Mitochondrial Oxidative Stress in Circulating Leukocytes as a Prognostic Marker in Hepatocellular Carcinoma

Background and Aims The relationship between oxidative stress (OS) and hepatocellular carcinoma (HCC) is well known, influencing both, hepatocarcinogenesis and subsequent tumor progression. Less understood is its potential role in antitumor defense mechanisms. This study examines the production of OS in circulating leukocytes in HCC patients, its anti or pro‐tumoral capacity, and its potential utility as a prognostic marker. Approach and Results The intracellular production of mitochondrial superoxide, total superoxide, hydrogen peroxide (H 2 O 2 ), and glutathione was analyzed by flow cytometry in peripheral blood samples from 36 HCC patients and 18 HCC‐free cirrhotic patients. Levels of mitochondrial superoxide in neutrophils and H 2 O 2 in lymphocytes and neutrophils from HCC patients were higher than in the same cell populations from HCC‐free cirrhotic patients ( p < 0.05). Glutathione was higher in lymphocytes, monocytes, and neutrophils from HCC patients ( p < 0.05). In HCC patients, for each 1000‐unit increase in mitochondrial superoxide in lymphocytes, monocytes, and neutrophils, the risk of death is reduced by 49.4%, 49.5%, and 34.8%, respectively, demonstrating its role as a protective factor. A cutoff point in each leukocyte subset allowed the estimation of survival at 6 months and 1 year. Mitochondrial superoxide also proved to be a protective factor against disease progression (HR 0.314, 95% CI 0.113–0.872). Conclusions Circulating leukocytes in HCC patients exhibit increased OS compared to HCC‐free cirrhotic patients. Specifically, the increase in mitochondrial OS in HCC patients shows a strong correlation with survival and could thus be considered a prognostic factor.