Abstract
Objectives: In the setting of surveillance for hepatocellular carcinoma (HCC) detection, the use of serum biomarkers in addition to ultrasonography (US) is still a matter of debate. Hence, we performed a meta-analysis to evaluate the diagnostic accuracy of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) alone or in combination for HCC detection in patients at risk of tumor development.Materials and methods: We performed a systematic search in PubMed and Scopus database for original articles published in English from 2011 to 2017, investigating the accuracy of PIVKA-II alone or in combination with AFP (reported as area under the curve [AUC]) for HCC detection among patients at risk of tumor development. Furthermore, we focused on studies in which serum PIVKA-II was assessed by highly sensitive chemiluminescence immunoassay (CLEIA).Results: A total of 11 studies (873 patients with HCC and 1244 patients with advanced liver disease/cirrhosis) were included in the meta-analysis. The weighted summary AUC (sAUC) of PIVKA-II and AFP for the discrimination between patients with HCC and those without was 0.791 (0.746–0.837) and 0.767 (0.732–0.803), respectively. The combination of PIVKA-II + AFP results in a sAUC of 0.859 (0.837–0.882). The performance for HCC detection of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.068, p = .032 and ΔsAUC = 0.092, p < .001, respectively).Conclusion: In clinical practice, the use of PIVKA-II + AFP in addition to US examination may improve the effectiveness of surveillance among patients at risk for HCC development.
Highlights
Despite the availability of direct-acting antiviral agents (DAAs) and potent nucleos(t)ide analogues (NAs) with high genetic barrier to resistance for treatment of patients with chronic hepatitis C and B, respectively, the prognosis of patients with advanced liver disease/cirrhosis responder to antiviral treatment is still characterized by a significant risk of hepatocellular carcinoma (HCC) development.[1,2] Currently, surveillance programs for HCC detection in high risk population are mainly based on abdominal ultrasonography (US).[3,4] US has no predictive power on HCC development
No differences were observed between PIVKA-II and AFP diagnostic accuracy (ΔsAUC = 0.013, p = 0.668), whereas the combination of PIVKA-II + AFP was significantly superior to each biomarker used alone (ΔsAUC = 0.084, p = 0.001 and ΔsAUC = 0.097, p < 0.001, respectively)
The use of serum biomarkers for HCC surveillance is a matter of debate since no unequivocal evidence in improving early HCC detection has been produced.[31]
Summary
Despite the availability of direct-acting antiviral agents (DAAs) and potent nucleos(t)ide analogues (NAs) with high genetic barrier to resistance for treatment of patients with chronic hepatitis C and B, respectively, the prognosis of patients with advanced liver disease/cirrhosis responder to antiviral treatment is still characterized by a significant risk of hepatocellular carcinoma (HCC) development.[1,2] Currently, surveillance programs for HCC detection in high risk population are mainly based on abdominal ultrasonography (US).[3,4] US has no predictive power on HCC development. Alpha-fetoprotein (AFP) is the most used worldwide despite showing suboptimal performance for HCC detection.[6] novel classes of biomarkers involved in epigenetic machinery such as microRNAs (miRNAs) showed promising results.[7,8] their use in clinical practice may be limited by the absence of a standardized analytical method and by a complex miRNA-messenger RNA interference network reflecting different genetic and epigenetic features, that in turn may significantly alter miRNAs expression.[9] Protein induced by vitamin K absence or antagonist II (PIVKA-II), known as des-gamma-carboxy prothrombin, is a biomarker specific for HCC firstly described in 1984.[10] PIVKA-II is an hypocarboxylated prothrombin released by the liver in absence of vitamin K or in presence of malignant cells; higher PIVKA-II serum levels are associated to tumor size, microvascular invasion and predict HCC recurrence.[11,12,13] The combination of PIVKA-II with AFP is currently used in Japan for surveillance of patients at risk of HCC development as recommended by the local HCC guidelines.[14] results regarding PIVKA-II performance in comparison or in combination with AFP are conflicting and available data mainly derive from studies involving Asiatic patients;[15,16] results from Western studies are limited by the relatively small sample size. Considering the availability of novel CLEIA-based methods for PIVKA-II measurement and the lack of consensus regarding the usefulness of PIVKA-II in the setting of HCC surveillance, we performed a meta-analysis on the diagnostic accuracy of PIVKA-II alone or in combination with AFP for HCC detection among patients at risk of tumor development
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