2 Gallbladder stones: diagnostic procedures JOSEPH T. FERRUCCI Commensurate with the rapid development of new techniques for the non-surgical management of gallstone disease, diagnostic imaging of gallstones has undergone similar refinements to reflect the needs of the new technologies. Prior to development of extracorporeal shockwave lithotripsy (ESWL), methyl-tert-butyl-ether (MTBE) and oral bile acid therapy (OBA), the only therapeutic option was cholecystectomy; therefore the radiological evaluation of gallstones dealt only with the presence or absence of stones. To a greater or lesser extent, the recent dissemination of laparoscopic cholecystectomy returns gallbladder stone imaging to that simpler position. However, in so far as the new therapeutic methods are still valid alternatives, their use is dependent upon the size, number and chemical composition of the gallstones as well as the functional status of the gallbladder (Berk et al, 1983; Allen et al, 1985; Ferrucci et al, 1989). Thus, there is still a residual need accurately to quantify and characterize the stone content of the gallbladder. This need has led to significant advances in radiographic, ultrasonographic, oral cholecystographic and computed tomographic techniques and interpretative criteria. In combination, these advances have yielded new insights into the radiographic and sonographic diagnosis of cholelithiasis, the assessment of stone composition, and the quantification of gallstone and fragment burden before and after therapy (Simeone et al, 1989).
IMAGING
CRITERIA
FOR‘NON-SURGICAL
THERAPIES
Eligibility for and triage among the non-surgical therapies relies heavily on imaging criteria. All candidates for non-surgical therapy are initially evaluated by plain abdominal radiography and sonography. The plain film serves to screen for radiographically visible calcification, while the sonogram serves to detect the stones and measure their size and number. Oral cholecystography (OCG) contributes further quantitative assessment of gallbladder contents as well as assessing gallbladder function. Thus, visualization of the gallbladder at OCG indicates patency of the cystic duct permitting inflow of bile acid-enriched bile and outflow of fragments and debris into the common bile duct. Baillit?re’s
Clinical
Gasrroenterology-
Vol. 6, No. 4, November 1992 ISBN 0-702&1625-X
659
Copyright 0 1992, by Baillikre Tindall All rights of reproduction in any form reserved
660
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Figure 1. Gallstone lithotripsy. (a) Sonogram and (b) OCG disclose a 2 -cm !iolitary radiolucent gallstone within a functioning gallbladder. Patient was treated on t he I Iornier MPL !I000 lithotript er. (c) Sonogram 6 weeks after therapy reveals innumerable tiny fragmt :nts layered along the: posterior gallbladder wall.
DIAGNOSIS
OF GALLBLADDER
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Oral bile acid therapy For treatment with OBA, gallstones must be limited in size to a maximal diameter of 20 mm, although optimal results are obtained with stones less than 1 .O cm. However, at present, there is no practical limit on the number of stones. The size limitation relates to the rate of stone dissolution; the instantaneous rate of cholesterol mass removed from the stone is proportional to the stone surface area. As the diameter of gallstones decrease, the rate of percentage reduction of cholesterol mass increases (Senior et al, 1990). In addition, smaller stones are more likely to be pure cholesterol than are larger stones, which are more likely to have a calcium or pigment cover (Wolpers, 1982). Stones which are densely calcified or show a calcific rim on plain films are excluded. However, a small central nidus of calcification less than 3 mm in size is considered suitable for OBA, realizing that a small, insoluble nidus will be present after therapy. The radiographic filming technique may be optimized by performing coned views of the right upper quadrant in the prone position, and using low kVp and high mAs to maximize detection of calcium. OCG confirms normal gallbladder function, indicating a patent cystic duct. Radiolucent stones which float in the bile on erect views indicate a predominantly cholesterol composition. Although this is a reliable diagnostic criterion (100% sensitivity), it is limited in specificity (37%) (Trotman et al, 1975). Not all cholesterol gallstones float because most contain varying admixtures of pigment and radiographically undetectable calcium. Such gallstones may be treated with OBA. However, one should expect some insoluble residue in the gallbladder following therapy. ESWL The major differences between patient eligibility for OBA therapy and ESWL are the size and number of gallstones (Sackmann et al, 1988). Although any number of stones measuring less than 2 cm in diameter may be treated with oral chemolitholysis, no more than three stones may be present and no stone may exceed 3 cm in diameter according to the widely accepted criteria developed by the Munich group (Sackmann et al, 1988) (Figure 1). This is due to the difficulty of sonographically targeting multiple stones, as fragments and debris obscure remaining intact stones or fragments. Larger fragment sizes and prolonged fragment clearance occur in patients with two or three stones; best results are achieved in patients with solitary gallstones (Sackmann et al, 1988).
MTBE Eligibility criteria for gallstone dissolution by MTBE are even more liberal than those with OBA therapy or ESWL (Allen et al, 1985). Any number or size of stones may be treated although stones must be non-calcified or only
(4
(b)
(cl
2. MTBE therapy. (a) Sonogram reveals multiple tiny gallstones. (b) Direct catheter cholecystography before and (c) after 8 h of MTBE therapy discloses complete dissolution of innumerable tiny gallstones. Figure
minimally calcified (Figure 2). Computed tomography (CT) is also used to confirm the absence of significant calcification and determine a safe access route for percutaneous catheter placement. Baron et al (1989) have shown that stones with rimmed and laminated calcification may dissolve with MTBE although insoluble debris may remain. Gallbladder function at OCG is not mandatory, as there is no reliance on bile acids and no requirement for a patent cystic duct for fragment passage. TECHNICAL CONSIDERATIONS AND FRAGMENT IMAGING
IN STONE
Because of the greater precision required in the imaging assessment of gallstones, increased attention must be paid to the technical factors in the performance and interpretation of these imaging studies. Ultrasonography By the early 1980s ultrasonography had virtually replaced OCG in the assessment of cholelithiasis due to its relative ease of performance, lack of ingestion of contrast material, lack of exposure to ionizing radiation, and its 20% greater sensitivity for detection of small gallstones. The diagnostic dilemma related to a poorly visualized or non-visualized gallbladder at OCG was circumvented, and the well-known lO-30% incidence of gastrointestinal side-effects following ingestion of oral cholecystographic contrast material was eliminated (Berk et al, 1981, 1983). In addition, the ability to survey other abdominal structures and to perform the study on an emergent or unscheduled basis also established sonography as the procedure of choice in the evaluation of the acute gallbladder. Before ultrasonographic examination, the patient should fast for at least 6 h to allow the gallbladder to become distended with bile, which enhances the acoustic visibility of calculi. However, in instances where an emergency
DIAGNOSIS
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STONES
663
examination of the right upper quadrant is required, real-time sonography can be utilized for evaluating the gallbladder without fasting. Real-time sonographic examination has virtually replaced static ultrasonographic examination methods. In addition, real-time sonography may demonstrate the mobility of calculi and help differentiate them from polyps or folds. The examination itself consists of recording a sufficient number of images to document that the entire gallbladder lumen has been examined. Because the diagnosis of calculi, or lack of calculi, is usually made during the real-time sonographic examination, only a few hard copy images are required for documentation. One must rely upon the person performing the examination, because innumerable images could be produced without showing a stone hiding in the neck. Initial examination of the gallbladder should include long axis views, which are preferred over short axis views because of the greater volume of the gallbladder displayed. If the gallbladder lies immediately under the right costal margin, the patient can be rolled to a left decubitus position, which allows the gallbladder to fall medial to the right costal margin. This position has the advantages of interposing the liver in front of the gallbladder to serve as an acoustic window and also of allowing the air-filled gastric antrum and duodenum to fall away. More importantly, examination in the left decubitus position allows small stones that previously were undetected in the neck of the gallbladder to roll down to the dependent fundus and become visible. Air pockets can often be distinguished from stones by the distinctive shadow formed by each. Bowel gas creates an irregular, poorly marginated, ‘dirty’ shadow caused by reverberation artefacts. Stones create a ‘clean’ shadow because of the fact that they reflect almost all sound. Cholelithiasis presents ultrasonographically in one of three general patterns: 1. 2. 3.
Shadowing echogenic foci within the gallbladder that may or may not move. An echogenic focus within the gallbladder fossa with posterior acoustic shadowing (no visualization of the gallbladder itself). Non-shadowing echogenic foci within the gallbladder, usually less than 5 mm in size, which may or may not move.
It has been shown conclusively in vitro that all gallstones will shadow when imaged under ideal conditions and with the correct transducer. This shadowing occurs regardless of surface characteristics, calcium content, size or composition of the stone. Therefore, optimal conditions should be sought in vivo to induce gallstone shadowing. The importance of demonstrating shadowing lies in the increased accuracy of diagnosis of gallstones when a shadowing focal opacity is demonstrated (Figure 3). When non-shadowing focal opacities are shown, the accuracy of the diagnosis of cholelithiasis declines to 80%. With a shadowing focal opacity, the accuracy is greater than 99%. Modern real-time ultrasound machines are generally furnished with transducers of 3.0, 5.0 and 7SMHz frequency, which can be used interchangeably to elicit the characteristic shadow. Generally, stones larger than 1 cm in diameter display an acoustic shadow with no difficulty at all,
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(4
Figul re3.1 echo genie an ec :hoger seen deep seen after
Typical ultrasonographic patterns of gallstones. (a) Single large stone show focus and subjacent acoustic shadow. (b) Multiple minute stones or gravel lit layer along the dependent gallbladder wall. A broad summated acoustb to the stone layer. This same appearance could be caused by tiny stone shockwave lithotripsy.
ting a la urge produc :ing c shado w is fragmc :nts
DIAGNOSIS OF GALLBLADDER
STONES
665
whereas stones smaller than 5 mm can often be made to shadow only with 5or 7.5 MHz transducers. Even in the absence of shadowing, demonstration of mobility of the echogenic focus within the gallbladder lumen will be sufficiently diagnostic to permit an accurate diagnosis of cholelithiasis. In the absence of shadowing and no demonstration of mobility, the differential diagnosis of a small echogenic focus expands to include benign polyps, cholesterolosis, adenomyosis and other gallbladder wall tumours. It is therefore always best to try to optimize shadow formation. Finally, erect sitting or standing
Figure 4. Sonographic misrepresentation of stone number. (a) Gallbladder sonogram discloses a broad curvilinear acoustic reflection with an acoustic shadow representing what appears to be a single large gallbladder calculus. (b) After vigorous alterations in patient position, the ‘stone’ separates and two smaller calculi are seen.
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sonographic observation may be the only way to visualize small stones in the gallbladder neck as they fall by gravity to the fundus. A standing or sitting scan is mandatory if supine and right anterior oblique views show no stones. For non-surgical management, additional considerations apply in order to size and count gallstones optimally (Brink et al, 1990). Overlap and
(a)
Figure 5. Incorrect sonographic measurement of size of large gallstone. (a) Sonogram reveals a solitary large ellipsoidal gallstone. (b) Attempts to measure the gallstone axially and laterally are limited by poor definition of the back wall of the gallbladder for axial measurement, and poor definition of the poles of the stone for lateral measurement. Sonographic measurement was 2.6~ 1.8cm. However, the gallstone measured over 3cm in greatest dimension at cholecystectomy.
DIAGNOSIS OF GALLBLADDER
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clustering of multiple stones may occur in the gallbladder fundus or neck such that individual stone size may be overestimated and stone number may be underestimated. To overcome this, the patient may be placed in prone or upright positions to utilize gravity to separate stones for individual counting and measuring (Figure 4). Accurate sonographic measurement of gallstone size is dependent upon a number of technical factors. Measurements should be performed in the axial direction as resolution in the axial plane is superior to lateral resolution. In addition, side lobe artefacts in the lateral plane may make assessment of the lateral diameter difficult. However, accurate axial measurement requires definition of the deep or non-presenting surface of the stone (Figure 5). If the stone is definitely positioned along the back wall of gallbladder, the gallbladder wall may be taken as the deep surface of the stone (Simeone et al, 1989). However, when multiple stones are clumped together, or when the stone is so large as to make definition of the back wall difficult, then the axial measurement becomes less reliable. Measurement of larger stones (> 2 cm in diameter) is also confounded by acoustic reflection and absorption of the ultrasound beam at the polar surfaces of the stone, further hampering measurement in the lateral plane. Stones under 15 mm in size are generally spherical in shape whereas stones greater than 15 mm in size tend to assume an ellipsoidal shape (Wolpers, 1982). Therefore, a single axial measurement for stones less than 15 mm in diameter generally suffices (Figure 6). However, stones greater than 15 mm in size generally require measurement of major and minor axes, which may be better performed with OCG.
Figure 6. Sonographic measurement of smaller gallstones (< 15mm in diameter) is best performed axially. Axial measurement is extrapolated to the back wall of the gallbladder (arrowheads). Measurement reflects diameter of generally spherically shaped stones.
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OCG Optimal OCG techniques should maximize the potential for precise stone measurement. The effects of radiographic magnification should be minimized; overhead radiographs should be obtained with the patient in the prone-oblique position and magnification factors for each individual radiographic unit should be calculated. Cholecystography may permit calcifications in the right upper quadrant to be more precisely defined as being in or not in the gallbladder, and subtle degrees of calcium within the stones may be more clearly visualized. However, care must be taken to obtain a recent plain radiograph as minor degrees of calcification may be obscured by oral cholecystographic contrast within the gallbladder (Figure 7). In addition, important detail within the gallstones may be better seen at OCG, such as gas-containing fissures within stones indicating predominantly cholesterol composition.
(a)
(b)
Figure 7. Importance of plain radiography prior to OCG. (a) Scout film clearly discloses thick (4mm) rim of peripheral calcification excluding patient for ESWL. (b) At OCG, thick peripherally calcified rim is obscured.
CHOLECYSTOGRAPHICSONOGRAPHIC
CORRELATIONS
Although sonography has been accepted as being more sensitive than OCG in the detection of small gallstones, a recent prospective study comparing OCG and sonography showed no significant difference between the two imaging techniques in detecting a broader spectrum of gallbladder disease (stones, adenomyosis, cholesterolosis and cholecystitis) (Gelfand et al, 1988). Sonography detected calculi more accurately than the OCG (93%
DIAGNOSIS
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669
versus 65% sensitive, respectively). However, in the detection of noncalculous gallbladder diseases, OCG was as sensitive as sonography. Despite its greater diagnostic sensitivity for gallstones, sonography may be less accurate than OCG in counting stones, especially when more than five or six stones are present within the gallbladder (Figure 8). This is because sonography is a tomographic technique and single sections of the gallbladder, even if repeated multiple times, may give misleading results because of overlap of multiple stones. OCG gives a more accurate depiction of stone number when more than six stones are present because it is a projection imaging technique and all the stones may be identified on a single radiographic image. Moreover, as discussed above, measurements
(4
(b) Figure 8. Superiority of OCG for counting stones when more than five or six stones arc present. (a) Sonogram showing three or four stones. Cursors indicate a large stone in gallbladder neck. (b) OCG showing at least six stones. OCG is often more accurate than sonography in stone counting because it is a projection technique rather than a sectional or tomographic technique.
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of gallstone size on sonography are accurate only for stones less than 15-20 mm in size. Thus, when sonographic techniques are not specifically directed to the questions of stone size and number, the results are poor. A retrospective study of routine, untailored sonographic studies in 110 patients from our institution undergoing cholecystectomy found only 23 of 111 (21%) to be accurate in estimating gallstone size and number (Brink et al, 1989). Further, stone size and number were equally as often overestimated as underestimated, emphasizing the unreliability of non-tailored sonography. Thus direct correlation and comparison between sonography and OCG will be necessary for precise assessment of stone size and number in almost every patient. In general, the imaging studies showing the greatest number and largest stones should be considered the correct result. ROLE OF COMPUTED
TOMOGRAPHY
CT is not a primary radiological method for evaluating patients with gallbladder disease because of the excellent results with cheaper and more available methods such as sonography and cholecystography. In addition, CT images disclose gallstones in only 79% of patients with sonographic or surgical evidence of cholelithiasis (Barakos et al, 1987). However, stones with minimal quantities of calcium carbonate and calcium phosphate are easy to visualize by CT as high attenuation densities surrounded by low density bile. Various calcification patterns have been recognized, including stones which are densely calcified throughout as well as stones with various layers of calcifications (core, laminated, rimmed) (Baron et al, 1988) (Figure 9). Occasionally, cholesterol stones may be seen as low attenuation filling defects within the surrounding bile (Figure 9b,c). More recently, investigators have tried to utilize CT scanning in order to select patients for non-surgical gallstone therapy (Baron et al, 1988; Brackel et al, 1990). However, precise apriori prediction of exact stone composition has been an elusive goal. As a result, use of CT Hounsfield numbers to discriminate between potential responders (lipid, low Hounsfield) and nonresponders (Ca*+ and pigment) has advocates as well as detractors. Our view has been somewhat cautious (Brink et al, 1991). We believe it is appropriate as part of the workshop for primary and bile acid therapy and MTBE dissolution, but not for ESWL. Small amounts of calcium are easily seen by CT, and the implications for patient eligibility when CT is used to evaluate gallbladder calculi are obvious. With increased detection of calcification, fewer patients would be eligible for OBA, ESWL and MTBE therapy because of the presumed diminished effectiveness of gallstone dissolution when calcium is present. Thus, CT could have a role as a discriminator when bile acids are to be used as primary therapy. In such cases, stones which measure more than 1OOIfI50HU would be likely to respond poorly and could be spared the 12-24 months of therapy. Although calcification implies impurity of cholesterol gallstones and
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therefore decreased potential efficacy with OBA dissolution therapy, the effect of subtle calcification on the outcome of ESWL is more doubtful. Schachler et al (1988) demonstrated that neither stone radiolucency nor CT density predict the degree of fragmentation with ESWL in vitro. Regardless, results of lithotripsy in patients with stones containing a calcified rim on plain films have been less favourable than in patients with truly radiolucent stones. This is likely because the non-cholesterol debris which remains following fragmentation of partially calcified stones is insoluble in bile acids and disappearance from the gallbladder is entirely dependent upon passage through the cystic duct. For lithotripsy, as long as stones are primarily radiolucent, stone mass is a greater predictor of fragmentation success than composition; simply put, in such cases CT may be too sensitive to calcification to be clinically relevant. In addition, given current examination costs, the widespread use of CT scanning (which is two to five times as expensive as sonography in most areas of the world) would make the preprocedure work-up of patients with gallstones quite expensive. For patients receiving MTBE, CT is considered essential to plan a safe access route, so the question of stone composition plays a secondary role and CT is more or less routinely performed. Fragment imaging Fragment imaging during and after gallbladder lithotripsy is mainly performed sonographically, but raises new issues. During ESWL, a swirling cloud of echogenic foci is often seen within the gallbladder and has been
Figure 10. Cavitation bubbles versus swirling gallstone debris. In vitro image obtained immediately after ten shocks to model gallbladder containing degassed water (Dornier MPL 9000 Lithotripter, in vitro study). Echogenic foci representing cavitation bubbles are seen in shock head (solid arrowhead). Experimental tank filled with degassed water (open arrowhead) and condom filled with degassed water (arrow). The appearance resembles fine swirling gallstone debris.
DIAGNOSIS
OF GALLBLADDER
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673
(4
Figure 11. Clumping of fragments. (a) Sonogram of the gallbladder stone fi .agments in the gallbladder neck producing a broad acoustic of the f ratient through 360”, the fragments have been dispersed and smaller fragments. Thus, retreatment by ESWL would have been
reveals three or four large shadow. (b) After rotation now appear as many more unnecessary.
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termed a ‘snow storm’ or ‘cloud of dust’. This may reflect cavitation bubbles, swirling gallstone debris, or both, and differentiation may be difficult (Figure 10). However, in the prone patient, cavitation bubbles tend to rise and clear more rapidly than gallstone debris, which settles along the dependent gallbladder wall (Brink et al, 1990). Unfortunately, the presence of cavitation bubbles may make it difficult to determine the absolute level of clinical success during the treatment session, and it is often necessary periodically to interrupt treatment to permit distinction between cavitation bubbles and gallstone debris. As a greater volume of gallstone debris is produced within the gallbladder, the focal area of the shockwaves must be moved to encompass a broader zone within the gallbladder lumen than at the beginning of therapy. This is continued until the maximum number of permissible shocks has been given, or until no further fragments are identified. Because it is difficult to determine the level of clinical success at the end of the treatment session, post-treatment sonograms are sometimes disappointing in revealing sizeable residual fragments.
(4 Figure 12. Effect of agitation of stone fragments (a-d). A series of sagittal gallbladder sonograms obtained immediately following patient agitation discloses multiple easily identifiable stone fragments so long as the fragments are suspended in bile. Once the fragments have layered along the back wall of the gallbladder (d), discrete identification of the stone fragments is no longer possible.
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Figure 13. Sonographic estimation of gallstone burden. (a) Supine sonogram reveals numerous gallstones layered along the dependent gallbladder wall. (b) Upright sonogram reveals multiple gallstones now pooled in the gallbladder fundus. (c) Depth and breadth of stone fragments in aggregate are measured as shown. Volume of aggregated stone fragments may be calculated by applying known geometric formulae for the volume of a semisphere.
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On follow-up sonograms, individual small fragments may settle, clump and adhere in thick viscid bile producing a large aggregated echogenic focus and acoustic shadow. This may suggest the need for retreatment of what appears to be a large shadowing fragment. In fact, turning the patient through 360”, or placing the patient erect, may disperse the fragments and reveal the actual degree of fragmentation (Figures 11 and 12). Fragment clumping is most often seen in the first 7 days after ESWL, possibly because of limited gallbladder contractility and poor emptying in the early posttreatment period. Varying degrees of gallbladder wall thickening and pericholecystic fluid are also commonly seen in the early post-treatment period and usually resolve without clinical sequelae. To date, the maximum stone or fragment diameter has served as the sole measure of success. However, the maximum stone or fragment diameter is often difficult to measure due to clumping of smaller fragments mimicking larger fragments and layering of smaller fragments obscuring larger fragments. Although ultrasonography may accurately measure intact gallstone size, accurate measurement of fragment size following ESWL has been shown to be as low as 50% (Mathieson et al, 1989). In addition, the maximum stone or fragment diameter is a poor reflector of the overall stone volume (burden) in patients with stones or fragments too numerous to count (generally more than six stones or fragments). In such instances, one may attempt to measure the aggregate volume of the gallstones as pooled in the gallbladder fundus on an upright sonogram (Figure 13). Researchers are currently investigating other means of quantitating gallstone or fragment burden.
REFERENCES Allen MH, Borody TH & Bugliosi TF (1985) Rapid dissolution of gallstones by methyl-tertbutyl ether: preliminary observations: New England Journal of Medicine 312: 217-220. Barakos JA, Ralls PW & Lapin SA (1987) Cholelithiasis: evaluation with CT. Radiology -. 162: 415-418. Baron RL, Rohrmann CA, Lee SP et al (1988) CT evaluation of gallstones in vitro: correlation with chemical analysis. American Journal of Roentgenology 151: 1123-1128. Baron RL, Kuyper SJ, Lee SP et al (1989) In vitro dissolution of gallstones with MTBE: correlation with characteristics at CT and MR imaging. Radiology 173: 117-121. Berk RN, Ferrucci JT, Fordtran JS et al (1981) Radiological diagnosis of gallbladder disease: an imaging symposium. Radiology 141: 49-52. Berk RN, Leopold G & Ferrucci JT (1983) Radiology of the Gallbladder and Bile Ducts. Diagnosis and intervention. Philadelphia: Saunders. Brake1 K, Lameris JS, Nijs HGT et al (1990) Predicting gallstone composition with CT: in vivo and in vitro analysis. Radiology 174: 337-341. Brink JA & Ferrucci JT (1991) Use of CT for predicting gallstone composition: a dissenting view. Radiology 178: 63M34. Brink JA, Simeone JF, Mueller PR et al (1988) Physical characteristics of gallstones removed at cholecystectomy: implications for extracorporeal shock wave lithotripsy. American Journal
of Roentgenology
151: 927-931.
Brink JA, Mueller PR, Simeone JF et al (1989) Routine preoperative sonography fails to quantify gallstone size and number. American Journal of Roentgenology 153: 503-506.
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Brink JA, Simeone JF, Saini S et al (1990) Simulation of gallstones fragments by cavitation bubbles during extracorporeal shock wave lithotripsy: physical basis and in vivo demonstration. Radiology 174: 787-791. Ferrucci JT, Delius M & Burhenne HJ (eds) (1989) Biliary Lithotripsy. Chicago: Yearbook Medical. Gelfand DW, Wolfman NT, Ott DJ et al (1988) Oral cholecystography vs. gallbladder sonography: a prospective blinded reappraisal. American Journal of Roentgenology 151: 69-72. Mathieson JR, So CB, Malone DE et al (1989) Accuracy of sonography for determining the number and size of gallbladder stones before and after lithotripsy. American Journal of Roentgenology
153: 977-980.
Sackmann M, Delius M, Sauerbruch T et al (1988) Shock wave lithotripsy of gallbladder stones. The first 175 patients. New England Journal of Medicine 318: 393-397. Schachler R, Sauerbruch T, Wosiewitz U et al (1988) Fragmentation of gallstones using extracorporeal shock waves: an in vitro study. Hepatology 8: 925-929. Senior JR, Johnson MF, DeTurck DM et al (1990) In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids. Gastroenterology 99: 243-251. Simeone JF, Mueller PR & Ferrucci JT (1989) Nonsurgical therapy of gallstones: implications for imaging. American Journal of Roentgenology 152: 11-17. Trotman BW, Petrella EJ, Soloway RD et al (1975) Evaluation of radiographic lucency oropaqueness of gallstones as a means of identifying cholesterol or pigment stones. Gastroenterology 68: 156>1566. Wolpers C (1982) Gallbladder Stones. Their morphogenesis and selection for litholysis (translated by J. Wolpers, MD). Basel: Karger.
IMAGING
CRITERIA
FOR‘NON-SURGICAL
THERAPIES
Eligibility for and triage among the non-surgical therapies relies heavily on imaging criteria. All candidates for non-surgical therapy are initially evaluated by plain abdominal radiography and sonography. The plain film serves to screen for radiographically visible calcification, while the sonogram serves to detect the stones and measure their size and number. Oral cholecystography (OCG) contributes further quantitative assessment of gallbladder contents as well as assessing gallbladder function. Thus, visualization of the gallbladder at OCG indicates patency of the cystic duct permitting inflow of bile acid-enriched bile and outflow of fragments and debris into the common bile duct. Baillit?re’s
Clinical
Gasrroenterology-
Vol. 6, No. 4, November 1992 ISBN 0-702&1625-X
659
Copyright 0 1992, by Baillikre Tindall All rights of reproduction in any form reserved
660
J. T. FERRUCCI
Figure 1. Gallstone lithotripsy. (a) Sonogram and (b) OCG disclose a 2 -cm !iolitary radiolucent gallstone within a functioning gallbladder. Patient was treated on t he I Iornier MPL !I000 lithotript er. (c) Sonogram 6 weeks after therapy reveals innumerable tiny fragmt :nts layered along the: posterior gallbladder wall.
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Oral bile acid therapy For treatment with OBA, gallstones must be limited in size to a maximal diameter of 20 mm, although optimal results are obtained with stones less than 1 .O cm. However, at present, there is no practical limit on the number of stones. The size limitation relates to the rate of stone dissolution; the instantaneous rate of cholesterol mass removed from the stone is proportional to the stone surface area. As the diameter of gallstones decrease, the rate of percentage reduction of cholesterol mass increases (Senior et al, 1990). In addition, smaller stones are more likely to be pure cholesterol than are larger stones, which are more likely to have a calcium or pigment cover (Wolpers, 1982). Stones which are densely calcified or show a calcific rim on plain films are excluded. However, a small central nidus of calcification less than 3 mm in size is considered suitable for OBA, realizing that a small, insoluble nidus will be present after therapy. The radiographic filming technique may be optimized by performing coned views of the right upper quadrant in the prone position, and using low kVp and high mAs to maximize detection of calcium. OCG confirms normal gallbladder function, indicating a patent cystic duct. Radiolucent stones which float in the bile on erect views indicate a predominantly cholesterol composition. Although this is a reliable diagnostic criterion (100% sensitivity), it is limited in specificity (37%) (Trotman et al, 1975). Not all cholesterol gallstones float because most contain varying admixtures of pigment and radiographically undetectable calcium. Such gallstones may be treated with OBA. However, one should expect some insoluble residue in the gallbladder following therapy. ESWL The major differences between patient eligibility for OBA therapy and ESWL are the size and number of gallstones (Sackmann et al, 1988). Although any number of stones measuring less than 2 cm in diameter may be treated with oral chemolitholysis, no more than three stones may be present and no stone may exceed 3 cm in diameter according to the widely accepted criteria developed by the Munich group (Sackmann et al, 1988) (Figure 1). This is due to the difficulty of sonographically targeting multiple stones, as fragments and debris obscure remaining intact stones or fragments. Larger fragment sizes and prolonged fragment clearance occur in patients with two or three stones; best results are achieved in patients with solitary gallstones (Sackmann et al, 1988).
MTBE Eligibility criteria for gallstone dissolution by MTBE are even more liberal than those with OBA therapy or ESWL (Allen et al, 1985). Any number or size of stones may be treated although stones must be non-calcified or only
(4
(b)
(cl
2. MTBE therapy. (a) Sonogram reveals multiple tiny gallstones. (b) Direct catheter cholecystography before and (c) after 8 h of MTBE therapy discloses complete dissolution of innumerable tiny gallstones. Figure
minimally calcified (Figure 2). Computed tomography (CT) is also used to confirm the absence of significant calcification and determine a safe access route for percutaneous catheter placement. Baron et al (1989) have shown that stones with rimmed and laminated calcification may dissolve with MTBE although insoluble debris may remain. Gallbladder function at OCG is not mandatory, as there is no reliance on bile acids and no requirement for a patent cystic duct for fragment passage. TECHNICAL CONSIDERATIONS AND FRAGMENT IMAGING
IN STONE
Because of the greater precision required in the imaging assessment of gallstones, increased attention must be paid to the technical factors in the performance and interpretation of these imaging studies. Ultrasonography By the early 1980s ultrasonography had virtually replaced OCG in the assessment of cholelithiasis due to its relative ease of performance, lack of ingestion of contrast material, lack of exposure to ionizing radiation, and its 20% greater sensitivity for detection of small gallstones. The diagnostic dilemma related to a poorly visualized or non-visualized gallbladder at OCG was circumvented, and the well-known lO-30% incidence of gastrointestinal side-effects following ingestion of oral cholecystographic contrast material was eliminated (Berk et al, 1981, 1983). In addition, the ability to survey other abdominal structures and to perform the study on an emergent or unscheduled basis also established sonography as the procedure of choice in the evaluation of the acute gallbladder. Before ultrasonographic examination, the patient should fast for at least 6 h to allow the gallbladder to become distended with bile, which enhances the acoustic visibility of calculi. However, in instances where an emergency
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examination of the right upper quadrant is required, real-time sonography can be utilized for evaluating the gallbladder without fasting. Real-time sonographic examination has virtually replaced static ultrasonographic examination methods. In addition, real-time sonography may demonstrate the mobility of calculi and help differentiate them from polyps or folds. The examination itself consists of recording a sufficient number of images to document that the entire gallbladder lumen has been examined. Because the diagnosis of calculi, or lack of calculi, is usually made during the real-time sonographic examination, only a few hard copy images are required for documentation. One must rely upon the person performing the examination, because innumerable images could be produced without showing a stone hiding in the neck. Initial examination of the gallbladder should include long axis views, which are preferred over short axis views because of the greater volume of the gallbladder displayed. If the gallbladder lies immediately under the right costal margin, the patient can be rolled to a left decubitus position, which allows the gallbladder to fall medial to the right costal margin. This position has the advantages of interposing the liver in front of the gallbladder to serve as an acoustic window and also of allowing the air-filled gastric antrum and duodenum to fall away. More importantly, examination in the left decubitus position allows small stones that previously were undetected in the neck of the gallbladder to roll down to the dependent fundus and become visible. Air pockets can often be distinguished from stones by the distinctive shadow formed by each. Bowel gas creates an irregular, poorly marginated, ‘dirty’ shadow caused by reverberation artefacts. Stones create a ‘clean’ shadow because of the fact that they reflect almost all sound. Cholelithiasis presents ultrasonographically in one of three general patterns: 1. 2. 3.
Shadowing echogenic foci within the gallbladder that may or may not move. An echogenic focus within the gallbladder fossa with posterior acoustic shadowing (no visualization of the gallbladder itself). Non-shadowing echogenic foci within the gallbladder, usually less than 5 mm in size, which may or may not move.
It has been shown conclusively in vitro that all gallstones will shadow when imaged under ideal conditions and with the correct transducer. This shadowing occurs regardless of surface characteristics, calcium content, size or composition of the stone. Therefore, optimal conditions should be sought in vivo to induce gallstone shadowing. The importance of demonstrating shadowing lies in the increased accuracy of diagnosis of gallstones when a shadowing focal opacity is demonstrated (Figure 3). When non-shadowing focal opacities are shown, the accuracy of the diagnosis of cholelithiasis declines to 80%. With a shadowing focal opacity, the accuracy is greater than 99%. Modern real-time ultrasound machines are generally furnished with transducers of 3.0, 5.0 and 7SMHz frequency, which can be used interchangeably to elicit the characteristic shadow. Generally, stones larger than 1 cm in diameter display an acoustic shadow with no difficulty at all,
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Figul re3.1 echo genie an ec :hoger seen deep seen after
Typical ultrasonographic patterns of gallstones. (a) Single large stone show focus and subjacent acoustic shadow. (b) Multiple minute stones or gravel lit layer along the dependent gallbladder wall. A broad summated acoustb to the stone layer. This same appearance could be caused by tiny stone shockwave lithotripsy.
ting a la urge produc :ing c shado w is fragmc :nts
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whereas stones smaller than 5 mm can often be made to shadow only with 5or 7.5 MHz transducers. Even in the absence of shadowing, demonstration of mobility of the echogenic focus within the gallbladder lumen will be sufficiently diagnostic to permit an accurate diagnosis of cholelithiasis. In the absence of shadowing and no demonstration of mobility, the differential diagnosis of a small echogenic focus expands to include benign polyps, cholesterolosis, adenomyosis and other gallbladder wall tumours. It is therefore always best to try to optimize shadow formation. Finally, erect sitting or standing
Figure 4. Sonographic misrepresentation of stone number. (a) Gallbladder sonogram discloses a broad curvilinear acoustic reflection with an acoustic shadow representing what appears to be a single large gallbladder calculus. (b) After vigorous alterations in patient position, the ‘stone’ separates and two smaller calculi are seen.
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sonographic observation may be the only way to visualize small stones in the gallbladder neck as they fall by gravity to the fundus. A standing or sitting scan is mandatory if supine and right anterior oblique views show no stones. For non-surgical management, additional considerations apply in order to size and count gallstones optimally (Brink et al, 1990). Overlap and
(a)
Figure 5. Incorrect sonographic measurement of size of large gallstone. (a) Sonogram reveals a solitary large ellipsoidal gallstone. (b) Attempts to measure the gallstone axially and laterally are limited by poor definition of the back wall of the gallbladder for axial measurement, and poor definition of the poles of the stone for lateral measurement. Sonographic measurement was 2.6~ 1.8cm. However, the gallstone measured over 3cm in greatest dimension at cholecystectomy.
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clustering of multiple stones may occur in the gallbladder fundus or neck such that individual stone size may be overestimated and stone number may be underestimated. To overcome this, the patient may be placed in prone or upright positions to utilize gravity to separate stones for individual counting and measuring (Figure 4). Accurate sonographic measurement of gallstone size is dependent upon a number of technical factors. Measurements should be performed in the axial direction as resolution in the axial plane is superior to lateral resolution. In addition, side lobe artefacts in the lateral plane may make assessment of the lateral diameter difficult. However, accurate axial measurement requires definition of the deep or non-presenting surface of the stone (Figure 5). If the stone is definitely positioned along the back wall of gallbladder, the gallbladder wall may be taken as the deep surface of the stone (Simeone et al, 1989). However, when multiple stones are clumped together, or when the stone is so large as to make definition of the back wall difficult, then the axial measurement becomes less reliable. Measurement of larger stones (> 2 cm in diameter) is also confounded by acoustic reflection and absorption of the ultrasound beam at the polar surfaces of the stone, further hampering measurement in the lateral plane. Stones under 15 mm in size are generally spherical in shape whereas stones greater than 15 mm in size tend to assume an ellipsoidal shape (Wolpers, 1982). Therefore, a single axial measurement for stones less than 15 mm in diameter generally suffices (Figure 6). However, stones greater than 15 mm in size generally require measurement of major and minor axes, which may be better performed with OCG.
Figure 6. Sonographic measurement of smaller gallstones (< 15mm in diameter) is best performed axially. Axial measurement is extrapolated to the back wall of the gallbladder (arrowheads). Measurement reflects diameter of generally spherically shaped stones.
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OCG Optimal OCG techniques should maximize the potential for precise stone measurement. The effects of radiographic magnification should be minimized; overhead radiographs should be obtained with the patient in the prone-oblique position and magnification factors for each individual radiographic unit should be calculated. Cholecystography may permit calcifications in the right upper quadrant to be more precisely defined as being in or not in the gallbladder, and subtle degrees of calcium within the stones may be more clearly visualized. However, care must be taken to obtain a recent plain radiograph as minor degrees of calcification may be obscured by oral cholecystographic contrast within the gallbladder (Figure 7). In addition, important detail within the gallstones may be better seen at OCG, such as gas-containing fissures within stones indicating predominantly cholesterol composition.
(a)
(b)
Figure 7. Importance of plain radiography prior to OCG. (a) Scout film clearly discloses thick (4mm) rim of peripheral calcification excluding patient for ESWL. (b) At OCG, thick peripherally calcified rim is obscured.
CHOLECYSTOGRAPHICSONOGRAPHIC
CORRELATIONS
Although sonography has been accepted as being more sensitive than OCG in the detection of small gallstones, a recent prospective study comparing OCG and sonography showed no significant difference between the two imaging techniques in detecting a broader spectrum of gallbladder disease (stones, adenomyosis, cholesterolosis and cholecystitis) (Gelfand et al, 1988). Sonography detected calculi more accurately than the OCG (93%
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versus 65% sensitive, respectively). However, in the detection of noncalculous gallbladder diseases, OCG was as sensitive as sonography. Despite its greater diagnostic sensitivity for gallstones, sonography may be less accurate than OCG in counting stones, especially when more than five or six stones are present within the gallbladder (Figure 8). This is because sonography is a tomographic technique and single sections of the gallbladder, even if repeated multiple times, may give misleading results because of overlap of multiple stones. OCG gives a more accurate depiction of stone number when more than six stones are present because it is a projection imaging technique and all the stones may be identified on a single radiographic image. Moreover, as discussed above, measurements
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(b) Figure 8. Superiority of OCG for counting stones when more than five or six stones arc present. (a) Sonogram showing three or four stones. Cursors indicate a large stone in gallbladder neck. (b) OCG showing at least six stones. OCG is often more accurate than sonography in stone counting because it is a projection technique rather than a sectional or tomographic technique.
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of gallstone size on sonography are accurate only for stones less than 15-20 mm in size. Thus, when sonographic techniques are not specifically directed to the questions of stone size and number, the results are poor. A retrospective study of routine, untailored sonographic studies in 110 patients from our institution undergoing cholecystectomy found only 23 of 111 (21%) to be accurate in estimating gallstone size and number (Brink et al, 1989). Further, stone size and number were equally as often overestimated as underestimated, emphasizing the unreliability of non-tailored sonography. Thus direct correlation and comparison between sonography and OCG will be necessary for precise assessment of stone size and number in almost every patient. In general, the imaging studies showing the greatest number and largest stones should be considered the correct result. ROLE OF COMPUTED
TOMOGRAPHY
CT is not a primary radiological method for evaluating patients with gallbladder disease because of the excellent results with cheaper and more available methods such as sonography and cholecystography. In addition, CT images disclose gallstones in only 79% of patients with sonographic or surgical evidence of cholelithiasis (Barakos et al, 1987). However, stones with minimal quantities of calcium carbonate and calcium phosphate are easy to visualize by CT as high attenuation densities surrounded by low density bile. Various calcification patterns have been recognized, including stones which are densely calcified throughout as well as stones with various layers of calcifications (core, laminated, rimmed) (Baron et al, 1988) (Figure 9). Occasionally, cholesterol stones may be seen as low attenuation filling defects within the surrounding bile (Figure 9b,c). More recently, investigators have tried to utilize CT scanning in order to select patients for non-surgical gallstone therapy (Baron et al, 1988; Brackel et al, 1990). However, precise apriori prediction of exact stone composition has been an elusive goal. As a result, use of CT Hounsfield numbers to discriminate between potential responders (lipid, low Hounsfield) and nonresponders (Ca*+ and pigment) has advocates as well as detractors. Our view has been somewhat cautious (Brink et al, 1991). We believe it is appropriate as part of the workshop for primary and bile acid therapy and MTBE dissolution, but not for ESWL. Small amounts of calcium are easily seen by CT, and the implications for patient eligibility when CT is used to evaluate gallbladder calculi are obvious. With increased detection of calcification, fewer patients would be eligible for OBA, ESWL and MTBE therapy because of the presumed diminished effectiveness of gallstone dissolution when calcium is present. Thus, CT could have a role as a discriminator when bile acids are to be used as primary therapy. In such cases, stones which measure more than 1OOIfI50HU would be likely to respond poorly and could be spared the 12-24 months of therapy. Although calcification implies impurity of cholesterol gallstones and
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therefore decreased potential efficacy with OBA dissolution therapy, the effect of subtle calcification on the outcome of ESWL is more doubtful. Schachler et al (1988) demonstrated that neither stone radiolucency nor CT density predict the degree of fragmentation with ESWL in vitro. Regardless, results of lithotripsy in patients with stones containing a calcified rim on plain films have been less favourable than in patients with truly radiolucent stones. This is likely because the non-cholesterol debris which remains following fragmentation of partially calcified stones is insoluble in bile acids and disappearance from the gallbladder is entirely dependent upon passage through the cystic duct. For lithotripsy, as long as stones are primarily radiolucent, stone mass is a greater predictor of fragmentation success than composition; simply put, in such cases CT may be too sensitive to calcification to be clinically relevant. In addition, given current examination costs, the widespread use of CT scanning (which is two to five times as expensive as sonography in most areas of the world) would make the preprocedure work-up of patients with gallstones quite expensive. For patients receiving MTBE, CT is considered essential to plan a safe access route, so the question of stone composition plays a secondary role and CT is more or less routinely performed. Fragment imaging Fragment imaging during and after gallbladder lithotripsy is mainly performed sonographically, but raises new issues. During ESWL, a swirling cloud of echogenic foci is often seen within the gallbladder and has been
Figure 10. Cavitation bubbles versus swirling gallstone debris. In vitro image obtained immediately after ten shocks to model gallbladder containing degassed water (Dornier MPL 9000 Lithotripter, in vitro study). Echogenic foci representing cavitation bubbles are seen in shock head (solid arrowhead). Experimental tank filled with degassed water (open arrowhead) and condom filled with degassed water (arrow). The appearance resembles fine swirling gallstone debris.
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Figure 11. Clumping of fragments. (a) Sonogram of the gallbladder stone fi .agments in the gallbladder neck producing a broad acoustic of the f ratient through 360”, the fragments have been dispersed and smaller fragments. Thus, retreatment by ESWL would have been
reveals three or four large shadow. (b) After rotation now appear as many more unnecessary.
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termed a ‘snow storm’ or ‘cloud of dust’. This may reflect cavitation bubbles, swirling gallstone debris, or both, and differentiation may be difficult (Figure 10). However, in the prone patient, cavitation bubbles tend to rise and clear more rapidly than gallstone debris, which settles along the dependent gallbladder wall (Brink et al, 1990). Unfortunately, the presence of cavitation bubbles may make it difficult to determine the absolute level of clinical success during the treatment session, and it is often necessary periodically to interrupt treatment to permit distinction between cavitation bubbles and gallstone debris. As a greater volume of gallstone debris is produced within the gallbladder, the focal area of the shockwaves must be moved to encompass a broader zone within the gallbladder lumen than at the beginning of therapy. This is continued until the maximum number of permissible shocks has been given, or until no further fragments are identified. Because it is difficult to determine the level of clinical success at the end of the treatment session, post-treatment sonograms are sometimes disappointing in revealing sizeable residual fragments.
(4 Figure 12. Effect of agitation of stone fragments (a-d). A series of sagittal gallbladder sonograms obtained immediately following patient agitation discloses multiple easily identifiable stone fragments so long as the fragments are suspended in bile. Once the fragments have layered along the back wall of the gallbladder (d), discrete identification of the stone fragments is no longer possible.
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Figure 13. Sonographic estimation of gallstone burden. (a) Supine sonogram reveals numerous gallstones layered along the dependent gallbladder wall. (b) Upright sonogram reveals multiple gallstones now pooled in the gallbladder fundus. (c) Depth and breadth of stone fragments in aggregate are measured as shown. Volume of aggregated stone fragments may be calculated by applying known geometric formulae for the volume of a semisphere.
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On follow-up sonograms, individual small fragments may settle, clump and adhere in thick viscid bile producing a large aggregated echogenic focus and acoustic shadow. This may suggest the need for retreatment of what appears to be a large shadowing fragment. In fact, turning the patient through 360”, or placing the patient erect, may disperse the fragments and reveal the actual degree of fragmentation (Figures 11 and 12). Fragment clumping is most often seen in the first 7 days after ESWL, possibly because of limited gallbladder contractility and poor emptying in the early posttreatment period. Varying degrees of gallbladder wall thickening and pericholecystic fluid are also commonly seen in the early post-treatment period and usually resolve without clinical sequelae. To date, the maximum stone or fragment diameter has served as the sole measure of success. However, the maximum stone or fragment diameter is often difficult to measure due to clumping of smaller fragments mimicking larger fragments and layering of smaller fragments obscuring larger fragments. Although ultrasonography may accurately measure intact gallstone size, accurate measurement of fragment size following ESWL has been shown to be as low as 50% (Mathieson et al, 1989). In addition, the maximum stone or fragment diameter is a poor reflector of the overall stone volume (burden) in patients with stones or fragments too numerous to count (generally more than six stones or fragments). In such instances, one may attempt to measure the aggregate volume of the gallstones as pooled in the gallbladder fundus on an upright sonogram (Figure 13). Researchers are currently investigating other means of quantitating gallstone or fragment burden.
REFERENCES Allen MH, Borody TH & Bugliosi TF (1985) Rapid dissolution of gallstones by methyl-tertbutyl ether: preliminary observations: New England Journal of Medicine 312: 217-220. Barakos JA, Ralls PW & Lapin SA (1987) Cholelithiasis: evaluation with CT. Radiology -. 162: 415-418. Baron RL, Rohrmann CA, Lee SP et al (1988) CT evaluation of gallstones in vitro: correlation with chemical analysis. American Journal of Roentgenology 151: 1123-1128. Baron RL, Kuyper SJ, Lee SP et al (1989) In vitro dissolution of gallstones with MTBE: correlation with characteristics at CT and MR imaging. Radiology 173: 117-121. Berk RN, Ferrucci JT, Fordtran JS et al (1981) Radiological diagnosis of gallbladder disease: an imaging symposium. Radiology 141: 49-52. Berk RN, Leopold G & Ferrucci JT (1983) Radiology of the Gallbladder and Bile Ducts. Diagnosis and intervention. Philadelphia: Saunders. Brake1 K, Lameris JS, Nijs HGT et al (1990) Predicting gallstone composition with CT: in vivo and in vitro analysis. Radiology 174: 337-341. Brink JA & Ferrucci JT (1991) Use of CT for predicting gallstone composition: a dissenting view. Radiology 178: 63M34. Brink JA, Simeone JF, Mueller PR et al (1988) Physical characteristics of gallstones removed at cholecystectomy: implications for extracorporeal shock wave lithotripsy. American Journal
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151: 927-931.
Brink JA, Mueller PR, Simeone JF et al (1989) Routine preoperative sonography fails to quantify gallstone size and number. American Journal of Roentgenology 153: 503-506.
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Brink JA, Simeone JF, Saini S et al (1990) Simulation of gallstones fragments by cavitation bubbles during extracorporeal shock wave lithotripsy: physical basis and in vivo demonstration. Radiology 174: 787-791. Ferrucci JT, Delius M & Burhenne HJ (eds) (1989) Biliary Lithotripsy. Chicago: Yearbook Medical. Gelfand DW, Wolfman NT, Ott DJ et al (1988) Oral cholecystography vs. gallbladder sonography: a prospective blinded reappraisal. American Journal of Roentgenology 151: 69-72. Mathieson JR, So CB, Malone DE et al (1989) Accuracy of sonography for determining the number and size of gallbladder stones before and after lithotripsy. American Journal of Roentgenology
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Sackmann M, Delius M, Sauerbruch T et al (1988) Shock wave lithotripsy of gallbladder stones. The first 175 patients. New England Journal of Medicine 318: 393-397. Schachler R, Sauerbruch T, Wosiewitz U et al (1988) Fragmentation of gallstones using extracorporeal shock waves: an in vitro study. Hepatology 8: 925-929. Senior JR, Johnson MF, DeTurck DM et al (1990) In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids. Gastroenterology 99: 243-251. Simeone JF, Mueller PR & Ferrucci JT (1989) Nonsurgical therapy of gallstones: implications for imaging. American Journal of Roentgenology 152: 11-17. Trotman BW, Petrella EJ, Soloway RD et al (1975) Evaluation of radiographic lucency oropaqueness of gallstones as a means of identifying cholesterol or pigment stones. Gastroenterology 68: 156>1566. Wolpers C (1982) Gallbladder Stones. Their morphogenesis and selection for litholysis (translated by J. Wolpers, MD). Basel: Karger.
