Digestive Diseases and Sciences

, Volume 40, Issue 12, pp 2587–2594 | Cite as

α-fetoprotein and p53 autoantibodies in patients with chronic hepatitis C

  • Jochen Readle
  • W. Kurt Roth
  • Gerhard Oremek
  • Wolfgang F. Caspary
  • Stefan Zeuzem
Liver: Infectious, Inflammatory, and Metabolic Disorders


Hepatitis C virus infection is a common cause of chronic liver disease and hepatocellular carcinoma. Recently, mutations in the p53 tumor suppressor gene with generation of circulating autoantibodies to p53 protein have been detected in a significant proportion of patients with different malignancies. Using ELISA methods we assessed α-fetoprotein and anti-p53 as serological screening parameters for hepatocellular carcinoma in 147 consecutive patients with chronic hepatitis C. Liver cirrhosis was histologically diagnosed in 58 patients (39.5%) and a hepatocellular carcinoma confirmed in seven patients (4.8%). Serum α-fetoprotein was raised above 20 ng/ml in 26/147 patients and above 100 ng/ml in 5/147 patients. In 6/7 patients with hepatocellular carcinoma, α-fetoprotein was raised above 20 ng/ml, but only in 3/7 cases above 100 ng/ml, resulting in a sensitivity and specificity of 85.7% and 85.7% (α-fetoprotein>20 ng/ml) and 42.9% and 98.6% (α-fetoprotein>100 ng/ml), for the detection of hepatocellular carcinoma, respectively. Autoantibodies to p53 were detected in 3/7 patients with hepatocellular carcinoma, but in 0/140 patients without malignancy (sensitivity 42.9%, specificity 100%). Screening for hepatocellular carcinoma was improved by combining α-fetoprotein measurement (level>100 ng/ml) with detection for anti-p53 (sensitivity 71.4%, specificity 98.6%). In conclusion, the presence of anti-p53 was highly specific for malignancy and independent of α-fetoprotein status. Further studies including a larger number of patients with hepatitis C virus-related hepatocellular carcinoma are required to investigate whether serological testing for anti-p53 in combination with α-fetoprotein might improve the detection of hepatocellular carcinoma in high-risk patients with liver cirrhosis.

Key Words

Hepatitis C virus chronic hepatitis C hepatocellular carcinoma tumor screening α-fetoprotein anti-p53 autoantibodies 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kurstak E: Hepatitis C and hepatitis E viruses: Epidemiology and transmission.In Viral Hepatitis. Current Status and Issues. E Kurstak (ed). Wien, Springer-Verlag, 1993, pp 181–184Google Scholar
  2. 2.
    Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H, Kawanishi M: A multivariate analysis of risk factors for hepatocellular carcinogenesis: A prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18:47–53, 1993Google Scholar
  3. 3.
    Liang TJ, Jeffers LJ, Reddy KR, De Medina M, Parker IT, Cheinquer H, Idrovo V, Rabassa A, Schiff ER: Viral pathogenesis of hepatocellular carcinoma in the United States. Hepatology 18:1326–1333, 1993Google Scholar
  4. 4.
    Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, Kawashima T: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328:1797–1801, 1993Google Scholar
  5. 5.
    Imberti D, Fornari F, Sbolli G, Buscarini E, Squassante L, Buscarini L: Hepatocellular carcinoma in liver cirrhosis. A prospective study. Scand J Gastroenterol 28:540–544, 1993Google Scholar
  6. 6.
    Bruix J, Calvet X, Costa J, Ventura M, Bruguera M, Castillo R, Barrera JM, Ercilla G, Sanchez-Tapias JM, Vall M, Bru C, Rodes J: Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 28:1004–1006, 1989Google Scholar
  7. 7.
    Colombo M, Rumi MG, Donato MF, Tommasini MA, Del Ninno E, Ronchi G, Kuo G, Houghton M: Hepatitis C antibody in patients with chronic liver disease and hepatocellular carcinoma. Dig Dis Sci 36: 1130–1133, 1991Google Scholar
  8. 8.
    Lee SD, Lee FY, Wu JC, Hwang SJ, Wang SS, Lo KJ: The prevalence of anti-hepatitis C virus among Chinese patients with hepatocellular carcinoma. Cancer 69:342–345, 1992Google Scholar
  9. 9.
    Tanaka K, Hirohata T, Koga S, Sugimachi K, Kanematsu T, Ohryohji F, Nawata H, Ishibashi H, Maeda Y, Kiyokawa H, Tokunaga K, Irita Y, Takeshita S, Arase Y, Nishino N: Hepatitis C and hepatitis B in the etiology of hepatocellular carcinoma in the Japanese population. Cancer Res 51:2842–2847, 1991Google Scholar
  10. 10.
    Colombo M, De Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, Donato MF, Piva A, Di Carlo V, Dioguardi N: Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 325:675–680, 1991Google Scholar
  11. 11.
    Munoz N, Bosch FX: Epidemiology of hepatocellular carcinoma.In Neoplasms of the Liver. K Okuda, KG Ishak (eds). Tokyo, Springer-Verlag, 1987, pp 3–19Google Scholar
  12. 12.
    Cottone M, Turri M, Caltagirone M, Maringhini A, Sciarrino E, Virdone R, Fusco G, Orlando A, Marino L, Pagliaro L: Early detection of hepatocellular carcinoma associated with cirrhosis by ultrasound and α-fetoprotein: A prospective study. Hepatogastroenterology 35:101–103, 1988Google Scholar
  13. 13.
    Okuda K: Early recognition of hepatocellular carcinoma. Hepatology 6:729–738, 1986Google Scholar
  14. 14.
    Ikeda K, Saitoh S, Koida I, Tsubota A, Arase Y, Chayama K, Kumada H: Imaging diagnosis of small hepatocellular carcinoma. Hepatology 20:82–87, 1994Google Scholar
  15. 15.
    Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S: Prospective study of α-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 19:61–66, 1994Google Scholar
  16. 16.
    Sato Y, Nakata K, Kato Y, Shima M, Ishii N, Koji T, Taketa K, Endo Y, Nagataki S: Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med 328:1802–1806, 1993Google Scholar
  17. 17.
    Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329:1318–1327, 1993Google Scholar
  18. 18.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 253:49–53, 1991Google Scholar
  19. 19.
    Levine AJ, Momand J, Finlay CA: The p53 tumour suppressor gene. Nature 351:453–456, 1991Google Scholar
  20. 20.
    Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K: Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res 53:2884–2887, 1993Google Scholar
  21. 21.
    Teramoto T, Satonaka K, Kitazawa S, Fujimori T, Hayashi K, Maeda S: p53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res 54:231–235, 1994Google Scholar
  22. 22.
    Volkmann M, Hofmann WJ, Müller M, Räth U, Otto G, Zentgraf H, Galle PR: p53 overexpression is frequent in European hepatocellular carcinoma and largely independent of the codon 249 hot spot mutation. Oncogene 9:195–204, 1994Google Scholar
  23. 23.
    Collier JD, Carpenter M, Burt AD, Bassendine MF: Expression of mutant p53 protein in hepatocellular carcinoma. Gut 35:98–100, 1994Google Scholar
  24. 24.
    Laurent-Puig P, Flejou JF, Fabre M, Bedossa P, Belghiti J, Gayral F, Franco D: Overexpression of p53: A rare event in a large series of white patients with hepatocellular carcinoma. Hepatology 16:1171–1175, 1992Google Scholar
  25. 25.
    Bourdon JC, D'Errico A, Paterlini P, Grigioni W, May E, Debuire B: p53 protein accumulation in European hepatocellular carcinoma is not always dependent on p53 gene mutation. Gastroenterology 108:1176–1182, 1995Google Scholar
  26. 26.
    Crawford LV, Pim DC, Bulbrook RD: Detection of antibodies against the cellular protein p53 in sera from patients with breast cancer. Int J Cancer 30:403–408, 1982Google Scholar
  27. 27.
    Legros Y, Meyer A, Ory K, Soussi T: Mutations in p53 produce a common conformational effect that can be detected with a panel of monoclonal antibodies directed toward the central part of the p53 protein. Oncogene 9:3689–3694, 1994Google Scholar
  28. 28.
    Volkmann M, Müller M, Hofmann WJ, Meyer M, Hagelstein J, Räth U, Kommerell B, Zentgraf H, Galle PR: The humoral immune response to p53 in patients with hepatocellular carcinoma is specific for malignancy and independent of the α-fetoprotein status. Hepatology 18:559–565, 1993Google Scholar
  29. 29.
    Winter SF, Minna JD, Johnson BE, Takahashi T, Gazdar AF, Carbone DP: Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation. Cancer Res 52:4168–4174, 1992Google Scholar
  30. 30.
    Bukh J, Purcell RH, Miller RH: Importance of primer selection for the detection of hepatitis C virus RNA with polymerase chain reaction assay. Proc Natl Acad Sci USA 89:187–189, 1992Google Scholar
  31. 31.
    Zeuzem S, Rüster B, Roth WK: Clinical evaluation of a new polymerase chain reaction assay (AmplicorTM HCV) for detection of hepatitis C virus. Z Gastroenterol 32:342–347, 1994Google Scholar
  32. 32.
    Nomura F, Ohnishi K, Tanabe Y: Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels. Cancer 64:1700–1707, 1989Google Scholar
  33. 33.
    Kondo F, Wada K, Nagato Y, Nakajima T, Kondo Y, Hirooka N, Ebara M, Ohto M, Okuda K: Biopsy diagnosis of well-differentiated hepatocellular carcinoma based on new morphologic criteria. Hepatology 9:751–755, 1989Google Scholar
  34. 34.
    Peng SY, Lai PL, Chu JS, Lee PH, Tsung PT, Chen DS, Hsu HC: Expression and hypomethylation of α-fetoprotein gene in unicentric and multicentric human hepatocellular carcinoma. Hepatology 17:35–41, 1993Google Scholar
  35. 35.
    Buetow KH, Sheffield VC, Zhu M, Zhou T, Shen FM, Hino O, Smith M, McMahon BJ, Lanier AP, London WT, Redeker AG, Govindarajan S: Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. Proc Natl Acad Sci USA 89:9622–9626, 1992Google Scholar
  36. 36.
    Davidoff AM, Iglehart JD, Marks JR: Immune response to p53 is dependent upon p53/HSP70 complexes in breast cancer. Proc Natl Acad Sci USA 89:3439–3442, 1992Google Scholar
  37. 37.
    Labrecque S, Naor N, Thomson D, Matlashewski G: Analysis of the anti-p53 antibody response in cancer patients. Cancer Res 53:3468–3471, 1993Google Scholar
  38. 38.
    Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P: Geographic variation of p53 mutational profile in nonmalignant human liver. Science 264:1317–1319, 1994Google Scholar
  39. 39.
    Unsal H, Yakicier C, Marçais C, Kew M, Volkmann M, Zentgraf H, Isselbacher KJ, Ozturk M: Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci USA 91:822–826, 1994Google Scholar

Copyright information

© Plenum Publishing Corporation 1995

Authors and Affiliations

  • Jochen Readle
    • 1
    • 2
  • W. Kurt Roth
    • 1
    • 2
  • Gerhard Oremek
    • 1
    • 2
  • Wolfgang F. Caspary
    • 1
    • 2
  • Stefan Zeuzem
    • 1
    • 2
  1. 1.Second Department of Medicine, Division of GastroenterologyJohann Wolfgang Goethe-UniversityFrankfurt/MainGermany
  2. 2.Chemotherapeutisches Forschungsinstitut Georg-Speyer-HausFrankfurt/MainGermany

Personalised recommendations