Serum levels of α-fetoprotein increased more than 10 Years before detection of hepatocellular carcinoma
Open accessAbstract
BACKGROUND & AIMS: Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. METHODS: We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). RESULTS: HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. CONCLUSIONS: We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Changes in AFP values across serial measurements are superior to single AFP values for the detection of early-stage HCC.
“Notably, changes in AFP values across serial measurements are superior to single AFP values for the detection of early-stage HCC. 254”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [254]
The Statistical Methods and Discussion describe using serial AFP measurements to predict future HCC risk, including identifying high-risk patients years before clinical detection. They do not show that serial changes outperform single AFP values for detecting early-stage HCC. The Discussion instead says the early AFP changes are unlikely to represent early or subclinical HCC. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma
Galle, P. R., Forner, A., Llovet, J. M., Mazzaferro, V., Piscaglia, F., Raoul, J.-L., Schirmacher, P., & Vilgrain, V. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.03.019 · Cited by 11,406 · see citing works
EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma
European Association for the Study of the Liver, & European Organisation for Research and Treatment of Cancer (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2011.12.001 · Cited by 5,218 · see citing works
El-Serag, H. B. (2011) · New England Journal of Medicine · doi:10.1056/nejmra1001683 · Cited by 3,529 · see citing works
Omata, M., Cheng, A., Kokudo, N., Kudo, M., Lee, J. M., Jia, J., Tateishi, R., Han, K., Chawla, Y. K., Shiina, S., et al. (2017) · Hepatology International · doi:10.1007/s12072-017-9799-9 · Cited by 2,187 · see citing works
Tzartzeva, K., Obi, J., Rich, N. E., Parikh, N. D., Marrero, J. A., Yopp, A., Waljee, A. K., & Singal, A. G. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.01.064 · Cited by 1,207 · see citing works
Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice
Singal, A. G., & El-Serag, H. B. (2015) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2015.08.014 · Cited by 530 · see citing works
Johnson, P. J., Pirrie, S. J., Cox, T. F., Berhane, S., Teng, M. J., Palmer, D. H., Morse, J., Hull, D., Patman, G., Kagebayashi, C., et al. (2013) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0870 · Cited by 360 · see citing works
Berhane, S., Toyoda, H., Tada, T., Kumada, T., Kagebayashi, C., Satomura, S., Schweitzer, N., Vogel, A., Manns, M. P., Benckert, J., et al. (2016) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2015.12.042 · Cited by 324 · see citing works
Yang, J. D., Addissie, B. D., Mara, K. C., Harmsen, W. S., Dai, J., Zhang, N., Wongjarupong, N., Ali, H. M., Ali, H. A., Hassan, F., et al. (2018) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-18-0281 · Cited by 226 · see citing works
Screening for Hepatocellular Carcinoma in Chronic Liver Disease
Kansagara, D. L., Papak, J., Pasha, A. S., O'Neil, M. E., Freeman, M., Relevo, R., Quiñones, A. R., Motu’apuaka, M. L., & Jou, J. H. (2014) · Annals of Internal Medicine · doi:10.7326/m14-0558 · Cited by 217 · see citing works
El‐Serag, H. B., Kanwal, F., Davila, J. A., Kramer, J. R., & Richardson, P. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.01.045 · Cited by 181 · see citing works
Tayob, N., Lok, A. S.-F., Do, K.-A., & Feng, Z. (2015) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2015.07.049 · Cited by 94 · see citing works
Cheah, Y. L., Chow, P. K. H., Torzilli, G., Donadon, M., Cimino, M., Liapi, E., Geschwind, J.-F. H., Cha, J., Seong, J., Lin, S., et al. (2012) · Liver Cancer · doi:10.1159/000342749 · Cited by 77 · see citing works
Johnson, P. J., Berhane, S., Kagebayashi, C., Satomura, S., Teng, M. J., Fox, R., Yeo, W., Mo, F. K. F., Lai, P. B. S., Chan, S. L., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2016.422 · Cited by 59 · see citing works
Komárek, A., & Komárková, L. (2014) · Journal of Statistical Software · doi:10.18637/jss.v059.i12 · Cited by 55 · see citing works
Bird, T. G., Dimitropoulou, P., Turner, R., Jenks, S. J., Cusack, P., Hey, S., Blunsum, A. E., Kelly, S., Sturgeon, C. M., Hayes, P. C., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0156801 · Cited by 38 · see citing works
Komárek, A., Hansen, B. E., Kuiper, E. M. M., van Buuren, H. R., & Lesaffre, E. M. E. H. (2010) · Statistics in Medicine · doi:10.1002/sim.3849 · Cited by 30 · see citing works
Dynamic longitudinal discriminant analysis using multiple longitudinal markers of different types
Hughes, D. M., Komárek, A., Czanner, G., & García‐Fiñana, M. (2016) · Statistical Methods in Medical Research · doi:10.1177/0962280216674496 · Cited by 27 · see citing works
A Bayesian Screening Approach for Hepatocellular Carcinoma Using Multiple Longitudinal Biomarkers
Tayob, N., Stingo, F. C., Do, K.-A., Lok, A. S.-F., & Feng, Z. (2017) · Biometrics · doi:10.1111/biom.12717 · Cited by 26 · see citing works
A comparison of group prediction approaches in longitudinal discriminant analysis
Hughes, D., Saeiti, R. E., & García-Fiñana, M. (2017) · Biometrical journal. Biometrische Zeitschrift · doi:10.1002/bimj.201700013 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tacke, F., Horn, P., Wai-Sun Wong, V., Ratziu, V., Bugianesi, E., Francque, S., Zelber-Sagi, S., Valenti, L., Roden, M., Schick, F., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.031 · Cited by 2,210 · see citing works
(2024) · Obesity Facts · doi:10.1159/000539371 · Cited by 510 · see citing works
Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma
Johnson, P. J., Zhou, Q. X., Dao, D. Y., & Lo, Y. M. D. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-022-00620-y · Cited by 322 · see citing works
Risk stratification and early detection biomarkers for precision HCC screening
Lee, Y., Fujiwara, N., Yang, J. D., & Hoshida, Y. (2022) · Hepatology · doi:10.1002/hep.32779 · Cited by 128 · see citing works
Loss of liver function in chronic liver disease: An identity crisis
Berasain, C., Arechederra, M., Argemí, J., Fernández-Barrena, M. G., & Avila, M. A. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2022.09.001 · Cited by 99 · see citing works
Serum Biomarkers for the Prediction of Hepatocellular Carcinoma
Debes, J. D., Romagnoli, P. A., Prieto, J. E., Arrese, M. A., de Mattos, Â. Z., & Boonstra, A. (2021) · Cancers · doi:10.3390/cancers13071681 · Cited by 76 · see citing works
Fujiwara, N., Kobayashi, M., Fobar, A. J., Hoshida, A., Marquez, C. A., Koneru, B., Panda, G., Taguri, M., Qian, T., Raman, I., et al. (2021) · Med · doi:10.1016/j.medj.2021.03.017 · Cited by 70 · see citing works
Current and Emerging Tools for Hepatocellular Carcinoma Surveillance
Adeniji, N., & Dhanasekaran, R. (2021) · Hepatology Communications · doi:10.1002/hep4.1823 · Cited by 61 · see citing works
Schotten, C., Ostertag, B., Sowa, J., Manka, P. P., Bechmann, L. P., Hilgard, G., Marquardt, C., Wichert, M., Toyoda, H., Lange, C. M., et al. (2021) · Pharmaceuticals · doi:10.3390/ph14080735 · Cited by 54 · see citing works
Fan, R., Chen, L., Zhao, S., Yang, H., Li, Z., Qian, Y.-S., Ma, H., Liu, X., Wang, C., Liang, X., et al. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.05.039 · Cited by 46 · see citing works
Xu, Y., Guo, Q., & Wei, L. (2021) · Cancers · doi:10.3390/cancers13205096 · Cited by 41 · see citing works
Fan, R., Zhao, S., Niu, J., Ma, H., Xie, Q., Song, Y., Xie, J., Dou, X., Shang, J., Rao, H., et al. (2024) · Gut · doi:10.1136/gutjnl-2024-332182 · Cited by 27 · see citing works
Qin, X., Pan, Y., Zhang, J., Shen, J., & Li, C. (2022) · Talanta · doi:10.1016/j.talanta.2022.123684 · Cited by 27 · see citing works
Sanchez, J. I., Fontillas, A. C., Kwan, S., Sanchez, C. I., Calderone, T. L., Lee, J., Elsaiey, A., Cleere, D. W., Wei, P., Vierling, J. M., et al. (2024) · JHEP Reports · doi:10.1016/j.jhepr.2024.101119 · Cited by 23 · see citing works
Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells
Huang, Y., Huang, X., Zeng, J., & Lin, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.667669 · Cited by 22 · see citing works
Clinical and Molecular Prediction of Hepatocellular Carcinoma Risk
Kubota, N., Fujiwara, N., & Hoshida, Y. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123843 · Cited by 19 · see citing works
Long-term prognosis and management of hepatocellular carcinoma after curative treatment
Nishida, N. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0208 · Cited by 19 · see citing works
Su, T., Chang, S.-H., Chen, C., Liao, S., Tseng, T., Hsu, S., Hong, C., Liu, C., Yang, H., Liu, C., et al. (2023) · Hepatology Research · doi:10.1111/hepr.13932 · Cited by 18 · see citing works
Semmler, G., López, S. A., Pons, M., Lens, S., Dajti, E., Griemsmann, M., Zanetto, A., Burghart, L., Hametner‐Schreil, S., Hartl, L., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000001005 · Cited by 17 · see citing works
Li, L., Li, X., Li, W., Ding, X., Zhang, Y., Chen, J., & Li, W. (2022) · BMC Cancer · doi:10.1186/s12885-022-09841-5 · Cited by 16 · see citing works
Lin, Y., Ma, Y., Chen, Y., Huang, Y., Lin, J., Xiao, Z., & Cui, Z. (2025) · BMC Cancer · doi:10.1186/s12885-025-14025-y · Cited by 12 · see citing works
The effect of random-effects misspecification on classification accuracy
Saeiti, R. E., García-Fiñana, M., & Hughes, D. (2021) · The International Journal of Biostatistics · doi:10.1515/ijb-2019-0159 · Cited by 5 · see citing works
Karagiannakis, D. S., Stefanaki, K., Paschou, S. Α., Papatheodoridi, Μ., Tsiodras, S., & Παπάνας, Ν. (2024) · HORMONES · doi:10.1007/s42000-024-00625-z · Cited by 4 · see citing works
Zhang, D.-L., Feng, D., He, X., Zhang, X.-F., Li, L., Li, Z., Niu, X., Zhuang, Y.-L., Liu, Z., Gao, X., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.959151 · Cited by 3 · see citing works
Fan, R., Yin, X., & Hou, J. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.01.005 · Cited by 3 · see citing works
Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts
Kubota, N., Fujiwara, N., & Hoshida, Y. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2022.01.005 · Cited by 2 · see citing works
Ibrahim, A. M. A., Ghazy, A., & Youssef, A. (2023) · ERU Research Journal · doi:10.21608/erurj.2023.211800.1028 · Cited by 2 · see citing works
Xia, L., Lin, L., Xiong, Q., Chen, J., & Zhou, R. (2026) · Microchemical Journal · doi:10.1016/j.microc.2025.116722 · Cited by 1 · see citing works
Toyoda, H., Yasuda, S., Shiota, S., Sone, Y., Maeda, A., Kaneoka, Y., Kumada, T., & Tanaka, J. (2022) · European Radiology · doi:10.1007/s00330-022-08570-4 · Cited by 1 · see citing works
Pinato, D. J., Fessas, P., Gibbin, A., Occhino, G., Boccato, E., Smirne, C., Minisini, R., & Pirisi, M. (2021) · Liver Cancer International · doi:10.1002/lci2.22
Malekzadeh, R., & Poustchi, H. (2021) · Springer eBooks · doi:10.1007/978-3-030-78737-0_14
Onken, J. E. (2020) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2020.11.013
Yamasaki, K., Ohashi, J., Sugiyama, M., Uoshima, H., Komori, A., Nagaoka, S., Saeki, A., Motoyasu, Y., Suehiro, T., Kugiyama, Y., et al. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4589853
Li, L., Li, X., Li, W., Ding, X., Zhang, Y., Chen, J., & Li, W. (2022) · Figshare · doi:10.6084/m9.figshare.20282190
Long-term outcomes of treated chronic HCV compensated cirrhotic patients in Egypt
Tantawi, O., Elsayed, E. M., Abdallah, M., Elakel, W., & Fouad, A. A. (2025) · Egyptian Liver Journal · doi:10.1186/s43066-025-00485-1
Trajectory Modelling of Prognostic Biomarkers Linked to Liver Cancer Risk: A Systematic Review
Aldawsari, B., Bonnett, L. J., Sudell, M., Johnson, P., & Hughes, D. M. (2026) · Liver Cancer · doi:10.1159/000551202
Kehar, M., Ramji, A. S., Swain, M., Singer, A. G., IVERS, N., Schaufert, W., Betel, M., Dasgupta, K., Sebastiani, G., & Patel, K. (2026) · Canadian Liver Journal · doi:10.3138/canlivj-2026-9-3-guidelines
Jin, S., Yu, J., Jiang, Y., & Li, M. (2026) · Frontiers in Chemistry · doi:10.3389/fchem.2026.1849931
Hao, K., Zhao, S., Liao, X., Fan, R., Naoumov, N. V., Yu, Y., & Hou, J. (2026) · Journal of Medical Virology · doi:10.1002/jmv.71129
- Authors
- Hughes, D. M., Berhane, S., Emily de Groot, C. A., Toyoda, H., Tada, T., Kumada, T., Satomura, S., Nishida, N., Kudo, M., Kimura, T., Osaki, Y., Kolamunage-Dona, R., Amoros, R., Bird, T., Garcίa-Fiñana, M., & Johnson, P.
- Affiliations
- Ogaki Municipal Hospital (JP)
- Gifu Kyoritsu University (JP)
- The University of Osaka (JP)
- Kindai University Hospital (JP)
- Osaka Red Cross Hospital (JP)
- University of Liverpool (GB)
- Corresponding author
- Johnson, Philip
- ORCID
- Venue
- Clinical Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 19
- Issue
- 1
- Pages
- 162-170.e4
- ISSN
- 1542-3565 (ISSN-L)
- PMC
- PMC7611145
- OpenAlex
- W3023707554
- Cited by
- 39
- References
- 20
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 9 · 2021: 10 · 2020: 3
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Gastroenterology and Hepatology (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Medical Research Council (MR/L010909/1, MR/R024847/1)
- Wellcome Trust (WT107492/Z/15/Z)
- Chief Scientist Office, Scottish Government Health and Social Care Directorate (CGA/17/19)
- Engineering and Physical Sciences Research Council (EP/N014499/1)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- hepatocellular carcinoma, alpha-fetoprotein, chronic liver disease, HCC surveillance, liver cirrhosis, serial biomarker measurement
- MeSH terms
- alpha-Fetoproteins, Fetal Proteins, Carcinoma, Hepatocellular, Humans, Liver Cirrhosis, Liver Neoplasms
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
