Long-Term Multisystem Comorbidity Patterns in Acute Pancreatitis: Insights From Observational and Genetic Analysis

Acute pancreatitis (AP) is an inflammatory pancreatic disorder with potentially severe systemic consequences. While its immediate clinical impact is well established, the long-term multisystem comorbidities of AP remain underexplored. Clarifying the temporal sequence of these comorbidities is essential for improving patient outcomes.

We conducted a phenome-wide association study (PheWAS) to investigate the associations between AP and 1429 clinical outcomes using Cox proportional hazards models in the UK Biobank. A total of 4767 AP cases were matched 1:10 with controls through birth year, sex, and Townsend deprivation index using incidence density sampling. Disease trajectory analyses were performed to characterize sequential diagnostic patterns of AP-associated comorbidities. Genetic approaches including polygenic risk score analysis, linkage disequilibrium score regression (LDSC), and two-sample Mendelian randomization (TSMR) were used as a genetic triangulation framework to provide complementary evidence for the observational findings and explore shared genetic architecture and potential causal relevance.

Over an average follow-up of 13.7 years, AP was associated with 250 incident comorbidities and all-cause death. Three major temporal patterns of AP-related comorbidities were identified, beginning with digestive diseases (e.g., chronic pancreatitis), metabolic and endocrine disorders (e.g., diabetes mellitus), as well as other systemic conditions (e.g., depression). Subsequently, increased risk of organ dysfunction such as myocardial infarction, renal failure, respiratory failure, and then dystrophia, sepsis, septicemia, acidosis followed by all-cause death were observed. The polygenic PheWAS, LDSC, and TSMR analyses provided complementary support for selected associations, including chronic pancreatitis, cyst and pseudocyst of pancreas, duodenal ulcer, diabetes mellitus, anxiety disorder, asthma, and myocardial infarction.

This study characterizes long-term multisystem comorbidity patterns associated with AP, highlighting temporal diagnostic patterns linked to adverse outcomes. These findings support the need for multidisciplinary monitoring and targeted interventions to mitigate long-term risks in AP patients.