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