Abstract
Cytokeratin (CK)-18 is the major intermediate filament protein in the liver and during hepatocyte apoptosis is cleaved by the action of caspases; the resulting fragments are released into the blood as caspase-cleaved cytokeratin (CCCK)-18. Higher circulating levels of CCCK-18 have been found in patients with hepatocellular carcinoma (HCC) than in healthy controls and than in cirrhotic patients. However, it is unknown whether serum CCCK-18 levels before liver transplantation (LT) in patients with HCC could be used as a prognostic biomarker of one-year survival, and this was the objective of our study with 135 patients. At one year after LT, non-survivors showed higher serum CCCK-18 levels than survivors (p = 0.001). On binary logistic regression analysis, serum CCCK-18 levels >384 U/L were associated with death at one year (odds ratio = 19.801; 95% confidence interval = 5.301–73.972; p < 0.001) after controlling for deceased donor age. The area under the receiver operating characteristic (ROC) curve of serum CCCK-18 levels to predict death at one year was 77% (95% CI = 69%–84%; p < 0.001). The new finding of our study was that serum levels of CCCK-18 before LT in patients with HCC could be used as prognostic biomarker of survival.
Highlights
Hepatocellular carcinoma (HCC) is one of the most frequent malignancies, the most frequent primary liver malignancy, and the second most frequent cause of cancer-related death worldwide
We found that one-year non-survivors showed higher liver transplantation (LT)-donor age (p = 0.03) and serum levels of caspase-cleaved cytokeratin (CCCK)-18 (p = 0.001) than survivors; only serum levels of CCCK-18 were significantly higher in non-survivors than in survivor patients after Bonferroni correction
The new findings of our study were that survivors at one year after LT for HCC showed lower serum CCCK-18 levels before LT than non-surviving patients, that there was an association between serum CCCK-18 levels before LT and one-year survival after LT, controlling for deceased donor age, and that pre-LT serum levels of CCCK-18 in patients with HCC could be used as a prognostic biomarker of survival
Summary
Hepatocellular carcinoma (HCC) is one of the most frequent malignancies, the most frequent primary liver malignancy, and the second most frequent cause of cancer-related death worldwide. For certain patients with HCC, the treatment of choice is liver transplantation (LT), which treats the underlying liver disease and removes the primary tumor [1,2,3,4,5,6]. Cell death by apoptosis occurs mainly by two pathways, the extrinsic and the intrinsic pathways. Apoptosis is activated by interleukin (IL)-1, IL-6, oxygen free radicals and nitric oxide (NO), which leads to the liberation of cytochrome from mitochondria. Both pathways activate caspase 3 leading to cell death. Hepatocytes express surface death receptors (which initiate the extrinsic cell death pathway) and require mitochondrial amplification for the intrinsic cell death pathway [7]
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