Cyanotoxin exposure as a novel risk factor for liver fibrosis and steatosis

Cyanobacteria are ubiquitous environmental bacteria capable of producing cyanotoxins, including potent liver tumor promoters. There is limited knowledge of exposure to cyanotoxins and their potential role in the pathogenesis of liver cancer The relationship of cyanotoxin exposure with two hallmarks of progressive liver disease-liver fibrosis and steatosis-was evaluated in a cross-sectional study of 399 adult residents of the state of Hawaii and the US territory of Guam without a history of cancer. Microcystins (MC), nodularins (NOD), cylindrospermopsin (CYN), and anabaenopeptins (AB) were analyzed in saliva, serum, and urine using direct competitive enzyme-linked immunosorbent assays. Liver fibrosis and steatosis were measured by transient elastography. Linear and non-linear associations of cyanotoxin levels with degree of fibrosis and steatosis were evaluated in multivariate generalized linear and additive models. One or more cyanotoxins were variably detected in all individuals. Moderate to severe fibrosis or cirrhosis was present in 18% and moderate to severe steatosis in 53%. Positive associations with fibrosis level were observed for salivary cyanotoxins: MC/NOD (linear: β = 9.07, 95% confidence interval [CI] 1.32-16.82, p = .022; non-linear p = .0011); CYN (linear: β = 24.21, 95% CI 14.12-34.30, p < .0001; non-linear p = .0001); AB (non-linear p = .0125). A positive association with steatosis level was observed for serum MC/NOD (non-linear p = .0120). Non-linear associations of cyanotoxins with fibrosis were specific to defined concentrations. Our novel findings suggesting that cyanotoxins are independent risk factors for liver disease are consistent with our prior study linking oral cyanobacteria to hepatocellular carcinoma and may have global implications for liver cancer prevention.