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Annu. Rev. Med. 1990.41:401-415. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
NONSURGICAL TREATMENT OF GALLSTONE DISEASE Alan F. Hofmann, M.D., Ph.D. Department of Medicine, University of California at San Diego, La Jolla, California 92093 KEY WORDS:
cholelithiasis, dissolution, cholesterol, lithotripsy, ursodiol, bile acids, therapy.
ABSTRACT
Gallstones can now be treated nonsurgically as well as surgically. The current view is that only symptomatic gallstones should be treated; of these, only cholesterol gallstones can be treated nonsurgically. Cholesterol gallstones in a functioning gallbladder will dissolve slowly when the secretion of unsaturated bile is induced by the ingestion of ursodiol or chenodiol, which arc naturally occurring bile acids. Stone dissolution can be accelerated by increasing the surface area via extracorporeal shock wave lithotripsy, which fragments stones rapidly and safely, enhancing their dissolution rate. A technique is being developed in which a catheter is inserted into the gallbladder via either a percutaneous transhepatic or endoscopic route and an organic solvent such as methyl tert-butyl ether is instilled, dissolving the stones rapidly without major side effects. Gall stones will eventually recur in about half of the patients treated by these nonsurgical approaches, because the gallbladder is left in place and the fundamental pathogenic abnormalities associated with this common dis ease are not corrected. However, the rate of recurrence of symptomatic gallstone disease is lower. INTRODUCTION: SCOPE OF CHAPTER
This chapter will summarize selected aspects of the three current non surgical treatments of cholesterol gallstones in the gallbladder: medical 401 0066--4219/90/0401-0401$02.00
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therapy with orally administered bile acids (medical therapy), extra corporeal shock wave lithotripsy (ESL), and invasive Iitholysis with organic solvents (ILOS). The last technique, which is still experimental, can be performed via a percutaneous transhepatic or endoscopic route. Two books (1, 2) and a monograph (3) dealing entirely with gallstone pathogenesis and treatment have been published recently. Medical therapy has been the subject of recent reviews (4, 5), and a recent congress summary describes the state of the art of ESL (6). This latter rcference also contains a thorough summary of the pioneering experience of the Mayo Clinic group using ILOS. Space does not permit a review of the fascinating history of the devel opment of each of these techniques nor of the experiments that have led to current concepts of gallstone formation. Review articles or monographs are available elsewhere on the physical chemistry of bile (7), the entero hepatic circulation of bile acids (8, 9), biliary lipid secretion (10), and the pathogenesis of cholesterol gallstones (11) and pigment gallstones (12). ELIGIBILITY CRITERIA
Symptomatic Gallstone Disease The current view is that no gallstone patient should be treated until she (or he) is symptomatic (13). In the prospective epidemiological study conducted in Sirmione, Italy, only one fourth of patients with gallstones imagable by ultrasonography were symptomatic (14); in some studies (15, 16), patients with gallstones are no more likely to have abdominal symp toms than patients without gallstones. Accordingly, patients with gall stones should not be treated when gallstones are discovered accidentally, for example, by abdominal sonography. The recommendation that silent gallstones should not be treated medi cally is an extrapolation from the study of Gracie and Ransohoff who, on the basis of the very benign history of asymptomatic gallstones in members of the University of Michigan faculty, concluded that elective chole cystectomy could not be justified (17, 18). However, this extrapolation is not necessarily correct for a number of reasons. First, medical therapy with ursodiol appears to be totally safe, as will be discussed below. Thus, medical therapy is safer than cholecystectomy, which has an age- and surgeon-dependent morbidity and mortality rate (19, 20). Second, the behavior of asymptomatic gallstones in the University of Michigan faculty may not be representative of the general population, and even if it is, the sample size is quite small. Third, when it first appears, an asymptomatic gallstone is likely to be eligible for medical therapy. As it grows, it may become calcified or induce chronic gallbladder inflammation with fibrosis,
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either of which precludes medical therapy. Finally, prospective epi demiological studies disagree about whether gallbladder stones cause a specific kind of pain (14-16). Prospective epidemiological studies suggest that the incidence of symptomatic gallstone disease in patients with asymptomatic gallstones is about 3% per year (21). It is also known that the natural tendency of most gallstones is to grow (22). Once a stone becomes severely symptomatic, it remains so in most instances, and there is a high probability that acute cholecystitis will occur in the next five years (23-25). Thus, a symptomatic stone is a dangerous stone-hence the recommendation that therapy should be initiated. The rapid culling of gallstone patients with severe biliary pain from the large cohort of gallstone patients without specific symptoms may explain why gallstone patients do not have pain more frequently than nongallstone patients. Why should the development of symptoms indicate that a gallstone has changed from nondangerous to dangerous? The simplest answer is that the development of symptoms indicates that the stone can obstruct the neck of the gallbladder, so that pressure increases when the gallbladder contracts. For a stone to obstruct, it must be of an appropriate size and shape to pack the infundibulum of the gallbladdcr and obstruct the passage of bile into the cystic duct when the gallbladder contracts. Gallstones probably enter the neck by gravitation-induced sedimentation or by con vective flow during contraction. My own view is that the dichotomous classification of gallstones into either symptomatic stones, which should be treated, or asymptomatic gallstones, which should not be treated, is simplistic and will be modified as more information is obtaincd on the natural history of gallstone disease. A method is needed to predict which asymptomatic gallstones are likely to become symptomatic and hence require intervention and which gall stones are likely to remain asymptomatic during the life of the patient. It is also necessary to develop new methods to distinguish typical gallstone pain, atypical gallstone pain, and pain that is unrelated to the presence of gallstones. Finally, the very low probability that the asymptomatic gall stone will induce gallbladder cancer must also be evaluated.
Presence of Cholesterol Gallstones Only cholesterol gallstones can be treated by nonsurgical means; therefore, gallstone composition is important. Any kind of gallstone can be frag mented by ESL; however, unless the fragments are small enough to be discharged from the gallbladder, they are more likely to remain there indefinitely than if their dissolution is induced by medical therapy or ILOS. However, only cholesterol fragments are responsive to such treatments.
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Virtually all gallbladder stones are a mixture of cholesterol and calcium salts,and most form under sterile conditions (11, 25). Stones that contain a majority of cholesterol (perhaps > 60%) are termed cholesterol gallstones. Stones that contain a mixture of cholesterol and calcium bilirubinate are termed mixed gallstones. Black gallstones contain polymerized calcium bilirubinate and calcium proteinate as well as hydroxyapatite (12). Gall stones may also contain calcium carbonate either throughout or as rim calcification. The problem is how to determine gallstone composition by an imaging procedure. In the early years of medical dissolution, a radiograph of the abdomen was used, based on the rationale that radiopaque stones con tained calcium and were therefore resistant to dissolution by unsaturated bile and that radiolucent gallstones were cholesterol gallstones and could be dissolved (26, 27). This view has been modified by recent studies. Stones that are radiopaque are rich in calcium inorganic salts: calcium carbonate and calcium phosphate (as hydroxyapatite). (This is because the pro portion of calcium atoms is so high in such stones.) Radiolucent gallstones may be either cholesterol gallstones, which can be dissolved, or black gallstones, which cannot. Two methods are currently
used to distinguish gallstone type. The first is flotation during oral chole cystography. Stones that float during oral cholecystography are cholesterol gallstones. The density of bile containing the iodinated contrast material increases to as much as 1.040 to 1.050. Cholesterol monohydrate has a density of 1.038. Thus, when stones float, their density is close to that of cholesterol monohydrate (28). The "flotation " method is believed to be specific, but it is not sensitive, because multiple factors influence the con centration of the cholecystographic agent in gallbladder bile and because all gallstones contain a mixture of cholesterol and caleium salts including calcium proteinate. Data are not available on the density of the various types of calcium bilirubinate (either the acid salt or calcium bilirubinate) or on the density of calcium proteinate. The second method that is emerging in importance is computed to mography (CT). With CT, patterns of calcification in stones examined in vitro can be detected and stones may be classified (relative to saline) as hypodense, isodense, or hyperdense (homogeneously dense). Calcification may be classified as rimmed or laminated (29, 30). Hypodense gallstones are unequivocally cholesterol stones, but the utility of the method for distinguishing which mixed gallstones are susceptible to medical dis solution remains uncertain. This is probably because the resolution of the method cannot assess the thickness or completeness of strata of calcium salts. In principle, strata can be much thinner than the resolution of CT. Nonetheless, the view is emerging that CT may be cost effective for
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detecting calcium-rich stones when medical dissolution or ILOS is con templated. This is because medical dissolution is costly and requires 1-2 years of patient compliance and because ILOS is invasive and should be initiated only if there is a good chance of gallstone dissolution.
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Presence of a Functioning Gallbladder The current recommendation is to assess gallbladder-concentrating ability by oral cholecystography for all patients in whom nonsurgical therapy is contemplated. Only the patient who has a gallbladder that visualizes well is considered eligible for medical therapy or ESL (followed by adjunctive medical therapy). Assuming that the cholecystographic agent is absorbed, failure of the gallbladder to opacify means failure to fill or, if filling is normal, failure to concentrate (31). The belief that a patient with a nonvisualizing gallbladder will not respond to medical therapy (or ESL followed by medical therapy) is based on the early Mayo Clinic experience (26). There are anecdotal reports of patients with nonvisualizing gall bladders responding to medical therapy, and in the National Cooperative Gallstone Study (NCGS) some patients who responded to medical therapy manifested nonvisualizing gallbladders during therapy (32). However, the recommendation not to accept patients with nonvisualizing gallbladders for medical therapy seems logical, albeit conservative. Whether the use of 99Tc-iminodiacetic acid derivatives to image the gallbladder will provide additional information beyond that obtained by oral cholecystography is as yet unknown. Studies are also being designed to see whether an ultrasonogram showing good gallbladder contraction renders the oral cholecystogram redundant. MEDICAL THERAPY WITH ORAL BILE ACIDS
History and Rationale The idea of treating gallstones with orally administered bile acids was suggested more than 100 years ago by the great physiologist Moritz Schiff, then working in Florence, Italy (33); a series of successful case reports was published three years later by Dabney in the United States (34). The modern era of medical dissolution of gallstones began about 20 years ago, when the Mayo Clinic group first reported successful dissolution by chenodiol (35). The rationale of oral bile acid therapy is to desaturate bile so that cholesterol molecules move from the surface of the gallstone to the unsaturated micelles surrounding it. Evidence suggests that the de saturation efficacy in compliant patients receiving the optimal dosage is >90% (36).
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Efficacy Three bile acid preparations are now widely used for medical dissolution: ursodiol, chenodiol, and a combination of the two agents (37). The effi cacies of these three preparations do not differ greatly and will be con sidered identical in this discussion. As noted above, the desaturation effi cacy is high, probably > 90%. The dissolution efficacy (38) in compliant patients completing a course of optimal dose is lower (40--70%), probably because patients with noncholesterol gallstones were included in early trials. Such stones are likely to be radiolucent pigment stones, some of which can now be identified by CT (29, 30). Medication should be ingested at bedtime, since absorption of the ingested dose during the night increases bile acid flux through the liver with an acute desaturating effect that is superimposed upon the chronic desaturating effect (39). Some patients develop surgical complications during therapy or develop acquired gallstone calcification. If efficacy is related to "intent to treat, " then the efficacy is still lower because of dropout during drug therapy and because of an appreciable incidence of acute cholecystitis during therapy. Analysis of the kinetics of gallstone dissolution during therapy with chenodiol or ursodiol indicates that the change in stone diameter size with time should be linear (40, 41). In a careful analysis of the kinetics of gallstone dissolution during therapy with chenodiol or ursodiol, Senior et al found that gallstone dissolution in responsive patients averaged 1-2 mm (change in diameter size) per month (41).
Side Effects and Complications Ursodiol has no important complications other than acquired gallstone calcification (with CaC03), which is likely to stop stone dissolution (42). However, in one large series, calcification occurred no more frequently during therapy with ursodiol than with chenodiol (43). A few patients develop diarrhea, perhaps because ursodiol is epimerized to chenodiol in the colon (44). Chenodiol induces a dose-related diarrhea (31), probably because of its direct secretory actions on the human colon (45). It also induces a dose related hepatotoxicity evidenced by elevated aminotransferase levels in plasma (31). Analyses of biliary bile acids indicate that this effect is likely to be caused by a direct toxic effect of chenodiol on the hepatocyte rather than by an effect of any of its biotransformation products, such as litho cholic acid (46). Lithocholic acid is formed in the colon by bacterial 7-dehydroxylation of chenodiol (or ursodiol) and is a potent hepatotoxin in animals (47). Its absorption from the colon is increased in patients receiving chenodiol (or
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ursodiol), but it does not accumulate in the circulating bile acids because of efficient sulfation in the liver (48,49). Such sulfation prevents subsequent absorption from the small intestine (50). To date, defective sulfation of lithocholate, causing hepatotoxicity, has not as yet been documented in the several thousand patient-years of chenodiol therapy, despite suggestive morphological evidence (51). Hepatotoxicity because of lithocholate accu mulation during chronic chenodiol or ursodiol ingestion occurs consis tently in animals incapable of sulfating lithocho1ate (52). The final side effect of chenodiol is an increased cholesterol con centration in plasma; this occurs predominantly in the low-density lipo protein (LDL) fraction (53). The increase in the LDL cholesterol level in plasma is likely to be caused by down-regulation of LDL receptors on the hepatocyte, which, in turn, is a response to the potent inhibition of 3hydroxy-3-methylglutaryl coenzyme A reductase (54, 55). Space does not permit discussion of the mechanism of action of cheno diol and/or ursodiol, nor can the uncommon pharmacology of these two bile acids be reviewed. Both have been discussed in detail elsewhere (56, 57).
EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY
History and Rationale Shock waves are high-intensity waves that can be produced by the under water discharge of a spark gap electrode or by a vibrating plate. They can then be focused, allciwing a semi-elliptical regulator to form a small volume of high-intensity waves close to or on the gallstone. Shock waves may also be produced by large hemispherical arrays of piezoelectric elements. Gallstone disintegration is believed to result from the pulses generated by collapse of cavitation bubbles in the bile surrounding the stones (58). For single gallstones, the required energy for fragmentation is proportional to the stone mass; stone composition is less important (6). Single stones are fragmented more efficiently than multiple stones (59, 60). In principle, successful lithotripsy should produce fragments sufficiently small to be expelled from the gallbladder without additional medical therapy. Experience, however, indicates that fragmentation is incomplete and that total fragment clearance requires 6-12 months despite continuous ingestion of oral bile acids (59). Single small stones clear faster than single large stones (59, 60). Two or three small stones clear faster than two or three large stones. The fraction of patients treated who will pass all of their fragments spontaneously is one third of that of patients receiving adjuvant ursodiol therapy, based on unpublished results from the Dornier
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National Lithotripsy Study. Most studies to date have used adjuvant ursodiol-chenodiol therapy, although one trial in which ursodiol alone was used obtained similar results (60). In the Munich study, bile acid therapy was begun two weeks prior to ESL therapy so that bile would be desaturated at the time of treatment; as yet, such pretreatment is no more efficacious than treatment begun at the time of ESL (60). Some 10,000 patients globally have been treated with ESL, and numerous multicenter trials under U.S. Food and Drug Administration sanction are being conducted at present. There are few data comparing one machine with another, but the general view is that shock wave machines have greater fragmentation efficacy than piezoelectric machines as they are now used (6). The electromagnetic membrane machines have unequivocal efficacy (61), but, again, no results of pro spective trials comparing this type of machine with spark gap or piezo electric machines have been published. The power of the shock waves destroys tissue, causing microhemor rhages in the liver, gallbladder, and kidney. These changes, in con trast to stone fragmentation, appear to be completely reversible in a matter of weeks or months; nonetheless, experience with biliary lithotripsy
is only five years old, and it is not inconceivable that some permanent damage may eventually be noted. Most side effects relate to fragment passage. Such passage causes frequent bouts of biliary pain in 30-50% of treated patients. Complications, such as cystic duct obstruction causing acute pancreatitis or common duct obstruction, occur in less than 2% of treated patients, at least in the published series (59, 60). There is some renal trauma, because microscopic hematuria is common; gross hematuria also occurs, but in less than 5% of treated patients. One death has occurred in association with the procedure hecause of an acute myocardial infarction in an elderly, high-risk patient.
Applicability Several problems suggest that although ESL is attractive because of its noninvasiveness and safety, it will have only a limited place in the treatment of symptomatic gallbladder stones. These include (a) the small fraction of patients with gallstones who qualify for the procedure if the restrictive criteria proposed by the Munich group continue to be obser' ved, some physicians have argued that current selection criteria should be broadened (62); (b) the high cost of the entire procedure, which includes one or more ESL procedures and adjuvant medical therapy for 6-15 months; (c) the frequent occurrence of biliary pain after treatment; (d) the length of time after therapy that involves pain and necessity of compliance with oral medication; and (e) the probability of recurrence.
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INVASIVE LITHOL YSIS WITH ORGANIC SOLVENTS
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History A group at the Mayo Clinic have carried out systemic studies of factors influencing gallstone dissolution (63). They found that the gasoline additive methyl tert-butyl ether (MTBE), a dialkyl ether with a boiling point of 57°C, would dissolve cholesterol gallstones rapidly in vitro (64). In contrast to diethyl ether, it remains liquid at body temperature. They then placed cholesterol gallstones in the gallbladder of dogs and found that such gallstones could be dissolved rapidly by introduction of MTBE via a percutaneous transhepatic catheter and that the anhydrous organic solvent did not appear to injure the gallbladder mucosa (65). With these findings, they collaborated with interventional radiologists to develop a rapid and simple method of placing a pigtail catheter in the gallbladder by a percutaneous transhepatic approach. They have recently reported details of the successful treatment of some 75 patients with MTBE (66). The Mayo Clinic approach has been confirmed by Hellstern et al in Frankfurt, Germany (67), the San Diego group (68), and Zakko et al at the University of Connecticut (69). Placement of a catheter via a percutaneous trans hepatic route is rapid and safe. Rare complications are a vasovagal reaction causing hypotension or a bile leak following withdrawal of the catheter (70).
Efficacy To dissolve the stone, MTBE is infused into the gallbladder and then aspirated. Initially, manual infusion and aspiration with a glass syringe were used. Because the technique requires several hours for complete stone dissolution, this was quite labor intensive. To reduce the labor involved in the procedure, the Mayo Clinic group have developed an oscillating pump that transfers a defined volume into and out of the gallbladder (71). The volume is set at less than that volume of infused contrast material that leaks from the gallbladder. In vitro results are encouraging (72), and animal studies with the pump are being initiated. A multicenter clinical trial is being planned. Zakko, working in the author's laboratory, has developed a solvent transfer system that pumps solvent into and out of the gallbladder simultaneously while continuously monitoring the intra luminal pressure (73). To keep the intraluminal pressure below the "escape pressure," a microprocessor controls the inflow pump rate. The pump has been used successfully in some 20 patients to achieve rapid, safe, and automatic dissolution of cholesterol gallbladder stones (69). The pump
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will be produced commercially, and a multicenter trial is in the planning stages.
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Side Effects MTBE is an anhydrous organic solvent, which is clearly destructive to the gastrointestinal mucosa (74); when given to rats intravenously in small doses, it is fatal (75). The resistance of the gallbladder mucosa is remark able, probably because of its need to be resistant to bile, which is a concentrated detergent solution. To date,the only major complication induced by MTBE has been a case of (reversible) renal failure (76), although nausea, vomiting, and pain are not uncommon with manual delivery. A small amount of MTBE is likely to be absorbed through the gallbladder wall and will be expired, as well as metabolized to methanol and tert-butanol.
Applicability MTBE is a rapid dissolution agent for cholesterol gallstones because of its high solvent capacity for cholesterol (180 mg ml-1) and its low viscosity (77). Whether a better solvent can be found is not clear. GALLSTONE RECURRENCE
All of the nonsurgical techniques described above will be followed by recurrence, as was cholecystotomy (78). After medical dissolution, the recurrence rate of detectable stones plateaus at about 50% in five years (79,80). No good data are available for the recurrence rate of symptomatic cholelithiasis, which is the disease condition that was originally present when therapy was initiated, or for the recurrence rate with ILOS or ESL, but recurrence definitely occurs (81). After medical dissolution, patients with multiple gallstones are more likely to develop recurrence than patients with a single gallstone. Thus, medical therapy, ESL, or ILOS is likely to cure more than half of the patients who respond, and such treatment eliminates pain for 1-10 years for the remainder. CHOICE OF NONSURGICAL THERAPY
At present, only medical therapy with ursodiol or chenodiol has been approved in the United States, although ESL is likely to be approved by the time this manuscript is published. ILOS is at least two years from approval,because multicenter studies have not even begun. An algorithm summarizing the consensus of experts for treatment of symptomatic
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patients in tertiary centers has been published (82). The recommenda tions are developed without consideration of costs, of the legal status of techniques such as ILOS, of the availability of skilled personnel, etc, so that widespread applicability is uncertain. Nonetheless, the algorithm is shown in Figure 1.
�
..,no
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•
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I
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00
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Example of management algorithm for patients with gallstones. At present, only
medical therapy has been approved by the U.S. Food and Drug Administration, so that this decision tree can be followed only at institutions where ILOS and ESL are also available under an experimental protocol. Reprinted from and publisher. Abbreviations: GB
=
(83),
with the permission of the authors
gallbladder; UDCA
CDCA
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chenodeoxycholic acid (chenodiol);
MTBE
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methyl tert-butyl ether.
US
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=
ursodeoxycholic acid (ursodiol);
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and
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Annu. Rev. Med. 1990.41:401-415. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
FUTURE CHALLENGES A number of areas for research are apparent. These include (a) quanti fication of the relative importance of supersaturated bile, accelerated nucleation, or defective gallbladder contraction in the pathogenesis of the stone; (b) understanding each of these pathogenetic abnormalities at a molecular level; (c) development of better imaging methods for defining gallstone composition so that the dissolution efficacy will be 100%; and (d) validation of better methods for identifying patients who will not develop recurrence, so that permanent cures will become more frequent. Finally, prospective studies are needed to define whether the gallbladder is a useful or superfluous organ in adults. All nonsurgical techniques preserve the organ, but such preservation may not have a rationale if the organ is truly superfluous. ACKNOWLEDGMENTS
The author's work is supported by Public Health Service grants DK 21506 and DK 32130 from the National Institutes of Health,as well as by grants in aid from the Falk Foundation e.V., Lithox Systems, and the Diamalt Company. Literature Cited 1. Cohen, S., Soloway, R. D. 1985. Con temporary Issues in Gastroenterology, Volume 4, Gallstones. New York: Chur chill Livingstone. 341 pp. 2. Bateson, M. C. 1986. Gallstone Disease and Its Management. Lancaster: MTP Press. 244 pp. 3. Schoenfield, L. J. 1988. Gallstone s. Clin. Symp. 40: 2-32 4. Fromm, H., Malavolti, M. 1988. Dis solving gallstones. Adv. Intern. Med. 33: 409-30 5. Hofmann, A. F. 1989. Medical dis solution of gallstones by oral bile acid therapy. Am. J. Surg. 158: 198-204 6. Ferrucci, J. T., Delius, M., Burhenne, H. J., eds. 1989. Biliary Lithotripsy. Chicago: Year Book Medica!. 309 pp. 7. Hofmann, A. F., 1984. The physical chemistry of bile in health and disease. Hepatology 4(Suppl. ): I S-2 52S 8. Hofmann, A. F. 1990. Enterohepatic cir culation of bile acids. In Handbook of Physiology. Section on the Gastro intestinal System, cd. S. G. Schultz, pp. 567-96. Bethesda: Am. Physio!. Soc. 9. Carey, M. C, Cahalane, M. J. 1988. Enterohepatic circulation. In The Liver: Biology and Pathobiology, ed. I. M.
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1L
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Arias, W. B. Jakoby, H. Popper, D. Schachter, D. A. Shafritz, pp. 573-616. New York: Raven. 1377 pp. 2nd ed. Carey, M. C., Cohen, D. E. 1986. Biliary transport of cholesterol in vesicles, micelles and liquid crystals. In Bile Acids and the Liver, t:d. G. P aumgartne r, A. Stiehl, W. Gerok, pp. 287-300. Lan caster: MTP Press. 384 pp. Hofmann, A. F. 1988. Pathogenesis of cholesterol gallstones. In Proc. Symp. on Current Concepts in the Management of Cholelithiasis. J. Clin. Gastroenterol. lO(Supp!. 2): SI-S1 I Cahalane, M. J., Neubrand, M. W., Carey, M. C 1988. Physical-chemical pathogenesis of pigment gallstones. Semin. Liver Dis. 8: 317-28 Schoenfield, L. J., Carulli, N., Dowling, R. H., Sarna, C, Wolpers, C 1989. Asymptomatic gallstones: definition and treatment. Gastroenterol. Int. 2: 25-29 Barbara, L., Sarna, C, Labate, A. M. M., Taroni, F., Rusticali, A. G., et al. 1987. A population study on the preva lence of gallstone disease: the Sirmione study. Hepatology 7: 913-17 Jorgensen, L. T. 1989. Abdominal symp toms and gallstone disease: an epidemi-
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ological investigation. Hepatology 9: 856--60 Glambek, I., Arnesjo, B., Soreide, O. 1989. Correlation between gallstones and abdominal symptoms in a random population. Results from a screening study. Seand. J. Gastroenterol. 24: 27781 Gracie, W. A., Ransohoff, D. F. 1982. The natural history of silent gallstones: the innocent gallstone is not a myth. N. Engl. J. Afed. 307: 798-800 Ransohoff, D. F., Gracie, W. A., Wolf enson, L. B., Neuhauser, D. 1983. Pro phylactic cholecystectomy or expectant management for silent gallstones. A decision analysis to assess survival. Ann. Intern. Med. 99: 199-204 Fitzpatrick, G., Neutra, R., Gilbert, J. P. 1977. Cost-effectiveness of chole cystectomy for silent gallstones. In Costs, Risks and Benefits of Surgery, ed. J. P. Bunker, B. A. Barnes, F. Mosteller, pp.
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28. Akerlund, A. 1938. Die Verfeinerung del' roentgenologischen Gallensteindiag nostik durch Untersuchung def Sedi mentierungs- und Schichtungsverhaelt nisse in der Gallenblase. Acta Radiol. 19: 23-43 29. Baron, R. L., Rohrmann, C. A. Jr., Lee, S. P. , Shuman, W. P., Teefey, S. A. 1988. CT evaluation of gallstones in vitro: cor relation with chemical analysis. Am. J. Roentgenol. 151: 1123-28 30. Wang, l.-T., Su, c.-T., Lin, l.-T., Liu, B.-F., Want, T.-H., Chen, D.-S. 1988. Evaluation of gallstones by ultra sonography, oral cholecystography and computed tomography. Chinese J. Gastroenterol. 5: 77-85 31. Berk, R. N. 1983. Oral cholecys tography. In Radiology of the Gal/ bladder and Bile Ducts. Diagnosis and Intervention, ed. R. N. Berk, J. T. Ferrucci, G. R. Leopold, pp. 83-162. Philadelphia: Saunders. 585 pp. 32. Schoenfield, L . .I., Lachin, 1. M., the Steering Committee, and the National Cooperative Gallstone Study Group. 1981. Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study. Ann. Intern. M ed. 95: 257-82 33. Schiff, M. 1873. II coleinato di soda nella cura dei calcoli biliari. L'Imparziale 13: 97-99 34. Dabney, W. C. 1876. The use of choleate of soda to prevent the formation of gall stones. Am. J. Med. Sci. 71: 410-13 35. Danzinger, R. G., Hofmann, A. F., Schoenfield, L. I., Thistle, I. L. 1972. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N. Engl. J. Med. 286: 1-8 36. Maton, P. N., Iser, J. H., Reuben, A., Saxton, H., Murphy, G. M., Dowling, R. H. 1982. The final outcome of CDCA-treatment in 125 patients with radiolucent gallstunes: factors influ encing efficacy, withdrawal, symptoms, and side effects and post-dissolution recurrence. Medicine 61: 86-96 37. Podda, M., Zuin, M., Battczzati, P. M., Ghezzi, C., de Fazio, C., Dioguardi, M. L. 1989. Efficacy and safety of a com bination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dis solution: a comparison with urso deoxycholic acid alone. Gastroenterol ogy 96: 222-29 3R. Hofmann, A. F. 1984. Medical treat ment of cholesterol gallstones by bile de saturating agents. Hepatology 4: 1995208S 39. Lanzini, A., Facchinetti, D., Northfield, T. C. 19SR. Maintenance of hepatic bile
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acid secretion rate during overnight fast ing by bedtime bile acid administration. Gastroenterology 95: 1029-35 40. Higuchi, W. I., Sjuib, F., Mufson, D., Simonelli, A. P., Hofmann, A. F. 1973. Dissolution kinetics of gallstones. Physi cal model approach. J. Pharm. Sci. 62: 942-45 41. Senior, J. R., Johnson, M. F., DeTurck, D. M., Bazzoli, F., Roda, E. 1990. In vivo cholesterol gallstone dissolution kinetics during oral ursodeoxycholic or chenodeoxycholic acid treatment. Gas troenterology. In press 42. Bateson, M. c., Bouchier, 1. A. D., Trash, D. B., Maudgal, D. P., North field, T. C. 1981. Calcification of radio lucent gall stones during treatment with ursodeoxycholic acid. Br. Med. J. 283: 645-46 43. Frabboni, R., Bazzoli, F., Mazzella, G., Festi, D., Villanova, N., Roda, E., Bar bara, L. 1985. Acquired gallstone cal cification during cholelitholytic treat ment with chenodeoxycholic, ursodeoxy cholic and tauroursodeoxycholic acids. Hepatology 4: 1004 (Abstr.) 44. Fedorowski, T., Saien, G., Coialliio, A., Tint, G. S., Mosbach, E. H ., Hall, J. C. 1977. Metabolism of ursodeoxycholic acid in man. Gastroenterology 73: 113137 45. Mekhjian, H. S., Phillips, S. F., Hofmann, A. F. 1971. Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man. J. Clin. Invest. 50: 1569-77 46. Fisher, R. L., Hofmann, A. E, Rossi, S., Converse, J. L., Lan, S. P. 1986. Pathogenesis of morphological damage and major serum amino-transferase (AT) elevations in NCGS patients: enhanced liver cell sensitivity-not de fective lithocholate metabolism. Hepa tology 6: 1169 (Abstr.) 47. Palmer, R. H. 1972. Bile acids, liver injury, and liver disease. Ar ch. Intern. Med. 130: 606-17 48. Cowen, A. E., Korman, M. G., Hof mann, A. F., Cass, O. W. 1975. Metabo lism of lithocholate in healthy man. 1. Biotransformation and biliary excre tion of intravenously administered litho cholate, lithocholylglycine, and their sulfates. Gastroenterology 69: 59-66 49. Allan, R. N., Thistle, J. L., Hofmann, A. F. 1976. Lithocholate metabolism during chenotherapy for gallstone dis solution. II. Absorption and sulphation. Gut 17: 413-19 50. Cowen, A. E., Korman, M. G., Hof mann, A. F., Cass, 0., Coffin, S. B . 1975. Metabolism of lithocholate in
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61. Burhenne, H. J., Becker, C. D., Malone, D. E., Rawat, B., Fache, J. S. 1989. Bili ary lithotripsy: early observations in 106 patie nts. Work in progress. Radiology 171: 363-67 62. Dharzi, A., Monson, J. R. T., O'Morain, C., Tanner W. A., Keane, F. B. V. 1988. Successful extracorporeal shock wave lithotripsy for ga llst ones unsuitable for chemical di ssolution. In Proc. 13th Int.
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pump system for dissolving gallstones using methyl tert-butyl ether (MTBE): in vitro comparison with the manual syringe method. Gastroenterology 96: A629 (A bstr .) 73. Zakko, S. F., Hofmann, A. F. 1990. Microprocessor assisted solven't trans f er system (MastSystemTM) for effec tive contact dissolution of gallbladder stones. Trans. Biomed. Eng. In press 74. Zakko, S. F., Hajjar, J. J., Oberstein, R., Tomicic, T. K., Hofmann, A. F. 1989. Intestinal cytotoxicity of contact gall stone dissol ution solv ents: a comp arison . of methyl tert- bu tyl ether (MTBE) with mono-octanoin (MOC). Gastroenter ology 96: A676 (Abstr.) 75. Akimoto, R. , Mayer, D., Rieger, E.,
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H. E. 1989. Liver necrosis and hemorrhagic pneumonitis caused by extra biliary injection of MTBE. Gastro enterology 96: A570 (Abstr.) Ponchon, T., Baroud, J., Puj ol, 8., Valette, P. J., Perrot, D. 1988. Renal failure dnring dissolution of gallstones by methyl-tert-butyl ether. Lancet 2: 276--7 7 (letter to editor) Bogardus, J. 8. 1984. Importance of vis cosity in the dissolution rate of chol strom,
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NONSURGICAL TREATMENT OF GALLSTONE DISEASE Alan F. Hofmann, M.D., Ph.D. Department of Medicine, University of California at San Diego, La Jolla, California 92093 KEY WORDS:
cholelithiasis, dissolution, cholesterol, lithotripsy, ursodiol, bile acids, therapy.
ABSTRACT
Gallstones can now be treated nonsurgically as well as surgically. The current view is that only symptomatic gallstones should be treated; of these, only cholesterol gallstones can be treated nonsurgically. Cholesterol gallstones in a functioning gallbladder will dissolve slowly when the secretion of unsaturated bile is induced by the ingestion of ursodiol or chenodiol, which arc naturally occurring bile acids. Stone dissolution can be accelerated by increasing the surface area via extracorporeal shock wave lithotripsy, which fragments stones rapidly and safely, enhancing their dissolution rate. A technique is being developed in which a catheter is inserted into the gallbladder via either a percutaneous transhepatic or endoscopic route and an organic solvent such as methyl tert-butyl ether is instilled, dissolving the stones rapidly without major side effects. Gall stones will eventually recur in about half of the patients treated by these nonsurgical approaches, because the gallbladder is left in place and the fundamental pathogenic abnormalities associated with this common dis ease are not corrected. However, the rate of recurrence of symptomatic gallstone disease is lower. INTRODUCTION: SCOPE OF CHAPTER
This chapter will summarize selected aspects of the three current non surgical treatments of cholesterol gallstones in the gallbladder: medical 401 0066--4219/90/0401-0401$02.00
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therapy with orally administered bile acids (medical therapy), extra corporeal shock wave lithotripsy (ESL), and invasive Iitholysis with organic solvents (ILOS). The last technique, which is still experimental, can be performed via a percutaneous transhepatic or endoscopic route. Two books (1, 2) and a monograph (3) dealing entirely with gallstone pathogenesis and treatment have been published recently. Medical therapy has been the subject of recent reviews (4, 5), and a recent congress summary describes the state of the art of ESL (6). This latter rcference also contains a thorough summary of the pioneering experience of the Mayo Clinic group using ILOS. Space does not permit a review of the fascinating history of the devel opment of each of these techniques nor of the experiments that have led to current concepts of gallstone formation. Review articles or monographs are available elsewhere on the physical chemistry of bile (7), the entero hepatic circulation of bile acids (8, 9), biliary lipid secretion (10), and the pathogenesis of cholesterol gallstones (11) and pigment gallstones (12). ELIGIBILITY CRITERIA
Symptomatic Gallstone Disease The current view is that no gallstone patient should be treated until she (or he) is symptomatic (13). In the prospective epidemiological study conducted in Sirmione, Italy, only one fourth of patients with gallstones imagable by ultrasonography were symptomatic (14); in some studies (15, 16), patients with gallstones are no more likely to have abdominal symp toms than patients without gallstones. Accordingly, patients with gall stones should not be treated when gallstones are discovered accidentally, for example, by abdominal sonography. The recommendation that silent gallstones should not be treated medi cally is an extrapolation from the study of Gracie and Ransohoff who, on the basis of the very benign history of asymptomatic gallstones in members of the University of Michigan faculty, concluded that elective chole cystectomy could not be justified (17, 18). However, this extrapolation is not necessarily correct for a number of reasons. First, medical therapy with ursodiol appears to be totally safe, as will be discussed below. Thus, medical therapy is safer than cholecystectomy, which has an age- and surgeon-dependent morbidity and mortality rate (19, 20). Second, the behavior of asymptomatic gallstones in the University of Michigan faculty may not be representative of the general population, and even if it is, the sample size is quite small. Third, when it first appears, an asymptomatic gallstone is likely to be eligible for medical therapy. As it grows, it may become calcified or induce chronic gallbladder inflammation with fibrosis,
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either of which precludes medical therapy. Finally, prospective epi demiological studies disagree about whether gallbladder stones cause a specific kind of pain (14-16). Prospective epidemiological studies suggest that the incidence of symptomatic gallstone disease in patients with asymptomatic gallstones is about 3% per year (21). It is also known that the natural tendency of most gallstones is to grow (22). Once a stone becomes severely symptomatic, it remains so in most instances, and there is a high probability that acute cholecystitis will occur in the next five years (23-25). Thus, a symptomatic stone is a dangerous stone-hence the recommendation that therapy should be initiated. The rapid culling of gallstone patients with severe biliary pain from the large cohort of gallstone patients without specific symptoms may explain why gallstone patients do not have pain more frequently than nongallstone patients. Why should the development of symptoms indicate that a gallstone has changed from nondangerous to dangerous? The simplest answer is that the development of symptoms indicates that the stone can obstruct the neck of the gallbladder, so that pressure increases when the gallbladder contracts. For a stone to obstruct, it must be of an appropriate size and shape to pack the infundibulum of the gallbladdcr and obstruct the passage of bile into the cystic duct when the gallbladder contracts. Gallstones probably enter the neck by gravitation-induced sedimentation or by con vective flow during contraction. My own view is that the dichotomous classification of gallstones into either symptomatic stones, which should be treated, or asymptomatic gallstones, which should not be treated, is simplistic and will be modified as more information is obtaincd on the natural history of gallstone disease. A method is needed to predict which asymptomatic gallstones are likely to become symptomatic and hence require intervention and which gall stones are likely to remain asymptomatic during the life of the patient. It is also necessary to develop new methods to distinguish typical gallstone pain, atypical gallstone pain, and pain that is unrelated to the presence of gallstones. Finally, the very low probability that the asymptomatic gall stone will induce gallbladder cancer must also be evaluated.
Presence of Cholesterol Gallstones Only cholesterol gallstones can be treated by nonsurgical means; therefore, gallstone composition is important. Any kind of gallstone can be frag mented by ESL; however, unless the fragments are small enough to be discharged from the gallbladder, they are more likely to remain there indefinitely than if their dissolution is induced by medical therapy or ILOS. However, only cholesterol fragments are responsive to such treatments.
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Virtually all gallbladder stones are a mixture of cholesterol and calcium salts,and most form under sterile conditions (11, 25). Stones that contain a majority of cholesterol (perhaps > 60%) are termed cholesterol gallstones. Stones that contain a mixture of cholesterol and calcium bilirubinate are termed mixed gallstones. Black gallstones contain polymerized calcium bilirubinate and calcium proteinate as well as hydroxyapatite (12). Gall stones may also contain calcium carbonate either throughout or as rim calcification. The problem is how to determine gallstone composition by an imaging procedure. In the early years of medical dissolution, a radiograph of the abdomen was used, based on the rationale that radiopaque stones con tained calcium and were therefore resistant to dissolution by unsaturated bile and that radiolucent gallstones were cholesterol gallstones and could be dissolved (26, 27). This view has been modified by recent studies. Stones that are radiopaque are rich in calcium inorganic salts: calcium carbonate and calcium phosphate (as hydroxyapatite). (This is because the pro portion of calcium atoms is so high in such stones.) Radiolucent gallstones may be either cholesterol gallstones, which can be dissolved, or black gallstones, which cannot. Two methods are currently
used to distinguish gallstone type. The first is flotation during oral chole cystography. Stones that float during oral cholecystography are cholesterol gallstones. The density of bile containing the iodinated contrast material increases to as much as 1.040 to 1.050. Cholesterol monohydrate has a density of 1.038. Thus, when stones float, their density is close to that of cholesterol monohydrate (28). The "flotation " method is believed to be specific, but it is not sensitive, because multiple factors influence the con centration of the cholecystographic agent in gallbladder bile and because all gallstones contain a mixture of cholesterol and caleium salts including calcium proteinate. Data are not available on the density of the various types of calcium bilirubinate (either the acid salt or calcium bilirubinate) or on the density of calcium proteinate. The second method that is emerging in importance is computed to mography (CT). With CT, patterns of calcification in stones examined in vitro can be detected and stones may be classified (relative to saline) as hypodense, isodense, or hyperdense (homogeneously dense). Calcification may be classified as rimmed or laminated (29, 30). Hypodense gallstones are unequivocally cholesterol stones, but the utility of the method for distinguishing which mixed gallstones are susceptible to medical dis solution remains uncertain. This is probably because the resolution of the method cannot assess the thickness or completeness of strata of calcium salts. In principle, strata can be much thinner than the resolution of CT. Nonetheless, the view is emerging that CT may be cost effective for
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detecting calcium-rich stones when medical dissolution or ILOS is con templated. This is because medical dissolution is costly and requires 1-2 years of patient compliance and because ILOS is invasive and should be initiated only if there is a good chance of gallstone dissolution.
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Presence of a Functioning Gallbladder The current recommendation is to assess gallbladder-concentrating ability by oral cholecystography for all patients in whom nonsurgical therapy is contemplated. Only the patient who has a gallbladder that visualizes well is considered eligible for medical therapy or ESL (followed by adjunctive medical therapy). Assuming that the cholecystographic agent is absorbed, failure of the gallbladder to opacify means failure to fill or, if filling is normal, failure to concentrate (31). The belief that a patient with a nonvisualizing gallbladder will not respond to medical therapy (or ESL followed by medical therapy) is based on the early Mayo Clinic experience (26). There are anecdotal reports of patients with nonvisualizing gall bladders responding to medical therapy, and in the National Cooperative Gallstone Study (NCGS) some patients who responded to medical therapy manifested nonvisualizing gallbladders during therapy (32). However, the recommendation not to accept patients with nonvisualizing gallbladders for medical therapy seems logical, albeit conservative. Whether the use of 99Tc-iminodiacetic acid derivatives to image the gallbladder will provide additional information beyond that obtained by oral cholecystography is as yet unknown. Studies are also being designed to see whether an ultrasonogram showing good gallbladder contraction renders the oral cholecystogram redundant. MEDICAL THERAPY WITH ORAL BILE ACIDS
History and Rationale The idea of treating gallstones with orally administered bile acids was suggested more than 100 years ago by the great physiologist Moritz Schiff, then working in Florence, Italy (33); a series of successful case reports was published three years later by Dabney in the United States (34). The modern era of medical dissolution of gallstones began about 20 years ago, when the Mayo Clinic group first reported successful dissolution by chenodiol (35). The rationale of oral bile acid therapy is to desaturate bile so that cholesterol molecules move from the surface of the gallstone to the unsaturated micelles surrounding it. Evidence suggests that the de saturation efficacy in compliant patients receiving the optimal dosage is >90% (36).
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Efficacy Three bile acid preparations are now widely used for medical dissolution: ursodiol, chenodiol, and a combination of the two agents (37). The effi cacies of these three preparations do not differ greatly and will be con sidered identical in this discussion. As noted above, the desaturation effi cacy is high, probably > 90%. The dissolution efficacy (38) in compliant patients completing a course of optimal dose is lower (40--70%), probably because patients with noncholesterol gallstones were included in early trials. Such stones are likely to be radiolucent pigment stones, some of which can now be identified by CT (29, 30). Medication should be ingested at bedtime, since absorption of the ingested dose during the night increases bile acid flux through the liver with an acute desaturating effect that is superimposed upon the chronic desaturating effect (39). Some patients develop surgical complications during therapy or develop acquired gallstone calcification. If efficacy is related to "intent to treat, " then the efficacy is still lower because of dropout during drug therapy and because of an appreciable incidence of acute cholecystitis during therapy. Analysis of the kinetics of gallstone dissolution during therapy with chenodiol or ursodiol indicates that the change in stone diameter size with time should be linear (40, 41). In a careful analysis of the kinetics of gallstone dissolution during therapy with chenodiol or ursodiol, Senior et al found that gallstone dissolution in responsive patients averaged 1-2 mm (change in diameter size) per month (41).
Side Effects and Complications Ursodiol has no important complications other than acquired gallstone calcification (with CaC03), which is likely to stop stone dissolution (42). However, in one large series, calcification occurred no more frequently during therapy with ursodiol than with chenodiol (43). A few patients develop diarrhea, perhaps because ursodiol is epimerized to chenodiol in the colon (44). Chenodiol induces a dose-related diarrhea (31), probably because of its direct secretory actions on the human colon (45). It also induces a dose related hepatotoxicity evidenced by elevated aminotransferase levels in plasma (31). Analyses of biliary bile acids indicate that this effect is likely to be caused by a direct toxic effect of chenodiol on the hepatocyte rather than by an effect of any of its biotransformation products, such as litho cholic acid (46). Lithocholic acid is formed in the colon by bacterial 7-dehydroxylation of chenodiol (or ursodiol) and is a potent hepatotoxin in animals (47). Its absorption from the colon is increased in patients receiving chenodiol (or
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ursodiol), but it does not accumulate in the circulating bile acids because of efficient sulfation in the liver (48,49). Such sulfation prevents subsequent absorption from the small intestine (50). To date, defective sulfation of lithocholate, causing hepatotoxicity, has not as yet been documented in the several thousand patient-years of chenodiol therapy, despite suggestive morphological evidence (51). Hepatotoxicity because of lithocholate accu mulation during chronic chenodiol or ursodiol ingestion occurs consis tently in animals incapable of sulfating lithocho1ate (52). The final side effect of chenodiol is an increased cholesterol con centration in plasma; this occurs predominantly in the low-density lipo protein (LDL) fraction (53). The increase in the LDL cholesterol level in plasma is likely to be caused by down-regulation of LDL receptors on the hepatocyte, which, in turn, is a response to the potent inhibition of 3hydroxy-3-methylglutaryl coenzyme A reductase (54, 55). Space does not permit discussion of the mechanism of action of cheno diol and/or ursodiol, nor can the uncommon pharmacology of these two bile acids be reviewed. Both have been discussed in detail elsewhere (56, 57).
EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY
History and Rationale Shock waves are high-intensity waves that can be produced by the under water discharge of a spark gap electrode or by a vibrating plate. They can then be focused, allciwing a semi-elliptical regulator to form a small volume of high-intensity waves close to or on the gallstone. Shock waves may also be produced by large hemispherical arrays of piezoelectric elements. Gallstone disintegration is believed to result from the pulses generated by collapse of cavitation bubbles in the bile surrounding the stones (58). For single gallstones, the required energy for fragmentation is proportional to the stone mass; stone composition is less important (6). Single stones are fragmented more efficiently than multiple stones (59, 60). In principle, successful lithotripsy should produce fragments sufficiently small to be expelled from the gallbladder without additional medical therapy. Experience, however, indicates that fragmentation is incomplete and that total fragment clearance requires 6-12 months despite continuous ingestion of oral bile acids (59). Single small stones clear faster than single large stones (59, 60). Two or three small stones clear faster than two or three large stones. The fraction of patients treated who will pass all of their fragments spontaneously is one third of that of patients receiving adjuvant ursodiol therapy, based on unpublished results from the Dornier
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National Lithotripsy Study. Most studies to date have used adjuvant ursodiol-chenodiol therapy, although one trial in which ursodiol alone was used obtained similar results (60). In the Munich study, bile acid therapy was begun two weeks prior to ESL therapy so that bile would be desaturated at the time of treatment; as yet, such pretreatment is no more efficacious than treatment begun at the time of ESL (60). Some 10,000 patients globally have been treated with ESL, and numerous multicenter trials under U.S. Food and Drug Administration sanction are being conducted at present. There are few data comparing one machine with another, but the general view is that shock wave machines have greater fragmentation efficacy than piezoelectric machines as they are now used (6). The electromagnetic membrane machines have unequivocal efficacy (61), but, again, no results of pro spective trials comparing this type of machine with spark gap or piezo electric machines have been published. The power of the shock waves destroys tissue, causing microhemor rhages in the liver, gallbladder, and kidney. These changes, in con trast to stone fragmentation, appear to be completely reversible in a matter of weeks or months; nonetheless, experience with biliary lithotripsy
is only five years old, and it is not inconceivable that some permanent damage may eventually be noted. Most side effects relate to fragment passage. Such passage causes frequent bouts of biliary pain in 30-50% of treated patients. Complications, such as cystic duct obstruction causing acute pancreatitis or common duct obstruction, occur in less than 2% of treated patients, at least in the published series (59, 60). There is some renal trauma, because microscopic hematuria is common; gross hematuria also occurs, but in less than 5% of treated patients. One death has occurred in association with the procedure hecause of an acute myocardial infarction in an elderly, high-risk patient.
Applicability Several problems suggest that although ESL is attractive because of its noninvasiveness and safety, it will have only a limited place in the treatment of symptomatic gallbladder stones. These include (a) the small fraction of patients with gallstones who qualify for the procedure if the restrictive criteria proposed by the Munich group continue to be obser' ved, some physicians have argued that current selection criteria should be broadened (62); (b) the high cost of the entire procedure, which includes one or more ESL procedures and adjuvant medical therapy for 6-15 months; (c) the frequent occurrence of biliary pain after treatment; (d) the length of time after therapy that involves pain and necessity of compliance with oral medication; and (e) the probability of recurrence.
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INVASIVE LITHOL YSIS WITH ORGANIC SOLVENTS
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History A group at the Mayo Clinic have carried out systemic studies of factors influencing gallstone dissolution (63). They found that the gasoline additive methyl tert-butyl ether (MTBE), a dialkyl ether with a boiling point of 57°C, would dissolve cholesterol gallstones rapidly in vitro (64). In contrast to diethyl ether, it remains liquid at body temperature. They then placed cholesterol gallstones in the gallbladder of dogs and found that such gallstones could be dissolved rapidly by introduction of MTBE via a percutaneous transhepatic catheter and that the anhydrous organic solvent did not appear to injure the gallbladder mucosa (65). With these findings, they collaborated with interventional radiologists to develop a rapid and simple method of placing a pigtail catheter in the gallbladder by a percutaneous transhepatic approach. They have recently reported details of the successful treatment of some 75 patients with MTBE (66). The Mayo Clinic approach has been confirmed by Hellstern et al in Frankfurt, Germany (67), the San Diego group (68), and Zakko et al at the University of Connecticut (69). Placement of a catheter via a percutaneous trans hepatic route is rapid and safe. Rare complications are a vasovagal reaction causing hypotension or a bile leak following withdrawal of the catheter (70).
Efficacy To dissolve the stone, MTBE is infused into the gallbladder and then aspirated. Initially, manual infusion and aspiration with a glass syringe were used. Because the technique requires several hours for complete stone dissolution, this was quite labor intensive. To reduce the labor involved in the procedure, the Mayo Clinic group have developed an oscillating pump that transfers a defined volume into and out of the gallbladder (71). The volume is set at less than that volume of infused contrast material that leaks from the gallbladder. In vitro results are encouraging (72), and animal studies with the pump are being initiated. A multicenter clinical trial is being planned. Zakko, working in the author's laboratory, has developed a solvent transfer system that pumps solvent into and out of the gallbladder simultaneously while continuously monitoring the intra luminal pressure (73). To keep the intraluminal pressure below the "escape pressure," a microprocessor controls the inflow pump rate. The pump has been used successfully in some 20 patients to achieve rapid, safe, and automatic dissolution of cholesterol gallbladder stones (69). The pump
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will be produced commercially, and a multicenter trial is in the planning stages.
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Side Effects MTBE is an anhydrous organic solvent, which is clearly destructive to the gastrointestinal mucosa (74); when given to rats intravenously in small doses, it is fatal (75). The resistance of the gallbladder mucosa is remark able, probably because of its need to be resistant to bile, which is a concentrated detergent solution. To date,the only major complication induced by MTBE has been a case of (reversible) renal failure (76), although nausea, vomiting, and pain are not uncommon with manual delivery. A small amount of MTBE is likely to be absorbed through the gallbladder wall and will be expired, as well as metabolized to methanol and tert-butanol.
Applicability MTBE is a rapid dissolution agent for cholesterol gallstones because of its high solvent capacity for cholesterol (180 mg ml-1) and its low viscosity (77). Whether a better solvent can be found is not clear. GALLSTONE RECURRENCE
All of the nonsurgical techniques described above will be followed by recurrence, as was cholecystotomy (78). After medical dissolution, the recurrence rate of detectable stones plateaus at about 50% in five years (79,80). No good data are available for the recurrence rate of symptomatic cholelithiasis, which is the disease condition that was originally present when therapy was initiated, or for the recurrence rate with ILOS or ESL, but recurrence definitely occurs (81). After medical dissolution, patients with multiple gallstones are more likely to develop recurrence than patients with a single gallstone. Thus, medical therapy, ESL, or ILOS is likely to cure more than half of the patients who respond, and such treatment eliminates pain for 1-10 years for the remainder. CHOICE OF NONSURGICAL THERAPY
At present, only medical therapy with ursodiol or chenodiol has been approved in the United States, although ESL is likely to be approved by the time this manuscript is published. ILOS is at least two years from approval,because multicenter studies have not even begun. An algorithm summarizing the consensus of experts for treatment of symptomatic
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patients in tertiary centers has been published (82). The recommenda tions are developed without consideration of costs, of the legal status of techniques such as ILOS, of the availability of skilled personnel, etc, so that widespread applicability is uncertain. Nonetheless, the algorithm is shown in Figure 1.
�
..,no
symptomatic?
•
Observation
I
yes
t
•
no
yes
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00
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yes
'-1----___ Figure 1
US
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i no
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-'1
________
Example of management algorithm for patients with gallstones. At present, only
medical therapy has been approved by the U.S. Food and Drug Administration, so that this decision tree can be followed only at institutions where ILOS and ESL are also available under an experimental protocol. Reprinted from and publisher. Abbreviations: GB
=
(83),
with the permission of the authors
gallbladder; UDCA
CDCA
=
chenodeoxycholic acid (chenodiol);
MTBE
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methyl tert-butyl ether.
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=
ursodeoxycholic acid (ursodiol);
ultrasound; 12/12
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and
412
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FUTURE CHALLENGES A number of areas for research are apparent. These include (a) quanti fication of the relative importance of supersaturated bile, accelerated nucleation, or defective gallbladder contraction in the pathogenesis of the stone; (b) understanding each of these pathogenetic abnormalities at a molecular level; (c) development of better imaging methods for defining gallstone composition so that the dissolution efficacy will be 100%; and (d) validation of better methods for identifying patients who will not develop recurrence, so that permanent cures will become more frequent. Finally, prospective studies are needed to define whether the gallbladder is a useful or superfluous organ in adults. All nonsurgical techniques preserve the organ, but such preservation may not have a rationale if the organ is truly superfluous. ACKNOWLEDGMENTS
The author's work is supported by Public Health Service grants DK 21506 and DK 32130 from the National Institutes of Health,as well as by grants in aid from the Falk Foundation e.V., Lithox Systems, and the Diamalt Company. Literature Cited 1. Cohen, S., Soloway, R. D. 1985. Con temporary Issues in Gastroenterology, Volume 4, Gallstones. New York: Chur chill Livingstone. 341 pp. 2. Bateson, M. C. 1986. Gallstone Disease and Its Management. Lancaster: MTP Press. 244 pp. 3. Schoenfield, L. J. 1988. Gallstone s. Clin. Symp. 40: 2-32 4. Fromm, H., Malavolti, M. 1988. Dis solving gallstones. Adv. Intern. Med. 33: 409-30 5. Hofmann, A. F. 1989. Medical dis solution of gallstones by oral bile acid therapy. Am. J. Surg. 158: 198-204 6. Ferrucci, J. T., Delius, M., Burhenne, H. J., eds. 1989. Biliary Lithotripsy. Chicago: Year Book Medica!. 309 pp. 7. Hofmann, A. F., 1984. The physical chemistry of bile in health and disease. Hepatology 4(Suppl. ): I S-2 52S 8. Hofmann, A. F. 1990. Enterohepatic cir culation of bile acids. In Handbook of Physiology. Section on the Gastro intestinal System, cd. S. G. Schultz, pp. 567-96. Bethesda: Am. Physio!. Soc. 9. Carey, M. C, Cahalane, M. J. 1988. Enterohepatic circulation. In The Liver: Biology and Pathobiology, ed. I. M.
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U.S. Patent No. 4,723,941 72. McCullough, J. E., Lesma, A., Thistle, J. L. 1989. A rapid stirring automatic
pump system for dissolving gallstones using methyl tert-butyl ether (MTBE): in vitro comparison with the manual syringe method. Gastroenterology 96: A629 (A bstr .) 73. Zakko, S. F., Hofmann, A. F. 1990. Microprocessor assisted solven't trans f er system (MastSystemTM) for effec tive contact dissolution of gallbladder stones. Trans. Biomed. Eng. In press 74. Zakko, S. F., Hajjar, J. J., Oberstein, R., Tomicic, T. K., Hofmann, A. F. 1989. Intestinal cytotoxicity of contact gall stone dissol ution solv ents: a comp arison . of methyl tert- bu tyl ether (MTBE) with mono-octanoin (MOC). Gastroenter ology 96: A676 (Abstr.) 75. Akimoto, R. , Mayer, D., Rieger, E.,
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Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether admin istered by percutaneous transhepatic catheter. N. Engl. J. Med. 320: 633-39 Hellstern, A., Leuschner, M., Fischer, H., Lazarovici, D., Guldutuna, S., Kurtz, W., Leuschner, U. 1988. Per kutan-transhepatische Lyse von Gal lenblasensteinen mit Methyl-tert-butyl ather. Dtsch. Med. Wschr. 113: 506--10 vanSonnenberg, E., Hofmann, A. F., Neoptolemos, J., Witt ich, G. R., Hof mann, A. F. 1988. Percutaneous therapy of gallbladder and bile duct stones: contact dissolution with MTBE, and the adjunctive value of basketing and other solvents. Radiology 169: 505-9 Zakko, S. F., Ramsby, G., v an Sonnenberg, E., H ofmann , A. F. 1989. Percutaneous contact dissolution of gallbladder stones using a micro processor solvent transfer system and methyl tert-butyl ether (MTBE): experi ence in 16 p atients. Gastroenterology 96: A676 (Abslr.) vanSonnenberg, E., Hofmann, A. F., Neoptolemos, J., Wit t ich , G. R., Prin
centhal, R. A., Willson, S. W. 1986. Gallstone dissolution with methyl-tert butyl ether via percutaneous chole cystostomy: success and caveats. Am. J.
Roentgenol. 146: 865--67 71. Thistle, J. L., Caskey, P. E., Fjerstad, H.
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