Current hepatocellular carcinoma (HCC) staging systems lack comprehensive assessment of tumor biologic characteristics. This study aimed to develop and validate a tumor biology characteristics score (TBCS) based on alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II) to predict long-term oncologic outcomes after HCC resection.

In this multicenter retrospective cohort study, patients who underwent curative resection for HCC between June 2018 and December 2022 were included. TBCS (range, 2-6 points) was calculated by combining preoperative AFP (<20, 20-199, and ≥200 ng/mL) and PIVKA-II levels (<40, 40-399, and ≥400 mAU/mL). Patients were stratified into low (2 points), medium (3-4 points), and high TBCS groups (5-6 points). The primary outcomes were recurrence-free survival (RFS) and overall survival (OS).

A total of 695 patients were analyzed; the low, medium, and high TBCS groups comprised 132 (19.0%), 233 (33.5%), and 330 patients (47.5%), respectively. Notably, 5-year RFS was 30.4%, 14.7%, and 9.7%, whereas 5-year OS was 42.1%, 35.5%, and 23.5% for low, medium, and high TBCS groups, respectively (both P <.001). Multivariate analysis identified TBCS as an independent predictor of both RFS (medium TBCS: hazard ratio [HR], 1.583; 95% CI, 1.219-2.057; P =.001; high TBCS: HR, 1.895; 95% CI, 1.473-2.438; P <.001) and OS (high TBCS: HR, 1.781; 95% CI, 1.353-2.343; P <.001).

The novel TBCS combining AFP and PIVKA-II effectively stratified patients with HCC into distinct prognostic groups after curative-intent resection, independently predicting both RFS and OS. This score may help identify high-risk patients for more intense postoperative recurrence surveillance and receipt of adjuvant therapies.

This retrospective multicenter study is aimed at evaluating the diagnostic accuracy and influence factors of serum des-gamma-carboxy prothrombin (DCP) as a diagnostic biomarker of hepatocellular carcinoma (HCC).

Clinical data were collected from 4555 subjects with DCP tests, composed of primary liver cancer (PLC), metastatic liver cancer (MLC), chronic hepatitis (CH), liver cirrhosis (LC), benign liver diseases (BLD), biliary tract diseases (BTD), non-liver cancers (NLC), and non-liver benign diseases (NLBD). The clinical data collected included medical history, treatment records, various serum tests, and imaging examination.

Serum DCP was measured with Abbott agents in each center. In HCC, serum DCP concentration was at 9086.00 ± 366.10 mAU/mL, higher than that in other diseases (p < 0.05). At 40.00 mAU/mL recommended by instruction, positive rates of serum DCP were at 85.11% in HCC, 30.12% in intrahepatic cholangiocellular carcinoma (ICC), 31.65% in MLC, 13.95% in BLD, 18.14% in CH, 27.87% in LC, 15.75% in BTD, 35.29% in NLC, and 20.00% in NLBD. In this study, the diagnostic specificity of serum DCP in HCC was affected by liver function. In HCC, serum AFP concentrations also increased compared to non-HCC diseases (p < 0.05), but specificity varied with agents from different providers. Serum DCP decreased after the surgical removal of HCC, but remained elusive in systemic treatment.

Serum DCP may serve as an optimal biomarker for the diagnosis of HCC, but its accuracy appears influenced by liver function; attention needs to be paid to the liver function of patients for false positivity.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the leading global liver disorder and is poised to become the primary cause of hepatocellular carcinoma (HCC). Research indicates that nearly 50% of HCC cases in MASLD patients occur without cirrhosis, often presenting with more advanced and larger tumors. Despite this, current guidelines primarily focus on HCC screening in cirrhotic patients, with limited guidance for non-cirrhotic MASLD individuals. This narrative review seeks to identify key risk factors for HCC development, consolidate available screening methods, and propose a practical, risk-stratified algorithm for HCC surveillance in non-cirrhotic MASLD patients. We conducted a comprehensive review of studies published between 2017 and 2023 using PubMed, Embase, and CNKI, focusing on HCC risk factors and emerging screening strategies for non-cirrhotic MASLD cohorts. Key risk factors for HCC development in these patients include male sex, age over 65, hypertension, diabetes, mild alcohol consumption, smoking, dyslipidemia, elevated alanine aminotransferase levels, and a platelet count ≤ 150 × 109/L. Among the screening methods evaluated, circulating free DNA, alpha-fetoprotein (AFP) combined with protein induced by vitamin K absence or antagonist-II (PIVKA-II), and the GALAD score (incorporating Glypican-3, AFP, alpha-1-Antitrypsin, and des-gamma-carboxy prothrombin) demonstrated the highest performance. Based on these findings, we proposed a risk-stratified HCC surveillance algorithm that integrates GALAD and PIVKA-II into the existing sonography and AFP screening protocols. This review aims to provide clinicians with actionable recommendations for HCC screening in non-cirrhotic MASLD patients.

Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as "silent pandemic", this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Much of the recognised health-care burden occurs in the minority of people with NAFLD who progress towards cirrhosis and require specialist follow-up, including risk stratification and hepatocellular carcinoma surveillance. NAFLD is projected to become the leading global cause of cirrhosis and hepatocellular carcinoma, but the frequency of non-cirrhotic hepatocellular carcinoma provides a challenge to existing surveillance strategies. Deaths from extrahepatic cancers far exceed those from hepatocellular carcinoma in NAFLD. Unlike hepatocellular carcinoma, the increased extrahepatic cancer risk in NAFLD is not dependent on liver fibrosis stage. Given that almost 30% of the world's adult population has NAFLD, extrahepatic cancer could represent a substantial health and economic issue. In this Review, we discuss current knowledge and controversies regarding hepatocellular carcinoma risk stratification and surveillance practices in people with NAFLD. We also assess the associations of extrahepatic cancers with NAFLD and their relevance both in the clinic and the wider community.

Liver cancer is globally the third leading cause of death from cancer. Hepatocellular carcinoma (HCC) develops in patients with underlying liver disease. The fraction of HCC attributed to nonalcoholic fatty liver disease (NAFLD) shows an accelerated increase in the last decades, being already responsible for 15% of all HCC cases. Similar to other causes of liver cirrhosis, patients with NAFLD-associated cirrhosis should be enrolled in HCC-screening programs, yet these patients are under-screened, and currently are less than half likely to be proposed for HCC screening as compared to patients with HCV-associated cirrhosis. NAFLD-associated HCC has the peculiarity of occurring in precirrhotic phases in 20-50% of the cases. Currently, HCC screening in precirrhotic NAFLD patients is not routinely recommended, since the risk of developing HCC is very low. However, because NAFLD affects one-third of the worldwide population, noncirrhotic NAFLD already accounts for 6% of HCC cases. As such, it is pressing to develop stratification tools, in order to personalize the individual risk of HCC development in a patient with NAFLD, allowing precision HCC-screening programs. This review summarizes the epidemiology of NAFLD-associated HCC with a critical analysis of current HCC-screening recommendations.

This study aims to describe the diagnostic performance of alpha-fetoprotein (AFP), alpha-fetoprotein L3 isoform (AFP-L3), protein induced by vitamin K absence II (PIVKA-II), and combined biomarkers for non-B non-C hepatocellular carcinoma (NBNC-HCC).

A total of 681 newly-diagnosed primary liver disease subjects (385 non-HCC, 296 HCC) who tested negativity for the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (anti-HCV) enrolled in this study. At the cut-off point of 3.8 ng/mL, AFP helps to discriminate HCC from non-HCC with an area under the curve (AUC) value of 0.817 (95% confidence interval [CI]: 0.785-0.849). These values of AFP-L3 (cut-off 0.9%) and PIVKA-II (cut-off 57.7 mAU/mL) were 0.758 (95%CI: 0.725-0.791) and 0.866 (95%CI: 0.836-0.896), respectively. The Bayesian Model Averaging (BMA) statistic identified the optimal model, including patients' age, aspartate aminotransferase, AFP, and PIVKA-II combination, which helps to classify HCC with better performance (AUC = 0.896, 95%CI: 0.872-0.920, P < 0.001). The sensitivity and specificity of the optimal model reached 81.1% (95%CI: 76.1-85.4) and 83.2% (95%CI: 78.9-86.9), respectively. Further analyses indicated that AFP and PIVKA-II markers and combined models have good-to-excellent performance detecting curative resected HCC, separating HCC from chronic hepatitis, dysplastic, and hyperplasia nodules.

In this study, we aimed to investigate the performance of GALAD, GALAD-C, and GAAP models in Chinese population in comparison to our newly build statistical model.

In this study, we built the AALP model based on age, α-fetoprotein (AFP), AFP-L3, and prothrombin induced by vitamin K absence-II (PIVKA II) to differentiate between patients with HCC and patients with CLD. We then compared the serum levels of AFP-L3 and PIVKA II in patients with HCC who were defined as remission or progression and showed the prognostic value of combined biomarkers.

The AUC value of the AALP model for HCC detection was 0.939 and AALP model exhibited a sensitivity of 81 % and a high specificity of 95 %. AALP model also exhibited good performance in the subgroups of patients with CLD. Furthermore, we demonstrated the consistency between imaging results and serum levels of AFP-L3 and PIVKA II.

The AALP model achieved a good diagnostic performance and a high sensitivity for predicting HCC patients. Our research also showed that AFP-L3 and PIVKA II are complementary to each other but irreplaceable in the clinical detection and monitoring of HCC.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with high mortality. The realization of precision medicine in HCC relies upon efficient biomarkers. Protein induced by vitamin K absence or antagonist II (PIVKA-II) is an immature prothrombin with insufficient coagulation activity, overexpressing in HCC cells. Previous evidence confirmed the role of PIVKA-II in screening and diagnosing HCC. However, the increased PIVKA-II was observed not only in HCC, but also in non-HCC individuals such as vitamin K deficiency. The joint detection of PIVKA-II and other biomarkers could significantly improve diagnostic accuracy in HCC. Furthermore, PIVKA-II serves as a valuable prognostic predictor, transplantation eligibility, resectability, tumor recurrence, therapeutic efficacy, and malignant tumor behaviors. Additionally, PIVKA-II represents a potential target for agent development to establish new therapeutic strategies. Besides HCC, PIVKA-II also serves as a biomarker of vitamin K status. In this review, we assess the role of PIVKA-II in diagnosis, prediction, and treatment. Over the past decades, substantial progress has been achieved in the application of PIVKA-II. Exploration and innovation are required for further advances in the field of PIVKA-II investigation.

Protein induced by vitamin K absence or antagonist-II (PIVKA-II) and α-fetoprotein (AFP) are promising tumor markers for the diagnosis of hepatocellular carcinoma (HCC). Yet, their diagnostic performance differs throughout HCC investigations. The aim of this meta-analysis was to assess the effectiveness of PIVKA-II and AFP in the diagnosis of HCC.

A systematic literature search was performed to identify relevant studies from eight databases, which were published up to February 2023, in order to compare the diagnostic performance of PIVKA-II and AFP for HCC. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic (SROC) curve was performed to assess the diagnostic accuracy of each biomarker.

Fifty-three studies were identified. The pooled sensitivity (95% confidence interval (CI)) of PIVKA-II and AFP was 0.71 (0.70 - 0.72) and 0.64 (0.63 - 0.65), respectively in diagnosis of HCC, and the corresponding pooled specificity (95% CI) was 0.90 (0.89 - 0.90) and 0.87 (0.87 - 0.88), respectively. The area under the ROC curve (AUC) of PIVKA-II and AFP was 0.89 (0.88 - 0.90) and 0.78 (0.77 - 0.79), respectively. Subgroup analysis demonstrated that PIVKA-II presented higher AUC values compared to AFP in terms of ethnic group (African, European, Asian, and American patients), etiology (mixed-type HCC, hepatitis C virus (HCV)-related, and hepatitis B virus (HBV)-related) and sample size of cases (≤ 100 and > 100).

This study reveals that PIVKA-II is a promising biomarker for identifying and tracking HCC, exhibiting greater accuracy than AFP. Our findings indicate that PIVKA-II outperforms AFP in detecting HCC across diverse racial groups and sample sizes, as well as in cases of HBV-related, HCV-related, or mixed-etiology HCC.

The incidence of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing globally. We aimed to assess the performance of alpha-fetoprotein (AFP), AFP-L3, des-gamma-carboxy prothrombin (DCP), and GALAD score in detecting NAFLD-related HCC.

We searched the relevant literature in PubMed, Embase and Cochrane. Conventional and network meta-analyses were performed for sensitivity, specificity, Youden index (YI), and the area under the summary receiver operator characteristic curve (AUC).

Fifteen studies involving 2031 NAFLD participants were included in this meta-analysis. When detecting early-stage NAFLD-related HCC, GALAD score and DCP process excellent performance. The sensitivity and AUC of DCP (0.60, 0.74, respectively) were higher than AFP (0.34, 0.59, respectively). The network meta-analysis showed that DCP and GALAD score had similar performance. In detecting all-stage NAFLD-related HCC, GALAD score (sensitivity = 0.87; YI = 0.77) performed better than AFP (sensitivity = 0.56; YI = 0.50), AFP-L3 (sensitivity = 0.39; YI = 0.36) and DCP (sensitivity = 0.73; YI = 0.62). Network meta-analysis obtained consistent results with conventional meta-analysis.

Due to the lower cost-effectiveness, DCP was more suitable for detecting early NAFLD-related HCC. AFP could be used in detecting all-stage NAFLD-related HCC.

Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.

the early diagnosis of hepatocellular carcinoma (HCC) benefits from the use of alpha-fetoprotein (AFP) together with imaging diagnosis using abdominal ultrasonography, CT, and MRI, leading to improved early detection of HCC. A lot of progress has been made in the field, but some cases are missed or late diagnosed in advanced stages of the disease. Therefore, new tools (serum markers, imagistic technics) are continually being reconsidered. Serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA II) diagnostic accuracy for HCC (global and early disease) has been investigated (in a separate or cumulative way). The purpose of the present study was to determine the performance of PIVKA II compared to AFP.

systematic research was conducted in PubMed, Web of Science, Embase, Medline and the Cochrane Central Register of Controlled Trials, taking into consideration articles published between 2018 and 2022.

a total number of 37 studies (5037 patients with HCC vs. 8199 patients-control group) have been included in the meta-analysis. PIVKA II presented a better diagnostic accuracy in HCC diagnostic vs. alpha-fetoprotein (global PIVKA II AUROC 0.851 vs. AFP AUROC 0.808, respectively, 0.790 vs. 0.740 in early HCC cases). The conclusion from a clinical point of view, concomitant use of PIVKA II and AFP can bring useful information, added to that brought by ultrasound examination.

Hepatocellular carcinoma (HCC) is among the world's third most lethal cancers. In resource-limited settings (RLS), up to 70% of HCCs are diagnosed with limited curative treatments at an advanced symptomatic stage. Even when HCC is detected early and resection surgery is offered, the post-operative recurrence rate after resection exceeds 70% in five years, of which about 50% occur within two years of surgery. There are no specific biomarkers addressing the surveillance of HCC recurrence due to the limited sensitivity of the available methods. The primary goal in the early diagnosis and management of HCC is to cure disease and improve survival, respectively. Circulating biomarkers can be used as screening, diagnostic, prognostic, and predictive biomarkers to achieve the primary goal of HCC. In this review, we highlighted key circulating blood- or urine-based HCC biomarkers and considered their potential applications in resource-limited settings, where the unmet medical needs of HCC are disproportionately highly significant.

Background GALAD score, comprising five clinical parameters, is a predictive model developed for hepatocellular carcinoma (HCC) detection. Since its emergence, its diagnostic ability has been validated in different populations with a wide variation. Therefore, we conducted a meta-analysis to investigate its overall diagnostic performance in differentiating HCC in chronic liver diseases. Methods Eligible studies were searched in the Web of Science, PubMed, Scopus, Ovid, Cochrane Library, and Embase databases by 29 May 2022. Pooled sensitivity, pooled specificity, and area under the receiver operating characteristic curve (AUC) with the corresponding 95% confidence intervals (CI) were estimated. Results Fifteen original studies (comprising 19,021 patients) were included. For detecting any-stage HCC, GALAD score yielded an excellent ability, with pooled sensitivity, specificity, and AUC of 0.82 (95%CI: 0.78-0.85), 0.89 (95%CI: 0.85-0.91), and 0.92 (95%CI: 0.89-0.94), respectively. Notably, further analyses demonstrated a good diagnostic accuracy of GALAD score for identifying Barcelona Clinic Liver Cancer staging (BCLC) 0/A HCC, with a moderate sensitivity (0.73 (95%CI: 0.66-0.79)) and a high specificity (0.87 (95%CI: 0.81-0.91)); by contrast, only 38% of early-stage patients can be identified by alpha-fetoprotein, with an AUC value of 0.70 (95%CI: 0.66-0.74). Following subgroup analyses based on different HCC etiologies, higher sensitivities and AUC values were observed in subgroups with hepatitis C or non-viral liver diseases. For detecting BCLC 0/A HCC in the cirrhotic population, GALAD score had a pooled sensitivity, specificity, and AUC of 0.78 (95%CI: 0.66-0.87), 0.80 (95%CI: 0.72-0.87), and 0.86 (95%CI: 0.83-0.89). Conclusions We highlighted the superior diagnostic accuracy of GALAD score for detecting any-stage HCC with a high sensitivity and specificity, especially for early-stage HCC, with a relatively stable diagnostic performance. The addition of GALAD score into ultrasound surveillance may identify more HCC patients. Our findings imply the robust power of the GALAD score as a HCC screening or diagnostic tool, and it should be further validated by more studies with high quality.

Patients with cirrhosis are at risk of hepatocellular carcinoma (HCC) development and, according to current guidelines, should undergo surveillance by ultrasound at six month intervals. Due to the known limitations of surveillance strategies based on ultrasonography, the use of tumor biomarkers, although debated, is common practice in many centers. The aim of the study was to identify the best cut-off value for one of such biomarkers, protein induced by vitamin K absence, or antagonist-II (PIVKA-II). We retrospectively enrolled 1187 patients with liver cirrhosis: 205 with a diagnosis of HCC (median age 67 years, 81.0% males) and 982 without tumor (median age 64 years, 56.2% males). During a median follow-up (FU) of 34.6 (11.4−43.7) months, 118 out of 982 (12.0%) patients developed HCC. Serum PIVKA-II was assessed by chemiluminescence immunoassay on the Lumipulse® G600 II platform (Fujirebio, Tokyo, Japan). In the overall cohort (n = 1187), PIVKA-II showed an area under the curve (AUC) of 0.802 for HCC detection. The best cut-off value that maximized sensitivity was 50 mAU/mL (sensitivity = 80%, specificity = 64%). In the 982 patients without HCC at baseline, PIVKA-II > 50 mAU/mL was associated with an increased risk of HCC development during the FU (HR = 1.74, 95% CI 1.21−2.51; p = 0.003)). In conclusion, the evaluation of serum PIVKA-II showed a good performance for HCC detection; a cut-off value > 50 mAU/mL could be suitable for the surveillance of patients who are at risk of developing HCC.