JOURNAL
OF SURGICAL
24, 62-64 (1978)
RESEARCH
Dissolution
of Human
Gallstone
with Clofibrate
E. GARCIA-R• MERO, M.D., M. LOPEZ-CANTARERO, M.D., AND I. M. ARCELUS., M.D. Hospital
Clinic0 San Cecilia,
University
of Granada,
Granada,
Spain
Submitted for publication October 28, 1976
INTRODUCTION
The frequency of retained common duct stones after cholecystectomy for cholelithiasis varies between 2 and 4% [IO, 241, reaching as high as 6.6% in cases of choledocholithiasis [25]. The stones are usually demonstrated by postoperative T-tube cholangiography [20]. Considering the grave complications that may arise when stones are retained after cholecystectomy [ 151,it is then necessary to put into practice one or more of the following therapeutic possibilities: (1) Await the spontaneous passing of the stones to the duodenum [l]; (2) reoperate [II]; (3) extract the gallstones by mechanical means [13, 141; (4) dissolve the stones by chemical means [S, 221. Dissolution of the stones by chemical means is the most innocuous method, being also one which, if it fails, permits us to try to remove the gallstone by one of the other three techniques. Among the substances that seem to possess litholitic properties are: ether and chloroform [2], alcohol [ 193, biliary salts [23], heparin [7], phenobarbital [5], and isotonic saline solution [4]. Based on the above facts it might be concluded that residual choledocholithiasis is no longer a problem. In reality, however, the use of the above-named litholitic substances has been demonstrated to be insufficient in a large number of cases [3, 241. Worse still, many undesirable side effects have been described in association with the use of litholitic substances [3, 12, 181. These motives have prompted us to study the litholitic action of various other substances on biliary cholesterol calculi, and, in our judgement, we obtained satisfactory results using clofibrate.’ 1 Ethyl p-chlorophenoxyisobutyrate 0022-4804/78/0241-0062$01.00/O Copyright 0 1978 by Academic Press, Inc. AU rights of reproduction in my form reserved.
(Atromid). 62
Clofibrate has been widely used in human clinical trials for the treatment of atherosclerosis, with individuals demonstrating perfect tolerance even at high dosage levels. MATERIALS
AND METHODS
Twenty-two gallstones were obtained from the gallbladder of a patient who had undergone cholecystectomy. The analytic study, by means of X-ray diffraction, of two stones demonstrated a composition of 9095% cholesterol. Before inmersion into solutions of 250, 500, 1000, and 1500 mg of clofibrate, each in 5 ml of ethyl alcohol, the stones were rinsed various times with distilled water and dried using dry heat at 80°C for a period of 1 hr. Every 5 days thereafter, the stones were rinsed and dried after removal from the solvent, in order to determine their weights and analyze the cholesterol content in the solution. The stones were then again placed in solutions of 250, 500, 1000, and 1500 mg of clofibrate in 5 ml of ethyl alcohol. RESULTS
The 22 stones were completely dissolved within 25 days of being placed in contact with the clofibrate solution. The higher the concentration of clofibrate, the more rapid the dissolution of the calculi (see Fig. 1). We were able to observe that, in 250 mg of clofibrate, the stones decreased in weight to 57.9% of the average initial weight after 20 days (P < 0.0001). With 500 mg, the average weight reduction, 55.3% after 15 days, was even more signiftcant (P < O.OtKlOl). When 1000mg of clofibrate were used, after 15 days the weight reduction achieved was 46.3% of the initial average weight of the gallstones.
GARCIA-ROMERO
5
15
ET AL.: DISSOLUTION
15
25
25 days
FIG. 1. The effect of varying concentrations of clofibrate on human gallstone dissolution. The concentration in milligrams of solution is indicated. The average weight on each of the days is expressed as a percentage of the original weight.
The most demonstrative gallstone weight reduction was obtained with the use of 1500 mg of clofibrate. Only 5 days after being placed in the clofibrate solution, the average weight of the gallstones decreased to 58.6% of the original weight (P < 0.005) and to 29.5% after 10 days (P < O.OOOOOl), being completely dissolved before 15 days. DISCUSSION
OF GALLSTONE
WITH CLOFIBRATE
63
the above-named mechanisms. Biliary salts are said to diminish the saturation of the cholesterol in the bile [6, 161. Heparin, as well as other solutions, produce softening of the calculi [17]. Possibly, clofibrate has a triple mechanism of action, since on one hand it increases the secretion of bile [9] thereby favoring the effect of desaturation of cholesterol in the bile. On the other hand, we have proven that a few days after the inmersion of cholesterol calculi into a clofibrate solution, the stones clearly undergo softening and are easily fragmented when gentle digital pressure is applied. Above all, we think that the rapid dissolution of the calculi is due to the effect of degradation of cholesterol in bile acids, this being a property which clofibrate has been demonstrated to possess 121, 261. It gives us profound satisfaction to communicate the results obtained using clofibrate as a new solvent of biliary cholesterol calculi and with the conviction that in addition to possessing a greater litholitic capacity than the other substances described up to now, clofibrate does not produce undesirable side effects when administered by the digestive route.
SUMMARY Of the various substances that have been used to dissolve retained biliary duct calculi, We have studied the effect of different none has been shown to be completely concentrations of clofibrate upon biliary effective. The best results have been obtained with irrigations of biliary salts 2555 through a T-tube, and using this method, i ,500 Way et al. obtained success in 54.5% of ~185@ -I his cases [24], Toouli et al. reached 75% [22], and Britton et al., in a recent work, were only able to dissolve the residual choledocholithiasis in 57% of their patients (3). The actual approach to the dissolution of biliary cholesterol calculi residues in three fundamental mechanisms: (1) increase in the capacity of bile to dissolve cholesterol; (2) I I I I I dissolution of the cholesterol precipitated from the gallstone; (3) softening and frag5 15 15 25 25 days mentation of the calculi. The substances to which a litholithic FIG. 2. Cholesterol released. The concentration of capacity is attributed only function by one of clofibrate in milligrams of solution is indicated.
64
JOURNAL OF SURGICAL RESEARCH: VOL. 24, NO. 1, JANUARY
cholesterol calculi. We have seen that all the calculi have completely dissolved within the first 25 days after being placed in contact with the clofibrate solution. The rate of dissolution of the calculi was directly proportional to the concentration of clofibrate in the solution used. With 1500 mg of clofibrate in the solution, the calculi were completely dissolved within 15 days. It is our wish to communicate these results obtained with the utilization of clofibrate as a new solvent and to emphasize that clofibrate possesses a greater litholitic capacity than any of the other substances discovered so far. We also wish to stress that clofibrate does not possess undesirable sideeffects. REFERENCES 1. Bartlett, M. K. Retained and recurrent common duct stones. Amer. Surg. 38: 63, 1972. 2. Best, R. R., Rasmussen, J. A., and Wilson, C. E. An evaluation of solutions for fragmentation and dissolution of gallstone and their effect on liver and ductal tissues. Ann. Surg. 138: 570, 1953. 3. Britton, D. C., Gill, B. S., Taylor, R. M. R., and James, 0. The removal of retained gallstones from the common bile duct: Experience with sodium cholate infusion and the Burhenhe catheter. Brit. J. Surg. 62: 520, 1975. 4. Catt, P. B., Hogg, D. F., Clunie, G. J. A., and Hardie, I. R. Retained biliary calculi: Removal by a simple non operative technique. Ann. Surg. 180: 247, 1974. 5. Coyne, M. J., Bonorris, G. G., and Goldstein, L. I. Dissolution of gallstones by chenodeoxycholic acid (CDC) and phenobarbital (PB). Gastroenterology 66: 679, 1974. 6. Danzinger, R. G., Hofmann, A. F., Schoenfield, L. J., and Thistle, J. L. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N. Engl. J. Med. 286: 1, 1972. 7. Garcia, Romero, E., Belda Poujoulet, R., CapiJla, P., Lopez Cantarero, M., and Arcelus lmaz. I. Ma. La heparina en el tratamiento de 10s calculos residuales en la via biliar. Cir. Esp. 28: 517, 1974. 8. Gardner, B. Experiences with the use of intracholedochal heparinized saline for the treatment of retained common duct stones. Ann. Surg. 177: 240, 1973. 9. Grundy, S. M., Ahrens, E. H., Salen, G., Schreib-
1978
man, P., and Nestel, P. Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J. Lipid Res. 13: 531, 1972. 10. Hicken, N. F., and McAllister, A. J. Operative cholangiography as an aid in reducing the incidence of “overlooked” common bile duct stones: A study of 1,293 choledocholithotomies. Surgery 55: 753, 1964. 11. Hughes, E. S. R. Recurrent and residual stones in the common bile-duct. B-it. J. Surg. 43: 198, 1955. 12. Lansford, C., Mehta, S., and Kern, F. The treatment of retained stones in the common bile duct with sodium cholate infusion. Gut 15: 48, 1974. 13. Magarey, C. J. Non-surgical removal of retained biliary calculi. Lancer 1: 1044, 1971. 14. Mazzariello, R. Review of 220 cases of residual biliary tract calculi treated without reoperation: An eight-year study. Surgery 73: 299, 1973. 15. Mercadier, M. “Trait6 de Therapeutique Chirurgitale,” Tome IV. Masson, Paris. 1964. 16. Northfield, T. C., Larusso, N. F., and Thistle, J. L. Effect of chenodeoxycholic acid therapy on biliary lipid secretion in gallstone patients. Gasrroenrerology 64: 780, 1973. 17. Ostrowitz, A., and Gardner, B. Studies of bile as a suspending medium and its relationship to gallstone formation. Surgery 68: 329, 1970. 18. Palmer, A. K., and Heywood, R. Pathological changes in the rhesus fetus associated with the oral administration of chenodeoxycholic acid. Toxicology 2: 239, 1974. 19. Robinson, C. L. N. Solution of residual duct stones. Canad. Med. Assoc. J. 95: 1205, 1966. 20. Smith Ill, R. B., Conklin, E. F., and Porter, M. R. Postoperative T-tube cholangiography. Surg. Gynecol.
O&et.
116: 731, 1963.
21. Sodhi, H. S., Hudchodkar, B. J., and Horlick, L. Hypocholesterolemic agents and mobilization of tissue cholesterol in man. Afherosclerosis 17: 1, 1973.
22. Toouli, J., Jablonski, P., and Watts, J. McK. Dissolution of stones in the common bile duct with bile-salt solutions. Aust. N. 2. J. Surg. 44: 336, 1974. 23. Toot& J., Jablonski, P., and Watts, J. McK. Dissolution of human gallstones: The efficacy of bile salt, bilt salt plus lecithin and heparin solutions. J. Surg. Res. 19: 47, 1975. 24. Way, L. W., Admirand, W., and Dunphy, E. Management of choledocholithiasis. Ann. Surg. 176: 347, 1972.
25. Way, L. W. Retained common duct stones. Surg. Clin. North. Amer. 53: 1139, 1973. 26. White, L. W. Regulation of hepatic cholesterol biosynthesis by clofibrate administration. J. Pharmacol.
Exp. Ther. 178: 361, 1971.
OF SURGICAL
24, 62-64 (1978)
RESEARCH
Dissolution
of Human
Gallstone
with Clofibrate
E. GARCIA-R• MERO, M.D., M. LOPEZ-CANTARERO, M.D., AND I. M. ARCELUS., M.D. Hospital
Clinic0 San Cecilia,
University
of Granada,
Granada,
Spain
Submitted for publication October 28, 1976
INTRODUCTION
The frequency of retained common duct stones after cholecystectomy for cholelithiasis varies between 2 and 4% [IO, 241, reaching as high as 6.6% in cases of choledocholithiasis [25]. The stones are usually demonstrated by postoperative T-tube cholangiography [20]. Considering the grave complications that may arise when stones are retained after cholecystectomy [ 151,it is then necessary to put into practice one or more of the following therapeutic possibilities: (1) Await the spontaneous passing of the stones to the duodenum [l]; (2) reoperate [II]; (3) extract the gallstones by mechanical means [13, 141; (4) dissolve the stones by chemical means [S, 221. Dissolution of the stones by chemical means is the most innocuous method, being also one which, if it fails, permits us to try to remove the gallstone by one of the other three techniques. Among the substances that seem to possess litholitic properties are: ether and chloroform [2], alcohol [ 193, biliary salts [23], heparin [7], phenobarbital [5], and isotonic saline solution [4]. Based on the above facts it might be concluded that residual choledocholithiasis is no longer a problem. In reality, however, the use of the above-named litholitic substances has been demonstrated to be insufficient in a large number of cases [3, 241. Worse still, many undesirable side effects have been described in association with the use of litholitic substances [3, 12, 181. These motives have prompted us to study the litholitic action of various other substances on biliary cholesterol calculi, and, in our judgement, we obtained satisfactory results using clofibrate.’ 1 Ethyl p-chlorophenoxyisobutyrate 0022-4804/78/0241-0062$01.00/O Copyright 0 1978 by Academic Press, Inc. AU rights of reproduction in my form reserved.
(Atromid). 62
Clofibrate has been widely used in human clinical trials for the treatment of atherosclerosis, with individuals demonstrating perfect tolerance even at high dosage levels. MATERIALS
AND METHODS
Twenty-two gallstones were obtained from the gallbladder of a patient who had undergone cholecystectomy. The analytic study, by means of X-ray diffraction, of two stones demonstrated a composition of 9095% cholesterol. Before inmersion into solutions of 250, 500, 1000, and 1500 mg of clofibrate, each in 5 ml of ethyl alcohol, the stones were rinsed various times with distilled water and dried using dry heat at 80°C for a period of 1 hr. Every 5 days thereafter, the stones were rinsed and dried after removal from the solvent, in order to determine their weights and analyze the cholesterol content in the solution. The stones were then again placed in solutions of 250, 500, 1000, and 1500 mg of clofibrate in 5 ml of ethyl alcohol. RESULTS
The 22 stones were completely dissolved within 25 days of being placed in contact with the clofibrate solution. The higher the concentration of clofibrate, the more rapid the dissolution of the calculi (see Fig. 1). We were able to observe that, in 250 mg of clofibrate, the stones decreased in weight to 57.9% of the average initial weight after 20 days (P < 0.0001). With 500 mg, the average weight reduction, 55.3% after 15 days, was even more signiftcant (P < O.OtKlOl). When 1000mg of clofibrate were used, after 15 days the weight reduction achieved was 46.3% of the initial average weight of the gallstones.
GARCIA-ROMERO
5
15
ET AL.: DISSOLUTION
15
25
25 days
FIG. 1. The effect of varying concentrations of clofibrate on human gallstone dissolution. The concentration in milligrams of solution is indicated. The average weight on each of the days is expressed as a percentage of the original weight.
The most demonstrative gallstone weight reduction was obtained with the use of 1500 mg of clofibrate. Only 5 days after being placed in the clofibrate solution, the average weight of the gallstones decreased to 58.6% of the original weight (P < 0.005) and to 29.5% after 10 days (P < O.OOOOOl), being completely dissolved before 15 days. DISCUSSION
OF GALLSTONE
WITH CLOFIBRATE
63
the above-named mechanisms. Biliary salts are said to diminish the saturation of the cholesterol in the bile [6, 161. Heparin, as well as other solutions, produce softening of the calculi [17]. Possibly, clofibrate has a triple mechanism of action, since on one hand it increases the secretion of bile [9] thereby favoring the effect of desaturation of cholesterol in the bile. On the other hand, we have proven that a few days after the inmersion of cholesterol calculi into a clofibrate solution, the stones clearly undergo softening and are easily fragmented when gentle digital pressure is applied. Above all, we think that the rapid dissolution of the calculi is due to the effect of degradation of cholesterol in bile acids, this being a property which clofibrate has been demonstrated to possess 121, 261. It gives us profound satisfaction to communicate the results obtained using clofibrate as a new solvent of biliary cholesterol calculi and with the conviction that in addition to possessing a greater litholitic capacity than the other substances described up to now, clofibrate does not produce undesirable side effects when administered by the digestive route.
SUMMARY Of the various substances that have been used to dissolve retained biliary duct calculi, We have studied the effect of different none has been shown to be completely concentrations of clofibrate upon biliary effective. The best results have been obtained with irrigations of biliary salts 2555 through a T-tube, and using this method, i ,500 Way et al. obtained success in 54.5% of ~185@ -I his cases [24], Toouli et al. reached 75% [22], and Britton et al., in a recent work, were only able to dissolve the residual choledocholithiasis in 57% of their patients (3). The actual approach to the dissolution of biliary cholesterol calculi residues in three fundamental mechanisms: (1) increase in the capacity of bile to dissolve cholesterol; (2) I I I I I dissolution of the cholesterol precipitated from the gallstone; (3) softening and frag5 15 15 25 25 days mentation of the calculi. The substances to which a litholithic FIG. 2. Cholesterol released. The concentration of capacity is attributed only function by one of clofibrate in milligrams of solution is indicated.
64
JOURNAL OF SURGICAL RESEARCH: VOL. 24, NO. 1, JANUARY
cholesterol calculi. We have seen that all the calculi have completely dissolved within the first 25 days after being placed in contact with the clofibrate solution. The rate of dissolution of the calculi was directly proportional to the concentration of clofibrate in the solution used. With 1500 mg of clofibrate in the solution, the calculi were completely dissolved within 15 days. It is our wish to communicate these results obtained with the utilization of clofibrate as a new solvent and to emphasize that clofibrate possesses a greater litholitic capacity than any of the other substances discovered so far. We also wish to stress that clofibrate does not possess undesirable sideeffects. REFERENCES 1. Bartlett, M. K. Retained and recurrent common duct stones. Amer. Surg. 38: 63, 1972. 2. Best, R. R., Rasmussen, J. A., and Wilson, C. E. An evaluation of solutions for fragmentation and dissolution of gallstone and their effect on liver and ductal tissues. Ann. Surg. 138: 570, 1953. 3. Britton, D. C., Gill, B. S., Taylor, R. M. R., and James, 0. The removal of retained gallstones from the common bile duct: Experience with sodium cholate infusion and the Burhenhe catheter. Brit. J. Surg. 62: 520, 1975. 4. Catt, P. B., Hogg, D. F., Clunie, G. J. A., and Hardie, I. R. Retained biliary calculi: Removal by a simple non operative technique. Ann. Surg. 180: 247, 1974. 5. Coyne, M. J., Bonorris, G. G., and Goldstein, L. I. Dissolution of gallstones by chenodeoxycholic acid (CDC) and phenobarbital (PB). Gastroenterology 66: 679, 1974. 6. Danzinger, R. G., Hofmann, A. F., Schoenfield, L. J., and Thistle, J. L. Dissolution of cholesterol gallstones by chenodeoxycholic acid. N. Engl. J. Med. 286: 1, 1972. 7. Garcia, Romero, E., Belda Poujoulet, R., CapiJla, P., Lopez Cantarero, M., and Arcelus lmaz. I. Ma. La heparina en el tratamiento de 10s calculos residuales en la via biliar. Cir. Esp. 28: 517, 1974. 8. Gardner, B. Experiences with the use of intracholedochal heparinized saline for the treatment of retained common duct stones. Ann. Surg. 177: 240, 1973. 9. Grundy, S. M., Ahrens, E. H., Salen, G., Schreib-
1978
man, P., and Nestel, P. Mechanisms of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia. J. Lipid Res. 13: 531, 1972. 10. Hicken, N. F., and McAllister, A. J. Operative cholangiography as an aid in reducing the incidence of “overlooked” common bile duct stones: A study of 1,293 choledocholithotomies. Surgery 55: 753, 1964. 11. Hughes, E. S. R. Recurrent and residual stones in the common bile-duct. B-it. J. Surg. 43: 198, 1955. 12. Lansford, C., Mehta, S., and Kern, F. The treatment of retained stones in the common bile duct with sodium cholate infusion. Gut 15: 48, 1974. 13. Magarey, C. J. Non-surgical removal of retained biliary calculi. Lancer 1: 1044, 1971. 14. Mazzariello, R. Review of 220 cases of residual biliary tract calculi treated without reoperation: An eight-year study. Surgery 73: 299, 1973. 15. Mercadier, M. “Trait6 de Therapeutique Chirurgitale,” Tome IV. Masson, Paris. 1964. 16. Northfield, T. C., Larusso, N. F., and Thistle, J. L. Effect of chenodeoxycholic acid therapy on biliary lipid secretion in gallstone patients. Gasrroenrerology 64: 780, 1973. 17. Ostrowitz, A., and Gardner, B. Studies of bile as a suspending medium and its relationship to gallstone formation. Surgery 68: 329, 1970. 18. Palmer, A. K., and Heywood, R. Pathological changes in the rhesus fetus associated with the oral administration of chenodeoxycholic acid. Toxicology 2: 239, 1974. 19. Robinson, C. L. N. Solution of residual duct stones. Canad. Med. Assoc. J. 95: 1205, 1966. 20. Smith Ill, R. B., Conklin, E. F., and Porter, M. R. Postoperative T-tube cholangiography. Surg. Gynecol.
O&et.
116: 731, 1963.
21. Sodhi, H. S., Hudchodkar, B. J., and Horlick, L. Hypocholesterolemic agents and mobilization of tissue cholesterol in man. Afherosclerosis 17: 1, 1973.
22. Toouli, J., Jablonski, P., and Watts, J. McK. Dissolution of stones in the common bile duct with bile-salt solutions. Aust. N. 2. J. Surg. 44: 336, 1974. 23. Toot& J., Jablonski, P., and Watts, J. McK. Dissolution of human gallstones: The efficacy of bile salt, bilt salt plus lecithin and heparin solutions. J. Surg. Res. 19: 47, 1975. 24. Way, L. W., Admirand, W., and Dunphy, E. Management of choledocholithiasis. Ann. Surg. 176: 347, 1972.
25. Way, L. W. Retained common duct stones. Surg. Clin. North. Amer. 53: 1139, 1973. 26. White, L. W. Regulation of hepatic cholesterol biosynthesis by clofibrate administration. J. Pharmacol.
Exp. Ther. 178: 361, 1971.
