This study shows that stone dissolution medications lowered CBD stone recurrence rates from 41.5% with no medication to 12.7% for single-agent and 9.8% for dual-agent C&U plus terpene therapy treatments. Subgroup analysis revealed that the CBD stone recurrence rate was significantly lower for C&U plus terpene than all other medication regimens combined (5.2% vs. 13.5%). The overall CBD recurrence rate of 17.2% was in line with previously reported recurrence rates of 1–20% [26]. Notably, dual-agent therapy was more effective than single-agent treatment or no medication for GB stone resolution; these treatments achieved > 30% stone reductions in 34.8%, 14.3%, and 5.3% of patients, respectively.

Medication use significantly reduced the risk of CBD stone recurrence, with HRs of 0.122 and 0.109 for single-agent or double-agent treatment, respectively, versus no therapy. In addition, the study showed an age > 70 years (HR, 2.041), bile duct diameter >13 mm (HR, 1.802), EST (HR, 0.445), and EST + EPBD (HR, 2.061) as risk factors of CBD stone recurrence. Previously reported risk factors were age, a large CBD diameter, CBD angle, periampullary diverticulum, EST, mechanical lithotripsy, biliary stenting, and remnant GB [27]. Periampullary diverticulum was not a risk factor via multivariate analysis in the current study, and mechanical lithotripsy was associated with the risk of CBD recurrence via univariate analysis but not multivariate analysis. When we set a cut-off value of 13 mm, according to receiver operating characteristic (ROC) curve analysis (area under the curve [AUC] of 0.610 and highest sensitivity and specificity at a mean bile duct diameter of 12.3 mm), a CBD diameter of >13 mm was also a risk factor for CBD recurrence via univariate but not multivariate analysis. When we set a cut-off value of 145° for the CBD angle based on the findings of another study [28], neither univariate nor multivariate analysis showed an association with CBD stone recurrence, and ROC analysis produced an AUC of 0.557. A large CBD diameter and periampullary diverticulum are associated with cholestatic effects. Furthermore, after ERCP, the possibility of reflux cholangitis increases because of EST, and cholestasis of bile promotes CBD stone recurrence. However, medications such as UDCA or CDCA that enhance bile acid synthesis [29] reduce bile reflux, and thus, stone recurrence.

Combining medications can have additive or synergistic effects on the prevention of CBD stone recurrence. Several studies have demonstrated that UDCA plus CDCA is more effective than either agent alone at dissolving gallstones [21,22,30]. Furthermore, the percentage of cholelitholytic bile acids in bile was nearly 80% for the combination and only ~65% for UDCA alone. Achieving these beneficial changes in bile acid composition is not feasible by administering UDCA or CDCA alone. Specifically, high UDCA doses reduce bile CDCA levels, and thus, reduce cholesterol solubilization into micelles [22]. When CDCA is administered alone, cholesterol does not dissolve in the liquid crystal phase, and bile may remain cholesterol-saturated, even at high CDCA doses, which are poorly tolerated [22]. Terpene alone also has a limited ability to dissolve gallstones, [13] but when combined with CDCA, it provided complete or partial gallstone dissolution in 41% of patients over 6 months [31]. In addition, for patients with CBD stones, three terpene capsules daily resulted in stone dissolution (complete or partial) in 46% of patients after 6 months and 67% of patients after 1 year [32]. Given that combining stone dissolution medications provides effective treatment for established GB or CBD stones, it is likely that combinations are also effective at preventing CBD stone formation.

Several studies have demonstrated gut microbiota dysbiosis after cholecystectomy [33,34] and in patients with GB stones [35], which resulted in studies on the effectiveness of stone dissolution therapy for gut dysbiosis. UDCA treatment restored gut microbiota in patients with non-alcoholic steatohepatitis or primary biliary cholangitis [36,37]. In another study, gut microbiota dysbiosis was partially reversed by C&U treatment in patients with GB stones [35]. Moreover, a recent study that analyzed changes in bile metabolism and composition after UDCA treatment found that UDCA might play a protective role related to gut microbiota in patients with CBD stones [38]. Thus, dissolution therapy may reduce CBD stone recurrence even after therapy by altering the gut microbiome. Moreover, although the effects of terpene on gut dysbiosis have not been evaluated, it might have similar protective effects.

Biliary stones are classified as cholesterol, black pigment, or brown pigment stones. Pigment stones are more common in East Asia and cholesterol stones are most common in Western countries [39,40], and understanding the mechanisms responsible for their formation is essential for the optimal use of stone-dissolving medicines. Cholesterol stones form mainly when bile concentrations of cholesterol are elevated, and all medications used for biliary stones (UDCA, CDCA, and terpene) reduce bile cholesterol levels by controlling HMG-CoA reductase [27,41]. On the other hand, pigment stones originate from increased unconjugated bilirubin levels when the hepatic glucuronic acid concentration is diminished. Reductions in glucuronic acid have many causes, including bacterial β-glucuronidase activity [11]. Regarding treatments, terpene is metabolized to menthol-glucuronic acid, which can combine with unconjugated bilirubin to reduce pigment stone formation. Recurrent CBD stones after EST are usually brown pigment stones [42]. Terpene is the only medication that can suppress bile glucuronic acid reductions and decrease bile cholesterol saturation. Thus, terpene alone might be considered to be capable of resolving or preventing biliary stones. However, clinical data indicate that terpene monotherapy is inadequate [12,23]. Furthermore, brown pigment stones are associated with bacterial ascending cholangitis, which can be caused by EST after ERCP. The use of UDCA or CDCA to enhance bile acid synthesis would be expected to reduce recurrent brown pigment stone formation by decreasing reflux cholangitis, and UDCA-CDCA combination therapy would be expected to be more effective for biliary stone resolution or prevention than a single therapy treatment with either agent. In a study of CBD stones, the complete dissolution rate was 42% for terpene monotherapy and 73% for terpene plus CDCA or UDCA [12], and in a study of GB stones, the complete resolution rate was 37.5% for UDCA monotherapy and 53% for UDCA plus terpene [23]. It has been reported that terpene is more effective when used in combination therapy, and that CDCA and UDCA function more effectively when combined [43]. In the current study, we found that C&U plus terpene was more effective at preventing CBD recurrence than the other treatments. Numerous studies have shown that UDCA, CDCA, and terpene in various combinations act additively or synergistically, and our results suggest that they provide the best CBD stone prevention when combined.

The duration of medication use required to prevent CBD stone recurrence has not been established, though theoretically, treatment should be continued for life. However, this would be difficult and not cost-effective. After initial complete GB stone resolution, stones recur in around 10% of patients during the year following medication discontinuation and in up to 50% of patients by 5 years [44], and the recurrence rate is even higher in patients who do not achieve complete GB stone resolution. Small stone particles or bile sludge may remain after apparent complete CBD stone removal by ERCP, which highlights the importance of determining the appropriate duration of medication administered to dissolve any remaining stone material. Our results suggest that 6–7 months is appropriate, and ROC curve analysis showed that a cut-off value of 6.4 months had the greatest sensitivity and specificity for preventing CBD stone recurrence (AUC, 0.605; sensitivity, 0.353; specificity, 0.773). Also, after removing CBD stone(s) by ERCP, clinical practice guidelines recommend cholecystectomy when GB stone(s) are confirmed upon imaging. However, in patients with significant co-morbidities or other reasons to avoid surgery, medications could be continued as an alternative treatment. Additionally, CBD dilation after cholecystectomy in young patients may be another risk factor for CBD stones [45].

Our study has several limitations. First, due to its retrospective design, medication duration was not controlled, and some differences in group baseline characteristics were detected. Furthermore, the adverse effects of the medications could not be thoroughly investigated. In particular, medication durations differed markedly between patients, and some patients changed medications during the follow-up period, which introduced potential bias. On the other hand, a large cohort of patients was enrolled to reduce the effects of bias. Second, patients probably stopped taking medications during follow-up, and thus, we could not determine how long medication effects persisted after discontinuation. However, beneficial effects probably persisted due to improvements in gut dysbiosis, especially if microlithiasis was completely removed by medications. Third, the number of patients enrolled in the GB cohort was too small to allow for definitive conclusions. Nonetheless, it can be assumed that medication was effective, and the results obtained provide ample evidence to support the design of future large-scale studies.