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Gallstone Dissolution
Biliary Tract Surgery
0039-6109/90 $0.00 + .20
Gallstone Dissolution
Mark A. Talamini, MD, * and Thomas R. Gadacz, MDt
Gallstone formation continues to be responsible for a significant measure of disease and disability throughout the world, particularly in the Western hemisphere. Over the last 50 years, removal of the gallbladder has been the primary mode of therapy for gallstone disease. Prevention of the formation of gallstones or the ability to dissolve gallstones would more easily and safely solve this problem. The concept of gallstone dissolution by oral or topical agents has been popular over the last decade as an alternative to cholecystectomy. This concept is not new. In 1873, Maurice Schiff proposed the ingestion of oral bile salts as a treatment for gallstones. Fifty years later, the first report of successful oral gallstone dissolution was reported by Newbridge from the University of Minnesota. In his report, two of five patients who were fed bile salt mixtures were rewarded with stone dissolution. The clinical use of chenodeoxycholate surfaced in the 1970s. It was found that this primary bile salt reduced the cholesterol saturation of bile. 47, 57 Clinical trials were then undertaken with both oral chenodeoxycholate and its 7-beta epimer, ursodeoxycholate." 12 Topical infusion for impacted stones is likewise not a new concept. In 1891, Walker used ether to dissolve such stones. Since then, a number of agents have been used, including chloroform, olive oil, ether, heparin, and warm saline. These all can be applied via a T-tube in an attempt to dissolve or dislodge retained common duct stones. The rapid development of interventional radiology and endoscopic retrograde cholangiopancreatography (ERCP) has made topical dissolution of gallstones more widely available and applicable. Further technological developments have included ultrasonic, electrohydraulic, or laser systems to fragment gallstones in conjunction with sophisticated access approaches. The rapid proliferation of these technologies has made the choices for an individual patient confusing. Knowledge of the pathogenesis of choles*Assistant Professor of Surgery, Department of Surgery, The Johns Hopkins University, Baltimore, Maryland tProfessor of Surgery, The Johns Hopkins University; and Chief, Surgical Service, Baltimore VA Medical Center, Baltimore, Maryland
Surgical Clinics of North America-Vol. 70, No.6, December 1990
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terol and pigment gallstone formation is helpful in making appropriate decisions.
GALLSTONE PATHOGENESIS A thorough discussion of gallstone pathogenesis is provided in the previous article. In brief, gallstones are classified as cholesterol or pigment stones on the basis of their predominant component. Cholesterol gallstones contain more than 60% cholesterol by weight, and pigment stones contain less than 25% cholesterol by weight. Cholesterol Gallstone Formation In the West, 70% to 80% of patients with cholelithiasis have gallstones that are primarily cholesterol. Bile contains cholesterol, bile salts, phospholipids, electrolytes, and proteins. When cholesterol represents more than 10% of the biliary lipid concentration, it tends to precipitate. For a cholesterol stone to form, the excess cholesterol must coalesce by a process termed "nucleation." In heterogenous nucleation (which creates type 1 stones), cholesterol precipitates about other particulate matter in the gallbladder such as sloughed cells, protein, or crystals. Most cholesterol stones are of this type. They tend to be multiple, ranging in size from 0.5 to 2.5 cm. Approximately one third are radiopaque. In homogenous nucleation (which creates type 2 stones), cholesterol crystals serve as their own nidus. These stones tend to be solitary and larger than type 1 stones. Fifty to seventy per cent of gallstones in patients in the United States are type 1 stones, whereas 5% to 20% are type 2. There are a number of factors that render a patient susceptible to cholesterol gallstone formation. 9 These include increased hepatic cholesterol synthesis, decreased bile-salt pool size, and hormonal influences. Increased hepatic cholesterol synthesis is directed primarily by genetic factors and secondarily by diet. Bile salt deficiencies occur most commonly in conditions that interrupt the enterohepatic circulation of bile, such as ileal resection, Crohn's disease, and cholestyramine administration. Hormonal balance can influence both cholesterol synthesis and biliary motility. Increased estrogen levels in pregnant women and in those taking oral contraceptives are probably responsible for the increased incidence of gallstones. 10 Because the pathogenesis of cholesterol stones involves a number of factors, a variety of approaches might be valuable for the dissolution or prevention of gallstones. One strategy is to decrease the hepatic synthesis of cholesterol. At present, our only means of accomplishing this is by influencing hepatic cholesterol synthesis. In the future, a more potent pharmacologic approach to the reduction of hepatic cholesterol synthesis may hold the key to the medical prevention of gallstone formation. Another potential tactic is to increase the synthesis of phospholipids. Attempts to do this with oral lecithin supplements have not been effective. The method that has had the most success is expansion of the bile salt pool via oral bile salt ingestion. Bile salts solubilize cholesterol, as well as bilirubin and calcium. This method allows dissolution of cholesterol gallstones by main-
I
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taining the cholesterol in solution. Another technique, frequent gallbladder emptying, can be accomplished pharmacologically. This mode of therapy prevents cholesterol gallstones in experimental animals;" but it has not been attempted clinically. Pigment Gallstone Formation Less is known about pigment gallstone formation. Two different types of pigment stones occur and probably form by different mechanisms. In both cases, ionized calcium complexes and bilirubinate exceed their solubility products and precipitate as an insoluble salt." Brown pigment stones occur commonly in Asian patients and are similar to the recurrent common bile duct stones found in Western patients." A diet low in protein and high in carbohydrate appears to predispose to brown pigment stones. Black pigment stones occur in three distinct clinical settings in the Western world: hemolysis, cirrhosis, and advanced AIDS. These stones also occur commonly in Occidental patients. In one study from the US, black pigment stones accounted for 27% of the stones recovered from patients undergoing cholecystectomy. 53 Black pigment stones contain calcium phosphate and calcium carbonate, causing 50% of these stones to be radiopaque. Any condition that decreases red cell life, such as malaria, hemoglobinopathy, red cell membrane defects, and prosthetic heart valves, is associated with the formation of pigment gallstones." Patients with sickle cell anemia have a IO-fold increase in bilirubin secretion, causing an increased incidence of pigment gallstone formation. In cirrhosis, the causative factors appear to be increased production of unconjugated bilirubin, decreased output of hepatic biliary bile salts, and possibly nutritional deficits. 9, 53 The incidence of both pigment and cholesterol stones increases with age in the US. 7 , 11 One potential explanation for this observation is diminished gallbladder emptying secondary to an altered hormonal milieu that develops with increasing age. Stasis may then predispose to pigment gallstone formation, as well as to cholesterol gallstone formation. The idea of biliary motility affecting gallstone formation has recently been resurrected, having initially been considered to be important more than a century ago. A number of clinical conditions provide indirect evidence that impaired biliary motility promotes gallstone formation. For instance, patients who have had a vagotomy or who are receiving total parenteral nutrition have unchanged cholesterol saturation levels, but both groups have impaired gallbladder emptying and increased frequencies of cholelithiasis. 8, 33, 34
ORAL BILE SALTS Dissolution of gallstones depends on several factors. The patient must be able to adhere to a long-term treatment program. Realistically, success can be anticipated only in patients with cholesterol stones, and 6 months to 4 years is required for complete dissolution of the stones. Dissolution usually will be successful if the stones significantly decrease in size during the first 9 months of treatment. The efficacy and safety of drugs must
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always be weighed against the slight morbidity and mortality rates of conventional operative therapy. Predictors of gallstone composition are helpful, because, as noted, dissolution is likely to be successful only for cholesterol stones. If radiolucency alone is used as a criterion, the success rate will be 20% to 30%,7 because this is the proportion of patients who will actually have cholesterol stones. The most reliable method for determining gallstone composition is an analysis of gallbladder bile. This method requires duodenal bile aspiration via a duodenoscope during gallbladder stimulation. If the cholesterol content exceeds 100/0, the bile can be assumed to be saturated with cholesterol, and the stones can be assumed to be cholesterol stones. This determination requires that the patient undergo an uncomfortable and costly procedure. 7 Alternatively, a multivariate analysis using gallstone size, buoyancy, surface characteristics, and calcification patterns has been developed. This methodology can predict gallstone composition accurately in 90% of patients. 13 Other clinical factors affect the success of dissolution therapy with oral bile salts. Obese patients have lower dissolution rates, although this may be a dosing problem. A normally functioning gallbladder, as documented by an oral cholecystogram, is necessary for the ingested bile salts to find their way into the gallbladder. Patients with very large numbers of stones or stones greater than 2 em in diameter have lower success rates. Currently, two approved drugs that can be taken orally are effective in dissolving gallstones. 19 Chenodeoxycholate has been available longer. It is a normally occurring bile salt in humans and is synthesized by the liver. Ursodeoxycholate has recently been approved and is now in clinical use. It is found only in trace amounts in human subjects. Ursodeoxycholate is an epimer of chenodeoxycholate that also happens to be the primary bile salt of the polar bear, hence the urso. Chenodeoxycholate Chenodeoxycholate is normally found in human bile and is a primary bile salt, comprising 30% to 40% of the total bile salt pool (Fig. 1). Chenodeoxycholate is more effective in decreasing cholesterol saturation than is the other predominant primary bile salt, chelate." 12 The mechanism of action appears to be alteration of bile composition by a decrease in the endogenous hepatic synthesis of cholesterol and the exogenous expansion of the bile salt pool. 23 It is not clear which of these mechanisms is of greater importance. The net result is the production of a bile that is less saturated
A OH·"
B OH··
Figure 1. Chemical structures of chenodeoxycholic acid (A) and ursodeoxycholic acid (B).
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with cholesterol. 14 The actual dissolution of gallstones probably takes place because of the molecular alteration of cholesterol from the simple crystalline state to that of unsaturated mixed micelles. A significant concern regarding the clinical use of chenodeoxycholate has been its conversion by enteric flora into lithocholate, a known hepatotoxin.f" Studies have reported elevated liver enzymes in as many as 25% of patients receiving chenodeoxycholate.:" In addition, as many as 25% of patients have had diarrhea. Both of these problems have led to cautious, and in some trials, subtherapeutic dosing. Considerable data concerning the use of chenodeoxycholate have come from the National Cooperative Gallstone Study. This was a multicenter, double-blind, prospective trial that assigned 916 patients to one of three treatment groups: (1) 375 mg of chenodeoxycholate daily; (2) 750 mg of chenodeoxycholate daily; or (3) a placebo." After 2 years, the result were analyzed (Table 1). This study demonstrated significant but reversible liver injury in 3% of the patients who were taking 750 mg per day. Eight per cent of the patients reported diarrhea, but no patient was forced to abandon the medication as a result. Of perhaps more concern was the mild elevation (10 mg/dl) of the mean total serum cholesterol and low-density lipoprotein cholesterol levels seen during chenodeoxycholate therapy. 38, 39 The patients in the high-dose chenodeoxycholate group experienced complete gallstone dissolution in only 14% of cases and partial dissolution (defined as a greater than 50% decrease in gallstone size) in 27%. These results were considerably poorer than those published previously in nonrandomized studies (up to 70% success). The best results were seen in women below ideal body weight who had stones less than 1.7 mm in size and a normal serum cholesterol level (Fig. 2). This group had a success rate of 38%. Dissolution was less successful in all groups when the lower dose was used. The conclusion of this study was that chenodeoxycholate at a dose of 750 mg per day does have a role in the treatment of selected patients with gallstones." Critics of the study point out that of the total 611 patients treated over a 2-year period, only 50 subjects had complete gallstone dissolution, for an overall 8% success rate. Further problems with the study include the 15.3% dropout rate, an unchanged frequency of abdominal pain in the patients studied, and a high rate of continued need for cholecystectomy in all treatment groups. This study also disclosed a recurrence rate of 25% to 50% after cessation Table 1. Results of the National Cooperative Gallstone Study PER CENT WITH DISSOLUTION
NO. OF GROUP
Placebo Chenodeoxycholate (mg/day) 375 750
PATIENTS
Partial
305
10
306 305
18 27
Complete
5 14
Data from Schoenfield LJ, Lachin JM, the Steering Committee and the National Cooperative Gallstone Study Group: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study. Ann Intern Med 95:257, 1981.
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Figure 2. Oral cholecystogram demonstrating a functioning gallbladder with multiple small, floating gallstones. A young, thin woman with this situation is likely to have the best results from oral bile acid therapy.
of therapy. Therefore, it is possible that patients who obtain gallstone dissolution will require further therapy, perhaps at a lower dose, although low-dose prophylactic chenodeoxycholate treatment has not been demonstrated to prevent recurrences. In addition, in patients with partially dissolved gallstones, administration of chenodeoxycholate after 2 years has shown only limited efficacy in further dissolution of the stones. Concern about the drug's effect on lipid metabolism caused the investigators to caution against use of chenodeoxycholate for longer than 2 years.:" There also are questions regarding its efficacy and risk during pregnancy. In summary, chenodeoxycholate is best used in patients with floating radiolucent gallstones, those who are under 60 years of age, and those who are at increased operative risk with cholecystectomy. The preferred dose is 14 to 16 mg/kg per day. Monitoring of liver enzymes is necessary, and treatment should be continued for 3 months beyond the point where stones are no longer evident radiologically or for 16 months if there are no evident changes in gallstone size. Close monitoring for recurrence is important. U rsodeoxycholate U rsodeoxycholate is the 7-beta-hydroxy epimer of chenodeoxycholate (see Fig. 1). Oral administration of ursodeoxycholate increases its contribution to the bile salt pool. The result is a bile salt composition consisting of as much as 500/0 ursodeoxycholate. U rsodeoxycholate was a component of an over-the-counter hepatic tonic sold in Japan, which was found to be effective in dissolving gallstones. Following this, in 1974, reports of gallstone dissolution appeared in the Japanese literature in patients who were treating themselves with large doses of a product containing ursodeoxycholate. When taken orally, ursodeoxycholate is absorbed efficiently in the ileum as an unconjugated bile salt and is transported to the liver in the portal blood. In the hepatocyte, ursodeoxycholate is conjugated with glycines or taurines and excreted into the bile. The conjugates are efficiently reabsorbed, transported to the liver, and re-excreted into the bile. In the small bowel, bile salts may be transformed to secondary bile salts by bacteria. In this manner, ursodeoxycholate can also form the toxic lithocholic
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salt. Other effects of ursodeoxycholate are increased bile output, choleresis, and increased secretion of phospholipids. Ursodeoxycholate and chenodeoxycholate differ fundamentally in their mechanism of gallstone dissolution. Ursodeoxycholate forms smaller micelles because of the orientation of a single hydroxyl group. Therefore, ursodeoxycholate accomplishes solubilization primarily by a non micellar mechanism. Another effect of this mechanism is that ursodeoxycholate causes a relative decrease in cholesterol absorption from the gut. Clinical trials have shown lower rates of diarrhea and hepatotoxicity in trials comparing ursodeoxycholate with chenodeoxycholate.F' 58 Ursodeoxycholate seems to be more resistent to bacterial transformation into lithocholate.:" In general, liver enzymes are not elevated as significantly in clinical trials with ursodeoxycholate.?" In addition, diarrhea occurs in less than 5% of patients. The placebo-controlled randomized studies available of the efficacy of ursodeoxycholate indicate that it does dissolve cholesterol gallstones over a period of 6 to 12 months when a dose of 8 to 10 mg/kg per day is used." Therapy beyond 12 months does not improve the response, although partially dissolved stones may continue to dissolve with additional treatment. Thirteen per cent of patients in one study experienced worsening of biliary symptoms progressing to cholecystectomy during treatment. This was also the case in trials of chenodeoxycholate. 29, 58 Stone recurrence may also be a problem with ursodeoxycholate. Patients not given long-term treatment after successful dissolution have been reported to have a recurrence rate of 69% at 5 years;" whereas those treated with ursodeoxycholate after dissolution had only a 32% recurrence rate at 7 years (Table 2). Overall, the recurrence rate plateaued at 7 years. The age of the patient and the number of stones influenced the rate of recurrence: those older than age 50 received no benefit from postdissolution therapy, whereas those younger than 50 had a 16% recurrence rate when treated and a 69% rate when not treated. With no postdissolution treatment, patients with solitary stones had a recurrence rate of 32% compared with 77% in those who had multiple stones. These data suggest that ursodeoxycholate will be less effective in older patients and in those with a single stone. In general, ursodeoxycholate appears to have fewer side effects, work more rapidly, and cause less hepatotoxicity. In patients with small, floating, radiolucent cholesterol gallstones, partial or complete dissolution can be expected in 40% to 55% of those treated with ursodeoxycholate for 6 to 12 months. 19 Table 2. Gallstone Recurrence Rates (Lifetable Analysis) after Dissolution GROUP
UDCA 300 mg/day None All
NO. OF PATIENTS
RECURRENCE (PER CENT)
36 60 96
32 (7 years) 68 (5 years) 61 (11 years)
Data from Villanova N, Bazzoli F, Taroni F, et al: Gallstone recurrence after successful oral bile acid treatment: A 12 year follow-up study and evaluation of long-term postdissolution treatment. Gastroenterology 97:726, 1989.
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Chenodeoxycholate Versus U rsodeoxycholate Clinically, ursodeoxycholate and chenodeoxycholate appear to be equally efficacious in accomplishing gallstone dissolution. Table 3 summarizes the published uncontrolled comparisons of the two agents. In some of these studies, success rates were similar when equivalent doses were used. In the study by Barbera and coworkers," a higher dose of chenodeoxycholate, 15 mg/kg of body weight per day, was required to achieve the same results as were achieved with 5 or 10 mg of ursodeoxycholate per kg per day. Table 4 reviews the available prospective randomized trials comparing ursodeoxycholate and chenodeoxycholate. One of these studies stands out in demonstrating greater efficacy of ursodeoxycholate than of chenodeoxycholate. 17 In this study, by Fromm and coworkers from the University of Pittsburgh, groups of patients were given ursodeoxycholate in doses of 400 mg or 800 mg per day or chenodeoxycholate in doses of 375 mg or 750 mg per day. At 12 months, with the groups analyzed together, significantly more stones were dissolved in the patients receiving ursodeoxycholate than in those receiving chenodeoxycholate. At 24 months, ursodeoxycholate continued to show increased dissolution, but the difference was not statistically significant. Thus, chenodeoxycholate appears to have the ability to "catch up" in time with the dissolution rate of ursodeoxycholate. Ursodeoxycholate may dissolve gallstones more rapidly because of its dual micellar and nonmicellar mode of action. Those investigators also demonstrated a decreased incidence of hepatic toxicity and diarrhea with ursodeoxycholate. Table 3. Results of Uncontrolled Comparisons of Ursodeoxycholic Acid (UDC) and Chenodeoxycholic Acid (CDC)
SOURCE
Barbara et al5
Bateson et al"
Iwamara et aF2 Meredith et al30 Fromm et al'? Roda et aP5
NA
=
NO. OF RESPONSES
DAILY
NO. OF
DRUG
DOSE (MG)
PATIENTS
Complete
Partial
UDC UDC CDC CDC UDC UDC CDC CDC UDC CDC UDC CDC UDC CDC UDC UDC CDC CDC
5/kg 10/kg 7/kg 15/kg
34 36 70 71
9 9 8 10
21 20 28 46
88 81 51 79
500 1000 750 1000
13 24 41 33
NA NA NA NA
NA NA NA NA
38 42 22 58
300-600 300-600
12 18
2 2
1 2
25 22
2.5-15/kg 13-15/kg
65 83
13 24
34 43
72 81
400-800 375-750
4 9
4 1
3 2
55 33
7-8/kg 14-15/kg 7-8/kg 14-15/kg
58 52 55 58
21 21 12 24
21 20 19 21
72 78 57 78
not available.
SUCCESS RATE
(%)
In addition, serum cholesterol and low-density lipoprotein cholesterol elevations occurred with chenodeoxycholate but not with ursodeoxycholate. 3 A comparison of the toxicities of these two agents is provided in Table 5. Because these two agents appear to work by slightly different mechanisms, it has been suggested that a combination administered concurrently might be more efficacious and less expensive. Preliminary data on such combination therapy have suggested that it is, in fact, more effective than either agent alone.!" With regard to cost, the average annual expense per year of chenodeoxycholate therapy ranges from $1300 to $1600. 58 This cost must be compared with the average one-time cost of cholecystectomy ($6000 to $10,000).
TOPICAL AGENTS Various solutions are effective in dissolving stones within the biliary tree when direct access to the stone is available via a tube. These substances are likely to be effective only in dissolving cholesterol stones. Table 5. Relative Toxicities of C henodeoxycholicAcid ( C DC) and Ursodeoxycholic Acid (UDC)
Transaminemia Diarrhea Increased LD L cholesterol Gallstone calcification
CDC
UDC
1+ 1+ 1+ ±
1+
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Success with such an approach depends on the compound's ability to dissolve the main constituents of the stone and good contact with the stone. Such a solution must also be safe with regard to its effect on the bile ducts, liver, intestine, and the patient as a whole. There are a number of commonsense precautions. First, the solution cannot be infused under pressure or into liver parenchyma. Second, the solution must be able to exit to the intestine or to the outside. Third, there should be no leak from the biliary tree into the peritoneal cavity. This situation could occur around a T-tube or after endoscopic papillotomy. The solution is administered by way of aT-tube or a biliary stent. 11 A manometer is placed in the circuit between the solvent and the patient and cut off between 20 and 30 em so that greater pressures within the circuit are impossible. This maneuver also allows intrabiliary pressure to be monitored by both the patient and the medical staff. If the stone is obstructing the distal portion of the duct, a small catheter can be inserted through the T-tube and the solution infused directly on the stone. This then allows fluid to exit back through the remaining lumen of the T-tube. Ether, Chloroform, Saline, and Heparin Ether, chloroform, saline, and heparin have all been used in the past for topical dissolution. Ether is dangerous because of its vaporization at body temperature: 1 ml of liquid ether becomes 2.24 L of gas above 95°F. 44 Chloroform is an excellent cholesterol solvent but has unacceptably severe side effects, such as central lobular hepatic necrosis, duodenal ulceration with hemorrhage, and even death." Infusion of saline is essentially a flushing technique, which has a success rate of 20%,37 not significantly different from the rate of spontaneous stone passage. Heparin has been used as a topical agent, although it is not a good cholesterol solvent. Prospective trials have shown no superiority of heparin over saline. 45, 55 Sodium Cholate Sodium cholate was the most commonly used topical dissolution agent for many years. It is synthesized naturally in the liver and can be manufactured easily. Because it is not a particularly good cholesterol solvent, therapy may require several weeks." and a success rate of only 65% to 70% can be expected. Severe side effects such as bacteremia, sepsis," and even death secondary to intrahepatic infusion" have essentially eliminated the use of this agent. Mono-octanoin Mono-octanoin is a medium-chain diglyceride that is a normal digestive product of medium-chain triglyceridcs.F: 49 Its primary advantages over sodium cholate are its effectiveness as a cholesterol solvent and its relative safety in terms of hepatic duct inflammation. One of the authors (TRG) has developed a modified infusion technique for mono-octanoin administration. 18 Sixty-two per cent of patients with retained stones obtained dissolution with mono-octanoin, which was buffered to pH 7.4 and infused at a rate of 3 to 7 ml/hour by pump. The average time required was 5 days.
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Intrabiliary pressures ranged from 2 to 12 em H 20 . Various studies have produced success rates between 50% and 86%.20,25,26,42,43,52 As with other solvents, gallstones composed mainly of cholesterol are far more like to dissolve than pigment stones. Gallstones with a cholesterol content of 40% or more have a 91% chance of dissolving within 7 days of therapy. 40 It is best to save gallstones removed from the gallbladder or common bile duct in a dry state. If stones are present on a postoperative T-tube cholangiogram, and if there is no leak from the choledochotomy, sample stones can be analyzed for cholesterol content or simply incubated with mono-octanoin at 37°C. If the stones appear to be soluble, therapy is likely to be successful. This method of treating retained common duct stones obviates the 6- to 8-week wait necessary for a T-tube tract to mature before mechanical extraction can be attempted. It also does not require the technical expertise of ERCP. Side effects of mono-octanoin have been reported. 1 Its instillation into the free peritoneal cavity in rats results in a high mortality rate with volumes in excess of 0.35 ml in a 150-gm rat. Mono-octanoin perfusion also disrupts the gastric mucosal barrier in dogs. This may explain the occasional occurrence of gastric and duodenal ulcerations reported with use of this compound in human subjects. 54 Side effects in patients can be either systemic or local. Systemic effects will result when mono-octanoin is infused under high pressure or when it gains access to the systemic circulation via the liver. The clinical indicator of such a problem is pain in the right upper quadrant or respiratory symptoms." If such symptoms occur, infusion must be stopped immediately and the biliary tree drained. Local effects usually result from the emptying of mono-octanoin into the duodenum: abdominal cramping, nausea, anorexia, vomiting, or diarrhea. These symptoms have been reported in 10% to 50% of patients'" and can be alleviated by stopping the infusion temporarily and then restarting it at a slower rate.
Methyl Tert-Butyl Ether Methyl tert-butyl ether is an aliphatic ether that is very effective in dissolving gallstones in vitro." Gallstones can be dissolved within several hours in dogs." 24, 25 Methyl tert-butyl ether should not be infused into the common bile duct because of its toxic effects. However, stones in the gallbladder can be dissolved using this compound. Access to the gallbladder must be achieved by percutaneous transhepatic catheter insertion. Methyl tert-butyl ether can then be instilled into the gallbladder in a volume of 10 ml and exchanged every 46 minutes. In this way, stones can be dissolved in 4 to 12 hours;" Minor complications of this method include duodenitis, hemolysis, and mild anesthesia. The compound is far more dangerous when it gains access to the systemic circulation or the peritoneal cavity, resulting in hemolysis, hemorrhagic pneumonitis, and death in experimental animals. In clinical experience with this technique, about half the patients experienced nausea, duodenitis, or hemolysis, and one patient had moderate anesthesia. 3, 17, 54
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SUMMARY Many methods are available for gallstone dissolution, including oral bile salts; cholesterol solvents such as mono-octanoin or methyl tert-butyl ether; and calcium or pigment solvents such as EDTA and polysorbate. Which of these approaches will be appropriate for an individual patient depends on the type of stones; whether they are in the gallbladder or the bile ducts; whether access to the biliary tree is available; the patient's age and general medical condition; and the availability of necessary expertise. In the US, both chenodeoxycholate and ursodeoxycholate are now available. Ursodeoxycholate is more expensive but appears to produce fewer side effects and may be more efficacious. These agents are most effective in thin women with small floating, radiolucent cholesterol stones in a functioning gallbladder. Only about half of the small subset of patients will experience partial or complete dissolution of stones within a year. Stone recurrence and the potential toxicity of long-term therapy are problems with this approach. Therefore, for most patients, cholecystectomy, either in the traditional fashion or using a laparoscopic approach (see article later in this issue by Gadacz et al), is the most cost-effective and perhaps the safest option. Intragallbladder instillation of methyl tert-butyl ether probably will be applicable only to a small subset of patients, and treatment is likely to be followed by a high recurrence rate. In patients with retained common duct cholesterol stones and access to the biliary tree, mono-octanoin therapy is advantageous in that it can be initiated as soon as cholangiography demonstrates no extravasation. In properly selected patients, a 90% success rate with this technique can be expected within 7 days.
REFERENCES 1. Abate M, Moore T: Monooctanoin use for gallstone dissolution. Drug Intell Clin Pharm 19:708-712, 1985 2. Allen MJ, Borody TJ, Bugliosi TF, et al: Cholelitholysis using methyl tertiary butyl ether. Gastroenterology 88:122-125, 1985 3. Allen MJ, Borody TJ, Bugliosi TF, et al: Rapid dissolution of gallstones by methyl tertbutyl ether. N Engl J Med 312:217-220, 1985 4. Angelin B, Ewerth S, Einarsson K: Ursodeoxycholic acid treatment in cholesterol gallstone disease: Effects on hepatic 3-hydroxy-3-methyl-glutarate coenzyme A reductase activity, biliary lipid composition, and plasma lipid levels. J Lipid Res 24:461-468, 1983 5. Barbara L, Roda A, Mazzeli G, et al: Efficacy of UDCA versus CDCA in cholesterol gallstone patients: A double blind trial. In Fumagalli R, et al (eds): Drugs Affecting Lipid Metabolism. Amsterdam, Elsevier/North Holland Biomedical Press, 1980, pp 109-114 6. Bateson MC, Hill A, Bouchier lAD, et al: Analysis of response to ursodeoxycholic acid for gallstone dissolution. Digestion 20:358-364, 1980 7. Bell GD, Dowling RH, Whitney B, et al: The value of radiology in predicting gallstone type when selecting patients for medical treatment. Gut 16:359-364, 1975 8. Bell GD, Whitney B, Dowling RH: Gallstone dissolution in man using chenodeoxycholic acid. Lancet 2:1213-1216, 1972 9. Bennion LJ, Grundy SM: Risk factors for the development of cholelithiasis in man. N Engl J Med 299:1161-1167; 1221-1226, 1978 10. Bochier DAD: Biochemistry of gallstone formation. Clin Gastroenterol 12:25-48, 1983 11. Crummy AB, Mack EM: Infusion therapy of choledocholithiasis: Technique for catheter placement. AJR 136:622-623, 1981
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12. Danzinger RG, Hoffman AF, Schoenfield LJ, et al: Dissolution of cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 286:1-8, 1972 13. Dolgin SM, Schwartz JS, Kressel HY, et al: Identification of patients with cholesterol or pigment gallstones by discriminant analysis of radiographic features. N Engl J Med 304:808-810, 1981 14. Einarsson K, Grundy S: Effects of feeding cholic acid and chenodeoxycholic acid on cholesterol absorption and hepatic secretion of biliary lipids in man. J Lipid Res 21:2324, 1980 15. Erlinger S, LeGo A, Husson J, et al: Franco-Belgian Cooperative Study ofUrsodeoxycholic Acid in the Medical Dissolution of Gallstones: A double blind randomized, doseresponse study, and comparison with chenodeoxycholic acid. Hepatology 4:308-314, 1984 16. Fromm H: Gallstone dissolution and the cholesterol-bile acid-lipoprotein axis: Propitious effects of ursodeoxycholic acid. Gastroenterology 87:229-233, 1984 17. Fromm H, Roat JW, Gonzales V, et al: Comparative efficacy and side effects of ursodeoxycholate and chenodeoxycholate acids in dissolving gallstones. Gastroenterology 85:1257-1264, 1983. 18. Gadacz TR: The effect of mono-octanoin on retained common duct stones. Surgery 89:527531, 1981 19. Hoffman AF: Medical treatment of cholesterol gallstones by bile desaturating agents. Hepatology 4:1995-2085, 1984 20. Hoffman AF, Schmack B, Thistle JL, et al: Clinical experience with mono-octanoin for dissolution of bile duct stones. Dig Dis Sci 26:954-955, 1981 21. Intra-Hospital Clinical Research Group: Treatment of radiolucent gallstones with CDCA or UDCA: A multicenter trial. Digestion 22:185-191, 1982 22. Iwamura K: Clinical studies on cheno- and ursodeoxycholic acid treatment for gallstone patients. Hepato-Gastroenterology 27:26-34, 1980 23. LaRusso NF, Hoffman NE, Hoffman AF, et al: Effect of primary bile acids ingestion on bile acid metabolism and biliary lipid secretions in gallstone patients. Gastroenterology 69:1301-1314, 1975 24. Leuschner U, Wurbs D, Landgraf H: Dissolution of biliary duct stones with monooctanoin. Lancet 2:203-204, 1979 25. Leuschner U, Wurbs D, Baumgarter H, et al: Alternating treatment of common bile duct stones with a modified glyceryl-1-mono-octanoate preparation and a bile acid-EDTA solution by nasobiliary tube. Scand J GastroenteroI16:497-503, 1981 26. Mack E, Crummy AB, Babyan VK: Percutaneous transhepatic dissolution of common bile duct stones in high risk patients. Surgery 90:584-587, 1981 27. Mack E, Patzer EM, Crummy AB, et al: Retained biliary tract stones: Nonsurgical treatment with Capmul 8210, a new cholesterol gallstone dissolution agent. Arch Surg 116:341-344, 1981 28. Mack E, Saito C, Goldfarb S, et al: Local toxicity of T-tube infused cholate in the Rhesus monkey. Surg Forum 28:408-409, 1977 29. McSherry CK: The National Cooperative Gallstone Study Report: A surgeon's perspective. Ann Intern Med 95:379-380, 1981 30. Meredith TJ, Williams GV, Murphy GM, et al: Retrospective comparison of "cheno" and "urso" in the medical treatment of gallstones. Gut 23:382-389, 1982 31. Minuk GY, Hoffnagle JH, Jones EA: Systemic side effects from the intrabiliary infusion of monooctanoin for the dissolution of gallstones. J Clin Gastroenterol 4:133-135, 1982 32. Nelisan P, Gateson MC, Trash DB, et al: Ursodeoxycholic acid for the dissolution of radiolucent gallbladder stones. Digestion 28:225-233, 1983 33. Pitt HA, Doty JE, Roslyn JJ, et al: The role of altered extrahepatic biliary function in the pathogenesis of gallstones following vagotomy. Surgery 90:418-425, 1981 34. Pitt HA, King W III, Man LL, et al: Increased risk of cholelithiasis with prolonged total parenteral nutrition. Am J Surg 145:106-112, 1983 35. Roda E, Bazzili F, Morselli-Lebate AM, et al: Ursodeoxycholic acid vs. chenodeoxycholic acid as a cholesterol dissolving agent: A comparative randomized study. Hepatology 2:804-810, 1982 36. Roslyn JJ, DenBesten L, Pitt HA, et al: Effects of cholecystokinin on gallbladder stasis and cholesterol gallstone formation. J Surg Res 30:200, 1981
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37. Sasson L: Dissolution and flushing techniques for removal of retained common duct stones. Am J Gastroenterol 51:394-409, 1969 38. Schoenfield LJ, Grundy SM, Hoffman AF: The National Cooperative Gallstone Study viewed by its investigators. Gastroenterology 84:644-647, 1983 39. Schoenfield LJ, Lachin JM, the Steering Committee and the National Cooperative Gallstone Study Group: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study. Ann Intern Med 95:257-282, 1981 40. Sharp KW, Gadacz TR: Selection of patients for dissolution of retained common duct stones with mono-octanoin. Ann Surg 196:137-139, 1982 41. Soloway RD, Trotman BW, Ostrow JD: Pigment gallstones. Gastroenterology 72:167182, 1977 42. Steinhasen RM, Pertsemlidis D: Mono-octanoin dissolution of retained biliary stones in high risk patients. Am J Gastroenterol 78:756-760, 1983 43. Strickler JH, Adkins DC, Rice CO: Ether flush treatment of retained postoperative common duct stones. Minn Med 37:490-497, 1954 44. Talamini MA, Pitt HA: Ursodeoxycholate: Recent advance in dissolution of gallstones. Intern Med Specialist 10:2:139-160, 1989 45. Teplick SK, Pavlides CA, Goodman LR, et al: In vitro dissolution of gallstones: Comparison of mono-octanoin, sodium dehydrocholate, heparin, and saline. AJR 138:271-273, 1982 46. Thistle JL, Hoffman AF: Efficacy and safety of CDCA for dissolving gallstones. N Engl J Med 289:655-659, 1973 47. Thistle JL, Schoenfield LJ: Induced alterations of bile composition in persons having cholelithiasis. Gastroenterology 61:488-496, 1971 48. Thistle JL, Newlson PE, May GR: Dissolution of cholesterol gallbladder stones using methyl tert-butyl ether. Gastroenterology 90:1775, 1986 49. Thistle JL, Carlson GL, Hoffman AF, et al: Mono-octanoin, a dissolution agent for retained cholesterol bile duct stones: Physical properties and clinical application. Gastroenterology 78:1016-1027, 1982 50. Tint GS, Salen G, Colelillo A, et al: Ursodeoxycholic acid: A safe and effective agent for dissolving cholesterol gallstones. Ann Intern Med 97:352-356, 1982 51. Tokyo Cooperative Gallstone Study Group. Gastroenterology 78:542, 1980 52. Tritapep R, Dipadova C, Pozzoli M, et al: The treatment of retained biliary stones with mono-octanoin: Report of sixteen patients. Am J Gastroenterol 79:710-714, 1984 53. Trotman BW, Soloway RD: Pigment vs. cholesterol cholelithiasis: Clinical and epidemiological aspects. Am J Dig Dis 20:735-739, 1975 54. Uribe M, Uscarga L, Farca S, et al: Dissolution of cholesterol ductal stones in the biliary tree with medium chain glycerides. Dig Dis Sci 26:634-640, 1981 55. Velasco N, Brashetto I, Osendes A: Treatment of retained common bile duct stones: A prospective controlled study comparing mono-octanoin and heparin. World J Surg 7:266-270, 1983 56. Villanova N, Bazzoli F, Taroni F, et al: Gallstone recurrence after successful oral bile acid treatment: A 12 year follow-up study and evaluation of long-term postdissolution treatment. Gastroenterology 97:726-731, 1989 57. Vlahcevic ZR, Bell CC Jr, Buhac I, et al: Diminished bile acid pool size in patients with gallstones. Gastroenterology 59:165-173, 1970 58. Way LW: The National Cooperative Gallstone Study and chenodiol. Gastroenterology 84:648-651, 1983
Address reprint requests to Mark A. Talamini, MD Department of Surgery The Johns Hopkins Hospital 600 North Wolfe Street Baltimore, Maryland 21205
0039-6109/90 $0.00 + .20
Gallstone Dissolution
Mark A. Talamini, MD, * and Thomas R. Gadacz, MDt
Gallstone formation continues to be responsible for a significant measure of disease and disability throughout the world, particularly in the Western hemisphere. Over the last 50 years, removal of the gallbladder has been the primary mode of therapy for gallstone disease. Prevention of the formation of gallstones or the ability to dissolve gallstones would more easily and safely solve this problem. The concept of gallstone dissolution by oral or topical agents has been popular over the last decade as an alternative to cholecystectomy. This concept is not new. In 1873, Maurice Schiff proposed the ingestion of oral bile salts as a treatment for gallstones. Fifty years later, the first report of successful oral gallstone dissolution was reported by Newbridge from the University of Minnesota. In his report, two of five patients who were fed bile salt mixtures were rewarded with stone dissolution. The clinical use of chenodeoxycholate surfaced in the 1970s. It was found that this primary bile salt reduced the cholesterol saturation of bile. 47, 57 Clinical trials were then undertaken with both oral chenodeoxycholate and its 7-beta epimer, ursodeoxycholate." 12 Topical infusion for impacted stones is likewise not a new concept. In 1891, Walker used ether to dissolve such stones. Since then, a number of agents have been used, including chloroform, olive oil, ether, heparin, and warm saline. These all can be applied via a T-tube in an attempt to dissolve or dislodge retained common duct stones. The rapid development of interventional radiology and endoscopic retrograde cholangiopancreatography (ERCP) has made topical dissolution of gallstones more widely available and applicable. Further technological developments have included ultrasonic, electrohydraulic, or laser systems to fragment gallstones in conjunction with sophisticated access approaches. The rapid proliferation of these technologies has made the choices for an individual patient confusing. Knowledge of the pathogenesis of choles*Assistant Professor of Surgery, Department of Surgery, The Johns Hopkins University, Baltimore, Maryland tProfessor of Surgery, The Johns Hopkins University; and Chief, Surgical Service, Baltimore VA Medical Center, Baltimore, Maryland
Surgical Clinics of North America-Vol. 70, No.6, December 1990
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terol and pigment gallstone formation is helpful in making appropriate decisions.
GALLSTONE PATHOGENESIS A thorough discussion of gallstone pathogenesis is provided in the previous article. In brief, gallstones are classified as cholesterol or pigment stones on the basis of their predominant component. Cholesterol gallstones contain more than 60% cholesterol by weight, and pigment stones contain less than 25% cholesterol by weight. Cholesterol Gallstone Formation In the West, 70% to 80% of patients with cholelithiasis have gallstones that are primarily cholesterol. Bile contains cholesterol, bile salts, phospholipids, electrolytes, and proteins. When cholesterol represents more than 10% of the biliary lipid concentration, it tends to precipitate. For a cholesterol stone to form, the excess cholesterol must coalesce by a process termed "nucleation." In heterogenous nucleation (which creates type 1 stones), cholesterol precipitates about other particulate matter in the gallbladder such as sloughed cells, protein, or crystals. Most cholesterol stones are of this type. They tend to be multiple, ranging in size from 0.5 to 2.5 cm. Approximately one third are radiopaque. In homogenous nucleation (which creates type 2 stones), cholesterol crystals serve as their own nidus. These stones tend to be solitary and larger than type 1 stones. Fifty to seventy per cent of gallstones in patients in the United States are type 1 stones, whereas 5% to 20% are type 2. There are a number of factors that render a patient susceptible to cholesterol gallstone formation. 9 These include increased hepatic cholesterol synthesis, decreased bile-salt pool size, and hormonal influences. Increased hepatic cholesterol synthesis is directed primarily by genetic factors and secondarily by diet. Bile salt deficiencies occur most commonly in conditions that interrupt the enterohepatic circulation of bile, such as ileal resection, Crohn's disease, and cholestyramine administration. Hormonal balance can influence both cholesterol synthesis and biliary motility. Increased estrogen levels in pregnant women and in those taking oral contraceptives are probably responsible for the increased incidence of gallstones. 10 Because the pathogenesis of cholesterol stones involves a number of factors, a variety of approaches might be valuable for the dissolution or prevention of gallstones. One strategy is to decrease the hepatic synthesis of cholesterol. At present, our only means of accomplishing this is by influencing hepatic cholesterol synthesis. In the future, a more potent pharmacologic approach to the reduction of hepatic cholesterol synthesis may hold the key to the medical prevention of gallstone formation. Another potential tactic is to increase the synthesis of phospholipids. Attempts to do this with oral lecithin supplements have not been effective. The method that has had the most success is expansion of the bile salt pool via oral bile salt ingestion. Bile salts solubilize cholesterol, as well as bilirubin and calcium. This method allows dissolution of cholesterol gallstones by main-
I
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GALLSTONE DISSOLUTION
taining the cholesterol in solution. Another technique, frequent gallbladder emptying, can be accomplished pharmacologically. This mode of therapy prevents cholesterol gallstones in experimental animals;" but it has not been attempted clinically. Pigment Gallstone Formation Less is known about pigment gallstone formation. Two different types of pigment stones occur and probably form by different mechanisms. In both cases, ionized calcium complexes and bilirubinate exceed their solubility products and precipitate as an insoluble salt." Brown pigment stones occur commonly in Asian patients and are similar to the recurrent common bile duct stones found in Western patients." A diet low in protein and high in carbohydrate appears to predispose to brown pigment stones. Black pigment stones occur in three distinct clinical settings in the Western world: hemolysis, cirrhosis, and advanced AIDS. These stones also occur commonly in Occidental patients. In one study from the US, black pigment stones accounted for 27% of the stones recovered from patients undergoing cholecystectomy. 53 Black pigment stones contain calcium phosphate and calcium carbonate, causing 50% of these stones to be radiopaque. Any condition that decreases red cell life, such as malaria, hemoglobinopathy, red cell membrane defects, and prosthetic heart valves, is associated with the formation of pigment gallstones." Patients with sickle cell anemia have a IO-fold increase in bilirubin secretion, causing an increased incidence of pigment gallstone formation. In cirrhosis, the causative factors appear to be increased production of unconjugated bilirubin, decreased output of hepatic biliary bile salts, and possibly nutritional deficits. 9, 53 The incidence of both pigment and cholesterol stones increases with age in the US. 7 , 11 One potential explanation for this observation is diminished gallbladder emptying secondary to an altered hormonal milieu that develops with increasing age. Stasis may then predispose to pigment gallstone formation, as well as to cholesterol gallstone formation. The idea of biliary motility affecting gallstone formation has recently been resurrected, having initially been considered to be important more than a century ago. A number of clinical conditions provide indirect evidence that impaired biliary motility promotes gallstone formation. For instance, patients who have had a vagotomy or who are receiving total parenteral nutrition have unchanged cholesterol saturation levels, but both groups have impaired gallbladder emptying and increased frequencies of cholelithiasis. 8, 33, 34
ORAL BILE SALTS Dissolution of gallstones depends on several factors. The patient must be able to adhere to a long-term treatment program. Realistically, success can be anticipated only in patients with cholesterol stones, and 6 months to 4 years is required for complete dissolution of the stones. Dissolution usually will be successful if the stones significantly decrease in size during the first 9 months of treatment. The efficacy and safety of drugs must
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always be weighed against the slight morbidity and mortality rates of conventional operative therapy. Predictors of gallstone composition are helpful, because, as noted, dissolution is likely to be successful only for cholesterol stones. If radiolucency alone is used as a criterion, the success rate will be 20% to 30%,7 because this is the proportion of patients who will actually have cholesterol stones. The most reliable method for determining gallstone composition is an analysis of gallbladder bile. This method requires duodenal bile aspiration via a duodenoscope during gallbladder stimulation. If the cholesterol content exceeds 100/0, the bile can be assumed to be saturated with cholesterol, and the stones can be assumed to be cholesterol stones. This determination requires that the patient undergo an uncomfortable and costly procedure. 7 Alternatively, a multivariate analysis using gallstone size, buoyancy, surface characteristics, and calcification patterns has been developed. This methodology can predict gallstone composition accurately in 90% of patients. 13 Other clinical factors affect the success of dissolution therapy with oral bile salts. Obese patients have lower dissolution rates, although this may be a dosing problem. A normally functioning gallbladder, as documented by an oral cholecystogram, is necessary for the ingested bile salts to find their way into the gallbladder. Patients with very large numbers of stones or stones greater than 2 em in diameter have lower success rates. Currently, two approved drugs that can be taken orally are effective in dissolving gallstones. 19 Chenodeoxycholate has been available longer. It is a normally occurring bile salt in humans and is synthesized by the liver. Ursodeoxycholate has recently been approved and is now in clinical use. It is found only in trace amounts in human subjects. Ursodeoxycholate is an epimer of chenodeoxycholate that also happens to be the primary bile salt of the polar bear, hence the urso. Chenodeoxycholate Chenodeoxycholate is normally found in human bile and is a primary bile salt, comprising 30% to 40% of the total bile salt pool (Fig. 1). Chenodeoxycholate is more effective in decreasing cholesterol saturation than is the other predominant primary bile salt, chelate." 12 The mechanism of action appears to be alteration of bile composition by a decrease in the endogenous hepatic synthesis of cholesterol and the exogenous expansion of the bile salt pool. 23 It is not clear which of these mechanisms is of greater importance. The net result is the production of a bile that is less saturated
A OH·"
B OH··
Figure 1. Chemical structures of chenodeoxycholic acid (A) and ursodeoxycholic acid (B).
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with cholesterol. 14 The actual dissolution of gallstones probably takes place because of the molecular alteration of cholesterol from the simple crystalline state to that of unsaturated mixed micelles. A significant concern regarding the clinical use of chenodeoxycholate has been its conversion by enteric flora into lithocholate, a known hepatotoxin.f" Studies have reported elevated liver enzymes in as many as 25% of patients receiving chenodeoxycholate.:" In addition, as many as 25% of patients have had diarrhea. Both of these problems have led to cautious, and in some trials, subtherapeutic dosing. Considerable data concerning the use of chenodeoxycholate have come from the National Cooperative Gallstone Study. This was a multicenter, double-blind, prospective trial that assigned 916 patients to one of three treatment groups: (1) 375 mg of chenodeoxycholate daily; (2) 750 mg of chenodeoxycholate daily; or (3) a placebo." After 2 years, the result were analyzed (Table 1). This study demonstrated significant but reversible liver injury in 3% of the patients who were taking 750 mg per day. Eight per cent of the patients reported diarrhea, but no patient was forced to abandon the medication as a result. Of perhaps more concern was the mild elevation (10 mg/dl) of the mean total serum cholesterol and low-density lipoprotein cholesterol levels seen during chenodeoxycholate therapy. 38, 39 The patients in the high-dose chenodeoxycholate group experienced complete gallstone dissolution in only 14% of cases and partial dissolution (defined as a greater than 50% decrease in gallstone size) in 27%. These results were considerably poorer than those published previously in nonrandomized studies (up to 70% success). The best results were seen in women below ideal body weight who had stones less than 1.7 mm in size and a normal serum cholesterol level (Fig. 2). This group had a success rate of 38%. Dissolution was less successful in all groups when the lower dose was used. The conclusion of this study was that chenodeoxycholate at a dose of 750 mg per day does have a role in the treatment of selected patients with gallstones." Critics of the study point out that of the total 611 patients treated over a 2-year period, only 50 subjects had complete gallstone dissolution, for an overall 8% success rate. Further problems with the study include the 15.3% dropout rate, an unchanged frequency of abdominal pain in the patients studied, and a high rate of continued need for cholecystectomy in all treatment groups. This study also disclosed a recurrence rate of 25% to 50% after cessation Table 1. Results of the National Cooperative Gallstone Study PER CENT WITH DISSOLUTION
NO. OF GROUP
Placebo Chenodeoxycholate (mg/day) 375 750
PATIENTS
Partial
305
10
306 305
18 27
Complete
5 14
Data from Schoenfield LJ, Lachin JM, the Steering Committee and the National Cooperative Gallstone Study Group: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallstone Study. Ann Intern Med 95:257, 1981.
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Figure 2. Oral cholecystogram demonstrating a functioning gallbladder with multiple small, floating gallstones. A young, thin woman with this situation is likely to have the best results from oral bile acid therapy.
of therapy. Therefore, it is possible that patients who obtain gallstone dissolution will require further therapy, perhaps at a lower dose, although low-dose prophylactic chenodeoxycholate treatment has not been demonstrated to prevent recurrences. In addition, in patients with partially dissolved gallstones, administration of chenodeoxycholate after 2 years has shown only limited efficacy in further dissolution of the stones. Concern about the drug's effect on lipid metabolism caused the investigators to caution against use of chenodeoxycholate for longer than 2 years.:" There also are questions regarding its efficacy and risk during pregnancy. In summary, chenodeoxycholate is best used in patients with floating radiolucent gallstones, those who are under 60 years of age, and those who are at increased operative risk with cholecystectomy. The preferred dose is 14 to 16 mg/kg per day. Monitoring of liver enzymes is necessary, and treatment should be continued for 3 months beyond the point where stones are no longer evident radiologically or for 16 months if there are no evident changes in gallstone size. Close monitoring for recurrence is important. U rsodeoxycholate U rsodeoxycholate is the 7-beta-hydroxy epimer of chenodeoxycholate (see Fig. 1). Oral administration of ursodeoxycholate increases its contribution to the bile salt pool. The result is a bile salt composition consisting of as much as 500/0 ursodeoxycholate. U rsodeoxycholate was a component of an over-the-counter hepatic tonic sold in Japan, which was found to be effective in dissolving gallstones. Following this, in 1974, reports of gallstone dissolution appeared in the Japanese literature in patients who were treating themselves with large doses of a product containing ursodeoxycholate. When taken orally, ursodeoxycholate is absorbed efficiently in the ileum as an unconjugated bile salt and is transported to the liver in the portal blood. In the hepatocyte, ursodeoxycholate is conjugated with glycines or taurines and excreted into the bile. The conjugates are efficiently reabsorbed, transported to the liver, and re-excreted into the bile. In the small bowel, bile salts may be transformed to secondary bile salts by bacteria. In this manner, ursodeoxycholate can also form the toxic lithocholic
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salt. Other effects of ursodeoxycholate are increased bile output, choleresis, and increased secretion of phospholipids. Ursodeoxycholate and chenodeoxycholate differ fundamentally in their mechanism of gallstone dissolution. Ursodeoxycholate forms smaller micelles because of the orientation of a single hydroxyl group. Therefore, ursodeoxycholate accomplishes solubilization primarily by a non micellar mechanism. Another effect of this mechanism is that ursodeoxycholate causes a relative decrease in cholesterol absorption from the gut. Clinical trials have shown lower rates of diarrhea and hepatotoxicity in trials comparing ursodeoxycholate with chenodeoxycholate.F' 58 Ursodeoxycholate seems to be more resistent to bacterial transformation into lithocholate.:" In general, liver enzymes are not elevated as significantly in clinical trials with ursodeoxycholate.?" In addition, diarrhea occurs in less than 5% of patients. The placebo-controlled randomized studies available of the efficacy of ursodeoxycholate indicate that it does dissolve cholesterol gallstones over a period of 6 to 12 months when a dose of 8 to 10 mg/kg per day is used." Therapy beyond 12 months does not improve the response, although partially dissolved stones may continue to dissolve with additional treatment. Thirteen per cent of patients in one study experienced worsening of biliary symptoms progressing to cholecystectomy during treatment. This was also the case in trials of chenodeoxycholate. 29, 58 Stone recurrence may also be a problem with ursodeoxycholate. Patients not given long-term treatment after successful dissolution have been reported to have a recurrence rate of 69% at 5 years;" whereas those treated with ursodeoxycholate after dissolution had only a 32% recurrence rate at 7 years (Table 2). Overall, the recurrence rate plateaued at 7 years. The age of the patient and the number of stones influenced the rate of recurrence: those older than age 50 received no benefit from postdissolution therapy, whereas those younger than 50 had a 16% recurrence rate when treated and a 69% rate when not treated. With no postdissolution treatment, patients with solitary stones had a recurrence rate of 32% compared with 77% in those who had multiple stones. These data suggest that ursodeoxycholate will be less effective in older patients and in those with a single stone. In general, ursodeoxycholate appears to have fewer side effects, work more rapidly, and cause less hepatotoxicity. In patients with small, floating, radiolucent cholesterol gallstones, partial or complete dissolution can be expected in 40% to 55% of those treated with ursodeoxycholate for 6 to 12 months. 19 Table 2. Gallstone Recurrence Rates (Lifetable Analysis) after Dissolution GROUP
UDCA 300 mg/day None All
NO. OF PATIENTS
RECURRENCE (PER CENT)
36 60 96
32 (7 years) 68 (5 years) 61 (11 years)
Data from Villanova N, Bazzoli F, Taroni F, et al: Gallstone recurrence after successful oral bile acid treatment: A 12 year follow-up study and evaluation of long-term postdissolution treatment. Gastroenterology 97:726, 1989.
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Chenodeoxycholate Versus U rsodeoxycholate Clinically, ursodeoxycholate and chenodeoxycholate appear to be equally efficacious in accomplishing gallstone dissolution. Table 3 summarizes the published uncontrolled comparisons of the two agents. In some of these studies, success rates were similar when equivalent doses were used. In the study by Barbera and coworkers," a higher dose of chenodeoxycholate, 15 mg/kg of body weight per day, was required to achieve the same results as were achieved with 5 or 10 mg of ursodeoxycholate per kg per day. Table 4 reviews the available prospective randomized trials comparing ursodeoxycholate and chenodeoxycholate. One of these studies stands out in demonstrating greater efficacy of ursodeoxycholate than of chenodeoxycholate. 17 In this study, by Fromm and coworkers from the University of Pittsburgh, groups of patients were given ursodeoxycholate in doses of 400 mg or 800 mg per day or chenodeoxycholate in doses of 375 mg or 750 mg per day. At 12 months, with the groups analyzed together, significantly more stones were dissolved in the patients receiving ursodeoxycholate than in those receiving chenodeoxycholate. At 24 months, ursodeoxycholate continued to show increased dissolution, but the difference was not statistically significant. Thus, chenodeoxycholate appears to have the ability to "catch up" in time with the dissolution rate of ursodeoxycholate. Ursodeoxycholate may dissolve gallstones more rapidly because of its dual micellar and nonmicellar mode of action. Those investigators also demonstrated a decreased incidence of hepatic toxicity and diarrhea with ursodeoxycholate. Table 3. Results of Uncontrolled Comparisons of Ursodeoxycholic Acid (UDC) and Chenodeoxycholic Acid (CDC)
SOURCE
Barbara et al5
Bateson et al"
Iwamara et aF2 Meredith et al30 Fromm et al'? Roda et aP5
NA
=
NO. OF RESPONSES
DAILY
NO. OF
DRUG
DOSE (MG)
PATIENTS
Complete
Partial
UDC UDC CDC CDC UDC UDC CDC CDC UDC CDC UDC CDC UDC CDC UDC UDC CDC CDC
5/kg 10/kg 7/kg 15/kg
34 36 70 71
9 9 8 10
21 20 28 46
88 81 51 79
500 1000 750 1000
13 24 41 33
NA NA NA NA
NA NA NA NA
38 42 22 58
300-600 300-600
12 18
2 2
1 2
25 22
2.5-15/kg 13-15/kg
65 83
13 24
34 43
72 81
400-800 375-750
4 9
4 1
3 2
55 33
7-8/kg 14-15/kg 7-8/kg 14-15/kg
58 52 55 58
21 21 12 24
21 20 19 21
72 78 57 78
not available.
SUCCESS RATE
(%)
In addition, serum cholesterol and low-density lipoprotein cholesterol elevations occurred with chenodeoxycholate but not with ursodeoxycholate. 3 A comparison of the toxicities of these two agents is provided in Table 5. Because these two agents appear to work by slightly different mechanisms, it has been suggested that a combination administered concurrently might be more efficacious and less expensive. Preliminary data on such combination therapy have suggested that it is, in fact, more effective than either agent alone.!" With regard to cost, the average annual expense per year of chenodeoxycholate therapy ranges from $1300 to $1600. 58 This cost must be compared with the average one-time cost of cholecystectomy ($6000 to $10,000).
TOPICAL AGENTS Various solutions are effective in dissolving stones within the biliary tree when direct access to the stone is available via a tube. These substances are likely to be effective only in dissolving cholesterol stones. Table 5. Relative Toxicities of C henodeoxycholicAcid ( C DC) and Ursodeoxycholic Acid (UDC)
Transaminemia Diarrhea Increased LD L cholesterol Gallstone calcification
CDC
UDC
1+ 1+ 1+ ±
1+
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Success with such an approach depends on the compound's ability to dissolve the main constituents of the stone and good contact with the stone. Such a solution must also be safe with regard to its effect on the bile ducts, liver, intestine, and the patient as a whole. There are a number of commonsense precautions. First, the solution cannot be infused under pressure or into liver parenchyma. Second, the solution must be able to exit to the intestine or to the outside. Third, there should be no leak from the biliary tree into the peritoneal cavity. This situation could occur around a T-tube or after endoscopic papillotomy. The solution is administered by way of aT-tube or a biliary stent. 11 A manometer is placed in the circuit between the solvent and the patient and cut off between 20 and 30 em so that greater pressures within the circuit are impossible. This maneuver also allows intrabiliary pressure to be monitored by both the patient and the medical staff. If the stone is obstructing the distal portion of the duct, a small catheter can be inserted through the T-tube and the solution infused directly on the stone. This then allows fluid to exit back through the remaining lumen of the T-tube. Ether, Chloroform, Saline, and Heparin Ether, chloroform, saline, and heparin have all been used in the past for topical dissolution. Ether is dangerous because of its vaporization at body temperature: 1 ml of liquid ether becomes 2.24 L of gas above 95°F. 44 Chloroform is an excellent cholesterol solvent but has unacceptably severe side effects, such as central lobular hepatic necrosis, duodenal ulceration with hemorrhage, and even death." Infusion of saline is essentially a flushing technique, which has a success rate of 20%,37 not significantly different from the rate of spontaneous stone passage. Heparin has been used as a topical agent, although it is not a good cholesterol solvent. Prospective trials have shown no superiority of heparin over saline. 45, 55 Sodium Cholate Sodium cholate was the most commonly used topical dissolution agent for many years. It is synthesized naturally in the liver and can be manufactured easily. Because it is not a particularly good cholesterol solvent, therapy may require several weeks." and a success rate of only 65% to 70% can be expected. Severe side effects such as bacteremia, sepsis," and even death secondary to intrahepatic infusion" have essentially eliminated the use of this agent. Mono-octanoin Mono-octanoin is a medium-chain diglyceride that is a normal digestive product of medium-chain triglyceridcs.F: 49 Its primary advantages over sodium cholate are its effectiveness as a cholesterol solvent and its relative safety in terms of hepatic duct inflammation. One of the authors (TRG) has developed a modified infusion technique for mono-octanoin administration. 18 Sixty-two per cent of patients with retained stones obtained dissolution with mono-octanoin, which was buffered to pH 7.4 and infused at a rate of 3 to 7 ml/hour by pump. The average time required was 5 days.
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Intrabiliary pressures ranged from 2 to 12 em H 20 . Various studies have produced success rates between 50% and 86%.20,25,26,42,43,52 As with other solvents, gallstones composed mainly of cholesterol are far more like to dissolve than pigment stones. Gallstones with a cholesterol content of 40% or more have a 91% chance of dissolving within 7 days of therapy. 40 It is best to save gallstones removed from the gallbladder or common bile duct in a dry state. If stones are present on a postoperative T-tube cholangiogram, and if there is no leak from the choledochotomy, sample stones can be analyzed for cholesterol content or simply incubated with mono-octanoin at 37°C. If the stones appear to be soluble, therapy is likely to be successful. This method of treating retained common duct stones obviates the 6- to 8-week wait necessary for a T-tube tract to mature before mechanical extraction can be attempted. It also does not require the technical expertise of ERCP. Side effects of mono-octanoin have been reported. 1 Its instillation into the free peritoneal cavity in rats results in a high mortality rate with volumes in excess of 0.35 ml in a 150-gm rat. Mono-octanoin perfusion also disrupts the gastric mucosal barrier in dogs. This may explain the occasional occurrence of gastric and duodenal ulcerations reported with use of this compound in human subjects. 54 Side effects in patients can be either systemic or local. Systemic effects will result when mono-octanoin is infused under high pressure or when it gains access to the systemic circulation via the liver. The clinical indicator of such a problem is pain in the right upper quadrant or respiratory symptoms." If such symptoms occur, infusion must be stopped immediately and the biliary tree drained. Local effects usually result from the emptying of mono-octanoin into the duodenum: abdominal cramping, nausea, anorexia, vomiting, or diarrhea. These symptoms have been reported in 10% to 50% of patients'" and can be alleviated by stopping the infusion temporarily and then restarting it at a slower rate.
Methyl Tert-Butyl Ether Methyl tert-butyl ether is an aliphatic ether that is very effective in dissolving gallstones in vitro." Gallstones can be dissolved within several hours in dogs." 24, 25 Methyl tert-butyl ether should not be infused into the common bile duct because of its toxic effects. However, stones in the gallbladder can be dissolved using this compound. Access to the gallbladder must be achieved by percutaneous transhepatic catheter insertion. Methyl tert-butyl ether can then be instilled into the gallbladder in a volume of 10 ml and exchanged every 46 minutes. In this way, stones can be dissolved in 4 to 12 hours;" Minor complications of this method include duodenitis, hemolysis, and mild anesthesia. The compound is far more dangerous when it gains access to the systemic circulation or the peritoneal cavity, resulting in hemolysis, hemorrhagic pneumonitis, and death in experimental animals. In clinical experience with this technique, about half the patients experienced nausea, duodenitis, or hemolysis, and one patient had moderate anesthesia. 3, 17, 54
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SUMMARY Many methods are available for gallstone dissolution, including oral bile salts; cholesterol solvents such as mono-octanoin or methyl tert-butyl ether; and calcium or pigment solvents such as EDTA and polysorbate. Which of these approaches will be appropriate for an individual patient depends on the type of stones; whether they are in the gallbladder or the bile ducts; whether access to the biliary tree is available; the patient's age and general medical condition; and the availability of necessary expertise. In the US, both chenodeoxycholate and ursodeoxycholate are now available. Ursodeoxycholate is more expensive but appears to produce fewer side effects and may be more efficacious. These agents are most effective in thin women with small floating, radiolucent cholesterol stones in a functioning gallbladder. Only about half of the small subset of patients will experience partial or complete dissolution of stones within a year. Stone recurrence and the potential toxicity of long-term therapy are problems with this approach. Therefore, for most patients, cholecystectomy, either in the traditional fashion or using a laparoscopic approach (see article later in this issue by Gadacz et al), is the most cost-effective and perhaps the safest option. Intragallbladder instillation of methyl tert-butyl ether probably will be applicable only to a small subset of patients, and treatment is likely to be followed by a high recurrence rate. In patients with retained common duct cholesterol stones and access to the biliary tree, mono-octanoin therapy is advantageous in that it can be initiated as soon as cholangiography demonstrates no extravasation. In properly selected patients, a 90% success rate with this technique can be expected within 7 days.
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Address reprint requests to Mark A. Talamini, MD Department of Surgery The Johns Hopkins Hospital 600 North Wolfe Street Baltimore, Maryland 21205