Digestive Diseases and Sciences

, Volume 64, Issue 1, pp 269–280 | Cite as

Serological Risk Index Based on Alpha-Fetoprotein and C-Reactive Protein to Indicate Futile Liver Transplantation Among Patients with Advanced Hepatocellular Carcinoma

  • Arno KornbergEmail author
  • Martina Schernhammer
  • Jennifer Kornberg
  • Helmut Friess
  • Katharina Thrum
Original Article



The aim of this study was to establish a preoperatively available serological risk index using alpha-fetoprotein (AFP) and C-reactive protein (CRP) for predicting oncologically futile liver transplantation (LT) in hepatocellular carcinoma (HCC) patients.


A total of 119 liver transplant patients with HCC were retrospectively analyzed. The prognostic impact of clinical and histopathologic factors including pre-LT serum AFP and CRP values was determined.


Apart from microvascular tumor invasion (MVI; odds ratio [OR] 15.77), pretransplant serum levels of AFP > 100 ng/ml (OR 13.31) and CRP > 0.8 mg/dl (OR 13.97) were identified as independent predictors of HCC recurrence. The cumulative risk of HCC relapse at 5 years post-LT was 2.3% in low serological tumor activity (STA) index (AFP ≤ 100 ng/ml + CRP ≤ 0.8 mg/dl), 17.1% in intermediate STA (AFP ≤ 100 ng/ml or CRP ≤ 0.8 mg/dl), and 91.6% in high STA index (AFP > 100 ng/ml + CRP > 0.8 mg/dl; p < 0.001), respectively. High STA index was identified as most powerful pre-LT available predictor of MVI (OR 15.31) and posttransplant HCC recurrence (OR 54.44). Five-year recurrence-free survival rate in Milan Out patients with high STA was 0%, compared to 91.7% and 83.6% in those with low or intermediate STA index (p < 0.001), respectively.


Our proposed serological risk index based on pretransplant serum AFP and CRP values is able to predict oncologically futile LT among advanced HCC patients.


Alpha-fetoprotein C-reactive protein Hepatocellular carcinoma Liver transplantation Tumor recurrence Milan criteria 





Area under the curve


Confidence interval


C-reactive protein


Computed tomography


Hepatocellular carcinoma




Liver transplantation


Lymphovascular invasion


Milan criteria


Model of end-stage liver disease


Magnetic resonance imaging


Microvascular invasion


Odds ratio


Overall survival


Recurrence-free survival


Serological tumor activity


Transarterial chemotherapy


Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest related to the article.


  1. 1.
    Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017;14:203–217.CrossRefGoogle Scholar
  2. 2.
    Aravinthan AD, Bruni SG, Doyle AC, et al. Liver transplantation is a preferable alternative to palliative therapy for selected patients with advanced hepatocellular carcinoma. Ann Surg Oncol. 2017;24:1843–1851.CrossRefGoogle Scholar
  3. 3.
    Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693–699.CrossRefGoogle Scholar
  4. 4.
    Mazzaferro V, Chun YS, Poon RT, et al. Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 2008;15:1001–1007.CrossRefGoogle Scholar
  5. 5.
    Taniguchi M. Liver transplantation in the MELD era—analysis of the OPTN/UNOS registry. Clin Transpl. 2012:41–65.Google Scholar
  6. 6.
    Adler M, De Pauw F, Vereerstraeten P, et al. Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system. Liver Transplant. 2008;14:526–533.CrossRefGoogle Scholar
  7. 7.
    Ecker BL, Hoteit MA, Forde KA, et al. Patterns of discordance between pretransplant imaging stage of hepatocellular carcinoma and posttransplant pathologic stage: a contemporary appraisal of the Milan criteria. Transplantation. 2018;102:648–655.CrossRefGoogle Scholar
  8. 8.
    Shah SA, Tan JC, McGilvray ID, et al. Accuracy of staging as a predictor for recurrence after liver transplantation for hepatocellular carcinoma. Transplantation. 2006;81:1633–1639.CrossRefGoogle Scholar
  9. 9.
    Yao FY, Xiao L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant. 2007;7:2587–2596.CrossRefGoogle Scholar
  10. 10.
    Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA. Ann Surg. 2007;246:502–509.CrossRefGoogle Scholar
  11. 11.
    Silva M, Moya A, Berenguer M, et al. Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma. Liver Transplant. 2008;14:1449–1460.CrossRefGoogle Scholar
  12. 12.
    Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35–43.CrossRefGoogle Scholar
  13. 13.
    El-Fattah MA. Hepatocellular carcinoma biology predicts survival outcome after liver transplantation in the USA. Indian J Gastroenterol. 2017;36:117–125.CrossRefGoogle Scholar
  14. 14.
    Emmanouilidis N, Peters R, Ringe BP, et al. Liver transplantation for hepatocellular carcinoma: a single center resume overlooking four decades of experience. J Transplant. 2016;2016:7895956. Scholar
  15. 15.
    Mehta N, Heimbach J, Harnois DM, et al. Validation of a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncol. 2017;3:493–500.CrossRefGoogle Scholar
  16. 16.
    Seehofer D, Öllinger R, Denecke T, et al. Blood transfusions and tumor biopsy may increase HCC recurrence rates after liver transplantation. J Transplant. 2017;2017:9731095. Scholar
  17. 17.
    Pawlik TM, Gleisner AL, Anders RA, Assumpcao L, Maley W, Choti MA. Preoperative assessment of hepatocellular carcinoma tumor grade using needle biopsy: implications for transplant eligibility. Ann Surg. 2007;245:435–442.CrossRefGoogle Scholar
  18. 18.
    Lai Q, Inostroza M, Rico Juri JM, Goffette P, Lerut J. Delta-slope of alpha-fetoprotein improves the ability to select liver transplant patients with hepatocellular cancer. HPB (Oxford). 2015;17:1085–1095.CrossRefGoogle Scholar
  19. 19.
    She WH, Chan ACY, Cheung TT, Lo CM, Chok KSH. Survival outcomes of liver transplantation for hepatocellular carcinoma in patients with normal, high and very high preoperative alpha-fetoprotein levels. World J Hepatol. 2018;10:308–318.CrossRefGoogle Scholar
  20. 20.
    Notarpaolo A, Layese R, Magistri P, et al. Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC. J Hepatol. 2017;66:552–559.CrossRefGoogle Scholar
  21. 21.
    Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A. OLT for HCC Consensus Group: recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 2012;13:e11–e22.CrossRefGoogle Scholar
  22. 22.
    Mazzaferro V, Sposito C, Zhou J, et al. Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma. Gastroenterology. 2018;154:128–139.CrossRefGoogle Scholar
  23. 23.
    Lai Q, Avolio AW, Manzia TM, et al. Role of alpha-fetoprotein in selection of patients with hepatocellular carcinoma waiting for liver transplantation: must we reconsider it? Int J Biol Markers. 2011;26:153–159.CrossRefGoogle Scholar
  24. 24.
    Hameed B, Mehta N, Sapisochin G, Roberts JP, Yao FY. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria. Liver Transplant. 2014;20:945–951.CrossRefGoogle Scholar
  25. 25.
    Agopian VG, Harlander-Locke MP, Markovic D, et al. Evaluation of patients with hepatocellular carcinomas that do not produce α-fetoprotein. JAMA Surg. 2017;152:55–64.CrossRefGoogle Scholar
  26. 26.
    Endig J, Buitrago-Molina LE, Marhenke S, et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell. 2016;30:308–323.CrossRefGoogle Scholar
  27. 27.
    Cescon M, Bertuzzo VR, Ercolani G, Ravaioli M, Odaldi F, Pinna AD. Liver transplantation for hepatocellular carcinoma: role of inflammatory and immunological state on recurrence and prognosis. World J Gastroenterol. 2013;19:9174–9182.CrossRefGoogle Scholar
  28. 28.
    Aravalli RN. Role of innate immunity in the development of hepatocellular carcinoma. World J Gastroenterol. 2013;19:7500–7514.CrossRefGoogle Scholar
  29. 29.
    Guo J, Chen S, Chen Y, Li S, Xu D. Combination of CRP and NLR: a better predictor of postoperative survival in patients with gastric cancer. Cancer Manag Res. 2018;10:315–321.CrossRefGoogle Scholar
  30. 30.
    Fang Y, Xu C, Wu P, et al. Prognostic role of C-reactive protein in patients with nasopharyngeal carcinoma: A meta-analysis and literature review. Medicine (Baltimore). 2017;96:e8463. Scholar
  31. 31.
    Dolan RD, McSorley ST, Horgan PG, Laird B, McMillan DC. The role of the systemic inflammatory response in predicting outcomes in patients with advanced inoperable cancer: systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017;116:134–146.CrossRefGoogle Scholar
  32. 32.
    Nakanishi H, Kurosaki M, Tsuchiya K, et al. Novel pretreatment scoring incorporating C-reactive protein to predict overall survival in advanced hepatocellular carcinoma with sorafenib treatment. Liver Cancer.. 2016;5:257–268.CrossRefGoogle Scholar
  33. 33.
    Li Z, Xue TQ, Chen XY. Predictive values of serum VEGF and CRP levels combined with contrast enhanced MRI in hepatocellular carcinoma patients after TACE. Am J Cancer Res. 2016;6:2375–2385.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Zheng Z, Zhou L, Gao S, Yang Z, Yao J, Zheng S. Prognostic role of C-reactive protein in hepatocellular carcinoma: a systematic review and meta-analysis. Int J Med Sci. 2013;10:653–664.CrossRefGoogle Scholar
  35. 35.
    Liu YB, Ying J, Kuang SJ, et al. Elevated preoperative serum Hs-CRP level as a prognostic factor in patients who underwent resection for hepatocellular carcinoma. Medicine (Baltimore). 2015;94:e2209. Scholar
  36. 36.
    Kim YK, Kim SH, Lee SD, Hong SK, Park SJ. Pretransplant serum levels of C-reactive protein predict prognoses in patients undergoing liver transplantation for hepatocellular carcinoma. Transplant Proc. 2015;47:686–693.CrossRefGoogle Scholar
  37. 37.
    Na GH, Kim DG, Han JH, et al. Inflammatory markers as selection criteria of hepatocellular carcinoma in living-donor liver transplantation. World J Gastroenterol. 2014;20:6594–6601.CrossRefGoogle Scholar
  38. 38.
    An HJ, Jang JW, Bae SH, et al. Serum C-reactive protein is a useful biomarker for predicting outcomes after liver transplantation in patients with hepatocellular carcinoma. Liver Transplant. 2012;18:1406–1414.CrossRefGoogle Scholar
  39. 39.
    Kornberg A, Witt U, Kornberg J, Müller K, Friess H, Thrum K. Postoperative peak serum C-reactive protein is a predictor of outcome following liver transplantation for hepatocellular carcinoma. Biomarkers. 2016;21:152–159.CrossRefGoogle Scholar
  40. 40.
    Roberts LR, Sirlin CB, Zaiem F, et al. Imaging for the diagnosis of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatology. 2018;67:401–421.CrossRefGoogle Scholar
  41. 41.
    Cillo U, Giuliani T, Polacco M, et al. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J Gastroenterol. 2016;22:232–252.CrossRefGoogle Scholar
  42. 42.
    Jonas S, Bechstein WO, Steinmüller T, et al. Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology. 2001;33:1080–1086.CrossRefGoogle Scholar
  43. 43.
    Lauerer M, Kaiser K, Nagel E. Organ transplantation in the face of donor shortage—ethical implications with a focus on liver allocation. Visc Med. 2016;32:278–285.CrossRefGoogle Scholar
  44. 44.
    Lai Q, Vitale A, Iesari S, et al. Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer. Hepatology. 2017;66:1910–1919.CrossRefGoogle Scholar
  45. 45.
    Giard JM, Mehta N, Dodge JL, Roberts JP, Yao FY. Alpha-fetoprotein slope > 7.5 ng/ml/month predicts micro-vascular invasion and tumor recurrence after liver transplantation for hepatocellular carcinoma. Transplantation. 2018. Scholar
  46. 46.
    Grąt M, Krasnodębski M, Patkowski W, et al. Relevance of pre-transplant α-fetoprotein dynamics in liver transplantation for hepatocellular cancer. Ann Transplant. 2016;21:115–124.CrossRefGoogle Scholar
  47. 47.
    Wu JF, Song SH, Lee CS, et al. Clinical predictors of liver fibrosis in patients with chronic hepatitis B virus infection from children to adults. J Infect Dis. 2018. Scholar
  48. 48.
    Gamil M, Alboraie M, El-Sayed M, et al. Novel scores combining AFP with non-invasive markers for prediction of liver fibrosis in chronic hepatitis C patients. J Med Virol. 2018. Scholar
  49. 49.
    Dupré A, Malik HZ. Inflammation and cancer: what a surgical oncologist should know. Eur J Surg Oncol. 2018;44:566–570. Scholar
  50. 50.
    Toso C, Meeberg G, Hernandez-Alejandro R, et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: a prospective validation. Hepatology. 2015;62:158–165.CrossRefGoogle Scholar
  51. 51.
    Lai Q, Avolio AW, Manzia TM, et al. Combination of biological and morphological parameters for the selection of patients with hepatocellular carcinoma for liver transplantation. Clin Transplant. 2012;26:125–131.CrossRefGoogle Scholar
  52. 52.
    Zheng SS, Xu X, Wu J, et al. Liver transplantation for hepatocellular carcinoma: Hangzhou experience. Transplantation. 2008;12:1726–1732.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Arno Kornberg
    • 1
    Email author
  • Martina Schernhammer
    • 1
  • Jennifer Kornberg
    • 2
  • Helmut Friess
    • 1
  • Katharina Thrum
    • 3
  1. 1.Department of Surgery, Klinikum rechts der IsarTechnical University MunichMunichGermany
  2. 2.Department of Anaesthesiology, Klinikum GroßhadernLMU MunichMunichGermany
  3. 3.Institute of PathologyHelios Klinikum BerlinBerlinGermany

Personalised recommendations