The mechanism of ICC caused by biliary calculi is not clear at present. Some studies have found that both inflammatory infection caused by gallstones and mechanical stimulation of the gallstones have long-term effect on the bile duct wall and lead to stepwise progression of pathology, such as changes in the mucosal epithelium of the bile duct, dysplasia, intraepithelial neoplasia and eventually cancer. Therefore, predicting the occurrence of ICC is of great significance to the treatment of ICC. In this study, we retrospectively analyzed the patients who underwent biliary surgery for stones. The results showed that the age > 60 years old, liver cirrhosis and the stone history were the factors affecting them to develop ICC, while the previous hepatitis B infection (HBsAg- and HBcAb+) was the protective factor. Based on this, a nomogram was constructed, which can be used to predict the probability of ICC in these patients with more intuitive methods.
Liver cirrhosis commonly results from chronic damage of liver parenchyma. Its formation is due to the replacement of normal liver tissue with fibrous scar tissue and regenerated nodules. Liver cirrhosis leads to clinical complications such as progressive liver insufficiency, portal hypertension and even death. Some studies have shown that liver cirrhosis is closely related to the occurrence of ICC[18, 19]. Palmer et al. performed a meta-analysis in 2012 and discovered that the odds ratio of ICC in patients with liver cirrhosis was 22.9 (95%CI:18.2–28.8). A case-control study from China reported similar results . The possible underlying mechanism that liver cirrhosis promotes the occurrence and development of ICC may be due to tissue microenvironmental changes in the cirrhotic liver, such as chronic inflammation, increased cell renewal and progressive fibrosis, which are similar to the microenvironment observed in many other high-risk conditions such as primary sclerosing cholangitis. In the present study, liver cirrhosis is also a risk factor for the occurrence and development of ICC in patients undergoing biliary surgery for gallstones, which confirms the appeal point of view. In addition, it was also found that the age (> 60 years old) and the long history of gallstones were also risk factors for the development of ICC. Liu et al. also confirmed that  symptom caused by cholelithiasis (such as long-term recurrent epigastric discomfort) lasting for more than 10 years is a powerful risk factor for ICC. Kim et al. reported that the incidence of ICC increased in patients older than 40 years old, and the incidence of ICC was the highest in patients aged 60–79 years old. We believe that the three risk factors, which are the age of the patient (> 60 years old), liver cirrhosis and the gallstone history, complement to each other. Repeated attacks of gallstones can lead to long-term mechanical stimulation, resulting in cholestasis and chronic inflammation, which may cause hepatocyte necrosis and liver cirrhosis. Moreover, the age of a patient might be related to the length of gallstone history as well as the length of chronic inflammation. Long-term chronic inflammation increases the risk of liver cirrhosis, and this persistent inflammation results in DNA damage, activated tissue repair and proliferation, and promotes carcinogenicity by creating a local environment rich in cytokines and other growth factors . These may lead to an increase in the risk of ICC in patients. Therefore, elderly patients who have received biliary surgery might have higher possibility of ICC when they are found with long-term unexplained epigastric discomfort.
In addition, previous hepatitis B infection (HBsAg- and HBcAb+) was considered to be a protective factor for ICC in our study. Some literatures have shown that current or past HBV-activated immune response infection can enhance the anti-ICC activity against the body. When ICC occurs, the immune memory activated by previous HBV infection produces strong and effective anti-tumor immunity, thus improving the prognosis of HBV-related ICC. From this, we can also boldly infer that the anti-ICC activity enhanced by HBV-activated immune response can also reduce the risk of ICC in these patients. Of course, this needs to be confirmed by further large sample research.
Some studies [19, 26, 27] believe that hepatitis B infection (HBsAg+) can promote the occurrence of ICC. However, in our study, there is no significant relationship between hepatitis B infection (HBsAg+) and the occurrence of ICC, and a previous study of China  expressed the same point of view as ours. It is reported that both diabetes and alcohol drinking are related to the development of ICC [18, 28], but no obvious relationship between them was found in this study. The possible reason is that the patients selected in this study are those who have received biliary surgery in the past, different from those in other researches. In addition, appeal studies are mostly performed in the Western countries, and the specific situation in China may be different.
Since the study was a single-center retrospective analysis, it may have its own shortcomings, which needs to be confirmed by further multicenter and large-sample research, and the lack of external verification of the nomogram may affect its large-scale application to some extent. Nevertheless, based on the results of the appeal study, we have established a novel and a practical nomogram to predict the risk of ICC in patients underwent previous biliary surgery for gallstones with good sensitivity and specificity. The nomogram has good prediction ability (AUC = 0.753). To the best of our knowledge, this is the first nomogram to predict the risk of ICC in patients with previous biliary tract surgery for gallstones, which is of certain significance in predicting the incidence of ICC in such patients.