1121
S, Pillay SP, Holzbach RT. Inhibition and crystallization by protein fractions from normal human gallbladder bile. J Lipid Res 1991; 32: 695-702. 25. Lipsett PA, Kaufman HS, Lillemoc KD, Pitt HA. Unique nonmucin glycoproteins are present in cholesterol and pigment gallstones. Gastroenterology 1991; 100: A767. 26. Been JM, Bills PM, Lewis D. Microstructure of gallstones. Gastroenterology 1979; 76: 548-55. 27. Holzbach RT. Gallbladder stasis: consequence of long-term parenteral hyperalimentation and risk factor of cholelithiasis. Gastroenterology 1983; 84: 1055-58. 24. Busch N, Matiuck N, Sahlin promotion of cholesterol
JV, Pitt HA, Steinborn PA, Pasha ZR, Sander RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170: 25-31. 29. Festi D, Frabboni R, Bazzoli F, et al. Gallbladder motility in cholesterol gallstone disease. Effect of ursodeoxycholic acid administration and gallstone dissolution. Gastroenterology 1990; 98: 1779-85. 30. Spengler U, Sackmann M, Sauerbruch T, Holl J, Paumgartner G. Gallbladder motility before and after extracorporeal shock-wave lithotripsy. Gastroenterology 1989; 96: 860-63. 31. Tera H. Stratification of human gallbladder bile in vivo. Acta Chir Scand (suppl) 1960; 256: 4-85. 28. Sitzmann
Gallbladder stones: management
Elective cholecystectomy was first described in 1882 in Berlin by Carl Langenbuch.1 The report, "A case of extirpation of the gallbladder because of chronic cholecystolithiasis. Cure", was provocative. In those days cholecystolithotomy was believed to be less invasive and superior. Because some animal species do not possess a gallbladder (eg, horse, deer, rat) Langenbuch believed this organ to be physiologically irrelevant. Furthermore, on the basis of cadaver experiments he concluded that extirpation of the gallbladder after ligation of the cystic duct was the "least invasive of all operations requiring laparotomy". His views proved to be prophetic. Cholecystectomy is currently the third most frequent operation in Germany and one of the commonest surgical procedures in Britain and the United States. Surgeons and physicians agree that cholecystectomy is the definitive treatment for symptomatic stones in the gallbladder and, furthermore, that silent gallstones do not require surgery or medical treatment because their natural history is benign. Cross-sectional studies have shown that symptom-free carriers account for between 60% and 80% of all adults with gallstones. Most physicians also believe that patients with biliary colic-arbitrarily defined as a steady pain lasting more than 15 to 30 minutes and usually located in the epigastrium or in the right hypochondrium, with or without radiation to the back or right shouldershould be treated, even though the specificity of these symptoms has been questioned. Symptomatic patients are at a higher risk of complications than those with silent stones. What surgeons and physicians disagree on is whether cholecystectomy is necessary in every symptomatic patient. This question has re-emerged with the development of new techniques, such as extracorporeal shock-wave lithotripsy,2 new percutaneous3 or transduodenal endoscopic approaches4 to the gallbladder, and the growing insight into the pathogenesis of gallbladder stones. In the light of these developments, doctors are obliged to take into account the reluctance of many patients to undergo open surgery or general anaesthesia. Parallel to the development of this plethora of non-surgical techniques has been that of a less invasive means of cholecystectomy-via the laparoscope.5 This review is an attempt to outline the advantages and disadvantages of these new forms of treatment. These options apply mainly to elective therapy.
orally,6 by the combination of extracorporeal shock-wave lithotripsy with bile acids,2or by direct instillation of cholesterol solvents into the gallbladder.3
Non-surgical approaches
ADDRESS: Medical Department II, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15 W-8000 Munich 70, Germany (Prof T Sauerbruch, MD, Prof G. Paumgartner, MD). Correspondence to Prof Tilman Sauerbruch
In industrialised countries, more than 80% of gallbladder consist mainly of cholesterol. These stones are amenable to dissolution either by certain bile acids taken stones
Dissolution
by bile acids taken orally In 1937 the American surgeon Rewbridge7 described the successful dissolution of gallbladder stones by oral administration of bile acids in two of five patients. In the early 1970s the Mayo-Group approached this problem in a more scientific way.8 They showed that chenodeoxycholic acid reduces cholesterol saturation of the bile and thus causes gradual dissolution of cholesterol stones. Later on, a group from Japan9 found that the 7p epimer of chenodeoxycholic acid, ursodeoxycholic acid, could likewise dissolve gallstones. It is now well established that the two bile acids have quite distinct physicochemical properties. The efficacy of both bile acids-at a dosage of 15 mg per kg/day for chenodeoxycholic acid and 10-13 mg per kg/day for ursodeoxycholic acid-is similar It has been reported that the two bile acids given together at a reduced dose (5 mg each per kg/day) may be somewhat more effective than monotherapy with ursodeoxycholic acid." However, this remains to be confirmed. Because of the doserelated side-effects of chenodeoxycholic acid such as diarrhoea, raised aminotransferases, and modest
hypercholesterolaemia (low-density lipoprotein cholesterol), monotherapy with this agent has been practically abandoned in favour of ursodeoxycholic acid monotherapy or combined therapy. In carefully selected patients with radiolucent stones less than 15 mm in diameter in an opacifying gallbladder, complete dissolution within 2 years may be achieved in approximately 60% of the patients." The highest success rate10 occurs in patients with small ( < 5 mm in diameter) floating radiolucent gallbladder stones (80 to 90% complete dissolution within 1 year). Ursodeoxycholic acid alone or in combination with chenodeoxycholic acid does not seem to produce toxic effects, but cystic duct obstruction,12 recurrent biliary pain, or pancreatitis or cholecystitis necessitating referral for surgery develops in about a fifth of patients. Controlled trials" indicate that these effects reflect the natural history of symptomatic gallstone disease rather than complications due to bile acids. If bile acid therapy is limited to patients
1122
with small floating stones, patients with symptomatic
probably no more than 10% of cholecystolithiasis are eligible.
Combination of extracorporeal shock wave lithotripsy and oral bile acid therapy Gallbladder stones may be disintegrated by shock waves generated extracorporeally by use of the electrohydraulic.’ the piezoceramic,14 or the electromagnetic principle.15 The shock waves are generated under water and bundled to a focal region, into which the stone is positioned. The waves represent pulses of rapidly increasing pressures that reach 500 to 1000 bars in the focal zone. The stones are gradually disintegrated after several hundred to several thousand shocks. Lithotripsy has two major objectives: first, to facilitate stone dissolution,2 especially in the case of stones larger than 1 cm in diameter, for which the efficacy of bile acid dissolution therapy is very low, and second, to allow spontaneous passage of fragments into the intestine.16 Patients with symptomatic radiolucent stones and an opacifying gallbladder are eligible for combined treatment with lithotripsy and bile acids. Those with solitary stones are the best candidates (table). In our experience, 70% of patients with solitary stones up to 2 cm are rendered stone free after 5 to 8 months (figure). The corresponding figures are 50% for large solitary stones (2-3 cm) and 30% for 2 or 3 stones. After 13 to 18 months nearly 90% of all patients with solitary stones up to 3 cm become completely free of stones and debris.17 Although the total stone mass may be considerably lower in patients with multiple small stones, the results in general are less satisfactory than those for single stones.15,17 A recently published multicentre triap8 underlines the importance of adjuvant bile acid therapy, which doubles the success rate of lithotripsy within six months. As adjuvant treatment the combination of chenodeoxycholic acid and ursodeoxycholic acid was no more effective than ursodeoxycholic acid alone.19 Although adjuvant bile acids are important for dissolution of stone fragments, sufficient disintegration of the stones is probably the most crucial factor influencing success rate.15.17 In this context it is of interest that some groups15 have reported complete clearance of stones and fragments in a substantial percentage of patients with single stones without adjuvant bile acid treatment-instead, patients underwent repeated shock wave sessions, receiving a total of several thousand pulses. This strategy is probably appropriate only in those patients who are willing to undergo many sessions and whose gallbladder contraction is adequate. Severe adverse effects, caused mostly by passage of fragments after lithotripsy, occur in about 3-5 % of patients (pancreatitis around 2%, cholestasis 1 %, cholecystitis 1 %), and cholecystectomy or emergency endoscopic sphincterotomy is required in less than 5 % of all patients.17
Cystic duct obstruction, generally symptomless and resolving spontaneously in half the patients, has been observed in 5 % of our series. In published trials on several thousands of patients, no fatalities attributable to lithotripsy have been reported. However, there is one anecdotal report of death due to septic cholangitis 9 weeks after lithotripsy,20 and out of 1200 of our patients 1 patient with severe coronary heart disease died from recurrent myocardial infarction 6 h after uneventful lithotripsy. Biliary pain, probably caused by passage of fragments, may occur during the first 2 to 3 months in 30% to 70% of the patients not rendered
stone
free.17,18
If
lithotripsy of gallstones is restricted to patients with symptomatic solitary gallbladder stones, the population of candidates ideal for the procedure ranges between 10% and 15% of all patients with symptomatic gallstones. HMG-CoA reductase inhibitors
Recently a new class of lipid-lowering drugs that competitively inhibit the enzyme 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) has been introduced. They not only lower serum low-density lipoprotein-cholesterol but also reduce the cholesterol saturation index in bile, an effect that may be enhanced by the combination with ursodeoxycholic acid.21 The combination of an HMG-CoA reductase inhibitor with ursodeoxycholic acid may therefore have a part to play in the dissolution of cholesterol gallstones or fragments,2z provided the HMG-CoA reductase inhibitors prove safe enough for the treatment of what is generally a benign disease with only rare fatalities. Contact dissolution of cholesterol stones The Mayo group, which pioneered the dissolution of cholesterol stones more than two decades ago, began their investigations of the direct administration of methyl tertbutyl ether into the gallbladder about 7 years ago.3 This agent has a high solvent capacity for cholesterol (14 g/dl), and its high boiling point (55 °C) prevents it from expanding in vivo as quickly as does diethyl ether (boiling point 35°C). Surprisingly, methyl tert-butyl ether, when instilled strictly into the gallbladder, causes only very slight tissue damage in man and in dogs.z3 The detailed technique is described elsewhere.z4,25 Patients whose gallbladder is attached to the liver bed as assessed by computed tomography or ultrasound, with an open cystic duct, and with radiolucent symptomatic stones are eligible. The number of calculi is less important than with shock-wave lithotripsy. Normally the ether is applied for a total of 10 to 15 h over several days (on average 3 to 4 days). Apart from the occasional occurrence of biliary pain, nausea, and sedation, treatment is quite well tolerated. Although severe complications such as haemolysis and renal insufficiency may occur if the ether
OPTIONS FOR ELECTIVE THERAPY OF SYMPTOMATIC GALLBLADDER STONES
1123
and
a
catheter
must
remain in situ for 10
days
to
prevent
postoperative leakage. Another method is based on the transhepatic introduction of an impeller30 that can crush large stones. The debris is aspirated from the gallbladder. Again this method requires gallbladder drainage for several days. Both methods are far from being established. It is questionable whether such invasive procedures that necessitate a large drainage catheter for nearly 10 days can really compete with laparoscopic cholecystectomy for a future place in gallbladder treatment.
Stone recurrence All forms of treatment in which the gallbladder remains in situ share the major drawback of stone recurrence. In recent studies on patients who had been successfully treated with oral bile acids, the recurrence curves levelled off within the first 3 to 5 years after discontinuation of treatment and it is believed that only every second patient will have recurrent stones. After successful lithotripsy plus oral bile acids,31 the recurrence rate after 1 year was 9%. After dissolution with methyl tert-butyl ether, the overall 1-year Clearance of fragments after extracorporeal shock wave lithotripsy and adjuvant bile acid treatment in patients with solitary radiolucent stones 20 mm or less in diameter. Current experience of the Munich group: diagram modified from Sackmann et al.17
systemic circulation,26 no deaths have yet been reported. Up to 5% of patients require cholecystectomy because of leakage after gallbladder puncture.25 Although practically all the cholesterol stone material can be dissolved in quite a short time, some debris does remain in the gallbladder in 34%zs to 70% of the patients.24 Pretreatment with lithotripsy is feasible27 and may lower the amount of residual debris and broaden the indications to include partly enters
the
calcified stones. Initially, the solvent was given by the percutaneous transhepatic routes3 Subsequently the solvent has been applied via an endoscope passed through the papilla and the cystic duct.4,Z8 Both routes have their pros and cons. Allthough there is no risk of gallbladder leakage in the case of retrograde cannulation of the gallbladder, pancreatitis or cystic duct perforation may occur. 28 Problems due to gallbladder leakage are easier to handle than severe pancreatitis and therefore transhepatic puncture seems preferable. Furthermore, it is easier, has a higher success rate, and allows better handling of the catheter. After
application of methyl tert-butyl ether, patients generally receive ursodeoxycholic acid for several months and eventually 50% to 90% of all treated patients24’z5 are rendered completely stone free. The total number of patients so treated in published reports is small. About 20% to 30% of patients with symptomatic gallbladder stones may be suitable for methyl tert-butyl ether.25 Like lithotripsy, ether-dissolution of cholesterol gallstones is still at an
investigational stage in the United States. Further investigational methods The non-surgical approaches described above are applicable only to cholesterol gallbladder stones. Therefore, to percutaneous cholecystolithotomy, analogous percutaneous nephrolithotomy,29 has been attempted. The gallbladder is punctured directly and dilated up to 28 Charriere. The procedure is done under general anaesthesia
recurrence rate was
higher (29%).32
If non-surgical methods for the treatment of gallbladder stones are to become a routine procedure, the problem of gallstone recurrence has to be solved. The fact that gallstones do not form again in half the patients even though cholesterol supersaturation of bile almost invariably recurs suggests that in these patients the disturbance leading to stone formation is transient. A major objective is the definition of those patients in whom stones will not recur. The recent research into the pathogenesis of gallbladder stones will certainly be a valuable aid in this respect. Patients least likely to have recurrence are probably those with solitary stones33 and those with adequate gallbladder contraction. Furthermore, strategies for the prevention of recurrent stones in patients at high risk of recurrence should be evaluated. At present prophylaxis with intermediate doses of ursodeoxycholic acid 33 or intermittent therapy with high doses of bile-acids34 are more realistic approaches than treatments aimed at influencing mucin formation 35 or
gallbladder motility.
Laparoscopic cholecystectomy Laparoscopic cholecystectomys is a minimal access approach for the removal of the gallbladder together with its stones. Length of hospital stay averages 1-2 days in the United States36 and 3 days in Europe.37 Most patients have been able to return to work or to normal activity in one to weeks. So far, results of several thousand procedures have been published in a short time.5 The proportion of patients suitable for laparoscopic cholecystectomy is believed to be approximately 80%. It is a novel method and there is still room for development, but it already seems to be safe, with a mortality of less than 1 %,36 which compares well with that of conventional elective cholecystectomy in young and fit patients. In about 4-5% of patients surgeons are compelled to convert to open cholecystectomy because of unexpected events such as obscured anatomy of the region by inflammatory processes, adhesions, or aberrant anatomy. During the learning phase, laparoscopic cholecystectomy is a time-consuming procedure, often requiring more than 2 h. In the United States, the procedure lasted an average of 90 minutes36 and in Europe a median of 50 minutes was reported.37,38 It may be difficult to extract large gallbladder two
1124
through the umbilical incision, where the main trocar placed. In such patients enlargement of the incision or a lithotriptic method is required. Despite a broadening of the indications, most centres still exclude patients with acute cholecystitis, high probability of adhesions in the upper abdomen, or biliary pancreatitis. The main area of concern with this procedure is bileduct injury, which may occur particularly during the learning phase.36 The overall rate is reported as being between 03% in a retrospective survey37 and 0-5% in the United States.36 The total complication rate 36 is about 5% (bileduct injury, bleeding, prolonged ileus, bowel injuries, and bile leakage). Laparoscopic cholecystectomy will be the procedure of choice for most patients referred for elective cholecystectomy. stones
is
Conclusion Because of the high prevalence of symptomatic gallbladder stones in western civilisation their management remains a major task in medicine. For patients in good general condition who are willing to undergo surgery, removal of the gallbladder is the treatment of choice. Most patients and doctors will opt for the laparoscopic variant of cholecystectomy nowadays. However, the surgeon should be properly trained in this procedure and the patient must be informed that the risk of bileduct injury is probably higher than with conventional cholecystectomy. Most non-surgical procedures do not require general anaesthesia. This makes them attractive for the patient. Provided that the cystic duct is open, patients with small floating radiolucent stones are good candidates for oral bile acid treatment and those with solitary radiolucent stones up to 2 cm in diameter can receive a combination of lithotripsy with bile acid therapy. The patient must realise that follow-up by ultrasound is required after successful therapy to rule out recurrent stones. Other treatment-such as methyl tert-butyl ether dissolution, lithotripsy of multiple stones or calcified stones, repeated lithotripsy without bile acid therapy, contact lithotripsy, or
percutaneous
investigational
extraction stage.
of
stones-are
still
at
an
We thank Martina Baurer for secretarial help.
REFERENCES C. Ein Fall von Exstirpation der Gallenblase wegen chronischer Cholelithiasis. Heilung. Berlin Klin Wschr 1882; 19: 725-27. 2. Sauerbruch T, Delius B, Paumgartner G, et al. Fragmentation of gallstones by extracorporeal shock waves. N Engl J Med 1986; 314: 818-22. 3. Allen MJ, Borody TJ, Bugliosi TG, et al. Rapid dissolution of gallstones by methyl ten-butyl ether. N Engl J Med 1985; 312: 217. 4. Foerster ECh, Auth J, Runge U, et al. ERCG: endoscopic retrograde catheterization of the gallbladder. Endsocopy 1988; 20: 30-33. 5. Dubois F, Icard P, Berthelot G, Levard H. Coelioscopic cholecystectomy: preliminary report of 36 cases. Ann Surg 1990; 211: 60-63. 6. Danzinger RG, Hofmann AF, Schoenfield LJ, Thistle JL. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 1972; 286: 1-8. 7. Rewbridge AG. The disappearance of gallstone shadows following the prolonged administration of bile salts. Surgery 1936; 33: 395-400. 8. Danzinger RG, Hofmann AF, Thistle JL, et al. Effect of oral chenodeoxycholic acid on bile acid kinetics and biliary lipid composition in women with cholelithiasis. J Clin Invest 1983; 52: 2809-21. 9. Nakagawa S, Makino I, Ishizaki T, et al. Dissolution of cholesterol gallstones by ursodeoxycholic acid. Lancet 1977; ii: 367-69. 10. Fromm H, Malavolti M. Dissolving gallstones. Adv Intern Med 1988; 33: 409-30.
1. Langenbuch
11. Podda M, Zuin M, Battezzati PM, et al. Efficacy and safety of a combination of chenodeoxycholic acid and ursodeoxycholic add for gallstone dissolution: a comparison with ursodeoxycholic add alone. Gastroenterology 1989; 96: 222-29. 12. Gleeson D, Ruppin DC, Saunders A, Murphy GM, Dowling RH. Final outcome of ursodeoxycholic acid treatment in 126 patients with radiolucent stones. Quart J Med 1990; 76: 711-29. 13. Schoenfield LJ, Lachin JM, the NCGS Steering Committee, and the NCGS Group. National cooperative gallstone study: a controlled trial of the efficacy and safety of chenodeoxycholic acid for dissolution of gallstones. Ann Intern Med 1981; 95: 257-82. 14. Ell Ch, Kerzel W, Schneider HTh, et al. Piezoelectric lithotripsy: stone disintegration and follow-up results in patients with symptomatic gallbladder stones. Gastroenterology 1990; 99: 1439-44. 15. Fache JS, Rawat B, Burhenne HJ. Extracorporeal cholecystolithotripsy without oral chemolitholysis. Radiology 1990; 177: 719-21. 16. Greiner L, Münks C, Heil W, Jakobeit Ch. Gallbladder stone fragments in feces after biliary extracorporeal shock-wave lithotripsy. Gastroenterology 1990; 98: 1620-24. 17. Sackmann M, Pauletzki J, Sauerbuch T, et al. The Munich gallbladder lithotripsy study: results of the first five years with 711 patients. Ann Intern Med 1991; 114: 290-96. 18. Schoenfield LJ, Berci G, Carnoval RL, et al. The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallbladder stones. The Dornier National Biliary Lithotripsy Study. N Engl J Med 1990; 323: 1239-45. 19. Sackmann M, Pauletzki J, Aydemir U, et al. Monotherapy with ursodeoxycholic acid is as efficient as a combination of urso-and chenodeoxycholic acid for dissolution of gallstone fragments. Hepatology 1990; 12: A869. 20. Wenzel H, Greiner L, Jakobeit Ch. Spätkomplikationen der ESWL von Gallenblasensteinen mit letalem Ausgang. Dtsch Med Wschr 1990; 115: 77. 21. Logan GM, Duane WC. Lovastatin added to ursodeoxycholic acid further reduces biliary cholesterol saturation. Gastroenterology 1990; 98: 1572-76. 22. Bateson MC. Simvastatin and ursodeoxycholic add for rapid gallstone dissolution. Lancet 1990; 336: 1196. 23. Allen MJ, Borody TJ, Bugliosi TF, et al. Cholelithiasis using methyl tertiary butyl ether. Gastroenterology 1985; 89: 122-25. 24. Thistle JL, May GR, Bender CE, et al. Dissolution of cholesterol gallbladder stones by methyl-tert-butyl ether administered by percutaneous transhepatic catheter. N Engl J Med 1989; 320: 633-39. 25. Leuschner U, Hellstern A, Schmidt K, et al. Gallstone dissolution with methyl tert-butyl ether in 120 patients—efficacy and safety. Dig Dis Sci
1991; 36: 193-99. 26. Ponchon T, Baroud J, Pujol B, Valette PJ, Perrot D. Renal failure during dissolution of gallstones by methyl-tert-butyl ether. Lancet 1988; ii: 276-77. 27. Holl J, Sauerbruch T, Sackmann M, Pauletzki J, Paumgartner G. Combined treatment of symptomatic gallbladder stones by extracorporeal shock-wave lithotripsy (ESWL) and instillation of methyl tert-butyl ether (MTBE). Dig Dis Sci 1991: 36: 1097-101. 28. Soehendra N, Schulz H, Nam VCh, et al. ESWL and gallstone dissolution with MTBE via a naso-vesicular catheter. Endoscopy 1990; 22: 176-79. 29. Chiverton SG, Inglis JA, Hudd C, et al. Percutaneous cholecystolithotomy: the first 60 patients. Br Med J 1990; 300: 1310-12. 30. Miller FJ, Rose SC, Buchi KN, Hunter JG, Nash JE, Kensey KR. Percutaneous rotational contact biliary lithotripsy: initial clinical results with the Kensey Nash lithotrite. Radiology 1991; 178: 781-85. 31. Sackmann M, Ippisch E, Sauerbruch T, et al. Early gallstone recurrence rate after successful shock-wave therapy. Gastroenterology 1990; 98: 392-96. 32. McCullough JE, Stadheim LM, Reading CC, Petersen BT, Thistle LJ. Gallstone recurrence after methyl tert-butyl ether dissolution. Gastroenterology 1990; 98: A255. 33. Villanova N, Bazzoli F, Taroni F, et al. Gallstone recurrence after successful oral bile acid treatment. A 12-year follow-up study and evaluation of long-term postdissolution treatment. Gastroenterology 1989; 97: 726-31. 34. Northfield TC, Jazrawi RP, Petroni ML. Medical dissolution therapy. In: Paumgartner G, Stiehl A, Barbara L, Roda E, eds. Strategies for the treatment of hepatobiliary diseases. Dordrecht: Kluwer, 1990: 163-84. 35. Hood K, Gleeson D, Ruppin DC, Dowling RH. Prevention of gallstone recurrence by non-steroidal anti-inflammatory drugs. Lancet 1988; ii: 1223-25. 36. The Southern Surgeons Club. A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med 1991; 324: 1073-78. 37. Cuschieri A, Dubois F, Mouiel J, et al. The European experience with laparoscopic cholecystectomy. Am J Surg 1991; 161: 385-87.
S, Pillay SP, Holzbach RT. Inhibition and crystallization by protein fractions from normal human gallbladder bile. J Lipid Res 1991; 32: 695-702. 25. Lipsett PA, Kaufman HS, Lillemoc KD, Pitt HA. Unique nonmucin glycoproteins are present in cholesterol and pigment gallstones. Gastroenterology 1991; 100: A767. 26. Been JM, Bills PM, Lewis D. Microstructure of gallstones. Gastroenterology 1979; 76: 548-55. 27. Holzbach RT. Gallbladder stasis: consequence of long-term parenteral hyperalimentation and risk factor of cholelithiasis. Gastroenterology 1983; 84: 1055-58. 24. Busch N, Matiuck N, Sahlin promotion of cholesterol
JV, Pitt HA, Steinborn PA, Pasha ZR, Sander RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170: 25-31. 29. Festi D, Frabboni R, Bazzoli F, et al. Gallbladder motility in cholesterol gallstone disease. Effect of ursodeoxycholic acid administration and gallstone dissolution. Gastroenterology 1990; 98: 1779-85. 30. Spengler U, Sackmann M, Sauerbruch T, Holl J, Paumgartner G. Gallbladder motility before and after extracorporeal shock-wave lithotripsy. Gastroenterology 1989; 96: 860-63. 31. Tera H. Stratification of human gallbladder bile in vivo. Acta Chir Scand (suppl) 1960; 256: 4-85. 28. Sitzmann
Gallbladder stones: management
Elective cholecystectomy was first described in 1882 in Berlin by Carl Langenbuch.1 The report, "A case of extirpation of the gallbladder because of chronic cholecystolithiasis. Cure", was provocative. In those days cholecystolithotomy was believed to be less invasive and superior. Because some animal species do not possess a gallbladder (eg, horse, deer, rat) Langenbuch believed this organ to be physiologically irrelevant. Furthermore, on the basis of cadaver experiments he concluded that extirpation of the gallbladder after ligation of the cystic duct was the "least invasive of all operations requiring laparotomy". His views proved to be prophetic. Cholecystectomy is currently the third most frequent operation in Germany and one of the commonest surgical procedures in Britain and the United States. Surgeons and physicians agree that cholecystectomy is the definitive treatment for symptomatic stones in the gallbladder and, furthermore, that silent gallstones do not require surgery or medical treatment because their natural history is benign. Cross-sectional studies have shown that symptom-free carriers account for between 60% and 80% of all adults with gallstones. Most physicians also believe that patients with biliary colic-arbitrarily defined as a steady pain lasting more than 15 to 30 minutes and usually located in the epigastrium or in the right hypochondrium, with or without radiation to the back or right shouldershould be treated, even though the specificity of these symptoms has been questioned. Symptomatic patients are at a higher risk of complications than those with silent stones. What surgeons and physicians disagree on is whether cholecystectomy is necessary in every symptomatic patient. This question has re-emerged with the development of new techniques, such as extracorporeal shock-wave lithotripsy,2 new percutaneous3 or transduodenal endoscopic approaches4 to the gallbladder, and the growing insight into the pathogenesis of gallbladder stones. In the light of these developments, doctors are obliged to take into account the reluctance of many patients to undergo open surgery or general anaesthesia. Parallel to the development of this plethora of non-surgical techniques has been that of a less invasive means of cholecystectomy-via the laparoscope.5 This review is an attempt to outline the advantages and disadvantages of these new forms of treatment. These options apply mainly to elective therapy.
orally,6 by the combination of extracorporeal shock-wave lithotripsy with bile acids,2or by direct instillation of cholesterol solvents into the gallbladder.3
Non-surgical approaches
ADDRESS: Medical Department II, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15 W-8000 Munich 70, Germany (Prof T Sauerbruch, MD, Prof G. Paumgartner, MD). Correspondence to Prof Tilman Sauerbruch
In industrialised countries, more than 80% of gallbladder consist mainly of cholesterol. These stones are amenable to dissolution either by certain bile acids taken stones
Dissolution
by bile acids taken orally In 1937 the American surgeon Rewbridge7 described the successful dissolution of gallbladder stones by oral administration of bile acids in two of five patients. In the early 1970s the Mayo-Group approached this problem in a more scientific way.8 They showed that chenodeoxycholic acid reduces cholesterol saturation of the bile and thus causes gradual dissolution of cholesterol stones. Later on, a group from Japan9 found that the 7p epimer of chenodeoxycholic acid, ursodeoxycholic acid, could likewise dissolve gallstones. It is now well established that the two bile acids have quite distinct physicochemical properties. The efficacy of both bile acids-at a dosage of 15 mg per kg/day for chenodeoxycholic acid and 10-13 mg per kg/day for ursodeoxycholic acid-is similar It has been reported that the two bile acids given together at a reduced dose (5 mg each per kg/day) may be somewhat more effective than monotherapy with ursodeoxycholic acid." However, this remains to be confirmed. Because of the doserelated side-effects of chenodeoxycholic acid such as diarrhoea, raised aminotransferases, and modest
hypercholesterolaemia (low-density lipoprotein cholesterol), monotherapy with this agent has been practically abandoned in favour of ursodeoxycholic acid monotherapy or combined therapy. In carefully selected patients with radiolucent stones less than 15 mm in diameter in an opacifying gallbladder, complete dissolution within 2 years may be achieved in approximately 60% of the patients." The highest success rate10 occurs in patients with small ( < 5 mm in diameter) floating radiolucent gallbladder stones (80 to 90% complete dissolution within 1 year). Ursodeoxycholic acid alone or in combination with chenodeoxycholic acid does not seem to produce toxic effects, but cystic duct obstruction,12 recurrent biliary pain, or pancreatitis or cholecystitis necessitating referral for surgery develops in about a fifth of patients. Controlled trials" indicate that these effects reflect the natural history of symptomatic gallstone disease rather than complications due to bile acids. If bile acid therapy is limited to patients
1122
with small floating stones, patients with symptomatic
probably no more than 10% of cholecystolithiasis are eligible.
Combination of extracorporeal shock wave lithotripsy and oral bile acid therapy Gallbladder stones may be disintegrated by shock waves generated extracorporeally by use of the electrohydraulic.’ the piezoceramic,14 or the electromagnetic principle.15 The shock waves are generated under water and bundled to a focal region, into which the stone is positioned. The waves represent pulses of rapidly increasing pressures that reach 500 to 1000 bars in the focal zone. The stones are gradually disintegrated after several hundred to several thousand shocks. Lithotripsy has two major objectives: first, to facilitate stone dissolution,2 especially in the case of stones larger than 1 cm in diameter, for which the efficacy of bile acid dissolution therapy is very low, and second, to allow spontaneous passage of fragments into the intestine.16 Patients with symptomatic radiolucent stones and an opacifying gallbladder are eligible for combined treatment with lithotripsy and bile acids. Those with solitary stones are the best candidates (table). In our experience, 70% of patients with solitary stones up to 2 cm are rendered stone free after 5 to 8 months (figure). The corresponding figures are 50% for large solitary stones (2-3 cm) and 30% for 2 or 3 stones. After 13 to 18 months nearly 90% of all patients with solitary stones up to 3 cm become completely free of stones and debris.17 Although the total stone mass may be considerably lower in patients with multiple small stones, the results in general are less satisfactory than those for single stones.15,17 A recently published multicentre triap8 underlines the importance of adjuvant bile acid therapy, which doubles the success rate of lithotripsy within six months. As adjuvant treatment the combination of chenodeoxycholic acid and ursodeoxycholic acid was no more effective than ursodeoxycholic acid alone.19 Although adjuvant bile acids are important for dissolution of stone fragments, sufficient disintegration of the stones is probably the most crucial factor influencing success rate.15.17 In this context it is of interest that some groups15 have reported complete clearance of stones and fragments in a substantial percentage of patients with single stones without adjuvant bile acid treatment-instead, patients underwent repeated shock wave sessions, receiving a total of several thousand pulses. This strategy is probably appropriate only in those patients who are willing to undergo many sessions and whose gallbladder contraction is adequate. Severe adverse effects, caused mostly by passage of fragments after lithotripsy, occur in about 3-5 % of patients (pancreatitis around 2%, cholestasis 1 %, cholecystitis 1 %), and cholecystectomy or emergency endoscopic sphincterotomy is required in less than 5 % of all patients.17
Cystic duct obstruction, generally symptomless and resolving spontaneously in half the patients, has been observed in 5 % of our series. In published trials on several thousands of patients, no fatalities attributable to lithotripsy have been reported. However, there is one anecdotal report of death due to septic cholangitis 9 weeks after lithotripsy,20 and out of 1200 of our patients 1 patient with severe coronary heart disease died from recurrent myocardial infarction 6 h after uneventful lithotripsy. Biliary pain, probably caused by passage of fragments, may occur during the first 2 to 3 months in 30% to 70% of the patients not rendered
stone
free.17,18
If
lithotripsy of gallstones is restricted to patients with symptomatic solitary gallbladder stones, the population of candidates ideal for the procedure ranges between 10% and 15% of all patients with symptomatic gallstones. HMG-CoA reductase inhibitors
Recently a new class of lipid-lowering drugs that competitively inhibit the enzyme 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) has been introduced. They not only lower serum low-density lipoprotein-cholesterol but also reduce the cholesterol saturation index in bile, an effect that may be enhanced by the combination with ursodeoxycholic acid.21 The combination of an HMG-CoA reductase inhibitor with ursodeoxycholic acid may therefore have a part to play in the dissolution of cholesterol gallstones or fragments,2z provided the HMG-CoA reductase inhibitors prove safe enough for the treatment of what is generally a benign disease with only rare fatalities. Contact dissolution of cholesterol stones The Mayo group, which pioneered the dissolution of cholesterol stones more than two decades ago, began their investigations of the direct administration of methyl tertbutyl ether into the gallbladder about 7 years ago.3 This agent has a high solvent capacity for cholesterol (14 g/dl), and its high boiling point (55 °C) prevents it from expanding in vivo as quickly as does diethyl ether (boiling point 35°C). Surprisingly, methyl tert-butyl ether, when instilled strictly into the gallbladder, causes only very slight tissue damage in man and in dogs.z3 The detailed technique is described elsewhere.z4,25 Patients whose gallbladder is attached to the liver bed as assessed by computed tomography or ultrasound, with an open cystic duct, and with radiolucent symptomatic stones are eligible. The number of calculi is less important than with shock-wave lithotripsy. Normally the ether is applied for a total of 10 to 15 h over several days (on average 3 to 4 days). Apart from the occasional occurrence of biliary pain, nausea, and sedation, treatment is quite well tolerated. Although severe complications such as haemolysis and renal insufficiency may occur if the ether
OPTIONS FOR ELECTIVE THERAPY OF SYMPTOMATIC GALLBLADDER STONES
1123
and
a
catheter
must
remain in situ for 10
days
to
prevent
postoperative leakage. Another method is based on the transhepatic introduction of an impeller30 that can crush large stones. The debris is aspirated from the gallbladder. Again this method requires gallbladder drainage for several days. Both methods are far from being established. It is questionable whether such invasive procedures that necessitate a large drainage catheter for nearly 10 days can really compete with laparoscopic cholecystectomy for a future place in gallbladder treatment.
Stone recurrence All forms of treatment in which the gallbladder remains in situ share the major drawback of stone recurrence. In recent studies on patients who had been successfully treated with oral bile acids, the recurrence curves levelled off within the first 3 to 5 years after discontinuation of treatment and it is believed that only every second patient will have recurrent stones. After successful lithotripsy plus oral bile acids,31 the recurrence rate after 1 year was 9%. After dissolution with methyl tert-butyl ether, the overall 1-year Clearance of fragments after extracorporeal shock wave lithotripsy and adjuvant bile acid treatment in patients with solitary radiolucent stones 20 mm or less in diameter. Current experience of the Munich group: diagram modified from Sackmann et al.17
systemic circulation,26 no deaths have yet been reported. Up to 5% of patients require cholecystectomy because of leakage after gallbladder puncture.25 Although practically all the cholesterol stone material can be dissolved in quite a short time, some debris does remain in the gallbladder in 34%zs to 70% of the patients.24 Pretreatment with lithotripsy is feasible27 and may lower the amount of residual debris and broaden the indications to include partly enters
the
calcified stones. Initially, the solvent was given by the percutaneous transhepatic routes3 Subsequently the solvent has been applied via an endoscope passed through the papilla and the cystic duct.4,Z8 Both routes have their pros and cons. Allthough there is no risk of gallbladder leakage in the case of retrograde cannulation of the gallbladder, pancreatitis or cystic duct perforation may occur. 28 Problems due to gallbladder leakage are easier to handle than severe pancreatitis and therefore transhepatic puncture seems preferable. Furthermore, it is easier, has a higher success rate, and allows better handling of the catheter. After
application of methyl tert-butyl ether, patients generally receive ursodeoxycholic acid for several months and eventually 50% to 90% of all treated patients24’z5 are rendered completely stone free. The total number of patients so treated in published reports is small. About 20% to 30% of patients with symptomatic gallbladder stones may be suitable for methyl tert-butyl ether.25 Like lithotripsy, ether-dissolution of cholesterol gallstones is still at an
investigational stage in the United States. Further investigational methods The non-surgical approaches described above are applicable only to cholesterol gallbladder stones. Therefore, to percutaneous cholecystolithotomy, analogous percutaneous nephrolithotomy,29 has been attempted. The gallbladder is punctured directly and dilated up to 28 Charriere. The procedure is done under general anaesthesia
recurrence rate was
higher (29%).32
If non-surgical methods for the treatment of gallbladder stones are to become a routine procedure, the problem of gallstone recurrence has to be solved. The fact that gallstones do not form again in half the patients even though cholesterol supersaturation of bile almost invariably recurs suggests that in these patients the disturbance leading to stone formation is transient. A major objective is the definition of those patients in whom stones will not recur. The recent research into the pathogenesis of gallbladder stones will certainly be a valuable aid in this respect. Patients least likely to have recurrence are probably those with solitary stones33 and those with adequate gallbladder contraction. Furthermore, strategies for the prevention of recurrent stones in patients at high risk of recurrence should be evaluated. At present prophylaxis with intermediate doses of ursodeoxycholic acid 33 or intermittent therapy with high doses of bile-acids34 are more realistic approaches than treatments aimed at influencing mucin formation 35 or
gallbladder motility.
Laparoscopic cholecystectomy Laparoscopic cholecystectomys is a minimal access approach for the removal of the gallbladder together with its stones. Length of hospital stay averages 1-2 days in the United States36 and 3 days in Europe.37 Most patients have been able to return to work or to normal activity in one to weeks. So far, results of several thousand procedures have been published in a short time.5 The proportion of patients suitable for laparoscopic cholecystectomy is believed to be approximately 80%. It is a novel method and there is still room for development, but it already seems to be safe, with a mortality of less than 1 %,36 which compares well with that of conventional elective cholecystectomy in young and fit patients. In about 4-5% of patients surgeons are compelled to convert to open cholecystectomy because of unexpected events such as obscured anatomy of the region by inflammatory processes, adhesions, or aberrant anatomy. During the learning phase, laparoscopic cholecystectomy is a time-consuming procedure, often requiring more than 2 h. In the United States, the procedure lasted an average of 90 minutes36 and in Europe a median of 50 minutes was reported.37,38 It may be difficult to extract large gallbladder two
1124
through the umbilical incision, where the main trocar placed. In such patients enlargement of the incision or a lithotriptic method is required. Despite a broadening of the indications, most centres still exclude patients with acute cholecystitis, high probability of adhesions in the upper abdomen, or biliary pancreatitis. The main area of concern with this procedure is bileduct injury, which may occur particularly during the learning phase.36 The overall rate is reported as being between 03% in a retrospective survey37 and 0-5% in the United States.36 The total complication rate 36 is about 5% (bileduct injury, bleeding, prolonged ileus, bowel injuries, and bile leakage). Laparoscopic cholecystectomy will be the procedure of choice for most patients referred for elective cholecystectomy. stones
is
Conclusion Because of the high prevalence of symptomatic gallbladder stones in western civilisation their management remains a major task in medicine. For patients in good general condition who are willing to undergo surgery, removal of the gallbladder is the treatment of choice. Most patients and doctors will opt for the laparoscopic variant of cholecystectomy nowadays. However, the surgeon should be properly trained in this procedure and the patient must be informed that the risk of bileduct injury is probably higher than with conventional cholecystectomy. Most non-surgical procedures do not require general anaesthesia. This makes them attractive for the patient. Provided that the cystic duct is open, patients with small floating radiolucent stones are good candidates for oral bile acid treatment and those with solitary radiolucent stones up to 2 cm in diameter can receive a combination of lithotripsy with bile acid therapy. The patient must realise that follow-up by ultrasound is required after successful therapy to rule out recurrent stones. Other treatment-such as methyl tert-butyl ether dissolution, lithotripsy of multiple stones or calcified stones, repeated lithotripsy without bile acid therapy, contact lithotripsy, or
percutaneous
investigational
extraction stage.
of
stones-are
still
at
an
We thank Martina Baurer for secretarial help.
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