This study represents the pioneering effort to systematically evaluate the causal link between genetic susceptibility to cholecystitis and the incidence of cholangiocarcinoma. Our findings elucidate that genetically predicted cholecystitis correlates with heightened risk of cholangiocarcinoma. This positive association between the two conditions was robustly affirmed through sensitivity analyses. Overall, our Mendelian randomization investigation underscores a causal, unidirectional relationship between cholecystitis and the susceptibility to cholangiocarcinoma, indicating an elevated risk of cholangiocarcinoma among individuals with cholecystitis.
Previous research has elucidated the intricate interplay between chronic inflammation of the intrahepatic bile duct and the pathogenesis of cholangiocarcinoma. This chronic inflammatory milieu triggers abnormal hyperplasia of the bile duct endothelium and glandular mucosal epithelium. Additionally, factors such as altered bile composition, cholestasis, and metabolic conditions contribute to the progressive damage of the bile duct endothelium and mucosal epithelium, including glandular structures. This cascade of events culminates in a spectrum of changes ranging from hyperplasia and metaplasia to atypical hyperplasia, eventually progressing to cancerous transformation31–33. Cholecystitis, a common inflammatory condition affecting the gallbladder, has been identified as a significant risk factor for the development of cholangiocarcinoma. A population-based case-control study conducted by Chang et al. highlighted various factors associated with an elevated risk of cholangiocarcinoma, including cholangitis, cholelithiasis, cholecystitis, cirrhosis of the liver, alcoholic liver disease, chronic non-alcoholic liver disease, diabetes, chronic pancreatitis, inflammatory bowel disease, and peptic ulcer11. Furthermore, a systematic review and meta-analysis underscored a substantially heightened risk of cholangiocarcinoma in patients with cholangitis (OR: 6.3, 95% CI: 2.3–17.5)32. In line with these observational findings, our study unveils a novel insight into the genetic underpinnings of cholecystitis and its causal relationship with cholangiocarcinoma. Utilizing rigorous Mendelian randomization methods including the IVW method, MR Egger regression, and the weighted median method, we observed a 27.00% increased risk of cholangiocarcinoma associated with genetic predisposition to cholecystitis. These robust findings further support the notion that cholecystitis may indeed heighten the risk of cholangiocarcinoma, as indicated by collective evidence from observational studies.
To reveal the intricate relationship between cholecystitis and cholangiocarcinoma development, it is essential to first consider a wide array of preventive measures, diagnostic techniques, and therapeutic strategies tailored for managing cholecystitis. Our primary investigation, meticulously incorporating genetic testing at a stringent significance threshold of P < 5×10− 8, has provided compelling evidence bolstering the hypothesis that heightened genetic susceptibility to cholecystitis correlates with an elevated risk of cholangiocarcinoma. This pivotal finding underscores the potential role of genetic factors in predisposing individuals to both conditions, offering valuable insights into the underlying molecular mechanisms and potential avenues for targeted intervention and precision medicine approaches.
The MR method offers a robust approach for assessing causality by establishing a link between an "exposure" and an "outcome," thereby mitigating the risk of confounding inherent in traditional observational studies. While observational studies are frequently relied upon to infer causality, they can be time-consuming and impractical. It is noteworthy that gallstones are implicated in 80–95% of acute cholecystitis cases, with acalculous cholecystitis comprising the remaining 5–10% of cases34,35. However, many studies predominantly focus on the impact of gallstones, overlooking the significant contribution of cholecystitis itself. In our study, we conducted a two-sample MR analysis, which revealed a causal relationship from cholecystitis to cholangiocarcinoma. Our findings underscore the critical importance of initiating treatment promptly following cholecystitis diagnosis to optimize clinical outcomes and mitigate potential complications, such as cholangiocarcinoma. Furthermore, we advocate for early screening for cholangiocarcinoma risk among cholecystitis patients, as this proactive approach may facilitate earlier diagnosis and timely initiation of curative interventions for cholangiocarcinoma. Overall, our systematic meta-analysis, conducted in a large population of European ancestry, sheds light on the relationship between cholecystitis and cholangiocarcinoma, offering valuable insights for informing preventive care strategies for cholangiocarcinoma and identifying pivotal intervention points for managing cholangiocarcinoma in patients with cholecystitis.
Our study delved into the causal association between cholangiocarcinoma and cholecystitis, guided by earlier research highlighting chronic inflammation as the primary driver of progression from cholecystitis to cholangiocarcinoma. This chronic inflammatory milieu can trigger a cascade of events, including epigenetic alterations, activation of proto-oncogenes, and deactivation of tumor suppressor genes, culminating in abnormal cell proliferation, differentiation, and an elevated cancer risk. For instance, an inflammatory microenvironment characterized by elevated levels of pro-inflammatory cytokines, growth factors, and toxic bile acids may foster accelerated mitosis of normal bile duct cells, predisposing them to mutations and uncontrolled proliferation. Epigenetic modifications in intrahepatic cholangiocarcinoma epithelial cells can be induced by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β), akin to tumor suppressor inactivation and oncogene activation mechanisms36,37. Of particular interest, IL-6, upon binding to the gp130 receptor, triggers JAK1/2 activation, leading to subsequent STAT3 phosphorylation and activation. This signaling cascade may also activate extracellular signal-regulated kinase 1/2 (ERK1/2) and p38/MAPK pathways, ultimately fueling tumor proliferation and cholangiocarcinoma progression38. Future studies should endeavor to explore additional potential mechanistic pathways to inform the development of pertinent clinical recommendations in the management of cholecystitis-associated cholangiocarcinoma.
It's important to recognize limitations in our study. The biological mechanisms of cholecystitis and cholangiocarcinoma are complex, involving many factors. Using certain genetic markers with unclear roles in Mendelian randomization may challenge our assumptions. Also, genetic differences can vary among ethnic groups. While our study focused on one population, more research on diverse populations is needed for stronger evidence. Additionally, we should conduct formal mediation analysis to understand how cholecystitis might lead to cholangiocarcinoma. Cholangiocarcinoma patients show diverse characteristics, suggesting cholecystitis could be linked to specific subtypes. Future studies should explore these subgroups further to better understand the relationships.
In conclusion, this study strengthened the argument for a genetic connection between susceptibility to cholecystitis and cholangiocarcinoma. Considering the high mortality and poor prognosis associated with cholangiocarcinoma patients, it is important to identify and manage the risk factor of cholecystitis for cholangiocarcinoma to reduce its morbidity.