The vagus nerve is the source of power for the movement of the gallbladder. Studies have confirmed that vagal nerve injury is an important cause of CL after gastric cancer surgery (12), and the 5-year follow-up incidence of CL after vagal nerve dissection is 9%-21% (13). Ihasz et al. (14) found that 34% of the patients in vagectomy group who received gastrectomy had impaired gallbladder systolic function, and 65% had virtually no gallbladder systolic function.

Studies have shown that the vagus nerve trunk has an important regulatory effect on the absorption and metabolism of nutrients (15), and damage to the hepatic and biliary branches of the vagus nerve causes the gallbladder to lose its innervation, changes the dynamic function of the gallbladder, and increases the tension of the Oddi sphincter, which promotes the development of CL (16). Cattey et al. (17) confirmed that the pyloric one-gallbladder reflex was lost after antral gastrectomy, thus inhibiting gallbladder contraction and easily causing CL. This also confirms that the reflex mechanism between pylorus and bile duct is involved in the formation of CL (18).

Cholecystokinin (CCK) can cause gallbladder contraction, Oddi-sphincter and duodenal relaxation (12). The main mechanism of gallbladder contraction is the release of CCK, even after gastrectomy (19). After gastrectomy, the secretory function of gastric mucosa is reduced or even lost; gastric acid is lacking; and after the digestive tract is reconstructed, food is redirected directly into the jejunum without passing through the duodenum, resulting in reduced CCK release (20), thereby promoting the development of CL. In addition, pancreatic hormone, gastrin, glucagon, motility hormone (21), substance P (SP), etc., can induce gallbladder contraction, while somatostatin (SS) and vasoactive intestinal peptide (11) can inhibit gallbladder contraction. These hormones interact with each other and eventually lead to CL development.

The development of CL after gastric cancer surgery is closely related to changes in gallbladder physiology and changes in bile stone-causing components (5). Most CL cases after gastric cancer surgery involve bile pigment stones (3) and their formation is mainly related to biliary tract infection and cholestasis. Chijiiwa et al. (22) evaluated the gallbladder bile, bile lipid composition, and bile redness in patients who had previously undergone gastrectomy. The stone-causing difference between calcium and ionized calcium was compared, and it was found that ionized calcium and unconjugated bilirubin were significantly increased. These results showed that gallbladder bile tended to contain pigment stones after gastrectomy were an important factor for CL formation, which may be caused by the elimination of gallbladder contraction by gastrectomies and the inactivation of gallbladder bile as well as the mixture of gallbladder bile and fresh hepatic bile, resulting in hypersaturation of the mucosal surface and increasing the tendency toward salt precipitation and gallstone formation.

The dysfunction of the Oddi sphincter may be related to the hepatobiliary branch of the vagus nerve injury, and also related to the release change of gastrointestinal hormones. Nabae et al. (13) recorded Oddi sphincter motility after vagus nerve transection and found that the base pressure of the Oddi sphincter is significantly reduced, but the amplitude is increased. But after meal ingestion, the contraction of the Oddi sphincter increases, and the frequency slows down. This partly explains the cause of CL after gastric cancer surgery.

In conclusion, vagal nerve injuries, include the vagus trunk, hepatobiliary branch of the vagus nerve, upper digestive tract movement and pyloric-bile duct reflex, changes in the secretion of intestinal hormone and the composition of bile, and Oddi sphincter dysfunction are the main causes and closely related to CL development after gastric cancer surgery. Based on the above evidence, we summarized the mechanism as shown in Figure 1 . We believe that injury or resection of the vagus nerve or changes in intestinal hormone secretion can lead to physiological dysfunction of the gallbladder (23) and Oddi sphincter, and the lithogenic components in the bile are also changed, ultimately leading to CL (12, 14, 16, 18, 20, 24).

Studies have shown that the type of gastrectomy is an independent risk factor for CL (3), especially total gastrectomy (5, 25, 26) and distal gastrectomy (13). The incidence of CL after total gastrectomy is significantly higher than that after other surgical methods, ranging from 6% to 71%, and the onset time is early (4, 5, 9, 26). Jun et al. (4) retrospectively studied 2480 patients undergoing gastrectomy, and the results showed that the incidence of CL after total gastrectomy (10%) was significantly higher than that after subtotal gastrectomy (3%) (P<0.001). A national retrospective cohort study in Korea found that CL was most common after total gastrectomy (6.6%), followed by proximal gastrectomy (5.4%), distal gastrectomy (4.8%), and pylorus-sparing distal gastrectomy (4.0%) (P < 0.001). Multivariate analysis showed that total gastrectomy is an independent risk factor for CL development after gastric cancer (26).

However, Park et al. (8) retrospectively reported that 110 (11.2%) of 979 patients who underwent distal gastrectomy for cancer developed CL after surgery. CL occurred in 32 (13.9%) of 230 patients who underwent total gastrectomy and in 6 (9.7%) of 62 patients who underwent proximal gastrectomy after gastric surgery. CL occurred in 2 (15.4%) of the 13 patients who received PPG, but the difference was not statistically significant (P=0.634), indicating that the type of gastric cancer surgery was not an influencing factor for the development of postoperative CL.

Although, there are conflicting evidences on the relationship between the type of gastrectomy and CL development after gastric cancer. We analyzed that the most likely reason is that the interference of other risk factors is not completely eliminated in the different studies. We still believe that the type of gastrectomy is one of the important risk factors for CL.

The reconstruction of the digestive tract during gastric cancer surgery is closely related to the formation of gallstones. Jun et al. (4) studied 2480 patients undergoing gastric cancer surgery; 128 patients (5.2%) developed CL after surgery, of which Roux-en-Y reconstruction accounted for 60 cases (46.9%), which had a higher risk than Billroth I and Billroth II (P < 0.001). Paik et al. (5) confirmed that the incidence of CL after B2 is higher than that after B1, possibly because the change in the CCK secretion pattern leads to weakened gallbladder systolic function and a high incidence of CL. Studies have shown that nonphysiological reconstruction is an important risk factor for the development of postoperative CL (5, 8) and that this incidence of CL is significantly higher than that after physiologic reconstruction (4), especially with Roux-en-Y (4, 8) and Billroth II (5). The high incidence of CL in the Roux-en-Y procedure can be explained by the extent of gastrectomy and duodenal dissection. Therefore, from above evidences, we believe that Roux-en-Y reconstruction was an independent risk factor for CL development after gastric cancer surgery.

Thorough lymph node dissection (D2 lymph nodes and enlarged lymph nodes dissection), especially the dissection of hepatoduodenal ligament lymph nodes(No.12), is closely related to the occurrence of postoperative CL. Akatsu et al. (27) studied 805 patients with gastric cancer who underwent D1 (n=490) and D2 (n=315) lymph node dissection. During the follow-up, 102 (12.7%) patients developed CL. D2 lymph node dissection was higher than D1 lymph node dissection (17.8% vs. 9.4%, P = 0.001). Fukagawa et al. (2) found that 173 (25.7%) of 672 patients with gastric cancer who underwent lymph node dissection developed CL after surgery and that enlarged lymph node dissection was a significant risk factor for CL development after surgery (P < 0.001: D1+α vs. D2+α; P < 0.01: D2 vs. D2+α). This may be No.12 lymph nodes are adjacent to the gallbladder and pyloric branches of the vagus nerve that innervate the gallbladder and the common bile duct. During the dissection of No. 12 lymph nodes, the hepatoduodenal ligament is completely “skeletal” (4), and lead to the injury of hepatobiliary branch of the vagus nerve (28). The above studies confirmed that hepatoduodenal ligament lymph node dissection is the most important independent risk factor for postoperative CL development.

Paik et al. (5) reported that BMI decline ≥4% (kg/m²) was an independent risk factor for CL development after gastric cancer surgery. Park et al. (8) reported that weight cycling (weight loss and weight gain) and large weight fluctuations are risk factors for the development of CL, and concluded from multivariate analysis that obesity is an independent risk factor for the development of CL after gastric cancer surgery. In general, all the proof suggesting a link between a high BMI value and a higher incidence of CL after gastric cancer surgery. Weight loss after gastric cancer surgery leads to the mobilization of cholesterol reserves. Without the activation of gallbladder bile, cholesterol and bile are supersaturated, thus leading to CL. In addition, excessive obesity may increase cholesterol secretion by the liver, which is the key reason for the formation of cholesterol stones.

Nakamura et al. (29) analyzed 698 patients with gastric cancer who underwent surgical treatment and found that abnormal liver function after surgery is related to the development of CL. Lee et al. (30) reported that a high preoperative serum total bilirubin value is an important independent risk factor for the development of CL after gastric cancer surgery. The reason may be that a high level of bilirubin easily leads to gallbladder crystallization, especially the formation of brown or melanin stones. Studies have reported a positive correlation between high triglycerides and gallstone disease. Triglyceride synthesis is stimulated by insulin; So it is concluded that the etiology of CL after gastric cancer surgery may be related to two variables, namely, triglycerides and insulin (31).

Most studies have reported that male sex is a risk factor for the development of CL after gastric cancer surgery (5, 8, 26). In a nationwide study conducted in South Korea, Seo et al. (26) reported that men had a higher incidence of CL after surgery than women (5.8% vs. 4.1%, P <0.001) and revolved that male sex was an independent risk factor for CL after gastric cancer.

Lai et al. (32) reported that elderly patients (aged over 60) are at high risk for the formation of gallbladder stones after gastric cancer surgery. Similarly, Seo et al. (33) reported that older patients (60~89 years old) have a higher incidence of CL (6.1% vs. 4.3%, P < 0.001) than younger patients (30~59 years old) and that advanced age (60~89 years). This may be due to increased bile secretion and intestinal absorption of cholesterol with age, reduced liver synthesis and secretion of bile salts, and reduced gallbladder contractility, all of which increase the susceptibility to cholesterol stones. In terms of genetics, elderly patients may exhibit an enhanced prevalence of the Lith (gallstone) gene, which would promote the formation of gallstones after gastric cancer (34). It was revolved that age is an independent risk factor for CL development after gastric surgery.

Paik et al. (5) studied 1480 patients who underwent gastrectomy without CL before surgery and concluded that diabetes is an independent risk factor for CL development after gastric cancer surgery. The effect of diabetes on CL is multifactorial, and the mechanism may be that diabetes leads to neuritis and neuromyopathy. In diabetic patients, oxidative stress from low heme oxygenase-1 levels increases, and insulin levels decrease. Insulin-like growth factor-1 signal transduction leads to loss of Cajal interstitial cells, leading to abnormal gallbladder emptying and promoting CL development (35).

Rieu et al. (23) conducted a prospective study to determine the effects of partial gastrectomy without vagus nerve transection on postprandial gallbladder contraction, CCK secretion, and pancreatic polypeptide PP and found that the basal gallbladder volume was larger after surgery than before (P < 0.02). Portincasa et al. (36) divided the study subjects into a gastrectomy group and a control group and concluded that the gastrectomy group had a larger gallbladder volume during fasting than the control group and that the gastrectomy patients’ gallbladders emptied faster after a meal. In these patients, the postoperative fasting gallbladder volume increased over time. After eating the experimental meal, the patients’ feelings of satiety, abdominal distension and epigastric pain were significantly higher than those in the control group. Therefore, it is believed that the increased gallbladder volume during fasting may lead to cholestasis, which may play an important role in the pathogenesis of CL development after gastrectomy.

Many other factors, such as bacterial translocation (BT), surgical methods(laparoscopic vs open) (8), parenteral nutrition, dietary lifestyle changes, length of the jejunal loop, postoperative complications (29), combined organ resection, blood supply, perioperative drugs, are also thought to be involved in gallstone formation after gastric cancer surgery.

From the above evidences, we found that the formation of gallstone after gastric cancer surgery is the result of the joint action of multiple factors and mechanisms. Single factor can hardly explain the cause and mechanism of CL development. Previous studies have identified many independent risk factors for postoperative CL, but have not elucidated their intrinsic association of them. Mechanistic research is complex and lengthy and do not provide useful therapeutic value. Instead of wasting time and resources on etiology and mechanism research, it is better to work directly on treatments.

Studies have reported that most postoperative CL cases associated with gastric cancer are asymptomatic (3, 9), so most scholars support watchful waiting as the most reasonable treatment method (41), but there are potentially fatal hazards, such as inducing acute pancreatitis, acute cholangitis and gallbladder cancer, with high mortality.

Studies have reported that retaining the vagus nerve that innervates the gallbladder during gastric cancer surgery can ensure the normal function of the gallbladder and significantly reduce the incidence of gallbladder stones (13, 19); however, there are also studies showing that some patients (10.1%) still relapse after surgery (19). A prospective case–control study by Wang et al. (42) compared the vagus nerve-sparing group (h-DG, n=85) and the dissected nerve group (s-DG, n=238) under laparoscopic distal gastrectomy and the vagus nerve preserving group (h-PPG, n=123) and dissected nerve group (s-PPG, n=21) under laparoscopic pylori-preserving gastrectomy. The results showed that the 3-year cumulative incidence of CL in the h-DG group was significantly lower than that in the s-DG group (2.7% vs. 14.6%, P=0.017). Similarly, this incidence in the h-PPG group was significantly lower than that in the s-PPG group (1.6%). vs. 12.9%, P=0.004). It suggested that both vagal-nerve-sparing gastrectomy and PPG can significantly reduce the incidence of CL development after gastric cancer surgery (38, 42). However, recent studies have suggested that PPG has no effect on the development of CL (10, 13, 26). In our view, vagal-nerve-sparing gastrectomy is complicated, which is not conducive to promotion and implementation. In addition, the formation of CL after gastric cancer surgery is multi-factor, and the effect of prevention from a certain factor is not certain. So, this approach is not valuable to be recommended.

Some studies have reported that prophylactic use of drugs such as erythromycin (15), ursodeoxycholic acid (39, 40), exogenous CCK-8, cisapride, motilin, domperidone, cimetidine, opioid antagonists, naloxone, and aspirin can reduce CL development after gastric cancer surgery. A prospective multicenter randomized controlled clinical trial conducted by Lee et al. (40) randomly divided 465 patients who underwent gastric cancer surgery into 151 patients who received 300 mg ursodeoxycholic acid (UDCA), 164 patients who received 600 mg UDCA, and 150 patients who received placebo. The results showed that after 12 months, the incidence of CL was 5.3% (8/151) in the 300 mg group, 4.3% (7/164) in the 600 mg group, and 16.7% (25/150) in the placebo group. Compared with the placebo group, the results indicating that 12 months of UDCA after gastric cancer surgery can significantly reduce the incidence of CL. However, studies have shown that gallstones after gastric cancer are dominated by bile pigment stones (3). Oral stone-dissolving drugs are less effective and require a long treatment period. So, the clinical effect of medical is not satisfactory. Long-term medication will increase the physical, psychological and economic burdens on patients.

Cholecystectomy is the “gold standard” for the treatment of CL. With the improvement of minimally invasive surgery concepts and techniques, laparoscopic cholecystectomy (LC) and endoscopic retrograde cholangiopancreatography (ERCP), endoscopic sphincterotomy (EST), endoscopic papillosphincter balloon dilatation (EPBD), percutaneous hepatobiliary drainage, and percutaneous puncture drainage have gradually been applied to patients with a history of gastric cancer surgery. Minimally invasive surgery (represented by LC and ERCP+EST) can significantly shorten the disease course and relieve patients’ pain and is considered to be safe and effective (33). However, some studies have shown that cholecystectomy after gastric cancer surgery increases the difficulty of surgery, mortality, and the cost of surgery (9, 16, 43, 44). Application of ERCP is technically difficult due to anatomical changes, such as after physiologic reconstruction (4), especially with Roux-en-Y (4, 8) and Billroth II (5).

At present, there is no unified guideline for the selection of CL treatment strategy after gastric cancer surgery. Due to the shortcomings and deficiencies of various treatment methods, the treatment effect is not satisfactory. As a new treatment strategy, PC is expected to become the most valuable treatment for CL after gastric cancer in the future. Surgeons have been devoted to the study of PC during gastric cancer surgery.

Most studies have reported that the incidence of CL within 5 years after gastric cancer surgery is as high as 15%-25%, with an average of 17%. In previous studies, the rate was as high as 47%-60% (33). Liang et al. (3) and Bernini et al. (45) reported that the incidence of CL after gastric surgery showed an increasing trend over time and had not yet reached an equilibrium level. Bencini et al. (3) reported that for patients with gastric cancer who survived 60 months after surgery, the incidence of postoperative CL increased by 18.5%. However, some studies reported that the incidence of CL after gastric surgery was less than 10% (4, 5, 9, 46, 47), and the incidence of cholangitis or cholecystitis in patients with CL after gastric cancer surgery was 20.3%, which was almost the same as that in the general population (9).

Liang et al. (9) and Fukagawa et al. (2) both reported that 64.7% of CL cases developed within 1 year after gastric surgery, and Murata A et al. (48) confirmed that the earlier the development of CL after gastric cancer surgery, the greater the threat to the prognosis and quality of life of patients.

Acute postoperative cholecystitis, defined as occurring during the same hospital stay or within 30 days after surgery (49), is a serious complication, especially for patients who have recently undergone gastrectomy (50–52); it is difficult to diagnose and has mortality rates as high as 10-50% (52). Table 2 show all the studies related to the acute postoperative cholecystitis and revolved that PC can minimize the risk of acute postoperative cholecystitis (53) and avoid the formation of gallstones (2, 3, 11).

Stones is also a common complication related to CL. Studies have shown that most CL cases occurring after gastric surgery involve multiple (72.5%) stones that are less than 10 mm in diameter (79.4%) (27); small stones are an independent risk factor for pancreatitis (54), which will increase the incidence of biliary complications. Bencini et al. (3) reported that 12.3% of patients ain the standard gastric surgery (SS) group had abnormal biliary tracts after surgery, while only 1.5% of patients in the PC group had common bile duct dilation (CBD) after surgery, and the difference was statistically significant. (8/65 vs. 1/65, P= 0.033). This suggests that PC can reduce the biliary tract related complications.

Studies have reported a high proportion of secondary surgical intervention due to biliary tract diseases after gastrectomy, and frequent biliary colic and cholecystitis are the main causes of subsequent cholecystectomy (32). Moreover, the upper abdominal inflammatory adhesions caused by previous gastrectomy make the subsequent operation difficult (9, 16, 33), and the incidence of surgical complications, common bile duct injury, mortality(20.0-57.0%) (51), medical expenses, average hospital stay, medical resources, conversion rate to laparotomy(10-50%) (54), and operation time of subsequent cholecystectomy after gastric cancer surgery increases, especially in emergency operations (9, 11, 16, 44). Gillen et al. (33) reported that the surgical risk of subsequent cholecystectomy after gastric cancer surgery is 15 times higher than that of PC during gastrectomy for cancer and the incidence of surgical complications, common bile duct injury, mortality, medical expenses, average hospital stay, medical resources, conversion rate to laparotomy, and operation time of subsequent cholecystectomy after gastric cancer surgery increases significantly, especially in emergency operations (9, 11, 16). Studies have reported mortality rates of subsequent cholecystectomy as high as 20.0-57.0% (51), and the laparoscopic conversion rate is 10-50% (54). The reasons may be related to a patient’s advanced age, poor physical condition (44) and difficulty in managing the inflammatory gallbladder in the surgical field due to prior gastrectomy and lymph node dissection (9).

Gastrectomy will result in secondary bile duct stones, and the change in anatomical structure after gastrectomy will increase the difficulty of reaching the duodenal papilla during elective surgery (5), especially when duodenal reconstruction (Billroth II or Roux-en-Y (45)) is applied. Paik et al. (5) reported that only 6 of the 20 patients with choledocholithiasis after gastrectomy successfully underwent ERCP. For patients with a history of gastrectomy, subsequent cholecystectomy is often accompanied by a risk of damage to the bile duct and surrounding tissues (55), among which bile duct injury is the most serious complication and has a high mortality rate.

Gastrectomy combined with cholecystectomy is a mostly laparoscopic surgery, as surgeons have gained experience in laparoscopic surgery and exceeded the “learning curve” (56). The safety and feasibility of surgery have been greatly improved (57). Combined gastric cancer surgery has been greatly improved. Therefore, some scholars believe that if PC does not increase serious surgical complications, it would be better than subsequent cholecystectomy after gastric cancer surgery (43).

In the surgeon’s clinical work, an effective assessment of a patient’s quality of life can affect the decision of whether to operate. Fukagawa et al. (2), Bernini et al. (45) and Wu et al. (50) all reported that PC could improve the quality of life of patients who survived. Mentes et al. (58) used the gastrointestinal quality of life score to evaluate the effect after cholecystectomy and concluded that PC during gastric cancer surgery at least does not reduce postoperative quality of life.

Due to the high incidence and short interval time for CL development after gastric cancer surgery, additional, PC can minimize the risk of acute postoperative cholecystitis, it also can avoid the difficulty of secondary surgical intervention after gastrectomy and surgical risk and the high incidence of surgical complications after the gastrectomy, these advantages provide the best opportunity for using PC.

However, it has been reported that almost all biliary abnormalities after gastrectomy were detected by ultrasound 4.5 years later (2, 3, 11). The 3-year mortality rate after gastrectomy was the highest, which would suggest that PC is not necessary for most people, since for some patients who undergo surgery for gastric cancer, gallstones rarely form before the end of their lives. Studies also have reported that almost 90% of CL cases developing after gastrectomy are asymptomatic (2, 5, 10), and the longer the time from surgery, the less likely patients are to develop symptoms (11). Hence, few patients have symptoms after surgery (0.6% to 4.6%) or require additional treatment (0.4% to 4.6%) (2, 3, 5, 9, 10, 32, 54) ( Table 3 ). Fukagawa et al. (2) studied 173 patients who developed CL after gastric cancer surgery. Among the asymptomatic group (161 cases), 77.0% (124 cases) had no change in the size or number of gallstones. Paik et al. (5) studied 1480 patients who underwent gastric cancer surgery, and the results showed that the incidence of postoperative choledocholithiasis was only 1.4% (20 patients), and its development was only related to CL, suggesting that the effect of secondary choledocholithiasis after gastric cancer surgery was negligible. Additional, with improvements in surgical techniques and medical equipment, some studies have reported that subsequent laparoscopic cholecystectomy is safe and reasonable for patients with a previous gastrectomy history (4, 31, 42, 44, 49, 59–62) ( Table 4 ).

From the above evidences, we can found that most of the evidences support the implementation of PC, although there were some arguments to the contrary. Some scholars believe PC is safe and effective ( Table 5 ) (15, 20, 21, 27, 54), while others disagree ( Table 6 ) (3, 5, 10, 29, 30). Moreover, certain scholars believe that the feasibility of PC should be individualized (9). Should PC be used as a routine treatment? We reviewed lots of studies supporting or against PC.