
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

72291
10.1038/s41598-024-72291-5
Article
Combined DeRitis ratio and alkaline phosphatase on the prediction of portal vein tumor thrombosis in patients with hepatocellular carcinoma
Miao Tong-Guo 1
Zhang Shi-Ya 3
Zhang Yun-Jing 3
Ma Dong mamamadong@163.com

23
Nan Yue-Min nanyuemin@163.com

1
1 https://ror.org/04eymdx19 grid.256883.2 0000 0004 1760 8442 Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital, Shijiazhuang, 050017 Hebei People’s Republic of China
2 https://ror.org/04eymdx19 grid.256883.2 0000 0004 1760 8442 Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, and Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, Hebei Medical University, Shijiazhuang, 050017 Hebei People’s Republic of China
3 https://ror.org/04z4wmb81 grid.440734.0 0000 0001 0707 0296 School of Public Health, North China University of Science and Technology, Tangshan, 063210 Hebei People’s Republic of China
16 9 2024
16 9 2024
2024
14 2161423 10 2023
5 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Portal vein tumor thrombosis (PVTT) is one of the common complications of HCC and represents a sign of poor prognosis. PVTT signifies advanced liver cancer, deteriorating liver function, and heightened susceptibility to intrahepatic dissemination, systemic metastasis, and complications related to portal hypertension. It is important to seek novel strategies for PVTT arising from HCC. Portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) represents a worse liver function, less treatment tolerance, and poor prognosis. This study aimed to investigate the diagnostic value of the combination of the DeRitis ratio (AST/ALT) and alkaline phosphatase (ALP) index (briefly named DALP) in predicting the occurrence risk of PVTT in patients with HCC. We performed a retrospective study enrolling consecutive patients with HCC from January 2017 to December 2020 in Hebei Medical University Third Hospital. ROC analysis was performed to estimate the predictive effectiveness and optimal cut-off value of DALP for PVTT occurrence in patients with HCC. Kaplan–Meier analysis revealed the survival probabilities in each subgroup according to the risk classification of DALP value. Univariate and multivariate Logistics regression analyses were applied to determine the independent risk for poor prognosis. ROC analysis revealed that the optimal cut-off value for DALP was 1.045, with an area under the curve (AUC) of 0.793 (95% CI 0.697–0.888). Based on the DALP classification (three scores: 0–2) with distinguishable prognoses, patients in the score 0 group had the best prognosis with a 1-year overall survival (OS) of 100%, whereas score 2 patients had the worst prognosis with 1-year OS of 72.4%. Similarly, there was a statistically different recurrence-free survival among the three groups. Besides, this risk classification was also associated with PVTT progression in HCC patients (odds ratio [OR] 5.822, P < 0.0001). Pathologically, patients in the score 2 group had more advanced tumors considering PVTT, extrahepatic metastasis, and ascites than those in score 0, 1 groups. Moreover, patients with a score of 2 had more severe hepatic inflammation than other groups. Combination of DeRitis ratio and ALP index presented a better predictive value for PVTT occurrence in patients with HCC, contributing to the tertiary prevention.

Keywords

Hepatocellular carcinoma
Portal vein tumor thrombosis
DeRitis ratio
Alkaline phosphatase
Subject terms

Cancer prevention
Gastrointestinal cancer
Metastasis
Tumour angiogenesis
Tumour biomarkers
Biomarkers
Risk factors
Key Research and Development Program of Hebei Province-Biomedical Innovation Project23377705D Nan Yue-Min issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Hepatocellular carcinoma (HCC) is a significant malignant tumor related to the digestive system. According to the Global Cancer Observatory (GLOBOCAN) in 2020, HCC ranks as the sixth most common malignancy and the third leading cause of cancer-related deaths worldwide, indicating a major global health challenge1,2. Particularly in China, HCC holds the fourth-highest incidence and the second-highest mortality rate among malignant tumors3,4. The main known risk factors associated with HCC include viral infections (chronic hepatitis B and C), metabolic disorders (diabetes and non-alcoholic fatty liver disease), toxic exposures (alcohol and aflatoxins), and abnormal immunity5. Unfortunately, the diagnosis of liver cancer at advanced stages leaves patients with limited treatment options and significantly poor survival rates.

Portal vein tumor thrombosis (PVTT), the most common form of microvascular invasion, is a frequent complication of HCC. Around 10–60% of patients diagnosed with PVTT have entered intermediate and advanced stages with the deterioration of liver function, which leads to intrahepatic and distant metastasis, contributing to merely around 2.7 months of the median survival time for HCC patients with PVTT (HCC-PVTT) after receiving supportive care6,7. Therefore, preventing PVTT occurrence in patients with HCC clinically represents tertiary prevention. Presently, PVTT is categorized into five grades by the Liver Cancer Study Group of Japan (LCSGJ) worldwide, including VP0, VP1, VP2, VP3, VP4. There is a significant decline in a grade-dependent manner in the overall survival rates of 1-year, 3-year, and 5-year patients. Previous studies have investigated the relationship between treatment and survival rates for patients with different grades of HCC-PVTT. However, a precise prediction of the initiation of PVTT in patients with HCC has yet been an unsolved problem8–10. Currently, the diagnosis of HCC-PVTT primarily relies on imaging techniques such as contrast-enhanced computer tomography (CT) and magnetic resonance imaging (MRI), lacking simple and cost-effective markers11,12.

Growing evidence indicates that active viral replication-induced chronic inflammation increases the risk of liver cancer by creating a microenvironment that alters tissue homeostasis, cell proliferation, and genetic stability, which further enables tumors to originate, develop, and metastasize13,14, suggestive of the compromised liver environment contributes to the PVTT and the metastasis of tumor cells. Meanwhile, liver damage caused by the persistent HBV/HCV infection triggers increases in liver enzyme levels, like as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), especially for the DeRitis ratio (AST/ALT) in recent years15–17, is significantly correlated with the severity of diseases and adverse outcomes. The DeRitis ratio is considered a reliable predictor of liver function damage, with an elevated ratio indicating tumor progression and deterioration of liver functional reserve. Studies have reported that the DeRitis ratio was greater than 1, representing severe liver inflammation, potentially contributing to the development of liver cancer and tumor metastasis18,19. Parallelly, as a hydrolytic enzyme primarily distributed in the liver, bone, and kidney, alkaline phosphatase (ALP) also plays an important role in the occurrence and development of HCC along positively correlated with poor prognosis. Moreover, recent literature also displays that ALP is considered an independent prognostic factor and the most predictive factor of HCC20,21. Potentially, combine of DeRitis ratio and ALP may be effective in the prediction of PVTT in patients with HCC22,23. Herein, we aim to establish a scoring system based on the combined DeRitis ratio and ALP to predict the occurrence risk of PVTT in patients with HCC.

Materials and methods

Participants and study design

In this retrospective study, patients with HCC admitted to Hebei Medical University Third Hospital from January 2017 to December 2020 were enrolled. This study conformed to the ethical standards of the Declaration of Helsinki and was approved by the Ethics Committee of Hebei Medical University Third Hospital (Approve Number: KS2023-068-1). Due to the study's retrospective nature, the requirement for informed consent was waived by the Ethics Committee of Hebei Medical University Third Hospital. The inclusion criteria for HCC patients were as follows: (a) newly diagnosed with HCC based on radiological diagnosis or pathological examination; (b) no history of radiotherapy, chemotherapy or anti-inflammatory treatment; (c) no other malignant tumors or related infectious diseases; and (d) complete clinical and pathological data. The exclusion criteria included: (a) simultaneous malignancies; (b) with secondary hepatic carcinoma; (c) incomplete clinical and follow-up data. Finally, 102 HCC patients (68 with and 34 without PVTT) were included in the current study (Fig. 1).Fig. 1 Participant flow. HCC hepatocellular carcinoma, PVTT portal vein tumor thrombus.

Clinicopathologic parameters and follow-up

Patient demographic information, including age and sex, and clinicopathological features, including liver function and tumor-related parameters, were obtained through a medical electronic record system. All the HCC patients were classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Size, number, neovascularization, and extrahepatic metastasis in tumors were evaluated by computed tomography (CT) scan or contrast-enhanced magnetic resonance imaging (MRI) and pathology examinations, respectively. Follow-up was defined as end up at the date (December 2023) of the final visit for patients alive or the date of death for patients with HCC before the final time.

Laboratory parameters and definitions

The laboratory data were obtained from the patients’ first venous blood samples taken at admission. The outcome of in-hospital patients with HCC was gotten from medical records, including alanine transaminase, aspartate transaminase, alpha-fetoprotein, alkaline phosphatase, white blood cell count, neutrophil count, lymphocyte count, etc.

Combination of DeRitis ratio (AST/ALT) and alkaline phosphatase (ALP) index was briefly named DALP24. Based on the DALP classification, three subgroups were defined as: score 0, AST/ALT ≤ 1.045 and ALP ≤ 120.5 U/L; score 1, AST/ALT ≤ 1.045, ALP > 120.5 U/L and AST/ALT > 1.045, ALP ≤ 120.5 U/L; score 2, AST/ALT > 1.045 and ALP > 120.5 U/L.

Statistical analysis

Statistical analyses were carried out using SPSS version 25.0 (IBM, Armonk, New York, USA). Quantitative data was described by a mean (SD). Among them, independent sample t test was used for comparing normally distributed data, Mann–Whitney U test was used for comparing non-normal distributed data between two groups. Categorical variables were shown as numbers (frequency) and were compared using Chi-squared test or Fisher's exact tests. Survival curve was plotted using the Kaplan–Meier method with log-rank test. The multiple comparisons was adjusted by the Bonferroni correction. The optimal cut-off value of the DALP was determined by receiver operating characteristic (ROC) curve. Logistics regression analysis was utilized to identify independent risk factors. Significant variables in univariate analyses were brought into the multivariate model analysis. Multivariate analysis with the forward stepwise method was used to avoid the multicollinearity. Two-sided P < 0.05 was considered statistically significant (P < 0.017 after Bonferroni correction).

Results

Characteristics of patients with HCC

In total, 102 patients were included in the study (Fig. 1), and baseline characteristics were displayed in Table 1. The mean age was 55.8 ± 9.3 years, 87 patients were males (85.3%). 27 patients (26.5%) had ascites. Aspects of oncology features, 69 patients (67.6%) showed AFP > 20 ng/mL. 50 cases (49%) with tumor size > 5 cm, 52 cases (50.9%) with multiple tumors, 37 cases (36.3%) in BCLC-C or -D stages, and 34 patients (33.3%) had PVTT. After comparison, statistical variables between the PVTT group (n = 34) and the non-PVTT group (n = 68) included ascites, BCLC Stage, extrahepatic metastasis, Tumor size, TBIL, DBIL, DeRitis ratio, NEUT, WBC, PLT, PT, ALP, A/G (all P < 0.05, Table 1). Table 1 Characteristics and laboratory data of patients with HCC (n = 102).

Variable	Total (n = 102)	None-PVTT (n = 68)	PVTT (n = 34)	P value	
Male	87 (85.3%)	58 (85.3%)	29 (85.3%)	1.000	
Age (years)	55.8 (9.3)	56.5 (9.2)	54.4 (9.6)	0.696	
Obesity	49 (48.0%)	32 (47.1%)	17 (50.0%)	0.779	
1-year death	11 (10.8%)	0 (0.0%)	11 (32.4%)	< 0.001	
Diabetes	6 (5.9%)	4 (5.9%)	2 (5.9%)	1.000	
Hypertension	30 (29.4%)	18 (26.5%)	12 (35.3%)	0.357	
Alcohol	36 (35.3%)	22 (32.4%)	14 (41.2%)	0.379	
Smoke	40 (39.2%)	25 (36.8%)	15 (44.1%)	0.473	
Ascites	27 (26.5%)	12 (17.6%)	15 (44.1%)	0.004	
AFP	0.073	
 ≤ 20 ng/mL	33 (32.4%)	26 (38.2%)	7 (20.6%)		
 > 20 ng/mL	69 (67.6%)	42 (61.8%)	27 (79.4%)		
BCLC stage	< 0.001	
 A	36 (35.3%)	36 (52.9%)	0 (0.0%)		
 B	29 (28.4%)	29 (42.6%)	0 (0.0%)		
 C + D	37 (36.3%)	3 (4.4%)	34 (100.0%)		
Extrahepatic metastasis	16 (15.7%)	3 (4.4%)	13 (38.2%)	< 0.001	
Tumor number	0.123	
 Single	50 (49%)	37 (54.4%)	13 (38.2%)		
 Multiple	52 (51%)	31 (45.6%)	21 (61.8%)		
Tumor size (cm)	0.025	
 ≤ 5	52 (51%)	40 (58.8%)	12 (35.3%)		
 > 5	50 (49%)	28 (41.2%)	22 (64.7%)		
TBIL (μmol/L)	52.85 (71.48)	42.15 (62.55)	74.24 (83.59)	0.002	
DBIL (μmol/L)	32.43 (56.36)	25.21 (50.14)	46.86 (65.54)	0.002	
TG (mmol/L)	1.28 (1.08)	1.06 (0.73)	1.71 (1.48)	0.086	
TC (mmol/L)	3.94 (1.26)	3.95 (1.17)	3.89 (1.45)	0.454	
AST (U/L)	98.17 (159)	59.60 (53.62)	175.32 (249.69)	0.002	
ALT (U/L)	75.09 (177.5)	54.60 (52.25)	116.08 (297.18)	0.180	
DeRitis ratio	1.48 (0.96)	1.24 (0.69)	1.97 (1.23)	0.001	
HDL (mmol/L)	0.98 (0.43)	1.01 (0.41)	0.93 (0.48)	0.427	
LDL (mmol/L)	2.27 (0.92)	2.36 (0.75)	2.09 (1.17)	0.196	
NEUT (109/L)	3.88 (2.58)	3.31 (2.04)	5.04 (3.15)	0.001	
WBC (109/L)	5.77 (3.09)	5.15 (2.60)	7.00 (3.64)	0.005	
LYM (109/L)	1.30 (0.69)	1.30 (0.67)	1.28 (0.74)	0.652	
MONO (1012/L)	0.50 (0.39)	0.45 (0.29)	0.60 (0.53)	0.072	
RBC (1012/L)	4.11 (0.83)	4.12 (0.71)	4.10 (1.05)	0.910	
HGB (g/L)	126.35 (21.85)	128.33 (21.24)	122.38 (22.83)	0.196	
PLT (109/L)	126.43 (74.41)	110.98 (57.58)	157.34 (93.47)	0.018	
PT (s)	14.07 (3.62)	13.36 (2.06)	15.49 (5.33)	0.010	
TP (g/L)	65.81 (8.13)	65.76 (7.53)	65.90 (9.31)	0.934	
ALB (g/L)	36.65 (7.25)	37.81 (6.43)	34.34 (8.30)	0.022	
GLB (g/L)	28.90 (7.57)	27.87 (6.41)	30.96 (9.26)	0.060	
A/G	1.37 (0.50)	1.43 (0.43)	1.25 (0.62)	0.028	
ALP (U/L)	129.51 (78.3)	107.51 (52.43)	173.5 (100.95)	< 0.001	
DALP	< 0.001	
 Score 0	32 (31.4%)	29 (42.6%)	3 (8.8%)		
 Score 1	41 (40.2%)	31 (45.6%)	10 (29.4%)		
 Score 2	29 (28.4%)	8 (11.8%)	21 (61.8%)		
AFP Alpha-fetoprotein, BCLC Barcelona clinic liver cancer, TBIL total bilirubin, DBIL direct bilirubin, TG triglyceride, TC total cholesterol, AST aspartate aminotransferase, ALT alanine aminotransferase; DeRitis ratio, AST/ALT, HDL high-density lipoprotein, LDL low-density lipoprotein, NEUT neutrophil, WBC white blood cell, LYM lymphocyte, MONO monocytes, RBC red blood cell, HGB hemoglobin, PLT platelet, PT prothrombin time, TP total protein, ALB albumin, GLB globulin, A/G albumin/globulin, ALP alkaline phosphatase, DAPL DeRitis ratio, ALP.

Patients in the PVTT group were typically diagnosed at the advanced stages of BCLC (C or even D stages), with a large tumor size and prone to extrahepatic metastasis. Moreover, the 1-year survival rate of patients with PVTT was apparently lower than that of patients in the none-PVTT group. Furthermore, they had significantly higher levels of TBIL, DBIL, DeRitis ratio, NEUT, WBC, PLT, PT, ALP, and DAPL compared to patients in the none-PVTT group (all P < 0.05), suggestive of higher levels of inflammation and altered coagulation function in the PVTT group compared to the none-PVTT group (Table 1).

Multivariate analysis of risk factors related to PVTT

To corroborate the independent risk factors impacting the occurrence of PVTT in patients with HCC, the above significant variables from Table 1 were included in the multivariate model with the forward stepwise method. The results of multivariate analysis revealed that WBC (OR 1.244, 95% CI 1.047–1.480, P = 0.013) and DALP (OR 5.822, 95% CI 2.717–12.477, P < 0.0001) were independent risk factors of PVTT, positively associated with their increase in patients with HCC (Table 2). Table 2 Multivariate logistic regression of risk factors for PVTT.

	β	SE	Wald χ2	P value	OR	95% CI	
Ascites				0.145			
AFP > 20/≤ 20 ng/mL				0.144			
Tumor size (cm): > 5/≤ 5				0.380			
TBIL (μmol/L)				0.775			
DBIL (μmol/L)				0.846			
TG (mmol/L)				0.075			
NEUT (109/L)				0.884			
WBC (109/L)	0.219	0.088	6.125	0.013	1.244	1.047–1.480	
MONO (1012/L)				0.815			
PLT (109/L)				0.622			
PT (s)				0.093			
A/G				0.715			
DALP (score 2 vs. 1 vs. 0)	1.762	0.389	20.518	< 0.001	5.822	2.717–12.477	
AFP Alpha-fetoprotein, TBIL total Bilirubin, DBIL direct bilirubin, TG triglyceride, NEUT neutrophil, WBC white blood cell, MONO monocytes, PLT platelet, PT prothrombin time, A/G albumin/globulin, ALP alkaline phosphatase, DAPL DeRitis ratio and ALP.

ROC curve analysis for the predictive value of DALP on PVTT

ROC curves analysis further showed that despite the AUC of DeRitis Ratio and ALP was 0.698 and 0.732, respectively, the AUC of the joint probability of DALP was 0.753 (95% CI 0.645–0.861), as well as the combined score of DALP was 0.793 (95% CI 0.697–0.888), as shown in Table 3. Visually shown in Fig. 2, the combined score of DALP had a significantly better predictive capability for the occurrence of PVTT in patients with HCC, compared to the combined probabilities of the two indicators or each marker. Table 3 ROC curve evaluation of different indicators for predicting PVTT.

Indicates	AUC	Cut-off value	Sensitivity%	Specificity%	P value	
DeRitis ratio	0.698	1.045	82.4	52.9	0.001	
ALP	0.732	120.5	70.6	77.9	< 0.001	
DALP joint probability	0.753	0.306	70.6	76.5	< 0.001	
DALP combined score	0.793	1.5	61.8	88.2	< 0.001	

Fig. 2 ROC curves assessing the predictive ability of DALP in PVTT.

DALP classification correlated with clinic pathological parameters

Next, HCC patients with different DALP scores were further classified into three groups (32 cases with a score of 0, 41 cases with a score of 1, and 29 cases with a score of 2). Of them, patients with score 2 exhibited significant characteristics of tumor invasiveness (including the presence of PVTT, BCLC-C, D stages, and extrahepatic metastasis) and ascites, together with the lowest levels of albumin and the A/G ratio. In contrast, patients with score 0 showed the highest proportion of early-stage BCLC and the highest levels of hemoglobin, as well as low levels of TBIL, DBIL, and GLB (all P < 0.05, Table 4). These results suggested that a higher score of DALP was positively associated with advanced-stage HCC. Table 4 Comparison of characteristics combined scoring based on serum DALP.

Variable	Combined scoring based on serum DALP	P value	
0 score (n = 32)	1 score (n = 41)	2 score (n = 29)	All	0 vs. 1	1 vs. 2	0 vs. 2	
Male	31 (96.9%)	31 (75.6%)	25 (86.2%)	0.031	0.028	0.275	0.182	
Age (years)	55.38 (8.90)	57.83 (8.78)	53.41 (10.23)	0.143				
Obesity	20 (62.5%)	15 (36.6%)	14 (48.3%)	0.095				
1-year death	0 (0.0%)	3 (7.3%)	8 (27.6%)	0.002*	0.251	0.050	0.001	
Diabetes	2 (6.3%)	1 (2.4%)	3 (10.3%)	0.371				
Hypertension	8 (25.0%)	11 (26.8%)	11 (37.9%)	0.537				
Alcohol	15 (46.9%)	13 (31.7%)	8 (27.6%)	0.241				
Smoke	14 (43.8%)	15 (36.6%)	11 (37.9%)	0.844				
Ascites	3 (9.4%)	13 (31.7%)	11 (37.9%)	0.024*	0.022	0.589	0.008	
AFP: > 20 ng/mL	19 (59.4%)	27 (65.9%)	23 (79.3%)	0.239				
BCLC stage	< 0.0001*	0.048	0.004	< 0.001	
 A	18 (56.3%)	14 (34.1%)	4 (13.8%)					
 B	11 (34.4%)	14 (34.1%)	4 (13.8%)					
 C + D	3 (9.4%)	13 (31.8%)	21 (72.4%)					
Extrahepatic metastasis	1 (3.1%)	7 (17.1%)	8 (27.6%)	0.021*	0.072	0.291	0.01	
Multiple tumor	14 (43.8%)	19 (46.3%)	19 (65.5%)	0.183				
Tumor size (cm): > 5	11 (34.4%)	21 (51.2%)	18 (62.1%)	0.095				
PVTT	3 (9.4%)	10 (24.4%)	21 (72.4%)	< 0.001	0.096	< 0.001	< 0.001	
TBIL (μmol/L)	28.76 (49.35)	55.13 (71.50)	76.20 (84.84)	< 0.001	0.012	< 0.001	0.522	
DBIL (μmol/L)	15.74 (40.50)	33.34 (54.34)	49.56 (69.28)	< 0.001	0.007	0.558	< 0.001	
TG (mmol/L)	1.24 (0.91)	0.97 (0.69)	1.76 (1.49)	0.006	0.196	0.005	0.599	
TC (mmol/L)	4.26 (1.12)	3.79 (1.41)	3.78 (1.15)	0.163				
HDL (mmol/L)	1.00 (0.36)	0.95 (0.46)	1.01 (0.46)	0.812				
LDL (mmol/L)	2.37 (0.80)	2.33 (0.83)	2.08 (1.13)	0.470				
NEUT (109/L)	3.54 (1.84)	3.60 (2.59)	4.67 (3.14)	0.150				
WBC (109/L)	5.68 (2.56)	5.38 (3.04)	6.41 (3.65)	0.330				
LYM (109/L)	1.48 (0.79)	1.28 (0.70)	1.12 (0.48)	0.161				
MONO (1012/L)	0.49 (0.37)	0.45 (0.23)	0.58 (0.56)	0.689				
RBC (1012/L)	4.28 (0.70)	4.07 (0.92)	4.00 (0.84)	0.210				
HGB (g/L)	134.4 (17.72)	124.46 (21.65)	120.07 (24.16)	0.030	0.118	1.000	0.038	
PLT (109/L)	113.54 (61.21)	113.12 (58.03)	159.48 (97.11)	0.099				
PT (s)	13.57 (1.90)	13.96 (3.98)	14.83 (4.46)	0.284				
TP (g/L)	64.61 (7.97)	66.30 (7.96)	66.44 (8.64)	0.882				
ALB (g/L)	39.38 (6.62)	37.18 (7.11)	32.89 (6.73)	0.001	0.805	0.013	0.001	
GLB (g/L)	25.31 (6.12)	29.11 (6.39)	32.55 (8.86)	< 0.001	0.035	0.269	< 0.001	
A/G	1.64 (0.47)	1.34 (0.39)	1.12 (0.54)	< 0.001	0.056	0.035	< 0.001	
AFP Alpha-fetoprotein, BCLC Barcelona clinic liver cancer, TBIL total bilirubin, DBIL direct bilirubin, TG triglyceride, TC total cholesterol, AST aspartate aminotransferase, ALT alanine aminotransferase; DeRitis ratio, AST/ALT, HDL high-density lipoprotein, LDL low-density lipoprotein, NEUT neutrophil, WBC white blood cell, LYM lymphocyte, MONO monocytes, RBC red blood cell, HGB hemoglobin, PLT platelet, PT prothrombin time, TP total protein, ALB albumin, GLB globulin, A/G albumin/globulin, ALP alkaline phosphatase, DAPL DeRitis ratio and ALP.

Survival curve analysis

Based on DALP score stratification, the results of survival analysis showed that patients with score 2 presented the poorest survival in terms of 1-year overall survival (score 0 vs. 1: P = 0.121, score 1 vs. 2: P = 0.019, score 0 vs. 2: P = 0.002) and recurrence-free survival (score 0 vs. 1: P = 0.843, score 1 vs. 2: P < 0.0001, score 0 vs. 2: P < 0.001) among three groups (Fig. 3).Fig. 3 Cumulative OS and RFS curves according to DALP score. (A) Cumulative OS curves of patients with HCC. (B) Cumulative RFS curves of patients with HCC. OS overall survival, RFS recurrence-free survival.

Discussion

PVTT is a common clinical manifestation of HCC and serves as a hallmark of advanced stages of the disease6,7. Currently, there is a scarcity of reliable methods or tools available for predicting the prognosis of HCC patients who have not yet developed PVTT. As key enzymes in metabolic processes, the serum levels of AST, ALT, and ALP are routinely assessed to evaluate liver function. Recent studies have highlighted the potential of inexpensive and readily accessible non-invasive biomarkers, such as the DeRitis ratio (AST/ALT) and ALP, as valuable prognostic indicators for predicting disease progression and long-term survival in HCC patients20,25 and other diseases26–30, irrespective of the etiology31. However, research on the association between baseline DeRitis ratio, ALP, and the development of PVTT in HCC patients is limited.

In this study, we established a simple scoring system based on the admission value of the combination of DeRitis ratio and ALP (DALP) to predict the occurrence of PVTT. ROC analysis revealed that this scoring system predicted PVTT occurrence better than using either marker alone (AUC 0.793, 95% CI 0.697–0.888, P < 0.0001), with the optimal cut-off value for the DeRitis ratio being 1.045. An DeRitis ratio > 1 often signifies severe liver inflammation as well as the occurrence and metastasis of liver cancer18,19. In our study, the optimal cut-off value of 1.045 for the DeRitis ratio was closely resembled the ratio of 1 used in prior research. Comparison of baseline characteristics between different DALP scores showed that the DALP score was associated with aggressive HCC, poor prognosis, and increased occurrence of PVTT. Univariate and multivariate analyses further confirmed that the DALP score is an independent risk factor for PVTT. Most importantly, the DALP score can be easily accessible, and its detection is affordable owing to the routine examination of AST, ALT, and ALP prior to clinical treatment. Therefore, we believe that the DALP score can serve as a new biomarker to accurately predict the development in HCC patients. Similarly, Liu et al.32 reported that combining the DeRitis ratio with the neutrophil–lymphocyte ratio (NLR) was able to improve prognostic accuracy in HCC patients undergoing TACE. Additionally, Mo et al.32,33 also developed a nomogram exhibited a superior predictive value of DeRitis ratio for the prognosis in HBV-related HCC patients.

The underlying pathophysiology mechanisms by which an elevated DALP score is associated with the occurrence of PVTT in HCC patients remains unclear. ALT is primarily found in the cytoplasm of hepatocytes, while AST is present in both the cytoplasm and mitochondria. When cellular and mitochondrial membrane integrity is compromised, both of them are released into the bloodstream, resulting in elevated serum levels. Due to the high energy demands for rapid proliferation, tumor cells often exhibit increased aerobic glycolysis, enhancing glucose uptake. AST plays a crucial role in the malate-aspartate shuttle pathway, and its activity, as well as the DeRitis ratio, is frequently elevated in cancer patients. Additionally, the hydrolytic enzyme ALP secreted by injured liver, bones, and intestine tissues acts as cell proliferation via a dephosphorylating mechanism. Particularly, it plays a pivotal role in promoting cancer cell proliferation, vascular invasion, and metastasis, significantly affecting the prognosis of cancer patients26,34, like as HCC35,36. Given the above mechanisms, high tumor progression activity and impaired mitochondrial function may lead to increased AST/ALT release into the bloodstream, along with decreased clearance of AST/ALT as liver function deteriorates. Therefore, an elevated baseline DeRitis ratio and ALP levels comprehensively reflect tumor progression and deterioration of liver functional reserve.

However, there were some limitations in the present study. Firstly, this was a single-center retrospective and observational study, which means selection bias and incomplete clinical information. Secondly, HBV-related indicators (HBsAg titers, HBV DNA levels, positive or negative test results, HBV treatment) were not included in the current analysis and these aspects were reported associated with PVTT37. In addition, the sample size of patients with HCC complicated by PVTT was small, and the diagnosis of these patients relied solely on clinical imaging without a gold standard. Recent literatures have shown that neoplastic thrombosis-associated PIVKA-II retains significant diagnostic capabilities for AFP-negative HCC patients, particularly among Asian populations. Combining PIVKA-II and AFP has been suggested as a potential new approach for surveillance38–40. Although our study did not include PIVKA-II data due to its absence in our database, the DALP scoring system also demonstrated good diagnostic performance for PVTT in HCC patients. In the future, larger-scale, multicenter, prospective studies are needed to incorporate these parameters to further validate their effectiveness.

Conclusion

Our study revealed significant risk factors associated with the occurrence of PVTT in patients with HCC and developed a prognostic DALP score classification, which could accurately predict PVTT, achieving early intervention and improving survival rate. These findings advocate for the active implementation of tertiary prevention strategies and hold promise for improving patient prognosis.

Acknowledgements

We thank Tong-Guo Miao and Yue-Min Nan doctors from the Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital, as well as all the staff during the study.

Author contributions

S.Z. and M.D. conceived the research. S.Z., T.M., M.D., and Y.N. conceived the paper. T.M. and Y.N. organized the data collection and coordinated the field teams. Y.Z. and M.D. offered administrative and technical support. S.Z. analyzed the data. S.Z. and T.M. drafted the manuscript. All authors read and revised the manuscript and approved the submitted version of the paper.

Funding

This work was supported by Key Research and Development Program of Hebei Province-Biomedical Innovation Project (Grant No. 23377705D).

Data availability

Raw data for this study were generated at Hebei Medical University Third Hospital. Derived data supporting the findings of this study are available from the corresponding author upon request.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Tong-Guo Miao and Shi-Ya Zhang.
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