vergani, et al.
atresia.
Jaundice at 14 days of age: exclude biliary
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... Even with well-established guidelines for the screening of neonatal CHB, actual referral for evaluation of CHB is frequently delayed to beyond 45 to 60 d of age [5][6][7] . Substantial observational evidence show that earlier diagnosis and surgical repair of biliary atresia (BA) result in better outcomes [8][9][10][11] . ...
... We acknowledge that this approach may not be applicable in centers relying on transcutaneous bilirubin (TcB) or in areas where BA prevalence is low. Hussein et al [6] discussed screening for CHB and suggested checking urine for conjugated bilirubin, its usefulness as an adjunctive test could be explored in scenarios where blood testing is deemed unnecessary and/or in units relying on TcB. ...
Article
Full-text available
AIM To describe the etiology and characteristics of early-onset conjugated hyperbilirubinemia (ECHB) presenting within 14 d of life in term neonates. METHODS Retrospective review was performed of term infants up to 28-d-old who presented with conjugated hyperbilirubinemia (CHB) at a tertiary center over a 5-year period from January 2010 to December 2014. CHB is defined as conjugated bilirubin (CB) fraction greater than 15% of total bilirubin and CB greater or equal to 25 μmol/L. ECHB is defined as CHB detected within 14 d of life. “Late-onset” CHB (LCHB) is detected at 15-28 d of life and served as the comparison group. RESULTS Total of 117 patients were recruited: 65 had ECHB, 52 had LCHB. Neonates with ECHB were more likely to be clinically unwell (80.0% vs 42.3%, P < 0.001) and associated with non-hepatic causes (73.8% vs 44.2%, P = 0.001) compared to LCHB. Multifactorial liver injury (75.0%) and sepsis (17.3%) were the most common causes of ECHB in clinically unwell infants, majority (87.5%) had resolution of CHB with no progression to chronic liver disease. Inborn errors of metabolism were rare (5.8%) but associated with high mortality (100%) in our series. In the subgroup of clinically well infants (n = 13) with ECHB, biliary atresia (BA) was the most common diagnosis (61.5%), all presented initially with normal stools and decline in total bilirubin but with persistent CHB. CONCLUSION Secondary hepatic injury is the most common reason for ECHB. BA presents with ECHB in well infants without classical symptoms of pale stools and deep jaundice.
... fat-soluble vitamin deficiencies, as well as from medical management to prevent or treat complications of cholestasis such as cholangitis, portal hypertension and/or pruritus. Unfortunately, delayed recognition of neonatal cholestasis and misdiagnosis as physiological jaundice or breastfeeding-related jaundice still remain a problem 11 . Reasons cited for late referral for evaluation of cholestasis include early hospital discharge of newborn babies, inadequate follow-up of persistent jaundice, improved jaundice as physiological indirect hyperbilirubinaemia resolves despite the persistence of cholestasis, a lack of a standard well-child visit at 1 month of life, false reassurance by the appearance of pigmented stool, fluctuating serum bilirubin levels and misdiagnosis of breast milkassociated jaundice [11][12][13][14] . ...
... Unfortunately, delayed recognition of neonatal cholestasis and misdiagnosis as physiological jaundice or breastfeeding-related jaundice still remain a problem 11 . Reasons cited for late referral for evaluation of cholestasis include early hospital discharge of newborn babies, inadequate follow-up of persistent jaundice, improved jaundice as physiological indirect hyperbilirubinaemia resolves despite the persistence of cholestasis, a lack of a standard well-child visit at 1 month of life, false reassurance by the appearance of pigmented stool, fluctuating serum bilirubin levels and misdiagnosis of breast milkassociated jaundice [11][12][13][14] . Unfortunately, although the average age of diagnosis of biliary atresia and HPE in some countries (for example, Taiwan) has decreased with improved screening techniques 15 , the median age at time of HPE in the USA is 63 days and has shown little change over the past 15 years despite many efforts to educate caregivers about the importance of early diagnosis 16 . ...
Article
Neonatal cholestasis is a group of rare disorders of impaired bile flow characterized by conjugated hyperbilirubinaemia in the newborn and young infant. Neonatal cholestasis is never physiological but rather is a sign of hepatobiliary and/or metabolic disorders, some of which might be fatal if not identified and treated rapidly. A step-wise timely evaluation is essential to quickly identify those causes amenable to treatment and to offer accurate prognosis. The aetiology of neonatal cholestasis now includes an expanding group of molecularly defined entities with overlapping clinical presentations. In the past two decades, our understanding of the molecular basis of many of these cholestatic diseases has improved markedly. Simultaneous next-generation sequencing for multiple genes and whole-exome or whole-genome sequencing now enable rapid and affordable molecular diagnosis for many of these disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Unfortunately, despite these advances, the aetiology and optimal therapeutic approach of the most common of these disorders, biliary atresia, remain unclear. The goals of this Review are to discuss the aetiologies, algorithms for evaluation and current and emerging therapeutic options for neonatal cholestasis.
... It is essential to determine the etiology of jaundice caused by unconjugated (indirect) or conjugated (direct) hyperbilirubinemia. Prolonged unconjugated hyperbilirubinemia may be associated with some pathological conditions such as breastfeeding, hemolytic diseases (Rh or AB0 incompatibility or glucose-6-phosphate dehydrogenase (G6PD) deficiency), congenital hypothyroidism, urinary infection, Crigler-Najjar or Gilbert syndromes [4,5]. However, the etiology of prolonged jaundice in infants mostly remained unidentified and reported in association with breastfeeding in the literature [6,7]. ...
Article
Full-text available
Objectives: Prolonged jaundice is a common condition among neonates. İt is defined as persisting hyperbilirubinemia after the 14th day following birth for term babies and after the 21st day for premature babies with serum bilirubin level higher than 5mg/dL. Prolonged unconjugated hyperbilirubinemia may be associated with some pathological conditions. We aimed to evaluate the etiological, clinical and laboratory findings of babies with prolonged jaundice. Methods: This descriptive cross-sectional study included 90 infants with prolonged jaundice in the pediatric outpatient clinic of Ordu University Training and Research Hospital between 1 January 2015 and 1 October 2020. Demographic characteristics, physical examination and laboratory findings of the babies were collected and analyzed to determine the etiology of neonatal hyperbilirubinemia. Results: In total 90 infants with prolonged jaundice were presented in this study, including 50 male and 40 female neonates. The most common causes of prolonged neonatal jaundice were breastfeeding, Rh or ABO incompatibility, and urinary tract infection 73%, 13% and 8% of neonates, respectively. Conclusion: Breast milk jaundice is the most common cause of prolonged jaundice in infants. Although there are some explanations for breast milk jaundice, the exact mechanism leading to breast milk jaundice is not clear. Other reasons that may affect the infants later in life should be investigated in a short time.
... U našoj seriji uzrast u vreme operacije i dijametar žučnih duktusa u fibroznom dugmetu imaju statistički značaj (p < 0,05), a histopatološke promene ciroza i fibroza imaju visok statistički značaj (p < 0,001), te su najznačajniji prognostički faktori. Većina autora se slaže da je uzrast u vreme operacije značajan (3,18), naši podaci su saglasni sa ovim tvrđenjem. ...
Article
Full-text available
Ekstrahepatična bilijarna atresija (EHBA) karakteriše oboljenje ili opstrukcijuekstrahepatičnog bilijarnog sistema, što rezultira opstrukcijom žučnog toka. Indikatoriloše prognoze u slučajevima ekstrahepatične bilijarne atresije i dalje ostaju kontroverzni.Ciljevi: Korelacija histopatoloških nalaza kliničke biopsije jetre i tkiva dobijenih izporte hepatis, tokom hepatične portoenterostomije, sa kliničkim ishodom.Materijal i metodi rada: Svi slučajevi EHBA su lečeni u Institutu za zaštitu zdravljamajke i dece Srbije Dr Vukan Čupić u sedmogodišnjem periodu. Perkutane biopsije jetrei biopsije iz porta hepatisa su analizirane sa bojenjem PAS (periodična kiselina Schiff).Patohistološki parametri u korelaciji sa kliničkim ishodom bili su: prisustvo velikihžučnih kanala (prečnika> 150μm) u pločici tkiva porte, stepena fibroze, ciroze, holestaze,transformacije gigantske ćelije, duktalne proliferacije i starosti u vreme operacije.Rezultati: Od 29 decesa EHBA operisano je 25 (86,2 %). Preživljavanje je bolje akose operacija uradi ranije (p < 0,05). Postojala je značajna korelacija između stepena fibroze,ciroze i lošeg kliničkog ishoda (p < 0,001). Na kraju našeg perioda praćenja,živo je 13-oro dece, 2 i više godine je preživelo 68,2 % (15/22), a 5 godina i više 27,3 %(6/22) pacijenata.Zaključak: Kod pacijenata sa EHBA sa velikom verovatnoćom, biopsijom se možeustanoviti stadijum bolesti, oceniti težina i predvideti dalji tok i ishod bolesti. Veći stepenfibroze, ciroze u vreme operacije, hepatične portoenterostomije i prisustvo malformacijeduktalne ploče povezan je sa značajno slabijim kliničkim ishodom.
Article
Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition–associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line–associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.
Chapter
Biliary Atresia (BA) affects approximately 1:20,000 babies and is the most frequent cause of surgical jaundice in children. BA presents in the first few weeks of life with pale stools and dark urine in otherwise healthy infants. It is the end result of a destructive inflammatory process of the bile ducts, with unclear origins. BA is a condition seemingly unique to the neonatal period, characterized by obliteration of both intra and extrahepatic bile ducts and amenable to surgical treatment by Kasai portoenterostomy, in the attempt to restore bile flow. In the most experienced centers, approximately half of children who underwent Kasai portoenterostomy achieve jaundice clearance, avoiding a rapid referral to liver transplantation, required in those in whom this approach is unsuccessful.
Thesis
The objective of this study was to assess the feasibility of screening for cholestatic hepatobiliary disease (CHD) and extrahepatic biliary atresia (EHBA) by using tandem mass spectrometry (TMS) to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7 to 10 days of age for the Guthrie test. Unused blood spots from the Guthrie test were retrieved for children presenting with CHD and from the two cards stored on either side of each card from an index child. Concentrations of glycodihydroxycholanoates (GD), glycotrihydroxycholanoates (GT), taurodihydroxycholanoates (TD) and taurotrihydroxycholanoates (TT) measured by TMS in the two groups were compared. Mean concentrations of all four bile acid species were significantly raised in children with CHD and EHBA compared with the unaffected children (P 0.0001). Of 177 children with CHD, 104 (59%) had a total bile acid (TBA) concentration 33 umol/L (97.5th centile value for comparison group). Of the 61 with EHBA, 47 (77%) had TBA concentrations 33 umol/L. Receiver operator curves were plotted to determine which parameter would best predict the cases of CHD and EHBA. The sensitivity and specificity at a selection of cut off values for each bile acid species and for TBA concentration for the detection of both conditions were calculated. Taurotrihydroxycholanoates and TBA concentrations were the best predictors of both conditions. For CHD a cut off level of TBA concentration of 30 umol/L gave a sensitivity of 62% and a specificity of 96%. The corresponding values for EHBA were 79% and 96%. Although most infants with EHBA and other forms of CHD had significantly raised concentrations of conjugated bile acids at 7 to 10 days of life, the separation between the concentrations in these infants and the general population was insufficient to make mass screening for CHD a feasible option with this method alone.
Chapter
Biliary atresia (BA) and congenital choledochal malformation (CCM) are the major surgical causes of obstructive jaundice in infancy with spontaneous bile duct perforation (SBDP) an important minor cause.
Article
Cholestatic jaundice in the first few weeks of life may herald potentially life-threatening pathology. It is therefore incumbent upon the pediatric practitioner to have a high index of suspicion for severe disease when investigating jaundice in a young infant. This article outlines the epidemiology, pathophysiology, differential diagnosis, and diagnostic workup for both the most common and the most severe causes of cholestasis in the neonatal period.
Article
Serious liver disease in infancy often presents as jaundice in an otherwise healthy baby. Recognition of these babies is made more difficult by the occurrence of physiological jaundice of the newborn. It is important for midwives to be aware that in most infants, including those who are breast fed, physiological jaundice has cleared by 14 days of age. Therefore any infant who remains jaundiced beyond 14 days should have a special split bilirubin blood test. If the conjugated bilirubin is greater than 20% of the total bilirubin, the infant should be referred immediately to a paediatrician for investigation and treatment of liver disease. Early management significantly improves the long term prognosis and avoids unnecessary complications.
Article
Full-text available
The difficulty of distinguishing surgically correctable causes of conjugated hyperbilirubinaemia in infants from other causes means that some infants may undergo laparotomy and intraoperative cholangiography unnecessarily, and others may be referred for surgery too late. In an attempt to improve the diagnostic accuracy in infants with conjugated hyperbilirubinaemia when standard methods produced equivocal results, we have been using prototype paediatric duodenoscopes (PJF 7.5 and XPJF 8.0; Olympus) to perform endoscopic retrograde cholangiopancreatography (ERCP). From 159 infants with conjugated hyperbilirubinaemia, 11 were referred for ERCP, which was performed in nine. In four in whom bile ducts were definitely visualised laparotomy was avoided. Operative cholangiography confirmed patent bile ducts in one in whom visualisation had been uncertain. Three of four in whom bile ducts were not seen had extrahepatic biliary atresia. Visible bile drainage in the fourth excluded atresia. No major complications ensued but there was radiological evidence of gall bladder perforation in one (common hepatic duct block) and overinflation with air was a problem until finer cannulae (Wilson-Cook) were introduced. In appropriately selected patients with conjugated hyperbilirubinaemia, ERCP with paediatric duodenoscopes in experienced hands may provide useful diagnostic information.
Article
Bacterial cholangitis is a frequent complication of successful surgical repair of biliary atresia, occurring in 93% of patients before the age of 1 year, but thought to be rare after 2 years of age. Among 76 children free of jaundice more than 5 years after operation, four presented with late cholangitis (7 to 13.5 years old), consisting of fever, jaundice, and abdominal pain with biochemical features of an inflammatory process and cholestasis. Liver biopsy specimens consistently demonstrated histological features of cholangitis, growth of microorganism, or both. Cholangitis subsided spontaneously in one patient or in response to intravenous administration of antibiotics. Cholangiography consistently demonstrated biliary abnormalities but no definite obstruction to the bilioenteric anastomosis. All the children had good hepatic function 3 weeks to 4 years after the episode of cholangitis. These results suggest that cholangitis may occur several years after surgery but does not seem to alter prognosis.
Article
Long-term results after surgery for biliary atresia (BA) in 48 patients, ranging in age from 10 to 33 years, were examined. There were 19 males and 29 females. Twelve had correctable type BA and 36 had the noncorrectable type. Forty-one cases had no jaundice; seven did. Thirty-seven of the 48 cases were leading normal lives. Among them, six cases were enjoying their lives after overcoming sequelae, such as portal hypertension. The main morbidities of the remaining 11 long-term survivors were jaundice and portal hypertension. The growth of most cases were comparable to those of the normal Japanese population. The data of liver function tests were variable and disclosed a moderate degree of abnormality in patients mainly complicated by cholangitis. Eleven cases, including six jaundice cases, required treatment for esophageal varices and/or hypersplenism. In conclusion, the cured states of most cases without jaundice are satisfactory and these former patients have achieved a favorable quality of life. Early operations are essential to obtain good short-term results as well as good long-term results.
Article
Of 139 children who received an orthotopic liver transplant in our center between March 1984 and July 1989, a total of 17 patients (12%) had transplants before their first birthday (mean age 10.3 months; range 8 to 11). The mean weight was 7.3 kg (range 5.2 to 13). Nine retransplantations were performed in five children because of primary nonfunction (three children), hepatic artery thrombosis (four), or rejection (two). A reduced donor liver was used for 11 of 26 transplants. Baseline immunosuppression included cyclosporine, prednisone, and azathioprine with OKT3 or anti-thymocyte globulin for steroid-resistant rejection episodes. Survivors were discharged after a mean hospital stay of 47 days (range 22 to 87), and nonsurvivors died within a mean of 40 days (range 0 to 120). The 1 year actuarial survival rate was 64.7%, in comparison with 75.8% in the whole series. One patient died perioperatively, two died from primary nonfunction, one from adenovirus infection, two from rejection, and one from bone marrow aplasia. Eighteen rejection episodes, of which 11 were steroid resistant, occurred in 11 patients. Our series shows that liver transplantation can be successful in this age group.
Article
To assess whether clinicopathological features other than the age at operation influence prognosis after surgery for extrahepatic biliary atresia (EHBA) and to determine whether the age at referral has fallen since a previous survey, 50 consecutive cases with EHBA referred between February, 1985, and December, 1987, were reviewed. Liver or spleen size, liver function tests, or histological appearance of liver biopsy specimen before surgery were not predictive of outcome. The jaundice cleared up in 12 of 14 children operated on by age 8 weeks, but in only 13 of 36 operated on later. In 41 referral was delayed. All 25 children in whom surgery was successful are alive and well, while 13 of 25 with unsuccessful surgery have died, at a median age of 1 year. To improve the prognosis of infants with EHBA parents and health staff need a better awareness of the early clinical features of EHBA and of the necessity for prompt referral. Liver disease should be suspected in any infant jaundiced after 14 days of age.
Article
Since the introduction of cyclosporine A, liver transplantation has become accepted as the therapy for end-stage liver disease. However, there are no definite criteria for liver replacement in biliary atresia. We investigated (a) the survival rate after hepatic portoenterostomy (n = 131), (b) liver function tests in fatal cases after an initially successful hepatic portoenterostomy (n = 9), and (c) liver function tests in the patients with episodes of cholangitis after a successful surgical treatment (n = 8). Patients with persisting jaundice after the surgery cannot be expected to survive long, and therefore they definitely should undergo liver transplantation. When total bilirubin concentration was above 10 mg/dl in patients with cholangitis after a successful operation, conservative therapy had almost no effect. Therefore, patients with total bilirubin levels above 10 mg/dl should be considered for liver transplantation. Of the liver function tests, only total bilirubin was reliable as a marker for hepatic failure in the end stage of biliary atresia. Prolongation of thrombo test and episodes of gastrointestinal bleeding also were used in selection of patients for liver replacement.