AP is characterized by acute onset, rapid progression and a high likelihood of developing severe acute pancreatitis (SAP), with severe complications and a high mortality rate of 30% (Guo et al., 2019). Gallstones are still one of the key causative factors of AP, and in the present study, approximately 20% of gallstone patients in hospitals were diagnosed with ABP (Zhu and Lin, 2012). Therefore, it is clinically important for clinicians to prevent gallstone patients from developing AP and SAP. Our study also suggests that risk factors, including age, diabetes history, gallbladder wall thickness, gallstone diameter, coexisting CBD stone, DBIL and WBC, are significantly associated with the incidence of ABP.

In line with the current literature, our data regarding incidence of ABP indicate that elderly patients with gallstones had higher risk of ABP during follow-up (HR: 3.491, 95% CI: 1.514~8.047). The relation between advanced age and incidence of AP is not surprising. For instance, most studies indicate that the mean age of the first AP attack is 60 years and with increasing age, the incidence and mortality of AP are also increasing, and there have been studies indicating a correlation between age and mortality as an independent risk factor (Spanier BW and Bruno, 2008; Beard et al., 2016). Relevant studies have demonstrated that although some controversy exists, diabetic patients are generally thought to have a twofold to threefold increased risk of cholesterol gallstones. Moreover, owing to poor anti-infection ability and immunity, when patients with diabetes suffer cholecystitis, they are prone to serious biliary tract infection and even other severe complications, such as gallbladder abscess, gangrene, and perforation (Ransohoff et al., 1987). In this study, diabetes history is an important risk factor for ABP (HR: 4.585, 95% CI: 1.926~10.914). We speculate that diabetes is more likely to be associated with biliary tract infection and that biliary tract function is worse in patients with diabetes than in the normal population. Therefore, gallstone incarceration is more likely to occur during the downward movement of gallstones, thus inducing ABP.

Among the factors related to gallstones and the biliary tract, this study showed that the thickness of the gallbladder wall, gallstone diameter, and coexisting CBD stone were all significant risk factors for ABP in patients with gallstones. The risk of ABP in the normal gallbladder group was significantly higher than that in the abnormal gallbladder group. In addition, gallbladder wall thickness ≤ 3 mm was a risk factor for ABP (in comparison, the HR of the thickness of > 3 mm was 0.195, 95% CI: 0.079~0.480); that is, the risk of ABP in patients with a thickness of the gallbladder wall ≤ 3 mm was 5.13 times as high as that of patients with a thickness of > 3 mm. The reason might be that when the gallbladder wall thickness is normal, the gallbladder’s contraction function is relatively good (Yamada and Yamada, 2001). Therefore, when the gallbladder contracts, the gallbladder tube is able to normally expand, thus making gallstones easily discharged into the CBD and inducing ABP. In contrast, long-term inflammation frequently leads to a thicker gallbladder wall and relatively poor gallbladder contraction function, and the gallbladder duct has difficulty expanding (Stads et al., 2007). Therefore, gallstones are difficult to discharge and are likely to remain in the gallbladder, making the risk of ABP relatively lower. In the gallstone size analysis, patients were divided into three groups according to stone diameter: < 3 mm, 3-10 mm and >10 mm, and patients with gallstone diameters < 3 mm were 3.22 times more likely to develop ABP than those with diameters 3-10 mm and 4.03 times more likely to develop ABP than those with diameters >10 mm. The reason may be that when the gallbladder contracts, stones with smaller diameters are more likely to enter the common channel, and they easily cause channel blockage and finally induce ABP. In contrast, larger diameter stones tend to be incarcerated in the gallbladder neck and do not easily enter the common channel. Therefore, the risk of inducing ABP is relatively reduced (van Geenen et al., 2010). Coexisting CBD stone were also an essential risk factor for ABP in gallstone patients (HR: 2.382, 95% CI: 1.177~4.821). Our analysis showed that the risk of ABP in patients with gallstones and bile duct stones was about twice as high as that in patients with only gallstones. The reason is possibly that compared with gallstones, bile duct stones are more likely to cause duodenal papillary edema or stenosis, especially in the ampullary segment and the lower CBD, which are more likely to result in ABP than the upper CBD (Lee et al., 2018).

In terms of biochemical indicators commonly used in clinical practice, combined with multivariate cox regression analysis, we demonstrated that DBIL and WBC were all important and independent risk factors for ABP development in patients with gallstones. Among them, the abnormal level of DBIL reflects the degree of bile duct obstruction during the pathogenesis of ABP and the degree of hepatocyte injury caused by bile reflux (Surlin et al., 2014). Moreover, the level of WBC is able to reflect the severity of biliary tract infection during ABP (Lankisch et al., 2015). In general, when patients with gallstones suffer severe obstruction and infection of the biliary tract, their risk of concurrent ABP is obviously higher, and these biochemical indicators have good prediction value for ABP.

There are no guidelines that indicate which patient to offer a cholecystectomy or conservative treatment. Therefore, the indication to perform a cholecystectomy always lies within the surgeons’ preference leading to variations in practice and consequently unnecessary cholecystectomies. Some findings show that asymptomatic gallstone patients should not undergo prophylactic cholecystectomy. In a study by Gracie et al., only 18% of asymptomatic gallstone carriers developed biliary pain or a gallstone complication during 15-year follow-up (Gracie and Ransohoff, 1982). Furthermore, symptomatic complicated gallstone patients, especially ones with mild-to-moderate acute cholecystitis, common bile duct stones, or mild biliary pancreatitis, are now recommended for same admission cholecystectomy as opposed to delayed cholecystectomy in previous guidelines (MP., 2018).

However, for symptomatic uncomplicated gallstone patients, who are primarily involved in this study, whether and when cholecystectomy should be performed remains controversial. Most studies recommend that cholecystectomy is the therapy of the first choice for patients with uncomplicated symptomatic gallstone disease. Many patients have had an unnecessary cholecystectomy with associated risks of complications and unnecessary healthcare expenses, and some studies indicated that up to 33% of patients do not experience relief of their abdominal symptoms, despite cholecystectomy (Lamberts et al., 2013). Moreover, some patients with suggested uncomplicated symptomatic gallstone disease should be treated conservatively because of a high risk of persistent symptoms or suboptimal benefit of cholecystectomy. However, from the perspective of ABP prevention, there are still no uniform guidelines for choosing the optimal timing of cholecystectomy. Although some patients are at high risk of ABP in clinical practice, they may still choose conservative treatment and refuse effective surgical treatment for some reasons. All these above may increase the potential risk of ABP in patients with gallstones. In this study, most of the samples are asymptomatic uncomplicated patients with gallstones. Therefore, the nomogram can be used to identify these patients’ potential risk for ABP through commonly used clinical indicators and to help clinicians make better clinical decisions on the optimal timing of cholecystectomy. Moreover, it is also beneficial to encourage patients to avoid risk factors for ABP and receive a medical check-up regularly. Finally, it is worth noting that in this study, decision curves indicate that when the risk of ABP in patients is greater than 10%, carrying effective intervention will bring the population positive overall benefit. However, the intervention may include regular follow-up, regular medical check-ups, endoscopic treatment and surgical treatment. According to patients’ different risks for ABP, which intervention effectively prevents the occurrence of ABP remains to be further studied.

Our study had some limitations. First, this analysis was based on data from a single institution; it is necessary to validate the results in other centers. Second, there are still many risk factors affecting the incidence of ABP in patients with gallstones. Due to limited data, the risk factors selected in this study were not complete. Some potential risk factors of patients, such as body mass index (BMI) and blood lipids, were not included in the study, and more risk factors should be included in this study to further improve the accuracy of the prediction model. Finally, although the nomogram is more convenient than the traditional statistical model, it is no denying that there are still some limitations in the actual application. In the future, we will put the scoring system on a website or an app for use on a smart phone for surgeons in the hospital, and the score could automatically calculate results online.