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

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 mu g/L is considered as normal range of AFP. Elevated pre-transplant serum AFP (> 20 mu g/L) predicts high HCC recurrence after LT. We further divided the 161 recipients into AFP group (n = 77, AFP 6 20 mu g/L) and AFP(+) group (n = 84, AFP > 20 mu g/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 mu mol/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.