Sanjiv Chopra, MD
Anne C Travis, MD, MSc, FACG
INTRODUCTION — The role of medical management of gallstone disease has decreased in recent years, particularly since the introduction of laparoscopic cholecystectomy. Cholecystectomy is preferred because of its reduced cost, definitive nature, and safety [1,2]. The laparoscopic approach has been associated with a significant increase in the number of cholecystectomies being performed in the United States each year, indicative of both its acceptability to patients and popularity with surgeons.
Nevertheless, medical management may be an alternative to cholecystectomy in selected patients with symptomatic gallstone disease. At present, three methods used alone or in combination are available for the nonsurgical management of patients with gallstone disease:
- Oral bile salt therapy (primarily ursodeoxycholic acid)
- Contact dissolution
- Extracorporeal shockwave lithotripsy
The method of choice depends upon the number, size, and composition of the stone(s). However, many symptomatic patients have stones that are not ideally suited to any of these methods, producing less than optimal results. In addition, few centers perform contact dissolution therapy or gallstone extracorporeal lithotripsy, limiting their availability and application for the treatment of gallstones.
This topic will review the selection of patients for nonsurgical treatment of gallstone disease. The methods used for the nonsurgical treatment of gallstones as well as the surgical approaches to patients with gallstones are discussed elsewhere. (See “Nonsurgical treatment of gallstone disease” and “Open cholecystectomy” and “Laparoscopic cholecystectomy: Techniques”.)
PATIENT SELECTION FOR NONSURGICAL THERAPY — The selection of patients for nonsurgical treatment of gallstone disease depends upon patient characteristics, gallbladder function, and a detailed understanding of the size, number, and composition of the stones. Dissolution therapy for gallstones should be considered as an alternative to surgery in carefully selected patients, and may also be useful as prophylaxis in patients at high risk for developing symptomatic gallstone disease.
Symptomatic gallstone disease — Patients with severe medical problems who are at high risk for or refuse surgery and who have mildly to moderately symptomatic gallstone disease should be considered for medical therapy. The definition of mild to moderate symptoms includes episodic biliary pain that occurs fewer than two to three times a month and can be controlled with the use of oral analgesics, and the absence of complications such as cholecystitis, cholangitis, pancreatitis, or obstructive jaundice. Ursodeoxycholic acid can reduce gallstone related symptoms and the risk of recurrent pancreatitis in individuals with microlithiasis or biliary sludge [3,4]. Patients with complicated gallstone disease who cannot undergo surgery are better treated by percutaneous stone removal gallbladder drainage, or endoscopic retrograde cholangiopancreatography (ERCP).
Characteristics of the gallstones also need to be considered before instituting medical therapy. This can usually be achieved by computed tomography (CT) combined with ultrasonography or cholescintigraphy (HIDA scan) of the gallbladder. (See “Pathogenesis, clinical features, and diagnosis of acute cholecystitis”, section on ‘Cholescintigraphy (HIDA scan)’.)
- CT of the gallbladder permits assessment of stone density and the pattern of calcification. Stones of high density (>100 Hounsfield units) dissolve poorly ; however, the pattern of calcification and morphologic appearance on CT imaging are equally important and formal density measurements are probably not necessary . Highly calcified stones and stones with dense surface calcification are unlikely to dissolve and are more resistant to lithotripsy. Unfortunately, 15 to 20 percent of lucent gallstones are not cholesterol rich and respond poorly to dissolution therapy despite having favorable radiologic features.
- A functioning gallbladder is necessary to ensure that gallbladder debris is expelled and to minimize stone recurrence. Gallbladder function can be assessed by ultrasonography or a HIDA scan with measurement of ejection fraction. Oral cholecystography (which is now seldom used) can also demonstrate stone buoyancy and assess gallbladder function by its ability to concentrate and contract in response to a fatty meal. Buoyant stones tend to be cholesterol rich and suitable for dissolution.
Prophylaxis in patients at high risk for developing symptomatic gallstone disease — The prevention of gallstone disease can be divided into primary, secondary, and tertiary. Primary prophylaxis refers to preventing the development of gallstones in high-risk patients; secondary to the prevention of symptoms in patients with gallstones; and tertiary to the prevention of recurrent gallstones in patients who have previously received medical therapy .
Primary prevention — Patients at highest risk of developing symptomatic gallstones are those with known biliary sludge, pregnant women, patients undergoing rapid weight loss, patients on long-term octreotide, and those receiving long-term total parenteral nutrition (TPN).
Biliary sludge, which is often detected incidentally during imaging testing performed for other reasons, frequently occurs during pregnancy, following prolonged fasting (eg, after total parenteral nutrition), and in patients treated with ceftriaxone. Pregnancy is associated with both a qualitative change in bile and delayed gallbladder emptying, both of which promote stone formation . Ceftriaxone, which is excreted in bile, can bind calcium and precipitate in bile . (See “Epidemiology of and risk factors for gallstones”.)
Patients with biliary sludge who are consuming an oral diet should be encouraged to eat three meals daily, with each meal containing sufficient fat or protein to ensure good gallbladder contraction. In addition, their diet should be high in fiber and calcium, and low in saturated fats. They should also be encouraged to maintain a low body weight through regular exercise (which may itself prevent gallstone formation)  and calorie restriction. However, care should be taken to maintain nutritional requirements, especially in pregnancy.
Biliary sludge and gallstones may resolve following pregnancy or when a normal diet is reinstituted in patients treated with TPN [11-13]. Prophylaxis in such cases is usually not necessary. However, in addition to dietary recommendations, we have used bile acid therapy in patients who develop pain and/or cholestasis that was thought to be secondary to biliary sludge, and who had no evidence of acalculous cholecystitis or serious complications. These patients have been followed with serial ultrasonography to confirm clearance of the sludge.
Patients receiving total parenteral nutrition (TPN) should be periodically assessed for possible enteral feeding. A number of modalities have been used in an attempt to minimize the risk of gallstone disease in these patients:
- One study suggested that, in patients who require prolonged TPN, daily injections of cholecystokinin may promote gallbladder emptying and clearance of sludge . However, subsequent data did not support this initial observation .
- High doses of crystalline amino acids may produce the same effect by inducing secretion of endogenous cholecystokinin .
Screening of patients on long-term TPN for the development of biliary sludge has not been established to be beneficial. However, some patients in whom sludge is documented (either because of clinical symptoms or when found incidentally) may benefit from prophylactic bile acid therapy. Such patients have a significant rate of subsequent gallstone formation, although most remain asymptomatic. We consider using prophylactic treatment in patients who would tolerate symptomatic gallstone disease or complications related to gallstones poorly.
The use of prophylactic bile acid therapy in individuals following surgery for weight reduction has received increased interest in recent years. The risk of developing gallstones is greatest during the period of rapid weight reduction and falls once the patient’s weight has stabilized . Several studies have suggested that the risk of gallstone formation is as high as 35 to 70 percent [17-19]. As a result, cholecystectomy is now performed in many patients undergoing bariatric surgery.
Some studies have shown a striking benefit from ursodeoxycholic acid in patients undergoing rapid weight reduction without a prophylactic cholecystectomy . On the other hand, treatment with ursodeoxycholic acid is not always successful, possibly because of poor compliance .
Secondary prevention — Secondary prevention refers to the prevention of symptoms in patients who have gallstones but are asymptomatic. These patients are usually identified by ultrasonography performed for some other reason. While dietary maneuvers and bile acid therapy may result in gallstone dissolution and prevent further progression of gallstone disease, there are few data suggesting that drug therapy is cost-effective or should be used in this setting. At the present time, medical therapy of asymptomatic stones is not indicated. (See “Approach to the patient with incidental gallstones”.)
Tertiary prevention — Symptomatic gallstone recurrence following successful medical therapy remains a major concern because the gallbladder is left in place and patients currently selected for medical management are frequently poor surgical candidates. Without treatment, approximately 60 percent of patients who have undergone extracorporeal shockwave lithotripsy (ESWL) or medical dissolution have recurrent gallstone disease. In such cases, retreatment may be effective. Recurrent gallstones are often not “true to type.” Even in the case of previous calcified gallstones, recurrent gallstones are usually lucent on CT, rich in cholesterol, and likely to be suitable for bile acid therapy .
Prevention of recurrence may be a more effective strategy than retreatment. Methods for the prevention of gallstone recurrence include dietary and other lifestyle modifications (see ‘Primary prevention’ above) and continued bile acid therapy. Long-term bile acid therapy is likely to prevent further gallstone recurrence and the development of symptoms, but is expensive [21-23]. Aspirin and other nonsteroidal antiinflammatory drugs have also been assessed . These agents are thought to work through the inhibition of mucin secretion and the alteration in gallbladder mucosal function. Their efficacy is not well established in humans and therefore cannot be recommended at the present time.
We use long-term bile salt therapy in patients whose medical condition precludes cholecystectomy, or in whom the risk of gallstone recurrence remains high because of lack of reversible predisposing features. (See “Nonsurgical treatment of gallstone disease”.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
- Basics topics (see “Patient information: Gallstones (The Basics)” and “Patient information: Gallbladder removal (cholecystectomy) (The Basics)”)
- Beyond the Basics topics (see “Patient information: Gallstones”)
SUMMARY AND RECOMMENDATIONS
- Medical management may be an alternative to cholecystectomy in selected patients with symptomatic gallstone disease. At present, three methods used alone or in combination are available for the nonsurgical management of patients with gallstone disease (see ‘Introduction’ above):
- Oral bile salt therapy (primarily ursodeoxycholic acid)
- Contact dissolution
- Extracorporeal shockwave lithotripsy
- Patients with complicated gallstone disease who cannot undergo surgery are better treated by percutaneous stone removal, gallbladder drainage, or endoscopic retrograde cholangiopancreatography (ERCP).
- Characteristics of the gallstones need to be considered before instituting medical therapy. This can usually be achieved by computed tomography (CT) combined with ultrasonography or cholescintigraphy (HIDA scan) of the gallbladder. (See ‘Symptomatic gallstone disease’ above.)
- We suggest medical therapy for gallstones in patients with severe medical problems who are at high risk for or refuse surgery and who have mild to moderately symptomatic gallstone disease (Grade 2B). Treatment should be continued until ultrasonography demonstrates clearance of the gallstones. This usually requires six months or longer and is effective in less than 40 percent of patients. In successfully treated patients, long-term therapy should be considered to minimize stone recurrence. (See “Nonsurgical treatment of gallstone disease”, section on ‘Medical gallstone dissolution’.)
- We suggest not treating asymptomatic patients with incidentally found gallstones. (See “Approach to the patient with incidental gallstones”.)
- In patients who develop pain and/or cholestasis thought to be due to biliary sludge, we suggest dietary changes and bile acid therapy, provided that they have no evidence of acalculous cholecystitis or serious complications (Grade 2C). Patients are followed with serial ultrasonography to confirm clearance of the sludge. (See ‘Primary prevention’ above.)
- In patients who have undergone nonsurgical treatment (such as extracorporeal shockwave lithotripsy) whose gallbladder is not removed, we suggest long-term bile acid therapy (Grade 2C). (See ‘Tertiary prevention’ above.)
- Darzi A, Geraghty JG, Williams NN, et al. The pros and cons of laparoscopic cholecystectomy and extracorporeal shock wave lithotripsy in the management of gallstone disease. Ann R Coll Surg Engl 1994; 76:42.
- Portincasa P, van de Meeberg P, van Erpecum KJ, et al. An update on the pathogenesis and treatment of cholesterol gallstones. Scand J Gastroenterol Suppl 1997; 223:60.
- Tomida S, Abei M, Yamaguchi T, et al. Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones: a cohort analysis. Hepatology 1999; 30:6.
- Testoni PA, Caporuscio S, Bagnolo F, Lella F. Idiopathic recurrent pancreatitis: long-term results after ERCP, endoscopic sphincterotomy, or ursodeoxycholic acid treatment. Am J Gastroenterol 2000; 95:1702.
- Caroli A, Del Favero G, Di Mario F, et al. Computed tomography in predicting gall stone solubility: a prospective trial. Gut 1992; 33:698.
- Petroni ML, Jazrawi RP, Grundy A, et al. Prospective, multicenter study on value of computerized tomography (CT) in gallstone disease in predicting response to bile acid therapy. Dig Dis Sci 1995; 40:1956.
- Hofmann AF. Primary and secondary prevention of gallstone disease: implications for patient management and research priorities. Am J Surg 1993; 165:541.
- Maringhini A, Ciambra M, Baccelliere P, et al. Biliary sludge and gallstones in pregnancy: incidence, risk factors, and natural history. Ann Intern Med 1993; 119:116.
- Shiffman ML, Keith FB, Moore EW. Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility. Gastroenterology 1990; 99:1772.
- Leitzmann MF, Giovannucci EL, Rimm EB, et al. The relation of physical activity to risk for symptomatic gallstone disease in men. Ann Intern Med 1998; 128:417.
- Valdivieso V, Covarrubias C, Siegel F, Cruz F. Pregnancy and cholelithiasis: pathogenesis and natural course of gallstones diagnosed in early puerperium. Hepatology 1993; 17:1.
- Quigley EM, Marsh MN, Shaffer JL, Markin RS. Hepatobiliary complications of total parenteral nutrition. Gastroenterology 1993; 104:286.
- Marks JW, Stein T, Schoenfield LJ. Natural history and treatment with ursodiol of gallstones formed during rapid loss of weight in man. Dig Dis Sci 1994; 39:1981.
- Sitzmann JV, Pitt HA, Steinborn PA, et al. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170:25.
- Dawes LG, Muldoon JP, Greiner MA, Bertolotti M. Cholecystokinin increases bile acid synthesis with total parenteral nutrition but does not prevent stone formation. J Surg Res 1997; 67:84.
- Zoli G, Ballinger A, Healy J, et al. Promotion of gallbladder emptying by intravenous aminoacids. Lancet 1993; 341:1240.
- Sugerman HJ, Brewer WH, Shiffman ML, et al. A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg 1995; 169:91.
- Shiffman ML, Sugerman HJ, Kellum JM, et al. Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity. Am J Gastroenterol 1991; 86:1000.
- Wudel LJ Jr, Wright JK, Debelak JP, et al. Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: results of a randomized controlled pilot study. J Surg Res 2002; 102:50.
- Pereira SP, Hussaini SH, Kennedy C, Dowling RH. Gallbladder stone recurrence after medical treatment. Do gallstones recur true to type? Dig Dis Sci 1995; 40:2568.
- Tudyka J, Wechsler JG, Kratzer W, et al. Gallstone recurrence after successful dissolution therapy. Dig Dis Sci 1996; 41:235.
- Rubin RA, Kowalski TE, Khandelwal M, Malet PF. Ursodiol for hepatobiliary disorders. Ann Intern Med 1994; 121:207.
- Tsumita R, Sugiura N, Abe A, et al. Long-term evaluation of extracorporeal shock-wave lithotripsy for cholesterol gallstones. J Gastroenterol Hepatol 2001; 16:93.
- Adamek HE, Buttmann A, Weber J, Riemann JF. Can aspirin prevent gallstone recurrence after successful extracorporeal shockwave lithotripsy? Scand J Gastroenterol 1994; 29:355.
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