Homocysteine: A novel prognostic biomarker in liver transplantation for alpha-fetoprotein- negative hepatocellular carcinoma

Article type: Research Article

Authors: Yang, Modan^{a; b; 1} | Tan, Winyen^{a; b; 1} | Yang, Xinyu^{a; b} | Zhuo, Jianyong^{a; b} | Lin, Zuyuan^{a; b} | Cen, Beini^{a; b} | Lian, Zhengxing^{a; b} | Li, Huihui^{a; b} | Lu, Di^{a; b} | Wei, Xuyong^{a; b} | Zheng, Shusen^{a; b; c} | Xu, Xiao^{a; b; *}

Affiliations: [a] Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China | [b] Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China | [c] Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, China

Correspondence: [*] Corresponding author: Xiao Xu, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, Zhejiang 310003, China. Tel.: +86 571 87236567; Fax: +86 571 87236567; E-mail: zjxu@zju.edu.cn.

Note: [1] The first 2 authors contributed equally to this work.

Abstract: BACKGROUND: Precise recipient selection optimizes the prognosis of liver transplantation (LT) for hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) is the most commonly used biomarker for diagnosis and prognosis of HCC in the clinical context. As a crucial molecule in methionine cycle, homocysteine (Hcy) level has been proved to be related to HCC progression and metastasis. OBJECTIVE: We aimed to explore the prognostic capacity of pre-transplant serum Hcy level in LT for HCC. METHODS: This study retrospectively enrolled 161 HCC patients who had underwent LT from donation after cardiac death (DCD) in the First Affiliated Hospital of Zhejiang University from 2015.01.01 to 2018.09.01. Pre-transplant serum Hcy level was incorporated into statistical analysis together with other clinical parameters and pathological features. RESULTS: From an overall perspective, significant difference was observed in Hcy level between recurrence (n= 61) and non-recurrence group (n= 100) though subsequent analysis showed unsatisfactory predicting performance. In the whole cohort, multivariate analysis showed that lnAFP (p= 0.010) and Milan criteria (MC, p< 0.001) were independent risk factors of HCC recurrence after LT. MA score based on MC and lnAFP performed well in predicting post-LT tumor recurrence with the AUROC at 0.836 (p< 0.001) and 3-year recurrence-free survival rate at 96.8% (p< 0.001) in the low risk group (n= 69). According to the clinical practice, serum concentration lower than 20 μg/L is considered as normal range of AFP. Elevated pre-transplant serum AFP (> 20 μg/L) predicts high HCC recurrence after LT. We further divided the 161 recipients into AFP- group (n= 77, AFP ⩽ 20 μg/L) and AFP+ group (n= 84, AFP > 20 μg/L). MA score was still well presented in the AFP+ group and the AUROC for tumor recurrence was 0.823 (p< 0.001), whereas the predicting accuracy was reduced in AFP- group (AUROC: 0.754, P< 0.001). After subsequent analysis, we found that elevated pre-transplant Hcy level (> 12.75 μmol/L) predicted increased tumor recurrence risk in AFP- group. The 3-year recurrence-free survival rates were 92.0% and 53.7% (p< 0.001) in low Hcy subgroup (n= 40) and high Hcy subgroup (n= 37) respectively. Multivariate analysis showed that Hcy (p= 0.040) and Milan criteria (p= 0.003) were independent risk factors for post-transplant tumor recurrence in AFP- group. Further combination of Hcy level and Milan criteria identified a subgroup of AFP- recipients with acceptable outcomes even though beyond Milan criteria (3-year recurrence-free survival rate: 77.7%, p< 0.001). CONCLUSION: As a classic predictor in HCC prognosis, AFP performed well in our study cohort when combined with Milan criteria. Homocysteine was an effective prognostic biomarker in LT for AFP- hepatocellular carcinoma. In recipients exceeding Milan criteria, acceptable post-transplant outcome could be seen in those with low Hcy and AFP level.

Keywords: Homocysteine, alpha-fetoprotein, Milan criteria, liver transplantation, hepatocellular carcinoma, tumor recurrence

DOI: 10.3233/CBM-201545

Journal: Cancer Biomarkers, vol. 29, no. 2, pp. 197-206, 2020