Trends in the Treatment of Gallstone Disease: Putting the Options Into Context

Lawrence W. Way, MD, San Francisco, California

The new nonsurgical methods of treating gallstone disease rely on fragmentation, such as with extra- corporeal shock-wave lithotripsy (ESWL) , or disso- lution, such as with ursodiol. Fragmentation alone is usually insufficient for gallbladder stones, and dissolution is only possible for cholesterol stones. Although oral dissolution with or without ESWL is an attractive alternative to surgery, only 25 percent of patients are candidates for this therapy. Dissolu- tion of gallbladder stones by topical application of methyl tert-butyl ether (MTBE) is another option whose safety is still open to question. Therefore, eholecysteetomy will remain the principal treatment for symptomatic gallbladder stones. Common duct stones can be eliminated in 90 percent of cases by endoscopic spbincterotomy alone, and fragmenta- tion of large common duct stones by mechanical endoscopic lithotripsy or ESWL can bring the sue- cess rate up to about 95 percent. Unless cholecys- tectomy is also required, surgery will have a secon- dary role in the treatment of common duct stones.

T he past 20 years have witnessed major changes in the therapy of gallstone disease, and still more are in the

offing. How will the surgeon’s role change? Can gall- stones be prevented? Should prophylactic treatment with oral agents be recommended? Which of the new methods of nonsurgical therapy deserve an important place in clin- ical practice, and will other new ones be devised that eclipse the current ones? The remarks that follow address these questions and assume at least some familiarity with the preceding papers in this symposium.

Gallstone disease is the result of genetic, cultural, and personal factors, and the last two are theoretically open to control. Considerable effort has gone into the search for etiologic dietary factors [I]. The results show that vege- tarians are less susceptible to gallstone disease than are nonvegetarians, but other than obesity, important quali-

From the Surgical Service, Veterans Affairs Medical Center and the Department of Surgery, University of California, San Francisco, Cali- fornia.

Requests for reprints should be addressed to Lawrence W. Way, MD, Surgical Service (112) Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121.

Presented as part of a postgraduate course during the 30th Annual Meeting of the Society for Surgery of the Alimentary Tract, Washing- ton, DC, May 14,1989.

tative differences in personal habits have not been discov- ered. An attempt at preventing recurrence of gallstones after dissolution by switching to a high-fiber, low-refined carbohydrate diet was unsuccessful [2]. However, Broomfield et al [3] showed that prophylactic aspirin decreased the incidence of gallstone formation in patients undergoing rapid weight loss, and aspirin is being tested as a means of preventing recurrence after dissolution. It is compelling to think an answer to prevention must be discoverable, but progress is slow, and gallstones seem here to stay, at least for a while.

For asymptomatic persons with gallstones, little ratio- nale exists for prophylactic therapy, because the natural history of the disease is so benign. Using decision analysis, Ransohoff et al [4] showed that prophylactic treatment of asymptomatic patients, even if the regimen could be made totally free of complications, would add only a few days to life expectancy. Although there may be special cases, it is hard to imagine a program of prophylaxis using present techniques whose screening and treatment ex- penses could be justified. Consequently, I predict physi- cians will continue to become involved with patients prin- cipally after symptoms have appeared.

In addition to surgery, gallstones are under assault by oral dissolution, external shock-wave lithotripsy (ESWL), percutaneous catheter dissolution, and endo- scopic techniques [5-131. Despite the plethora of new methods being tried, there are a few general principles that can be discerned. First, only two different effects are produced by the new methods: gallstone dissolution or fragmentation. Dissolution can be brought about by di- rect application of solvents or indirectly by feeding urso- diol or chenodiol. Fragmentation can be produced by ESWL or by direct application of energy through endo- scopic or transhepatic instrumentation. Examples of the latter include mechanical (basket) and laser lithotripsy. In specific cases, the effectiveness of chemical dissolution or fragmentation varies with the location of the stones, in addition to factors peculiar to the methods themselves. For example, gallbladder stones can be fragmented by ESWL, but fragmentation alone rarely proves to be enough to eradicate gallbladder stones, because the piec- es tend to remain in the gallbladder [F&e S: unpub- lished data]. Thus, fragmentation has a role in the treat- ment of gallbladder stones, but principally as an adjunct to dissolution. Dissolution can be achieved by oral agents, such as chenodiol, by direct instillation of solvents after percutaneous puncture of the gallbladder, or by catheters passed through an endoscope into the gallbladder through the cystic duct.

In the common duct, the requirements are different. After endoscopic sphincterotomy, stones in the duct, in contrast to those in the gallbladder, usually do pass spon- taneously or with a push from a balloon catheter [14].

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Consequently, dissolution is less important in the treat- ment of common duct stones. Large common duct stones that are difficult to extract can first be fragmented by endoscopic methods or by ESWL, which will then allow them to pass.

Two other factors influence the success of therapy: the chemical nature of the stones and the presence or absence of cystic duct obstruction. Safe, effective solvents are available for cholesterol stones, but not for calcified or pigment stones [15]. Cystic duct obstruction, which is present in many patients with gallbladder stones, poses a major obstacle to any therapy except cholecystectomy.

Finally, all the nonsurgical methods of treating gall- bladder stones leave the gallbladder in place, which pro- duces two potential problems. Stones recur in a high percentage of cases (more than 50 percent), and gallblad- der cancer remains a potential risk in later life [ 16,171. At the moment, the importance of these two concerns is unclear, but it is inappropriate to ignore them, since mor- bidity will almost certainly result from each.

ESWL for gallbladder stones has the advantage of good patient acceptance because it is noninvasive, rela- tively painless, and almost free of side effects. The draw- backs include a very high cost for the machine; limited application (to about 20 percent of gallstone patients), because pigment stones, a blocked cystic duct, or too great a stone load are contraindications; and a high recur- rence rate after successful treatment. As indicated above, ESWL should probably not be considered an indepen- dent treatment for gallbladder stones, because unless an oral dissolution agent is also given, the stone fragments produced by ESWL usually remain in the gallbladder. Therefore, ESWL is more an adjunct to ursodiol therapy, useful mainly to increase the surface-to-volume ratio of stones between 5 mm and 20 mm in diameter. Neverthe- less, for the few patients with gallbladder stones who are suitable candidates, ESWL plus dissolution will undoubt- edly rival surgery, because it will be preferred by many patients.

Most patients with acute cholecystitis will still come to surgery, either during or after recovery from the acute attack, because the cystic duct obstruction accompanying this condition is usually permanent. For poor-risk pa- tients with acute cholecystitis, percutaneous cholecystos- tomy has proved to be an excellent alternative to surgical cholecystostomy, and the latter should become increas- ingly rare.

Patients with gallstone pancreatitis would seem to be amenable to nonsurgical therapy, and if so, this approach could become common. Characteristically, these patients have small cholesterol gallstones and a large patent cystic duct. By facilitating passage of common duct stones, en- doscopic sphincterotomy improves the outcome of acute severe biliary pancreatitis if performed early in the at- tack, and it probably also prevents additional attacks later [18,19]. This disease seems potentially vulnerable to sphincterotomy plus oral dissolution as definitive therapy (that is, without subsequent cholecystectomy), but there are no reports as yet to support this contention. Neverthe- less, in the future cholecystectomy will undoubtedly re main the most popular treatment for patients who have had biliary pancreatitis.

What will be the role of methyl tert-butyl ether (MTBE)? It will probably be used for the treatment of cholesterol gallbladder stones too big or too numerous for ESWL treatment [9]. But even though the track record so far is excellent, a drawback of this therapy is the potential for complications. I suspect the results of truly widespread use would probably underscore the diligence and skill of the Mayo physicians who pioneered it. Percu- taneous dissolution should probably remain for some time as a method confined to specialized centers.

In general, endoscopists have done quite well in treat- ing common duct stones, particularly when the gallblad- der has been previously removed. Furthermore, compli- cations are not all that common after endoscopic sphincterotomy, even when the gallbladder is left in place [20-231. Efforts to determine who among such patients will develop gallbladder complications have produced conflicting results, with different investigators suggesting that either the presence of an occluded cystic duct or severe cholangitis as a presenting symptom are risk fac- tors [22,22]. It appears, therefore, that sphincterotomy without cholecystectomy is acceptable treatment for common duct stones when the gallbladder is still present and the risks of surgery are high. On the other hand, most common duct stones will still be extracted as part of a scheduled cholecystectomy. Evidence has been presented which shows that preliminary endoscopic sphincterotomy is not useful before a planned cholecystectomy and com- mon duct exploration, since it increases rather than de- creases the overall risk of therapy [23]. For patients who have already had a cholecystectomy, surgeons as well as gastroenterologists would usually agree that endoscopic sphincterotomy is now preferred.

If these predictions are accurate, lithotripsy will be used in a significant minority of cases, MTBE therapy will be used for selected patients with large cholesterol gallbladder stones who are poor candidates for surgery, and cholecystectomy will continue to have the dominant role in treating gallbladder stone disease. Thus, cholecys- tectomy will remain the clear choice for patients with pigment stones, an occluded cystic duct, or large or nu- merous cholesterol stones; it will also continue to be se- lected by many ESWL and dissolution candidates who wish to avoid the risk of recurrent disease.

About 90 percent of common duct stones can be suc- cessfully removed endoscopically after a sphincterotomy and use of balloon catheters and stone baskets [8]. How- ever, when the stone is large (as a rule of thumb, when it exceeds the diameter of the endoscope), difficulties can be anticipated. For these 10 percent of cases, a number of new procedures have been developed to fracture the stone and facilitate extraction. Dissolution has proved to be disappointing and has only a minor role, but the mechani- cal methods are good. EWSL, successful in 80 percent of such patients, is an excellent but expensive option [8]. However, future improvements in endoscopic methods are on the horizon that will allow the endoscopist to succeed in all but a few patients. Pulsed tunable dye lasers

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are one method, but like EBWL, this is expensive and tricky to use [13]. Mechanical lithotripsy through the endoscope is still at an early stage of development, but new methods are being devised, and unexplored options exist that might be expected to produce still better results [IO]. I predict we will soon see practical advances in this area.

In summary, surgery has advantages that the new techniques cannot match, but the reverse is also true. Consequently, a team approach is needed so each patient receives the very best treatment, not simply the treatment performed by the first physician he or she encounters.

REFERENCES 1. Pixley F, Mann J. Dietary factors in the aetiology of gallstones: a case control study. Gut 1988; 29: 151 l-5. 2. Grundy SM, Kaiser SC. Highlights of the meeting on prevention of gallstones. Hepatology 1987; 7: 946-51. 3. Broomfield PH, Chopra R, Sheinbaum RC, et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. N Engl J Med 1988; 319: 1567-72. 4. Ransohoff DE, Gracie WA, Colfenson LB, et al. Prophylactic cholecystectomy or expectant management for silent gallstones. Ann Intern Med 1983; 99: 199. 5. Erlinger S, Qo AL, Husson JM, et al. France-Belgian coopera- tive study of ursodeoxycholic acid in the medical dissolution of gallstones. Hepatology 1984; 4: 308. 6. Sackmann M, Delius M, Sauerbruch T, et al. Shock-wave litho- tripsy of gallbladder stones. The first 175 patients. N Engl J Med 1988; 318: 393-7. 7. Heberer G, Paumgartner G, Sauerbruch T, et al. A retrospective analysis of 3 year’s experience of an interdisciplinary approach to gallstone disease including shock-waves. Ann Surg 1988; 208: 274- 8. 8. Sauerbruch T, Stem M. Fragmentation of bile duct stones by extracorporeal shock waves. A new approach to biliary calculi after failure of routine endoscopic measures. Gastroenterology 1989; 96: 146-52.

9. Thistle JL, May GR, Bender CE, et al. Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by per- cutaneous transhepatic catheter. N Engl J Med 1989; 320: 633-9. 10. Schneider MU, Matek W, Bauer R, Domshke W. Mechanical lithotripsy of common bile duct stones in 232 patients. Gastroenter- ology 1989; 96: A451. 11. El1 CH, Lux G, Hochberger J, Muller D, Demling L. Laserlith- otripsy of common bile duct stones. Gut 1988; 29: 746-51. 12. Faulkner DJ, Kozarek RA. Gallstones: fragmentation with a tunable dye laser and dissolution with methyl tert-butyl ether in vitro. Radiology 1989; 170: 185-9. 13. Nishioka NS, Levins PC, Murray SC, Parrish JA, Anderson RR. Fragmentation of biliary calculi with tunable dye lasers. Gas- troenterology 1987; 93: 250-5. 14. Cotton PB. Endoscopic treatment of bile duct stones. Gut 1984; 25: 587. 15. Leuschner U, Wosiewitz U, Baumgartel H. Dissolution of calcified cholesterol stones and of brown and black pigment stones of the gallbladder. Digestion 1988; 39: 100-10. 16. O’Donnell LDJ, Heaton KW. Recurrence and re-recurrence of gallstones after medical dissolution: a longterm followup. Gut 1988; 29: 655-8. 17. Diehl AK, Beral V. Cholecystectomy and changing mortality from gallbladder cancer. Lancet 1981; 2: 187-9. 18. Neoptolemos JP, Carr-Locke DL, London N, Bailey IA, Fos- sard DP. ERCP findings and the role of endoscopic sphincterotomy in acute gallstone pancreatitis. Br J Surg 1988; 75: 954-60. 19. Neoptolemos JP, Carr-Locke DL, London NJ, Bailey IA, James D, Fossard DP. Controlled trial of urgent endoscopic retro- grade cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gall- stones. Lancet 1988; 2: 979-83. 20. Tanaka M, Ikeda S, Yoshimoto H, Matsumoto S.. The long- term fate of the gallbladder after endoscopic sphincterotomy. Com- plete follow-up study of 122 patients. Am J Surg 1987; 154: 505-9. 21. Davidson BR, Neoptolemos JP, Carr-Locke DL. Endcscopic sphincterotomy for common bile duct calculi in patients with gall- bladder in situ considered unfit for surgery. Gut 1988; 29: 114-20. 22. Worthley CS, Toouli J. Gallbladder non-filling: an indication for cholecystectomy after endoscopic sphincterotomy. Br J Surg 1988; 75: 796-8.

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