To Örebro University

Background: Normal gastrointestinal (GI) mucosa on endoscopy has been linked to a lower risk of colorectal cancer (CRC) but its association to overall death is unknown.

Methods: We identified 466,987 individuals with a first GI biopsy 1965-2016 with normal mucosa (60.6% upper GI and 39.4% lower GI) through all Swedish pathology departments (n = 28). They were individually matched to 2,321,217 reference individuals without a GI biopsy and also compared to 505,076 full siblings. Flexible parametric models were applied to estimate hazard ratio (HRs) and 95% confidence interval (95% CI) for death.

Results: During a median follow-up of ~11 years, 85,859 (18.39%) of individuals with normal mucosa and 377,653 (16.27%) of reference individuals died. This corresponded to incidence rates of 147.56/10,000 vs 127.90/10,000 person-years respectively (rate difference: 19.66/10,000 person-years), with the multivariable-adjusted HR of 1.21 (95% CI: 1.20-1.22). Excess mortality was seen for both upper and lower biopsy with normal mucosa. Particularly higher HRs for death were seen in males, individuals biopsied when aged <40 years, those without a prior record of GI disease, and those with high education. Mortality risk was most increased in the first five years after biopsy (HR = 1.34; 95% CI: 1.32-1.36) but decreased thereafter. Having a GI biopsy with normal mucosa was associated with excess mortality from cardiovascular (CVD)disease (HR = 1.02; 95% CI: 1.01-1.03), cancer (HR = 1.58; 95% CI: 1.56-1.61), GI disease (HR = 1.65; 95% CI: 1.58-1.71), and other causes (HR = 1.10; 95% CI: 1.08-1.11). Sibling comparisons yielded similar results.

Conclusion: Compared with individuals without a GI biopsy, those with a normal GI biopsy due to clinical symptoms had a higher mortality particularly in the first five years after biopsy, and especially from GI disease and cancer.