Gallstones -- Approach to Medical Management

Fred M. Konikoff, MD

In This Article

Oral Bile-Acid Treatment

Successful dissolution of gallstones by the oral administration of bile-acid mixtures was reported almost 70 years ago.[22] It was, however, only in the 1970s that this form of therapy was tested on a larger scale.[23,24,25] Initially, CDCA was used,[26] but due to a dose-dependent increase in aminotransferases, an increase in serum low-density lipoprotein cholesterol, and the development of bile salt-induced diarrhea, the treatment raised concerns. Because the more hydrophilic UDCA appeared to be as effective in gallstone dissolution but was practically devoid of side effects, it rapidly replaced the use of CDCA.[27,28]

The idea behind oral administration of CDCA and UDCA was to enrich the bile with these bile acids and thereby decrease cholesterol supersaturation and dissolve the stones. In fact, total bile salt concentration in bile did not change appreciably, and the decrease in cholesterol saturation was achieved primarily by a decrease in biliary cholesterol concentration. While both bile acids do decrease biliary cholesterol secretion,[29] they do so by different mechanisms. CDCA decreases cholesterol synthesis by inhibiting hepatic HMG-CoA reductase activity, whereas UDCA does not affect cholesterol synthesis but reduces intestinal cholesterol absorption.[30] CDCA also decreases hepatic bile-acid synthesis, but UDCA does not, and may even slightly increase it. There is also a difference between the 2 agents in terms of the physical chemical mechanism of gallstone dissolution: CDCA removes cholesterol from the stones by micellar solubilization, whereas UDCA does so primarily by formation of a liquid crystalline phase.[31,32]

In 1981, the National Cooperative Gallstone Study established the efficacy and safety of CDCA therapy.[26] Although gallstones could be dissolved by oral administration of CDCA, its efficacy was low. Less than half (40.8%) of patients responded to the highest dose tested (750 mg/day), and only 13.5% had complete dissolution of their stones within 2 years. Moreover, the response was slow. In over half, more than 9 months of treatment were needed for complete dissolution. Subsequently, the introduction of UDCA with a better safety profile and equal or better efficacy made bile salt litholysis more attractive.

The efficacy of CDCA is dose-dependent, but so are its side effects. Hence, a full dose of 15 mg/kg/day will induce diarrhea in up to 60% of patients, increase cholesterol levels in most patients, and cause hepatotoxicity in over 3%. In comparison, the recommended dose of UDCA (10-12 mg/kg/day) has essentially no side effects except occasional diarrhea. Therefore, monotherapy with CDCA cannot be recommended and has been completely replaced by UDCA therapy. Combination therapy with a reduced dose of both bile acids (5-8 mg/kg/day of each) has also been suggested, and may be as safe and efficient as full-dose UDCA monotherapy, as well as less costly.[33,34] UDCA monotherapy does, however, cause less diarrhea, and therefore it remains the treatment of choice today.

UDCA is usually given at a dose ranging between 8 and 15 mg/kg/day. Bedtime administration is preferable because it maintains hepatic bile-acid secretion rate overnight, thus reducing secretion of supersaturated bile and increasing the dissolution rate.[35,36] Dissolution is assessed by ultrasonography every 6 months. The expected dissolution rate is approximately a 1-mm decrease in stone diameter per month of treatment.[37] Treatment is usually continued for another 3 months after successful dissolution.

In up to 10% of patients, cholesterol gallstones acquire a surface calcification during treatment, rendering them nondissolvable and unsuitable for further therapy with bile acids.[38]

Not all patients are suitable candidates for oral dissolution therapy. Selection criteria are based on 3 main aspects: (1) patient, (2) gallbladder, and (3) stone characteristics. Patients with complications or with frequent and severe attacks of biliary colic are not suitable candidates. Patients with mildly symptomatic gallstones are the best candidates.[28,39] Patients with increased surgical risks or those who do not want to undergo surgery due to personal preferences should be considered for medical dissolution therapy. Asymptomatic patients are currently not treated. For medical therapy to be effective, the gallbladder needs to fill and function. Finally, only cholesterol stones can be dissolved by bile acids, and any significant calcification of the stones will render them nondissolvable.

Gallbladder function -- as well as cholesterol content of stones -- can be assessed by oral cholecystography.[40] After oral intake of an iopanoic acid derivative, a plain abdominal x-ray will show radiolucent cholesterol stones floating within a radiopaque contrast-filled gallbladder.[41] Gallbladder function can be further evaluated by measuring the emptying or ejection fraction following a fatty meal. Ultrasonography is the easiest and most precise method for detecting the presence of stones. Ultrasonography as well as cholescintigraphy may also be used to assess cystic duct patency and gallbladder function by measuring the ejection fraction after a fatty meal or cholecystokinin injection.[42,43,44] Some clinicians have even suggested that ultrasonography may predict stone composition prior to bile-acid or shock-wave lithotripsy treatment.[45,46] Several investigators have shown that the degree of stone calcification and suitability for bile-acid dissolution therapy can be accurately assessed by computed tomography (CT).[47,48,49] Hence, a combination of CT for stone composition and ultrasonography for gallbladder filling and function is also a good alternative for appropriate patient selection.

The success of oral dissolution treatment is defined as complete disappearance of gallstones as documented by oral cholecystography or, preferably, ultrasonography. This is achieved in 10% to over 80% of patients. The wide range of success reflects differences in patient selection, treatment duration, dosage, and ways of assessing success.[50] In a meta-analysis comprising almost 2000 patients treated until 1992, complete dissolution was achieved in 18.2% with CDCA, in 37.3% with UDCA, and in 62.8% with combination therapy.[51] In patients with small stones (< 10 mm), a dissolution rate of 48.5% was seen with UDCA therapy.

By employing more strict selection criteria, the efficacy of this treatment can be increased, but at the expense of the number of suitable candidates.[52] Thus, an optimal lean patient with small (< 5 mm) radiolucent stones (approximately 3% of all symptomatic patients) will have a 90% likelihood of complete dissolution within 6 months.[53] In contrast, patients with 5- to 10-mm radiolucent stones (approximately 12%) will have only a 50% chance of successful dissolution within 9 months.

Initially, extracorporeal shock-wave lithotripsy (ESWL) was introduced as an adjunct to bile-acid therapy.[54,55] The rationale was to use ESWL to fragment larger stones to increase dissolvable surface area, shorten treatment time, and increase the pool of patients suitable for bile-acid dissolution. With increasing experience it became clear that ESWL was actually an independent treatment modality.[56] After pulverizing gallstones to tiny sand-like fragments, there seems to be little if any benefit of or need for additional bile-acid therapy.[56,57,58]

A significant drawback of gallstone dissolution therapy is the possibility of gallstone recurrence. Stones will recur because the gallbladder is left in place and the underlying cause of gallstone formation has not been corrected. The recurrence rate is about 10% annually for up to 5 years,[59] and is often preceded by sludge formation.[60] Thereafter, recurrence is uncommon. Most stones recur without symptoms[50] and will respond to re-treatment with bile acids.[61,62] Maintenance therapy with low-dose UDCA has been reported to decrease the recurrence rate but it is costly.[63] Patients with multiple primary stones have an increased recurrence rate.[63] Additional factors that have been reported to predict recurrence after successful lithotripsy are obesity,[64] poor gallbladder emptying,[65] an increased deoxycholic acid pool,[66] and an apoE4 genotype.[67] Whether these factors are important after medical dissolution is unclear.

Because successful dissolution therapy is not inevitably followed by gallstone recurrence, there is a group of patients in whom the initial lithogenic process is transient. Pregnancy, rapid weight loss, and convalescence from abdominal surgery are recognized transient risk factors.[68,69] Trying to identify and characterize patients with transient lithogenicity for dissolution therapy is an important challenge for future studies.


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