Professional Documents
Culture Documents
Journal IJC STLH Edit
Journal IJC STLH Edit
Journal IJC STLH Edit
Division of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Jinan, China
Unit of Disease Control Genome Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
3
Division of Hyperbaric Medicine, Shandong Province Hospital, Jinan, China
4
Division of Internal Medicine, Unit of Digestive Disease, Qihe Peoples Hospital, Shandong, China
5
Division of Infectious Disease, Qilu Hospital, Shandong University, Jinan, China
2
C 2011 UICC
Int. J. Cancer: 131, 11971202 (2012) V
A number of cohort and casecontrol studies have investigated the relationship between diabetes mellitus and HCC
risk.615 Type 2 diabetes has been suggested as an independent risk factor for the development of HCC. However, the
role of Type 2 diabetes in the development of HCC in the
presence of chronic hepatitis B (CHB) has not been well
documented. First, only a few cohort studies have followed a
population with chronic HBV infection. In addition, most of
the casecontrol studies used a normal population or cancers
other than HCC as controls, and chronic HBV infection status was not well matched between cases and controls.16 Second, none of these studies followed a cohort of patients with
CHB or matched cirrhosis status between cases and controls
with CHB. The majority of HBV-related HCC develops in
patients with cirrhosis,17 in which the prevalence of Type 2
diabetes is higher than in the general population, and in
CHB patients without cirrhosis.18 So, these studies may also
inappropriately estimate the role of Type 2 diabetes in HCC
development in the presence of CHB. Third, whether Type 2
diabetes plays the same role in HCC development between
men and women in the presence of CHB is not clear. It has
been speculated that in the absence of other strong etiological
risk factors for HCC, such as cirrhosis and male gender,
Type 2 diabetes plays an additional role on its development.
Thus, we have conducted this hospital-based casecontrol
study to more precisely evaluate the role of Type 2 diabetes
Epidemiology
Type 2 diabetes has been suggested as an independent risk factor for the development of hepatocellular carcinoma (HCC).
However, the role of Type 2 diabetes on the development of HCC in the presence of chronic hepatitis B (CHB) remains
inconclusive. We conducted this hospital-based casecontrol study to evaluate the roles of Type 2 diabetes in HCC
development in patients with CHB. From January 2004 to December 2008, a total of 6,275 eligible consecutive patients with
chronic hepatitis B virus (HBV) infection were recruited. A total of 1,105 of them were patients with HBV-related HCC and
5,170 patients were CHB but without HCC. We used multivariate logistic regression models to investigate the association
between Type 2 diabetes and HCC risk. The prevalence of Type 2 diabetes is higher among HCC patients without cirrhosis
than among those with cirrhosis (12.1% vs. 6.7%, p 5 0.003). Type 2 diabetes was associated with a significantly high risk
of HCC in female patients after adjusting for age, family history of HCC, city of residence, hepatitis B e antigen and cirrhosis
with an odds ratio (95% confidence interval, CI) of 1.9 (1.13.4). Restricted analyses among female patients without cirrhosis
indicated that Type 2 diabetes was strongly associated with HCC risk with adjusted odds ratio (95% CI) of 5.6 (2.214.1). In
conclusion, Type 2 diabetes is independently associated with the increased risk of HCC in female CHB patients. Female CHB
patients with Type 2 diabetes are of a high HCC risk population and should be considered for HCC close surveillance program.
1198
Methods
Epidemiology
1199
Li et al.
Table 1. Demographic and clinical characteristics of hepatitis B virus-related HCC cases and hospital cross-sectional CHB controls
All
Variables
Cases,
N 1,105
(%)
Women
Controls,
N 5,170
(%)
Cases,
N 169
(%)
Men
Controls,
N 1,353
(%)
Cases,
N 936
(%)
Controls,
N 3,817
(%)
Sex
Female
169 (15.3)
1,353 (26.2)
Male
936 (84.7)
3,817 (73.8)
Age (years)
3039
82 (7.4)
2,014 (39.0)
10 (5.9)
393 (29.0)
72 (7.7)
4049
250 (22.6)
1,385 (26.8)
30 (17.8)
393 (29.0)
220 (23.5)
1,621 (42.5)
992 (26.0)
5059
470 (42.5)
1,247 (24.1)
63 (37.3)
363 (26.8)
407 (43.5)
884 (23.2)
60
303 (27.4)
524 (10.1)
66 (39.0)
204 (15.1)
237 (25.3)
320 (8.4)
Jinan
464 (42.0)
2,137 (41.3)
73 (43.1)
637 (47.1)
391 (41.8)
1,500 (39.3)
Other cities
641 (58.0)
3,033 (58.7)
96 (56.8)
716 (52.9)
545 (58.2)
2,317 ( 60.7)
4,832 (93.5)
153 (90.5)
1,268 (93.7)
877 (93.7)
3,564 (93.4)
338 (6.5)
16 (9.5)
59 (6.3)
253 (6.6)
4,842 (93.7)
149 (88.2)
863 (91.6)
2,561 (93.7)
93 (8.4)
328 (6.3)
20 (11.8)
72 (5.3)
73 (7.8)
256 (6.7)
HBeAg
256 (23.2)
3,144 (60.8)
32 (18.9)
827 (61.1)
224 (23.2)
2,317 (60.8)
HBeAg
849 (76.8)
2,026 (39.2)
137 (81.1)
526 (38.9)
712 (76.8)
1,500 (39.2)
City of residence
1,030 (93.2)
Yes
75 (6.8)
85 (6.3)
Type 2 diabetes
No
1,012 (91.6)
Yes
1,281 (94.7)
HBeAg status
308 (28.9)
1,852 (35.3)
40 (28.9)
478 (35.3)
268 (28.6)
1,374 (36.0)
Yes
797 (71.1)
3,318 (64.7)
129 (71.1)
875 (64.7)
668 (71.4)
2,443 (64.0)
No
346 (31.3)
3,559 (68.8)
54 (32.0)
895 (66.1)
292 (31.2)
2,664 (69.8)
Yes
759 (68.7)
1,611 (31.2)
115 (68.0)
458 (33.9)
644 (68.8)
1,153 (30.2)
174 (22.9)
365 (22.7)
29 (25.2)
120 (26.2)
145 (22.5)
245 (21.2)
345 (45.5)
543 (33.7)
55 (47.8)
138 (30.1)
290 (45.0)
405 (35.1)
240 (31.6)
703 (43.6)
31 (27.0)
200 (43.7)
209 (32.5)
503 (43.6)
Child-pugh grade
Abbreviations: HCC, hepatocellular carcinoma; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen.
Results
Patient characteristics
Epidemiology
Cirrhosis
1200
Variables
Cases,
N (%)
Controls,
N (%)
p Value*
Age (years)
3039
50 (2.4)
1 (1.2)
49 (2.4)
0.72
4049
110 (6.7)
18 (7.2)
92 (6.6)
0.78
5059
144 (11.5)
0.05
78 (9.4)
35 (11.6)
43 (8.2)
0.14
92 (6.0)
20 (11.8)
72 (5.3)
0.003
329 (6.9)
73 (7.8)
256 (6.7)
0.25
No
230 (5.9)
Yes
191 (8.1)
51 (6.7)
60
Sex
Female
Male
Epidemiology
Cirrhosis
Duration of
diabetes >5 years
97 (23.0) 34 (36.6)
140 (8.7)
<0.001
0.10
63 (19.2) <0.001
As shown in Table 3, in multivariate logistic regression comparing all HCC cases with the hospital cross-sectional controls, no association between Type 2 diabetes and HCC risk
was observed. However, in subgroup analysis in female subjects, a signicant association between Type 2 diabetes and
HCC risk was observed with an AOR of 1.9 (95% CI, 1.1
3.4). In contrast, subgroup analysis in male subjects, no association between Type 2 diabetes and HCC risk was observed.
These indicate effect modication (heterogeneity) of gender.
The estimated X2 for homogeneity between AORs in men
and women was 5.7. In addition, including an interaction
term of gender and Type 2 diabetes in the logistic regression
model along with the main effects of gender and Type 2 diabetes revealed a signicant interaction between gender and
Type 2 diabetes on HCC development (p 0.008). The AOR
(95% CI) for the interaction term of diabetes and sex was
0.42 (0.220.79), and the b coefcient was 0.88. Besides,
including an interaction term of cirrhosis and Type 2 diabetes in the logistic regression model along with the main
effects of cirrhosis status and Type 2 diabetes revealed a signicant interaction between cirrhosis status and Type 2 diabetes on HCC development (p 0.004). The AOR (95%) for
Table 3. Prevalence of Type 2 diabetes and AOR for the association between Type 2 diabetes and the development of HCC in the presence
of CHB: Multivariate logistic regression analyzes
Men
Type 2 diabetes
Cases
All1
All2
Without
cirrhosis3
Women
With
cirrhosis4
Without
cirrhosis6
All5
With
cirrhosis7
93 (8.4%)
73 (7.8%)
28 (9.6%)
45 (7.0%)
20 (11.8%)
14 (25.9%)
6 (5.2%)
Controls
328 (6.3%)
256 (6.7%)
152 (5.7%)
104 (9.0%)
72 (5.3%)
36 (4.0%)
36 (7.9%)
0.9 (0.71.2)
0.8 (0.61.1)
1.0 (0.61.6)
0.9 (0.61.4)
1.9 (1.13.4)
5.6 (2.214.1)
0.4 (0.21.2)
Model 1: Adjusted for age, sex, city of residence, family history of liver cancer, HBeAg status and cirrhosis. Model 2: Adjusted for age, city of
residence, family history of liver cancer, HBeAg status and cirrhosis. 3Model 3: Adjusted for age, city of residence, family history of liver cancer,
HBeAg status and platelet. 4Model 4: Adjusted for age, city of residence, family history of liver cancer, HBeAg status and Child-pugh grade. 5Model
5: Adjusted for age, city of residence, family history of liver cancer, HBeAg status and cirrhosis. 6Model 6: Adjusted for age, city of residence, family
history of liver cancer, HBeAg status and platelet. 7Model 7: Adjusted for age, city of residence, family history of liver cancer, HBeAg status and
Child-pugh grade.
Abbreviations: AOR, adjusted odds ratio; HCC, hepatocellular carcinoma; CHB, chronic hepatitis B; CI, confidence interval.
C 2011 UICC
Int. J. Cancer: 131, 11971202 (2012) V
Discussion
In this large casecontrol study in patients with CHB, Type 2
diabetes was a signicant risk factor for HCC in women. The
study revealed a high prevalence of Type 2 diabetes among
female patients with HCC, but not among male patients with
HCC, yielding a two-fold higher risk of HCC for female
patients with Type 2 diabetes than for those without Type 2
diabetes. To our knowledge, this nding has not been
reported in previous studies.
It is possible that a true relationship exists between Type
2 diabetes and HCC risk in female patients. A gender-based
dimorphic pattern for leptin in patients with diabetes mellitus
may partially explain the association. There is a strong link
between leptin and cancer growth and development,27 with
increasing evidence for the involvement of leptin in HCC
development. Higher plasma leptin levels in females with diabetes mellitus may increase HCC risk. Additionally, higher
serum ferritin and iron overload in women with diabetes
mellitus may also account, in part, for the association
between diabetes and HCC risk.28,29 Liver iron overload is
known to be a risk factor for HCC in patients with hemochromatosis, noncirrhotic liver, alcoholic cirrhosis or nonalcoholic steatohepatitis.3032 Thus, iron overload might also
be a possible link between diabetes mellitus and HCC.
Another important nding of our study is that we
observed a signicantly higher prevalence of Type 2 diabetes
among HCC patients without cirrhosis than among those
with cirrhosis (12.1% vs. 6.7%, respectively, p < 0.001).
Accordingly, we noted a marginal signicant AOR 1.44 (95%
CI, 0.962.16) of HCC risk for those with Type 2 diabetes
among subjects without cirrhosis. Moreover, restricted multivariate logistic regression analyses stratied by sex and cirrhosis status indicated that for female CHB patients without
cirrhosis, those who had Type 2 diabetes had an approximately six times higher risk of HCC than did those without
Type 2 diabetes (p < 0.001). Our nding indicates a synergistic association between Type 2 diabetes and cirrhosis status
on HCC risk. Because of the small number of female HCC
patients without cirrhosis in our study, this result should be
considered with caution. However, this result is in consistent
C 2011 UICC
Int. J. Cancer: 131, 11971202 (2012) V
1201
Epidemiology
Li et al.
1202
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Epidemiology
10.
11.
12.
13.
C 2011 UICC
Int. J. Cancer: 131, 11971202 (2012) V