Hepatitis B virus infection, diabetes mellitus, and their synergism for cholangiocarcinoma development: A case-control study in Korea

Table 1 Comparison of risk factors in patients with cholangiocarcinoma and matched controls n (%)

Variable	CCA patient (n = 276)	Control (n = 552)	Univariable analysis		Multivariable analysis
			OR (95%CI)	P value	AOR (95%CI)	P value
Cigarette smoking	84 (30.4)	157 (28.4)	1.14 (0.79-1.66)	0.487	-	-
< 20 pack-years1	35 (12.7)	53 (9.6)	1.39 (0.85-2.27)	0.191	-	-
≥ 20 pack-years	49 (17.8)	104 (18.8)	1.01 (0.66-1.55)	0.972	-	-
Heavy alcohol consumption2	35 (12.7)	50 (9.1)	1.53 (0.94-2.51)	0.088	1.45 (0.82-2.55)	0.199
Obesity3	64 (23.2)	134 (24.3)	0.94 (0.66-1.33)	0.722	-	-
Cholecystolithiasis	47 (17.0)	42 (7.6)	2.34 (1.52-3.61)	< 0.001	1.74 (1.04-2.90)	0.035
Choledocholithiasis	34 (12.3)	7 (1.3)	13.31 (5.20-34.07)	< 0.001	12.35 (4.31-35.38)	< 0.001
Hepatolithiasis	20 (7.2)	1 (0.2)	20.00 (4.68-85.57)	< 0.001	39.87 (7.25-219.17)	< 0.001
Cholecystectomy	17 (6.2)	23 (4.2)	1.49 (0.79-2.82)	0.216	-	-
Ulcerative colitis	2 (0.7)	3 (0.5)	1.33 (0.22-7.98)	0.753	-	-
Alcoholic liver disease	14 (5.1)	26 (4.7)	1.08 (0.55-2.13)	0.816	-	-
Thyroid disease	6 (2.2)	22 (4.0)	0.51 (0.20-1.31)	0.164	-	-
Chronic pancreatitis	1 (0.4)	5 (0.9)	0.40 (0.05-3.42)	0.403	-	-
Hypertension	113 (40.9)	254 (46.0)	0.80 (0.59-1.08)	0.150	-	-
Diabetes mellitus	65 (23.6)	69 (12.5)	2.22 (1.51-3.28)	< 0.001	2.55 (1.66-3.91)	< 0.001
Without complications	36 (13.0)	47 (8.5)	1.82 (1.12-2.96)	0.015	2.20 (1.30-3.70)	0.003
With complications4	29 (10.5)	22 (4.0)	2.98 (1.67-5.32)	< 0.001	3.25 (1.69-6.25)	< 0.001
HBV infection	28 (10.1)	18 (3.3)	3.34 (1.80-6.19)	< 0.001	4.12 (2.01-8.44)	< 0.001
HCV infection	11 (4.0)	13 (2.4)	1.69 (0.76-3.78)	0.199	-	-
Liver fluke infestation	6 (2.2)	4 (0.7)	3.00 (0.85-10.63)	0.089	3.49 (0.86-14.07)	0.079

¹One pack-year = 1 pack per day for a year;

²Daily amount of ≥ 80 g (male) or ≥ 40 g (female);

³Obesity was defined as a body mass index > 25 kg/m² according to the Asian-Pacific criteria for obesity;

⁴Any stage of retinopathy, nephropathy or macrovascular complications. CCA: Cholangiocarcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AOR: Adjusted odds ratio.

Table 2 Comparison of risk factors in patients with extrahepatic cholangiocarcinoma and matched controls n (%)

Variable	ECC patient (n = 193)	Control (n = 386)	Univariable analysis		Multivariable analysis
			OR (95%CI)	P value	AOR (95%CI)	P value
Cigarette smoking	53 (27.5)	91 (23.6)	1.32 (0.83-2.10)	0.240	-	-
< 20 pack-years	20 (10.4)	30 (7.8)	1.51 (0.79-2.87)	0.212	-	-
≥ 20 pack-years	33 (17.1)	61 (15.8)	1.23 (0.73-2.08)	0.444	-	-
Heavy alcohol consumption	18 (9.3)	24 (6.2)	1.62 (0.83-3.17)	0.161	-	-
Obesity	42 (21.8)	90 (23.3)	0.91 (0.59-1.40)	0.658	-	-
Cholecystolithiasis	33 (17.1)	28 (7.3)	2.49 (1.48-4.20)	0.001	2.01 (1.12-3.58)	0.019
Choledocholithiasis	24 (12.4)	2 (0.5)	24.00 (5.67-101.55)	< 0.001	18.08 (4.18-78.19)	< 0.001
Hepatolithiasis	9 (4.7)	1 (0.3)	18.00 (2.28-142.08)	0.006	14.87 (1.79-123.74)	0.013
Cholecystectomy	13 (6.7)	19 (4.9)	1.38 (0.67-2.84)	0.376	-	-
Ulcerative colitis	2 (1.0)	1 (0.3)	4.00 (0.36-44.11)	0.258	-	-
Alcoholic liver disease	7 (3.6)	13 (3.4)	1.08 (0.42-2.78)	0.871	-	-
Thyroid disease	5 (2.6)	15 (3.9)	0.64 (0.22-1.84)	0.408	-	-
Chronic pancreatitis	1 (0.5)	5 (1.3)	0.40 (0.05-3.42)	0.403	-	-
Hypertension	84 (43.5)	185 (47.9)	0.83 (0.58-1.19)	0.301	-	-
Diabetes mellitus	44 (22.8)	54 (14.0)	1.88 (1.19-2.98)	0.007	1.99 (1.22-3.27)	0.006
Without complications	27 (14.0)	38 (9.8)	1.64 (0.95-2.85)	0.077	1.78 (0.99-3.19)	0.055
With complications	17 (8.8)	16 (4.1)	2.43 (1.18-5.00)	0.016	2.48 (1.16-5.32)	0.020
HBV infection	9 (4.7)	9 (2.3)	2.10 (0.80-5.49)	0.131	-	-
HCV infection	6 (3.1)	10 (2.6)	1.20 (0.44-3.30)	0.724	-	-
Liver fluke infestation	3 (1.6)	2 (0.5)	3.00 (0.50-17.95)	0.229	-	-

HBV: Hepatitis B virus; HCV: Hepatitis C virus; ECC: Extrahepatic cholangiocarcinoma.

Table 3 Comparison of risk factors in patients with intrahepatic cholangiocarcinoma and matched controls n (%)

Variable	ICC patient (n = 83)	Control (n =166)	Univariable analysis		Multivariable analysis
			OR (95%CI)	P value	AOR (95%CI)	P value
Cigarette smoking	31 (37.3)	66 (39.8)	0.87 (0.47-1.63)	0.670	-	-
< 20 pack-years	15 (18.1)	23 (13.9)	1.17 (0.54-2.51)	0.689	-	-
≥ 20 pack-years	16 (19.3)	43 (25.9)	0.68 (0.33-1.44)	0.318	-	-
Heavy alcohol consumption	17 (20.5)	26 (15.7)	1.44 (0.70-2.97)	0.319	-	-
Obesity	22 (26.5)	44 (26.5)	1.00 (0.56-1.80)	0.999	-	-
Cholecystolithiasis	14 (16.9)	14 (8.4)	2.06 (0.96-4.41)	0.062	1.04 (0.33-3.29)	0.941
Choledocholithiasis	10 (12.0)	4 (2.4)	6.20 (1.70-22.71)	0.006	8.63 (1.30-57.33)	0.026
Hepatolithiasis	11 (13.3)	1 (0.6)	22.00 (2.84-170.40)	0.003	157.37 (9.36-2646)	< 0.001
Cholecystectomy	4 (4.8)	4 (2.4)	2.00 (0.50-8.00)	0.327	-	-
Ulcerative colitis	0 (0.0)	2 (1.2)	0.03 (0.0-5748.1)	0.561	-	-
Alcoholic liver disease	7 (8.4)	13 (7.8)	1.09 (0.41-2.87)	0.868	-	-
Thyroid disease	1 (1.2)	7 (4.2)	0.25 (0.03-2.19)	0.211	-	-
Chronic pancreatitis	0 (0.0)	0 (0.0)	-	-	-	-
Hypertension	29 (34.9)	69 (41.6)	0.73 (0.41-1.31)	0.291	-	-
Diabetes mellitus	21 (25.3)	15 (9.0)	3.34 (1.60-7.01)	0.001	4.87 (1.88-12.59)	0.001
Without complications	9 (10.8)	9 (5.4)	2.52 (0.90-7.03)	0.078	4.00 (1.18-13.61)	0.027
With complications	12 (14.5)	6 (3.6)	4.28 (1.59-11.49)	0.004	6.13 (1.57-24.00)	0.009
HBV infection	19 (22.9)	9 (5.4)	4.58 (2.00-10.50)	< 0.001	5.27 (1.93-14.38)	0.001
HCV infection	5 (6.0)	3 (1.8)	3.33 (0.80-13.95)	0.099	1.71 (0.25-11.45)	0.582
Liver fluke infestation	3 (3.6)	2 (1.2)	3.00 (0.50-17.95)	0.229	-	-

HBV: Hepatitis B virus; HCV: Hepatitis C virus; ICC: Intrahepatic cholangiocarcinoma.

Table 4 Interaction between diabetes mellitus and hepatitis B virus infection for cholangiocarcinoma: logistic regression analysis with adjusted odds ratio

Interaction variables		n	βCoefficient (± SE)	P value	AOR1 (95%CI)	S (95%CI)2
DM	HBV
Negative	Negative	658			1
Positive	Negative	124	0.909 (0.22)	< 0.001	2.5 (1.6-3.8)
Negative	Positive	36	1.259 (0.39)	0.001	3.5 (1.6-7.6)
Positive	Positive	10	2.502 (0.96)	0.009	12.2 (1.9-80.1)	2.80 (1.54-5.08)
Complicated DM	HBV
Negative	Negative	740			1
Positive	Negative	42	0.967 (0.34)	0.005	2.6 (1.3-5.1)
Negative	Positive	37	1.107 (0.38)	0.004	3.0 (1.4-6.4)
Positive	Positive	9	3.423 (1.32)	0.009	30.7 (2.3-403.4)	8.12 (4.92-13.38)

¹AOR: Odds ratio adjusted for the other significant risk factors for cholangiocarcinoma;

²S = Synergy index described by Rothman = (OR₁₁ - 1)/(OR₀₁ + OR₁₀ - 2), where OR₁₁ = OR of the joint effect of 2 risk factors; OR₀₁ and OR₁₀ = OR of each risk factor in the absence of the other. DM: Diabetes mellitus; HBV: Hepatitis B virus; AOR: Adjusted odds ratio.

Table 5 Interaction between diabetes mellitus and hepatitis B virus infection for intrahepatic cholangiocarcinoma: logistic regression analysis with adjusted odds ratio

Interaction variables		n	βCoefficient (± SE)	P value	AOR1 (95%CI)	S (95%CI)
DM	HBV
Negative	Negative	194			1
Positive	Negative	27	1.670 (0.51)	0.001	5.3 (2.0-14.3)
Negative	Positive	19	1.718 (0.58)	0.003	5.6 (1.8-17.4)
Positive	Positive	9	3.120 (1.15)	0.006	22.7 (2.4-214.1)	2.44 (1.30-4.58)
Complicated DM	HBV
Negative	Negative	211			1
Positive	Negative	10	1.660 (0.77)	0.031	5.3 (1.2-23.8)
Negative	Positive	20	1.528 (0.56)	0.006	4.6 (1.5-13.7)
Positive	Positive	8	3.782 (1.51)	0.012	43.9 (2.3-849.5)	5.45 (3.16-9.42)

¹AOR: Odds ratio adjusted for the other significant risk factors for intrahepatic cholangiocarcinoma. DM: Diabetes mellitus; HBV: Hepatitis B virus; AOR: Adjusted odds ratio; S: Synergism index.