Gallbladder Stones: Oral Dissolution Therapy

Abstract

Chenodiol is noninvasive, safe and moderately expensive. Because
of diarrhea, the need for aminotransferase monitoring, the long duration
of therapy required, and the minority of patients who are appropriate candidates,
it has had limited use. Ursodiol is generally preferred because it has minimal side
effects. Patients with increased surgical risk, mild to moderate symptoms, and
gallstones which are either floatable with oral radiopaque contrast media or
radiolucent by computed tomography scan in a nonobstructed gallbladder arc
appropriate candidates for oral bile acid therapy. Silent stones should not be
treated under most circumstances.

Full text

STONE DIS
EASE
OF
TH
E BILIARY
TRA
CT
AND
PANCREAS
Gallbladder stones:
Oral dissolution therapy
JOI
IN~ON L THl~TLE,
MD
ABSTRACT:
Chenodiol
is
noninvasive,
safe
and
moderately expensive. Be-
cause
of
diarrhea,
the
need
for aminotransferase
monitoring,
the
long
duration
of
therapy required,
and
the
minority
of
patients
who
are
appropriate
candidates,
it
has had
limit
ed
use.
Ur
so
diol
is generally preferred because
it
ha
s minimal side
effects.
Patient
s
with
increa
se
d surgical
ri
s
k,
mild
to
moderate
symptoms,
and
gallstones
which
are
either
floatablc with oral radiopaquc
contrast
media
or
radiolucenr by
computed
tomography
scan
in a
nonobstructed
gallblad<ler
arc
appropriate
candidates
for
oral
bile acid therapy.
Silent
sto
nes s
hould
not
be
treated
under
most circumstances.
Cao
J
Gastroeoterol
l 990;4(9):621-623
Key
Words:
Chenodiol,
Gallbladder
stones,
Oral
disolution
therapy
,
Ursodiol
l
~
dissolution des calculs biliaires
par
voie orale
RESUME:
L
'ac
ide
chenodesoxycholique
(Chenodio
l)
est
non
invasit, sur
et
de
cout
mo<l
ere. Vu les
diarrh
ees fre
quente
s qu'il prnvoque, la necess
1te
de
verifier
les
transaminases, la duree prolnngee du
traitement
requis,
et
le
nombrc
reduit
Je
candidats
appropr
ies, son
utilit
e a
ete
lim1cee. L'ac
1de
ursodesoxycholique
(UrsoJiol) lui
est
generalement
prcfcrc a cause
de
ses effets indesirnbles
minime
s.
Les
patient
s
presentant
une
co
ntre
-
mdication
majeur
e a la chirurgie,
de
s
symptomes faiblcs a
modcr
es, des calculs
bien
visibles
dans
une
vcsicule qui
s'opacifie
ou
de
s
lithia
ses radiotransparentes cholesteroliques,
et
une
vesi
cule
fnnctionnelle objecrivee par cholecystographie, so
nt
lcs
candidats
au
traitement
par les acides biliaircs per o
s.
Dan
s la
majorite
de
s circonstances, les
ca
lculs
;isymptomatiques
ne
dev
raient
pas
etre
traites.
B
OT
H CHENODEOXYCl101
It'
Al'JI)
(chenod
i
ol)
an
d ur
sndeoxycho
l i
(.
acid
(ursodinl) are approved for u
se
in
the
United
S
tate
s by rhc Federal
Food
and
Drug
AJm
intstrati
on.
Either
alone
or in
co
mbination
,
these
bile ac
id
s
arc
effective in slowly dissolving gallstones
whi
ch are almost pure cholesterol.
Both
bile
acids
de
crease
ht!patic
biliary
cholesterol secretion res
ultin
g in mi
ccl-
lardesatura
tio
n in chole:.t
ero
l. Ursodinl
Mayo
Med1rnl
Center,
Roc/1ester,
Mmnesota
also dissolves hiltary
cho
lesterol
hy
liq-
uid crystal forma
tion.
CHENODIOL
Predictable
cho
le
stero
l
de
sat
uration
of
hile requires mgest
ion
of
12 t<) 15
mg/kg/day
of
c
henodiol
in
non,
)bese
patients
(I).
In
obesity, hiliary c
hole
s-
terol secr
etio
n 1s increased m propor-
tton
to
excess body weig
ht
and
18 to 20
m
g/
kg/
da
y
ma
y be required
to
achieve
Correspondence
and
re/m
nt
.1.
f)r·
Johnson L
Tiu.Hie.
Dinsion of
lias
rro
enicrology,
Mayo
Clinic,
Rochester,
MN 55905, USA
CAN J GASTROEl\!TEROL
VOL
4
N()
9
DEl
EMflER i 990
mice
ll
ar
desacurnu
on
m these patients.
This
may he difficult
to
tolerate
because
of dnse-related side e
ffe
ct
s;
howeve
r,
ingestion of a
Jo
sage
insuffiuenr
ro
de
sarurnte hile
is
of
no value.
Most
pacicn1s initially d
ev
elop
at
lease
transient
intermittent
increased
stool frequency with
or
without cramp-
ing
when
a fully
tb
ernpeuttc dosage is
in
gested
(2).
The
drnrrhea
is
often
ep
isodic,
L'g,
ncc
umn
g on
ce
every week
or
two,
and
u
sua
ll
y d
ec
reases
after
several weeks
to
m,
mth
, if
th
e
patient
cont
inues
to
titre
th
e dose as tolerated.
The
diarrhe
a effect b
do
se-related
and
imm
cJiate
ly resolves
when
th
e dose is
decreased sufficiently.
The
mechanism
of
the
diarrhea b
inhibiti
on
of n
or
mal
water
and
electrolyte ahsorpt ion by
the
co
lon.
No
long term consequ
ence
of
this
diarrhea has been
do
cume
nted
.
A
m1n
,1r
ransferase
elevations
(usual-
ly less
than
threefold)
occur
com
monly
a
nd
arc also
do
sc-r
clateJ
(2). Like
th
e
diarrhea,
this s
id
e effect abo usua
ll
y
r~
't
um
s
to
normal during
the
first
few
month
s
of
cr
eat
me
nt
.
Hi
gher enzyme
levels arc rare, hut chenodiol s
h,
)uld be
disconcmued if
th
ese
occ
ur.
An
accept-
ably
prudent
mo
nit
ori
ng
regimen
would be
to
assess
aminotramfcrase
lev
el
s mo
nthl
y for
three
mo
nth
s
and
then
at
six, 1
2,
18 and 24 mo
nth
s.
In
the
National
Coo
p
erative
Ga
lbron
e
Study
in
the
United
Sta
tes
(2),
cleva-
t inn of scrum total cholest
ero
l IO mg/
JL
g
reater
than
111
th
e pl
acebo
group was
observed
,
and
thi
s el
eva
ti
on was
predominantly
in
the
l
ow
densit
y
lipnprotein fraction. Oiernry restriction
621

T,m,,u:
Figure
l)
Swnes
wh1cl1
layer
our
(float)
in
orally administered radwpaque ccmrrasr
material
demonstrated
rm
decubiws
film
of
cholesterol
anJ
saturateJ
fat
might
minimize this slight
tendency
for eleva-
tion
of
cholesterol
and
may
enhance
efficacy,
although
these benefits
have
nor
been
proven.
Serum
total
cholesterol
levels
shoulJ
be
assesseJ
before
anJ
six
months
after
initiating
therapy.
Because
of
the
potential
for
diarrhea,
an
initial
<lady
<lose
of
500 mg
should
be
prescribe
Hor
the
first week
or
two.
This
can
then
be incrcaseJ by 250 mg
at
weekly
intervals
umil
a
therapeutic
dose
is
achieved,
usually 750
LO
1250 mg
daily
dependmg
on
body
weight.
Taking
most
of
the
chenoJiol
before
bed with a stimulus
to
gallbladder
con-
traction
(fat
or
protein),
may
enhance
its cholesrerol
desaturating
effect
(3).
Chenodiol
costs
about
US
$1000
an-
nually,
anc.l
complete
stone
dissolution
for most patients requires
one
to
two
years
of
treatment.
URSODIOL
This
bile
acic.l
is
at
least as effective
as
chenodiol
in decreasing cholesterol
saturation
of
bile, bur
can
abo
solubilizt'
cholesterol
by
inducing
liquid crystal
formation (4,5). Its effective Josage
is
8
to
10 mg/kg daily in nonobese patients.
The
only
well
documented
side effect
of
ursodiol
is
diarrhea,
hut
this
is
substan-
tially less frequent
than
with
chenoJ
iol.
Depending
on
how it
is
defined,
about
5%
of
patients
may get
Jiarrhea;
oc-
casionally
this
1s
sufficient
to
prevent
treatment
with this agent.
It
seems like-
622
ly
that
the
mechanism
for
this
diarrhea
is
similar
to
that
associated
with
chenodiol.
and
that
tolerance
might
abo
develop.
The
development
of
stone
surface calcification
Junng
ursodiol
has
been
described
but
is
infrequent
and
has
not
been
proven
to
be
more
common
than
that
during
chenodiol
therapy.
A before
bee.I
dose with chis bile
aciJ
may
also
opumize
efficacy,
although
this
has
not
been
thoroughly
estab-
lished. Bioavailability
of
a large single
dose is
of
some
concern.
A compromise
involves admmistrat1on
of
up
to
750 mg
before bed
and
any
additional
ursodinl
with breakfast.
lntraluminal
solubiliza-
uon
and
absorption
of
ursodiol
1s
en-
hanced
by bile,
and
admimstration
with
a stimulus
to
gallbladder
contraction
seems empirically appropriate.
UrsQdiol
has
largely
replaced
chenodiol
because
of
infrequent
diar-
rhea
and
the
absence
of
amino-
transferase
clevarnm.
Indeed, ursodiol
has
been
shown
to
decrease
hepatic
en-
zyme levels in several
chronic,
especial-
ly
cholestatic,
liver diseases.
The
major
disadvantage
of
ursodiol
is
its
expense
of
about
US
$2 per 300 mg capsule.
Mose
patients
require
two
or
three
cap-
sules a day, leading ro a cost
of
at
least
US
$1500
per
year for most
patients.
A
combination
of
chcno<liol
and
ur-
sod
iol
has
been
proposed
hoth
to
Jecrease
expense
and
possibly
to
in-
crease efficacy
(6).
Some
evidence
sug-
gests chat
the
combination
may be
more
effective
than
either
bile acid
alone
during
the
first six
months,
but
the
dif-
ferences are
minor
after 12
months
of
treatment.
It
would be
of
interest
to
Cl)mpare
the
usefulness
of
the
comhina-
tion
versus ursodiol
alone
after
extra-
corporeal
shock
wave
lithotnpsy
Lo
see
if
complete
dissolution
of
the
fragments
ar six
months
woulJ
be
greater.
The
effect
of
either
bile acid
on
gallbladder
motility
and
on
biliary
symptoms
before
stone
dissolunon
is
achieved
remaim
controversial.
PATIENT
SELECTION
Bile acid therapy induces
secretion
of
bile with a reduced cholesrerol
con-
tent
and,
in sufficient doses, produces a
milieu
which
can
resoluhil1ze
the
crys-
talline
cholesterol in srnncs.
The
stone
cholesterol, however, must
be
acces-
sible;
even
a
very
ihin
layer
of
calc1u111
hilirubmate
or
calcium
carho
natc
will
prevent
Jbsolutinn.
Many stones
which
cannot
be
JetectcJ
lm
abJommal
plain
film will
have
calcification
Jemon-
strable by
computed
tomography
scan.
It
is
unreasonable
ro
expect
bile
acid
therapy
to
dissolve this calcifieJ
scone
material
(7).
Since
all patients
w,th
gallsrones
developed
them
parrl\'
~.
cause
their
gallbladder
d1<l
nor
spon
taneously
evacuate
them
when
they
were microscopic
or
san<llike, there"
no
reason
to
imagmc
that
fine
rcs1Jual
Jehris
will
be
preJ
icrably
an<l
complete,
ly
emptied
at
a lacer date.
Consc4uently,
if
complete
gal~
bladder
clearance
is
the
obiecnve,
on~
swncs
which
arc
virtually
purt
cholesterol
can
he
expected to
have
a
high
rate
of
complete
disappearnnce
with
oral
bile
acid
therapy.
Stones
which
float ( layer
out)
at
oral
cholcq1-
tography
usually
have
a very
high
cholesccrol
content
and
are the
most
appropnaie
candidates
for oral
<lis,o[u,
tion
therapy
if symptoms are
sufficient~
infrequent
(Figure I). Most
floatable
stones
arc
10
mm
or
less
in
<l1amerei
Pigment
scones,
which
comprise
aho1t
20%
of
gallstones, are also
almost
al
ways small, usually less
than
5
mm
111
diameter.
Pigment
stones,
however,do
nm
float
and
they
are often
very
ir,
regular
in
contour.
On
computed
tomography
sea
n,
hlac
k
bd1rubin
polymer
pigment
srnnes m the
gallhlad,
der
can
usually be seen
to
be calcificdl
3
mm
slices
are
obtained
without
con-
trast.
Note
that
after
oral
cholccy,to,
graphy, it may
take
at
least a
week
before
sufficient
contrast
has
heen
cleared from
the
gallblacJJer
so
rhat
stone
calcification
1s
not
mash>d
hf
contrast
when
computed
tomography
scan
is
performed.
ConsiJermg
the
c~
of
a
12
month
mal
of
oral
bile
acid
therapy, a
computed
tomography
scan
would be a cost effective pauenc
selec,
tion
parameter
if
the
stones
Jo
nor
float
on
oral cholecystography (7).
Obviously,
the
cysti<.
c.luct
must~
patent
for oral hilc acid therapy to
bea
consideration.
Th
1s
is
usually
best
demonstrated
by oral
cholecystography
because
of
the
additional
information
CAN
J
GA
STROENTEROL
VOL
4 NO 9
DE
C
EMBER
199.J

...
obtained, but an isotope biliary scan
or
convincing
evidence
of
gallbladder
emptying
by
ulrrasonography arc ac-
ceptable
alternative
methods.
Oc-
casionally cystic
duct
patency will have
been
demonstrated
by
endoscopic
retrograde cholangiopancreacography.
If
so,
even patients who have had an
endoscopic
papilloromy may have
the
plltencial
to
respond
to
oral bile acid
therapy if they have appropriate stones.
GALLSTONE
RECURRENCE
Data
on
gallsrone recurrence has
been
limited
by
the
thoroughness with
which
complete dissolution has heen
documented.
At
least two thorough
ultrasonograms provide
the
most con-
vincing baseline.
The
recurrence
data
available are almost all relevant
to
oral
bile
acid therapy, which, reflects a high-
ly
selected subpopulation
of
patients
with
gallstones who
have
very high
cholesterol
content
stones.
These
usually
small
stones
may have been
present for only a few months
or
years
and
may be associated with very little
chronic gallbladder inflammation or
scarring. In
these
selected patiencs,
~tones
recur m
about
I
0°;(1
of
patients
per
year for the first four
or
five years
(8).
Some
studies
suggest
that
the
greatest risk
is
in
the
first year (9). If
the
patient continues
co
have all of the
prerequisites for
stone
formation, it
is
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stuuy, :md compaw,on
with
logical
to
expect
that
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again
rapidly after rherapy
is
discon-
tinued. It makes equal intuitive sense
that
if stones
have
not
recurred within
five years,
the
patient
may
no
longer be
in
an
acuve
stone-forming
phase.
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period
of
rapid weight loss or estrogen
therapy may be less likely to develop
recurrence
when
these predisposing
factors arc
no
longer present. Patients
who
have
had
solitary stones
are
less
likely
to
develop
stone
recurrence
than
those
with
multiple stones (10).
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risk
of
stone
recurrence appears
to
be
40
to
60% after five years following oral
bile acid therapy (
11
).
Although a stone-free gallbladder
is
usually considered
the
goal
of
oral dis-
solution therapy,
the
more specific ob-
jective
of
galbwne
treatment
is
the
elimination
of
biliary symptoms.
If
stones recur but remain asymptomatic,
one
might consider
treatment
co
have
been
successfu
I.
The
frequency with
which recurrent
stones have become
symptomatic
has
vaned
widely,
but
they
often
remain silent
at
least for
several years.
There
is
general agree-
ment
that
silent stones
Jo
not
require
treatment
except
under
rare
cir
-
cumsrances.
Encouraging
progress
111
under
-
standing
the
pathogenesis
of
chol-
esterol gallstones has evolved during
chcno<lcoxychol
ic.
,lCtll.
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1984;4:
308-
14
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CC, I
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WI,
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AF.
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urso-
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71.
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CAN
J
GA
S
TROENTl:ROL
VOL
4
No
9
DE
C
l:~!BLR
1990
Oral dissolution
therapy
the past five
yec1rs.
Abnllrmally rapid
nucleanon
of
cholesterol in hile has
been demonstrnteu in most patients
with cholesterol gallstones and charac-
terizauon
of
nucleating factors as well
as
aminucleating
factors
is
well under
way
(12). Cholesterol gallstone fonua-
tion
can
he prevented
by
administra-
tion
of
nonsteroiual anti-inflammatory
agents
in
the
prairie dog model system,
and
preliminary darn suggest
that
this
approach
may
have
potential
in
humans
(l
2
).
Cholesterol synchesis in-
hibitors induce some desaturation
of
cholesterol
in
bile; further work in this
area may also provide a practical phar-
macologic approach
to
sLonc preven-
tion
(13 ).
The
search
continues
for a
nnvd
bile
acid
which
will
desacurnte
bile
111
cholesterol and resist hepatic
or
bac-
terial
degradation
yet
be
acuvely
tramponed
by
the
ileum
and
liver. A
useful
ager,t must
have
no
acute
or
chronic
serious side effects
such
as
hcpatotoxic1ty
or
detrimental effects
lll1
lipid metaholism. Alternatively,
the
cm,1
of
msodiol
may be
markedly
reduced as
patent
protection runs its
course
and
manufacturing methods are
refined.
Development
of
a
safe,
ecnnomical,
well
tolerated
prophy-
lactic agent would greatly
enhance
the
usefulness
of
all nonsurgical treatments
for
gallstones which arc evolving.
9.
Htx><l
K,
Gleeson
D,
Ruppin
D,
Dowling
11.
Can gallsrone recurrence
he
pn:
vcnreu?
The
Rriush/P,elgian
po~r
-
ubsolution trial. Gastrocmcrology
J 988;94:A548. (Ahst)
I
0.
Villanova
N,
Bazzoli
F,
Taroni
F,
ct
al.
Gal btorn: recurrence after
:,uccessfu
I
oral hilc aciu treatment. A
12
-
ycar
follow-up
study and evaluation
of
lung-
term
postdissolution rrcacmcnl.
Ga,rroentcrolngy
l 989;97:726-
31.
l
I.
Thistle
JL.
Postd1ssl1lut1on
g:illsmne
recurrence. A
di111cal
perspective.
Dig
Dis
Sci
J989;34:44S-
8S.
12.
Grunuy
SM,
K;ilscr
SC.
Highlights
nf
rhe mecung on prcvennon of
gallstones. I
leparology
I
987;7:946-51.
I
3.
Duane WC, I lunninghakc
DB,
Freeman
ML,
ct
al.
Simvasrnrm, a
competitive
111hih1tor
of I IMG-CoA
rcducrnsc,
lowers
cholesterol smurauon
index of gallhldddcr
hile.
I lepatology
1988;8:1147-50.
62~

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