Gut, 1992, 33, 381-386

Optimum bile acid treatment for rapid gall stonedissolution

R P Jazrawi, M G Pigozzi, G Galatola, A Lanzini, T C Northfield

AbstractTo determine the optimum bile acid regimenfor rapid gail stone dissolution, 48 gall stonepatients were divided into four groups of 12according to stone diameter and were ran-domly allocated to receive one of four treat-ment regimens: bedtime or mealtimechenodeoxycholic acid (CDCA, 12 mg/kg/day)and bedtime or mealtime ursodeoxycholic acid(UDCA, 12 mg/kg/day). An additional 10patients treated with a combination of CDCAplusUDCA (each 6 mg/kg/day) at bedtime werematched with the 10 patients on bedtimeCDCA and the 10 on bedtime UDCA. The gallstone dissolution rates at six and 12 monthswere determined by standardised oral chole-cystography and expressed as the percentagereduction in the gall stone volume after treat-ment. The gall stone dissolution rate at sixmonths was higher for UDCA than CDCAtreatment (median 78% v 48%, p<001), andfor bedtime than mealtime administration (69%v 39%, p<002). Both differences were greaterfor stones <8 mm diameter. The dissolutionrate was faster for combination therapy thanfor 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. Weconclude that bile acid treatment should beconfined to patients with smail gail stones andthat bedtime administration of combinedUDCA and CDCA is likely to provide the mosteffective and safe combination.

Division of BiochemicalMedicine, St George'sHospital Medical School,LondonR P JazrawiM G PigozziG GalatolaA LanziniT C NorthfieldCorrespondence to:Professor T C Northfield,Division of BiochemicalMedicine, St George'sHospital Medical School,Cranmer Terrace, LondonSW17 ORE.

Accepted for publication:2 July 1991

Since the introduction of chenodeoxycholic acid(CDCA) in the early 70s" and ursodeoxycholicacid (UDCA) in the late 70s,35 many controlledand uncontrolled trials have been carried out toassess the efficacy ofthe two bile acids in terms ofthe proportion of gall stones for which completeor partial dissolution is achieved over a definedtime interval. Available data suggest that theoverall efficacy is similar; both bile acids achievecomplete dissolution in 10-60% of patients andpartial dissolution in another 10-45% ofpatients."3' The wide variation in the responserate can be attributed to differences in the dose ofbile acid used, in treatment length, and inpatient's weight in relation to ideal body weightand to different approaches to the inclusion of'dropouts' in the final analysis. Only three con-

trolled studies have directly compared CDCAwithUDCA, and each reported that UDCA had a

slight though not significant advantage overCDCA.'82228 A recent study has reported that acombination of CDCA plus UDCA is moreeffective than UDCA alone.32 We have alsoshown that bedtime administration of CDCA is

more effective than mealtime administration inimproving the gall stone dissolution rate.33

Previous studies have expressed their results interms of the percentage of patients who achievepartial or complete gall stone dissolution, orboth, within a defined time.22-24 26 28 12 34 The disad-vantage ofthese studies is that only those patientswho achieved complete dissolution are used forstatistical analysis, and therefore there is arequirement for large numbers of patients to beenrolled, or for long periods of treatment followup. This has prevented the demonstration ofclearcut differences between the two bile acids.We have previously developed and validated astandard oral cholecystographic technique35 formeasurement of the gall stone dissolution rate,defined as the percentage reduction in gall stonevolume at predetermined intervals after the startof treatment. This measurement is quantitativeand allows the use of all patients data in a trial ofdissolution 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 ofUDCA 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 treat-

ment.For all these comparisons individual patients

were matched for initial gall stone diameter, aswe have previously shown that this is the mostimportant factor affecting the gall stone dissolu-tion rate.35

SubjectsFifty eight of a total of 72 consecutive patientswith radiolucent gall stones in functioning gallbladders were entered in the study on thegrounds of best matching of initial gall stone size.This matching was carried out before measuringthe gall stone dissolution rate. All patients gaveinformed consent, and the studies were approvedby the local hospital ethical committee.

EXPERIMENT IForty eight of the first 59 consecutive patientswere prospectively matched in four groups of 12to within 2 mm according to the diameter of theirlargest stone and were randomly allocated to oneof four treatment regimens: CDCA at bedtime orat mealtimes and UDCA at bedtime or atmealtimes. Each patient grouped had a represen-tative patient with diameter matched gall stones

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in each of the other three groups. In eightpatients with large stones (two in each of theabove groups) the matching was not to within 2mm of stone diameter. The diameters of thelargest stones in these patients were 18 mm, 19mm, 28 mm, and 30 mm in the first matchedquartet, and 18 mm, 18 mm, 20 mm, and 26 mmin the second quartet of patients on mealtimeCDCA, bedtime CDCA, mealtime UDCA, andbedtime UDCA respectively. The bile acids weregiven in a mean total daily dose of 12 mg/kg/dayeither at bedtime or in three equal divided dosesat mealtimes.

EXPERIMENT IITen ofa total of 13 consecutive patients receivingbedtime combination therapy were matched forinitial gall stone diameter with 20 patientsalready studied - 10 taking CDCA and 10 takingUDCA at bedtime. The patients on combinationtherapy received CDCA and UDCA, both in adose of 6 mg/kg/day, giving a total daily dose of12 mg/kg administered at bedtime.

Clinical details of the patient groups are shownin Table I. There were no significant differencesin terms of age and percentage ideal body weightbetween the groups in either of the experiments.For all patients, we used a dose of approxi-

mately 12 mg/kg/day, as this dose maintains anunsaturated gall bladder bile for CDCA' as wellas for UDCA.37 For the combination treatment,we used the same total dose of 12 mg/kg/day,because we wished to study an equimolar dose ofthe two bile acids.

TABLE I Clinical details ofpatients treated with chenodeoxycholic acid (CDCA),ursodeoxycholic acid (UCCA), or a combination ofboth

Age* Stone diameterTreatment regimen No MIF (yrs) % IBW* (mm)

CDCA (MT) 12 2/10 55 (8) 109 (5) 10-9 (2)CDCA (BT) 12 3/9 47(8) 114(4) 10-9 (2)UDCA (MT) 12 2/10 55 (6) 107 (5) 11-8 (3)UDCA (BT) 12 4/8 55 (9) 102 (6) 12-3 (3)Combination (BT) 10 2/8 50 (6) 118 (5) 13-2 (2)

MT=mealtime; BT= bedtime; IBW= ideal body weight* Results expressed as mean (SEM)

TABLE II Gall stone dissolution rates (% reduction in pretreatment stone volumes) in 48patients in experiment I. Each patient in the first column is matchedfor initial gall stonediameter with the corresponding patient in the other three columns.

Chenodeoxycholic acid Ursodeoxycholic acid

Mealtime Bedtime Mealtime Bedtime

DIA DR6 DRI2 DIA DR6 DR12 DIA DR6 DR12 DIA DR6 DR12

30 0 0 30 0 0 28 0 0 30 25 3818 20 30 19 23 52 28 10 10 30 27 2718 48 80 18 8 8 20 25 40 26 43 6513 45 50 12 50 100 13 100 100 14 68 9012 65 78 11 100 100 13 75 93 10 60 8011 27 52 11 0 0 10 73 73 9 90 957 47 80 7 100 100 7 85 85 6 80 925 0 0 5 40 56 6 26 76 7 70 905 50 70 5 90 100 4 80 100 4 100 1004 50 100 4 100 100 4 100 100 4 100 1004 36 56 4 60 78 3 85 85 4 100 1004* 60 100 5* 90 100 5* 90 90 3* 90 100

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 stonenumbers.

METHODS AND MEASUREMENTSA standardised oral cholecystogram was used tovisualise the gall stones within the gall bladder.This technique involved placing a 450 woodenblock under the left side ofthe patient as he or shelay in the supine position. Hence views takenwere in the right supine oblique position. In fivepatients in whom abdominal gas prevented com-plete visualisation of the gall bladder in thisposition, right prone oblique views wereobtained and used for subsequent studies on thesame patients. The distance between patient andx ray tube was always kept constant at 100 cm. Inall patients except four, the diameter of thelargest stone was measured and used for calculat-ing the gall stone dissolution rates achieved bythe different bile acids by comparing gall stonevolume before and after treatment. In the fourexceptions (randomised to the four differenttreatment regimens), there were multiple smallstones of similar diameter (3-5 mm). In thesepatients the number of stones was calculated andthe percentage reduction in number was used asan estimate of the gall stone dissolution rateduring treatment. The standardised oral chole-cystogram was repeated in each patient after sixand 12 months of treatment. Standardisation ofthe procedure in this manner allows valid quan-titative determination of the relative change insize or number of gall stones.33

CALCULATION AND ANALYSIS OF RESULTSFrom the standardised oral cholecystogram, theinitial gall stone diameter and the diameters at sixand 12 months were measured. We also meas-ured the volume of gall stones at the same timeintervals by the method of multiple cylinders.38Although this method38 was developed to meas-ure gall bladder volume, we have previouslyvalidated it for measurement ofgall stone volumeby comparison with the water displacementmethod.33 Gall stone dissolution rates at six and12 months were calculated by comparing thepercentage reduction in gall stone volume atthese times with the volume before treatment.Complete gall stone dissolution was confirmed byultrasonography carried out at the time of nega-tive oral cholecystogram and repeated after threemonths, during which time the patient continuedon treatment. Partial gall stone dissolution wasdefined as a reduction in gall stone volume ofmore than 50%. This is thus a semiquantitativemeasurement, by contrast with the quantitativemeasurement of gall stone dissolution rate(above).

STATISTICAL ANALYSISResults are described as medians. The pairedWilcoxon test was used for comparison betweenregimens, comparisons being made between gallstone patients matched for gall stone size. The X2test and simple regression analysis were also usedwhere appropriate. P values of <0 05 wereconsidered significant in the present study.

ResultsThe dissolution rate (percentage reduction in gall

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Optimum bile acid treatment for rapid gall stone dissolution

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Figure 1: Effect ofdifferent bile acids on the gall stone dissolution rate (expressed as the percentage reduction in gall stonevolume over six and 12 months). Chenodeoxycholic acid and ursodeoxycholic acid are comparedfor small stones andfor largestones.

stone volume after treatment) for all patients isgiven in Table II.

GALLSTONE DISSOLUTION RATE: EXPERIMENT I

Effect ofindividual bile acidsUDCA treatment resulted in a significantlygreater gall stone dissolution rate than CDCA atsix months (n=24, median 78% v 48%, p<0 01),but the difference between the two bile acids wassmaller and no longer significant at 12 months(90% v 74%, NS). For small stones (Fig 1), thegall stone dissolution rate was significantly fasterduring UDCA than CDCA treatment at sixmonths (90% v 55%, p<0 001, n= 12), and alsoat 12 months (95% v 90%, p<001). By contrast,for large stones there was no difference betweenthe two bile acids at six or 12 months (52% v 25%,NS, n=12; and 69% v 51%, NS, n=12 respec-tively).

Effect ofdose timingPooling the results for both bile acids, the gallstone dissolution rate was higher for bedtimethan mealtime administration at six months (69%v 49%, p<0 02, n=24). The difference betweenthe two dose times was no longer significant at 12months (91% v 77%, NS, n=24).The gall stone dissolution rate for small stones

was significantly higher for bedtime thanmealtime administration both at six months(90% v 55% p<0 005, n=12) and 12 months(100% v 85%, p<0005, n=12; Fig 2). Bycontrast, there was no difference between six and12 month gall stone dissolution rate for mealtimeand bedtime administration in patients with largestones (35% v 37%, NS (n= 12) and 51% v 58%,NS (n= 12) respectively (Fig 2).When the two bile acids are compared in terms

of dose timing, UDCA was found to be moreeffective than CDCA for both mealtime andbedtime administration (83% v 47%, p<001

Small stones

p < 0.005

Figure 2: Effect ofdosetiming on the gallstonedissolution rate (expressed asin Figure 1). Mealtime andbedtime administration arecomparedfor small stonesandfor large stones, theresults for both individualbile acids being groupedtogether.

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Figure 3: Relation between chenodeoxycholic acid and

ursodeoxycholic acid in reduction in gall stone diameter in

matched patients after six months of treatment (n = 16, top)and after 12 months oftreatment (n= 14, bottom). At both

times, there is a greater reductionfarursodeoxycholic acid

than for chenodeoxycholic acid.

and 75% v 65%, p<005 respectively). This

difference was more clearly shown for small

stones during mealtime administration (85% v

50%,p<0f005)pWhen the effect of dose timing was compared

for each bile acid, bedtime administration was

more effective than mealtime administration for

CDCA (55% v 45%, p<0h01), but not for

UDCA. Again, the difference was more notice-

able for the small stones (90% v 50%, p<0C005).

Effect oftreatment periodWhen the reduction in gall stone diameter in the

first six months was related to that in the second

six months (excluding those patients who had

achieved complete dissolution at six months), a

significant linear correlation was found for both

bile acids. However, the slope for CDCA

(Y= 1-12 X) was steeper than that for UDCA(Y=0V37 X), and the data points for CDCA lay

close to the line of identity, while the majoritywere below the line of identity for UDCA. Theseresults indicate that while gall stone dissolution

continued during the second six months atalmost the same rate as during the first sixmonths for CDCA, it decreased considerably forUDCA.However, when the cumulative decrease in

diameter during CDCA treatment was plottedagainst that for matched stones on UDCA, mostof the data points were above the identity line atboth six and 12 months (Figs 3A and 3B)indicating that although the gall stone dissolutionrate during UDCA decreased during the secondsix-month period compared with the first, itremained quantitatively higher than for CDCAduring both periods.

EXPERIMENT II

Effect ofcombination treatment (Fig 4)Combination treatment given at bedtime wasmore effective than bedtime CDCA after sixmonths (82% v 36%, p<0 05) and 12 months oftreatment (100% v 54%, p<0 05). However,there was no difference between combinationtherapy and UDCA at six months (82% v 85%,NS) or at 12 months (100% v 93%, NS, Fig 4).

PATIENTS ACHIEVING PARTIAL AND COMPLETEGALL STONE DISSOLUTIONBoth UDCA and combination treatment showeda trend towards higher total (partial and com-plete) dissolution rates than CDCA at six months(70% and 60% on combination therapy andUDCA respectively, compared with 45% onCDCA). This trend was mainly due to a highercomplete gall stone dissolution rate, with similarpartial dissolution rates for all three regimens.There was no difference between the regimens at12 months.

Dissolution failure at six months (0% dis-solution rate), and arrested dissolution (nochange in dissolution rate between six and 12months) were found in 5/24 patients on CDCA,7/24 patients on UDCA, and 3/10 patients oncombination therapy. There was no significantdifference between the three groups in thisrespect.

DiscussionIn this study, we have combined two approachesin order to determine, in a controlled manner,the most effective oral treatment regimen forcholesterol gall stone dissolution. Firstly, weused a standardised cholecystographic techniqueto produce a quantitative measurement of gallstone dissolution rate. Secondly, we matched ourgall stone patients according to the initial gallstone diameter when comparing differing treat-ment regimens, because gall stone size is the mostimportant factor determining the gall stone dis-solution rate.35 These two elements in techniquehave enabled us to compare several differenttreatment regimens and to detect significantdifferences between them.We defined two categories of gall stone size,

small (<8 mm) and large (>8 mm). We chose8 mm as the cut offpoint because it enabled us todivide all four treatment groups in experiment I

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p < 0.05 NS p < 0-05 NS100 r

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12Time (months)

Figure 4: Effect ofcombination 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 two equalgroups of six with large or small stones. The issueof gall stone size has become of great importancein recent years since the establishment of extra-corporeal shockwave lithotripsy (ESWL) as anon-surgical treatment option for cholesterol gallstones.39 ESWL converts large stones into smallfragments which then have to be dissolved byoral bile acid therapy. This, coupled with the factthat very large stones are unsuitable for bile acidtherapy,'535 has modified the role of bile acidtherapy for gall stone treatment. Our compari-sons for small stones should apply also for smallstone fragments after ESWL.Our results show that UDCA was more effec-

tive than CDCA at six months but that thedifference disappeared at 12 months (Fig 1). Thiscomparison was based on all patients (24matched pairs) encompassing a wide range of gallstone diameters (3-30 mm). Simnilar results havebeen reported for the proportion of patientsachieving complete gall stone dissolution.22There are two possible reasons for the reduc-

tion in efficacy of UDCA over time. Firstly,subradiological calcification during UDCA couldarrest further dissolution.' Alternatively, smallstones that dissolve completely with UDCA at sixmonths are excluded from the analysis of resultsat 12 months, giving the impression of CDCAcatching uip with UDCA when the results are

expressed as the proportion achievinig completedissolution."2 Our experinmental design allowedus to differentiate between these two explana-tions. By separating small and large stones (Fig1), 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 differencebetween the two bile acids even at six months.However, when the reduction in diameter for

CDCA was compared with that for UDCA (Fig3), we found a larger reduction in diameter forUDCA than CDCA both at six and 12 months.The finding that a similar proportion of

patients on CDCA and UDCA showed no disso-lution (0% dissolution rate) or arrested dissolu-tion suggests that acquired calcification does notplay a major role. Since computed tomographywas not performed before treatment, we cannotstate whether failure of dissolution was due tosubradiological calcification or to radiolucentnon-cholesterol stones. However, 7/8 patientswith radiolucent stones on oral cholecystographywho had failed or arrested dissolution had cal-cification on computed tomogram. This suggeststhat computed tomographic scanning may be an

important factor in selecting patients for bile acidtreatrnent.

In assessinig the effect of dose timing, regard-less ofthe type of bile acid, we found a higher gallstone dissolution rate for bedtime than mealtimeadmiinistrationi at six but not 12 months. Theeftect of bedtime administration was more pro-nounced for small stones with the differencepersisting at 12 months (Fig 2). When the effectof dose timing was assessed for the two differentbile acids, bedtimne was more efficacious thanniealtime for CDCA but not for UDCA. How-

ever, we have shown in a separate study a higherefficacy of bedtimne over mealtime UDCA whenthe bile acid is given in a lower dose of 4 mrg/kg/day.4' The inability to show a difference at thehigher dose is probably because this doseachieves an optimal effect that cannot beiinproved upon by further increasing the dose, as

reported by Erlinger et al, or by givinlg it atbedtime. Looking at all the different variablestogether, we found that mealtime CDCA is theleast and bedtime UDCA the most effectivetreatment, especially for small stones (95% disso-

100

50 -

c0

E0C)

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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 UDCAwas to determine whether combination treat-ment has an additive effect (in which case itsefficacy should lie between that of CDCA andUDCA in the full monotherapeutic dose) orwhether it has a synergistic effect (in which case itshould have a higher efficacy than either of theother two bile acids given alone). Our resultssuggest the latter. A comparison of three groupsof patients with matched gall stones showed thatcombination treatment at bedtime achieved adissolution rate at six months that was signifi-cantly higher than for bedtime CDCA, but nothigher than for bedtime UDCA. These results donot confirm those of Podda et al,32 who reported,in a much larger group of patients, that combina-tion treatment was significantly better thanUDCA in achieving complete gall stone dissolu-tion, but extend Podda's study by showing thatcombination therapy is significantly better thanCDCA (Fig 4).We conclude that bile acid treatment should be

confined to patients with small gall stones (orsmall fragments after ESWL). Bedtime adminis-tration is more effective than that at mealtime forCDCA, but UDCA is more effective thanCDCA. Combination treatment is more effectivethan CDCA alone, although we could not con-firm its superiority over UDCA alone.

These studies were supported financially by Merrell Pharmaceuti-cals. The authors thank Miss Marion Amos for secretarialassistance.

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