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Primary liver cancer is a malignant tumor occurring in hepatocytes or intrahepatic bile duct cells, which is mainly associated with hepatitis, cirrhosis, aflatoxin, genetic factors, alcoholism and other factors. Liver cancer is the forth most-common cause of cancer death globally, accounting for over 800,000 deaths annually [1,2]. Hepatocellular carcinoma (HCC) represents approximately 90% of primary liver cancer, followed by intrahepatic cholangiocarcinoma (ICC) and other primary liver malignancies. If it can be detected and diagnosed at an early stage, the prognosis of liver cancer patients can be significantly improved and the long-term survival rate of patients can be increased. Therefore, early detection, diagnosis are the keys to reduce mortality and improve the efficacy of liver cancer treatment.
Figure 1: Global burden of primary liver cancer in 2020 and predictions to 2040[3]
According to American Association for the Study of Liver Diseases (AASLD) practice guidance, the early screening methods of liver cancer mainly include risk assessment, serological detection, imaging-based method, liquid biopsy, puncture biopsy and others [4].
Serological detection, due to its non-invasive nature, simple operation, dynamic monitoring and other characteristics, is a clinically important monitoring tool in early screening, postoperative efficacy evaluation and prognosis assessment of HCC.
Currently, the most commonly used serological markers for HCC in clinical practice include serum alpha-fetoprotein (AFP) and abnormal prothrombin (PIVKA-II or DCP). In addition, ferritin, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have also been used in liver cancer screening.
Figure 2: Pyramid model for early liver cancer screening
Alpha-Fetoprotein (AFP) is the most prevalent tumor marker to aid in the diagnosis of primary HCC, which performs well at specificity with a positivity rate up to 70-90%. Serum AFP ≥ 400 μg/L is a highly suggestive fact of primary HCC, when the possibility of pregnancy, chronic or active liver diseases and gastrointestinal tumor has been ruled out.
AASLD recommends that screening of ultrasonography coupled with serum AFP detection should be performed at least every 6 months in high-risk populations to facilitate early detection, diagnosis and treatment of HCC and to significantly reduce the risk of death in patients [5].
Protein induced by vitamin K absence-II (PIVKA-II), also known as degamma-carboxy-prothrombinogen (DCP), which plays a unique role in screening, diagnosis and prognostic monitoring of HCC.
The Guidelines for the Diagnosis and Treatment of Primary Hepatocellular Carcinoma (2024 Edition) recommends PIVKA-II as a screening indicator for early-stage HCC diagnosis. Asia Pacific Association of Study of Liver (APASL) and Japanese Society of Hepatology (JSH) also suggested the application of PIVKA-II for the screening of high-risk groups, adjuvant diagnosis of HCC, and monitoring treatment, prognosis and recurrence.
Ferritin is a spherical glycoprotein with a molecular weight of 450 kD, reflecting the body's iron storage function. In the presence of tumor, apoferritin synthesis has been promoted, which consequently increases the concentration of ferritin and that will be released into the blood in large quantities when tumor cells cytoclasis happens. The Ferritin levels decrease in HCC patients with effective treatment and increase in those with disease progression and recurrence. Persistent elevation of Ferritin usually indicates a poor prognosis [6].
There is no correlation between PIVKA-II and AFP, but they complement each other: AFP has poor effect for early diagnosis of liver cancer, while PIVKA-II has higher sensitivity and compensates the insufficient accuracy of AFP [7]. Currently various researches and international guidelines have proved that combined detection of AFP and PIVKA-II performs higher sensitivity and specificity for screening and early diagnosis of HCC [8,9], and combined testing is superior to the single one of each (Figure 2) [10,11]. It is also reported that diagnostic accuracy of AFP and PIVKA-II at early stage of HCC is only 68.8% and 80.0% respectively, while that of the combined testing is up to 81.2%. Besides, combining ferritin and AFP is of great accuracy more than 90% for HCC screening [12].
Figure 3: Combined testing of AFP+PIVKA-II to increase accuracy [10,11]
Snibe has developed a comprehensive liver cancer screening panel, which includes but not limited to the test menu of AFP, PIVKA-II and Ferritin, and better meets clinical demands. At the same time, SATLARSTM-T8, the total laboratory automation solution offering extraordinary efficiency, flexibility, compatibility, and intelligence, is compatible with Snibe comprehensive analytical solutions for multiple disciplines, which can effectively meet the needs of different medical institutions for early liver cancer screening and provide a complete solution for different customers.
Figure 4: SATLARSTM-T8 overview
References:
[1] Arnold M, Abnet CC, Neale RE, et al. Global Burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020; 159(1): 335–349. e15.
[2] Zeng HM, Cao MM, Xia CF, et al. Performance and effectiveness of hepatocellular carcinoma screening in individuals with HBsAg seropositivity in China: a multicenter prospective study. Nat Cancer. 2023; 4(9): 1382-1394.
[3] Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022; 77(6): 1598-1606.
[4] Singal AG, Llovet JM, Yarchoan M, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023; 78(6): 1922-1965.
[5] Zhang BH, Yang BH, and Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology. 2004; 130(7): 417-422.
[6] Jiang B, Yan L, Zhang JL, et al. Biomineralization Synthesis of the Cobalt Nanozyme in SP94-Ferritin Nanocages for Prognostic Diagnosis of Hepatocellular Carcinoma. ACS applied materials & interfaces. 2019: 11(10): 9747-9755.
[7] Chen L, Abou-Alfa GK, Zheng B, et al. Genome-scale profiling of circulating cell-free DNA signatures for early detection of hepatocellular carcinoma in cirrhotic patients. Cell Research. 2021: 589–592.
[8] Liu ZB, Wu M, Lin DD, and Li N. Des-gamma-carboxyprothrombin is a favorable biomarker for the early diagnosis of alfa-fetoprotein-negative hepatitis B virus-related hepatocellular carcinoma. The Journal of international medical research. 2020; 48(2).
[9] Kokudo N, Hasegawa K, Akahane M, et al. Evidence‐based Clinical Practice Guidelines for Hepatocellular Carcinoma: The Japan Society of Hepatology 2013 update (3rd JSH‐HCC Guidelines). Hepatology Research. 2015: 45(2).
[10] Xi Q, Sun GR, Cong PS, Liu MJ, and Zong JB. The clinical value of serum PIVKA-Ⅱ and AFP detection for hepatocellular carcinoma. Chinese Journal of Laboratory Medicine. 2019: 16(12): 928-932.
[11] N Poté, F Cauchy, M Albuquerque, et al. Valerie.Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. Journal of Hepatology: The Journal of the European Association for the Study of the Liver. 2015: 62(4): 848-854.
[12] Li YZ, Zhang YM. Diagnostic value of serum Fer, AFP and AFP-L3 combined detection in primary hepatic cancer. Cancer Research and Clinic. 2014: 26(07): 468-469, 472.
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