Fifteen-year impact of cholecystectomy on multiple organs

Cholecystectomy, the surgical removal of the gallbladder, has long been the gold standard therapy for symptomatic cholelithiasis (gallstones) [1,2], performed globally in approximately 5.0% of the population, with rates ranging from 1.9% in Asia to 9.9% in North America [3]. As one of the most common surgical procedures worldwide [4], it is estimated that around 934,000 cholecystectomies are conducted annually in the United States alone [5]. While cholecystectomy is generally considered safe in terms of acute postsurgical complications, the absence of the gallbladder is associated with a range of gastrointestinal (GI) disorders [6,7], collectively termed post-cholecystectomy syndrome [3,8]. This syndrome, which can persist for years following surgery, raises important questions regarding the long-term consequences of gallbladder removal, especially concerning bile acid metabolic dysregulation, altered gut motility, and microbiome disruptions [9].

While the gastrointestinal sequelae of cholecystectomy have been the focus of numerous studies, the broader multi-organ impacts, particularly those extending beyond the gastrointestinal system, remain largely unexplored. Notably, many patients with disorders of gut-brain interaction (DGBI) have reported the onset or exacerbation of their symptoms following cholecystectomy [3], suggesting potential connections between gallbladder removal and extra-intestinal consequences. However, the attribution of these symptoms to the surgical procedure remains debated, with some questioning whether these disorders were misattributed to biliary disease in patients with a history of gallbladder removal [3]. Thus, it is crucial to distinguish between pre-existing, co-occurring, and new cholecystectomy-related disorders.

This study employed a large-scale, longitudinal, disease-wide association study (DWAS) to comprehensively evaluate the multi-organ consequences of cholecystectomy over a span of one to fifteen years [10]. Through interrogating the Finn-Gen cohort of 392,423 participants [11], this study identified 26,778 individuals who had undergone cholecystectomy. This study analyzed a total of 122 cholecystectomy-comorbid medical conditions and clinical outcomes (Supplementary Fig. 1; Supplementary Methods).

Cholecystectomy is significantly associated with an increased prevalence of multiple comorbidities across a range of organ systems (Supplementary Fig. 2), including digestive system (K11), musculoskeletal system and connective tissue (M13), circulatory system (I9), endocrine, nutritional and metabolic diseases (E4), nervous system (G6), mental and behavioral disorders (F5), eye and adnexa (H7), as well as cancer (CD2; ICD−O−3).

Figure 1.

Comorbidity Trajectories of cholecystectomy. A Disease-Wide Association Study (DWAS) was conducted using a populationbased registry data of 392,423 individuals, including 26,778 cases with cholecystectomy between 1998 and 2021. In total, 122 cholecystectomy-comorbid medical conditions were examined for their association with cholecystectomy via Cox proportional hazards regression comparing individuals with and without cholecystectomy, adjusted for gender and age. The heatmap shows cholecystectomy comorbidities meeting the criteria of FDR-adjusted P<0.05, HR>2 or <0.5, and a prevalence >0.1%. Dot shapes indicate whether each comorbidity is associated with elevated or reduced risk. Comorbidities are categorized as pre-cholecystectomy (occurring before diagnosis) or postcholecystectomy (arising after diagnosis) and grouped into major disease categories according to ICD-10, ICD-O-3, and FinnGen classification systems.

To explore the temporal dynamics of cholecystectomy-related comorbidities, this study conducted an in-depth examination of the persistence of high-risk conditions over multiple time points, namely the short-term (1-year), midterm (5-year), and long-term (15-year) periods following surgery. Comorbidities were classified as high risk based on stringent criteria, including: (1) an FDR-adjusted p-value of less than 0.05, (2) a hazard ratio (HR) greater than 2 or less than 0.5, indicating a substantial increase or decrease in risk, and (3) a disease prevalence greater than 0.1% in the study cohort.

Moreover, to differentiate post-surgical effects from preexisting comorbidities, this study applied an additional set of stringent criteria to identify the most likely consequences of cholecystectomy: (1) Post-cholecystectomy high-risk comorbidities, which were defined as conditions that emerged following gallbladder removal; (2) Consistent associations with cholecystectomy, identified across at least two distinct time points post-surgery, ensuring that the relationship was not transient; and (3) Differing association trends before and after surgery, which highlighted how the risk for specific comorbidities evolved in response to the surgical procedure. These criteria were essential in isolating the true effects of gallbladder removal, providing insights into the dynamic physiological changes induced by the surgery. By applying these standards, I minimized potential confounding from pre-existing conditions and the underlying effects of cholelithiasis itself, ensuring that the observed associations were attributed primarily to the surgical intervention.

The results, shown in Figure 1, were consistent with previous studies, confirming that conditions such as heart failure, non-melanoma and melanoma skin cancer, Parkinson’s disease, and diaphragmatic injury exhibited significant subsequent associations following cholecystectomy [12-14]. This longitudinal data substantiates the enduring nature of these conditions, reinforcing the notion that cholecystectomy exerts lasting effects on overall health. Additionally, several novel high-risk conditions were identified in this study, including varicose veins, malignant neoplasm of the prostate, Coxarthrosis, spinal stenosis, giant cell arteritis, atopic dermatitis, idiopathic pulmonary fibrosis (IPF), stroke, Alzheimer’s disease, and dementia. Moreover, several comorbidities, including basal cell carcinoma, squamous cell neoplasms and carcinomas of the skin, spinal stenosis, idiopathic pulmonary fibrosis, Alzheimer’s disease, and dementia, exhibit an elevated and sustained risk across one to fifteen years, indicating a potential causal relationship with the surgical procedure itself.

This large-scale longitudinal DWAS offers compelling evidence of the significant, persistent, and often expanding health risks following cholecystectomy. From an increased susceptibility to GI disorders to broader effects on the circulatory, endocrine, and neurological systems, the findings underscore the multi-systemic nature of the procedure’s consequences. This study advocates for further investigation into the long-term effects of gallbladder removal on overall health, especially in the context of identifying early signs of comorbidities and improving post-surgical patient care protocols. The data presented here will be instrumental in guiding future research and clinical practices aimed at mitigating the broad health impacts of cholecystectomy.

Abbreviations

DGBI

disorders of gut-brain interaction

DWAS

disease-wide association study

GI

gastrointestinal

HR

hazard ratio

IPF

idiopathic pulmonary fibrosis

SUPPLEMENTARY MATERIAL

Supplementary material is available at Clinical and Molecular Hepatology website (http://www.e-cmh.org).

Supplementary Fig 1.

Design of the Disease-Wide Association Study (DWAS) within the Human Disease Continuum Project (HDCP). This diagram illustrates the study design for investigating comorbidities associated with cholecystectomy within the framework of the Human Disease Continuum Project (HDCP). The HDCP is a pioneering initiative aimed at exploring the complex interconnections between various diseases across the lifespan, from preclinical stages to advanced disease states and their subsequent comorbidities. The DWAS analysis was conducted using clinical data from 392,423 participants, this study identified 26,778 individuals who had undergone cholecystectomy. A total of 122 cholecystectomy-related comorbid medical events and clinical outcomes were assessed as potential comorbidities. These comorbidities were categorized based on their temporal association with the onset of cholecystectomy, classifying them as either pre-cholecystectomy (occurring prior to diagnosis) or post-cholecystectomy (developing after diagnosis), and grouped according to disease taxonomy.

Supplementary Fig 2.

Disease Taxonomy and Temporal Dynamics of Comorbidities Associated with cholecystectomy. This figure illustrates the associations between cholecystectomy and its comorbidities, determined using Cox proportional hazards regression models adjusted for age and sex. A medical event was considered a comorbidity if it showed a significant association with cholecystectomy, defined by an FDR-adjusted P-value <0.05. Pre-cholecystectomy comorbidities are those that increase the risk of receiving cholecystectomy, while post-cholecystectomy comorbidities are those that emerge or worsen after cholecystectomy diagnosis. The comorbidities were classified according to the International Classification of Diseases, 10th Revision (ICD-10), ICD-O-3 guidelines, and the FinnGen disease categorization system.