Skip to main content
SpringerLink
Log in

Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review

  • ORIGINAL ARTICLE
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background and aims The role of alphafetoprotein (AFP) in the diagnosis and surveillance of hepatocellular carcinoma (HCC) is getting smaller owing to the advances in imaging modalities. The aims of this study were to assess the diagnostic accuracy of tumor markers in small HCC and to find the optimal cutoff value of each tumor marker for efficient surveillance. Methods Studies in all languages were identified by searching MEDLINE from 1982 to 2002. Studies were included when they showed sensitivity and specificity for HCCs 5 cm or smaller and recruited only patients with chronic hepatitis or liver cirrhosis as control. We assessed diagnostic odds ratios (DORs) for the evaluation of diagnostic accuracy of tumor markers and positive likelihood ratios (LRs+) to find the optimal cutoff value. DORs and LRs+ were combined according to the random effect model. The summary receiver operating characteristics (ROC) curve was also assessed. Results Seventeen articles on three tumor markers—AFP, des-gamma-carboxyprothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3)—were enrolled after full-text evaluation. AFP was inferior to DCP and AFP-L3 in both DOR (4.50 vs. 8.16 and 10.50) and area under the ROC curve (0.647 vs. 0.688 and 0.695). Optimal cutoff values that provide the best LR+ were 200 ng/ml for AFP, 40 mAU/ml for DCP, and 15% for AFP-L3. Conclusions Diagnostic accuracy of AFP in small HCC was substantially limited. Surveillance including other tumor markers with optimal cutoff value should be conducted to confirm the efficacy of the policy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AFP:

Alphafetoprotein

AFP-L3:

Lens culinaris agglutinin-reactive fraction of AFP

AUC:

Area under the curve

CI:

Confidence interval

DCP:

Des-gamma-carboxyprothrombin

DOR:

Diagnostic odds ratio

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

LR+:

Positive likelihood ratio

ROC:

Receiver operating characteristics

SE:

Standard error

References

  1. Di Bisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM, Lotze MT. NIH conference. Hepatocellular carcinoma. Ann Intern Med 1988;108:390–401.

    PubMed  CAS  Google Scholar 

  2. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–50.

    Article  PubMed  CAS  Google Scholar 

  3. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127:S5–S16.

    Article  PubMed  Google Scholar 

  4. Blumberg BS, Larouze B, London WT, Werner B, Hesser JE, Millman I, et al. The relation of infection with the hepatitis B agent to primary hepatic carcinoma. Am J Pathol 1975;81:669–82.

    PubMed  CAS  Google Scholar 

  5. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797–801.

    Article  PubMed  CAS  Google Scholar 

  6. Shiratori Y, Shiina S, Imamura M, Kato N, Kanai F, Okudaira T, et al. Characteristic difference of hepatocellular carcinoma between hepatitis B- and C- viral infection in Japan. Hepatology 1995;22:1027–33.

    PubMed  CAS  Google Scholar 

  7. Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al., for the EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. Hepatology 1995;21:77–82.

    Google Scholar 

  8. Kato Y, Nakata K, Omagari K, Furukawa R, Kusumoto Y, Mori I, et al. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses. Cancer 1994;74:2234–8.

    Article  PubMed  CAS  Google Scholar 

  9. Cottone M, Turri M, Caltagirone M, Parisi P, Orlando A, Fiorentino G, et al. Screening for hepatocellular carcinoma in patients with Child’s A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein. J Hepatol 1994;21:1029–34.

    Article  PubMed  CAS  Google Scholar 

  10. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al., for the IHIT (Inhibition of Hepatocarcinogenesis by Interferon Therapy) Study Group. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med 1999;131:174–81.

    Google Scholar 

  11. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997;112:463–72.

    Article  PubMed  CAS  Google Scholar 

  12. Torzilli G, Minagawa M, Takayama T, Inoue K, Hui AM, Kubota K, et al. Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology 1999;30:889–93.

    Article  PubMed  CAS  Google Scholar 

  13. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36.

    Article  PubMed  Google Scholar 

  14. Kew MC. Alpha-fetoprotein. In: Read AE, editor. Modern trends in gastroenterology. London: Butterworths; 1975. p. 91.

    Google Scholar 

  15. Sherman M, Peltekian KM, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995;22:432–8.

    PubMed  CAS  Google Scholar 

  16. Bloomer JR, Waldmann TA, McIntire KR, Klatskin G. Alpha-fetoprotein in noneoplastic hepatic disorders. JAMA 1975;233:38–41.

    Article  PubMed  CAS  Google Scholar 

  17. Alpert E, Feller ER. Alpha-fetoprotein (AFP) in benign liver disease. Evidence that normal liver regeneration does not induce AFP synthesis. Gastroenterology 1978;74:856–8.

    PubMed  CAS  Google Scholar 

  18. Liebman HA, Furie BC, Tong MJ, Blanchard RA, Lo KJ, Lee SD, et al. Des-gamma-carboxy (abnormal) prothrombin as a serum marker of primary hepatocellular carcinoma. N Engl J Med 1984;310:1427–31.

    Article  PubMed  CAS  Google Scholar 

  19. Okuda H, Obata H, Nakanishi T, Furukawa R, Hashimoto E. Production of abnormal prothrombin (des-gamma-carboxy prothrombin) by hepatocellular carcinoma. A clinical and experimental study. J Hepatol 1987;4:357–63.

    Article  PubMed  CAS  Google Scholar 

  20. Aoyagi Y, Isemura M, Yosizawa Z, Suzuki Y, Sekine C, Ono T, et al. Fucosylation of serum alpha-fetoprotein in patients with primary hepatocellular carcinoma. Biochim Biophys Acta 1985;830:217–23.

    PubMed  CAS  Google Scholar 

  21. Sato Y, Nakata K, Kato Y, Shima M, Ishii N, Koji T, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med 1993;328:1802–6.

    Article  PubMed  CAS  Google Scholar 

  22. Izzo F, Cremona F, Delrio P, Leonardi E, Castello G, Pignata S, et al. Soluble interleukin-2 receptor levels in hepatocellular cancer: a more sensitive marker than alfa fetoprotein. Ann Surg Oncol 1999;6:178–85.

    Article  PubMed  CAS  Google Scholar 

  23. Sacco R, Leuci D, Tortorella C, Fiore G, Marinosci F, Schiraldi O, et al. Transforming growth factor beta1 and soluble Fas serum levels in hepatocellular carcinoma. Cytokine 2000;12:811–4.

    Article  PubMed  CAS  Google Scholar 

  24. Kakumu S, Ito S, Ishikawa T, Mita Y, Tagaya T, Fukuzawa Y, et al. Decreased function of peripheral blood dendritic cells in patients with hepatocellular carcinoma with hepatitis B and C virus infection. J Gastroenterol Hepatol 2000;15:431–6.

    Article  PubMed  CAS  Google Scholar 

  25. Irwig L, Tosteson AN, Gatsonis C, Lau J, Colditz G, Chalmers TC, et al. Guidelines for meta-analyses evaluating diagnostic tests. Ann Intern Med 1994;120:667–76.

    PubMed  CAS  Google Scholar 

  26. Irwig L, Macaskill P, Glasziou P, Fahey M. Meta-analytic methods for diagnostic test accuracy. J Clin Epidemiol 1995; 48:119–30; discussion 31–2.

    Google Scholar 

  27. Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med 1993;12:1293–316.

    PubMed  CAS  Google Scholar 

  28. Walter SD. Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med 2002;21:1237–56.

    Article  PubMed  CAS  Google Scholar 

  29. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34.

    PubMed  CAS  Google Scholar 

  30. Jaeschke R, Guyatt G, Lijimer J. Diagnostic tests. In: Guyatt G, Rennie D, editors. User’s guide to the medical literature. Chicago: AMA Press; 2002. p. 121–40.

    Google Scholar 

  31. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.

    Article  PubMed  CAS  Google Scholar 

  32. Zarmora J, Abraira V, Muriel A, Khan KS, Coomarasamy A. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol 2006;6:31

    Google Scholar 

  33. Gebo KA, Chander G, Jenckes MW, Ghanem KG, Herlong HF, Torbenson MS, et al. Screening tests for hepatocellular carcinoma in patients with chronic hepatitis C: a systematic review. Hepatology 2002;36:S84–92.

    Article  PubMed  Google Scholar 

  34. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Ann Intern Med 2003;139:46–50.

    PubMed  CAS  Google Scholar 

  35. Fujiyama S, Izuno K, Yamasaki K, Sato T, Taketa K. Determination of optimum cutoff levels of plasma des-gamma-carboxy prothrombin and serum alpha-fetoprotein for the diagnosis of hepatocellular carcinoma using receiver operating characteristic curves. Tumour Biol 1992;13:316–23.

    PubMed  CAS  Google Scholar 

  36. Tong MJ, Blatt LM, Kao VW. Surveillance for hepatocellular carcinoma in patients with chronic viral hepatitis in the United States of America. J Gastroenterol Hepatol 2001;16:553–9.

    Article  PubMed  CAS  Google Scholar 

  37. Pateron D, Ganne N, Trinchet JC, Aurousseau MH, Mal F, Meicler C, et al. Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 1994;20:65–71.

    Article  PubMed  CAS  Google Scholar 

  38. Piantino P, Arrigoni A, Brunetto MR, Gindro T. Alpha-fetoprotein in hepatic pathology and hepatocarcinoma. J Nucl Med Allied Sci 1989;33:34–8.

    PubMed  CAS  Google Scholar 

  39. Khien VV, Mao HV, Chinh TT, Ha PT, Bang MH, Lac BV, et al. Clinical evaluation of lentil lectin-reactive alpha-fetoprotein-L3 in histology-proven hepatocellular carcinoma. Int J Biol Markers 2001;16:105–11.

    PubMed  CAS  Google Scholar 

  40. Trevisani F, D’Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001;34:570–5.

    Article  PubMed  CAS  Google Scholar 

  41. McMahon BJ, Bulkow L, Harpster A, Snowball M, Lanier A, Sacco F, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 2000;32:842–6.

    Article  PubMed  CAS  Google Scholar 

  42. Peng YC, Chan CS, Chen GH. The effectiveness of serum alpha-fetoprotein level in anti-HCV positive patients for screening hepatocellular carcinoma. Hepatogastroenterology 1999;46:3208–11.

    PubMed  CAS  Google Scholar 

  43. Kuromatsu R, Tanaka M, Shimauchi Y, Shimada M, Tanikawa K, Watanabe K, et al. Usefulness of ED036 kit for measuring serum PIVKA-II levels in small hepatocellular carcinoma. J Gastroenterol 1997;32:507–12.

    Article  PubMed  CAS  Google Scholar 

  44. Furui J, Furukawa M, Kanematsu T. The low positive rate of serum alpha-fetoprotein levels in hepatitis C virus antibody-positive patients with hepatocellular carcinoma. Hepatogastroenterology 1995;42:445–9.

    PubMed  CAS  Google Scholar 

  45. Grazi GL, Mazziotti A, Legnani C, Jovine E, Miniero R, Gallucci A, et al. The role of tumor markers in the diagnosis of hepatocellular carcinoma, with special reference to the des-gamma-carboxy prothrombin. Liver Transpl Surg 1995;1:249–55.

    Article  PubMed  CAS  Google Scholar 

  46. Tsai JF, Chang WY, Jeng JE, Ho MS, Lin ZY, Tsai JH. Frequency of raised alpha-fetoprotein level among Chinese patients with hepatocellular carcinoma related to hepatitis B and C. Br J Cancer 1994;69:1157–9.

    PubMed  CAS  Google Scholar 

  47. Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S. Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 1994;19:61–6.

    PubMed  CAS  Google Scholar 

  48. Tu Z, Yin Z, Wu M. Prospective study on the diagnosis of hepatocellular carcinoma by using alpha-fetoprotein reactive to lentil lectin. Chin Med Sci J 1992;7:191–6.

    PubMed  CAS  Google Scholar 

  49. Taketa K, Sekiya C, Namiki M, Akamatsu K, Ohta Y, Endo Y, et al. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology 1990;99:508–18.

    PubMed  CAS  Google Scholar 

  50. Deyashiki Y, Nishioka Y, Takahashi K, Kosaka Y, Suzuki K. Evaluation of des-gamma-carboxy prothrombin as a marker protein of hepatocellular carcinoma. Cancer 1989;64:2546–51.

    Article  PubMed  CAS  Google Scholar 

  51. King MA, Kew MC, Kuyl JM, Atkinson PM. A comparison between des-gamma-carboxy prothrombin and alpha-fetoprotein as markers of hepatocellular carcinoma in southern African blacks. J Gastroenterol Hepatol 1989;4:17–24.

    PubMed  CAS  Google Scholar 

  52. Aoyagi Y, Suzuki Y, Isemura M, Nomoto M, Sekine C, Igarashi K, et al. The fucosylation index of alpha-fetoprotein and its usefulness in the early diagnosis of hepatocellular carcinoma. Cancer 1988;61:769–74.

    Article  PubMed  CAS  Google Scholar 

  53. Chan DW, Kelsten M, Rock R, Bruzek D. Evaluation of a monoclonal immunoenzymometric assay for alpha-fetoprotein. Clin Chem 1986;32:1318–22.

    PubMed  CAS  Google Scholar 

  54. Saitoh S, Ikeda K, Koida I, Suzuki Y, Kobayashi M, Tsubota A, et al. Diagnosis of hepatocellular carcinoma by concanavalin A affinity electrophoresis of serum alpha-fetoprotein. Cancer 1995;76:1139–44.

    Article  PubMed  CAS  Google Scholar 

  55. Chalasani N, Horlander JC Sr, Said A, Hoen H, Kopecky KK, Stockberger SM Jr, et al. Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol 1999;94:2988–93.

    Article  PubMed  CAS  Google Scholar 

  56. Izzo F, Cremona F, Ruffolo F, Palaia R, Parisi V, Curley SA. Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis. Ann Surg 1998;227:513–8.

    Article  PubMed  CAS  Google Scholar 

  57. Cedrone A, Covino M, Caturelli E, Pompili M, Lorenzelli G, Villani MR, et al. Utility of alpha-fetoprotein (AFP) in the screening of patients with virus-related chronic liver disease: does different viral etiology influence AFP levels in HCC? A study in 350 western patients. Hepatogastroenterology 2000;47:1654–8.

    PubMed  CAS  Google Scholar 

  58. Nguyen MH, Garcia RT, Simpson PW, Wright TL, Keeffe EB. Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis. Hepatology 2002;36:410–7.

    Article  PubMed  CAS  Google Scholar 

  59. Larcos G, Sorokopud H, Berry G, Farrell GC. Sonographic screening for hepatocellular carcinoma in patients with chronic hepatitis or cirrhosis: an evaluation. Am J Roentgenol 1998;171:433–5.

    CAS  Google Scholar 

  60. Tsai JF, Jeng JE, Ho MS, Chang WY, Lin ZY, Tsai JH. Clinical evaluation of serum alpha-fetoprotein and circulating immune complexes as tumour markers of hepatocellular carcinoma. Br J Cancer 1995;72:442–6.

    PubMed  CAS  Google Scholar 

  61. Izzo F, Cremona F, Ruffolo F, Palaia R, Parisi V, Curley S. Detection of hepatocellular cancer during screening of 1125 patients with chronic hepatitis virus infection. J Chemother 1997;9:151–2.

    PubMed  CAS  Google Scholar 

  62. Curley SA, Izzo F, Gallipoli A, de Bellis M, Cremona F, Parisi V. Identification and screening of 416 patients with chronic hepatitis at high risk to develop hepatocellular cancer. Ann Surg 1995;222:375–80; discussion 80–3

    Google Scholar 

  63. Gambarin-Gelwan M, Wolf DC, Shapiro R, Schwartz ME, Min AD. Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation. Am J Gastroenterol 2000;95:1535–8.

    Article  PubMed  CAS  Google Scholar 

  64. Izuno K, Fujiyama S, Yamasaki K, Sato M, Sato T. Early detection of hepatocellular carcinoma associated with cirrhosis by combined assay of des-gamma-carboxy prothrombin and alpha-fetoprotein: a prospective study. Hepatogastroenterology 1995;42:387–93.

    PubMed  CAS  Google Scholar 

  65. Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47–53.

    PubMed  CAS  Google Scholar 

  66. Tradati F, Colombo M, Mannucci PM, Rumi MG, De Fazio C, Gamba G, et al., for the Study Group of the Association of Italian Hemophilia Centers. A prospective multicenter study of hepatocellular carcinoma in Italian hemophiliacs with chronic hepatitis C. Blood 1998;91:1173–7.

    Google Scholar 

  67. Solmi L, Primerano AM, Gandolfi L. Ultrasound follow-up of patients at risk for hepatocellular carcinoma: results of a prospective study on 360 cases. Am J Gastroenterol 1996;91:1189–94.

    PubMed  CAS  Google Scholar 

  68. Cottone M, Turri M, Caltagirone M, Parisi P, Orlando A, Fiorentino G, et al. Screening for hepatocellular carcinoma in patients with Child’s A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein. J Hepatol 1994;21:1029–34.

    Article  PubMed  CAS  Google Scholar 

  69. Fujiyama S, Morishita T, Hashiguchi O, Sato T. Plasma abnormal prothrombin (des-gamma-carboxy prothrombin) as a marker of hepatocellular carcinoma. Cancer 1988;61:1621–8.

    Article  PubMed  CAS  Google Scholar 

  70. Ikoma J, Kaito M, Ishihara T, Nakagawa N, Kamei A, Fujita N, et al. Early diagnosis of hepatocellular carcinoma using a sensitive assay for serum des-gamma-carboxy prothrombin: a prospective study. Hepatogastroenterology 2002;49:235–8.

    PubMed  CAS  Google Scholar 

  71. Kasahara A, Hayashi N, Fusamoto H, Kawada Y, Imai Y, Yamamoto H, et al. Clinical evaluation of plasma des-gamma-carboxy prothrombin as a marker protein of hepatocellular carcinoma in patients with tumors of various sizes. Dig Dis Sci 1993;38:2170–6.

    Article  PubMed  CAS  Google Scholar 

  72. Maringhini A, Cottone M, Sciarrino E, Marceno MP, La Seta F, Fusco G, et al. Ultrasonography and alpha-fetoprotein in diagnosis of hepatocellular carcinoma in cirrhosis. Dig Dis Sci 1988;33:47–51.

    Article  PubMed  CAS  Google Scholar 

  73. Mita Y, Aoyagi Y, Yanagi M, Suda T, Suzuki Y, Asakura H. The usefulness of determining des-gamma-carboxy prothrombin by sensitive enzyme immunoassay in the early diagnosis of patients with hepatocellular carcinoma. Cancer 1998;82:1643–8.

    Article  PubMed  CAS  Google Scholar 

  74. Nomura F, Ishijima M, Horikoshi A, Nakai T, Ohnishi K. Determination of serum des-gamma-carboxy prothrombin levels in patients with small-sized hepatocellular carcinoma: comparison of the conventional enzyme immunoassay and two modified methods. Am J Gastroenterol 1996;91:1380–3.

    PubMed  CAS  Google Scholar 

  75. Nomura F, Ishijima M, Kuwa K, Tanaka N, Nakai T, Ohnishi K. Serum des-gamma-carboxy prothrombin levels determined by a new generation of sensitive immunoassays in patients with small-sized hepatocellular carcinoma. Am J Gastroenterol 1999;94:650–4.

    Article  PubMed  CAS  Google Scholar 

  76. Oka H, Saito A, Ito K, Kumada T, Satomura S, Kasugai H, et al. Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of lens culinaris agglutinin-reactive alpha-fetoprotein. J Gastroenterol Hepatol 2001;16:1378–83.

    Article  PubMed  CAS  Google Scholar 

  77. Sassa T, Kumada T, Nakano S, Uematsu T. Clinical utility of simultaneous measurement of serum high-sensitivity des-gamma-carboxy prothrombin and lens culinaris agglutinin A-reactive alpha-fetoprotein in patients with small hepatocellular carcinoma. Eur J Gastroenterol Hepatol 1999;11:1387–92.

    Article  PubMed  CAS  Google Scholar 

  78. Saitoh S, Ikeda K, Koida I, Tsubota A, Arase Y, Chayama K, et al. Serum des-gamma-carboxyprothrombin concentration determined by the avidin–biotin complex method in small hepatocellular carcinomas. Cancer 1994;74:2918–23.

    Article  PubMed  CAS  Google Scholar 

  79. Shimauchi Y, Tanaka M, Kuromatsu R, Ogata R, Tateishi Y, Itano S, et al. A simultaneous monitoring of lens culinaris agglutinin A-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin as an early diagnosis of hepatocellular carcinoma in the follow-up of cirrhotic patients. Oncol Rep 2000;7:249–56.

    PubMed  CAS  Google Scholar 

  80. Shiraki K, Takase K, Tameda Y, Hamada M, Kosaka Y, Nakano T. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 1995;22:802–7.

    PubMed  CAS  Google Scholar 

  81. Suehiro T, Sugimachi K, Matsumata T, Itasaka H, Taketomi A, Maeda T. Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma. Comparison with alpha-fetoprotein. Cancer 1994;73:2464–71.

    Article  PubMed  CAS  Google Scholar 

  82. Taketa K, Endo Y, Sekiya C, Tanikawa K, Koji T, Taga H, et al. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma. Cancer Res 1993;53:5419–23.

    PubMed  CAS  Google Scholar 

  83. Tanabe Y, Ohnishi K, Nomura F, Iida S. Plasma abnormal prothrombin levels in patients with small hepatocellular carcinoma. Am J Gastroenterol 1988;83:1386–9.

    PubMed  CAS  Google Scholar 

  84. Tsai SL, Huang GT, Yang PM, Sheu JC, Sung JL, Chen DS. Plasma des-gamma-carboxyprothrombin in the early stage of hepatocellular carcinoma. Hepatology 1990;11:481–8.

    Article  PubMed  CAS  Google Scholar 

  85. Giannini E, Arzani L, Borro P, Botta F, Fasoli A, Risso D, et al. Does surveillance for hepatocellular carcinoma in HCV cirrhotic patients improve treatment outcome mainly due to better clinical status at diagnosis? Hepatogastroenterology 2000;47:1395–8.

    PubMed  CAS  Google Scholar 

  86. Koike Y, Shiratori Y, Sato S, Obi S, Teratani T, Imamura M, et al. Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients. Cancer 2001;91:561–9.

    Article  PubMed  CAS  Google Scholar 

  87. Imamura H, Matsuyama Y, Miyagawa Y, Ishida K, Shimada R, Miyagawa S, et al. Prognostic significance of anatomical resection and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg 1999;86:1032–8.

    Article  PubMed  CAS  Google Scholar 

  88. Begg CB, Berlin JA. Publication bias and dissemination of clinical research. J Natl Cancer Inst 1989;81:107–15.

    Article  PubMed  CAS  Google Scholar 

  89. Lijmer JG, Mol BW, Heisterkamp S, Bonsel GJ, Prins MH, van der Meulen JH, et al. Empirical evidence of design-related bias in studies of diagnostic tests. JAMA 1999;282:1061–6.

    Article  PubMed  CAS  Google Scholar 

  90. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: The STARD Initiative. Ann Intern Med 2003;138:40–4.

    PubMed  Google Scholar 

  91. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med 2003;138:W1–12.

    PubMed  Google Scholar 

  92. Lok AS, Lai CL. Alpha-fetoprotein monitoring in Chinese patients with chronic hepatitis B virus infection: role in the early detection of hepatocellular carcinoma. Hepatology 1989;9:110–5.

    Article  PubMed  CAS  Google Scholar 

  93. The Study Group for Evidence Based Guideline for the Diagnosis and Treatment of Hepatocellular Carcinoma. Evidence based guideline for the diagnosis and treatment of hepatocellular carcinoma. Tokyo: Kanehara & Co; 2005.

Download references

Acknowledgment

The authors thank Hiromichi Suzuki and Ayami Nishioka at the International Medical Information Center for technical support in article searching and managing the reference database.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Ryosuke Tateishi, Haruhiko Yoshida, Norio Mine, Yuji Kondo & Masao Omata

  2. Department of Biostatistics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Yutaka Matsuyama

Authors
  1. Ryosuke Tateishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruhiko Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yutaka Matsuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norio Mine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuji Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masao Omata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryosuke Tateishi.

Additional information

This study was supported by the Ministry of Health, Labour and Welfare in Japan (H14-Iryo-032).

Appendix

Appendix

Fig. A1
figure 5

Funnel plots of DOR of AFP (a), DCP (b), and AFP-L3 (c). Inverse of standard error of natural logarithm of the odds ratio against natural logarithm of the DOR is plotted. The area of the circle is proportional to the inverse of standard error of natural logarithm of the odds ratio. AFP, alphafetoprotein; AFP-L3, Lens culinaris agglutinin-reactive fraction of AFP; DCP, des-gamma-carboxyprothrombin; DOR, diagnostic odds ratio

Full size image
Appendix 1 Primary research
Full size table
Appendix 2 Secondary research
Full size table

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tateishi, R., Yoshida, H., Matsuyama, Y. et al. Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review. Hepatol Int 2, 17–30 (2008). https://doi.org/10.1007/s12072-007-9038-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-007-9038-x

Keywords

Search

Navigation