Abstract
Individualized assessment of hepatocellular carcinoma (HCC) risk in chronic liver disease remains challenging. Serum biomarkers including cytokines may offer helpful adjuncts to standard parameters for risk prediction. Our aim was to identify markers associated with increased HCC incidence. This was a prospective cohort study of 282 patients with both viral or non-viral chronic liver disease. Baseline serum cytokines and other markers were measured in multiplex with a commercially-available Luminex-based system. Patients were followed until death or HCC diagnosis. We performed Lasso-based survival analysis to determine parameters associated with HCC development. Cytokine mean florescence intensity (MFI) was the primary predictor and HCC development the primary outcome. 25 patients developed HCC with total follow-up of 1,363 person-years. Parameters associated with increased HCC incidence were cirrhosis, hepatic decompensation, and soluble serum intercellular adhesion molecule 1 (sICAM-1) MFI. No other molecules increased predictive power for HCC incidence. On univariate analysis, the parameters associated with HCC incidence in patients with cirrhosis were age, antiviral treatment, and high sICAM-1 MFI; on multivariate analysis, sICAM-1 remained associated with HCC development (adjusted HR = 2.75). On unbiased screening of serum cytokines and other markers in a diverse cohort, baseline sICAM-1 MFI is associated with HCC incidence.
Highlights
Prior studies suggest that several cytokines have important effects in the pathogenesis of and survival after hepatocellular carcinoma (HCC)
The hazard ratio (HR) was 3.33 (p = 0.011; Fig. 3B) and for patients without cirrhosis there was no association between sICAM-1 and HCC incidence (p = 0.69; Fig. 3C); of note the total number of patients without cirrhosis who developed HCC was very low as detailed above. These results indicate that in the overall cohort and in patients with cirrhosis, sICAM-1 median fluorescence intensity (MFI) is associated with increased HCC incidence
Our comprehensive profiling of 51 cytokines in 282 patients with various chronic liver diseases who were free of HCC at baseline identified sICAM-1 to highly associate with development of future HCC (AUROC 0.74 at year 10 and 0.955 at year 2)
Summary
Serum IL-6 concentration in HCC patients correlates with larger tumor size and decreased survival[11, 12]; and among at-risk patients with chronic www.nature.com/scientificreports/. High sICAM-1 concentration is associated with larger HCC tumor size[27] and increased risk of HCC recurrence following resection[28]. High sICAM-1 concentration may correlate with HCC incidence, based on one small study of 99 HCV patients[29]. It is associated with poor prognosis in other malignancies such as breast cancer[30] and non-Hodgkin lymphomas[31]. In order to investigate this question, we performed a prospective cohort study of HCC-free patients to determine how baseline cytokine profile may influence future risk of HCC
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