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Therapeutics

Review: High-dose ursodeoxycholic acid for more than 6 months and combined ursodeoxycholic and cherodeoxycholic acids have the highest rate of gallstone dissolution

ACP J Club. 1993 Nov-Dec;119:69. doi:10.7326/ACPJC-1993-119-3-069


Source Citation

May GR, Sutherland LR, Shaffer EA. Efficacy of bile acid therapy for gallstone dissolution: a meta-analysis of randomized trials. Aliment Pharmacol Ther. 1993 Apr;7:139-48.


Abstract

Objective

To determine the efficacy of bile-acid therapy for dissolution of cholesterol gallstones.

Data sources

Studies were identified using MEDLINE (1966 to September 1992) and the terms gallstones and drug therapy, lists of conference proceedings, textbooks, and bibliographies of relevant papers and review articles.

Study selection

Clinical trials were selected if the following criteria were met: patients randomized to bile-acid therapy (chenodeoxycholic acid [CDCA] or ursodeoxycholic acid [UDCA], visualization of the gallbladder determined by oral cholecystography (OCG), radiolucent gallstones, and complete dissolution confirmed by OCG or ultrasonography.

Data extraction

Study quality was determined and scored. Bile acid used and dosages were recorded for each treatment group, stone size (small stones < 10 mm) was categorized, and percentages of participants achieving complete dissolution were recorded. Heterogeneity was assessed. Data were pooled and confidence intervals calculated.

Main results

66 trials were identified and 23 analyzed (1949 patients). 9 of the trials were placebo controlled. 6 trials (467 patients) studied low-dose CDCA (< 10 mg/kg body weight per d) and dissolution rates ranged from 0% to 20% (overall 8.1 %, 95% CI 5.8% to 11.0%). 10 trials (595 patients) studied high-dose CDCA and dissolution rates ranged from 0.0% to 47.4% (overall 18%, CI 14.9% to 21.1 %). Heterogeneity calculations showed variable results for high-dose CDCA trials ( P< 0.001) and for low-dose CDCA trials ( P < 0.02). 12 trials (280 patients) studied low-dose UDCA (< 7 mg/kg daily) and the overall dissolution rate was 18.6% (CI 14% to 23 %). 16 trials (539 patients) studied high-dose UDCA and the overall dissolution rate was 31.9% (CI 28% to 37%). The low-dose UDCA trials were homogeneous ( P> 0.05) and the high-dose trials showed heterogeneity ( P< 0.001). When UDCA was taken for > 6 months the overall dissolution rates increased to 20.6% (CI 15.0% to 26.1 %) for low doses and 37.3% (CI 32.7% to 42.0%) for high doses. 2 studies (78 patients) used a combination of CDCA and UDCA; the overall dissolution rate was 62.8% (CI 51.1% to 73.5%). Combination therapy had better dissolution rates than UDCA ( P< 0.001). The dissolution rate with UDCA was better for small stones (< 10 mm) than for large stones (48.5% [CI 41 % to 56%] vs 28.8% [CI 22% to 36%], P< 0.001 for the difference).

Conclusions

The highest rates of gallstone dissolution with bile acids were in patients taking high-dose ursodeoxycholic acid for more than 6 months and in patients taking a combination of ursodeoxycholic acid and chenodeoxycholic acid. Stone size was strongly related to the probability of therapeutic success.

Source of finding: Medical Research Council of Canada.

For article reprint: Dr. E.A. Shaffer, Department of Medicine, C-210, Foothills Hospital, 1403 29 Street NW, Calgary, Alberta, T2N OC8, Canada. FAX 403-670-1095.


Commentary

Interest in the nonsurgical management of gallstones has plummeted since the introduction of laparoscopic cholecystectomy. Hence, it is ironic that we are only now learning the clinical efficacy of oral bile-acid therapy for cholesterol cholelithiasis. This well-done meta-analysis concludes that UDCA is superior to CDCA, that high doses have better success rates than low doses, and that outcomes are markedly better in persons with stones < 10 mm in diameter. Even under such favorable circumstances, only roughly half of patients will be free of gallstones after treatment for 6 months or more.

Bile-acid therapy has other drawbacks besides its low success rate. Treatment is often required for 1 year or longer. Compliance with twice-daily dosing is generally required. UDCA is relatively expensive, with medication charges exceeding $1500 annually. Finally, gallstones recur at a rate of 10% per year among those who initially responded to treatment (1). The principal advantage of bile-acid therapy is, of course, the avoidance of surgery. Many patients fear hospitals and surgical procedures or, for cosmetic reasons, wish to avoid incision scars. Others are at high risk for cholecystectomy because of advanced age, comorbid conditions, or both. Nonsurgical treatments should be considered for these patients.

Laparoscopic cholecystectomy has become the primary treatment for symptomatic gallstones because of its high success rate and its advantages over open surgery. Oral bile acids may be considered for the 15% of patients who have radiolucent stones measuring ≥ 10 mm in diameter in a functioning gallbladder (2). Even among such patients, a successful therapeutic outcome is not guaranteed.

Andrew K. Diehl, MD, MSc
University of Texas Science Center at San AntonioSan Antonio, Texas, USA


References

1. Johnston DE, Kaplan MM. Pathogenesis and treatment of gallstones. N Engl J Med. 1993;328:412-21.

2. Weinstein DF, Brink JA, Richter JM. Nonsurgical treatment of cholelithiasis. Int J Technol Assess Health Care. 1990;6:643-54.