Search for Effective Serum Tumor Markers for Early Diagnosis of Hepatocellular Carcinoma Associated with Hepatitis C

Abstract

The aim of the study was to identify the most effective serum tumor markers for early diagnosis of hepatocellular carcinoma based on the combination of diagnostic characteristics and correlations. Materials and Methods. There were observed 55 patients with chronic hepatitis C in the stage of liver cirrhosis with a verified diagnosis of hepatocellular carcinoma. The control group consisted of 55 patients with chronic hepatitis C at the stage of liver cirrhosis without hepatocellular carcinoma, comparable to the experimental group in terms of basic clinical profile. The following tumor markers were estimated in both groups: alpha-fetoprotein (AFP), alpha-fetoprotein-L3 (AFP-L3), annexin A2 (ANXA2), heparin-binding growth factor Midkine (MDK), glypican-3 (GPC3), des-gamma-carboxyprothrombin (DCP, PIVKA-II), dickkopf-related protein 1 (DKK-1), osteopontin (OPN), and Golgi protein 73 (GP73). There were also evaluated such indices as diagnostic sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio of a positive test, the possible correlation between alpha-fetoprotein and other tumor markers. The area under the ROC curve (AUC) was calculated at the 95% confidence interval. Results. The greatest sensitivity was revealed when using heparin-binding growth factor, annexin A2, osteopontin. Alpha-fetoprotein, alpha-fetoprotein-L3, glypican-3, des-gamma-carboxyprothrombin, dickkopf-related protein 1 had the best specificity. AUC>0.75 was found in annexin A2, heparin-binding growth factor, glypican-3, des-gamma-carboxyprothrombin, osteopontin, Golgi protein 73. The likelihood ratio of a positive test result was the highest for glypican-3. A significant correlation was found between alpha-fetoprotein and alphafetoprotein-L3, annexin A2, des-gamma-carboxyprothrombin. Conclusion. According to the aggregate indicators of diagnostic efficiency, heparin-binding growth factor, glypican-3, and osteopontin are the most promising tumor markers of those studied. When they are used, integral AUC values are above the average, the level of these tumor markers in the blood of patients with hepatocellular cancer does not correlate with alpha-fetoprotein. They are applicable for diagnosing liver cancer in AFP-negative patients. The combined use of AFP + GPC3, AFP + OPN has already shown their advantages. However, the efficacy of the combination of AFP + MDK, GPC3 + OPN has not been determined yet; therefore, significance of the combined use of these tumor markers in the diagnosis of liver cancer should be investigated in the near future.

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“…But their results have been conflicting and controversial. For example, Malov et al (2021) [24] found that serum GPC-3 has excellent diagnostic ability in distinguishing patients with chronic Hepatitis C in the stage of liver cirrhosis from patients with Hepatitis C in the stage of liver cirrhosis and HCC; in this study, serum GPC-3 showed a sensitivity of 60% and a specificity of 96.4%. Another research by Caviglia et al (2021) [25] showed that serum GPC-3 was also outstanding (sensitivity of 62.5% and specificity of 82.4%) in a group of patients with NAFLD/NASH in distinguishing between the ones with HCC and the ones without HCC.…”

“…Therefore, it captured the most recent studies published between 2019 and the date of the literature search. (Studies that were not captured in other meta-analyses) [24][25][26][27]36]. Thus, this meta-analysis captured the most recent evidence on the diagnostic value of GPC-3 in diagnosing HCC.…”

“…Secondly, the most recent meta-analysis on the diagnostic value of serum GPC-3 in HCC was published in 2019 [29]. And since then, new studies have been published on the diagnostic value of serum GPC-3 [24][25][26][27]36]. These new studies were captured in this meta-analysis.…”

“…Due to increasing evidence supporting the use of serum GPC-3 as a non-invasive marker for the detection of HCC, several researchers have carefully explored this topic in connection to the diagnostic potency of serum GPC-3, but their results, though promising, have been inconsistent and controversial [24][25][26][27][28]. In this systematic review and meta-analysis, the objective is to compile and evaluate the findings from investigations that assessed the diagnostic efficacy of serum GPC-3 in the diagnosis of HCC.…”

Advances in multi-omics research on viral hepatitis

“…Lee et al (2006) identified complement C3a as a candidate biomarker for HCV-related HCC by proteomics. Malov et al (2021) confirmed that heparin binds to growth factors, glypican-3 and osteopontin could serve as HCV-associated HCC markers. The screening of specific proteins is conducive to accurate diagnosis and prognosis in patients with HCV infection and related diseases.…”