Comment on <scp> <i>Helicobacter pylori</i> </scp> Infection Associated With an Increased Incidence of Cholelithiasis: A Retrospective Real‐World Cohort Study of 50 832 Patients

We read with interest the recent article by Loosen et al., which examines the association between Helicobacter pylori (H. pylori) infection and subsequent development of cholelithiasis in a large German primary care cohort [1]. Here, several points warrant deeper discussion. First, although the authors matched for age, sex, comorbidities, and consultation frequency, the phenomenon of “detection bias” associated with healthcare utilization remains a concern. Patients diagnosed with H. pylori in primary care likely undergo more frequent imaging (ultrasound, CT), endoscopic evaluation, and other diagnostic work-ups that can increase the likelihood of incidental gallstone detection compared to the general population. Previous studies have underscored how increased medical surveillance can artificially inflate the observed incidence of non-specific and often asymptomatic conditions like gallstones in select subgroups [2]. Adjustment for consultation frequency is important but may not fully account for differences in diagnostic intensity or imaging utilization between exposure groups. Second, another concern pertains to the documentation and classification of H. pylori infection and eradication status. In real-world data, the diagnosis of H. pylori is often based on non-invasive tests such as serology, which detect past exposure rather than active infection, or may occasionally be coded based on clinical suspicion alone. Without information on specific diagnostic methods (e.g., urea breath test, stool antigen, histology), the potential for exposure misclassification remains. Moreover, as a significant proportion of patients received no pharmacologic eradication, it is unclear whether this reflects clinical management preferences or incomplete data capture. Such nuances can affect risk estimates and complicate interpretation, especially regarding the purported limited effect of eradication therapy on subsequent cholelithiasis [3]. Third, while the large sample size allows for detection of statistically significant differences, the clinical relevance of the observed association deserves cautious interpretation. Gallstones are common and often asymptomatic [4]; many detected cases may not result in clinical events (biliary colic, cholecystitis, etc.). The study relies exclusively on ICD-10 coding for cholelithiasis, without validation through procedure codes (e.g., cholecystectomy) or clinical outcomes. Without data on symptomatology or complications, it is difficult to gauge the true impact of excess cases identified—particularly as no difference in more severe outcomes (hospitalization, cholecystectomy) was assessed. Lastly, while the authors cite the novelty of providing large-scale data from Germany, health system differences in diagnostic practices, antibiotic use, and H. pylori screening/eradication strategies limit generalizability, especially to non-European or low-to-middle-income contexts. International data consistently reveal significant heterogeneity in gallstone epidemiology and clinical management, further emphasizing the need for local validation of these associations [5]. In summary, while the work substantially contributes to understanding potential extragastric sequelae of H. pylori, caution should be exercised in causal inference and clinical extrapolation. The authors have nothing to report. The authors have nothing to report.