Copper Isotope Evidence of Oxidative Stress-Induced Hepatic Breakdown and the Transition to Hepatocellular Carcinoma

Background and aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and finding a single reliable biomarker to follow liver degradation is a challenging task. To document the relationship between liver failure, hypoxia, and HCC, copper isotope variations (δ⁶⁵Cu) were evaluated in the serum of HCC-negative and HCC-positive patients as a biomarker of hepatic failure.

Methods: We analyzed Cu isotope variations in serum samples from 293 patients with potentially degraded liver functions presenting hepatitis B virus, hepatitis C virus, nonalcoholic steatohepatitis, and alcohol uptake (OH) etiologies and 105 controls. Ninety-five of the patients were diagnosed with HCC.

Results: On average, the δ⁶⁵Cu values of the serum of patients with F3-F4 fibrosis score or HCC-positive are low. The Cu isotope data are strikingly bimodal with well-defined δ⁶⁵Cu modes which imperfectly reflect etiology. The population with normal values (ca -0.3‰) is progressively replaced by a population with atypical δ⁶⁵Cu values (ca -0.8‰), which reflects the progressive degradation of hepatic functions.

Conclusion: The clear bimodality does not correspond to a progressive shift of the δ⁶⁵Cu values but to a replacement of one population by another. This bimodality sheds light on the persisting difficulties epitomized by α-fetoprotein in finding high-sensitivity and high-specificity HCC biomarkers. It is interpreted as a switch in the resistance of hepatic tissues to the oxidative stress that eventually leads to HCC oncogenesis.