3 Gallbladder stones: choice of treatment GUSTAV
PAUMGARTNER
Many patients in whom gallstones are detected have not had biliary pain or complications of their gallstone disease (Barbara et al, 1987; GREPCO, 1987). The natural history of asymptomatic gallstone disease in these patients is generally benign and expectant management is justified (Ransohoff et al, 1983; Paumgartner et al, 1988; Paumgartner, 1990). By contrast, patients who have had one or more episodes of biliary pain or complications are at an increased risk of suffering repeated attacks of pain or complications (Thistle et al, 1984; Ransohoff and Gracie, 1986; Paumgartner, 1990). In these symptomatic patients, therapeutic interventions are indicated (Paumgartner et al, 1988; Paumgartner, 1990). While the question as to whether or not therapeutic intervention is indicated can usually be answered easily, the choice of the most appropriate treatment is more difficult. For a long time cholecystectomy was the only treatment available. It could be performed irrespective of the type of the stone as long as the patient was fit for open abdominal surgery. Recently, the introduction of laparoscopic cholecystectomy has made open abdominal surgery unnecessary in about 80% of patients undergoing cholecystectomy (Sauerbruch and Paumgartner, 1991). In the past two decades, non-invasive or less invasive therapeutic alternatives have been developed for selected patients (Sauerbruch and Paumgartner, 1991). Oral bile acid dissolution therapy, extracorporeal shockwave lithotripsy and direct solvent dissolution with methyl-tert-butylether (MTBE) have in common that they remove the stone while maintaining the gallbladder and that they are less invasive than surgical or laparoscopic removal of the gallbladder. Each of these treatments is limited to certain stones and stages of the disease and each has its specific advantages and drawbacks which must be discussed with the patient. Therefore, proper evaluation of the gallstone disease of the individual patient is mandatory before the appropriate therapy modality is selected. CLASSIFICATION
OF STONES AND PATIENTS
Before a decision on the appropriate therapeutic approach, the following characteristics of the stones and the patients must be defined. BaiNit?re’s Clinical GastroenterologyVol. 6, No. 4, November 1992 ISBN 0-702(t1625-X
679 Copyright 0 1992, by Baillikre All rights of reproduction in any form
Tindall reserved
680 Radiolucency
G.
PAUMGARTNER
of stones
Oral bile acid dissolution, direct solvent dissolution and extracorporeal shockwave lithotripsy, in so far as it depends on fragment dissolution by bile acids, have in common that they are effective only in patients with cholesterol stones. Since no method is available to determine the cholesterol content of gallstones in vivo, assessment of the radiolucency of the stones by radiography or computed tomography (CT) is required to exclude calcified stones. The best indicator of the cholesterol composition of the stones is flotation of the stones in bile during oral cholecystography, because the specific gravity of cholesterol stones is close to that of bile enriched with radiographic contrast material (Figure 1).
Figure 1. Oral cholecystogram showing multiple small radiolucent floating stones in an opacifying gallbladder: excellent candidate for oral bile acid dissolution therapy.
Small black pigment stones are difficult to exclude by radiography, but represent fewer than 10% of the gallstones in the general population. Since their incidence is much higher in haemolytic disorders, patients with these disorders should not be treated by the above non-surgical modalities. Cholesterol stones with a thin calcified shell, appearing on radiography or CT as radiolucent stones with a calcified rim (Figure 2), cannot be dissolved by bile acid therapy or MTBE, but can be fragmented sufficiently (Schachler
CHOICE
OF TREATMENT
FOR
GALLSTONES
681
Figure 2. Oral cholecystogram showing a single radiolucent stone 30 mm in diameter with a thin radiopaque rim in an opacifying gallbladder. The calcified shell precludes oral bile acid dissolution therapy or direct solvent dissolution with MTBE, but extracorporeal shockwave lithotripsy can be considered.
et al, 1988; Sackmann et al, 1992b) to achieve complete clearance of all stone fragments by shockwave lithotripsy. Size and number of stones Since the time required for gallstone dissolution by bile acid therapy depends on the size of the largest stone (Senior et al, 1990), the efficacy of oral bile acid dissolution therapy decreases dramatically with stone diameters greater than 5-10 mm. The efficacy of shockwave lithotripsy also decreases with stone size, but this is a problem only with stone diameters greater than 20-30mm (Sackmann et al, 1991b). Careful determination of the diameter of the stones is therefore essential. The diameter of small stones can be measured with highest precision with ultrasonography whereas for larger stones oral cholecystography is preferable (Simeone et al, 1989). Both methods, however, can be used in the investigation for stone characterization if ultrasonography is complemented with a plain film of the abdomen, or preferably CT to exclude stone calcifications. The number of stones is of little importance with regard to oral bile acid dissolution or direct solvent dissolution, but it is critical for the success of shockwave lithotripsy. Thus, much better results are obtained in patients with a single stone than in patients with multiple stones (Sackmann et al, 1991b). This is caused mainly by the difficulty of targeting multiple stones
682
G. PAUMGARTNER
and as a consequence less complete fragmentation. For these reasons our group has limited the number of stones eligible for shockwave lithotripsy to three (Sauerbruch et al, 1986). Another advantage of patients with solitary stones is their lower rate of stone recurrence (Villanova et al, 1989; Sackmann et al, 1990). No restrictions on stone size and number are imposed on the selection of patients for direct solvent dissolution with MTBE. With this therapy only exclusion of any form of calcification is essential for success (Thistle et al, 1989). Gallbladder
function
It is obvious that the cystic duct must be patent for both oral bile acid dissolution and shockwave lithotripsy to allow for filling and emptying of unsaturated bile and passage of fragments (Paumgartner, 1989). The standard and most widely used method to document patency of the cystic duct is oral cholecystography (Simeone et al, 1989; Sackmann et al, 1991b). This technique also permits the evaluation of gallbladder emptying following a test meal. If the gallbladder opacifies well, this also proves that the concentrating function of the gallbladder mucosa is preserved and that severe pathology of the gallbladder wall is unlikely. As an alternative to oral cholecystography, ultrasonography in the fasting state and following a test meal or cholecystokinin (CCK) infusion has been used successfully to document patency of the cystic duct and gallbladder emptying (El1 et al, 1990; Donald et al, 1991). Gallbladder emptying can be studied more precisely with ultrasonography if the sum of cylinders method is used for calculation of gallbladder volume and gallbladder contraction is stimulated by CCK infusion (Spengler et al, 1989). Recently, our group has compared gallbladder emptying assessed by ultrasonography and CCK infusion in patients whose stone fragments cleared within 18 months of shockwave lithotripsy with that in patients whose fragments did not clear within this time period. Patients whose stone fragments had cleared within 18 months emptied their gallbladder on average by about 60%, whereas those whose fragments did not clear until 18 months after lithotripsy emptied only about 25% of the gallbladder volume after CCK infusion (Eder et al, 1991). These findings and those of others (Donald et al, 1991) suggest that gallbladder emptying should be determined before a decision on the choice of treatment is made. Patients with gallbladder emptying of less than 30% should be excluded from shockwave lithotripsy. Most likely, gallbladder emptying after a test meal, which is more practical in the diagnostic investigation than CCK infusion, is sufficient to serve this purpose. Characteristics
of gallstone disease
As mentioned above, therapeutic intervention with any of the surgical or non-surgical treatment options is indicated only in patients with symptomatic gallstones. An exception are patients with porcelain gallbladder who
CHOICE
OF TREATMENT
683
FOR GALLSTONES
should undergo cholecystectomy because of an increased risk of gallbladder cancer. Patients with symptoms may have uncomplicated gallstone disease (Paumgartner et al, 1988) or gallstone disease complicated by cholecystitis, cystic duct obstruction, common duct or intrahepatic stones, obstructive jaundice or biliary pancreatitis. All these complications preclude nonsurgical treatment modalities and require cholecystectomy with or without choledochotomy. In selected patients at high surgical risk, non-surgical treatment may be considered after the complication has resolved. In patients with uncomplicated disease, frequent and/or severe attacks of biliary pain preclude oral bile acid dissolution therapy. For these patients cholecystectomy is the standard therapy although direct solvent dissolution or shockwave lithotripsy may be considered as non-surgical alternatives. General factors Substantial risk factors for morbidity and mortality for surgery as well as for non-surgical treatments must be assessed in each patient. TREATMENT
OPTIONS
AND BEST CANDIDATES
Cholecystectomy In spite of the introduction of non-surgical therapies, cholecystectomy must still be regarded as the standard treatment. It can be performed in the classic way by open abdominal surgery or by laparoscopy, which avoids some disadvantages of open abdominal surgery (Sauerbruch and Paumgartner, 1991). Cholecystectomy can be performed irrespective of stone characteristics and gallbladder function as long as the patient is fit for abdominal surgery. Thus, only a few patients would not be eligible for this treatment. Cholecystectomy is the only effective treatment in patients with radiopaque and other non-cholesterol stones, but is also the treatment of choice in all patients with complicated gallstone disease. Gallbladder
preserving treatments
Patients who have undergone a gallbladder preserving treatment are at risk of stone recurrence (O’Donnell and Heaton, 1988; Villanova et al, 1989; Sackmann et al, 1990,1992a). This risk appears to be higher in patients with single stones than in those with multiple stones (Villanova et al, 1989). No methods are available as yet to predict the risk of stone recurrence in the individual patient. Progress along these lines may be expected to improve the selection of patients for gallbladder preserving treatments. Oral bile acid dissolution therapy Presently,
ursodeoxycholic
acid monotherapy
(10-13 mg kg-’ day-‘)
or
684
G.
PAUMGARTNER
therapy with a combination of ursodeoxycholic acid and chenodeoxycholic acid (5-8mg each kg-’ day-‘) are the preferred treatment regimens (Fromm and Malavolti, 1988; Sackmann et al, 1991). It has been reported that the combination is somewhat more effective than monotherapy with ursodeoxycholic acid (Podda et al, 1989). However, this remains to be confirmed. In carefully selected patients with radiolucent stones less than 5 mm in diameter in an opacifying gallbladder, complete dissolution of the stones may be achieved in approximately 60% of the patients within 1 year (Podda et al, 1989). For stones of 5-15 mm in diameter the success rate is lower. The highest success rates (complete dissolution in 80-90% in 1 year) are obtained in patients with small (< 5 mm in diameter) floating radiolucent stones (Fromm and Malavolti, 1988). Patients with frequent and severe attacks of biliary pain should not be treated. Pregnancy is an exclusion criterion. Ursodeoxycholic acid alone or in combination with chenodeoxycholic acid does not seem to produce toxic effects, but cystic duct obstruction, recurrent biliary pain, pancreatitis or cholecystitis necessitating referral for surgery develop in about one fifth of patients during the relatively long time period required for treatment, during which the patient is exposed to the risks of the natural history of symptomatic gallstone disease (Gleeson et al, 1990). The best candidates for oral bile acid dissolution therapy are patients with symptomatic uncomplicated gallstone disease who have infrequent and mild attacks of biliary pain and harbour multiple small floating radiolucent stones not larger than 5 mm in a functioning gallbladder. Extracorporeal shockwave lithotripsy dissolution therapy
combined with oral bile acid
Electrohydraulic (Paumgartner, 1989), piezoceramic (El1 et al, 1990) or electromagnetic (Burhenne et al, 1991) lithotripters equipped with sonographic stone detection and targeting may be used. Only patients with symptomatic uncomplicated gallstone disease are eligible for this treatment. They may have a single radiolucent stone (a thin calcified rim is acceptable) of 30 mm or less in diameter, or two to three radiolucent stones with a similar total stone volume in a functioning gallbladder (Paumgartner, 1989; Sackmann et al, 1991b, 1992b). Exclusion criteria are aneurysms in the path of the shockwave and pregnancy, as well as coagulopathy and/or current medication with anticoagulants or drugs with anticoagulant effects. The percentage of stone-free patients 12 months after lithotripsy is about 80% in patients with a single stone of 20mm or less in diameter. The percentage is about 70% if a thin (C 3 mm) calcified rim is present. For patients with large solitary stones (21-30mm in diameter) or with two to three stones, the percentages of stone-free patients at 12 months are about 60% and 50%) respectively. Severe adverse effects, caused mostly by passage of fragments after lithotripsy, occur in about 3-5% of patients (pancreatitis around 2%,
CHOICE
OF TREATMENT
FOR
GALLSTONES
685
cholestasis 1% , cholecystitis 1%)) and cholecystectomy or emergency endoscopic sphincterotomy is required in fewer than 5% of all patients (Sackmann et al, 1991b). Cystic duct obstruction has been observed in 5% (Sackmann et al, 1991b). It is generally symptomless and resolves spontaneously in half of the patients. 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 (Wenzel et al, 1990), and out of 1200 of our patients one patient with severe coronary heart disease and unstable angina died from recurrent myocardial infarction 8 h after uneventful lithotripsy. Biliary pain, probably caused by passage of fragments, occurs in about one third of the patients within the first 3 months after lithotripsy. The best candidates for extracorporeal shockwave lithotripsy are patients with symptomatic uncomplicated gallstone disease who harbour a single radiolucent stone with a diameter of 5-20 mm in a functioning gallbladder (Figure 3) that empties more than 30% of its volume after stimulation by CCK or a test meal.
Figure 3. Oral cholecystogram showing a single radiolucent stone 13 mm in diameter in an opacifying gallbladder after stimulation by a test meal: excellent candidate for extracorporeal shockwave lithotripsy combined with oral bile acid dissolution therapy of fragments.
Direct solvent dissolution therapy with MTBE
With this form of treatment, stone dissolution can be achieved much more rapidly than with other treatments (Thistle et al, 1989; Ho11 et al, 1991;
686
G. PAUMGARTNER
Leuschner et al, 1991). Patients with symptomatic non-complicated gallstone disease are eligible for this treatment if their stones are radiolucent on oral cholecystography and CT and if their anatomy is suitable for transhepatic gallbladder catheter placement (presence of some attachment of the gallbladder to the liver as assessed by CT). The number and the size of the stones are not critical. Contraindications are hepatic cysts, abscesses or haemangiomas in the anticipated catheter pathway as well as coagulopathy or current medication with anticoagulant effects. The best candidates for direct solvent dissolution with MTBE are patients with symptomatic uncomplicated gallstone disease having multiple large radiolucent stones. Algorithm Patients with gallstones frequently ask for the least invasive treatment that can be justified from a medical point of view. With this in mind, we have summarized our current approach in a simplified algorithm (Figure 4). This algorithm is based on the selection and exclusion criteria for the various treatments as well as on their ranking with regard to invasiveness, cholecystectomy being regarded as the most invasive therapy, followed by direct solvent dissolution, extracorporeal shockwave lithotripsy and oral bile acid dissolution therapy.
Gallbladder
stones no
Biiiai
l
colic?
yes 1 Compiications?~+
Yes
Choiecystectomy (surgical or iaparoscopic)
Radioiucency no and normal gallbladder function?
Yes 1 Stone diameter
I Choiecystectomy (surgical or iapllroscopic)
Expectant management
4 rnrn?%&$~~,
ye= 1 Oral bile acid dissolution therapy
Ye= 4 .-c Shockwave iithotripsy combined with bile acids
no
Direct solvent dissoiutlon (MTBE)
Figure 4. Algorithm for the therapy of gallbladder stones, if the least invasive method is to be chosen (for details see text). * Single stones with a thin (< 3 mm) radiopaque rim may be considered for shockwave lithotripsy. Two or three stones may be considered for shockwave lithotripsy if the sum of their diameters does not exceed 30mm. The success rate in these patients will, however. be lower.
CHOICE OF TREATMENT FOR GALLSTONES
687
REFERENCES Barbara L, Sama C, Morselli Labate AM et al (1987) A population study on the prevalence of gallstone disease: the Sirmione study. Hepatology 7: 913-917. Burhenne HJ, Fache JS, Rawat B & Lee SH (1991) Electromagnetic cholelithotripsy. In Paumgartner G, Sauerbruch T, Sackmann M & Burhenne HJ (eds) Lithofripsy and Related Techniques for Gallstone Treatment, pp 39-42. St Louis: Mosby-Yearbook. Donald JJ, Fache JS & Burhenne HJ (1991) Biliary lithotripsy: correlation between gallbladder contractility before treatment and the success of treatment. American Journal of Roentgenology
157: 287-290.
Eder H, Sackmann M, Spengler U et al (1991) Die Gallenblasen-motilitat beeinfluat das Ergebnis der StoBwellen-therapie von Gallensteinen. Zeitschrift fiir Gastroenterologie 29: 140-141. El1 Ch, Kerzel W, Schneider HT et al (1990) Piezoelectric lithotripsy: stone disintegration and follow-up results in patients with symptomatic gallbladder stones. Gustroenterology 99: 1439-1444. Fromm H & Malavolti M (1988) Dissolving gallstones. Advances in Internal Medicine 33: 409-430. Gleeson D, Ruppin DC, Saunders A, Murphy GM & Dowling RH (1990) Final outcome of ursodeoxycholic acid treatment in 126 patients with radiolucent stones. Quarterly Journal of Medicine 76: 71 l-729. Ho11 J, Sauerbruch T, Sackmann M, Pauletzki J & Paumgartner G (1991) Combined treatment of symptomatic gallbladder stones by extracorporeal shock-wave lithotripsy (ESWL) and instillation of methyl tert-butyl ether (MTBE). Digestive Diseases and Sciences 36: 10971101. Leuschner U, Hellstern A, Schmidt K et al (1991) Gallstone dissolution with methyl tert-butyl ether in 120 patients+fficacy and safety. Digestive Diseases and Sciences 36: 193-199. O’Donnell LDJ & Heaton KW (1988) Recurrence and re-recurrence of gall stones after medical dissolution: a longterm follow up. Gut 29: 655-658. Paumgartner G (1989) Shock-wave lithotripsyofgallstones. American JournalofRoentgenology 153: 235-242.
Paumgartner G (1990) Therapeutic interventions in patients with gallbladder stones: the internist’s view. In Swobodnik W, Ditschuneit H, Soloway RD (eds) Gallstone Disease. Pathophysiology and Therapeutic Approaches, pp 103-107. Berlin: Springer. Paumgartner G, Carr-Locke DL, Roda E & Thistle JL (1988) Biliary stones: non-surgical therapeutic approach. Gastroenterology International 1: 17-24. Podda M, Zuin M, Battezzati PM, Ghezzi C, de Fazio C & Dioguardi ML (1989) Efficacy and safety of a combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: a comparison with ursodeoxycholic acid alone. Gustroenterology 96: 222-229. Ransohoff DF & Gracie WA (1986) Symptomatic gallstones: three management strategies assessed by decision analysis. Gastroenterology 90: 1598. Ransohoff DF, Gracie WA, Wolfenson LB & Neuhauser D (1983) Prophylactic cholecystectomy or expectant management for persons with silent gallstones: a decision analysis to assesssurvival. Annals of Internal Medicine 99: 199-204. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO) (1987) Radiologic appearance of gallstones and its relationship with biliary symptoms and awareness of having gallstones. Observations during epidemiological studies. Digestive Diseases and Sciences
32: 349-353.
Sackmann M, Ippisch E, Sauerbruch T, Ho11 J, Brendel W & Paumgartner G (1990) Early gallstone recurrence rate after successful shock-wave therapy. Gustroenferology 98: 392396. Sackmann M, Pauletzki J, Aydemir U et al (1991a) Efficacy and safety of ursodeoxycholic acid for dissolution of gallstone fragments: comparison with the combination of ursodeoxycholic acid and chenodeoxycholic acid. Hepatology 14: 1136-1141. Sackmann M, Pauletzki J, Sauerbruch T, Ho11 J, Schelling G & Paumgartner G (1991b) The Munich gallbladder lithotripsy study. Results of the first 5 years with 711 patients. Annuls
of Internal
Medicine
114: 290-296.
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Sackmann M, Niller H, Ippisch E et al (1992a) Gallstone recurrence after lithotripsy. Gastroenterology 102: (abstract) (A332). Sackmann M, Pauletzki J, Delius M et al (1992b) Noninvasive therapy of gallbladder calculi with a radiopaque rim. Gmtroenterology 102: 988-993. Sauerbruch T & Paumgartner G (1991) Gallbladder stones: management. Lancet 338: 11211124. Sauerbruch T, Delius M, Paumgartner G et al (1986) Fragmentation of gallstones by extracorporeal shock waves. New England Journal of Medicine 314: 818-822. Schachler R, Sauerbruch T, Wosiewitz U et al (1988) Fragmentation of gallstones using extracorporeal shock waves: an in vitro study. Hepatology 8: 92.5-929. Senior JR, Johnson MF, DeTurck DM, Bazzoli F & Roda E (1990) In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids. Gusrroenrerology 99: 243251. Simeone JF & Ferruci JT (1989) Nonsurgical therapy of gallstones: implications for imaging. In Ferruci JT, Delius M & Burhenne HJ (eds) Biliary Lithotripsy, pp 205-214. Chicago: Year Book Medical Publishers. Spengler U, Sackmann M, Sauerbruch T, Ho11J & Paumgartner G (1989) Gallbladder motility before and after extracorporeal shock wave lithotripsy. Gustroenterology 96: 860-863. Thistle JL, Cleary PA, Lachin JM, Tyor MP, Hersh Th and the National Cooperative Gallstone Study Group (1984) The natural history of cholelithiasis: the national cooperative gallstone study. Annuls of Internal Medicine 101: 171-175. Thistle JL, May GR, Bender CE et al (1989) Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter. New England Journal
of Medicine
320: 63S639.
Villanova N, Bazzoli F, Taroni Fet al (1989) Gallstone recurrence after successful oral bile acid treatment. Gastroenterology 97: 726731. Wenzel H, Greiner L & Jakobeit Ch (1990) Spltkomplikationen der ESWL von Gallenblasensteinen mit letalem Ausgang. Deutsche Medizinische Wochenschrift 115: 77.
PAUMGARTNER
Many patients in whom gallstones are detected have not had biliary pain or complications of their gallstone disease (Barbara et al, 1987; GREPCO, 1987). The natural history of asymptomatic gallstone disease in these patients is generally benign and expectant management is justified (Ransohoff et al, 1983; Paumgartner et al, 1988; Paumgartner, 1990). By contrast, patients who have had one or more episodes of biliary pain or complications are at an increased risk of suffering repeated attacks of pain or complications (Thistle et al, 1984; Ransohoff and Gracie, 1986; Paumgartner, 1990). In these symptomatic patients, therapeutic interventions are indicated (Paumgartner et al, 1988; Paumgartner, 1990). While the question as to whether or not therapeutic intervention is indicated can usually be answered easily, the choice of the most appropriate treatment is more difficult. For a long time cholecystectomy was the only treatment available. It could be performed irrespective of the type of the stone as long as the patient was fit for open abdominal surgery. Recently, the introduction of laparoscopic cholecystectomy has made open abdominal surgery unnecessary in about 80% of patients undergoing cholecystectomy (Sauerbruch and Paumgartner, 1991). In the past two decades, non-invasive or less invasive therapeutic alternatives have been developed for selected patients (Sauerbruch and Paumgartner, 1991). Oral bile acid dissolution therapy, extracorporeal shockwave lithotripsy and direct solvent dissolution with methyl-tert-butylether (MTBE) have in common that they remove the stone while maintaining the gallbladder and that they are less invasive than surgical or laparoscopic removal of the gallbladder. Each of these treatments is limited to certain stones and stages of the disease and each has its specific advantages and drawbacks which must be discussed with the patient. Therefore, proper evaluation of the gallstone disease of the individual patient is mandatory before the appropriate therapy modality is selected. CLASSIFICATION
OF STONES AND PATIENTS
Before a decision on the appropriate therapeutic approach, the following characteristics of the stones and the patients must be defined. BaiNit?re’s Clinical GastroenterologyVol. 6, No. 4, November 1992 ISBN 0-702(t1625-X
679 Copyright 0 1992, by Baillikre All rights of reproduction in any form
Tindall reserved
680 Radiolucency
G.
PAUMGARTNER
of stones
Oral bile acid dissolution, direct solvent dissolution and extracorporeal shockwave lithotripsy, in so far as it depends on fragment dissolution by bile acids, have in common that they are effective only in patients with cholesterol stones. Since no method is available to determine the cholesterol content of gallstones in vivo, assessment of the radiolucency of the stones by radiography or computed tomography (CT) is required to exclude calcified stones. The best indicator of the cholesterol composition of the stones is flotation of the stones in bile during oral cholecystography, because the specific gravity of cholesterol stones is close to that of bile enriched with radiographic contrast material (Figure 1).
Figure 1. Oral cholecystogram showing multiple small radiolucent floating stones in an opacifying gallbladder: excellent candidate for oral bile acid dissolution therapy.
Small black pigment stones are difficult to exclude by radiography, but represent fewer than 10% of the gallstones in the general population. Since their incidence is much higher in haemolytic disorders, patients with these disorders should not be treated by the above non-surgical modalities. Cholesterol stones with a thin calcified shell, appearing on radiography or CT as radiolucent stones with a calcified rim (Figure 2), cannot be dissolved by bile acid therapy or MTBE, but can be fragmented sufficiently (Schachler
CHOICE
OF TREATMENT
FOR
GALLSTONES
681
Figure 2. Oral cholecystogram showing a single radiolucent stone 30 mm in diameter with a thin radiopaque rim in an opacifying gallbladder. The calcified shell precludes oral bile acid dissolution therapy or direct solvent dissolution with MTBE, but extracorporeal shockwave lithotripsy can be considered.
et al, 1988; Sackmann et al, 1992b) to achieve complete clearance of all stone fragments by shockwave lithotripsy. Size and number of stones Since the time required for gallstone dissolution by bile acid therapy depends on the size of the largest stone (Senior et al, 1990), the efficacy of oral bile acid dissolution therapy decreases dramatically with stone diameters greater than 5-10 mm. The efficacy of shockwave lithotripsy also decreases with stone size, but this is a problem only with stone diameters greater than 20-30mm (Sackmann et al, 1991b). Careful determination of the diameter of the stones is therefore essential. The diameter of small stones can be measured with highest precision with ultrasonography whereas for larger stones oral cholecystography is preferable (Simeone et al, 1989). Both methods, however, can be used in the investigation for stone characterization if ultrasonography is complemented with a plain film of the abdomen, or preferably CT to exclude stone calcifications. The number of stones is of little importance with regard to oral bile acid dissolution or direct solvent dissolution, but it is critical for the success of shockwave lithotripsy. Thus, much better results are obtained in patients with a single stone than in patients with multiple stones (Sackmann et al, 1991b). This is caused mainly by the difficulty of targeting multiple stones
682
G. PAUMGARTNER
and as a consequence less complete fragmentation. For these reasons our group has limited the number of stones eligible for shockwave lithotripsy to three (Sauerbruch et al, 1986). Another advantage of patients with solitary stones is their lower rate of stone recurrence (Villanova et al, 1989; Sackmann et al, 1990). No restrictions on stone size and number are imposed on the selection of patients for direct solvent dissolution with MTBE. With this therapy only exclusion of any form of calcification is essential for success (Thistle et al, 1989). Gallbladder
function
It is obvious that the cystic duct must be patent for both oral bile acid dissolution and shockwave lithotripsy to allow for filling and emptying of unsaturated bile and passage of fragments (Paumgartner, 1989). The standard and most widely used method to document patency of the cystic duct is oral cholecystography (Simeone et al, 1989; Sackmann et al, 1991b). This technique also permits the evaluation of gallbladder emptying following a test meal. If the gallbladder opacifies well, this also proves that the concentrating function of the gallbladder mucosa is preserved and that severe pathology of the gallbladder wall is unlikely. As an alternative to oral cholecystography, ultrasonography in the fasting state and following a test meal or cholecystokinin (CCK) infusion has been used successfully to document patency of the cystic duct and gallbladder emptying (El1 et al, 1990; Donald et al, 1991). Gallbladder emptying can be studied more precisely with ultrasonography if the sum of cylinders method is used for calculation of gallbladder volume and gallbladder contraction is stimulated by CCK infusion (Spengler et al, 1989). Recently, our group has compared gallbladder emptying assessed by ultrasonography and CCK infusion in patients whose stone fragments cleared within 18 months of shockwave lithotripsy with that in patients whose fragments did not clear within this time period. Patients whose stone fragments had cleared within 18 months emptied their gallbladder on average by about 60%, whereas those whose fragments did not clear until 18 months after lithotripsy emptied only about 25% of the gallbladder volume after CCK infusion (Eder et al, 1991). These findings and those of others (Donald et al, 1991) suggest that gallbladder emptying should be determined before a decision on the choice of treatment is made. Patients with gallbladder emptying of less than 30% should be excluded from shockwave lithotripsy. Most likely, gallbladder emptying after a test meal, which is more practical in the diagnostic investigation than CCK infusion, is sufficient to serve this purpose. Characteristics
of gallstone disease
As mentioned above, therapeutic intervention with any of the surgical or non-surgical treatment options is indicated only in patients with symptomatic gallstones. An exception are patients with porcelain gallbladder who
CHOICE
OF TREATMENT
683
FOR GALLSTONES
should undergo cholecystectomy because of an increased risk of gallbladder cancer. Patients with symptoms may have uncomplicated gallstone disease (Paumgartner et al, 1988) or gallstone disease complicated by cholecystitis, cystic duct obstruction, common duct or intrahepatic stones, obstructive jaundice or biliary pancreatitis. All these complications preclude nonsurgical treatment modalities and require cholecystectomy with or without choledochotomy. In selected patients at high surgical risk, non-surgical treatment may be considered after the complication has resolved. In patients with uncomplicated disease, frequent and/or severe attacks of biliary pain preclude oral bile acid dissolution therapy. For these patients cholecystectomy is the standard therapy although direct solvent dissolution or shockwave lithotripsy may be considered as non-surgical alternatives. General factors Substantial risk factors for morbidity and mortality for surgery as well as for non-surgical treatments must be assessed in each patient. TREATMENT
OPTIONS
AND BEST CANDIDATES
Cholecystectomy In spite of the introduction of non-surgical therapies, cholecystectomy must still be regarded as the standard treatment. It can be performed in the classic way by open abdominal surgery or by laparoscopy, which avoids some disadvantages of open abdominal surgery (Sauerbruch and Paumgartner, 1991). Cholecystectomy can be performed irrespective of stone characteristics and gallbladder function as long as the patient is fit for abdominal surgery. Thus, only a few patients would not be eligible for this treatment. Cholecystectomy is the only effective treatment in patients with radiopaque and other non-cholesterol stones, but is also the treatment of choice in all patients with complicated gallstone disease. Gallbladder
preserving treatments
Patients who have undergone a gallbladder preserving treatment are at risk of stone recurrence (O’Donnell and Heaton, 1988; Villanova et al, 1989; Sackmann et al, 1990,1992a). This risk appears to be higher in patients with single stones than in those with multiple stones (Villanova et al, 1989). No methods are available as yet to predict the risk of stone recurrence in the individual patient. Progress along these lines may be expected to improve the selection of patients for gallbladder preserving treatments. Oral bile acid dissolution therapy Presently,
ursodeoxycholic
acid monotherapy
(10-13 mg kg-’ day-‘)
or
684
G.
PAUMGARTNER
therapy with a combination of ursodeoxycholic acid and chenodeoxycholic acid (5-8mg each kg-’ day-‘) are the preferred treatment regimens (Fromm and Malavolti, 1988; Sackmann et al, 1991). It has been reported that the combination is somewhat more effective than monotherapy with ursodeoxycholic acid (Podda et al, 1989). However, this remains to be confirmed. In carefully selected patients with radiolucent stones less than 5 mm in diameter in an opacifying gallbladder, complete dissolution of the stones may be achieved in approximately 60% of the patients within 1 year (Podda et al, 1989). For stones of 5-15 mm in diameter the success rate is lower. The highest success rates (complete dissolution in 80-90% in 1 year) are obtained in patients with small (< 5 mm in diameter) floating radiolucent stones (Fromm and Malavolti, 1988). Patients with frequent and severe attacks of biliary pain should not be treated. Pregnancy is an exclusion criterion. Ursodeoxycholic acid alone or in combination with chenodeoxycholic acid does not seem to produce toxic effects, but cystic duct obstruction, recurrent biliary pain, pancreatitis or cholecystitis necessitating referral for surgery develop in about one fifth of patients during the relatively long time period required for treatment, during which the patient is exposed to the risks of the natural history of symptomatic gallstone disease (Gleeson et al, 1990). The best candidates for oral bile acid dissolution therapy are patients with symptomatic uncomplicated gallstone disease who have infrequent and mild attacks of biliary pain and harbour multiple small floating radiolucent stones not larger than 5 mm in a functioning gallbladder. Extracorporeal shockwave lithotripsy dissolution therapy
combined with oral bile acid
Electrohydraulic (Paumgartner, 1989), piezoceramic (El1 et al, 1990) or electromagnetic (Burhenne et al, 1991) lithotripters equipped with sonographic stone detection and targeting may be used. Only patients with symptomatic uncomplicated gallstone disease are eligible for this treatment. They may have a single radiolucent stone (a thin calcified rim is acceptable) of 30 mm or less in diameter, or two to three radiolucent stones with a similar total stone volume in a functioning gallbladder (Paumgartner, 1989; Sackmann et al, 1991b, 1992b). Exclusion criteria are aneurysms in the path of the shockwave and pregnancy, as well as coagulopathy and/or current medication with anticoagulants or drugs with anticoagulant effects. The percentage of stone-free patients 12 months after lithotripsy is about 80% in patients with a single stone of 20mm or less in diameter. The percentage is about 70% if a thin (C 3 mm) calcified rim is present. For patients with large solitary stones (21-30mm in diameter) or with two to three stones, the percentages of stone-free patients at 12 months are about 60% and 50%) respectively. Severe adverse effects, caused mostly by passage of fragments after lithotripsy, occur in about 3-5% of patients (pancreatitis around 2%,
CHOICE
OF TREATMENT
FOR
GALLSTONES
685
cholestasis 1% , cholecystitis 1%)) and cholecystectomy or emergency endoscopic sphincterotomy is required in fewer than 5% of all patients (Sackmann et al, 1991b). Cystic duct obstruction has been observed in 5% (Sackmann et al, 1991b). It is generally symptomless and resolves spontaneously in half of the patients. 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 (Wenzel et al, 1990), and out of 1200 of our patients one patient with severe coronary heart disease and unstable angina died from recurrent myocardial infarction 8 h after uneventful lithotripsy. Biliary pain, probably caused by passage of fragments, occurs in about one third of the patients within the first 3 months after lithotripsy. The best candidates for extracorporeal shockwave lithotripsy are patients with symptomatic uncomplicated gallstone disease who harbour a single radiolucent stone with a diameter of 5-20 mm in a functioning gallbladder (Figure 3) that empties more than 30% of its volume after stimulation by CCK or a test meal.
Figure 3. Oral cholecystogram showing a single radiolucent stone 13 mm in diameter in an opacifying gallbladder after stimulation by a test meal: excellent candidate for extracorporeal shockwave lithotripsy combined with oral bile acid dissolution therapy of fragments.
Direct solvent dissolution therapy with MTBE
With this form of treatment, stone dissolution can be achieved much more rapidly than with other treatments (Thistle et al, 1989; Ho11 et al, 1991;
686
G. PAUMGARTNER
Leuschner et al, 1991). Patients with symptomatic non-complicated gallstone disease are eligible for this treatment if their stones are radiolucent on oral cholecystography and CT and if their anatomy is suitable for transhepatic gallbladder catheter placement (presence of some attachment of the gallbladder to the liver as assessed by CT). The number and the size of the stones are not critical. Contraindications are hepatic cysts, abscesses or haemangiomas in the anticipated catheter pathway as well as coagulopathy or current medication with anticoagulant effects. The best candidates for direct solvent dissolution with MTBE are patients with symptomatic uncomplicated gallstone disease having multiple large radiolucent stones. Algorithm Patients with gallstones frequently ask for the least invasive treatment that can be justified from a medical point of view. With this in mind, we have summarized our current approach in a simplified algorithm (Figure 4). This algorithm is based on the selection and exclusion criteria for the various treatments as well as on their ranking with regard to invasiveness, cholecystectomy being regarded as the most invasive therapy, followed by direct solvent dissolution, extracorporeal shockwave lithotripsy and oral bile acid dissolution therapy.
Gallbladder
stones no
Biiiai
l
colic?
yes 1 Compiications?~+
Yes
Choiecystectomy (surgical or iaparoscopic)
Radioiucency no and normal gallbladder function?
Yes 1 Stone diameter
I Choiecystectomy (surgical or iapllroscopic)
Expectant management
4 rnrn?%&$~~,
ye= 1 Oral bile acid dissolution therapy
Ye= 4 .-c Shockwave iithotripsy combined with bile acids
no
Direct solvent dissoiutlon (MTBE)
Figure 4. Algorithm for the therapy of gallbladder stones, if the least invasive method is to be chosen (for details see text). * Single stones with a thin (< 3 mm) radiopaque rim may be considered for shockwave lithotripsy. Two or three stones may be considered for shockwave lithotripsy if the sum of their diameters does not exceed 30mm. The success rate in these patients will, however. be lower.
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687
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