1. No category

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381
Gut, 1992, 33, 381-386
Optimum bile acid treatment for rapid gall stone
dissolution
R P Jazrawi, M G Pigozzi, G Galatola, A Lanzini, T C Northfield
more effective than mealtime administration in
improving the gall stone dissolution rate.33
Previous studies have expressed their results in
terms of the percentage of patients who achieve
partial or complete gall stone dissolution, or
both, within a defined time.22-24 26 28 12 34 The disadvantage ofthese studies is that only those patients
who achieved complete dissolution are used for
statistical analysis, and therefore there is a
requirement for large numbers of patients to be
enrolled, or for long periods of treatment follow
up. This has prevented the demonstration of
clearcut differences between the two bile acids.
We have previously developed and validated a
standard oral cholecystographic technique35 for
measurement of the gall stone dissolution rate,
defined as the percentage reduction in gall stone
volume at predetermined intervals after the start
of treatment. This measurement is quantitative
and allows the use of all patients data in a trial of
dissolution treatment.
The aims of the present study were as follows:
(1) To compare the efficacy of CDCA and
UDCA in terms of the gall stone dissolution rate.
(2) To compare bedtime with mealtime
administration for both bile acids.
(3) To compare a combination of UDCA plus
CDCA with both bile acids alone.
(4) To study the effects of initial gall stone size
on these comparisons.
(5) To study the effect of the length of treatment.
For all these comparisons individual patients
were matched for initial gall stone diameter, as
we have previously shown that this is the most
Since the introduction of chenodeoxycholic acid important factor affecting the gall stone dissolu(CDCA) in the early 70s" and ursodeoxycholic tion rate.35
acid (UDCA) in the late 70s,35 many controlled
and uncontrolled trials have been carried out to
assess the efficacy of the two bile acids in terms of
Subjects
the proportion of gall stones for which complete Fifty eight of a total of 72 consecutive patients
with radiolucent gall stones in functioning gall
or partial dissolution is achieved over a defined
time interval. Available data suggest that the bladders were entered in the study on the
overall efficacy is similar; both bile acids achieve grounds of best matching of initial gall stone size.
complete dissolution in 10-60% of patients and This matching was carried out before measuring
partial dissolution in another 10-45% of the gall stone dissolution rate. All patients gave
patients."3' The wide variation in the response informed consent, and the studies were approved
rate can be attributed to differences in the dose of by the local hospital ethical committee.
bile acid used, in treatment length, and in
patient's weight in relation to ideal body weight
and to different approaches to the inclusion of EXPERIMENT I
'dropouts' in the final analysis. Only three con- Forty eight of the first 59 consecutive patients
trolled studies have directly compared CDCA were prospectively matched in four groups of 12
withUDCA, and each reported that UDCA had a to within 2 mm according to the diameter of their
slight though not significant advantage over largest stone and were randomly allocated to one
CDCA.'82228 A recent study has reported that a of four treatment regimens: CDCA at bedtime or
combination of CDCA plus UDCA is more at mealtimes and UDCA at bedtime or at
effective than UDCA alone.32 We have also mealtimes. Each patient grouped had a represenshown that bedtime administration of CDCA is tative patient with diameter matched gall stones
Abstract
To determine the optimum bile acid regimen
for rapid gail stone dissolution, 48 gall stone
patients were divided into four groups of 12
according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime
chenodeoxycholic acid (CDCA, 12 mg/kg/day)
and bedtime or mealtime ursodeoxycholic acid
(UDCA, 12 mg/kg/day). An additional 10
patients treated with a combination of CDCA
plus UDCA (each 6 mg/kg/day) at bedtime were
matched with the 10 patients on bedtime
CDCA and the 10 on bedtime UDCA. The gall
stone dissolution rates at six and 12 months
were determined by standardised oral cholecystography and expressed as the percentage
reduction in the gall stone volume after treatment. The gall stone dissolution rate at six
months was higher for UDCA than CDCA
treatment (median 78% v 48%, p<001), and
for bedtime than mealtime administration (69%
v 39%, p<002). Both differences were greater
for stones <8 mm diameter. The dissolution
rate was faster for combination therapy than
for CDCA alone at both six (82% v 36%,
p<0O05) and 12 months (100% v 54%, p<005),
but was not different from UDCA alone. We
conclude that bile acid treatment should be
confined to patients with smail gail stones and
that bedtime administration of combined
UDCA and CDCA is likely to provide the most
effective and safe combination.
Division of Biochemical
Medicine, St George's
Hospital Medical School,
London
R P Jazrawi
M G Pigozzi
G Galatola
A Lanzini
T C Northfield
Correspondence to:
Professor T C Northfield,
Division of Biochemical
Medicine, St George's
Hospital Medical School,
Cranmer Terrace, London
SW17 ORE.
Accepted for publication:
2 July 1991
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382
2Jazrawi, Pigozzi, Galatola, Lanzini, Northfield
in each of the other three groups. In eight
patients with large stones (two in each of the
above groups) the matching was not to within 2
mm of stone diameter. The diameters of the
largest stones in these patients were 18 mm, 19
mm, 28 mm, and 30 mm in the first matched
quartet, and 18 mm, 18 mm, 20 mm, and 26 mm
in the second quartet of patients on mealtime
CDCA, bedtime CDCA, mealtime UDCA, and
bedtime UDCA respectively. The bile acids were
given in a mean total daily dose of 12 mg/kg/day
either at bedtime or in three equal divided doses
at mealtimes.
EXPERIMENT II
METHODS AND MEASUREMENTS
A standardised oral cholecystogram was used to
visualise the gall stones within the gall bladder.
This technique involved placing a 450 wooden
block under the left side of the patient as he or she
lay in the supine position. Hence views taken
were in the right supine oblique position. In five
patients in whom abdominal gas prevented complete visualisation of the gall bladder in this
position, right prone oblique views were
obtained and used for subsequent studies on the
same patients. The distance between patient and
x ray tube was always kept constant at 100 cm. In
all patients except four, the diameter of the
largest stone was measured and used for calculating the gall stone dissolution rates achieved by
the different bile acids by comparing gall stone
volume before and after treatment. In the four
exceptions (randomised to the four different
treatment regimens), there were multiple small
stones of similar diameter (3-5 mm). In these
patients the number of stones was calculated and
the percentage reduction in number was used as
an estimate of the gall stone dissolution rate
during treatment. The standardised oral cholecystogram was repeated in each patient after six
and 12 months of treatment. Standardisation of
the procedure in this manner allows valid quantitative determination of the relative change in
size or number of gall stones.33
Ten of a total of 13 consecutive patients receiving
bedtime combination therapy were matched for
initial gall stone diameter with 20 patients
already studied - 10 taking CDCA and 10 taking
UDCA at bedtime. The patients on combination
therapy received CDCA and UDCA, both in a
dose of 6 mg/kg/day, giving a total daily dose of
12 mg/kg administered at bedtime.
Clinical details of the patient groups are shown
in Table I. There were no significant differences
in terms of age and percentage ideal body weight
between the groups in either of the experiments.
For all patients, we used a dose of approximately 12 mg/kg/day, as this dose maintains an
unsaturated gall bladder bile for CDCA' as well
as for UDCA.37 For the combination treatment,
we used the same total dose of 12 mg/kg/day, CALCULATION AND ANALYSIS OF RESULTS
because we wished to study an equimolar dose of From the standardised oral cholecystogram, the
the two bile acids.
initial gall stone diameter and the diameters at six
and 12 months were measured. We also measured the volume of gall stones at the same time
intervals by the method of multiple cylinders.38
TABLE I Clinical details ofpatients treated with chenodeoxycholic acid (CDCA),
Although this method38 was developed to measursodeoxycholic acid (UCCA), or a combination of both
ure gall bladder volume, we have previously
validated it for measurement ofgall stone volume
Stone diameter
Age*
Treatment regimen
No
MIF
% IBW*
(mm)
(yrs)
by comparison with the water displacement
method.33
Gall stone dissolution rates at six and
10-9 (2)
12
2/10
55 (8)
109 (5)
CDCA (MT)
12 months were calculated by comparing the
12
3/9
10-9 (2)
CDCA (BT)
114(4)
47(8)
55 (6)
107 (5)
12
2/10
11-8 (3)
UDCA (MT)
percentage reduction in gall stone volume at
12-3 (3)
102 (6)
12
4/8
55 (9)
UDCA (BT)
these times with the volume before treatment.
118 (5)
13-2 (2)
10
2/8
50 (6)
Combination (BT)
Complete gall stone dissolution was confirmed by
MT= mealtime; BT= bedtime; IBW= ideal body weight
ultrasonography carried out at the time of nega* Results expressed as mean (SEM)
tive oral cholecystogram and repeated after three
months, during which time the patient continued
on treatment. Partial gall stone dissolution was
as a reduction in gall stone volume of
defined
TABLE II Gall stone dissolution rates (% reduction in pretreatment stone volumes) in 48
more than 50%. This is thus a semiquantitative
patients in experiment I. Each patient in the first column is matched for initial gall stone
diameter with the corresponding patient in the other three columns.
measurement, by contrast with the quantitative
measurement of gall stone dissolution rate
Ursodeoxycholic acid
Chenodeoxycholic acid
(above).
Mealtime
Bedtime
Mealtime
Bedtime
DIA
DR6
DRI2 DIA
DR6
DR12
DIA
DR6
DR12 DIA
DR6
DR12
30
18
18
13
12
11
7
5
5
4
4
4*
0
20
48
45
65
27
47
0
50
50
36
60
0
30
80
50
78
52
80
0
70
100
56
100
0
23
8
50
100
0
100
40
90
100
60
90
0
52
8
100
100
0
100
56
100
100
78
100
28
28
20
13
13
10
7
6
4
4
3
5*
0
10
25
100
75
73
85
26
80
100
85
90
0
10
40
100
93
73
85
76
100
100
85
90
25
27
43
68
60
90
80
70
100
100
100
90
38
27
65
90
80
95
92
90
100
100
100
100
STATISTICAL ANALYSIS
30
19
18
12
11
11
7
5
5
4
4
5*
30
30
26
14
10
9
6
7
4
4
4
3*
DIA=initial gallstone diameter; DR6 and DR12=dissolution rate at 6 and 12 months respectively;
*= DR in this matched quartet of patients is calculated from % reduction in pretreatment gall stone
numbers.
Results are described as medians. The paired
Wilcoxon test was used for comparison between
regimens, comparisons being made between gall
stone patients matched for gall stone size. The X2
test and simple regression analysis were also used
where appropriate. P values of <0 05 were
considered significant in the present study.
Results
The dissolution rate (percentage reduction in gall
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Optimum bile acid treatment for rapid gall stone dissolution
383
Small stones
p < 0 001
Large stones
NS
p < 0.01
+.'CD 80
NS
100r
loor
80 F
80
60
60
V
40
40
F
20F
20
100
H
co
0
* 60 H
0
Un
U)
0 40
a)
0
c
U
Zu20
0'1
0
0
'O
-a
-
0
0
x
0
a)
x
o
a)
*0
o
0
-o
0
2-aG
.2a50-0
.O
o U
Co
0
x
0
a)
2
0o
x
0
0
a)
0
c
.*
x
0
0
a)
a)
-o
.C
*o0
'o
0
en
L-
0)
Cu
x
0
a)
x
0
c
Uj)
C
a)
a)
D
a~)
-0
00
*0
-a
0
-0
0
D
-C
U
6
12
6
12
Time (months)
Figure 1: Effect ofdifferent bile acids on the gall stone dissolution rate (expressed as the percentage reduction in gall stone
volume over six and 12 months). Chenodeoxycholic acid and ursodeoxycholic acid are comparedfor small stones andfor large
stones.
stone volume after treatment) for all patients is Effect of dose timing
given in Table II.
Pooling the results for both bile acids, the gall
stone dissolution rate was higher for bedtime
than mealtime administration at six months (69%
GALLSTONE DISSOLUTION RATE: EXPERIMENT I
v 49%, p<0 02, n=24). The difference between
the two dose times was no longer significant at 12
Effect of individual bile acids
months (91% v 77%, NS, n=24).
UDCA treatment resulted in a significantly
The gall stone dissolution rate for small stones
greater gall stone dissolution rate than CDCA at was significantly higher for bedtime than
six months (n=24, median 78% v 48%, p<0 01), mealtime administration both at six months
but the difference between the two bile acids was (90% v 55% p<0 005, n=12) and 12 months
smaller and no longer significant at 12 months (100% v 85%, p<0005, n=12; Fig 2). By
(90% v 74%, NS). For small stones (Fig 1), the contrast, there was no difference between six and
gall stone dissolution rate was significantly faster 12 month gall stone dissolution rate for mealtime
during UDCA than CDCA treatment at six and bedtime administration in patients with large
months (90% v 55%, p<0 001, n= 12), and also stones (35% v 37%, NS (n= 12) and 51% v 58%,
at 12 months (95% v 90%, p<001). By contrast, NS (n= 12) respectively (Fig 2).
for large stones there was no difference between
When the two bile acids are compared in terms
the two bile acids at six or 12 months (52% v 25%, of dose timing, UDCA was found to be more
NS, n=12; and 69% v 51%, NS, n=12 respec- effective than CDCA for both mealtime and
bedtime administration (83% v 47%, p<001
tively).
Small stones
p < 0.005
Large stones
NS
NS
p < 0.005
100 r
lOr
100
0a)
Cu
80
F
80
F
80
60
F
60 F
60
40 F
40 F
401-
201F
20
20 _
C
c
0
-5
cn
U)
.a_
Figure 2: Effect of dose
timing on the gallstone
dissolution rate (expressed as
in Figure 1). Mealtime and
bedtime administration are
comparedfor small stones
and for large stones, the
results for both individual
bile acids being grouped
together.
a:)
0
en
=
U)
0
OL
0
Mealtime
Bedtime
6
Mealtime
Bedtime
Mealtime
Bedtime
6
12
Time
(months)
j.
Mealtime
Bedtime
12
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4Jazrawi, Pigozzi, Galatola, Lanzini, Northfield
384
-
continued during the second six months at
almost the same rate as during the first six
months for CDCA, it decreased considerably for
UDCA.
However, when the cumulative decrease in
diameter during CDCA treatment was plotted
against that for matched stones on UDCA, most
of the data points were above the identity line at
both six and 12 months (Figs 3A and 3B)
indicating that although the gall stone dissolution
rate during UDCA decreased during the second
six-month period compared with the first, it
remained quantitatively higher than for CDCA
during both periods.
4
0
cs
M
0I
3
D2 *I/
v
O
EXPERIMENT II
Chenodeoxycholic acid
(A
diameter 0-6
months (mm))
Effect of combination treatment (Fig 4)
Combination treatment given at bedtime was
more effective than bedtime CDCA after six
months (82% v 36%, p<0 05) and 12 months of
treatment (100% v 54%, p<0 05). However,
there was no difference between combination
therapy and UDCA at six months (82% v 85%,
NS) or at 12 months (100% v 93%, NS, Fig 4).
0
E
acid
*
Chenodeoxycholic
(A diameter 0 12 months (mm))
°E 2
PATIENTS ACHIEVING PARTIAL AND COMPLETE
GALL STONE DISSOLUTION
and 75%
4
3
0
0~~~~
thncor chndoxcoi acd
3
2
(A
6
5
4
Chenodeoxycholic
8
7
acid
diameter 0-12 months (mm))
Figure 3: Relation between chenodeoxycholic acid and
diameter in
ursodeoxycholic acid in reduction in gall
stone
patients after six months of treatment (n = 16, top)
after 12 months of treatment (n 14, bottom). At both
matched
and
=
times,
greater reduction
than for chenodeoxycholic acid.
there is
a
ursodeoxycholic
far
acid
75% v 65%, p<005 respectively).
difference was more clearly shown for
and
stones
during
mealtime administration
This
small
(85%
Both UDCA and combination treatment showed
a trend towards higher total (partial and complete) dissolution rates than CDCA at six months
(70% and 60% on combination therapy and
UDCA respectively, compared with 45% on
CDCA). This trend was mainly due to a higher
complete gall stone dissolution rate, with similar
partial dissolution rates for all three regimens.
There was no difference between the regimens at
12 months.
Dissolution failure at six months (0% dissolution rate), and arrested dissolution (no
change in dissolution rate between six and 12
months) were found in 5/24 patients on CDCA,
7/24 patients on UDCA, and 3/10 patients on
combination therapy. There was no significant
difference between the three groups in this
respect.
v
p<0f005)p
50%,
When the effect of dose timing was compared
for each bile acid, bedtime administration was
more effective than mealtime administration for
CDCA
(55%
UDCA.
Again,
v
45%,
the
p<0h01),
difference was
able for the small stones (90%
Effect of treatment period
gall
When the reduction in
first six months
was
related
v
50%,
stone
to
but
not
more
for
notice-
p<0C005).
diameter in the
that in the second
(excluding those patients who had
complete dissolution at six months), a
significant linear correlation was found for both
bile acids. However, the slope for CDCA
six months
achieved
(Y= 1-12 X)
(Y=0V37
X),
was steeper than that for UDCA
and the data points for CDCA lay
close to the line of identity, while the majority
These
results indicate that while gall stone dissolution
were below the line of identity for UDCA.
Discussion
In this study, we have combined two approaches
in order to determine, in a controlled manner,
the most effective oral treatment regimen for
cholesterol gall stone dissolution. Firstly, we
used a standardised cholecystographic technique
to produce a quantitative measurement of gall
stone dissolution rate. Secondly, we matched our
gall stone patients according to the initial gall
stone diameter when comparing differing treatment regimens, because gall stone size is the most
important factor determining the gall stone dissolution rate.35 These two elements in technique
have enabled us to compare several different
treatment regimens and to detect significant
differences between them.
We defined two categories of gall stone size,
small (<8 mm) and large (>8 mm). We chose
8 mm as the cut off point because it enabled us to
divide all four treatment groups in experiment I
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Optimum bile acid treatment for rapid gall stone dissolution
385
NS
p < 0.05
p < 0-05
50
NS
100 r
100
501--
-
c
On:00 ~
0
-O i
o
x
c- -a
~0
oC
C
iE
x
E
0
-C
c)
E0
~~0
-CCuD
~~~
c
.°
m~~~
X
Ono
c
0
c
C.)
x
CD
D
E
0)
-o
0
-o
0
U
0
0
u
~
x
c
L-
-CCua)
D
E
0
C)
12
6
Time (months)
Figure 4: Effect of combination therapy given at bedtime on the gall stone dissolution rate (expressed as in Figure 1). This is
compared with bedtime chenodeoxycholic acid and with bedtime ursodeoxycholic acid alone.
(each containing 12 patients), into
equal
The issue
of gall stone size has become of great importance
in recent years since the establishment of extracorporeal shockwave lithotripsy (ESWL) as a
non-surgical treatment option for cholesterol gall
stones.39 ESWL converts large stones into small
fragments which then have to be dissolved by
oral bile acid therapy. This, coupled with the fact
that very large stones are unsuitable for bile acid
therapy,'535 has modified the role of bile acid
therapy for gall stone treatment. Our comparisons for small stones should apply also for small
stone fragments after ESWL.
Our results show that UDCA was more effective than CDCA at six months but that the
difference disappeared at 12 months (Fig 1). This
comparison was based on all patients (24
matched pairs) encompassing a wide range of gall
stone diameters (3-30 mm). Simnilar results have
been reported for the proportion of patients
achieving complete gall stone dissolution.22
There are two possible reasons for the reduction in efficacy of UDCA over time. Firstly,
subradiological calcification during UDCA could
arrest further dissolution.' Alternatively, small
stones that dissolve completely with UDCA at six
months are excluded from the analysis of results
at 12 months, giving the impression of CDCA
catching uip with UDCA when the results are
expressed as the proportion achievinig complete
dissolution."2 Our experinmental design allowed
us to differentiate between these two explanations. By separating small and large stones (Fig
1), we found that for small stones UDCA had a
higher efficacy than CDCA at six months (90% v
55%) and that this was still present at 12 months,
whereas for large stones there was no difference
between the two bile acids even at six months.
However, when the reduction in diameter for
two
groups of six with large or small stones.
CDCA was compared with that for UDCA (Fig
3), we found a larger reduction in diameter for
UDCA than CDCA both at six and 12 months.
The finding that a similar proportion of
patients on CDCA and UDCA showed no dissolution (0% dissolution rate) or arrested dissolution suggests that acquired calcification does not
play a major role. Since computed tomography
was not performed before treatment, we cannot
state whether failure of dissolution was due to
subradiological calcification or to radiolucent
non-cholesterol stones. However, 7/8 patients
with radiolucent stones on oral cholecystography
who had failed or arrested dissolution had calcification on computed tomogram. This suggests
that computed tomographic scanning may be an
important factor in selecting patients for bile acid
treatrnent.
In assessinig the effect of dose timing, regardless ofthe type of bile acid, we found a higher gall
stone dissolution rate for bedtime than mealtime
admiinistrationi at six but not 12 months. The
eftect of bedtime administration was more pronounced for small stones with the difference
persisting at 12 months (Fig 2). When the effect
of dose timing was assessed for the two different
bile acids, bedtimne was more efficacious than
niealtime for CDCA but not for UDCA. However, we have shown in a separate study a higher
efficacy of bedtimne over mealtime UDCA when
the bile acid is given in a lower dose of 4 mrg/kg/
day.4' The inability to show a difference at the
higher dose is probably because this dose
achieves an optimal effect that cannot be
iinproved upon by further increasing the dose, as
reported by Erlinger et al, or by givinlg it at
bedtime. Looking at all the different variables
together, we found that mealtime CDCA is the
least and bedtime UDCA the most effective
treatment, especially for small stones (95% disso-
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Jazrawi, Pigozzi, Galatola, Lanzini, Northfield
386
lution at six months and 100% at 12 months).
For combination therapy, the reason for using
equal doses (6 mg/kg/day) of CDCA and UDCA
was to determine whether combination treatment has an additive effect (in which case its
efficacy should lie between that of CDCA and
UDCA in the full monotherapeutic dose) or
whether it has a synergistic effect (in which case it
should have a higher efficacy than either of the
other two bile acids given alone). Our results
suggest the latter. A comparison of three groups
of patients with matched gall stones showed that
combination treatment at bedtime achieved a
dissolution rate at six months that was significantly higher than for bedtime CDCA, but not
higher than for bedtime UDCA. These results do
not confirm those of Podda et al,32 who reported,
in a much larger group of patients, that combination treatment was significantly better than
UDCA in achieving complete gall stone dissolution, but extend Podda's study by showing that
combination therapy is significantly better than
CDCA (Fig 4).
We conclude that bile acid treatment should be
confined to patients with small gall stones (or
small fragments after ESWL). Bedtime administration is more effective than that at mealtime for
CDCA, but UDCA is more effective than
CDCA. Combination treatment is more effective
than CDCA alone, although we could not confirm its superiority over UDCA alone.
These studies were supported financially by Merrell Pharmaceuticals. The authors thank Miss Marion Amos for secretarial
assistance.
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3 Sugata F, Shimizu M. Retrospective studies on gallstone
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4 Nakagawa S, Makino I, Ishizaki T, et al. Dissolution of
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5 Weis HJ, Holtermuller KH, Stiehl A, et al. Clinical experience
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6 Maton PN, Iser JH, Reuben A, et al. Outcome ofchenodeoxycholic acid (CDCA) in 125 patients with radiolucent gallstones. Medicine 1982; 61: 86-97.
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Optimum bile acid treatment for rapid gall
stone dissolution.
R P Jazrawi, M G Pigozzi, G Galatola, et al.
Gut 1992 33: 381-386
doi: 10.1136/gut.33.3.381
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