SEMINARS IN LIVER DISEASE-VOL.
10, NO. 3. 1990
Topical Treatment of Calcified and Pigment Stones U. LEUSCHNER, M.D.
TOPICAL TREATMENT OF CALCIFIED AND PIGMENT STONES: PROBLEMS TO BE OVERCOME Chemical dissolution of calcified cholesterol stones and of pigment stones has to overcome four problems: exact classification of the stones may prove difficult, the causes of stone formation often cannot be treated. therapeutic technique may prove complicated and the stone constituents may be difficult to dissolve. The following paragraphs amplify these issues.
Classification of Stones Diffuse calcification or thin calcium layers frequently cannot be diagnosed using conventional x-ray technique, and therefore it is only unsuccessful lytic therapy that lets us discover the nature of the stone. Uncalcified pigment coatings on large, old cholesterol stones cannot be diagnosed radiologically, and even small pigment concretions cannot be distinguished from small cholesterol stones with certainty. Having acquired a certain routine, one can establish the correct diagnosis by means of conventional radiology in 80 to 90% of cases. The sensitivity of computed tomography (CT) in detection of calcium salts is still a matter of controversy; the specificity is high.'-' However, it is still unclear whether CT scan is not too sensitive, that is, it indicates a calcium content that would not have negatively affected litholysis with the direct cholesterol solvents glyceromonooctanoate or methyl tert-butyl ether (MTBE). Using CT scan seems to be advantageous in the detection of pigment salts. A density of more than 50 Hounsfield
units (HU), or of more than 90 HU according to other authors, seems to indicate pigment.
Underlying or Predisposing Conditions Alterations responsible for the formation of pigment concretions cannot be treated, or are treatable only with difficulty. Thus, for instance, antibiotic therapy in recurrent ascending bile duct infections is often tedious and followed by frequent relapses. Yet, it is precisely these persistent Escherichia coli bacteria, the most frequent cause of these infections, which may contribute to pigment stone formation in some settings. They have a high P-glucuronidase activity by which bilirubin diglucuronide is transformed to monogl~curonide;~ the monoglucuronide is less water soluble, and together with mucoproteins, cholesterol, calcium salts, and heavy metals forms de novo pigment stones, or coats cholesterol stones with pigment. Although it is still debatable what part infections play in the formation of European pigment stones," relapsing inflammations promote the formation of new concretions. Even obstructions of the biliary tree causing pigment stones are difficult to overcome. Cicatricial strictures after injuries or surgery can be managed surgically, by balloon dilation or stents, but the relapse rate is high (15 to 30%)'-" and the stents are often blocked. Postoperative intrahepatic bile duet dilation, or Caroli's syndrome, with chronic infection sometimes results in liver resection. Suture material and parasites or their eggs are negligible contributors to the development of pigment stones in the United States and Europe and, moreover, are easily manageable. However, in South and East Asia parasites have often to be taken into account as a nidus for pigment stones. "-I4
Technical Considerations
Since pigment stones frequently develop in anatomically altered bile ducts, the direct approach to the concretions is difficult. For the rare pigment stones of the gallbladder, the percutaneous transhepaticI5 or the transpapillary approach via the cystic ductihmay be feasible. Crrltrr ~ / ' I r ~ f e ~Mrdic.irlr. r i ~ ~ i l Ilrpcrrtmrrlt 01 Gtr.vtrorr~te~rolog~, lntrahepatic stones can be reached either transhepatically Johrrr~rl Wovgur~g Goc,the Univrr.sit~, Frcir~X.firrtiMoin. F~d~'rci1 or via the papilla, but the problem is that usually one has R c ~ ~ ~ u hofl i cGermcrn~ to intubate several branches of the bile duct system. Reprint requests: Prof. Leuschner, Zentrum der Inneren MediEven the approach to common bile duct stones can be zin, Abteilung fur Gastroenterologie der Universitat, TheodorStern-Kai 7, 6000 FrankfurtIMain, FRG. difficult, for example, in the presence of strictures, in Copyright 0 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York. NY 10016. All rights reserved.
191
Downloaded by: Universite Laval. Copyrighted material.
In pigment stones we have to differentiate between the so-called black pigment stones, predominantly found in the gallbladder, and the earthy, brown calcium bilirubinate concrements of the bile duct system. Etiology and pathogenesis of black stones are unknown; the brown concretions probably develop during biliary infections.'
SEMINARS IN LIVER DISEASE-VOLUME
10, NUMBER 3, 1990
the case of a blind pouch after choledochoduodenostomy, or in patients after Billroth 11 resection.
ment of appropriate solvents in the section on treatment of bile duct stones.
Physicochemical Limitations
Calcified Cholesterol Stones and Pigment Stones in the Bile Ducts
However, the biggest problem is caused by the fact that calcium salts, the so-called organic stone matrix, and pigments are not soluble with lipid solvents administered for cholesterol stone dissolution (bile salt solutions, glyceromonooctanoate, MTBE). Furthermore, it is not only stone composition but stone architecture as well" that can impair dissolution considerably, since different stone layers require different solvents. These four concerns are much less formidable for the treatment of cholesterol stones: the concrements are usually found in a functioning gallbladder, which is easily accessible for oral or percutaneous transhepatic therapy; or, if we are faced with concretions that have migrated from the gallbladder. they can be extracted endoscopically after sphincterotomy in more than 90% of cases from the usually anatomically regular bile ducts. Furthermore, there are several potent cholesterol solvents that will accomplish stone dissolution easily within a few hoursIx see article by Thistle in this issue of Setninars, whereas pigment stone solvents are still at an experimental stage.
In the bile ducts we find predominantly the earthy, friable, brown calcium bilirubinate stone, and to a lesser extent black pigment stones. The latter and calcified cholesterol stones originate from the gallbladder. These concretions can be treated with contact solvents after sphincterotomy via a nasobiliary tube, postsurgically via a T-tube, or even after percutaneous bile duct puncture. Since the chemical dissolution of the major components of pigment stones, and to a lesser degree even of calcified cholesterol stones, that is, of calcium salts, pigments, and the organic matrix, comes about very slowly, the treatment takes. in contrast to contact litholysis of cholesterol stones, not simply a few hours but on average 3 weeks, and in special cases even 3 months. This should be discussed with the patient before treatment.
Solvents
In 1980 we reported on the dissolution of gallstones using an alternating therapy with glyceromonooctanoate and a buffered. 1% ethylene diaminetetraacetic acid (EDTA) solution (Table I). Glyceromonooctanoate extracted cholesterol and EDTA extracted the calcium biTOPICAL DISSOLUTION lirubinate." In an alkaline milieu (pH 9.4) EDTA chelates calcium from calcium bilirubinate. Subsequently, Calcified Cholesterol Stones and Pigment bilirubin is converted to water-soluble sodium bilirubiStones of the Gallbladder nate. The admixture of the detergents cholic acid, ursodeoxycholic acid, and chenodeoxycholic acid enhances Depending on the time of diagnosis. 10 to 40% of the wetability of the stone's surface by the aqueous solall cholesterol stones of the gallbladder are calcified and vent and promotes the nonmicellar, colloidal solution of therefore no longer eligible for oral litholysis with unconjugated bilir~bin.".'~Organic calcium salts that cheno- or ursodeoxycholic acid. "."' Pigment stones are are not dissolved hereby are flushed from the stone texfound with an age-dependent frequency in between 5 and ture, and the stone is disaggregated. 30% of all stone patients." After the diagnosis has been A major problem is the disaggregation of the ormade, surgery is usually performed, and chemical disganic stone matrix, the composition of which is only parsolution is not discussed any further. However, direct tially known2'-" and is subject to remarkable individual stone dissolution with MTBE.I5 introduced in 1985, and variations. Even its proportion in the stone weight is unextracorporeal shockwave lithotripsy (ESWL) with subknown; it may be present only in traces or up to 50% by sequent lysis of stone fragments,?' have brought to the weight. Since the pigment portions of the stones are fore the question of dissolution of calcium salts and pigembedded in this matrix like islands,33." it is evident that ment compounds. MTBE and ESWL can disaggregate the matrix might prolong stone disaggregation or even or break calcium salts and pigment-containing conprevent it.3i cretions, but for the complete dissolution of the calcium In 1982 we attempted to disaggregate the organic pigment remnants special solvents are required. They matrix using a trypsin or SH-activated papaine-EDTA could be injected directly into the gallbladder, as in solution. The experiment was successful in vitro at pH MTBE therapy, but in the individual cases reported thus 6.5 to 8.2; the solvent was not used in vivo (Table 1 , far the insol-uble compounds were flushed through the Solvent III).3hAnother group reported in 1987 on the use cystic duct, and special solvents for chemical dissolution of a zinc-independent alkaline proteinase in an EDTA were not used." solvent (pH 9 to 9.3)." Of special interest is the dissolution of the so-called In 1987, under the assumption that thio compounds sludge after MTBE therapy of cholesterol stones. that is, reduce disulfide bridges participating in the network forthe debris that is left over in some 30 to 700/0'".?5of the mation of mucoproteins, we reported the use of N-acesuccessfully treated patients. The sludge consists of pigtylcysteine (NAC) as 10% solution and as a mixture with ment remnants, organic stone matrix, and probably even 1% EDTA solution in in vitro experiment^.^^ Not only of mucus from the gallbladder wall. This sludge is not always drained from the gallbladder spontaneou~ly'~.~' the pure 10% NAC solution but the NAC-EDTA solution as well induced disaggregation of complete black and and therefore it has to be dissolved if it is not to become brown pigment stones. In 1988 there were several rethe nidus of new stones. We will report on the develop-
up
Downloaded by: Universite Laval. Copyrighted material.
192
TOPICAL TREATMENT OF STONES-LEUSCHNER
193
TABLE 1. Solvents for Pigment Stone Dissolution
Solvent 1 (Bile acid-EDTA)"
Sodium ED'SA Carnoh~ne Argininc Chollc acld Ursodcoxycholic acid Water Sodium EDTA Na TCA:' N-acetylcysteine ( N A C ) Sodiunl EDTA Cholic acid Ursodcoxycholic acid Carno\inc Trypure Novo. 9 0 000 NF1ml.t Papaine Merck. 3000 m - Anson Eiml
Solvent 114'
Solvent 111'"
ports on similar result^.^'-^' However, in numerous investigations on the effect of different detergents, of EDTA and of different thio compounds in varying concentrations under standardized conditions, we found that the influence of NAC on the dissolution of pigment stone powder is rather limited (Table 2). The best result was achieved with NAC in 2% concentration. As a cosolvent in an EDTA (I gmldl) and sodium taurocholate ( 1 gml dl) solution NAC (2 gmldl) increases the dissolution effect in brown calcium bilirubinate stones by 21%; however, in black pigment stones dissolution is increased only by 896.'' Since even disaggregation experiments with lyophilied mucin from porcine bile, using five different thio compounds (NAC, P-mercaptosulfonate, P-mercaptoethanol, DL-dithiothreitol, D-penicillamine) gave disappointing results," further data on the benefit of thio compounds have to be awaited. At present, we believe the most suitable solvents are solvents I and I1 in
TABLE 2. Soh~rrrr 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
M M M M M M
b o r a t e l S o d ~ u ncarbonate ~ boratelSodium carbonate borate1Sodiurn carbonate borateISod~umcarbonate borate1Sodium carbonate borateISodium carbonate M h o r a t e l S o d ~ u ~carbonate n M borateiSod~unicarbonate M borateiSodium carbonate
0 . 2 M borateiSodium carbonate 0 . 2 M borate1Sodiuni carbonate 0 . 2 M borate1Sodium carbonate
Table I . in which the major effects are caused by EDTA and cholic acid.
Clinical Results Reports on the chemical dissolution of pigment stones in patients are very rare, but sporadic treatments in West Germany are frequent. It is mainly the surgeons who use the therapy in the presence of bile duct stones. They usually treat brown calcium bilirubinate stones of the biliary tree as genuine relapsing stones years after cholecystectomy. However, even cholesterol stones in which pigment coatings are suspected are being treated. These are residual stones after recent surgery. Clinical reports on contact litholysis of the rare brown calcium bilirubinate stones of the gallbladder, on the therapy of so-called black polybilirubinate stones, and of layer-wise calcified concretions of the gallbladder are not known.
List of Solvent Systems Used for Pigment Stone Powder Dissolution* Cocoh~rrrr -
Bile salts Pluronic F6X Palrnidrol Th~olh NAC" EDTA Sodium TCAl Sodium TCA and NAC EDTA and sodium TCA EDTA and NAC EDTA and sodium TCA and NAC
"'See W o s i e w i t ~el 'Four bile salts and their taurine and glycine conjugates. N-acetylcysteine, D-penicillamine, DL-dithiothreitol, 2-mercaptopropionylglycine. F o u r different concentrations. T C A = taurocholic acid: NAC = N-acetylcysteine.
Corr~.crrrrtrriorr -
5 0 mM 5 gnildl 5 gmidl 5 gmidl 1-16 gmidl I gmldl I gmldl I gmldl 2 gmidl I gmldl I g~nidl 2 gnlidl I gmidl I gmidl 2 gmidl
Frrrt11pH 9.25-9.30 9.10-925 9.1 9.1 9.2 9.0-9.2 9.2 9.2 9.2 9.2 9.2 9.2
Downloaded by: Universite Laval. Copyrighted material.
*Sodium salt of taurocholic acid. t N o v o Company, FRG. Trypsine: NF: National Forrnular Unit\ ( U S A ) "'"Not available in the FRG since 1985: Merck Company. FRG. Anson-E: I unit i\ able to liberate I mequ Thyrosin from henloplobin en~yniatically.
SEMINARS IN LIVER DISEASE-VOLUME
194 TABLE 3.
10. NUMBER 3. 1990
Dissolution of Bile Duct Stones with Glyceromonooctanoate and Bile Acid-EDTA
No. Poricrrr.\
Mrtrli Agc. f Y1.J
llo.\(~,q
10, NO. 3. 1990
Topical Treatment of Calcified and Pigment Stones U. LEUSCHNER, M.D.
TOPICAL TREATMENT OF CALCIFIED AND PIGMENT STONES: PROBLEMS TO BE OVERCOME Chemical dissolution of calcified cholesterol stones and of pigment stones has to overcome four problems: exact classification of the stones may prove difficult, the causes of stone formation often cannot be treated. therapeutic technique may prove complicated and the stone constituents may be difficult to dissolve. The following paragraphs amplify these issues.
Classification of Stones Diffuse calcification or thin calcium layers frequently cannot be diagnosed using conventional x-ray technique, and therefore it is only unsuccessful lytic therapy that lets us discover the nature of the stone. Uncalcified pigment coatings on large, old cholesterol stones cannot be diagnosed radiologically, and even small pigment concretions cannot be distinguished from small cholesterol stones with certainty. Having acquired a certain routine, one can establish the correct diagnosis by means of conventional radiology in 80 to 90% of cases. The sensitivity of computed tomography (CT) in detection of calcium salts is still a matter of controversy; the specificity is high.'-' However, it is still unclear whether CT scan is not too sensitive, that is, it indicates a calcium content that would not have negatively affected litholysis with the direct cholesterol solvents glyceromonooctanoate or methyl tert-butyl ether (MTBE). Using CT scan seems to be advantageous in the detection of pigment salts. A density of more than 50 Hounsfield
units (HU), or of more than 90 HU according to other authors, seems to indicate pigment.
Underlying or Predisposing Conditions Alterations responsible for the formation of pigment concretions cannot be treated, or are treatable only with difficulty. Thus, for instance, antibiotic therapy in recurrent ascending bile duct infections is often tedious and followed by frequent relapses. Yet, it is precisely these persistent Escherichia coli bacteria, the most frequent cause of these infections, which may contribute to pigment stone formation in some settings. They have a high P-glucuronidase activity by which bilirubin diglucuronide is transformed to monogl~curonide;~ the monoglucuronide is less water soluble, and together with mucoproteins, cholesterol, calcium salts, and heavy metals forms de novo pigment stones, or coats cholesterol stones with pigment. Although it is still debatable what part infections play in the formation of European pigment stones," relapsing inflammations promote the formation of new concretions. Even obstructions of the biliary tree causing pigment stones are difficult to overcome. Cicatricial strictures after injuries or surgery can be managed surgically, by balloon dilation or stents, but the relapse rate is high (15 to 30%)'-" and the stents are often blocked. Postoperative intrahepatic bile duet dilation, or Caroli's syndrome, with chronic infection sometimes results in liver resection. Suture material and parasites or their eggs are negligible contributors to the development of pigment stones in the United States and Europe and, moreover, are easily manageable. However, in South and East Asia parasites have often to be taken into account as a nidus for pigment stones. "-I4
Technical Considerations
Since pigment stones frequently develop in anatomically altered bile ducts, the direct approach to the concretions is difficult. For the rare pigment stones of the gallbladder, the percutaneous transhepaticI5 or the transpapillary approach via the cystic ductihmay be feasible. Crrltrr ~ / ' I r ~ f e ~Mrdic.irlr. r i ~ ~ i l Ilrpcrrtmrrlt 01 Gtr.vtrorr~te~rolog~, lntrahepatic stones can be reached either transhepatically Johrrr~rl Wovgur~g Goc,the Univrr.sit~, Frcir~X.firrtiMoin. F~d~'rci1 or via the papilla, but the problem is that usually one has R c ~ ~ ~ u hofl i cGermcrn~ to intubate several branches of the bile duct system. Reprint requests: Prof. Leuschner, Zentrum der Inneren MediEven the approach to common bile duct stones can be zin, Abteilung fur Gastroenterologie der Universitat, TheodorStern-Kai 7, 6000 FrankfurtIMain, FRG. difficult, for example, in the presence of strictures, in Copyright 0 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York. NY 10016. All rights reserved.
191
Downloaded by: Universite Laval. Copyrighted material.
In pigment stones we have to differentiate between the so-called black pigment stones, predominantly found in the gallbladder, and the earthy, brown calcium bilirubinate concrements of the bile duct system. Etiology and pathogenesis of black stones are unknown; the brown concretions probably develop during biliary infections.'
SEMINARS IN LIVER DISEASE-VOLUME
10, NUMBER 3, 1990
the case of a blind pouch after choledochoduodenostomy, or in patients after Billroth 11 resection.
ment of appropriate solvents in the section on treatment of bile duct stones.
Physicochemical Limitations
Calcified Cholesterol Stones and Pigment Stones in the Bile Ducts
However, the biggest problem is caused by the fact that calcium salts, the so-called organic stone matrix, and pigments are not soluble with lipid solvents administered for cholesterol stone dissolution (bile salt solutions, glyceromonooctanoate, MTBE). Furthermore, it is not only stone composition but stone architecture as well" that can impair dissolution considerably, since different stone layers require different solvents. These four concerns are much less formidable for the treatment of cholesterol stones: the concrements are usually found in a functioning gallbladder, which is easily accessible for oral or percutaneous transhepatic therapy; or, if we are faced with concretions that have migrated from the gallbladder. they can be extracted endoscopically after sphincterotomy in more than 90% of cases from the usually anatomically regular bile ducts. Furthermore, there are several potent cholesterol solvents that will accomplish stone dissolution easily within a few hoursIx see article by Thistle in this issue of Setninars, whereas pigment stone solvents are still at an experimental stage.
In the bile ducts we find predominantly the earthy, friable, brown calcium bilirubinate stone, and to a lesser extent black pigment stones. The latter and calcified cholesterol stones originate from the gallbladder. These concretions can be treated with contact solvents after sphincterotomy via a nasobiliary tube, postsurgically via a T-tube, or even after percutaneous bile duct puncture. Since the chemical dissolution of the major components of pigment stones, and to a lesser degree even of calcified cholesterol stones, that is, of calcium salts, pigments, and the organic matrix, comes about very slowly, the treatment takes. in contrast to contact litholysis of cholesterol stones, not simply a few hours but on average 3 weeks, and in special cases even 3 months. This should be discussed with the patient before treatment.
Solvents
In 1980 we reported on the dissolution of gallstones using an alternating therapy with glyceromonooctanoate and a buffered. 1% ethylene diaminetetraacetic acid (EDTA) solution (Table I). Glyceromonooctanoate extracted cholesterol and EDTA extracted the calcium biTOPICAL DISSOLUTION lirubinate." In an alkaline milieu (pH 9.4) EDTA chelates calcium from calcium bilirubinate. Subsequently, Calcified Cholesterol Stones and Pigment bilirubin is converted to water-soluble sodium bilirubiStones of the Gallbladder nate. The admixture of the detergents cholic acid, ursodeoxycholic acid, and chenodeoxycholic acid enhances Depending on the time of diagnosis. 10 to 40% of the wetability of the stone's surface by the aqueous solall cholesterol stones of the gallbladder are calcified and vent and promotes the nonmicellar, colloidal solution of therefore no longer eligible for oral litholysis with unconjugated bilir~bin.".'~Organic calcium salts that cheno- or ursodeoxycholic acid. "."' Pigment stones are are not dissolved hereby are flushed from the stone texfound with an age-dependent frequency in between 5 and ture, and the stone is disaggregated. 30% of all stone patients." After the diagnosis has been A major problem is the disaggregation of the ormade, surgery is usually performed, and chemical disganic stone matrix, the composition of which is only parsolution is not discussed any further. However, direct tially known2'-" and is subject to remarkable individual stone dissolution with MTBE.I5 introduced in 1985, and variations. Even its proportion in the stone weight is unextracorporeal shockwave lithotripsy (ESWL) with subknown; it may be present only in traces or up to 50% by sequent lysis of stone fragments,?' have brought to the weight. Since the pigment portions of the stones are fore the question of dissolution of calcium salts and pigembedded in this matrix like islands,33." it is evident that ment compounds. MTBE and ESWL can disaggregate the matrix might prolong stone disaggregation or even or break calcium salts and pigment-containing conprevent it.3i cretions, but for the complete dissolution of the calcium In 1982 we attempted to disaggregate the organic pigment remnants special solvents are required. They matrix using a trypsin or SH-activated papaine-EDTA could be injected directly into the gallbladder, as in solution. The experiment was successful in vitro at pH MTBE therapy, but in the individual cases reported thus 6.5 to 8.2; the solvent was not used in vivo (Table 1 , far the insol-uble compounds were flushed through the Solvent III).3hAnother group reported in 1987 on the use cystic duct, and special solvents for chemical dissolution of a zinc-independent alkaline proteinase in an EDTA were not used." solvent (pH 9 to 9.3)." Of special interest is the dissolution of the so-called In 1987, under the assumption that thio compounds sludge after MTBE therapy of cholesterol stones. that is, reduce disulfide bridges participating in the network forthe debris that is left over in some 30 to 700/0'".?5of the mation of mucoproteins, we reported the use of N-acesuccessfully treated patients. The sludge consists of pigtylcysteine (NAC) as 10% solution and as a mixture with ment remnants, organic stone matrix, and probably even 1% EDTA solution in in vitro experiment^.^^ Not only of mucus from the gallbladder wall. This sludge is not always drained from the gallbladder spontaneou~ly'~.~' the pure 10% NAC solution but the NAC-EDTA solution as well induced disaggregation of complete black and and therefore it has to be dissolved if it is not to become brown pigment stones. In 1988 there were several rethe nidus of new stones. We will report on the develop-
up
Downloaded by: Universite Laval. Copyrighted material.
192
TOPICAL TREATMENT OF STONES-LEUSCHNER
193
TABLE 1. Solvents for Pigment Stone Dissolution
Solvent 1 (Bile acid-EDTA)"
Sodium ED'SA Carnoh~ne Argininc Chollc acld Ursodcoxycholic acid Water Sodium EDTA Na TCA:' N-acetylcysteine ( N A C ) Sodiunl EDTA Cholic acid Ursodcoxycholic acid Carno\inc Trypure Novo. 9 0 000 NF1ml.t Papaine Merck. 3000 m - Anson Eiml
Solvent 114'
Solvent 111'"
ports on similar result^.^'-^' However, in numerous investigations on the effect of different detergents, of EDTA and of different thio compounds in varying concentrations under standardized conditions, we found that the influence of NAC on the dissolution of pigment stone powder is rather limited (Table 2). The best result was achieved with NAC in 2% concentration. As a cosolvent in an EDTA (I gmldl) and sodium taurocholate ( 1 gml dl) solution NAC (2 gmldl) increases the dissolution effect in brown calcium bilirubinate stones by 21%; however, in black pigment stones dissolution is increased only by 896.'' Since even disaggregation experiments with lyophilied mucin from porcine bile, using five different thio compounds (NAC, P-mercaptosulfonate, P-mercaptoethanol, DL-dithiothreitol, D-penicillamine) gave disappointing results," further data on the benefit of thio compounds have to be awaited. At present, we believe the most suitable solvents are solvents I and I1 in
TABLE 2. Soh~rrrr 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2
M M M M M M
b o r a t e l S o d ~ u ncarbonate ~ boratelSodium carbonate borate1Sodiurn carbonate borateISod~umcarbonate borate1Sodium carbonate borateISodium carbonate M h o r a t e l S o d ~ u ~carbonate n M borateiSod~unicarbonate M borateiSodium carbonate
0 . 2 M borateiSodium carbonate 0 . 2 M borate1Sodiuni carbonate 0 . 2 M borate1Sodium carbonate
Table I . in which the major effects are caused by EDTA and cholic acid.
Clinical Results Reports on the chemical dissolution of pigment stones in patients are very rare, but sporadic treatments in West Germany are frequent. It is mainly the surgeons who use the therapy in the presence of bile duct stones. They usually treat brown calcium bilirubinate stones of the biliary tree as genuine relapsing stones years after cholecystectomy. However, even cholesterol stones in which pigment coatings are suspected are being treated. These are residual stones after recent surgery. Clinical reports on contact litholysis of the rare brown calcium bilirubinate stones of the gallbladder, on the therapy of so-called black polybilirubinate stones, and of layer-wise calcified concretions of the gallbladder are not known.
List of Solvent Systems Used for Pigment Stone Powder Dissolution* Cocoh~rrrr -
Bile salts Pluronic F6X Palrnidrol Th~olh NAC" EDTA Sodium TCAl Sodium TCA and NAC EDTA and sodium TCA EDTA and NAC EDTA and sodium TCA and NAC
"'See W o s i e w i t ~el 'Four bile salts and their taurine and glycine conjugates. N-acetylcysteine, D-penicillamine, DL-dithiothreitol, 2-mercaptopropionylglycine. F o u r different concentrations. T C A = taurocholic acid: NAC = N-acetylcysteine.
Corr~.crrrrtrriorr -
5 0 mM 5 gnildl 5 gmidl 5 gmidl 1-16 gmidl I gmldl I gmldl I gmldl 2 gmidl I gmldl I g~nidl 2 gnlidl I gmidl I gmidl 2 gmidl
Frrrt11pH 9.25-9.30 9.10-925 9.1 9.1 9.2 9.0-9.2 9.2 9.2 9.2 9.2 9.2 9.2
Downloaded by: Universite Laval. Copyrighted material.
*Sodium salt of taurocholic acid. t N o v o Company, FRG. Trypsine: NF: National Forrnular Unit\ ( U S A ) "'"Not available in the FRG since 1985: Merck Company. FRG. Anson-E: I unit i\ able to liberate I mequ Thyrosin from henloplobin en~yniatically.
SEMINARS IN LIVER DISEASE-VOLUME
194 TABLE 3.
10. NUMBER 3. 1990
Dissolution of Bile Duct Stones with Glyceromonooctanoate and Bile Acid-EDTA
No. Poricrrr.\
Mrtrli Agc. f Y1.J
llo.\(~,q
