Inflammation Markers and HCC Aggressiveness

Brian Irving Carra*; Rossella Donghiab

**Brian Irving Carra* and Rossella Donghiab**

Volume6-Issue4
Dates: Received: 2025-04-15 | Accepted: 2025-04-26 | Published: 2025-04-28
Pages: 378-387

Abstract

Background: Inflammation is thought to be important in the development and progression of Hepatocellular Carcinoma (HCC), but which inflammatory indices are more useful in clinical practice is not clear.

Aims: Several inflammatory indices were examined with respect to Maximum Tumor Diameter (MTD), Portal Vein Thrombosis by Tumor (PVT) and survival.

Results: Serum C-Reactive Protein (CRP) and Platelet Lymphocyte Ratio (PLR) each significantly increased with increasing MTD as did percent patients with higher Glasgow index; whereas albumin levels and HALP (Hemoglobin, Albumin, Lymphocytes and Platelets) score decreased, as expected. Lower (abnormal) albumin was associated with higher alpha-fetoprotein and percentage PVT patients. Cox proportional hazard models for death showed a significant protective effect for albumin, whereas CRP and the Glasgow score had significant Hazard Ratios (HR) for death, but neither PLR nor the HALP score had significant HRs. Kaplan-Meier analysis showed reduced survival at each MTD for patients with low versus high albumin levels. All parameters were significantly different for presence versus absence of PVT, but only albumin and CRP had significance in Cox proportional hazard models for death in patients with PVT and only albumin for patients with high alpha-fetoprotein.

Conclusion: Each inflammation parameter worsened with increase in MTD, but only albumin and CRP (and the Glasgow index) were significant for survival in the total cohort. Only serum albumin had significance for survival in patients with PVT or high alpha-fetoprotein.

FullText HTML FullText PDF DOI: 10.37871/jbres2093

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How to cite this article

Carra BI, Donghiab R. Infl ammation Markers and HCC Aggressiveness. J Biomed Res Environ Sci. 2025 Apr 28; 6(4): 378-387. doi: 10.37871/jbres2093, Article ID: JBRES2093, Available at: https://www.jelsciences.com/articles/jbres2093.pdf

Subject area(s)

Oncology

Pathology

Hepatology

References

Virchow RLK. Die krankhaften Geschwülste. Berlin: Hirschwald; 1863.
Refolo MG, Messa C, Guerra V, Carr BI, D'Alessandro R. Inflammatory Mechanisms of HCC Development. Cancers (Basel). 2020 Mar 10;12(3):641. doi: 10.3390/cancers12030641. PMID: 32164265; PMCID: PMC7139884.
Sengez B, Carr BI, Alotaibi H. EMT and Inflammation: Crossroads in HCC. J Gastrointest Cancer. 2023 Mar;54(1):204-212. doi: 10.1007/s12029-021-00801-z. Epub 2022 Jan 12. PMID: 35020133.
Suner A, Carr BI, Akkiz H, Uskudar O, Kuran S, Tokat Y, Tokmak S, Ballı T, Ulku A, AkCam T, Delik A, Arslan B, Doran F, YalCın K, Ekinci N, Yilmaz S, Ozakyol A, Yücesoy M, BahCeci HI, Polat KY, Şimsek H, Ormeci N, Sonsuz A, Demir M, KılıC M, Uygun A, Demir A, Altıntas E, Karakulah G, Temel T, Bektas A. Inflammatory markers C-reactive protein and PLR in relation to HCC characteristics. J Transl Sci. 2019 Jun;5(3):10.15761/JTS.1000260. doi: 10.15761/JTS.1000260. Epub 2018 Jun 22. PMID: 30662766; PMCID: PMC6333412.
Fabris C, Pirisi M, Soardo G, Toniutto P, Falleti E, Vitulli D, Pezzetta F, Gonano F, Bartoli E. Diagnostic usefulness of acute-phase protein measurement in hepatocellular carcinoma. Cancer Invest. 1996;14(2):103-8. doi: 10.3109/07357909609018884. PMID: 8597894.
Sheinenzon A, Shehadeh M, Michelis R, Shaoul E, Ronen O. Serum albumin levels and inflammation. Int J Biol Macromol. 2021 Aug 1;184:857-862. doi: 10.1016/j.ijbiomac.2021.06.140. Epub 2021 Jun 25. PMID: 34181998.
Carr BI, Guerra V. Serum albumin levels in relation to tumor parameters in hepatocellular carcinoma patients. Int J Biol Markers. 2017 Oct 31;32(4):e391-e396. doi: 10.5301/ijbm.5000300. PMID: 28862714.
Zhou J, Yang D. Prognostic Significance of Hemoglobin, Albumin, Lymphocyte and Platelet (HALP) Score in Hepatocellular Carcinoma. J Hepatocell Carcinoma. 2023 Jun 2;10:821-831. doi: 10.2147/JHC.S411521. PMID: 37288141; PMCID: PMC10243610.
Xu H, Zheng X, Ai J, Yang L. Hemoglobin, albumin, lymphocyte, and platelet (HALP) score and cancer prognosis: A systematic review and meta-analysis of 13,110 patients. Int Immunopharmacol. 2023 Jan;114:109496. doi: 10.1016/j.intimp.2022.109496. Epub 2022 Nov 30. PMID: 36462339.
Carr BI, Guerra V, Donghia R, Farinati F, Giannini EG, Piscaglia F, Rapaccini GL, Di Marco M, Caturelli E, Zoli M, Sacco R, Cabibbo G, Marra F, Mega A, Morisco F, Gasbarrini A, Svegliati-Baroni G, Foschi FG, Missale G, Masotto A, Nardone G, Raimondo G, Azzaroli F, Vidili G, Oliveri F, Trevisani F. Changes in hepatocellular carcinoma aggressiveness characteristics with an increase in tumor diameter. Int J Biol Markers. 2021 Mar;36(1):54-61. doi: 10.1177/1724600821996372. Epub 2021 Feb 27. PMID: 33641486.
Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013 Mar;144(3):512-27. doi: 10.1053/j.gastro.2013.01.002. Epub 2013 Jan 9. PMID: 23313965; PMCID: PMC3578068.
Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, Kammula US, Chen Y, Qin LX, Tang ZY, Wang XW. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006 Aug;10(2):99-111. doi: 10.1016/j.ccr.2006.06.016. PMID: 16904609.
Arroyo V, García-Martinez R, Salvatella X. Human serum albumin, systemic inflammation, and cirrhosis. J Hepatol. 2014 Aug;61(2):396-407. doi: 10.1016/j.jhep.2014.04.012. Epub 2014 Apr 18. PMID: 24751830.
Carr BI, Guerra V. Serum Inflammation Parameters and Survival in Hepatocellular Carcinoma Patients: Importance of Albumin and Gamma-Glutamyltranspeptidase. Oncology. 2023;101(5):313-320. doi: 10.1159/000527650. Epub 2023 Mar 6. PMID: 36878197; PMCID: PMC10238618.
Chen S, Ma W, Cao F, Shen L, Qi H, Xie L, Wu Y, Fan W. Hepatocellular Carcinoma Within the Milan Criteria: A Novel Inflammation-Based Nomogram System to Assess the Outcomes of Ablation. Front Oncol. 2020 Sep 14;10:1764. doi: 10.3389/fonc.2020.01764. PMID: 33042823; PMCID: PMC7521362.
Casadei Gardini A, Foschi FG, Conti F, Petracci E, Vukotic R, Marisi G, Buonfiglioli F, Vitale G, Ravaioli F, Gitto S, Verucchi G, Lenzi M, Bolondi L, Mazzella G, Brillanti S, Andreone P; member of the Bologna DAA group. Immune inflammation indicators and ALBI score to predict liver cancer in HCV-patients treated with direct-acting antivirals. Dig Liver Dis. 2019 May;51(5):681-688. doi: 10.1016/j.dld.2018.09.016. Epub 2018 Sep 22. PMID: 30327251.
Shimizu T, Ishizuka M, Suzuki T, Tanaka G, Park KH, Matsumoto T, Shiraki T, Sakuraoka Y, Kato M, Aoki T, Kubota K. The preoperative globulin-to-albumin ratio, a novel inflammation-based prognostic system, predicts survival after potentially curative liver resection for patients with hepatocellular carcinoma. J Surg Oncol. 2017 Dec;116(8):1166-1175. doi: 10.1002/jso.24772. Epub 2017 Aug 29. PMID: 28853157.
Chan SL, Chan AW, Chan AK, Jian P, Mo F, Chan CM, Mok K, Liu C, Chong CC, Chan AT, Mok T, Yeo W. Systematic evaluation of circulating inflammatory markers for hepatocellular carcinoma. Liver Int. 2017 Feb;37(2):280-289. doi: 10.1111/liv.13218. Epub 2016 Aug 29. PMID: 27501075.
Hirano Y, Nouso K, Kariyama K, Hiraoka A, Shiota S, Wakuta A, Yasuda S, Toyoda H, Tsuji K, Hatanaka T, Kakizaki S, Naganuma A, Tada T, Itobayashi E, Ishikawa T, Shimada N, Takaguchi K, Tsutsui A, Nagano T, Imai M, Nakamura S, Kumada T; Real-Life Practice Experts for HCC (RELPEC) Study Group in Japan. Prognostic Efficacy of the Albumin Grade in Patients with Hepatocellular Carcinoma. Acta Med Okayama. 2024 Oct;78(5):377-386. doi: 10.18926/AMO/67662. PMID: 39467656.
Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Tanaka K, Fushiya N, Koike K, Nishino H, Matsushima M, Saeki C, Tajiri H. The Glasgow Prognostic Score, an inflammation based prognostic score, predicts survival in patients with hepatocellular carcinoma. BMC Cancer. 2013 Feb 2;13:52. doi: 10.1186/1471-2407-13-52. PMID: 23374755; PMCID: PMC3571892.
Takahashi H, Kawanaka M, Fujii H, Iwaki M, Hayashi H, Toyoda H, Oeda S, Hyogo H, Morishita A, Munekage K, Kawata K, Tsutsumi T, Sawada K, Maeshiro T, Tobita H, Yoshida Y, Naito M, Araki A, Arakaki S, Kawaguchi T, Noritake H, Ono M, Masaki T, Yasuda S, Tomita E, Yoneda M, Tokushige A, Kamada Y, Ueda S, Aishima S, Sumida Y, Nakajima A, Okanoue T, Japan Study Group Of Nonalcoholic Fatty Liver Disease Jsg-Nafld. Association of Serum Albumin Levels and Long-Term Prognosis in Patients with Biopsy-Confirmed Nonalcoholic Fatty Liver Disease. Nutrients. 2023 Apr 22;15(9):2014. doi: 10.3390/nu15092014. PMID: 37432160; PMCID: PMC10180563.
Carr BI, Guerra V, Donghia R, Yilmaz S. Tumor multifocality and serum albumin levels can identify groups of patients with hepatocellular carcinoma and portal vein thrombosis having distinct survival outcomes. Ann Med Surg (Lond). 2021 Jun 2;66:102458. doi: 10.1016/j.amsu.2021.102458. PMID: 34141428; PMCID: PMC8187816.
Wang L, Li Q, Zhang J, Lu J. A Novel Prognostic Scoring Model Based on Albumin and γ-Glutamyltransferase for Hepatocellular Carcinoma Prognosis. Cancer Manag Res. 2019 Dec 23;11:10685-10694. doi: 10.2147/CMAR.S232073. PMID: 31920379; PMCID: PMC6934113.
Bağırsakçı E, Şahin E, Atabey N, Erdal E, Guerra V, Carr BI. Role of Albumin in Growth Inhibition in Hepatocellular Carcinoma. Oncology. 2017;93(2):136-142. doi: 10.1159/000471807. Epub 2017 May 10. PMID: 28486226.
Nojiri S, Joh T. Albumin suppresses human hepatocellular carcinoma proliferation and the cell cycle. Int J Mol Sci. 2014 Mar 24;15(3):5163-74. doi: 10.3390/ijms15035163. PMID: 24663086; PMCID: PMC3975446.
Fu X, Yang Y, Zhang D. Molecular mechanism of albumin in suppressing invasion and metastasis of hepatocellular carcinoma. Liver Int. 2022 Mar;42(3):696-709. doi: 10.1111/liv.15115. Epub 2021 Dec 7. PMID: 34854209; PMCID: PMC9299813.
Smith C, Halliwell B, Aruoma OI. Protection by albumin against the pro-oxidant actions of phenolic dietary components. Food Chem Toxicol. 1992 Jun;30(6):483-9. doi: 10.1016/0278-6915(92)90099-7. PMID: 1379971.
Shahid M, Mubeen A, Tse J, Kakar S, Bateman AC, Borger D, Rivera MN, Ting DT, Deshpande V. Branched chain in situ hybridization for albumin as a marker of hepatocellular differentiation: evaluation of manual and automated in situ hybridization platforms. Am J Surg Pathol. 2015 Jan;39(1):25-34. doi: 10.1097/PAS.0000000000000343. PMID: 25353287; PMCID: PMC4698370.
Carr B, Guerra V, Ince V, Isik B, Yilmaz S. Alpha-fetoprotein and albumin inversely relate to each other and to tumor parameters in patients with hepatocellular carcinoma. Hepatol Forum. 2024 Jan 16;5(1):11-17. doi: 10.14744/hf.2023.2023.0023. PMID: 38283277; PMCID: PMC10809334.
Wu GX, Lin YM, Zhou TH, Gao H, Pei G. Significant down-regulation of alpha-albumin in human hepatoma and its implication. Cancer Lett. 2000 Nov 28;160(2):229-36. doi: 10.1016/s0304-3835(00)00589-9. PMID: 11053653.
Tsutsumi T, Ido A, Nakao K, Hamasaki K, Kato Y, Ohtsuru A, Nakata K, Tamaoki T, Nagataki S. Reciprocal regulation of alpha-fetoprotein and albumin gene expression by butyrate in human hepatoma cells. Gastroenterology. 1994 Aug;107(2):499-504. doi: 10.1016/0016-5085(94)90177-5. PMID: 7518784.
Ishikawa H, Nakata K, Tsuruta S, Nakao K, Kato Y, Tamaoki T, Eguchi K. Differential regulation of albumin gene expression by heparin-binding epidermal growth factor-like growth factor in alpha-fetoprotein-producing and -nonproducing human hepatoma cells. Tumour Biol. 1999 May-Jun;20(3):130-8. doi: 10.1159/000030055. PMID: 10213920.
Kar S, Carr BI. Detection of liver cells in peripheral blood of patients with advanced-stage hepatocellular carcinoma. Hepatology. 1995 Feb;21(2):403-7. PMID: 7843713.
Cheung ST, Fan ST, Lee YT, Chow JP, Ng IO, Fong DY, Lo CM. Albumin mRNA in plasma predicts post-transplant recurrence of patients with hepatocellular carcinoma. Transplantation. 2008 Jan 15;85(1):81-7. doi: 10.1097/01.tp.0000298003.88530.11. PMID: 18192916.