SEMINARS IN LIVER DISEASE-VOL.
10. NO. 3 , 1990
Oral Dissolution Treatment of Gallstones with Bile Acids GERALD SALEN, M.D., G.S. TINT, Ph.D., and SARAH SHEFER, Ph.D.
From the UMD-NJ Mediccil School, Newark. New J r r s r ~ the , Vc.tc,run.sAdministration Mrdicul Center, Eust Ortinge, New' Jer.se?., cind the Cuhrini Medical Center, New York, New York. Reprint requests: Dr. Salen, VA Medical Center, East Orange, NJ.
PATHOGENESIS OF CHOLESTEROL GALLSTONES In the United States, about 80% of gallstones are composed chiefly of cholesterol.' The remaining stones either contain mostly pigment or are calcified. Although not all the mechanisms of cholesterol stone formation are known, the liver plays a key role, because lithogenic bile, supersaturated with cholesterol, is produced in this organ. Briefly stated, the liver secretes an increased cholesterol load, which is too large to be solubilized in micelles that are formed by detergent bile acids synthesized by the liver.x During the interdigestive phase, when supersaturated bile is diverted to be stored in the gallbladder, nucleation and precipitation of cholesterol occur. Not only does diminished gallbladder motility favor gallstone formation,"" but nucleation is more rapid in gallbladder bile from subjects who have gallstones as the imbalance between nucleating and antinucleating factors induces crystallization and precipitation of cholesterol. I?-'' Thus, several abnormalities coexist: supersaturated bile, decreased gallbladder motility, and the presence of nucleating factors inherent in the bile. However, the secretion of supersaturated bile by the liver is the key pathogenic ingredient (see review by Hay and Carey in this issue of Seminars in Liver Disease). In many subjects who have cholesterol gallstones, the formation of lithogenic bile can be related to a hepatic metabolic abnormality, which has been identified as the combination of increased cholesterol synthesis and decreased cholesterol degradation to bile acids." Both pathways are shown in ~ i g u r e1 . Cholesterol is produced from acetate, and, although many enzymatic reactions are involved, the reduction of hydroxymethyl glutaryl coenzyme A (HMG-CoA) to mevalonic acid is considered the rate-limiting step, since virtually every molecule of mevalonic acid is committed to cholesterol biosynthesis. This reaction is catalyzed by the microsomal enzyme HMG-CoA reductase, and cholesterol biosynthesis is considered proportional to the activity of HMGCoA reductase. Similarly, in the formation of bile acids, the first step is the 7a-hydroxylation of cholesterol, which is also considered rate-limiting since every molecule of 7a-hydroxycholesterol passes to bile acids. This reaction takes place only in the liver and is catalyzed by the microsomal enzyme cholesterol 7a-hydroxylase. In
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It is estimated that 25 million Americans, or about 10% of the U.S. population, have gallstones." Although 1 million new cases are diagnosed annually, the magnitude of this problem may actually be underestimated, because most patients with gallstones remain asymptomatic and therefore often go ~ndetected.'.~ The most typical symptom of gallstones is pain (biliary colic), which is caused by the passage of small stones or gravel through the bile ducts. Generally, the pain is located in the right upper quadrant and radiates to the midline and back as the stones pass from the gallbladder through the cystic duct to reach the common bile duct and exit into the duodenum. Other common symptoms found in subjects who have gallstones include abdominal distension, belching, flatulence, nausea, and vomiting. These symptoms are often grouped together and called biliary dyspepsia. The etiology of biliary dyspepsia has not been defined and may not be related directly to the movement of the stones, but rather to muscular dysfunction of the gallbladder and bile ducts. Apparently, the presence of gallstones may adversely affect coordinated muscular contractions and may lead to dyskinesia of the gallbladder and bile ducts. This abnormal motor function may also allow for increased bile reflux into the stomach, resulting in so-called bile-reflux gastritis. Despite the imprecise knowledge of the cause, these symptoms, when present, tend to be recurrent, often follow eating, produce discomfort, and presage the development of more serious complications such as cholecystitis, obstructive jaundice, ascending cholangitis, and pancreatitis. The latter complications occur when stones move and obstruct the cystic, common bile, or pancreatic ducts. According to present therapeutic recommendations, the development of these complications of gallstones often requires immediate surgical intervention: about one-third (150,000) of the 500,000 cholecystectomies performed in 1987 were emergency operations.' The other two-thirds (350,000) of the cholecystectomies were performed as elective operations at a time when the patients were not acutely ill.
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Acetate
10, NUMBER 3, 1990
abnormalities often leads to the accumulation of cholesterol in the liver and in turn to the hypersecretion of cholesterol into the bile, making it l i t h ~ g e n i c . ' ~
LITHOLYTIC BILE ACIDS At the present time, two bile acids are available for use in gallstone dissolution the rap^:^ chenodeoxycholic acid, or chenodiol (3a,7a-dihydroxy cholanoic acid), and ursodeoxycholic acid, or ursodiol (3cr,7P-dihydroxy cholanoic acid). Both occur naturally and both are present in human bile.Ix
Cholesterol
Chenodeoxycholic Acid
7-Alpha Hydroxycholesterol Cholic Acid FIG. 1. Synthesis of cholesterol and bile acids. By measuring HMG-CoA activity, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid, cholesterol biosynthesis can be quantified. Similarly, bile acid synthesis is proportional to the formation of 7 a-hydroxycholesteroI, catalyzed by cholesterol 7 a-hydroxylase.
general, bile acid production is coupled to cholesterol formation, since newly synthesized cholesterol is the preferred substrate for cholesterol 7a-hydroxylase. A number of studies have examined the activities of both these enzymes in liver microsomes from subjects who had gallstones and control subjects who did not. The results are shown in Figure 2. In the subjects who had gallstones, bile acid synthesis is reduced, as evidenced by a 50% reduction in cholesterol 7a-hydroxylase activity. In contrast, HMG-CoA reductase activity is increased, which indicates that cholesterol is being overproduced. We believe that the combination of both
It has now been almost 20 years since chenodiol acid was demonstrated to be effective dissolution therapy for gallstones by Danzinger and others at the Mayo Clinic, IY.?" These investigators showed that chenodiol acid works by reducing hepatic cholesterol secretion and desaturating the bile. The mechanism apparently involves the suppression of hepatic cholesterol synthesis via the inhibition of the rate-controlling enzyme, HMGCoA reductase.?'.?' When chenodiol is given at a dose of 750 mglday, only 15% of patients' gallstones will be dissolved. Because only stones composed of cholesterol are effectively treated, the success rate can be increased when patients who have low body weights and who have small, floating, radiolucent (noncalcified) gallstones are selected." When stones are calcified or are composed of pigment, chenodiol is ineffective.
Side Effects and Toxicity Side effects and hepatic toxicity occur in a high percentage of patients treated with chenodiol, and, thus, the initial enthusiasm for this bile acid soon waned. Diarrhea, biochemical and morphologic evidence of hepato-
Cholesterol 7-alpha hydroxylase (b)
HMG-CoA Reductase (a)
p moles 60 rng protelnl minute 40
p moles l5 mg protein1 minute 10
5
20
0
0 Normal Controls (N = 8)
Gallstone Pat~ents (N=12)
Normal Controls (N = 4)
Gallstone Patlents (N = 9)
FIG. 2. Activities of the rate-controlling enzymes of cholesterol (a) and bile acid (b) synthesis in liver microsomes from subjects who had gallstones and control subjects who did not. Bar above represents + 1 SD. Statistical significance was determined by Student's t-test; (a) p = < 0.005 (b) p = < 0.001 .I7
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Mevalonate
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Ursodeoxycholic Acid Ursodiol is normally found in small amounts ( 1 to 2% of total bile acids) in human bile.35.'" It is also the major bile acid in several species of bears (hence the prefix "urso"). In the form of dried bear bile, or yu-tan, ursodiol has been part of Chinese and Japanese folk medicine for at least 1000 years. When it is administered in therapeutic doses (8 to 10 mgikgiday), complete dissolution of gallstone will occur over a period of 2 years in 30 to 60% of subjects, depending on the size and number of stones.3740Similarly to chenodiol, ursodiol works by reducing hepatic cholesterol secretion to desaturate the bile, although it is more potent than ~ h e n o d i o l . ~It' accomplishes this by several mechanisms. First, long-term treatment with ursodiol inhibits hepatic microsomal HMG-CoA reductase activity and, in turn, cholesterol synthesis." Since this enzyme controls the availability of mevalonic acid, suppression of enzyme activity correlates with decreased liver cholesterol synthesis. Second, intestinal cholesterol absorption is r e d u ~ e d . 'Two ~ factors seem to be responsible. Ursodiol micelles have less capacity to solubilize cholesterol; therefore less intestinal cholesterol is solubilized for absorption. Also, because hepatic cholesterol secretion into bile is reduced, less cholesterol is in the intestine to be absorbed." Finally, ursodiol does not inhibit hepatic bile acid ~ynthesis.'~."Apparently, 7P-hydroxy bile acids, unlike their 7a-hydroxy isomers, do not suppress cholesterol 7a-hydroxylase, the rate-controlling enzyme for bile acid synthesis. As a result, 300 to 600 mg of hepatic cholesterol continues to be transformed to bile acid each day and removed from the hepatic cholesterol pool. However, although less cholesterol enters the bile of ursodiol-treated subjects, this advantage is partially offset by the fact that bile acid micelles that are composed principally of ursodiol conjugates have a reduced capacity to solubilize and transport c h ~ l e s t e r o l . ~Thus ' . ~ ~., it would appear that less cholesterol can be removed from the gallstones. Fortunately, an additional mechanism operates to eliminate cholesterol, which involves the formation of liquid crystal complexes of cholesterol.434' These stable dispersions result when cholesterol is removed from the stone, and they are apparently prevented from reprecipitating by the ursodiol-rich bile. When the gallbladder contracts, the liquid crystals of cholesterol are secreted from the gallbladder into the intestine.
Toxicity and Side Effects No abnormal liver morphology or elevations in liver function test values have been noted even after 5 or more years of ursodiol therapy.is,3hIn fact, ursodiol is now being used experimentally to treat patients who have several chronic progressive liver diseases: primary biliary cirrhosis, sclerosing cholangitis, and chronic active hepa t i t i ~ . ~ ' - 'Preliminary ~ results are most encouraging in that both the clinical manifestations (pruritus and fatigue) and the biochemical parameters improve with ursodiol therapy. No patients' conditions worsened and liver histology actually improved in several patients who
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toxicity, and hypercholesterolemia are the principal problems reported. Since chenodiol is synthesized in the human liver at a rate of 150 to 250 mgiday, it was expected to be reasonably safe when administered orally. However, about 20% of patients develop watery diarrhea when they are given 750 mgiday. Transient elevations of serum transaminases, alkaline phosphatase, and unconjugated bilirubin are also noted in 15% of subjects.'" Biopsy specimens taken from 126 subjects showed liver damage with ballooning of hepatocytes, lipofuscin-like pigment deposition, ductular proliferation, and fibrosis in the portal triads after 2 years of therapy with 750 mgiday of chenodeoxycholic acid.'%lthough these changes were not judged to be clinically significant, they preclude the use of chenodiol in individuals who have preexisting liver disease or moderately abnormal liver function tests. Plasma cholesterol levels generally increase up to 15% in patients who are taking therapeutic doses (750 to I000 mglday). Most of the increase is confined to the low density lipoprotein (LDL) cholesterol fraction." Apparently, chenodiol down-regulates the formation of LDL receptors and slows the clearance of plasma LDL." Because of this rise in plasma cholesterol, chenodiol is not recommended for use in the treatment of symptomatic gallstones in patients who have hypercholesterolemia or atherosclerosis. Elevated plasma triglyceride levels may decline by as much as 2O%." Unfortunately. little symptomatic relief is afforded during chenodiol therapy until gallstones have dissolved.'" This may limit compliance to long-term therapy. During treatment with 750 to 1000 mglday, chenodiol becomes the major bile acid secreted into the bile, accounting for more than 80% of the biliary bile acid^.'^.?^ The proportions of cholic acid and its 7-dehydroxylated bacterial derivative, deoxycholic acid ( 3 a , l2a-dihydroxy cholanoic acid) decline. This is indicative of the suppression of endogenous bile acid synthesis via the inhibition of the rate-controlling enzyme, cholesterol 7a-hydroxylase. Another important chemical characteristic of treatment with chenodiol is that the level of lithocholic acid (3a-hydroxy cholanoic acid), a potentially toxic cholestatic bile acid, increases in the bile." This monohydroxy bile acid is produced from chenodiol through the action of anaerobic intestinal bacteria, which remove the 7a-hydroxy group."' In humans, as contrasted with rabbits and monkeys, most lithocholic acid is conjugated and secreted as the sulfate derivative, which increases its solubility and lessens its toxicity."." However, the capacity to sulfate varies among humans and "low sulfators" may be more susceptible to potential lithocholic acid-induced hepatic toxicity. This may account for the rise in serum transaminase levels in some chenodiol-treated subjects. Another important bacterial product of chenodiol is its 7P-hydroxy epimer, ursodiol. In patients treated with therapeutic doses of chenodiol (750 to 1000 mglday) 3 to 50% of the biliary acids become ursodi01."~'~ This metabolic pathway involves 7-keto-lithocholic acid as the key intermediate; the 7Preduction of the keto group is carried out by intestinal bacteria rather than by the liver.
SHEFER
SEMINARS IN LIVER DISEASE-VOLUME
have chronic active hepatitis during treatment.16 Serum cholesterol levels do not increase during ursodiol therapy, a finding that may reflect the fact that hepatic LDL receptors are not down-regulated, as seen with chenodi~l.'~ Diarrhea has been infrequently encountered in ursodiol-treated subjects. About 1% of subjects have reported loose stools that have improved either spontaneously or after a temporary downward adjustment of the dose.-" Furthermore, symptoms of biliary colic and dyspepsia (bloating, belching, abdominal distension, flatulence, nausea, and vomiting) were reported much less frequently during ursodiol treatment. Interestingly, this improvement in symptoms occurred within the first 3 months of therapy, before the gallstones have dissolved completely, and the improvement persists throughout the duration of treatment.35-4' Although our study was not rigorously controlled, several reports from Italy performed in double-blind fashion indicated similar relief of symptoms with ursodiol and virtually no improvement " explanation for the relief of sympwith p l a ~ e b o . ~The toms may relate to desaturation of the bile (disappearance of cholesterol crystals), choleresis, or possibly to relaxation of the smooth muscle of the gallbladder and bile duct. Nevertheless, the improved quality of life (less pain and diet restriction) for the subjects with gallstones is a major advantage of treatment with ursodiol and improves the compliance since long-term therapy is required to dissolve stones. When ursodiol is administered orally, it is absorbed and excreted mostly as the glycine conjugate. Since more ursodiol is conjugated by the liver and excreted into the bile, the hepatic taurine pool becomes depleted when the daily dosage is increased from 4 up to 20 mgl kglday. However, after treatment. only about 50% of the biliary bile acids are ursodiol." This is unlike treatment with chenodiol, in which more than 80% of the biliary bile acids are chenodiol.".'* Actually. there is very little further enrichment of the bile with ursodiol when a dosage of more than 10 mglkglday is administered. For that reason, the recommended therapeutic dosage of ursodiol for dissolving gallstones is 600 mglday. The explanation for the inability to increase the amount of ursodiol in the bile may lie in the fact that 7P-hydroxy bile acids like ursodiol do not inhibit cholesterol 7a-hydroxylase, the rate-limiting enzyme for bile acid synthesis. As a consequence, there is continued synthesis of endogenous cholic acid and chenodiol. Also, chenodiol is produced from ursodiol by intestinal bacteria." Therefore, the endogenous bile acid pool cannot be replaced by ursodiol. After gallstones have dissolved, discontinuation of either chenodiol or ursodiol therapy leads to the reexpression of the hepatic metabolic abnormality. With the renewed secretion of lithogenic bile, stones may recur. It has been reported that stones have reappeared at the rate of 10% per year, and up to half of the subjects have reformed stones." However, if the recurring stones produce symptoms, then retreatment with ursodiol should effectively redissolve the stones. In some subjects, treatment with nonsteroidal anti-inflammatory agents or low doses of ursodiol may retard stone recurrence, but main-
10, NUMBER 3, 1990
tenance therapy to prevent stone reformation cannot be recommended at this time.
Combination Bile Acid Treatment Recent reports have suggested that the combination of ursodiol with chenodiol is a more effective choice for litholysis than either bile acid alone.",53 The putative advantage of the combined therapy is that the dose of each bile acid in the combination is only approximately 50% of the dosage required for individual therapy. Also, the side effects and toxicity of chenodiol are not encountered when it is combined with ursodiol. Apparently, ursodiol exerts a protective action when it is given with chenodiol. The efficacy of the combination is similar to that of the individual bile acids, but may be more rapid initi all^.'^ Despite these apparent advantages, it is important to emphasize that when ursodiol is administered individually, bile contains substantial quantities of chen ~ d i o l . ~Apparently, ' some of the ursodiol that is administered is transformed to chenodiol by intestinal bacteria." In addition, because ursodiol does not suppress hepatic bile acid synthesis, the formation of endogenous chenodiol continues. Thus, treating with ursodiol alone results in a mixture of ursodiol and chenodiol in the enterohepatic circulation.
SELECTION OF PATIENTS Litholytic bile acid therapy is not suitable for all patients who have gallstones; unlike surgery, in which all stones as well as the gallbladder are removed, the orally administered litholytic bile acids, chenodiol and ursodiol, are only effective on noncalcified cholesterol stones. Therefore, a knowledge of the stone composition is a helpful prerequisite for selecting medical therapy. In addition, the biggest stones should be less than 2.0 cm in greatest diameter; smaller stones dissolve more rapidly. Also, it is important to note that the cystic duct must be patent to ensure that hepatic bile that is enriched with the litholytic bile acids can reach the gallstones. Several techniques are available to assist in the diagnosis and evaluation of gallstones for nonsurgical treatment. Ultrasound imaging is the most widely used and is the most sensitive technique to establish the diagnosis and the number of stones.54 It can also be used to estimate size when the stones are smaller than 2.0 cm in diameter. Also, since it is not invasive, ultrasound is useful to follow the course of dissolution of stones that are being treated medically. The oral cholecystogram is an older x-ray technique, in which a iodinated fatty acid is administered orally, absorbed from the intestine, conjugated in the liver, and concentrated in the gallbladder. Radiographs taken the next day reveal the opacified gallbladder, and stones are visualized as negative images. A positive oral cholecystogram proves that the cystic duct is patent and also is helpful in demonstrating the presence of calcium in gallstones. Because the density of the concentrated contrast medium is greater than that of water, stones that float are considered to be enriched
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with cholesterol. An inability to visualize the gallbladder after the ingestion of the radiopaque dye may indicate obstruction of the cystic duct by stones, a find that precludes the use of orally administered bile acid therapy. Alternatively, the cystic duct may be patent, but the gallbladder may be nonfunctional as a result of damaged mucosa after an attack of cholecystitis. In that case, the gallbladder cannot be visualized because of its inability to concentrate the dye. To detect this situation, intestinal bile drainage followed by the injection of cholecystokinin to stimulate the gallbladder to contract may yield concentrated bile from the gallbladder. This technique also helps to establish the patency of the cystic duct. Microscopic examination of the bile often shows the presence of cholesterol crystals, which signifies that the gallstones are composed of cholesterol and will be suitable for litholytic bile acid therapy.s5 Alternatively, the demonstration by ultrasound imaging of a 50% decrease in gallbladder volume after stimulating the gallbladder with cholecystokinin or a fatty meal is good evidence for a patent cystic duct.
CONCLUSIONS Cholesterol gallstone disease is reversible. These gallstones may be dissolved medically with either chenodiol or ursodiol. Both bile acids work by correcting the hepatic metabolic defect that is responsible for the hypersecretion of cholesterol into the bile and by desaturating the bile. Ursodiol is the preferred treatment because it is more effective; it desaturates bile to a greater degree than chenodiol does, and it eliminates cholesterol as stable liquid crystalline dispersions. Also, neither toxicity nor significant side effects have been noted during therapy with ursodiol. Marked improvement of symptoms and quality of life are often seen early during this treatment and help ensure compliance with long-term therapy. A ~ . k r l o \ t ~ l e d g ~ n r n Supported t. by U.S. Public Health Service grants DK 18707 and HL I78 I 8 and the Veteran\ Adnlinistration Research Service.
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Healthweek. Desktop Resource. Top 25 most frequently performed surgeries. June 20, 1988. Salen G. Tint GS: Nonsurgical treatment of gallstones. N Engl J Med 320:655-666, 1989. Carey MC, Small DM: The physical chemistry of cholesterol solubility in bile: Relationship to gallstones formation and dissolution in man. J Clin Invest 61:998-1026. 1978. Fisher R, Stelzer F. Rock E . Malmud L: Abnormal gallbladder emptying in patients with gallstones. Dig Dis Sci 27:10191024. 1982. Kishk SMA, Darweesh RMA, Dodds WJ, et al: Sonographic evaluation of resting gallbladder volume and postprandial emptying in patients with gallstones. AJR 148:875-879. 1987. Pomeranz IS. Shaffer EA: Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 88:787-791, 1985. Hoaln KR. Holzbach T. Hermann RE, et al: Nucleation time: A key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 77:61 1-6 17. 1979. Gollish SH. Burnstein MJ. Ilson RG, et al: Nucleation of cholesterol monohydrate crystals from hepatic and gallbladder bile of patients with cholesterol gallstones. Gut 24:836-844, 1983. Burnstein MJ, Ilson RG, Petrunka CN. Taylor RD, Strasherg SM: Evidence for potent nucleating factor in the gallbladder bile of patients with cholesterol gallstones. Gastroenterology 85:XOl-807. 1983. Kihe A. Holzbach RT. LaRusso NF. Mao SJT: Inhibition of cholesterol crystal formation by apolipoproteins in supersaturated model bile. Science 225:514-516. 1984. Smith BF. LaMont JT: The central issue of cholesterol gallstones. Hepatology 6529-531. 1986. Salen G. Nicolau G. Shefer S. Moshach EH: Hepatic cholesterol metabolism in patients with gallstones. Gastroenterology 69:676-684. 1975. Fromm H, Malavolti M: Dissolving gallstones. Adv Int Med 33:409-430. 1988. Danzinger RG, Hofmann AF. Schoenfield LJ, Thistle JL: Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 286:l-8. 1972. Schoenfield LJ, Lachin JM: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: the National Cooperative Gallstone Study. A controlled trial of efficacy and safety. Ann Intern Med 95:257-282. 1981. Salen G . Nicolau G , Shefer S: Chenodeoxycholic acid (CDCA) inhibits elevated hepatic HMG-CoA reductase activity in subjects with gallstones. Clin Res 21:523, 1973. Ahlberg J. Angelin B. Einarsson K: Hepatic 3-hydroxy-3methylglutaryl coenzyme A reductase activity and hiliary lipid composition in man: relation to cholesterol gallstone disease effects of cholic acid and chenodeoxycholic acid treatment. J Lipid Res 22:410-422, 198 1 . Schoenfield LJ. Marks JW: Formation and treatment of gallstones. In Schiff L. Schiff ER (Eds): Diseases of the Liver. Philadelphia, J.B. Lippincott. 1987. pp 1267-1288. Phillips MJ. Fisher RL. Anderson D, et al: Ultrastructural evidence of intrahepatic cholestasis before and after chenodeoxycholic acid therapy in patients with cholelithiasis: The National Cooperative Study. Hepatology 3:209-220, 1983. Albers JJ, Grundy SM. Cleary PA, et al: National Cooperative Gallstone Study: The effect of chenodeoxycholic acid on lipoproteins and apolipoproteins. Gastroenterology 82:638646. 1982. Tint GS, Ginsherg H. Salen G , et al: Chenodeoxycholic acid nornlalizes elevated lipoprotein secretion and catabolism in cerehrotendinous xanthomatosis. J Lipid Res 30:633-640, 1989.
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SEMINARS IN LIVER DISEASE-VOLUME Fedorowski T, Salen G. Colalillo A, et al: Metabolism of ursodeoxycholic acid in man. Gastroenterology 73: 1 13 1-1 137, 1977. Nilsell K, Angelin B. Leijd B, et al: Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid on bile acid kinetics and biliary lipid secretion in man: Evidence for different modes of action on bile acid synthesis. Gastroenterology 85: 1248-1256, 1983. Danzinger RG, Hofmann AF, Thistle JL. et al: Effect of oral chenodeoxycholic acid on bile acid kinetics and biliary lipid composition in women with cholelithiasis. J Clin Invest 52:2809-282 1 , 1973. Fedorowski T, Salen G, Tint GS. Mozbach EH: Transformation of chenodeoxycholic acid and ursodeoxycholic acid by human intestinal bacteria. Gastroenterology 77:1068-1073, 1979. Stiehl A, Raedsch R, Kommerell B: Increased sulfate of lithocholate in patients with cholesterol gallstones during chenodeoxycholate treatment. Digestion 12: 105-1 10, 1975. Marks JW, Sue SO, Pearlman BJ, et al: Sulfation of lithocholate as a possible modifier of chenodeoxycholic acid-induced elevations of serum transaminase in patients with gallstones. J Clin lnvest68:1190-1196, 1981. Salen G, Tint GS, Eliav B, et al: Increased formation of ursodeoxycholic acid in patients treated with chenodeoxycholic acid. J Clin Invest 53:612-661, 1974. Fromm H, Erbler HC, Eschler A, et al: Alterations of bile acid metabolism during treatment with chenodeoxycholic acid: Studies of the role of the appearance of ursodeoxycholic acid in the dissolution of gallstones. Klin Wochenschr 54:l 1251131, 1976. Bachrach WH, Hofmann AF: Ursodeoxycholic acid in the treatment of cholesterol lithiasis. Dig Dis Sci 27:333-356, 1982. Ward A. Brogden RN, Heel RC, et al: Ursodeoxycholic acid: A review of its pharmacologic properties and therapeutic efficacy. Drugs 27:95-13 I, 1984. Nakagawa S, Makino I. Ishizaki T, et al: Dissolution of cholesterol gallstones by ursodeoxycholic acid. Lancet 2:367369, 1977. Maton PN, Murphy GM, Dowling RH: Ursodeoxycholic acid treatment of gallstones: Dose-response study and possible mechanism of action. Lancet 2: 1297-1 301. 1977. Tint GS, Salen G. Colalillo A, et al: Ursodeoxycholic acid: A safe and effective agent for dissolving cholesterol gallstones. Ann Intern Med 97:351-356. 1982. Fromm H, Roat JW, Gonzalez V, et al: Comparative efficacy and side effects of ursodeoxycholic and chenodeoxycholic acids in dissolving gallstones. A double-blind study. Gastroenterology 85: 125 1-1264. 1983. von Bergmann K , Epple-Gutsfeld M. Leiss 0 : Differences in the effects of chenodeoxycholic and ursodeoxycholic acids on biliary lipid secretion and bile acid synthesis in patients with gallstones. Gastroenterology 87: 136-143, 1984.
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Salen G , Colalillo A, Verga D. et al: The effect of high and low doses of ursodeoxycholic acid in gallstone dissolution in humans. Gastroenterology 78: 14 12-141 8, 1980. Corrigan 01. Su CC, Higuchi WI. et al: Mesophase formation during cholesterol dissolution in ursodeoxycholate-lecithin solutions: A new mechanism for gallstone dissolution in man. J Pharm Sci 69:869-87 1 , 1980. Salvioli G, lgimi H, Carey MC: Cholesterol gallstone dissolution in bile: Dissolution kinetics of crystalline cholesterol monohydrate by conjugated chenodeoxycholate-lecithin and conjugated ursodeoxycholate-lecithin mixtures. Dissimilar phase equilibria and dissolution mechanisms. J Lipid Res 24:701720, 1983. Park Y-H, lgimi H, Carey MC: Dissolution of human cholesterol gallstones in simulated chenodeoxycholate-rich and ursodeoxycholate-rich biles: An in-vitro study of dissolution rates and mechanisms. Gastroenterology 87: 150-1 58, 1984. Leuschner U, Leuschner M, Sieratzki J. et al: Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up: A pilot study. Dig Dis Sci 30:642-649. 1985. Poupon R, Chretien Y, Poupon RE, et al: Is ursodeoxycholic acid an effective treatment for primary biliary cirrhosis'? Lancet 1 :834-836, 1987. Batta A, Salen G, Arora R. et al: Effect of ursodeoxycholic acid on b ~ l ea c ~ dmetabolism in primary biliary cirrhosis. Hepatology 10:4 14-419, 1989. Salen G: Clinical perspective on the treatment of gallstones with ursodeoxycholic acid. J Clin Gastroenterol 10 (Suppl 2):512-417. 1988. Frigerio G: Ursodeoxycholic acid (UDCA) in the treatment of dyspepsia: A report of a multicenter controlled trial. Curr Ther Res 26:214-224, 1979. Dowling RH. Gleeson D, Rupp~nDC. et al: Gallstone recurrence and post-dissolution management. In Paumgartner G, Stiehl A. Gerok W (Eds): Enterohepatic Circulation of Bile Acids and Sterol Metabolism, Falk Symposium 42. Lancaster, PA, MTP Press. 1985, pp 361-369. Roehrkasse R. Fromm. Malavolti M, et al: Gallstone dissolution treatment with a combination of chenodeoxycholic and ursodeoxycholic acids: Studies of safety. efficacy and effects on bile lithogenicity, bile acid pool and serum lipids. Dig Dis Sci 31: 1032-1040, 1986. Podda M. Zuin M, Battezzati M, et al: Efficacy and safety of a combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: A comparison with ursodeoxycholic acid alone. Gastroenterology 96:222-229, 1989. Ferrucci JT: Radiologic and ultrasonographic diagnosis of gallstones. J Clin Gastroenterol 10:522-524. 1988. Poupon R. Chretien Y, Darnis F: Cholesterol crystals, cholesterol saturation of bile and gallstones. Gastroenterol Clin Biol 8:260-263. 1984.
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10. NO. 3 , 1990
Oral Dissolution Treatment of Gallstones with Bile Acids GERALD SALEN, M.D., G.S. TINT, Ph.D., and SARAH SHEFER, Ph.D.
From the UMD-NJ Mediccil School, Newark. New J r r s r ~ the , Vc.tc,run.sAdministration Mrdicul Center, Eust Ortinge, New' Jer.se?., cind the Cuhrini Medical Center, New York, New York. Reprint requests: Dr. Salen, VA Medical Center, East Orange, NJ.
PATHOGENESIS OF CHOLESTEROL GALLSTONES In the United States, about 80% of gallstones are composed chiefly of cholesterol.' The remaining stones either contain mostly pigment or are calcified. Although not all the mechanisms of cholesterol stone formation are known, the liver plays a key role, because lithogenic bile, supersaturated with cholesterol, is produced in this organ. Briefly stated, the liver secretes an increased cholesterol load, which is too large to be solubilized in micelles that are formed by detergent bile acids synthesized by the liver.x During the interdigestive phase, when supersaturated bile is diverted to be stored in the gallbladder, nucleation and precipitation of cholesterol occur. Not only does diminished gallbladder motility favor gallstone formation,"" but nucleation is more rapid in gallbladder bile from subjects who have gallstones as the imbalance between nucleating and antinucleating factors induces crystallization and precipitation of cholesterol. I?-'' Thus, several abnormalities coexist: supersaturated bile, decreased gallbladder motility, and the presence of nucleating factors inherent in the bile. However, the secretion of supersaturated bile by the liver is the key pathogenic ingredient (see review by Hay and Carey in this issue of Seminars in Liver Disease). In many subjects who have cholesterol gallstones, the formation of lithogenic bile can be related to a hepatic metabolic abnormality, which has been identified as the combination of increased cholesterol synthesis and decreased cholesterol degradation to bile acids." Both pathways are shown in ~ i g u r e1 . Cholesterol is produced from acetate, and, although many enzymatic reactions are involved, the reduction of hydroxymethyl glutaryl coenzyme A (HMG-CoA) to mevalonic acid is considered the rate-limiting step, since virtually every molecule of mevalonic acid is committed to cholesterol biosynthesis. This reaction is catalyzed by the microsomal enzyme HMG-CoA reductase, and cholesterol biosynthesis is considered proportional to the activity of HMGCoA reductase. Similarly, in the formation of bile acids, the first step is the 7a-hydroxylation of cholesterol, which is also considered rate-limiting since every molecule of 7a-hydroxycholesterol passes to bile acids. This reaction takes place only in the liver and is catalyzed by the microsomal enzyme cholesterol 7a-hydroxylase. In
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It is estimated that 25 million Americans, or about 10% of the U.S. population, have gallstones." Although 1 million new cases are diagnosed annually, the magnitude of this problem may actually be underestimated, because most patients with gallstones remain asymptomatic and therefore often go ~ndetected.'.~ The most typical symptom of gallstones is pain (biliary colic), which is caused by the passage of small stones or gravel through the bile ducts. Generally, the pain is located in the right upper quadrant and radiates to the midline and back as the stones pass from the gallbladder through the cystic duct to reach the common bile duct and exit into the duodenum. Other common symptoms found in subjects who have gallstones include abdominal distension, belching, flatulence, nausea, and vomiting. These symptoms are often grouped together and called biliary dyspepsia. The etiology of biliary dyspepsia has not been defined and may not be related directly to the movement of the stones, but rather to muscular dysfunction of the gallbladder and bile ducts. Apparently, the presence of gallstones may adversely affect coordinated muscular contractions and may lead to dyskinesia of the gallbladder and bile ducts. This abnormal motor function may also allow for increased bile reflux into the stomach, resulting in so-called bile-reflux gastritis. Despite the imprecise knowledge of the cause, these symptoms, when present, tend to be recurrent, often follow eating, produce discomfort, and presage the development of more serious complications such as cholecystitis, obstructive jaundice, ascending cholangitis, and pancreatitis. The latter complications occur when stones move and obstruct the cystic, common bile, or pancreatic ducts. According to present therapeutic recommendations, the development of these complications of gallstones often requires immediate surgical intervention: about one-third (150,000) of the 500,000 cholecystectomies performed in 1987 were emergency operations.' The other two-thirds (350,000) of the cholecystectomies were performed as elective operations at a time when the patients were not acutely ill.
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Acetate
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abnormalities often leads to the accumulation of cholesterol in the liver and in turn to the hypersecretion of cholesterol into the bile, making it l i t h ~ g e n i c . ' ~
LITHOLYTIC BILE ACIDS At the present time, two bile acids are available for use in gallstone dissolution the rap^:^ chenodeoxycholic acid, or chenodiol (3a,7a-dihydroxy cholanoic acid), and ursodeoxycholic acid, or ursodiol (3cr,7P-dihydroxy cholanoic acid). Both occur naturally and both are present in human bile.Ix
Cholesterol
Chenodeoxycholic Acid
7-Alpha Hydroxycholesterol Cholic Acid FIG. 1. Synthesis of cholesterol and bile acids. By measuring HMG-CoA activity, the enzyme that catalyzes the reduction of HMG-CoA to mevalonic acid, cholesterol biosynthesis can be quantified. Similarly, bile acid synthesis is proportional to the formation of 7 a-hydroxycholesteroI, catalyzed by cholesterol 7 a-hydroxylase.
general, bile acid production is coupled to cholesterol formation, since newly synthesized cholesterol is the preferred substrate for cholesterol 7a-hydroxylase. A number of studies have examined the activities of both these enzymes in liver microsomes from subjects who had gallstones and control subjects who did not. The results are shown in Figure 2. In the subjects who had gallstones, bile acid synthesis is reduced, as evidenced by a 50% reduction in cholesterol 7a-hydroxylase activity. In contrast, HMG-CoA reductase activity is increased, which indicates that cholesterol is being overproduced. We believe that the combination of both
It has now been almost 20 years since chenodiol acid was demonstrated to be effective dissolution therapy for gallstones by Danzinger and others at the Mayo Clinic, IY.?" These investigators showed that chenodiol acid works by reducing hepatic cholesterol secretion and desaturating the bile. The mechanism apparently involves the suppression of hepatic cholesterol synthesis via the inhibition of the rate-controlling enzyme, HMGCoA reductase.?'.?' When chenodiol is given at a dose of 750 mglday, only 15% of patients' gallstones will be dissolved. Because only stones composed of cholesterol are effectively treated, the success rate can be increased when patients who have low body weights and who have small, floating, radiolucent (noncalcified) gallstones are selected." When stones are calcified or are composed of pigment, chenodiol is ineffective.
Side Effects and Toxicity Side effects and hepatic toxicity occur in a high percentage of patients treated with chenodiol, and, thus, the initial enthusiasm for this bile acid soon waned. Diarrhea, biochemical and morphologic evidence of hepato-
Cholesterol 7-alpha hydroxylase (b)
HMG-CoA Reductase (a)
p moles 60 rng protelnl minute 40
p moles l5 mg protein1 minute 10
5
20
0
0 Normal Controls (N = 8)
Gallstone Pat~ents (N=12)
Normal Controls (N = 4)
Gallstone Patlents (N = 9)
FIG. 2. Activities of the rate-controlling enzymes of cholesterol (a) and bile acid (b) synthesis in liver microsomes from subjects who had gallstones and control subjects who did not. Bar above represents + 1 SD. Statistical significance was determined by Student's t-test; (a) p = < 0.005 (b) p = < 0.001 .I7
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Mevalonate
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Ursodeoxycholic Acid Ursodiol is normally found in small amounts ( 1 to 2% of total bile acids) in human bile.35.'" It is also the major bile acid in several species of bears (hence the prefix "urso"). In the form of dried bear bile, or yu-tan, ursodiol has been part of Chinese and Japanese folk medicine for at least 1000 years. When it is administered in therapeutic doses (8 to 10 mgikgiday), complete dissolution of gallstone will occur over a period of 2 years in 30 to 60% of subjects, depending on the size and number of stones.3740Similarly to chenodiol, ursodiol works by reducing hepatic cholesterol secretion to desaturate the bile, although it is more potent than ~ h e n o d i o l . ~It' accomplishes this by several mechanisms. First, long-term treatment with ursodiol inhibits hepatic microsomal HMG-CoA reductase activity and, in turn, cholesterol synthesis." Since this enzyme controls the availability of mevalonic acid, suppression of enzyme activity correlates with decreased liver cholesterol synthesis. Second, intestinal cholesterol absorption is r e d u ~ e d . 'Two ~ factors seem to be responsible. Ursodiol micelles have less capacity to solubilize cholesterol; therefore less intestinal cholesterol is solubilized for absorption. Also, because hepatic cholesterol secretion into bile is reduced, less cholesterol is in the intestine to be absorbed." Finally, ursodiol does not inhibit hepatic bile acid ~ynthesis.'~."Apparently, 7P-hydroxy bile acids, unlike their 7a-hydroxy isomers, do not suppress cholesterol 7a-hydroxylase, the rate-controlling enzyme for bile acid synthesis. As a result, 300 to 600 mg of hepatic cholesterol continues to be transformed to bile acid each day and removed from the hepatic cholesterol pool. However, although less cholesterol enters the bile of ursodiol-treated subjects, this advantage is partially offset by the fact that bile acid micelles that are composed principally of ursodiol conjugates have a reduced capacity to solubilize and transport c h ~ l e s t e r o l . ~Thus ' . ~ ~., it would appear that less cholesterol can be removed from the gallstones. Fortunately, an additional mechanism operates to eliminate cholesterol, which involves the formation of liquid crystal complexes of cholesterol.434' These stable dispersions result when cholesterol is removed from the stone, and they are apparently prevented from reprecipitating by the ursodiol-rich bile. When the gallbladder contracts, the liquid crystals of cholesterol are secreted from the gallbladder into the intestine.
Toxicity and Side Effects No abnormal liver morphology or elevations in liver function test values have been noted even after 5 or more years of ursodiol therapy.is,3hIn fact, ursodiol is now being used experimentally to treat patients who have several chronic progressive liver diseases: primary biliary cirrhosis, sclerosing cholangitis, and chronic active hepa t i t i ~ . ~ ' - 'Preliminary ~ results are most encouraging in that both the clinical manifestations (pruritus and fatigue) and the biochemical parameters improve with ursodiol therapy. No patients' conditions worsened and liver histology actually improved in several patients who
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toxicity, and hypercholesterolemia are the principal problems reported. Since chenodiol is synthesized in the human liver at a rate of 150 to 250 mgiday, it was expected to be reasonably safe when administered orally. However, about 20% of patients develop watery diarrhea when they are given 750 mgiday. Transient elevations of serum transaminases, alkaline phosphatase, and unconjugated bilirubin are also noted in 15% of subjects.'" Biopsy specimens taken from 126 subjects showed liver damage with ballooning of hepatocytes, lipofuscin-like pigment deposition, ductular proliferation, and fibrosis in the portal triads after 2 years of therapy with 750 mgiday of chenodeoxycholic acid.'%lthough these changes were not judged to be clinically significant, they preclude the use of chenodiol in individuals who have preexisting liver disease or moderately abnormal liver function tests. Plasma cholesterol levels generally increase up to 15% in patients who are taking therapeutic doses (750 to I000 mglday). Most of the increase is confined to the low density lipoprotein (LDL) cholesterol fraction." Apparently, chenodiol down-regulates the formation of LDL receptors and slows the clearance of plasma LDL." Because of this rise in plasma cholesterol, chenodiol is not recommended for use in the treatment of symptomatic gallstones in patients who have hypercholesterolemia or atherosclerosis. Elevated plasma triglyceride levels may decline by as much as 2O%." Unfortunately. little symptomatic relief is afforded during chenodiol therapy until gallstones have dissolved.'" This may limit compliance to long-term therapy. During treatment with 750 to 1000 mglday, chenodiol becomes the major bile acid secreted into the bile, accounting for more than 80% of the biliary bile acid^.'^.?^ The proportions of cholic acid and its 7-dehydroxylated bacterial derivative, deoxycholic acid ( 3 a , l2a-dihydroxy cholanoic acid) decline. This is indicative of the suppression of endogenous bile acid synthesis via the inhibition of the rate-controlling enzyme, cholesterol 7a-hydroxylase. Another important chemical characteristic of treatment with chenodiol is that the level of lithocholic acid (3a-hydroxy cholanoic acid), a potentially toxic cholestatic bile acid, increases in the bile." This monohydroxy bile acid is produced from chenodiol through the action of anaerobic intestinal bacteria, which remove the 7a-hydroxy group."' In humans, as contrasted with rabbits and monkeys, most lithocholic acid is conjugated and secreted as the sulfate derivative, which increases its solubility and lessens its toxicity."." However, the capacity to sulfate varies among humans and "low sulfators" may be more susceptible to potential lithocholic acid-induced hepatic toxicity. This may account for the rise in serum transaminase levels in some chenodiol-treated subjects. Another important bacterial product of chenodiol is its 7P-hydroxy epimer, ursodiol. In patients treated with therapeutic doses of chenodiol (750 to 1000 mglday) 3 to 50% of the biliary acids become ursodi01."~'~ This metabolic pathway involves 7-keto-lithocholic acid as the key intermediate; the 7Preduction of the keto group is carried out by intestinal bacteria rather than by the liver.
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have chronic active hepatitis during treatment.16 Serum cholesterol levels do not increase during ursodiol therapy, a finding that may reflect the fact that hepatic LDL receptors are not down-regulated, as seen with chenodi~l.'~ Diarrhea has been infrequently encountered in ursodiol-treated subjects. About 1% of subjects have reported loose stools that have improved either spontaneously or after a temporary downward adjustment of the dose.-" Furthermore, symptoms of biliary colic and dyspepsia (bloating, belching, abdominal distension, flatulence, nausea, and vomiting) were reported much less frequently during ursodiol treatment. Interestingly, this improvement in symptoms occurred within the first 3 months of therapy, before the gallstones have dissolved completely, and the improvement persists throughout the duration of treatment.35-4' Although our study was not rigorously controlled, several reports from Italy performed in double-blind fashion indicated similar relief of symptoms with ursodiol and virtually no improvement " explanation for the relief of sympwith p l a ~ e b o . ~The toms may relate to desaturation of the bile (disappearance of cholesterol crystals), choleresis, or possibly to relaxation of the smooth muscle of the gallbladder and bile duct. Nevertheless, the improved quality of life (less pain and diet restriction) for the subjects with gallstones is a major advantage of treatment with ursodiol and improves the compliance since long-term therapy is required to dissolve stones. When ursodiol is administered orally, it is absorbed and excreted mostly as the glycine conjugate. Since more ursodiol is conjugated by the liver and excreted into the bile, the hepatic taurine pool becomes depleted when the daily dosage is increased from 4 up to 20 mgl kglday. However, after treatment. only about 50% of the biliary bile acids are ursodiol." This is unlike treatment with chenodiol, in which more than 80% of the biliary bile acids are chenodiol.".'* Actually. there is very little further enrichment of the bile with ursodiol when a dosage of more than 10 mglkglday is administered. For that reason, the recommended therapeutic dosage of ursodiol for dissolving gallstones is 600 mglday. The explanation for the inability to increase the amount of ursodiol in the bile may lie in the fact that 7P-hydroxy bile acids like ursodiol do not inhibit cholesterol 7a-hydroxylase, the rate-limiting enzyme for bile acid synthesis. As a consequence, there is continued synthesis of endogenous cholic acid and chenodiol. Also, chenodiol is produced from ursodiol by intestinal bacteria." Therefore, the endogenous bile acid pool cannot be replaced by ursodiol. After gallstones have dissolved, discontinuation of either chenodiol or ursodiol therapy leads to the reexpression of the hepatic metabolic abnormality. With the renewed secretion of lithogenic bile, stones may recur. It has been reported that stones have reappeared at the rate of 10% per year, and up to half of the subjects have reformed stones." However, if the recurring stones produce symptoms, then retreatment with ursodiol should effectively redissolve the stones. In some subjects, treatment with nonsteroidal anti-inflammatory agents or low doses of ursodiol may retard stone recurrence, but main-
10, NUMBER 3, 1990
tenance therapy to prevent stone reformation cannot be recommended at this time.
Combination Bile Acid Treatment Recent reports have suggested that the combination of ursodiol with chenodiol is a more effective choice for litholysis than either bile acid alone.",53 The putative advantage of the combined therapy is that the dose of each bile acid in the combination is only approximately 50% of the dosage required for individual therapy. Also, the side effects and toxicity of chenodiol are not encountered when it is combined with ursodiol. Apparently, ursodiol exerts a protective action when it is given with chenodiol. The efficacy of the combination is similar to that of the individual bile acids, but may be more rapid initi all^.'^ Despite these apparent advantages, it is important to emphasize that when ursodiol is administered individually, bile contains substantial quantities of chen ~ d i o l . ~Apparently, ' some of the ursodiol that is administered is transformed to chenodiol by intestinal bacteria." In addition, because ursodiol does not suppress hepatic bile acid synthesis, the formation of endogenous chenodiol continues. Thus, treating with ursodiol alone results in a mixture of ursodiol and chenodiol in the enterohepatic circulation.
SELECTION OF PATIENTS Litholytic bile acid therapy is not suitable for all patients who have gallstones; unlike surgery, in which all stones as well as the gallbladder are removed, the orally administered litholytic bile acids, chenodiol and ursodiol, are only effective on noncalcified cholesterol stones. Therefore, a knowledge of the stone composition is a helpful prerequisite for selecting medical therapy. In addition, the biggest stones should be less than 2.0 cm in greatest diameter; smaller stones dissolve more rapidly. Also, it is important to note that the cystic duct must be patent to ensure that hepatic bile that is enriched with the litholytic bile acids can reach the gallstones. Several techniques are available to assist in the diagnosis and evaluation of gallstones for nonsurgical treatment. Ultrasound imaging is the most widely used and is the most sensitive technique to establish the diagnosis and the number of stones.54 It can also be used to estimate size when the stones are smaller than 2.0 cm in diameter. Also, since it is not invasive, ultrasound is useful to follow the course of dissolution of stones that are being treated medically. The oral cholecystogram is an older x-ray technique, in which a iodinated fatty acid is administered orally, absorbed from the intestine, conjugated in the liver, and concentrated in the gallbladder. Radiographs taken the next day reveal the opacified gallbladder, and stones are visualized as negative images. A positive oral cholecystogram proves that the cystic duct is patent and also is helpful in demonstrating the presence of calcium in gallstones. Because the density of the concentrated contrast medium is greater than that of water, stones that float are considered to be enriched
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with cholesterol. An inability to visualize the gallbladder after the ingestion of the radiopaque dye may indicate obstruction of the cystic duct by stones, a find that precludes the use of orally administered bile acid therapy. Alternatively, the cystic duct may be patent, but the gallbladder may be nonfunctional as a result of damaged mucosa after an attack of cholecystitis. In that case, the gallbladder cannot be visualized because of its inability to concentrate the dye. To detect this situation, intestinal bile drainage followed by the injection of cholecystokinin to stimulate the gallbladder to contract may yield concentrated bile from the gallbladder. This technique also helps to establish the patency of the cystic duct. Microscopic examination of the bile often shows the presence of cholesterol crystals, which signifies that the gallstones are composed of cholesterol and will be suitable for litholytic bile acid therapy.s5 Alternatively, the demonstration by ultrasound imaging of a 50% decrease in gallbladder volume after stimulating the gallbladder with cholecystokinin or a fatty meal is good evidence for a patent cystic duct.
CONCLUSIONS Cholesterol gallstone disease is reversible. These gallstones may be dissolved medically with either chenodiol or ursodiol. Both bile acids work by correcting the hepatic metabolic defect that is responsible for the hypersecretion of cholesterol into the bile and by desaturating the bile. Ursodiol is the preferred treatment because it is more effective; it desaturates bile to a greater degree than chenodiol does, and it eliminates cholesterol as stable liquid crystalline dispersions. Also, neither toxicity nor significant side effects have been noted during therapy with ursodiol. Marked improvement of symptoms and quality of life are often seen early during this treatment and help ensure compliance with long-term therapy. A ~ . k r l o \ t ~ l e d g ~ n r n Supported t. by U.S. Public Health Service grants DK 18707 and HL I78 I 8 and the Veteran\ Adnlinistration Research Service.
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