Hepatology International

, Volume 2, Issue 1, pp 17–30 | Cite as

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

  • Ryosuke TateishiEmail author
  • Haruhiko Yoshida
  • Yutaka Matsuyama
  • Norio Mine
  • Yuji Kondo
  • Masao Omata


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.


Hepatocellular carcinoma Alphafetoprotein Des-gamma-carboxyprothrombin Lens culinaris agglutinin-reactive fraction of alphafetoprotein Metaanalysis 





Lens culinaris agglutinin-reactive fraction of AFP


Area under the curve


Confidence interval




Diagnostic odds ratio


Hepatitis B virus


Hepatocellular carcinoma


Hepatitis C virus


Positive likelihood ratio


Receiver operating characteristics


Standard error



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.


  1. 1.
    Di Bisceglie AM, Rustgi VK, Hoofnagle JH, Dusheiko GM, Lotze MT. NIH conference. Hepatocellular carcinoma. Ann Intern Med 1988;108:390–401.PubMedGoogle Scholar
  2. 2.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–50.PubMedCrossRefGoogle Scholar
  3. 3.
    Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127:S5–S16.PubMedCrossRefGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 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. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 13.
    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36.PubMedCrossRefGoogle Scholar
  14. 14.
    Kew MC. Alpha-fetoprotein. In: Read AE, editor. Modern trends in gastroenterology. London: Butterworths; 1975. p. 91.Google Scholar
  15. 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.PubMedGoogle Scholar
  16. 16.
    Bloomer JR, Waldmann TA, McIntire KR, Klatskin G. Alpha-fetoprotein in noneoplastic hepatic disorders. JAMA 1975;233:38–41.PubMedCrossRefGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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. 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.PubMedGoogle Scholar
  28. 28.
    Walter SD. Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med 2002;21:1237–56.PubMedCrossRefGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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. 31.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88.PubMedCrossRefGoogle Scholar
  32. 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;6:31Google Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 53.
    Chan DW, Kelsten M, Rock R, Bruzek D. Evaluation of a monoclonal immunoenzymometric assay for alpha-fetoprotein. Clin Chem 1986;32:1318–22.PubMedGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.PubMedGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.Google Scholar
  60. 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.PubMedGoogle Scholar
  61. 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.PubMedGoogle Scholar
  62. 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 80–3Google Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.PubMedGoogle Scholar
  66. 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. 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.PubMedGoogle Scholar
  68. 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.PubMedCrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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.PubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 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.PubMedCrossRefGoogle Scholar
  77. 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.PubMedCrossRefGoogle Scholar
  78. 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.PubMedCrossRefGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 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.PubMedGoogle Scholar
  81. 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.PubMedCrossRefGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 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.PubMedGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 88.
    Begg CB, Berlin JA. Publication bias and dissemination of clinical research. J Natl Cancer Inst 1989;81:107–15.PubMedCrossRefGoogle Scholar
  89. 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.PubMedCrossRefGoogle Scholar
  90. 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.PubMedGoogle Scholar
  91. 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.PubMedGoogle Scholar
  92. 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.PubMedCrossRefGoogle Scholar
  93. 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.Google Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2007

Authors and Affiliations

  • Ryosuke Tateishi
    • 1
    Email author
  • Haruhiko Yoshida
    • 1
  • Yutaka Matsuyama
    • 2
  • Norio Mine
    • 1
  • Yuji Kondo
    • 1
  • Masao Omata
    • 1
  1. 1.Department of Gastroenterology, Graduate School of MedicineUniversity of TokyoTokyoJapan
  2. 2.Department of Biostatistics, Graduate School of MedicineUniversity of TokyoTokyoJapan

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