Differential Expression and Diagnostic Significance of Pre-Albumin, Fibrinogen Combined with D-Dimer in AFP-Negative Hepatocellular Carcinoma


Hepatocellular carcinoma (HCC) is one of the most malignant cancers with high morbidity and mortality. Nowadays, AFP-negative hepatocellular carcinoma (AFP-NHCC) has been found in many HCC patients and AFP analysis can’t be used to screen HCC in these cases. In this study, we have examined the expression patterns of pre-albumin (PA), fibrinogen, D-Dimer and their clinical significance in AFP-NHCC. We recruited 214 AFP-NHCC patients and 210 controls in the study. PA, fibrinogen and D-Dimer levels were detected by turbidimetry, clauss and immunoturbidimetry methods, respectively. Serum PA levels were significantly lower in AFP-NHCC (84.5 ± 24.7 mg/L) than that in the controls (240.6 ± 59.4 mg/L, P < 0.05). For plasma fibrinogen levels, there was no difference between the controls (2.9 ± 0.7 g/L) and AFP-NHCC (2.5 ± 0.7 g/L). Compared with AFP-NHCC (0.8 ± 0.2 mg/L), plasma D-Dimer levels were significantly lower in controls (0.1 ± 0.0 mg/L, P < 0.05). The levels of PA, fibrinogen and D-Dimer were significantly correlated with differentiation (P < 0.01), and the PA and D-Dimer values were correlated with TNM stage (P < 0.05). Moreover, PA levels were correlated with tumor size (P = 0.034). Receiver operating characteristic curve (ROC) analyses elaborated that combination of PA, fibrinogen and D-Dimer possessed a higher sensitivity (93.4%) for differentiating AFP-NHCC from the controls, but the diagnostic specificity was reduced due to the combination of fibrinogen. After adjusting for all significant outcome predictors of the univariate logistic regression analysis, low levels of PA and high levels of D-Dimer were remained independent unfavorable outcome predictors (P < 0.05). Our data suggested that the expression levels of PA, fibrinogen and D-Dimer played critical roles in AFP-NHCC tumorigenesis. Moreover, PA and D-Dimer might be considered as potential diagnostic indicators in AFP-NHCC.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. 1.

    Corwin MT, Lee AY, Fananapazir G, Loehfelm TW, Sarkar S, Sirlin CB (2018) Nonstandardized terminology to describe focal liver lesions in patients at risk for hepatocellular carcinoma: implications regarding clinical communication. AJR Am J Roentgenol 210(1):85–90. https://doi.org/10.2214/ajr.17.18416

    Article  PubMed  Google Scholar 

  2. 2.

    Nadinskaia MY, Kodzoeva KB, Ulyanova KA, Volkova AS, Rogacheva SI, Dekhanov AS, Strelkova DA, Ivashkin VT (2019) Risk factors associated with portal vein thrombosis in liver cirrhosis: a case-control study. Terapevticheskii arkhiv 91(2):73–81. https://doi.org/10.26442/00403660.2019.02.000153

    Article  PubMed  Google Scholar 

  3. 3.

    Monfardini L, Orsi F, Caserta R, Sallemi C, Della Vigna P, Bonomo G, Varano G, Solbiati L, Mauri G (2018) Ultrasound and cone beam CT fusion for liver ablation: technical note. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 35(1):500–504. https://doi.org/10.1080/02656736.2018.1509237

  4. 4.

    Wang M, Devarajan K, Singal AG, Marrero JA, Dai J, Feng Z, Rinaudo JA, Srivastava S, Evans A, Hann HW, Lai Y, Yang H, Block TM, Mehta A (2016) The Doylestown algorithm: a test to improve the performance of AFP in the detection of hepatocellular carcinoma. Cancer Prev Res (Phila) 9(2):172–179. https://doi.org/10.1158/1940-6207.capr-15-0186

    CAS  Article  Google Scholar 

  5. 5.

    Chen ZZ, Huang L, Wu YH, Zhai WJ, Zhu PP, Gao YF (2016) LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression. Nat Commun 7:12598. https://doi.org/10.1038/ncomms12598

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Arbab K, Majid H, Jafri L, Akram B, Raheem A, Jamil B, Hashmi M, Khan AH (2019) Assessing nutritional status of critically ill patients using serum Prealbumin levels. J Ayub Med Coll, Abbottabad : JAMC 31(2):178–181

    Google Scholar 

  7. 7.

    Wen X, Yao M, Lu Y, Chen J, Zhou J, Chen X, Zhang Y, Lu W, Qian X, Zhao J, Zhang L, Ding S, Lu F (2018) Integration of Prealbumin into child-Pugh classification improves prognosis predicting accuracy in HCC patients considering curative surgery. J Clin Transl Hepatol 6(4):377–384. https://doi.org/10.14218/jcth.2018.00004

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hou C, Jiang F, Ma H, Zhu Q, Wang Z, Zhao B, Xue T, Tan S, Yang R, Qian Y, Luo X, Zhao M, Xu X, Chen L, Li J (2019) Prognostic role of preoperative platelet, fibrinogen, and D-dimer levels in patients with non-small cell lung cancer: a multicenter prospective study. Thoracic Cancer 10(2):304–311. https://doi.org/10.1111/1759-7714.12956

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Cai HX, Li XQ, Wang SF (2018) Prognostic value of fibrinogen and D-dimer-fibrinogen ratio in resectable gastrointestinal stromal tumors. World J Gastroenterol 24(44):5046–5056. https://doi.org/10.3748/wjg.v24.i44.5046

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Fan S, Zhao G, An G (2019) High pretreatment plasma D-dimer levels are associated with shorter overall survival in patients with small cell lung cancer. J Int Med Res 47(1):215–224. https://doi.org/10.1177/0300060518799869

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Darweesh SK, Gad AA (2019) Percutaneous microwave ablation for HCV-related hepatocellular carcinoma: efficacy, safety, and survival. Turk J Gastroenterol 30(5):445–453. https://doi.org/10.5152/tjg.2019.17191

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Yamada R, Bassaco B, Bracewell S, Gillen K, Kocher M, Collins H, Anderson MB, Guimaraes M (2019) Long-term follow-up after conventional transarterial chemoembolization (c-TACE) with mitomycin for hepatocellular carcinoma (HCC). J Gastrointest Oncol 10(2):348–353. https://doi.org/10.21037/jgo.2019.01.01

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Fung J, Cheung KS, Wong DK, Mak LY, To WP, Seto WK, Lai CL, Yuen MF (2018) Long-term outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance. Hepatology (Baltimore, Md) 68(2):462–472. https://doi.org/10.1002/hep.29874

    CAS  Article  Google Scholar 

  14. 14.

    Fan L, Chi C, Guo S, Wang Y, Cai W, Shao X, Xu F, Pan J, Zhu Y, Shangguan X, Xin Z, Hu J, Qian H, Xie S, Wang R, Zhou L, Dong B, Xue W (2017) Serum pre-albumin predicts the clinical outcome in metastatic castration-resistant prostate Cancer patients treated with Abiraterone. J Cancer 8(17):3448–3455. https://doi.org/10.7150/jca.21134

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Braverman LE, Vagenakis A, Downs P, Foster AE, Sterling K, Ingbar SH (1973) Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man. J Clin Invest 52(5):1010–1017. https://doi.org/10.1172/jci107265

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Yang F, Wei L, Huo X, Ding Y, Zhou X, Liu D (2018) Effects of early postoperative enteral nutrition versus usual care on serum albumin, prealbumin, transferrin, time to first flatus and postoperative hospital stay for patients with colorectal cancer: a systematic review and meta-analysis. Contemp Nurse 54(6):561–577. https://doi.org/10.1080/10376178.2018.1513809

    Article  PubMed  Google Scholar 

  17. 17.

    Jia RR, Zhong JH, Huo RR, Su QB, Xiang X, Zhao FL, Qin ZB, Chen JH, Liao YY, Ma L, Xiang BD, Zhang CY, Li LQ (2019) Correlation between serum prealbumin and prognosis of patients with hepatocellular carcinoma after hepatectomy. J Surg Oncol 119(6):794–800. https://doi.org/10.1002/jso.25378

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Tennent GA, Brennan SO, Stangou AJ, O'Grady J, Hawkins PN, Pepys MB (2007) Human plasma fibrinogen is synthesized in the liver. Blood 109(5):1971–1974. https://doi.org/10.1182/blood-2006-08-040956

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Mosesson MW (2005) Fibrinogen and fibrin structure and functions. J Thromb Haemost 3(8):1894–1904. https://doi.org/10.1111/j.1538-7836.2005.01365.x

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Arigami T, Okumura H, Matsumoto M, Uchikado Y, Uenosono Y, Kita Y, Owaki T, Mori S, Kurahara H, Kijima Y, Ishigami S, Natsugoe S (2015) Analysis of the fibrinogen and neutrophil-lymphocyte ratio in esophageal squamous cell carcinoma: a promising blood marker of tumor progression and prognosis. Medicine 94(42):e1702. https://doi.org/10.1097/md.0000000000001702

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Son HJ, Park JW, Chang HJ, Kim DY, Kim BC, Kim SY, Park SC, Choi HS, Oh JH (2013) Preoperative plasma hyperfibrinogenemia is predictive of poor prognosis in patients with nonmetastatic colon cancer. Ann Surg Oncol 20(9):2908–2913. https://doi.org/10.1245/s10434-013-2968-8

    Article  PubMed  Google Scholar 

  22. 22.

    Garcia MG, Bayo J, Bolontrade MF, Sganga L, Malvicini M, Alaniz L, Aquino JB, Fiore E, Rizzo MM, Rodriguez A, Lorenti A, Andriani O, Podhajcer O, Mazzolini G (2011) Hepatocellular carcinoma cells and their fibrotic microenvironment modulate bone marrow-derived mesenchymal stromal cell migration in vitro and in vivo. Mol Pharm 8(5):1538–1548. https://doi.org/10.1021/mp200137c

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Zheng S, Shen J, Jiao Y, Liu Y, Zhang C, Wei M, Hao S, Zeng X (2009) Platelets and fibrinogen facilitate each other in protecting tumor cells from natural killer cytotoxicity. Cancer Sci 100(5):859–865. https://doi.org/10.1111/j.1349-7006.2009.01115.x

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T (2012) Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 126(23):2739–2748. https://doi.org/10.1161/circulationaha.112.122556

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Adam SS, Key NS, Greenberg CS (2009) D-dimer antigen: current concepts and future prospects. Blood 113(13):2878–2887. https://doi.org/10.1182/blood-2008-06-165845

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Man YN, Wang YN, Hao J, Liu X, Liu C, Zhu C, Wu XZ (2015) Pretreatment plasma D-dimer, fibrinogen, and platelet levels significantly impact prognosis in patients with epithelial ovarian cancer independently of venous thromboembolism. Int J Gynecol Cancer 25(1):24–32. https://doi.org/10.1097/igc.0000000000000303

    Article  PubMed  Google Scholar 

  27. 27.

    Batschauer AP, Figueiredo CP, Bueno EC, Ribeiro MA, Dusse LM, Fernandes AP, Gomes KB, Carvalho MG (2010) D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer. Ann Oncol 21(6):1267–1272. https://doi.org/10.1093/annonc/mdp474

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Yamamoto M, Yoshinaga K, Matsuyama A, Iwasa T, Osoegawa A, Tsujita E, Yamashita Y, Tsutsui S, Ishida T (2012) Plasma D-dimer level as a mortality predictor in patients with advanced or recurrent colorectal cancer. Oncology 83(1):10–15. https://doi.org/10.1159/000338329

    Article  PubMed  Google Scholar 

  29. 29.

    Fukumoto K, Taniguchi T, Usami N, Kawaguchi K, Fukui T, Ishiguro F, Nakamura S, Yokoi K (2015) Preoperative plasma D-dimer level is an independent prognostic factor in patients with completely resected non-small cell lung cancer. Surg Today 45(1):63–67. https://doi.org/10.1007/s00595-014-0894-4

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Liu P, Zhu Y, Liu L (2015) Elevated pretreatment plasma D-dimer levels and platelet counts predict poor prognosis in pancreatic adenocarcinoma. Onco Targets Ther 8:1335–1340. https://doi.org/10.2147/ott.s82329

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Buller HR, van Doormaal FF, van Sluis GL, Kamphuisen PW (2007) Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 5(Suppl 1):246–254. https://doi.org/10.1111/j.1538-7836.2007.02497.x

    CAS  Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Wei Jing.

Ethics declarations

Competing Interests

The authors have declared that no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jing, W., Peng, R., Zhu, M. et al. Differential Expression and Diagnostic Significance of Pre-Albumin, Fibrinogen Combined with D-Dimer in AFP-Negative Hepatocellular Carcinoma. Pathol. Oncol. Res. 26, 1669–1676 (2020). https://doi.org/10.1007/s12253-019-00752-8

Download citation


  • Pre-albumin
  • Fibrinogen
  • D-Dimer
  • AFP-negative hepatocellular carcinoma
  • Diagnosis