Elevated Plasma IL-6 Associates with Increased Risk of Advanced Fibrosis and Cholangiocarcinoma in Individuals Infected by Opisthorchis viverrini

Abstract

Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and increasing risk of advanced fibrosis and bile duct cancer; for example, in age and sex adjusted analyses, individuals with the highest quartiles of plasma IL-6 had a 19 times greater risk of developing advanced periductal fibrosis and a 150 times greater risk of developing of bile duct cancer than individuals with no detectable level of plasma IL-6. Finally, we show that a single plasma IL-6 measurement has excellent positive predictive value for the detection of both advanced bile duct fibrosis and bile duct cancer in regions with high O. viverrini transmission. These data support our hypothesis that common mechanisms drive bile duct fibrosis and bile duct tumorogenesis from chronic O. viverrini infection. Our study also adds a unique aspect to the literature on circulating levels of IL-6 as an immune marker of hepatobiliary pathology by showing that high levels of circulating IL-6 in plasma are not related to infection with O. viverrini, but to the development of the advanced and often lethal pathologies resulting from chronic O. viverrini infection.

Differential Protein Expression Marks the Transition From Infection With Opisthorchis viverrini to Cholangiocarcinoma

“…Protein markers that could discriminate between Ov infection and Ov-associated CCA are of particular interest in areas where Ov is endemic and the prevalence of Ov infection rates can reach as high as 75% of the population (4). In our previous work, we have shown that systemic and Ov-specific interleukin-6, a known inflammatory cytokine, are associated with Ov-associated CCA and that this cytokine possesses a positive association with advanced periductal fibrosis, a precursor stage to CCA and to Ovassociated CCA itself (34). However, the low diagnostic specificity of IL-6, which has been proposed as a inflammatory marker for many conditions (e.g.…”

Lateral Flow Assay with Near-Infrared Dye for Multiplex Detection

“…Whereas the IL-6 concentration in blood can range from 0.1 to Ͼ1000 pg/mL (18,19 ), other popular biomarkers are considerably more abundant. CRP is a biomarker of cardiovascular risk, infection, trauma, tissue necrosis, autoimmunity, and some cancers (20 ).…”

Evaluation of concentrations of pro/anti-inflammatory cytokines after complication-free ECRP in cholangiocarcinoma

“…Secretion and interaction of IL-6, transforming growth factor-beta (TGF-β), TNF-α, and platelet-derived growth factor (PDGF) are necessary for proliferation of cholangiocytes (3). Higher levels of IL-6 have been found (221-fold higher) in CCA patients than control volunteers (4). It has been found that peritumoral chronic inflammation is associated with the migration and invasion of malignant cells and that LPS-active macrophages are secreting inflammatory cytokines, such as IL-4, IL-6, IL-10, TNF-α, and TGFβ1 (5).…”