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Genetic cholestasis, causes and consequences for hepatobiliary transport.
[benign recurrent intrahepatic cholestasis]
Bile
salts
take
part
in
an
efficient
enterohepatic
circulation
in
which
most
of
the
secreted
bile
salts
are
reclaimed
by
absorption
in
the
terminal
ileum
.
In
the
liver
,
the
sodium-dependent
taurocholate
transporter
at
the
basolateral
(
sinusoidal
)
membrane
and
the
bile
salt
export
pump
at
the
canalicular
membrane
mediate
hepatic
uptake
and
hepatobiliary
secretion
of
bile
salts
.
Canalicular
secretion
is
the
driving
force
for
the
enterohepatic
cycling
of
bile
salts
and
most
genetic
diseases
are
caused
by
defects
of
canalicular
secretion
.
Impairment
of
bile
flow
leads
to
adaptive
changes
in
the
expression
of
transporter
proteins
and
enzymes
of
the
cytochrome
P-
450
system
involved
in
the
metabolism
of
cholesterol
and
bile
acids
.
Bile
salts
act
as
ligands
for
transcription
factors
.
As
such
,
they
stimulate
or
inhibit
the
transcription
of
genes
encoding
transporters
and
enzymes
involved
in
their
own
metabolism
.
Together
these
changes
appear
to
serve
mainly
a
hepatoprotective
function
.
Progressive
familial
intrahepatic
cholestasis
(
PFIC
)
results
from
mutations
in
various
genes
encoding
hepatobiliary
transport
proteins
.
Mutations
in
the
FIC
1
gene
cause
relapsing
or
permanent
cholestasis
.
The
relapsing
type
of
cholestasis
is
called
benign
recurrent
intrahepatic
cholestasis
,
the
permanent
type
of
cholestasis
PFIC
type
1
.
PFIC
type
2
results
from
mutations
in
the
bile
salt
export
pump
(
BSEP
)
gene
.
This
is
associated
with
permanent
cholestasis
since
birth
.
Serum
gamma-glutamyltransferase
(
gamma-
GT
)
activity
is
low
to
normal
in
PFIC
types
1
and
2
.
Bile
diversion
procedures
,
causing
a
decreased
bile
salt
pool
,
have
a
beneficial
effect
in
a
number
of
patients
with
these
diseases
.
However
,
liver
transplantation
is
often
necessary
.
PFIC
type
3
is
caused
by
mutations
in
the
MDR
3
gene
.
MDR
3
is
a
phospholipid
translocator
in
the
canalicular
membrane
.
Because
of
the
inability
to
secrete
phospholipids
,
patients
with
PFIC
type
3
produce
bile
acid-rich
toxic
bile
that
damages
the
intrahepatic
bile
ducts
.
Serum
gamma-
GT
activity
is
elevated
in
these
patients
.
Ursodeoxycholic
acid
therapy
is
useful
for
patients
with
a
partial
defect
.
Liver
transplantation
is
a
more
definitive
therapy
for
these
patients
.
Diseases
Validation
Diseases presenting
"the permanent type of cholestasis pfic type 1"
symptom
benign recurrent intrahepatic cholestasis
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