Serum lipopolysaccharides predict advanced liver disease in the general population

Abstract

Background & aims: Gut-derived endotoxemia has been implicated in the development of chronic liver disease, but its relevance at the population level remains unclear. We analyzed whether endotoxemia is associated with incident advanced liver disease in the general population.

Methods: Serum lipopolysaccharide (LPS) was measured in 6,727 (3,455 male and 3,272 female, mean age 53.4 ± 10.9 years, mean body mass index 27.2 ± 4.5) individuals participating in the Finnish population-based health examination survey FINRISK 1997. Data were linked with electronic health registers for incident advanced liver disease (hospitalization, cancer or death related to liver disease). During a mean follow-up of 16.3 ± 3.8 years (109,282 person-years), 86 liver events occurred. Univariate and multivariate Cox regression, and Kaplan-Meier analyses were performed.

Results: Serum LPS predicted incident advanced liver disease with a hazard ratio per 1 SD of 1.41 (95% CI 1.24-1.59; p ≪0.001) when adjusted for age, sex, gamma-glutamyltransferase, metabolic syndrome, alcohol use, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M, waist-hip ratio and type 2 diabetes. This association remained robustly significant in additional multivariate analyses with various levels of adjustment. The association was accentuated among carriers of the PNPLA3 risk variant. The population attributable fraction of the highest LPS tertile for liver events was 29.7%. However, LPS was not associated with all-cause mortality.

Conclusion: Serum LPS is associated with hospitalization, cancer or death related to liver disease in the general population, with the highest tertile potentially accounting for 30% of the risk of liver disease.

Lay summary: Lipopolysaccharide, a gut-derived bacterial endotoxin, has been implicated in the development of chronic liver disease, but its relevance at the population level remains unclear. We found that serum lipopolysaccharide levels were associated with incident advanced liver disease in the general population, with the highest tertile accounting for up to 30% of the risk of hospitalization, cancer or death related to liver disease.

Keywords: Cirrhosis; Endotoxemia; Genetics; Gut; Hospitalization.

Graphical abstract

Fig. 1

Cumulative incidence by Kaplan-Meier analysis and age- and sex-adjusted hazards ratios by Cox regression analysis of LPS tertiles for incident advanced liver disease. LPS, lipopolysaccharide.

Fig. 2

Hazard ratios for incident liver disease stratified by the PNPLA3 I143M carrier status (heterozygote/homozygote vs. no risk variant). Mean ± SD of LPS level is shown according to groups. LPS, lipopolysaccharide; PNPLA3, patatin-like phospholipase domain-containing protein 3.

Fig. 3

Cumulative incidence by Kaplan-Meier analysis for overall survival by LPS tertile. LPS, lipopolysaccharide.