Significance and prognostic value of increased serum direct bilirubin level for lymph node metastasis in Chinese rectal cancer patients

Table 1 Basic characteristics of 469 rectal adenocarcinoma patients n (%)

Characteristic	Total patients (n = 469)1	RAC patients with LNM(n = 231)1	RAC patients without LNM (n = 238)1	P value
Male sex	286 (61.0)	146 (63.2)	140 (58.8)	0.331
Mean age, yr	62.1 ± 12.6	60.6 ± 12.8	63.6 ± 12.2	0.012
BMI3, kg/m2	23.95 ± 3.54	23.90 ±3.67	24.0 ± 3.41	0.779
Hypertension	131 (27.9)	58 (25.1)	73 (30.7)	0.179
Alcohol intake	29 (6.2)	18 (7.8)	11 (4.6)	0.154
Smoking	129 (27.5)	55 (23.8)	74 (31.1)	0.077
White blood cell, × 109/L	6.66 ± 2.10	6.70 ± 2.09	6.61 ± 2.11	0.666
Hemoglobin, g/L	132 ± 20	131 ± 20	132 ± 19	0.553
Platelet count, × 109/L	233 ± 79	235 ± 74	232 ± 84	0.659
Total bilirubin2, mmol/L	10.26 (7.70-14.40)	10.26 (7.40-15.0)	10.26 (8.13-13.68)	0.451
Direct bilirubin2, mmol/L	2.30 (1.60-3.42)	2.50 (1.70-3.42)	2.10 (1.40-3.42)	0.025
ALT2, U/L	16 (12-22)	15 (12-22)	16 (12-22)	0.262
AST2, U/L	19 (16-23)	18 (15-22)	19 (16-24)	0.076
ALP2, U/L	66 (55-81)	66 (54-82)	66 (55-80)	0.905
GGT2, U/L	17 (13-25)	18 (13-26)	16 (12-23)	0.136
Serum cholinesterase4, U/L	161.3 ± 50.0	158.1 ± 50.1	164.5 ± 50.0	0.170
Total bile acid2, μmol/L	4.4 (2.4-7.3)	4.5 (2.4-8.5)	4.2 (2.5-7.1)	0.546
Prothrombin time5, s	13.2 ± 1.4	13.2 ± 1.7	13.2 ± 1.1	0.651
International normalized ratio/INR5	1.02 ± 0.14	1.02 ± 0.17	1.01 ± 0.11	0.313
Albumin level6, g/L	42.3 ± 4.5	42.3 ± 4.4	42.2 ± 4.6	0.908
Creatinine, mg/dL	82.1 ± 18.0	80.8 ± 15.5	83.3 ± 20.1	0.128
Serum sodium7, mmol/L	141.0 ± 3.0	141.0 ± 3.1	142.0 ± 2.9	0.028
Serum potassium7, mmol/L	4.1 ± 0.5	4.1 ± 0.4	4.1 ± 0.5	0.282
Carcinoembryonic antigen28, ng/mL	4.33 (2.22-11.91)	5.40 (2.40-13.95)	3.50 (2.08-8.67)	0.009
Serum CA19-929, kU/L	14.02 (7.20-28.63)	15.10 (7.39-33.91)	13.41 (7.10-23.10)	0.109

¹Plus-minus value indicates mean ± SD;

²Median (inter-quartile range, Q1-Q3). Data were available in

³403 (202 + 201),

⁴461 (226 + 235),

⁵456 (225 + 231),

⁶463 (227 + 236),

⁷457 (226 + 231),

⁸392 (192 + 200) and

⁹370 (178 + 192) patients. The numbers before the brackets indicate the total available cases in the two groups. BMI: Body mass index; LNM: Lymph node metastasis; RAC: Rectal adenocarcinoma.

Table 2 Pathological characteristics and follow-up results of 469 rectal adenocarcinoma patients n (%)

Characteristic	Total patient s(n = 469)1	RAC patients with LNM (n = 231)1	RAC patients without LNM (n = 238)1	P value
Pathological lymph node stage				< 0.001
pN0	238 (50.7)	0 (0.0)	238 (100.0)	-
pN1	136 (29.0)	136 (58.9)	0 (0.0)	-
pN2	95 (20.3)	95 (41.1)	0 (0.0)	-
Pathological tumor classification (pT)				< 0.001
pT1	18 (3.8)	1 (0.4)	17 (7.1)	-
pT2	90 (19.2)	21 (9.1)	69 (29.0)	-
pT3	118 (25.2)	54 (23.4)	64 (26.9)	-
pT4	243 (51.8)	155 (67.1)	88 (37.0)	-
Pathological distant metastasis (pM)
pM0	439 (93.6)	213 (92.2)	226 (95.0)	0.224
pM1	30 (6.4)	18 (7.8)	12 (5.0)	-
Tumor differentiation
Moderately/well	388 (82.7)	166 (71.9)	222 (93.3)	< 0.001
Poorly	57 (12.2)	46 (19.9)	11 (4.6)	-
Unknown	24 (5.1)	19 (8.2)	5 (2.1)	-
Number of lymph node
Lymph node-positive (metastasis)	2.2 ± 4.5	4.5 ± 5.5	-	-
Total number of lymph node removal	13.3 ± 8.4	15.0 ± 9.1	11.6 ± 7.3	< 0.001
Results of follow-up
Death	72 (15.4)	46 (19.9)	26 (10.9)	0.007
Survival	277 (59.1)	118 (51.1)	159 (66.8)	0.001
Lost	120 (25.6)	67 (29.0)	53 (22.3)	0.095
Time of follow-up2 (mo)	24.0 (9.0-44.3)	20 (9.0-37.9)	29.1 (10.5-48.5)	0.013

¹Plus-minus value indicates mean ± SD;

²Median (inter-quartile range, Q1-Q3). LNM: Lymph node metastasis; RAC: Rectal adenocarcinoma.

Table 3 Multivariate analysis: significance of increased serum direct bilirubin for rectal cancer patients with lymph node metastasis

Variable	Adjusted OR	95%CI	P value
Direct bilirubin ≥ 2.60 μmol/L	1.602	1.098-2.338	0.015
Age < 60 yr	1.851	1.259-2.724	0.002
Serum sodium ≤ 141 mmol/L	-	-	0.090

Four hundred and fifty-seven patients were included because the data were not available for 12 patients. Carcinoembryonic antigen (CEA) was excluded because data were not available in 77 patients and preliminary multivariate analysis results showed that CEA was not associated with lymph node metastasis in our patients. For clinical practice, these continuous variables were changed to categorical variables, and the cutoff values were determined based on the combination of sensitivity, specificity, Youden index, receiver operator characteristics curves and areas under the curve.

Table 4 Association between increased serum direct bilirubin level and clinicopathological data n (%)

Variable	Direct bilirubin≥2.60μmol/L	Direct bilirubin < 2.60μmol/L	P value
Gender
Male	148 (70.5)	138 (53.3)	< 0.001
Female	62 (29.5)	121 (46.7)	-
Age, yr
< 60	79 (37.6)	102 (39.4)	0.697
≥ 60	131 (62.4)	157 (60.6)	-
Serum sodium, mmol/L
≤ 141	101 (49.5)	142 (56.1)	0.159
> 141	103 (50.5)	111 (43.9)	-
Carcinoembryonic antigen, ng/mL
< 5.0	85 (50.0)	129 (58.1)	0.110
≥ 5.0	85 (50.0)	93 (41.9)	-
Tumor differentiation
Moderately/well	171 (86.8)	217 (87.5)	0.827
Poorly	26 (13.2)	31 (12.5)	-
Pathological tumor classification (pT)
pT1/ pT2	39 (18.6)	69 (26.6)	0.039
pT3/ pT4	171 (81.4)	190 (73.4)	-
Pathological lymph node stage (pN)
pN1	65 (57.0)	71 (60.7)	0.571
pN2	49 (43.0)	46 (39.3)	-
Pathological distant metastasis (pM)
pM0	200 (95.2)	239 (92.3)	0.193
pM1	10 (4.8)	20 (7.7)	-

Table 5 Association between concentrations of increased serum direct bilirubin and lymph node metastasis n (%)

Direct bilirubin/DBil (μmol/L)	Patients with LNM	Patients without LNM	OR (95%CI)	P value
DBil ≤ 1.50	50 (43.1)	66 (56.9)	1 (reference)	-
1.50 < DBil ≤ 2.50	67 (46.9)	76 (53.1)	1.164 (0.711-1.905)	0.547
2.50 < DBil ≤ 3.50	60 (50.4)	59 (49.6)	1.342 (0.803-2.244)	0.261
DBil > 3.50	54 (59.3)	37 (40.7)	1.926 (1.104-3.362)	0.020

LNM: Lymph node metastasis.