Ann Liver Transplant.  2022 May;2(1):34-42. 10.52604/alt.22.0012.

Diagnostic predictability of hepatocellular carcinoma tumor markers in patients waiting for living donor liver transplantation

• Park CS
• Chung YK
• Kang SH
• Hwang S

• KMID: 2560879
• DOI: http://doi.org/10.52604/alt.22.0012

Abstract

Background
This study analyzed the expression and diagnostic values of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) in patients who underwent living donor liver transplantation.
Methods
The number of patients with and without hepatocellular carcinoma (HCC) was 1,297 and 719 in hepatitis B virus (HBV) group; 128 and 90 in hepatitis C virus (HCV) group; 109 and 381 in alcoholic liver disease (ALD) group; and 61 and 306 in other disease group, respectively.
Results
In all patients, the median AFP and PIVKA-II were 9.0 ng/mL and 25 mAU/ mL in HCC patients and 4.0 ng/mL and 23 mAU/mL in non-HCC patients (p<0.001 for AFP and p=0.274 for PIVKA-II), respectively. In HBV patients, they were 9.0 ng/ mL and 24 mAU/mL in HCC patients and 4.6 ng/mL and 17 mAU/mL in non-HCC patients, respectively (p=0.002 and p=0.045). In HCV patients, they were 9.0 ng/ mL and 24 mAU/mL in HCC patients and 5.3 ng/mL and 24 mAU/mL in non-HCC patients, respectively (p=0.184 and p=0.216). In ALD patients, they were 6.2 ng/mL and 54 mAU/mL in HCC patients and 3.6 ng/mL and 48 mAU/mL in non-HCC patients, respectively (p<0.001 and p=0.456). In other disease patients, they were 9.9 ng/mL and 30 mAU/mL in HCC patients and 3.1 ng/mL and 25 mAU/mL in non-HCC patients, respectively (p<0.001 and p=0.190). A combination of 7.5 ng/mL for AFP cutoff or 40 mAU/mL for PIVKA-II cutoff resulted in sensitivity of 65.7%, specificity of 45.9%, positive predictive value of 56.4%, negative predictive value of 55.7%, and accuracy of 56.1%.
Conclusion
This study indicated that serum AFP and PIVKA-II may be expressed variably regardless of the background liver diseases. Serum PIVKA-II was highly expressed in liver cirrhosis patients with non-viral etiology. Therefore, the values of HCC tumor markers should be cautiously interpreted in liver transplant candidates.

Keyword

Hepatocellular carcinoma; Tumor marker; Tumor biology; Carcinogenesis; Viral hepatitis

Figure

• 

  Figure 1 Comparison of alpha-fetoprotein (AFP) (A) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) (B) levels according to the presence and absence of hepatocellular carcinoma (HCC) in all 3,091 patients. Bars indicate 25–75 percentiles.

• 

  Figure 2 Scatter plots on distribution of alpha-fetoprotein (AFP) and vitamin K absence or antagonist-II (PIVKA-II) values in patients with (A) and without (B) hepatocellular carcinoma (HCC).

• 

  Figure 3 Receiver operating characteristic curve analysis of alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) for diagnosis of hepatocellular carcinoma.

• 

  Figure 4 Comparison of alpha-fetoprotein (AFP) (A) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) (B) levels according to the presence and absence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus-associated liver cirrhosis. Bars indicate 25–75 percentiles. (C) Receiver operating characteristic curve analysis of AFP and PIVKA-II for diagnosis of HCC.

• 

  Figure 5 Comparison of alpha-fetoprotein (AFP) (A) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) (B) levels according to the presence and absence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus-associated liver cirrhosis. Bars indicate 25–75 percentiles. (C) Receiver operating characteristic curve analysis of AFP and PIVKA-II for diagnosis of HCC.

• 

  Figure 6 Comparison of alpha-fetoprotein (AFP) (A) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) (B) levels according to the presence and absence of hepatocellular carcinoma (HCC) in patients with alcoholic liver disease. Bars indicate 25–75 percentiles. (C) Receiver operating characteristic curve analysis of AFP and PIVKA-II for diagnosis of HCC.

• 

  Figure 7 Comparison of alpha-fetoprotein (AFP) (A) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) (B) levels according to the presence and absence of hepatocellular carcinoma (HCC) in patients with other liver diseases. Bars indicate 25-75 percentiles. (C) Receiver operating characteristic curve analysis of AFP and PIVKA-II for diagnosis of HCC.

Reference

1. Ha TY, Hwang S, Kim KH, Lee YJ, Ahn CS, Moon DB, et al. 2014; Expression pattern analysis of hepatocellular carcinoma tumor markers in viral hepatitis B and C patients undergoing liver transplantation and resection. Transplant Proc. 46:888–893. DOI: 10.1016/j.transproceed.2013.12.037. PMID: 24767373.

2. Hwang S, Song GW, Lee YJ, Kim KH, Ahn CS, Moon DB, et al. 2016; Multiplication of tumor volume by two tumor markers is a post-resection prognostic predictor for solitary hepatocellular carcinoma. J Gastrointest Surg. 20:1807–1820. DOI: 10.1007/s11605-016-3187-y. PMID: 27311982.

3. Arrigoni A, Andriulli A, Gindro T, Piantino P, Capussotti L, Rizzetto M. 1988; Pattern analysis of serum alpha-fetoprotein in the early diagnosis of hepatocellular carcinoma in liver cirrhosis. Int J Biol Markers. 3:172–176. DOI: 10.1177/172460088800300305. PMID: 2466093.

4. Tang W, Miki K, Kokudo N, Sugawara Y, Imamura H, Minagawa M, et al. 2003; Des-gamma-carboxy prothrombin in cancer and non-cancer liver tissue of patients with hepatocellular carcinoma. Int J Oncol. 22:969–975. DOI: 10.3892/ijo.22.5.969.

5. Nakamura S, Nouso K, Sakaguchi K, Ito YM, Ohashi Y, Kobayashi Y, et al. 2006; Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size. Am J Gastroenterol. 101:2038–2043. DOI: 10.1111/j.1572-0241.2006.00681.x. PMID: 16848811.

6. Nagaoka S, Yatsuhashi H, Hamada H, Yano K, Matsumoto T, Daikoku M, et al. 2003; The des-gamma-carboxy prothrombin index is a new prognostic indicator for hepatocellular carcinoma. Cancer. 98:2671–2677. DOI: 10.1002/cncr.11839. PMID: 14669288.

7. Sell S. 2008; Alpha-fetoprotein, stem cells and cancer: how study of the production of alpha-fetoprotein during chemical hepatocarcinogenesis led to reaffirmation of the stem cell theory of cancer. Tumour Biol. 29:161–180. DOI: 10.1159/000143402. PMID: 18612221. PMCID: PMC2679671.

8. Tomasi TB Jr. 1977; Structure and function of alpha-fetoprotein. Annu Rev Med. 28:453–465. DOI: 10.1146/annurev.me.28.020177.002321. PMID: 67821.

9. Behne T, Copur MS. 2012; Biomarkers for hepatocellular carcinoma. Int J Hepatol. 2012:859076. DOI: 10.1155/2012/859076. PMID: 22655201. PMCID: PMC3357951.

10. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. 1993; Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med. 328:1797–1801. DOI: 10.1056/NEJM199306243282501. PMID: 7684822.

11. Ryder SD. British Society of Gastroenterology. 2003; Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut. 52 Suppl 3:iii1–iii8. DOI: 10.1136/gut.52.suppl_3.iii1. PMID: 12692148. PMCID: PMC1867754.

12. Sherman M. 2010; The resurrection of alphafetoprotein. J Hepatol. 52:939–940. DOI: 10.1016/j.jhep.2010.02.006. PMID: 20395007.

13. Liu C, Xiao GQ, Yan LN, Li B, Jiang L, Wen TF, et al. 2013; Value of α-fetoprotein in association with clinicopathological features of hepatocellular carcinoma. World J Gastroenterol. 19:1811–1819. DOI: 10.3748/wjg.v19.i11.1811. PMID: 23555170. PMCID: PMC3607758.

14. Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Lee SD, et al. 1984; Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med. 310:1427–1431. DOI: 10.1056/NEJM198405313102204. PMID: 6201741.

15. Kobayashi M, Ikeda K, Kawamura Y, Yatsuji H, Hosaka T, Sezaki H, et al. 2009; High serum des-gamma-carboxy prothrombin level predicts poor prognosis after radiofrequency ablation of hepatocellular carcinoma. Cancer. 115:571–580. DOI: 10.1002/cncr.24031. PMID: 19117347.

16. Zinkin NT, Grall F, Bhaskar K, Otu HH, Spentzos D, Kalmowitz B, et al. 2008; Serum proteomics and biomarkers in hepatocellular carcinoma and chronic liver disease. Clin Cancer Res. 14:470–477. DOI: 10.1158/1078-0432.CCR-07-0586. PMID: 18223221.

17. Sherman M, Peltekian KM, Lee C. 1995; Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology. 22:432–438. DOI: 10.1002/hep.1840220210. PMID: 7543434.

18. Trevisani F, D'Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, et al. 2001; Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol. 34:570–575. DOI: 10.1016/S0168-8278(00)00053-2.

19. Charrière B, Maulat C, Suc B, Muscari F. 2016; Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma. World J Hepatol. 8:881–890. DOI: 10.4254/wjh.v8.i21.881. PMID: 27478538. PMCID: PMC4958698.

20. Ricco G, Cavallone D, Cosma C, Caviglia GP, Oliveri F, Biasiolo A, et al. 2018; Impact of etiology of chronic liver disease on hepatocellular carcinoma biomarkers. Cancer Biomark. 21:603–612. DOI: 10.3233/CBM-170551. PMID: 29278878.

21. Kang KH, Kim JH, Kang SH, Lee BJ, Seo YS, Yim HJ, et al. 2015; The influence of alcoholic liver disease on serum PIVKA-II levels in patients without hepatocellular carcinoma. Gut Liver. 9:224–230. DOI: 10.5009/gnl14047. PMID: 25473073. PMCID: PMC4351030.

22. Cantarini MC, Trevisani F, Morselli-Labate AM, Rapaccini G, Farinati F, Del Poggio P, et al. Italian Liver Cancer (ITA. DOI: 10.1111/j.1572-0241.2006.00364.x. PMID: 16405539.

23. Wands JR. 2004; Prevention of hepatocellular carcinoma. N Engl J Med. 351:1567–1570. DOI: 10.1056/NEJMe048237. PMID: 15470221.

24. Anzola M. 2004; Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis. J Viral Hepat. 11:383–393. DOI: 10.1111/j.1365-2893.2004.00521.x. PMID: 15357643.