Diabetes mellitus may affect the long-term survival of hepatitis B virus-related hepatocellular carcinoma patients after liver transplantation

Table 1 Baseline characteristics of patients with diabetes mellitus and without diabetes mellitus n (%)

Category	Diabetic (n = 295)	Non-diabetic (n = 1336)	Value	df	P value
Sex			2.999	1	0.083
Male	278 (94.2)	1218 (91.2)
Female	17 (5.8)	118 (8.8)
Age, yr			23.690	1	0.000
≤ 50	96 (32.5)	643 (48.1)
> 50	199 (67.5)	693 (51.9)
Tumor size			4.333	3	0.228
≤ 3	163 (55.3)	704 (52.7)
3-5	85 (28.8)	350 (26.2)
5-7	28 (9.5)	157 (11.8)
> 7	19 (6.4)	125 (9.4)
Number of tumor nodules			0.245	2	0.885
Singer	147 (49.8)	666 (49.9)
≥ 2, ≤ 3	72 (24.4)	341 (25.5)
≥ 4	76 (25.8)	329 (24.6)
Venous invasion			0.641	1	0.423
Absent	256 (86.8)	1135 (85.0)
Present	39 (13.2)	201 (15.0)
Lymph node invasion			1.272	1	0.304
Absent	284 (96.3)	1265 (94.7)
Present	11 (3.7)	71 (5.3)
Capsular invasion			0.005	1	0.942
Absent	259 (87.8)	1175 (87.9)
Present	36 (12.2)	161 (12.1)
Microsatellite lesions			0.430	1	0.512
Absent	234 (79.3)	1082 (81.0)
Present	61 (20.7)	254 (19.0)
Edmondson			4.359	2	0.108
1	12 (4.1)	27 (2.0)
2	168 (56.9)	797 (59.7)
3 + 4 + 5	115 (39.0)	512 (38.3)
Serum AFP level, in ng/mL			5.518	4	0.236
< 200	231 (78.3)	966 (72.3)
200-400	18 (6.1)	87 (6.5)
400-1000	17 (5.8)	122 (9.1)
1000-2000	13 (4.4)	65 (4.9)
> 2000	16 (5.4)	96 (7.2)
MELD score			14.184	2	0.001
< 10	97 (32.9)	582 (43.6)
10-15	94 (31.9)	406 (30.4)
> 15	104 (35.3)	348 (26.0)
Child-Pugh score			12.456	2	0.002
A	125 (42.4)	715 (53.5)
B	104 (35.3)	396 (29.6)
C	66 (22.4)	225 (16.8)
Fasting blood glucose, in mmol/L			678.412	1	0.000
< 7	101 (34.2)	1273 (95.3)
≥ 7	194 (65.8)	63 (4.7)
BMI, in kg/m2			7.937	3	0.047
< 18.5	19 (6.4)	69 (5.2)
18.5-24	164 (55.6)	856 (64.1)
24-28	84 (28.5)	295 (22.1)
> 28	28 (9.5)	116 (8.7)
ALP, in IU/L			1.546	1	0.214
≤ 112	179 (60.7)	862 (64.5)
> 112	116 (39.3)	474 (35.5)
GGT, in IU/L			2.196	1	0.138
≤ 54	107 (36.3)	547 (40.9)
> 54	188 (63.7)	789 (59.1)
AST, in IU/L			2.682	2	0.262
≤ 40	102 (34.6)	481 (36.0)
40-80	107 (36.3)	526 (39.4)
> 80	86 (29.2)	329 (24.6)
ALT, in IU/L			3.142	2	0.208
≤ 40	121 (41.0)	566 (42.4)
40-80	105 (35.6)	517 (38.7)
> 80	69 (23.4)	253 (18.9)
TC, in mmol/L			22.536	1	0.000
≤ 1.7	250 (84.7)	1245 (93.2)
> 1.7	45 (15.3)	91 (6.8)
CH, in mmol/L			3.840	2	0.147
< 3.88	185 (62.7)	865 (64.7)
3.88-5.2	67 (22.7)	329 (24.6)
> 5.2	43 (14.6)	142 (10.6)
Pre-LT antitumor therapy			0.451	2	0.798
No	219 (74.5)	1016 (76.2)
local therapy	48 (16.3)	209 (15.7)
Resection	27 (9.2)	109 (8.2)
HBeAg			0.670	1	0.413
Negative	232 (78.6)	1021 (76.4)
Positive	63 (21.4)	315 (23.6)
HBV DNA, in IU/mL			6.140	1	0.013
Negative, ≤ 103	191 (64.7)	760 (56.9)
Positive, ≥ 103	104 (35.3)	576 (43.1)
Post-LT HBV recurrence			0.217	1	0.740
No	285 (96.6)	1283 (96.0)
Yes	10 (3.4)	53 (4.0)

BMI: Body mass index; DM: Diabetes mellitus; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; TG: Triglyceride; CH: Cholesterol; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; LT: Liver transplantation.

Table 2 Antiviral prophylaxis before and after liver transplantation for hepatitis B virus reinfection

Patients with high risk of HBV reinfection[HBV-DNA ≥ 105 copies/mL or HBeAg(+)]	Patients with low risk of HBV reinfection[HBV-DNA < 105 copies/mL or HBeAg(-)]
Pre-LT: nucleoside analogues, qd 2-4 w	Pre-LT: nucleoside analogues, qd 0-2 w
Intraoperative: HBIG 4000 IU, iv	Intraoperative: HBIG 2000 IU, iv
Post-LT: HBIG 1000 IU, iv, qd, 1-7 d	Post-LT: HBIG 1000 IU, iv, qd, 1-7d
After 7 d, HBIG 1000 IU, iv, once a week; or HBIG 400 IU, im, qd or qod or twice a week. Adjust frequency of HBIG administration to reach target therapeutic concentration	After 7 d, HBIG 1000 IU, iv, once a week; or HBIG 400 IU, im, qd or qod or twice a week. Adjust frequency of HBIG administration to reach target therapeutic concentration
Target therapeutic concentration post-LT	Target therapeutic concentration post-LT
≤ 6 mo post-LT: anti-HBs titer ≥ 500 IU/L	≤ 6 mo post-LT: anti-HBs titer ≥ 300 IU/L
6-12 mo post-LT: anti-HBs titer ≥ 200 IU/L	6-12 mo post-LT: anti-HBs titer ≥ 200 IU/L
≥ 12 mo post-LT: anti-HBs titer ≥ 100 IU/L	≥ 12 mo post-LT: anti-HBs titer ≥ 100 IU/L

HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; LT: Liver transplantation.

Table 3 Univariate analysis of overall 1-, 3- and 5-year survival rates post-liver transplantation between patients with diabetes mellitus and without diabetes mellitus

Variables	DM, %			Non-DM, %			P value
	1 yr	3 yr	5 yr	1 yr	3 yr	5 yr
Sex
Male	80	74	72	84	77	75	0.140
Female	76	62	62	90	88	86	0.016
Age, yr
≤ 50	80	73	73	80	74	71	0.970
> 50	79	73	71	88	83	80	0.002
Tumor size, in cm
≤ 3	83	79	79	90	86	83	0.047
3-5	86	79	74	87	79	77	0.689
5-7	66	49	43	71	65	63	0.171
> 7	36	30	30	63	49	48	0.055
Number of tumor nodules
Single	85	82	79	90	84	82	0.325
2-3	73	68	68	86	81	79	0.007
≥ 4	76	62	60	72	64	61	0.961
Venous invasion
Absent	85	80	79	88	84	82	0.113
Present	45	28	25	63	47	42	0.033
Lymph node invasion
Absent	80	74	72	85	79	76	0.032
Present	73	64	64	78	70	66	0.979
Capsular invasion
Absent	80	74	72	85	79	77	0.050
Present	75	61	61	79	72	70	0.554
Edmondson
1	91	91	91	100	100	100	0.134
2	82	77	75	87	81	78	0.124
3 + 4 + 5	74	66	64	79	73	71	0.229
Serum AFP level, in ng/mL
< 200	85	81	79	88	83	82	0.161
200-400	64	64	64	78	68	66	0.502
400-1000	71	51	42	82	72	66	0.189
1000-2000	68	41	41	73	61	55	0.454
> 2000	34	26	26	62	56	51	0.052
MELD score
< 10	79	68	68	84	77	74	0.101
10-15	78	70	70	84	78	76	0.197
> 15	82	80	75	85	80	78	0.423
Child-Pugh class
A (5-6)	83	78	78	85	79	76	0.792
B (7-9)	75	67	63	83	78	75	0.018
C (≥ 9)	79	74	72	82	77	75	0.479
Fasting blood glucose, in mmol/L
≤ 7	77	73	71	85	79	76	0.145
> 7	80	73	71	80	73	67	0.955
BMI, in kg/m2
< 18.5	68	62	62	81	79	76	0.156
18.5-24	77	72	70	84	78	76	0.048
24-28	86	78	76	85	79	76	0.951
> 28	81	72	72	85	80	74	0.656
ALP
≤ 112	83	78	76	87	81	78	0.281
> 112	74	66	65	80	74	72	0.102
GGT
≤ 54	87	86	85	92	88	85	0.559
> 54	75	66	63	79	72	69	0.104
ALT, in IU/L
≤ 40	86	81	80	89	85	83	0.339
40-80	73	68	65	83	77	74	0.017
> 80	77	68	66	75	68	64	0.633
AST, in IU/L
≤ 40	88	82	80	91	86	84	0.307
40-80	76	71	70	85	78	76	0.038
> 80	74	67	64	74	68	64	0.872
TC, in mmol/L
≤ 1.7	79	72	71	85	79	77	0.021
> 1.7	82	79	76	79	71	64	0.473
CH, in mmol/L
≤ 3.88	81	75	73	85	80	77	0.151
3.88-5.2	74	69	67	86	78	75	0.058
> 5.2	83	71	71	77	71	68	0.737
Pre-LT antitumor therapy
No	77	73	71	85	79	76	0.020
local therapy	83	71	71	79	73	71	0.910
Resection	92	80	72	88	84	80	0.809
HBeAg
Negative	79	73	71	85	78	76	0.055
Positive	82	75	73	83	79	76	0.446
HBV-DNA, in × 103 U/mL
< 1	80	73	71	85	79	78	0.072
> 1	77	73	72	84	77	74	0.236
Post-LT HBsAg reinfection
Negative	79	73	72	84	79	76	0.045
Positive	80	70	60	87	73	69	0.678

BMI: Body mass index; DM: Diabetes mellitus; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; TG: Triglyceride; CH: Cholesterol; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; LT: Liver transplantation.

Table 4 Univariate analysis of tumor recurrence-free 1-, 3- and 5-year survival rates post-liver transplantation between patients with diabetes mellitus and without diabetes mellitus

Variables	DM, %			Non-DM, %			P value
	1 yr	3 yr	5 yr	1 yr	3 yr	5 yr
Sex
Male	73	69	67	77	71	69	0.204
Female	76	63	63	83	82	80	0.110
Age, yr
≤ 50	73	68	68	73	69	67	0.940
> 50	73	69	66	81	75	73	0.015
Tumor size, in cm
≤ 3	78	75	75	85	81	79	0.076
3-5	82	75	71	80	73	71	0.823
5-7	52	43	31	58	54	53	0.174
> 7	31	25	25	47	39	39	0.087
Number of tumor nodules
Single	81	77	75	83	79	77	0.475
2-3	67	64	64	79	75	73	0.031
≥ 4	64	57	55	63	55	53	0.825
Venous invasion
Absent	80	76	74	82	78	76	0.301
Present	28	22	19	48	37	35	0.005
Lymph node invasion
Absent	74	69	67	78	73	71	0.058
Present	64	64	64	67	59	55	0.580
Capsular invasion
Absent	75	71	69	78	73	71	0.201
Present	60	55	55	69	67	62	0.192
Microsatellite lesions
Absent	79	74	72	80	75	73	0.542
Present	52	49	46	63	60	58	0.039
Edmonton
1	91	91	91	100	100	100	0.134
2	77	73	72	80	74	72	0.375
3 + 4 + 5	67	59	57	72	67	66	0.175
Serum AFP level, in ng/mL
< 200	80	76	75	82	78	76	0.272
200-400	59	59	59	72	63	62	0.484
400-1000	65	46	37	77	65	63	0.251
1000-2000	61	43	43	62	55	49	0.682
> 2000	17	17	17	44	42	39	0.055
MELD score
< 10	68	60	58	75	69	67	0.058
10-15	72	70	70	78	73	70	0.412
> 15	79	76	72	79	76	74	0.534
Child-Pugh class
A	75	71	69	78	72	70	0.672
B	69	65	61	77	72	70	0.052
C	76	71	71	76	73	71	0.610
Fasting blood glucose, in mmol/L
≤ 7	72	68	67	77	72	70	0.154
> 7	74	69	67	70	68	63	0.914
BMI, in kg/m2
< 18.5	63	57	57	80	72	69	0.223
18.5-24	73	70	68	77	72	70	0.216
24-28	76	69	69	78	73	71	0.524
> 28	77	69	63	76	71	67	0.774
ALP, in IU/L
≤ 112	80	75	73	81	75	73	0.747
> 112	63	60	57	71	67	65	0.056
GGT, in IU/L
≤ 54	85	84	82	87	82	80	0.957
> 54	67	60	58	70	65	63	0.101
AST, in IU/L
≤ 40	81	76	73	84	79	78	0.201
40-80	69	65	65	78	72	70	0.103
> 80	70	65	62	66	61	58	0.767
ALT, in IU/L
≤ 40	79	76	75	82	79	77	0.318
40-80	68	63	60	77	70	68	0.033
> 80	72	65	64	65	60	58	0.376
TC, in mmol/L
≤ 1.7	74	69	67	78	73	71	0.113
> 1.7	71	68	65	66	63	60	0.894
CH, in mmol/L
< 3.88	75	70	68	78	74	72	0.175
3.88-5.2	68	66	64	79	72	71	0.092
> 5.2	76	68	68	66	60	57	0.415
Pre-LT antitumor therapy
No	73	68	67	78	72	70	0.061
local therapy	68	66	66	70	67	64	0.939
Resection	81	77	70	83	79	76	0.758
HBeAg
Negative	72	69	66	78	71	70	0.095
Positive	77	69	69	75	74	71	0.633
HBV-DNA, in × 103 IU/mL
< 1	75	69	68	78	74	72	0.165
> 1	71	68	65	76	70	67	0.256
Post-LT HBsAg reinfection
Negative	73	69	67	77	73	70	0.092
Positive	70	60	60	72	60	58	0.899

BMI: Body mass index; DM: Diabetes mellitus; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; TG: Triglyceride; CH: Cholesterol; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen; LT: Liver transplantation.

Table 5 Multivariate proportional hazard model for overall survival after liver transplantation in 1631 patients with hepatitis B virus-related hepatocellular carcinoma

Variables	B	SE	Wald	P value	OR (95%CI)
Venous invasion, absent vs present	0.893	0.117	57.882	0.000	2.442 (1.940-3.074)
Pre-LT antitumor therapy			7.129	0.032
Local therapy	-0.319	0.138	5.368	0.021	1.375 (1.050-1.801)
Resection	-0.227	0.212	1.146	0.284	0.797 (0.526-1.208)
Age, ≤ 50 vs > 50	-0.248	0.104	5.655	0.017	0.781 (0.636-0.957)
ALP, ≤ 112 IU/L vs > 112 IU/L	-0.264	0.111	5.630	0.018	0.768 (0.618-0.955)
GGT, ≤ 54 IU/L vs > 54 IU/L	0.332	0.128	6.681	0.010	1.394 (1.084-1.793)
ALT			13.416	0.001
≤ 40 IU/L vs 40-80 IU/L	0.340	0.123	7.575	0.006	1.404 (1.103-1.789)
≤ 40 IU/L vs > 80 IU/L	0.496	0.141	12.396	0.000	1.642 (1.246-2.164)
Serum AFP level, in ng/mL			30.829	0.000
< 200 vs 200-400	0.525	0.185	8.097	0.004	1.691 (1.178-2.427)
< 200 vs 400-1000	0.399	0.163	6.012	0.014	1.491 (1.083-2.052)
< 200 vs 1000-2000	0.621	0.189	10.804	0.001	1.860 (1.285-2.693)
< 200 vs > 2000	0.725	0.160	20.569	0.000	2.065 (1.509-2.825)
Number of tumor nodules			47.936	0.000
Single vs 2-3	0.528	0.138	14.631	0.000	1.695 (1.293-2.221)
Single vs≥ 4	0.851	0.124	47.265	0.000	2.342 (1.837-2.984)
Tumor size, in cm			78.643	0.000
≤ 3 vs 3-5	0.152	0.132	1.314	0.252	1.164 (0.898-1.509)
≤ 3 vs 5-7	0.739	0.149	24.596	0.000	2.093 (1.563-2.802)
≤ 3 vs > 7	1.252	0.152	67.571	0.000	3.496 (2.594-4.711)
DM, yes vs no	0.464	0.128	13.230	0.000	1.591 (1.239-2.043)

LT: Liver transplantation; GGT: Gamma-glutamyl transpeptidase; AFP: α-fetoprotein; DM: Diabetes mellitus; ALT: Alanine aminotransferase.

Table 6 Multivariate proportional hazard model for tumor recurrence after liver transplantation in 1631 patients with hepatitis B virus-related hepatocellular carcinoma

Variables	B	SE	Wald	P value	OR (95%CI)
Venous invasion, absent vs present	0.780	0.124	39.825	0.000	2.182 (1.712-2.780)
Pre-LT antitumor therapy			11.093	0.005
Local therapy	-0.404	0.138	8.555	0.003	1.498 (1.143-1.964)
Resection	-0.285	0.230	1.536	0.215	0.752 (0.480-1.180)
GGT, ≤ 54 IU/L vs > 54 IU/L	0.360	0.131	7.559	0.006	1.433 (1.109-1.851)
TC, ≤ 1.7 mmol/L vs > 1.7 mmol/L	0.425	0.165	6.682	0.010	1.530 (1.108-2.113)
Serum AFP level, in ng/mL			27.634	0.000
< 200 vs 200-400	0.330	0.198	2.767	0.096	1.391 (0.943-2.051)
< 200 vs 400-1000	0.031	0.193	0.026	0.872	1.032 (0.707-1.506)
< 200 vs 1000-2000	0.378	0.212	3.161	0.075	1.459 (0.962-2.212)
< 200 vs > 2000	0.794	0.158	25.372	0.000	2.213 (1.625-3.015)
Number of tumor nodules			34.680	0.000
Single vs 2-3	0.377	0.144	6.885	0.009	1.457 (1.100-1.931)
Single vs≥ 4	0.763	0.130	34.674	0.000	2.144 (1.664-2.764)
Tumor size, in cm			110.647	0.000
≤ 3 vs 3-5	0.143	0.146	0.953	0.329	1.154 (0.866-1.537)
≤ 3 vs 5-7	1.112	0.150	55.206	0.000	3.042 (2.268-4.079)
≤ 3 vs > 7	1.402	0.158	78.831	0.000	4.065 (2.983-5.540)

LT: Liver transplantation; GGT: Gamma-glutamyl transpeptidase; AFP: α-fetoprotein.