Prevention of Gallstones After Bariatric Surgery using Ursodeoxycholic Acid: A Narrative Review of Literatures

Abstract

Obesity by itself is a factor in the development of gallstone disease, and periods of weight loss after bariatric surgery further increase the risk of gallstone formation. In patients with obesity, hypersecretion of cholesterol may increase the risk of gallstone formation, which is approximately five-fold higher than that in the general population. The incidence of gallstone formation after bariatric surgery is 10–38% and often associated with a proportional increase in the risk of developing biliary complications. Routine postoperative administration of ursodeoxycholic acid (UDCA) is recommended to prevent gallstone formation. Several randomized trials have indicated that UDCA can effectively prevent gallstones and reduce the risk of cholecystectomy after bariatric procedures. The effective daily dose of UDCA in each study ranged from 500 to 1,200 mg, and it may be considered at least during the period of rapid weight loss (first 3–6 months postoperatively) to decrease the incidence of symptomatic gallstones.

INTRODUCTION

Bariatric surgery is an effective treatment for obesity. However, it is associated with a high risk of gallstone formation [1,2]. Gallstones are a common complication of bariatric surgery, and they can cause symptoms such as abdominal pain, jaundice, and pancreatitis. In some cases, surgery or endoscopic procedures may be required. Therefore, the prevention of gallstone formation after bariatric surgery is an important management strategy to improve the quality of life of patients.

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid that has been proven to prevent gallstone formation. UDCA works by decreasing the saturation of bile with cholesterol, which reduces the risk of cholesterol crystal formation and gallstone development. Recent studies have investigated the use of UDCA for the prevention of gallstone formation after bariatric surgery and reported promising results [3,4]. This literature review aimed to evaluate the current evidence on the effectiveness of UDCA in preventing gallstone formation after bariatric surgery.

INCIDENCE OF GALLSTONES AFTER BARIATRIC SURGERY AND PREDISPOSING FACTORS

The incidence of gallstones after bariatric surgery can vary depending on the type of surgery, follow-up period, and study population. However, some studies have reported overall rates of up to 40% [5,6,7,8]. Several studies published within the last 3 years are listed in Table 1 [9,10,11,12,13,14]. The incidence of gallstones after bariatric surgery increased over time in the Swedish Obese Subjects study, and the difference in the incidence of gallstones between the surgery and control groups also increased from 2.5% at 2 years postoperatively to 5.2% at 20 years postoperatively [15]. The surgery group was associated with increased risk of symptomatic gallstone disease and increased risk for cholecystectomy (P<0.001 and P=0.002, respectively). In a recent systematic review, gallstone disease was classified as symptomatic or asymptomatic, and the risk of de novo post-bariatric gallstones was not substantially higher (8.2%) than that of asymptomatic gallstone disease (20.7%) [16,17].

Table 1. Incidence of gallstones after bariatric surgery: summary of recent data from 2020 to 2022.

Country	Study	Year	Sample size	Procedures		Interventions	Incidence of gallstones
Switzerland	Dirnberger et al. [9]	2022	1,174	RYGB	817 (70%)				6.5%
				SG	357 (30%)				4.2%
Taiwan	Han et al. [10]	2022	152	SG or MGB		Probiotics vs. Digestive enzyme vs. UDCA			15.3% at 6 months
Iran	Barzin et al. [11]	2022	2,629	RYGB	891 (34%)	UDCA 600 mg for 6 months			10.8% at 24 months
				SG	1,738 (66%)
Netherland	Haal et al. [12] (UPGRADE trial)	2021	959	RYGB	881 (92%)	900 mg for 6 months vs. Placebo	Preoperative asymptomatic		20%
				SG	78 (8%)		Postoperative symptomatic		8% at 24 months
Iran	Golzarand et al. [13]	2021	1,163	RYGB	377 (32%)	-	Symptomatic		8.3% at 34months
				SG	786 (68%)
Sweden	Anveden et al. [15] (SOS study)	2020	3,597	Surgery	1,755	-	Surgery vs. Control		3.7% vs. 1.2% at 2 years
				Control	1,842				7.2% vs. 3.5% at 5 years
									11.9% vs. 7.7% at 10 years
									19.7% vs. 14.5% at 20 years
Israel	Sneineh et al. [14]	2020	580			-	Symptomatic		6.2% at 12 months
				RYGB	55 (9.5%)			- RYGB		- 14.5%
				SG	203 (35%)			- SG		- 4.4%
				LAGB	175 (30%)			- LAGB		- 4.1%
				MGB	147 (2.5%)			- MGB		- 7.5%

RYGB = Roux-en-Y gastric bypass, SG = sleeve gastrectomy, MGB = mini gastric bypass, LAGB = laparoscopic adjustable gastric banding, UDCA = ursodeoxycholic acid.

Obesity is an established risk factor for the development of gallstone disease; therefore, weight reduction may reduce the risk of gallstone formation [18,19]. However, the following two specific settings are exceptions: extremely rapid (>1.5 kg/week) or excessive weight reduction (>25% of the total body weight) [20,21,22]. Both cases may occur after bariatric surgery or administration of weight loss medications, which may lead to a lithogenic state and subsequently initiate biliary sludge and gallstones [22]. Interestingly, a retrospective study has demonstrated that this association between weight loss and gallstone formation was particularly pronounced when the nadir was reached [23]. The amount and rate of weight loss may also vary depending on the type of procedure, and previous studies have demonstrated that the time of gallstone formation differs according to the type of procedure; approximately 30% of gallstones were reported within 6 months after Roux-en-Y gastric bypass (RYGB) or biliopancreatic diversion, whereas a comparable incidence was reported at 6–12 months after sleeve gastrectomy (SG) [24,25,26].

The type of bariatric procedure performed may affect the incidence of gallstone formation. RYGB surgery was associated with a higher risk of gallstone formation than other types of bariatric surgery such as SG. A prospective study has reported that the incidence of gallstones was 34% after RYGB and 28% after SG. In a recent meta-analysis of eight cohort studies (94,855 SGs and 106,844 RYGBs), the SG group had a 35% lower rate of gallstones (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.49–0.86) and a significantly lower incidence of cholecystectomy (OR, 0.54; 95% CI, 0.30–0.99) than the RYGB group [27].

Numerous studies have identified several predisposing factors, including an increased risk of gallstone formation in patients undergoing bariatric procedures.

• 1. Rapid weight loss: Rapid weight loss due to bariatric surgery can increase the risk of gallstone formation [13,22]. This is because the liver starts to produce more cholesterol in response to the weight loss, which can lead to gallstone formation.

• 2. Sex: Female patients have a higher risk of gallstone formation after bariatric surgery compared to male patients [28].

• 3. Obesity: Obesity is a known risk factor for gallstone formation, and patients with obesity are more likely to develop gallstones after bariatric surgery [18,19].

• 4. Age: Younger patients have a higher risk of gallstone formation after bariatric surgery [12,13].

• 5. Type of surgery: Different types of bariatric surgery have been associated with different rates of gallstone formation. For example, RYGB surgery has been reported to have a higher risk of gallstone formation than SG [24–27].

• 6. Metabolic factors: Some metabolic factors such as hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia are associated with an increased risk of gallstone formation after bariatric surgery [13].

PATHOPHYSIOLOGY OF GALLSTONES AFTER BARIATRIC SURGERY

The exact mechanism by which gallstones form after bariatric surgery remains unclear; however, a combination of changes in bile composition and increased biliary tract pressure may be involved in gallstone formation. Bariatric surgeries, such as RYGB and SG, lead to rapid weight loss, which can cause changes in the saturation of bile with cholesterol. This increased saturation can cause the formation of cholesterol monohydrate crystals, which can then aggregate to form gallstones [29]. Another factor may be an increase in biliary tract pressure [30]. This may be caused by a reduction in the size of the stomach and small intestine, which can lead to changes in the secretion and transport of bile through the biliary tract. Lastly, the decrease in bile acid secretion associated with reduced gallbladder motility after bariatric surgery can also lead to an increased risk of gallstone formation [31,32]. Normally, bile acids help to emulsify fats and neutralize acids in the gut, which helps to prevent gallstone formation. However, when bile acid secretion decreases, the bile becomes more viscous, thus leading to an increased risk of gallstone formation.

ROLE OF PROPHYLACTIC CHOLECYSTECTOMY DURING BARIATRIC SURGERY FOR PREVENTING GALLSTONES

Cholecystectomy is the gold standard treatment for symptomatic gallstones; however, the role of prophylactic cholecystectomy (PC) during bariatric procedures remains debatable.

PC was historically recommended in the era of open surgery; however, many studies have reported that PC is associated not only with a longer operative time, but also with a higher rate of complications, longer hospital stays, and even increased mortality [33,34,35]. More recent studies have indicated that concomitant laparoscopic cholecystectomy with SG or RYGB did not affect mortality or the risk of major complications, and it was only associated with a 0.6% increased risk of surgical site infection, although the practice of routine concomitant cholecystectomy has steadily decreased over the past decades [36,37]. Moreover, the popularity of SG has further reduced the impetus for the prophylactic treatment of gallstones. This is because unlike RYGB, SG ensures endoscopic access when endoscopic retrograde cholangiography and stone extraction for common duct stones are required [37].

Hence, the current clinical practice guidelines do not recommend ultrasound screening for asymptomatic gallstones yet recommend concomitant cholecystectomy only for symptomatic patients undergoing bariatric surgery [38].

EFFICACY OF UDCA FOR THE RESOLUTION OF GALLSTONES

UDCA, also known as ursodiol, is a hydrophilic bile acid that is effective in the resolution of gallstones or biliary sludge. UDCA works by reducing the saturation of bile with cholesterol and by increasing the solubility of cholesterol, which can help to prevent the formation of new gallstones and dissolve existing gallstones.

Several studies have investigated the efficacy of UDCA for the resolution of gallstones. UDCA has demonstrated promising results with a minimum dose of 500 mg/day, and even higher doses did not yield greater benefits (Table 2) [39,40,41,42,43]. The prophylactic use of UDCA during the weight reduction phase, regardless of the method of weight loss (low-calorie diet, bariatric surgery, etc.), has been proven to reduce gallstone formation, with reduction rates of up to 58% in a few clinical trials [20,25,44,45,46,47,48,49]. However, only 11 randomized controlled trials have reported the effect of UDCA on gallstone formation after bariatric surgery (Table 3) [12,25,26,48,49,50,51,52,53,54,55]. Most studies used 500–600 mg of UDCA daily for 6–12 months postoperatively; consequently, the incidence of gallstone formation was lower in the UDCA group. A recent meta-analysis of these randomized controlled trials has reported that UDCA decreases bile lithogenicity, concluding that UDCA can effectively prevent gallstones and reduce the risk of cholecystectomy after bariatric surgery [3]. Therefore, based on the results of several clinical trials, the American Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic, and Nonsurgical Support of the Bariatric Surgery Patient recommend oral administration of UDCA 500–1,000 mg daily during the first 3–6 months postoperatively [56].

Table 2. Efficacy of UDCA on resolution of gallstones.

Study	Journal	Year	Sample size	Study design	Period	Resolution or Improvement
Tokyo Cooperative Gallstone Study Group [39]	Gastroenterology	1980	151	600 mg/150 mg UDCA vs. Placebo for asymptomatic gallstones	6–12 months	600 mg		41.7%
						150 mg		18.8%
						Placebo		6.7%
Tint et al. [40]	Ann Intern Med	1982	53	250–300 mg vs. 500–600 mg vs. 900–1,000 mg for gallstones with size of <30 mm	6–38 months	High dose		80.0%
						Middle dose		78.9%
						Low dose		78.9%
Erlinger et al. [41]	Hepatology	1984	197	125 mg vs. 250 mg vs. 500 mg vs. 1,000 mg for gallstones	Up to 12 months	1,000 mg		48.7%
						500 mg		55.2%
						250 mg		37.8%
						125 mg		29.4%
May et al. [42]	Aliment Pharmacol Ther	1993	1,949	CDCA (>10 or <10 mg/kg/d) vs. UDCA (>7 mg/kg/d) for gallstones	More than 6 months	High dose UDCA		37.3%
						Low dose UDCA		20.6%
						High dose CDCA		18.0%
						Low dose CDCA		8.1%
Tomida et al. [43]	Hepatology	1999	527	Long-term 600 mg UDCA vs. Control for asymptomatic gallstones	Followed up to 18 years	UDCA vs. Control
							- Symptomatic	62% vs. 92%
							- Cholecystectomy	26% vs. 88%

UDCA = ursodeoxycholic acid, CDCA = chenodeoxycholic acid.

Table 3. RCTs for the impact of UDCA on gallstone formation after bariatric surgery.

Country	Study	Year	Sample size	Surgery type	Dosage of UDCA	Period in medication	Incidence of gallstones
USA	Sugerman et al. [25]	1995	233	GBP	300 mg (n=53) vs. 600 mg (n=61) vs. 1,200 mg (n=63) vs. Placebo (n=56)	6 months	13% vs. 2% vs. 6% vs. 32%
USA	Wudel et al. [48]	2002	41	RYGB	600 mg (n=15) vs. Ibuprofen (n=15) vs. Placebo (n=11)	6 months	46.7% vs. 93.3% vs. 93.3%
Austria	Miller et al. [49]	2003	152	AGB, VBG	500 mg (n=76) vs. Placebo (n=76)	6 months	17% vs. 25%
USA	Adams et al. [26]	2016	75	SG	600 mg (n=37) vs. Control (n=38)	6 months	9.1% vs. 21.4%
Egypt	Abouzeid et al. [50]	2018	89	SG	500 mg (n=44) vs. Control (n=45)	12 months	5.8% vs. 14.7%
Egypt	Nabil et al. [51]	2019	200	SG	500 mg (n=100) vs. Control (n=100)	6 months	6% vs. 40%
Italy	Pizza et al. [52]	2020	190	OAGB	600 mg (n=95) vs. Control (n=95)	6 months	4.2% vs. 25.2%
Israel	Sakran et al. [53]	2020	92	OAGB, RYGB	600 mg (n=46) vs. Placebo (n=46)	6 months	23.9% vs. 45.7%
Egypt	Talha et al. [54]	2020	1,432	OAGB, SG, GCP	500 mg (n=1,137) vs. Placebo (n=295)	6 months	6.5% vs. 22%
Egypt	Salman et al. [55]	2021	258	SG	500 mg (n=130) vs. Control (n=128)	12 months	8.5% vs. 32.0%
Netherland	Haal et al. [12]	2021	985	RYGB, SG	900 mg (n=492) vs. Placebo (n=493)	6 months	Symptomatic 6.5% vs. 9.7%

RCT = randomized control trial, UDCA = ursodeoxycholic acid, GBP = gastric bypass, RYGB = Roux-en-Y gastric bypass, AGB = adjustable gastric banding, VBG = vertical banded gastroplasty, SG = sleeve gastrectomy, OAGB = one anastomosis gastric bypass, GCP = great curvature plication.

FUTURE PERSPECTIVES OF CLINICAL TRIALS ON UDCA AFTER BARIATRIC SURGERY

To date, the results of the clinical trials demonstrate a great benefit of UDCA for preventing gallstones after bariatric surgery. However, several issues need to be addressed in the near future. First, most studies were from Western or Middle Eastern countries; therefore, the results should be interpreted or implemented cautiously in Asian countries. For instance, the PEGASUS-D study has reported that both 300 and 600 mg UDCA were effective in reducing the incidence of gallstones after gastrectomy for gastric cancer [57]. Based on these results, 300 mg UDCA may be sufficient for Asian patients undergoing bariatric surgery. Second, whether the long-term administration of UDCA (12–24 months) is more effective than 6–12 months of administration is unclear. This is because the lowest body weight is commonly achieved 18–24 months after bariatric surgery compared to that after gastric cancer surgery. Lastly, different dosages of UDCA may be required depending on the surgical procedure. Several studies have implied that the type of bariatric procedure is associated with the incidence and timing of gallstone formation. Therefore, determining a tailored strategy for the prophylactic use of UDCA that is suitable for each procedure may be necessary.

CONCLUSION

Weight reduction after bariatric surgery increases the risk of developing gallstones. The prophylactic use of UDCA (at least 500 mg daily) during the first 6 months postoperatively is effective in reducing the incidence of gallstone formation. More robust studies are required to determine the optimal dosage and administration period.