A Novel Probe Technology for Detecting Native Albumin Activity as a Biomarker in Patients with Hepatitis B-related Cirrhosis and Hepatocellular Carcinoma and Its Clinical Applications

Abstract

Background and objectives Albumin is a major prognostic factor for patients with advanced liver disease, dependent on its concentration and biological activity. This study aimed to improve the method of active albumin detection and elucidate its predictive validity of albumin activity across hepatic disease progression and etiology.

Methods This study synthesized a novel ratiometric fluorescent probe with an improved structure of 2′-FBPBN. The technique was used to detect native human albumin (HA) activity in 244 patients with hepatitis B cirrhosis (LC) and 66 patients with hepatocellular carcinoma (HCC). Clinical and laboratory data were also collected.

Results Patients with LC and HCC were divided into normal albumin and low albumin (LA) groups. The median levels of albumin and HA activity in LC patients were 41.44 g/L and 51.85%, 28.51 g/L and 53.89%, respectively, while in HCC patients, they were 43.19 g/L and 33.69%, 30.77 g/L and 43.63%, respectively. The levels of total bilirubin, prothrombin time, international normalized ratio, native HA activity, Child-Pugh score, model for end-stage liver disease score, and model for end-stage liver disease-Na score were significantly higher in the LA groups, while the levels of platelet, cholesterol, and cholinesterase were lower compared to the normal albumin group (P < 0.05). The LA groups were more likely to suffer from hepatic encephalopathy and ascites. Patients with normal active HA had significantly higher survival rates than those with low active HA.

Conclusions Native HA activity may outperform albumin as a prognostic indicator for assessing the severity of liver disease.

Keywords

Hepatitis B / Liver cirrhosis / Hepatocellular carcinoma / Albumin / Fluo-rescent probe / Prognosis

Acknowledgments

We thank all the colleagues who participated in data collection, sample preparation, testing, and analysis.

Funding

This work was funded by grants from the Study on Detection Method and Clinical Application of Active Protein in Chronic Wasting Diseases (Project number:2020020209-JH2/103).

Conflict of interest

Among the authors, Mingyu Duan, affiliated with Shenyang Bei-chuang Laboratory Limited Liability Company, has a patent ap-plication related to the research presented in this manuscript (pat-ent number CN114858763A). The patent is currently pending. No other conflicts of interest have been declared by the other authors.

Author contributions

Study design, patient recruitment, sample acquisition (YW, GLC, FYC, MYD, YG, XL, XFW, TYC), data collection and analysis (XL, CL, XYL, JMQ, MYXL, LGZ), manuscript drafting, editing, and revising (XL, ZZL, MYD). All the authors have read, revised, and approved the final version of the manuscript.

Ethical statement

This study was approved by the Ethics Committee of the Sixth People’s Hospital of Shenyang (2020-08-001-02) and registered on the Medical Research Registration and Information System (Website: https://www.medicalresearch.org.cn/login, Registration number: MR-21-22-002630). The clinical cohort study was used in this research, and informed consent was obtained from all patients. All procedures were performed in accordance with the ethical standards of the Institutional Review Board of the Sixth People’s Hospital of Shenyang, and the principles outlined in the Helsinki Declaration of 1975 and its later amendments.

Data sharing statement

No additional data are available.

References

[1] Sharma A, Nagalli S. Chronic Liver Disease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. PMID:32119484.

[2] Nault JC, Ningarhari M, Rebouissou S, Zucman-Rossi J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gas-troenterol Hepatol 2019; 16(9):544-558. doi:10.1038/s41575-019-0165-3,PMID:31253940.

[3] Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20(23):7312-7324. doi:10.3748/wjg.v20.i23.7312,PMID:24966602.

[4] Yang YM, Kim SY, Seki E.Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets. Semin Liver Dis 2019; 39(1):26-42. doi:10.1055/s-0038-1676806,PMID:30809789.

[5] Domenicali M, Baldassarre M, Giannone FA, Naldi M, Mastroroberto M, Biselli M, et al. Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cir-rhosis. Hepatology 2014; 60(6):1851-1860. doi:10.1002/hep.27322,PMID:25048618.

[6] Sun L, Yin H, Liu M, Xu G, Zhou X, Ge P, et al. Impaired albumin func-tion: a novel potential indicator for liver function damage? Ann Med 2019; 51(7-8):333-344. doi:10.1080/07853890.2019.1693056,PMID:31714153.

[7] Carvalho JR, Verdelho Machado M. New Insights About Al-bumin and Liver Disease. Ann Hepatol 2018; 17(4):547-560. doi:10.5604/01.3001.0012.0916,PMID:29893696.

[8] Alves de Mattos A. Current indications for the use of albumin in the treatment of cirrhosis. Ann Hepatol 2011; 10(Suppl 1):S15-S20. PMID:21566250.

[9] Zaccherini G, Bernardi M. The role and indications of albumin in ad-vanced liver disease. Acta Gastroenterol Belg 2019; 82(2):301-308. PMID:31314192.

[10] Valerio C, Theocharidou E, Davenport A, Agarwal B. Human albumin solution for patients with cirrhosis and acute on chronic liver failure: Beyond simple volume expansion. World J Hepatol 2016; 8(7):345-354. doi:10.4254/wjh.v8.i7.345, PMID:26981172.

[11] Ge GB, Ai CZ, Hu WB, Hou J, Zhu LL, He GY, et al.The role of se-rum albumin in the metabolism of Boc5:molecular identification, species differences and contribution to plasma metabolism. Eur J Pharm Sci 2013; 48(1-2):360-369. doi:10.1016/j.ejps.2012.11.011,PMID:23220486.

[12] Ge GB, Feng L, Jin Q, Wang YR, Liu ZM, Zhu XY, et al. A novel substrate-inspired fluorescent probe to monitor native albumin in human plas-ma and living cells. Anal Chim Acta 2017; 989:71-79. doi:10.1016/j.aca.2017.07.048,PMID:28915944.

[13] Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association. The guidelines of prevention and treatment for chronic hepatitis B (2019 version). Zhonghua Gan Zang Bing Za Zhi 2019;27(12):938-961. doi:10.3760/cma.j.issn.1007-3418.2019.12.007, PMID:31941257.

[14] Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M, et al. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition). Liver Cancer 2020; 9(6):682-720. doi:10.1159/000509424,PMID:33442540.

[15] Ren M, Li J, Xue R, Wang Z, Coll SL, Meng Q. Liver function and energy me-tabolism in hepatocellular carcinoma developed in patients with hepa-titis B-related cirrhosis. Medicine (Baltimore) 2019; 98(19):e15528. doi:10.1097/MD.0000000000015528,PMID:31083199.

[16] Meng QH, Hou W, Yu HW, Lu J, Li J, Wang JH, et al. Resting energy expenditure and substrate metabolism in patients with acute-on-chronic hepatitis B liver failure. J Clin Gastroenterol 2011; 45(5):456-461. doi:10.1097/MCG.0b013e31820f7f02, PMID:21422948.

[17] Woreta TA, Alqahtani SA. Evaluation of abnormal liver tests. Med Clin North Am 2014; 98(1):1-16. doi:10.1016/j.mcna.2013.09.005,PMID:24266911.

[18] Carr BI, Giannelli G, Guerra V, Giannini EG, Farinati F, Rapac-cini GL, et al. Plasma cholesterol and lipoprotein levels in relation to tumor aggressiveness and survival in HCC patients. Int J Biol Markers 2018; 33(4):423-431. doi:10.1177/1724600818776838,PMID:29874983.

[19] Michalak A, Cichoż-Lach H, Guz M, Kozicka J, Cybulski M, Jeleniewicz W. Plateletcrit and Mean Platelet Volume in the Evaluation of Alco-holic Liver Cirrhosis and Nonalcoholic Fatty Liver Disease Patients. Biomed Res Int 2021; 2021:8867985. doi:10.1155/2021/8867985,PMID:33644233.

[20] Peng Y, Qi X, Guo X. Child-Pugh Versus MELD Score for the Assessment of Prognosis in Liver Cirrhosis: A Systematic Review and Meta-Analy-sis of Observational Studies. Medicine (Baltimore) 2016; 95(8):e2877. doi:10.1097/MD.0000000000002877,PMID:26937922.

[21] Tsoris A, Marlar CA. Use Of The Child Pugh Score In Liver Dis-ease. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. PMID:31194448.

[22] Ruf A, Dirchwolf M, Freeman RB. From Child-Pugh to MELD score and beyond: Taking a walk down memory lane. Ann Hepatol 2022; 27(1):100535. doi:10.1016/j.aohep.2021.100535,PMID:34560316.

[23] Lowe D, Sanvictores T, Zubair M, John S. Alkaline Phos-phatase. StatPearls. Treasure Island (FL): StatPearls Publishing; 2023PMID:29083622.