Revisiting the Association Between Gallstones and Gallbladder Cancer: Is Reverse Causation an Under-explored Explanation?

Background: Gallstones have long been considered a major risk factor for gallbladder cancer (GBC), based primarily on observational and epidemiological studies. However, most available evidence assumes a unidirectional causal relationship, without adequately considering the possibility of reverse causation. Objective: This article aims to critically analyze existing epidemiological evidence linking gallstones and gallbladder cancer and to propose an alternative hypothesis: that early gallbladder malignancy or pre-malignant pathology may impair gallbladder function, leading to secondary gallstone formation. Methods: A narrative review of epidemiological studies, case-control analyses, and meta-analyses examining the gallstone-GBC association was conducted, with a focus on study design, temporality, and potential biases. Results: While multiple studies report an increased relative risk of gallbladder cancer in patients with gallstones, most lack detailed information regarding the duration, size, and chronology of gallstone development. This raises uncertainty about the direction of causality. Conclusion: The relationship between gallstones and gallbladder cancer may be more complex than traditionally believed. Reverse causation-where early cancer-related gallbladder dysfunction leads to stone formation-cannot be excluded. Future prospective studies with precise temporal documentation are needed.