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Pancreatic exocrine insufficiency (PEI) is a common serious complication in chronic pancreatitis (CP); however, little is known about its effect on mortality in these patients. In this study, we assessed the mortality risk of PEI in patients with CP.A prospective, longitudinal cohort study conducted in patients with CP under long-term follow-up. CP and PEI were diagnosed using pancreatic imaging and the 13C-labeled mixed triglyceride breath test, respectively. Multivariate analysis was performed to evaluate the impact of PEI and other clinical features on mortality risk.Patients (N=430) were analyzed (79.1% male; mean age, 47.8 y) during a mean follow-up of 8.6±4.6 years. PEI prevalence was 29.3% and mortality was 10.9%. Most frequent causes of death were cancer (40.4%), infection (21.3%), and acute cardiovascular event (14.9%). Multivariate analyses showed associations between increased mortality and presence of PEI [hazard ratio (HR), 2.59; 95% confidence interval (CI), 1.42-4.71; P<0.003], liver cirrhosis (HR, 3.87; 95% CI, 1.95-7.69; P<0.001), age at diagnosis (HR, 1.05; 95% CI, 1.03-1.09; P<0.001), toxic etiology of CP (HR, 3.11; 95% CI, 1.11-8.70; P<0.05) and respiratory comorbidity (HR, 2.19; 95% CI, 1.12-4.31; P<0.03). Nutritional markers were significantly lower in patients with PEI versus those without PEI (P<0.001) and in those who died versus survivors (P<0.001).PEI was a significant independent risk factor for mortality in patients with CP. These results support further research into the optimal treatment of PEI to reduce mortality in this population.