Evaluation of Lactate Dehydrogenase and Alkaline Phosphatase as Predictive Biomarkers in the Prognosis of Hepatocellular Carcinoma and Development of a New Nomogram

Figures & data

Table 1 Baseline Characteristics Before Propensity Score Matching

Variable	Total	ALP < 172 ng/mL	ALP ≥ 172 ng/mL	p	LDH < 241 ng/mL	LDH ≥ 241 ng/mL	p
Patients	2327	1509	818		1419	908
Male sex	1886 (81.0)	1213 (80.4)	673 (82.3)	0.267	1150 (81.0)	736 (81.1)	0.993
Age ≥ 60 years	972 (41.8)	648 (42.9)	324 (39.6)	0.12	615 (43.3)	357 (39.3)	0.055
HBV	1254 (53.9)	849 (56.3)	405 (49.5)	0.002	754 (53.1)	500 (55.1)	0.362
HCV	39 (1.7)	38 (2.5)	1 (0.1)	<0.001	28 (2.0)	11 (1.2)	0.163
Alcohol	867 (37.3)	549 (36.4)	318 (38.9)	0.235	533 (37.6)	334 (36.8)	0.705
Diabetes mellitus	242 (10.4)	165 (10.9)	77 (9.4)	0.251	149 (10.5)	93 (10.2)	0.842
Hypertension	384 (16.5)	260 (17.2)	124 (15.2)	0.199	232 (16.3)	152 (16.7)	0.804
Child–Pugh class				<0.001			<0.001
A	1627 (69.9)	1228 (81.4)	399 (48.8)		1100 (77.5)	527 (58.0)
B	635 (27.3)	258 (17.1)	377 (46.1)		294 (20.7)	341 (37.6)
C	65 (2.8)	23 (1.5)	42 (5.1)		25 (1.8)	40 (4.4)
ALBI grade				<0.001			<0.001
1	670 (28.8)	566 (37.5)	104 (12.7)		496 (35.0)	174 (19.2)
2	1433 (61.6)	877 (58.1)	556 (68.0)		821 (57.9)	612 (67.4)
3	224 (9.6)	66 (4.4)	158 (19.3)		102 (7.2)	122 (13.4)
ALP, median, U/L	133.0 (91.0–220.0)	102.0 (80.1–130.0)	287.0 (213.1–426.3)	<0.001	114.2 (84.0–175.0)	172.0 (119.0–300.0)	<0.001
LDH, median, U/L	216.0 (175.0–295.0)	199.0 (165.2–260.0)	260.0 (203.0–371.0)	<0.001	184.0 (158.0–208.2)	330.0 (277.0–453.0)	<0.001
Serum AFP, ng/mL				<0.001			<0.001
< 200	1289 (55.4)	881 (58.4)	408 (49.9)		879 (61.9)	410 (45.2)
≥ 200, < 400	127 (5.5)	80 (5.3)	47 (5.7)		80 (5.6)	47 (5.2)
≥ 400	911 (39.1)	548 (36.3)	363 (44.4)		460 (32.4)	451 (49.7)
Platelet count ≥ 100 × 10^9/L	1661 (71.4)	1028 (68.1)	633 (77.4)	<0.001	984 (69.3)	677 (74.6)	0.007
ALT levels ≥ 40 U/L	1205 (51.8)	616 (40.8)	589 (72.0)	<0.001	611 (43.1)	594 (65.4)	<0.001
Leukocyte ≥ 4 × 10^9/L	1924 (82.7)	1210 (80.2)	714 (87.3)	<0.001	1120 (78.9)	804 (88.5)	<0.001
BCLC stage				<0.001			<0.001
0/A	462 (19.9)	389 (25.8)	73 (8.9)		345 (24.3)	117 (12.9)
B	346 (14.9)	277 (18.4)	69 (8.4)		250 (17.6)	96 (10.6)
C	1454 (62.5)	820 (54.3)	634 (77.5)		799 (56.3)	655 (72.1)
D	65 (2.8)	23 (1.5)	42 (5.1)		25 (1.8)	40 (4.4)
Number of tumors ≥ 2	1573 (67.6)	940 (62.3)	633 (77.4)	<0.001	897 (63.2)	676 (74.4)	<0.001
Tumor diameter, cm				<0.001			<0.001
< 3	408 (17.5)	319 (21.1)	89 (10.9)		315 (22.2)	93 (10.2)
≥ 3, < 5	538 (23.1)	400 (26.5)	138 (16.9)		389 (27.4)	149 (16.4)
≥ 5, < 10	850 (36.5)	555 (36.8)	295 (36.1)		510 (35.9)	340 (37.4)
≥ 10	531 (22.8)	235 (15.6)	296 (36.2)		205 (14.4)	326 (35.9)
PVTT	853 (36.7)	410 (27.2)	443 (54.2)	<0.001	409 (28.8)	444 (48.9)	< 0.001
Lymph node metastasis	1022 (43.9)	560 (37.1)	462 (56.5)	<0.001	554 (39.0)	468 (51.5)	< 0.001
Extrahepatic metastases	537 (23.1)	264 (17.5)	273 (33.4)	<0.001	281 (19.8)	256 (28.2)	< 0.001
Lung	311 (13.4)	137 (9.1)	174 (21.3)		146 (10.3)	165 (18.2)
Bone	149 (6.4)	74 (4.9)	75 (9.2)		79 (5.6)	70 (7.7)
Other	198 (8.5)	109 (7.2)	89 (10.9)		112 (7.9)	86 (9.5)
Treatments				<0.001			< 0.001
Supportive care	575 (24.7)	277 (18.4)	298 (36.4)		311 (21.9)	264 (29.1)
Liver resection	330 (14.2)	272 (18.0)	58 (7.1)		227 (16.0)	103 (11.3)
RFA	90 (3.9)	84 (5.6)	6 (0.7)		66 (4.7)	24 (2.6)
TACE	702 (30.2)	448 (29.7)	254 (31.1)		406 (28.6)	296 (32.6)
Targeted therapy + ICI	84 (3.6)	47 (3.1)	37 (4.5)		54 (3.8)	30 (3.3)
Adjuvant TACE	90 (3.9)	85 (5.6)	5 (0.6)		73 (5.1)	17 (1.9)
Other	456 (19.6)	296 (19.6)	160 (19.6)		282 (19.9)	174 (19.2)

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; ALBI, albumin–bilirubin; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; ICI, immune checkpoint inhibitor.

Figure 1 Survival graph for every patient (A). Survival curve stratified by alkaline phosphatase concentration (B) and lactate dehydrogenase concentration (C).

Figure 2 Survival curve for patients after PSM with ALP (A) and LDH (C). Survival curve stratified based on ALP (B) and LDH (D) levels.

Abbreviations: ALP, alkaline phosphatase; LDH, lactate dehydrogenase.

Table 2 Univariate and Multivariate Cox Regression Analyses of Overall Survival Before Propensity Score Matching

Variable	Univariable Cox Regression			Multivariable Cox Regression
	HR	95CI	p	HR	95CI	p
Sex (male/female)	1.085	0.934–1.259	0.286
Age (≥ 60/< 60 years)	0.975	0.867–1.096	0.668
HBV (positive/negative)	0.976	0.869–1.095	0.678
HCV (positive/negative)	0.551	0.319–0.952	0.033	1.049	0.521–1.577	0.729
Alcoholism (positive/negative)	1.129	1.003–1.270	0.044	1.124	1.001–1.27	0.048
Diabetes mellitus (positive/negative)	0.999	0.824–1.211	0.988
Hypertension (positive/negative)	0.823	0.698–0.971	0.021	0.858	0.724–1.009	0.065
Child–Pugh class (B + C/A)	2.067	1.835–2.327	< 0.001	1.271	1.101–1.463	0.001
ALBI grade (2+3/1)	1.573	1.374–1.802	< 0.001	0.969	0.833–1.132	0.708
ALP (≥ 172/< 172 U/L)	2.673	2.380–3.002	< 0.001	1.594	1.377–1.820	< 0.001
LDH (≥ 241/241 U/L)	1.918	1.709–2.153	< 0.001	1.367	1.205–1.554	< 0.001
AFP (≥ 400/< 400 ng/mL)	1.199	1.067–1.347	0.002	0.925	0.819–1.048	0.224
Platelet (< 100,000/≥ 100,000/μL)	1.010	0.890–1.147	0.873
ALT (≥ 40/< 40 U/L)	1.361	1.211–1.529	< 0.001	0.968	0.856–1.102	0.649
Leukocyte (< 4000/≥ 4000/μL)	0.885	0.759–1.032	0.118
BCLC stage			<0.001			<0.001
0/A	1.000			1.000
B	1.351	1.053–1.732	0.018	0.982	0.740–1.302	0.897
C	2.940	2.436–3.547	< 0.001	1.575	1.216–2.045	0.001
D	5.643	4.062–7.838	< 0.001	1.836	1.257–2.675	0.002
Number of tumor (≥ 2/< 2)	1.825	1.594–2.090	< 0.001	1.255	1.069–1.472	0.005
Tumor diameter (≥ 5/< 5 cm)	1.849	1.633–2.094	< 0.001	1.243	1.086–1.425	0.002
PVTT (positive/negative)	2.079	1.852–2.335	< 0.001	1.140	0.990–1.324	0.069
Lymph node metastasis (yes/no)	1.696	1.511–1.904	< 0.001	0.912	0.787–1.053	0.206
Extrahepatic metastases (yes/no)	1.958	1.728–2.219	< 0.001	1.224	1.063–1.401	0.005
Antitumor therapy			<0.001			<0.001
Supportive care	1.000			1.000
Liver resection	0.288	0.231–0.359	<0.001	0.463	0.368–0.587	<0.001
RFA	0.126	0.072–0.218	<0.001	0.225	0.129–0.397	<0.001
TACE	0.580	0.502–0.670	<0.001	0.611	0.528–0.716	<0.001
Targeted therapy+ ICI	0.819	0.610–1.101	0.186	0.794	0.593–1.078	0.142
Adjuvant TACE	0.257	0.171–0.385	<0.001	0.437	0.292–0.666	<0.001
Other	0.548	0.464–0.647	<0.001	0.610	0.518–0.728	<0.001

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; ALBI, albumin–bilirubin; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization; ICI, immune checkpoint inhibitor.

Table 3 Univariate and Multivariate Cox Regression Analyses of Overall Survival in the Training Set

Variable	Univariable Cox Regression			Multivariable Cox Regression
	HR	95CI	p	HR	95CI	p
Sex (male/female)	1.059	0.89–1.261	0.516
Age (≥60/<60 years)	0.982	0.854–1.128	0.793
HBV (positive/negative)	1.003	0.874–1.151	0.961
HCV (positive/negative)	0.555	0.288–1.07	0.079
Alcoholism (positive/negative)	1.147	0.998–1.318	0.054
Diabetes mellitus (positive/negative)	0.969	0.775–1.212	0.785
Hypertension (positive/negative)	0.879	0.724–1.066	0.190
Child–Pugh class (B + C/A)	2.045	1.775–2.355	<0.001	1.264	1.066–1.498	0.007
ALBI grade (2 + 3/1)	1.499	1.275–1.761	<0.001	0.976	0.815–1.169	0.792
ALP (≥ 172/< 172 U/L)	2.551	2.223–2.929	<0.001	1.506	1.276–1.777	<0.001
LDH (≥ 241/ 241 U/L)	1.917	1.671–2.2	<0.001	1.379	1.187–1.603	<0.001
AFP (≥ 400/< 400 ng/mL)	1.160	1.01–1.334	0.036	0.914	0.79–1.058	0.227
Platelet (< 100,000/≥ 100,000/μL)	1.054	0.906–1.227	0.495
ALT (≥ 40/< 40 U/L)	1.320	1.15–1.516	<0.001	0.999	0.86–1.16	0.987
Leukocyte (< 4000/≥ 4000/μL)	1.270	1.054–1.529	0.012	1.059	0.873–1.283	0.563
BCLC stage			<0.001			0.001
0/A	1.000	–		1.000
B	1.212	0.901–1.632	0.204	0.963	0.686–1.353	0.830
C	2.839	2.288–3.521	<0.001	1.608	1.189–2.175	0.002
D	4.893	3.245–7.378	<0.001	1.748	1.093–2.796	0.020
Number of tumor (≥ 2/< 2)	1.730	1.476–2.028	<0.001	1.146	0.946–1.387	0.163
Tumor diameter (≥ 5/< 5 cm)	1.916	1.653–2.221	<0.001	1.323	1.125–1.555	0.001
PVTT (positive/negative)	2.032	1.77–2.332	<0.001	1.105	0.93–1.312	0.256
Lymph node metastasis (yes/no)	1.693	1.476–1.942	<0.001	0.943	0.793–1.122	0.508
Extrahepatic metastases (yes/no)	2.203	1.902–2.551	<0.001	1.379	1.171–1.623	<0.001
Antitumor therapy			<0.001			<0.001
Supportive care	1.000
Liver resection	0.325	0.252–0.418	<0.001	0.500	0.383–0.652	<0.001
RFA	0.143	0.08–0.255	<0.001	0.260	0.144–0.469	<0.001
TACE	0.591	0.497–0.702	<0.001	0.598	0.498–0.717	<0.001
Targeted therapy+ ICI	0.806	0.568–1.143	0.226	0.748	0.525–1.065	0.107
Adjuvant TACE	0.274	0.168–0.448	<0.001	0.486	0.294–0.803	0.005
Other	0.568	0.466–0.692	<0.001	0.598	0.488–0.733	<0.001

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; ALBI, albumin–bilirubin; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; AFP, alpha-fetoprotein; ALT, alanine aminotransferase; BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus.

Figure 3 Nomograph is constructed based on independent risk factors determined by multifactor Cox analysis.

Abbreviations: ALP, alkaline phosphatase; LDH, lactate dehydrogenase; BCLC, Barcelona Clinic Liver Cancer.