Gallbladder Stones: Oral Dissolution Therapy

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.

B OTH CHENODEOXYCl101 It' Al 'JI)   (chenod iol) and ursndeoxychol i(.acid (ursodinl) are approved for use in the United States by rhc Federal Food and Drug AJm intstration.Either alone or in combination, these bile ac ids arc effective in slowly dissolving gallstones which are almost pure cho lesterol.Both bile acids decrease ht!pa ti c biliary cholesterol secretion resulting in miccllardesatura tion in chole:.terol.U rsodinl Mayo Med1rnl Center, Roc/1ester, Mmnesota also d issolves hiltary cholesterol hy liquid crystal forma tion.CHENODIOL Predictable cholesterol desaturation of hile requires mgest ion of 12 t<) 15 mg/kg/day of chenodiol in non,)bese patients (I).In obesity, hiliary cholesterol secretion 1s increased m proportton to excess body weight and 18 to 20 mg/kg/day may be required to achieve micellar desacurnuon m these patients.This may he difficult to tolerate because of dnse-related side effects; however, ingestion of a Josage insuffiuenr ro desarurnte hile is of no value.
Most pacicn1s initially develop at lease transient intermittent increased stool frequency with or without cramping when a fully tbernpeu ttc dosage is ingested (2).The drnrrhea is often episodic, L'g, ncc umng once every week or two, and usua ll y d ecreases after several weeks to m,mth, if the patient continues to titre the dose as tolerated.The diarrhea effect b dose-related and immcJiately resolves when the dose is decreased sufficiently.The mechanism of the diarrhea b inhibition of normal water and electrolyte ahsorpt io n by the colon.No long term conseq uence of this diarrhea has been doc umented.
A m1n,1rransferase elevations (usually less than threefold) occur com monl y and arc also dosc-rclateJ (2).Like the diarrhea, this side effect abo usually r~'tums to normal during the first few months of creatment.Higher enzyme levels arc rare, hut chenodiol sh,)uld be disconcmued if th ese occur.An acceptably prudent mo nitori n g regimen wou ld be to assess aminotramfcrase levels monthl y for three mo nths and then at six, 12, 18 and 24 mo nths.In the National Cooperative Galbrone S tudy in the United States (2), clevat inn of scrum total cholesterol IO mg/JL greater than 111 the placebo group was observed , and thi s e levati o n was predominantly in the low density lipnprote in fraction.Oiernry restriction

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 substantially less frequent than with chenoJ iol.Depending on how it is defined, about 5% of patients may get Jiarrhea; occasionally this 1s sufficient to prevent treatment with this agent.It seems like-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 established.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 solubilizauon and absorption of ursodiol 1s enhanced by bile, and admimstration with a stimulus to gallbladder contraction seems empirically appropriate.
UrsQdiol has largely replaced chenodiol because of infrequent diarrhea and the absence of aminotransferase clevarnm.Indeed, ursodiol has been shown to decrease hepatic enzyme levels in several chronic, especially 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 capsules a day, leading ro a cost of at least US $1500 per year for most patients.
A combination of chcno<liol and ursod iol has been proposed hoth to Jecrease expense and possibly to increase efficacy (6).Some evidence suggests chat the combination may be more effective than either bile acid alone during the first six months, but the differences are minor after 12 months of treatment.It would be of interest to Cl)mpare the usefulness of the comhination versus ursodiol alone after extracorporeal 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 content and, in sufficient doses, produces a milieu which can resoluhil1ze the crystalline cholesterol in srnncs.The stone cholesterol, however, must be accessible; even a very ihin layer of calc1u111 hilirubmate or calcium carhonatc will prevent Jbsolutinn.Many stones which cannot be JetectcJ lm abJommal plain film will have calcification Jemonstrable 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 cholcq1tography 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 contrast.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 .. obtained, but an isotope biliary scan or convincing evidence of gallbladder emptying by ulrrasonography arc acceptable alternative methods.Occasionally 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 convincing baseline.The recurrence data available are almost all relevant to oral bile acid therapy, which, reflects a highly 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) The search continues for a nnvd bile acid which will desacurnte bile 111 cholesterol and resist hepatic or bacterial 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 prophylactic agent would greatly enhance the usefulness of all nonsurgical treatments for gallstones which arc evolving.