Repeatedly elevated γ-glutamyltransferase levels are associated with an increased incidence of digestive cancers: A population-based cohort study

Table 1 Baseline characteristics according to the γ-glutamyltransferase points

			Total	GGT points1
				0	1	2	3	4
Men			2569773	1595879	260084	177029	181702	355079
Age, yr			42.41 ± 10.53	41.64 ± 10.84	43.19 ± 10.47	43.31 ± 10.13	43.64 ± 9.82	44.19 ± 9.29
Smoking
		Non-smoker	720342 (28.03)	511103 (32.03)	65347 (25.13)	39900 (22.54)	37994 (20.91)	65998 (18.59)
		Ex-smoker	662215 (25.77)	410064 (25.7)	70316 (27.04)	47571 (26.87)	47955 (26.39)	86309 (24.31)
		Current	1187216 (46.2)	674712 (42.28)	124421 (47.84)	89558 (50.59)	95753 (52.7)	202772 (57.11)
Alcohol consumption
		No	720354 (28.03)	540201 (33.85)	64798 (24.91)	36701 (20.73)	32092 (17.66)	46562 (13.11)
		Mild	1583612 (61.62)	952992 (59.72)	165116 (63.49)	114805 (64.85)	118787 (65.37)	231912 (65.31)
		Heavy	265807 (10.34)	102686 (6.43)	30170 (11.6)	25523 (14.42)	30823 (16.96)	76605 (21.57)
Lowest quartile of yearly income (Q1)			399370 (15.54)	244182 (15.3)	42615 (16.39)	28596 (16.15)	28873 (15.89)	55104 (15.52)
Regular PA			790381 (30.76)	496084 (31.09)	80897 (31.1)	54551 (30.81)	55753 (30.68)	103096 (29.03)
BMI (kg/m2)			24.19 ± 3.01	23.55 ± 2.79	24.71 ± 2.91	25.1 ± 2.98	25.34 ± 3.03	25.64 ± 3.13
WC (cm)			83.14 ± 7.56	81.48 ± 7.16	84.46 ± 7.22	85.43 ± 7.25	86.08 ± 7.33	86.96 ± 7.45
SBP (mmHg)			123.78 ± 12.99	122 ± 12.45	124.88 ± 12.85	125.93 ± 13.02	126.8 ± 13.23	128.37 ± 13.68
DBP (mmHg)			77.98 ± 9.17	76.71 ± 8.79	78.75 ± 9.07	79.51 ± 9.16	80.19 ± 9.32	81.27 ± 9.6
Hypertension			543619 (21.15)	249986 (15.66)	63584 (24.45)	48861 (27.6)	55827 (30.72)	125361 (35.31)
Dyslipidemia			394282 (15.34)	169026 (10.59)	47739 (18.36)	37512 (21.19)	42552 (23.42)	97453 (27.45)
Diabetes
	No		1747553 (68)	1178083 (73.82)	168406 (64.75)	108469 (61.27)	105608 (58.12)	186987 (52.66)
	IFG		633865 (24.67)	343650 (21.53)	69127 (26.58)	50151 (28.33)	54139 (29.8)	116798 (32.89)
	DM		188355 (7.33)	74146 (4.65)	22551 (8.67)	18409 (10.4)	21955 (12.08)	51294 (14.45)
Fasting glucose (mg/dL)			97.2 ± 22.15	94.38 ± 18.25	98.47 ± 22.98	100.13 ± 24.85	101.84 ± 26.59	105.13 ± 29.72
Total cholesterol (mg/dL)			195.09 ± 34.85	190.25 ± 32.83	198.57 ± 34.96	201.16 ± 35.5	202.95 ± 36.32	207.29 ± 37.85
LDL (mg/dL)			112.94 ± 32.32	112.28 ± 30.41	114.88 ± 33.13	114.76 ± 34.14	114.17 ± 35.16	112.95 ± 37.16
HDL (mg/dL)			52.16 ± 13.63	52.38 ± 13.38	51.6 ± 13.93	51.57 ± 14.01	51.58 ± 13.9	52.18 ± 14.14
Triglyceride (mg/dL)2			129.81 (129.72-129.9)	112.69 (112.6-112.78)	141.48 (141.19-141.77)	154 (153.61-154.38)	164.57 (164.16-164.98)	187.2 (186.86-187.54)
AST (IU/L)2			25.9 (25.89-25.91)	23.64 (23.63-23.65)	27.11 (27.08-27.15)	28.47 (28.43-28.51)	29.84 (29.79-29.89)	33.52 (33.47-33.56)
ALT (IU/L)2			26.41 (26.4-26.43)	22.44 (22.43-22.46)	29.54 (29.49-29.6)	32.15 (32.07-32.22)	34.42 (34.34-34.51)	40.07 (40-40.14)
GGT (U/L)2			36.3 (36.28-36.33)	24.79 (24.78-24.81)	43.21 (43.14-43.27)	53.64 (53.54-53.73)	66.15 (66.02-66.28)	107.44 (107.26-107.61)
Women			989336	566518	153299	83247	70183	116089
Age, yr			41.61 ± 11.55	39.36 ± 11.04	42.51 ± 11.54	44.13 ± 11.57	45.34 ± 11.47	47.33 ± 10.9
Smoking
		Non-smoker	950040 (96.03)	547422 (96.63)	147238 (96.05)	79376 (95.35)	66593 (94.88)	109411 (94.25)
		Ex-smoker	16273 (1.64)	8976 (1.58)	2493 (1.63)	1454 (1.75)	1294 (1.84)	2056 (1.77)
		Current	23023 (2.33)	10120 (1.79)	3568 (2.33)	2417 (2.9)	2296 (3.27)	4622 (3.98)
Alcohol consumption
		No	661884 (66.9)	383621 (67.72)	103332 (67.41)	55147 (66.25)	45838 (65.31)	73946 (63.7)
		Mild	318233 (32.17)	179199 (31.63)	48446 (31.6)	26984 (32.41)	23345 (33.26)	40259 (34.68)
		Heavy	9219 (0.93)	3698 (0.65)	1521 (0.99)	1116 (1.34)	1000 (1.42)	1884 (1.62)
Lowest quartile of yearly income (Q1)			365612 (36.96)	181102 (31.97)	61625 (40.2)	35775 (42.97)	31499 (44.88)	55611 (47.9)
Regular PA			270758 (27.37)	155736 (27.49)	42388 (27.65)	22839 (27.44)	18923 (26.96)	30872 (26.59)
BMI (kg/m2)			22.45 ± 3.22	21.79 ± 2.82	22.56 ± 3.15	23.14 ± 3.39	23.64 ± 3.53	24.36 ± 3.71
WC (cm)			73.52 ± 8.28	71.77 ± 7.42	73.86 ± 8.07	75.36 ± 8.49	76.6 ± 8.78	78.47 ± 9.09
SBP (mmHg)			116.17 ± 13.59	114.11 ± 12.72	116.63 ± 13.55	118.33 ± 14.04	119.76 ± 14.23	121.91 ± 14.56
DBP (mmHg)			72.92 ± 9.26	71.68 ± 8.83	73.17 ± 9.25	74.2 ± 9.46	75.08 ± 9.54	76.39 ± 9.73
Hypertension			130992 (13.24)	45016 (7.95)	21361 (13.93)	15255 (18.32)	15700 (22.37)	33660 (28.99)
Dyslipidemia			128796 (13.02)	45810 (8.09)	21112 (13.77)	14928 (17.93)	15084 (21.49)	31862 (27.45)
Diabetes
		No	805990 (81.47)	489351 (86.38)	124149 (80.98)	64211 (77.13)	51316 (73.12)	76963 (66.3)
		IFG	148818 (15.04)	68823 (12.15)	24264 (15.83)	15071 (18.1)	14042 (20.01)	26618 (22.93)
		DM	34528 (3.49)	8344 (1.47)	4886 (3.19)	3965 (4.76)	4825 (6.87)	12508 (10.77)
Fasting glucose (mg/dL)			91.41 ± 16.31	89.21 ± 12.41	91.39 ± 15.32	93.13 ± 17.79	94.99 ± 20.38	98.8 ± 25.3
Total cholesterol (mg/dL)			190.33 ± 34.94	185.48 ± 32.85	191.82 ± 35.03	195.68 ± 35.98	198.31 ± 36.74	203.37 ± 37.76
LDL (mg/dL)			110.02 ± 31.3	106.75 ± 29.16	111.38 ± 31.72	113.91 ± 33.05	115.34 ± 33.97	118.18 ± 35.21
HDL (mg/dL)			60.82 ± 15.16	61.63 ± 14.7	60.57 ± 15.3	59.93 ± 15.73	59.3 ± 15.65	58.74 ± 16.1
Triglyceride (mg/dL)2			85.34 (85.25-85.42)	76.5 (76.4-76.59)	87.69 (87.47-87.91)	95.8 (95.47-96.13)	103.29 (102.89-103.69)	115.13 (114.78-115.49)
AST (IU/L)2			21.38 (21.36-21.39)	20.06 (20.05-20.08)	21.64 (21.61-21.67)	22.58 (22.54-22.63)	23.6 (23.55-23.66)	25.95 (25.89-26)
ALT (IU/L)2			16.82 (16.81-16.84)	14.74 (14.73-14.76)	17.38 (17.34-17.41)	19.11 (19.05-19.17)	20.85 (20.78-20.92)	24.6 (24.53-24.67)
GGT (U/L)2			17.53 (17.51-17.54)	13.52 (13.51-13.53)	18.15 (18.12-18.18)	21.94 (21.89-21.99)	26.28 (26.21-26.35)	39.57 (39.46-39.69)

¹Participants receive 1 point at each examination if γ-glutamyltransferase (GGT) is in the highest quartile at each examination. GGT points were calculated as the sum of points at 4 consecutive examinations.

²Geometric mean. Categorical variables are expressed as numbers (%); continuous variables are expressed means ± SD. PA: Physical activity; BMI: Body mass index; WC: Waist circumference; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; IFG: Impaired fasting glucose; DM: Diabetes mellitus; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma-glutamyltransferase.

Table 2 Incidence of all digestive cancers, gastrointestinal cancers (including esophagus, stomach and colorectal cancers), and hepatobiliary pancreatic cancers (including liver, biliary tract and pancreas) according to the γ-glutamyltransferase points

GGT points	Number	Event	Duration	IR per 1000	Age-adjusted	Model 1	Model 2	Model 3
					IR (95%CI)	HR (95%CI)	HR (95%CI)	HR (95%CI)
Men
Total digestive cancer
0	1595879	17789	10257993.68	1.734	3.20 (3.14, 3.26)	1 (reference)	1 (reference)	1 (reference)
1	260084	4058	1667865.93	2.433	4.19 (3.88, 4.52)	1.40 (1.36, 1.45)	1.30 (1.26, 1.34)	1.28 (1.24, 1.33)
2	177029	2982	1133122.25	2.632	4.70 (4.25, 5.19)	1.52 (1.46, 1.58)	1.43 (1.38, 1.49)	1.40 (1.35, 1.46)
3	181702	3341	1161757.06	2.876	5.06 (4.63, 5.53)	1.66 (1.60, 1.72)	1.57 (1.51, 1.62)	1.52 (1.46, 1.58)
4	355079	8106	2250566.91	3.602	6.36 (6.14, 6.59)	2.08 (2.03, 2.13)	1.96 (1.91, 2.01)	1.88 (1.83, 1.94)
P for trend						< 0.001	< 0.001	< 0.001
Gastrointestinal cancer
0	1595879	14709	10263671.88	1.433	2.64 (2.59, 2.69)	1 (reference)	1 (reference)	1 (reference)
1	260084	3023	1669790.42	1.810	3.11 (2.87, 3.37)	1.26 (1.22, 1.31)	1.17 (1.12, 1.22)	1.12 (1.08, 1.17)
2	177029	2169	1134702.18	1.912	3.39 (3.03, 3.78)	1.33 (1.28, 1.40)	1.26 (1.20, 1.32)	1.18 (1.13, 1.24)
3	181702	2372	1163597.98	2.039	3.55 (3.21, 3.93)	1.42 (1.36, 1.49)	1.34 (1.28, 1.40)	1.24 (1.19, 1.30)
4	355079	5075	2256426.45	2.249	3.94 (3.76, 4.12)	1.57 (1.52, 1.62)	1.48 (1.43, 1.53)	1.34 (1.29, 1.39)
P for trend						< 0.001	< 0.001	< 0.001
Hepatobiliary pancreatic cancer
0	1595879	5616	10294767.52	0.546	1.01 (0.98, 1.03)	1 (reference)	1 (reference)	1 (reference)
1	260084	1584	1675373.07	0.945	1.62 (1.49, 1.76)	1.73 (1.64, 1.83)	1.60 (1.52, 1.70)	1.65 (1.56, 1.75)
2	177029	1217	1138317.76	1.069	1.92 (1.73, 2.13)	1.96 (1.84, 2.09)	1.86 (1.75, 1.98)	1.93 (1.82, 2.06)
3	181702	1399	1167524.64	1.198	2.13 (1.95, 2.34)	2.20 (2.07, 2.33)	2.08 (1.96, 2.21)	2.18 (2.05, 2.32)
4	355079	4109	2262184.82	1.816	3.22 (3.13, 3.32)	3.34 (3.20, 3.47)	3.16 (3.04, 3.29)	3.35 (3.21, 3.50)
P for trend						< 0.001	< 0.001	< 0.001
Women
Total digestive cancer
0	566518	3367	3558510.54	0.946	1.81 (1.77, 1.85)	1 (reference)	1 (reference)	1 (reference)
1	153299	1124	959235.81	1.172	1.75 (1.65, 1.86)	1.24 (1.16, 1.33)	1.00 (0.93, 1.07)	0.99 (0.93, 1.06)
2	83247	694	519023.27	1.337	1.80 (1.63, 1.98)	1.42 (1.30, 1.54)	1.03 (0.95, 1.12)	1.02 (0.94, 1.11)
3	70183	682	435747.09	1.565	1.95 (1.78, 2.15)	1.66 (1.53, 1.80)	1.12 (1.03, 1.22)	1.11 (1.02, 1.21)
4	116089	1431	714960.09	2.002	2.25 (2.15, 2.35)	2.12 (1.99, 2.26)	1.30 (1.22, 1.38)	1.27 (1.19, 1.36)
P for trend						< 0.001	< 0.001	< 0.001
Gastrointestinal cancer
0	566518	2891	3559398.08	0.812	1.55 (1.51, 1.59)	1 (reference)	1 (reference)	1 (reference)
1	153299	913	959636.19	0.951	1.43 (1.33, 1.53)	1.17 (1.09, 1.26)	0.95 (0.88, 1.03)	0.95 (0.88, 1.02)
2	83247	548	519282.68	1.055	1.44 (1.28, 1.61)	1.30 (1.19, 1.43)	0.96 (0.88, 1.05)	0.95 (0.87, 1.04)
3	70183	526	436048.99	1.206	1.51 (1.34, 1.69)	1.49 (1.36, 1.63)	1.03 (0.93, 1.13)	1.01 (0.92, 1.11)
4	116089	1006	715795.75	1.405	1.58 (1.49, 1.68)	1.74 (1.62, 1.86)	1.08 (1.01, 1.17)	1.06 (0.98, 1.14)
P for trend						< 0.001	0.052	0.232
Hepatobiliary pancreatic cancer
0	566518	884	3565741.17	0.248	0.47 (0.45,0.49)	1 (reference)	1 (reference)	1 (reference)
1	153299	337	961504.59	0.350	0.53 (0.48, 0.57)	1.42 (1.25, 1.60)	1.11 (0.98, 1.25)	1.10 (0.97, 1.25)
2	83247	238	520353.15	0.457	0.58 (0.52, 0.66)	1.85 (1.60, 2.13)	1.29 (1.12, 1.49)	1.29 (1.11, 1.49)
3	70183	241	437047.77	0.551	0.69 (0.62, 0.77)	2.23 (1.94, 2.57)	1.44 (1.25, 1.66)	1.43 (1.23, 1.65)
4	116089	608	717322.51	0.848	0.95 (0.91, 0.99)	3.44 (3.10, 3.81)	1.98 (1.78, 2.20)	1.95 (1.74, 2.18)
P for trend						< 0.001	< 0.001	< 0.001

Model 1: Unadjusted model. Model 2: Age-adjusted model. Model 3: Age, smoking, drinking, income, hypertension, diabetes, dyslipidemia, body mass index, and physical activity-adjusted model. IR: Incidence rate; HR: Hazard ratio; CI: confidence interval; GGT: Gamma-glutamyltransferase.

Table 3 Incidence of site-specific digestive cancers according to the γ-glutamyltransferase points based on four consecutive examinations

	Esophagus		Stomach		Colorectal		Liver		Biliary		Pancreas
	IR per 1000	HR (95%CI)	IR per 1000	HR (95%CI)	IR per 1000	HR (95%CI)	IR per 1000	HR (95%CI)	IR per 1000	HR (95%CI)	IR per 1000	HR (95%CI)
Men
0	0.037	1 (reference)	0.772	1 (reference)	0.757	1 (reference)	0.215	1 (reference)	0.126	1 (reference)	0.293	1 (reference)
1	0.073	1.78 (1.45, 2.18)	0.968	1.12 (1.06, 1.19)	0.938	1.09 (1.03, 1.15)	0.505	2.39 (2.21, 2.59)	0.203	1.46 (1.29, 1.64)	0.389	1.18 (1.08, 1.28)
2	0.082	1.99 (1.58, 2.51)	1.011	1.18 (1.10, 1.25)	0.984	1.14 (1.07, 1.21)	0.624	3.13 (2.87, 3.41)	0.203	1.49 (1.30, 1.72)	0.392	1.19 (1.08, 1.32)
3	0.103	2.43 (1.97, 3.00)	1.063	1.22 (1.15, 1.29)	1.051	1.19 (1.12, 1.27)	0.727	3.74 (3.45, 4.06)	0.203	1.49 (1.30, 1.72)	0.425	1.27 (1.15, 1.40)
4	0.134	3.07 (2.61, 3.62)	1.127	1.26 (1.21, 1.33)	1.209	1.34 (1.28, 1.40)	1.293	6.89 (6.49, 7.32)	0.257	1.91 (1.72, 2.12)	0.501	1.48 (1.37, 1.59)
Women
0	0.005	1 (reference)	0.319	1 (reference)	0.534	1 (reference)	0.067	1 (reference)	0.065	1 (reference)	0.150	1 (reference)
1	0.007	1.00 (0.42, 2.39)	0.345	0.87 (0.77, 0.99)	0.651	0.99 (0.90, 1.08)	0.114	1.41 (1.12, 1.77)	0.102	1.12 (0.88, 1.42)	0.186	0.97 (0.81, 1.14)
2	0.008	0.92 (0.31, 2.74)	0.390	0.89 (0.77, 1.04)	0.720	0.99 (0.89, 1.11)	0.150	1.70 (1.32, 2.20)	0.138	1.30 (0.99, 1.70)	0.238	1.10 (0.90, 1.34)
3	0.009	1.01 (0.34, 3.02)	0.462	0.98 (0.84, 1.14)	0.804	1.03 (0.92, 1.16)	0.199	2.14 (1.66, 2.74)	0.162	1.36 (1.03, 1.78)	0.279	1.18 (0.96, 1.44)
4	0.014	1.38 (0.61, 3.12)	0.542	1.04 (0.92, 1.17)	0.924	1.06 (0.97, 1.17)	0.396	3.91 (3.25, 4.71)	0.203	1.45 (1.16, 1.80)	0.354	1.32 (1.13, 1.55)

Multivariate analysis was adjusted for age, smoking, drinking, income, hypertension, diabetes, dyslipidemia, body mass index and physical activity. IR: Incidence rate; HR: Hazard ratio; CI: Confidence interval.