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Association between Traditional Chinese Medicine Use and Liver Cancer in Patients with Liver Cirrhosis: A Population-based Study

Chen YL1, Lung CC2,3, Huang JY2, Ndi O2, Ko PC2, Chen M1 and Liaw YP2,3*

1Beijing University of Chinese Medicine, Beijing, China

2School of Public Health, Chung Shan Medical University, Tai-Chung, Taiwan

3Department of Family and Community Medicine, Chung Shan Medical University Hospital, Tai-Chung, Taiwan

*Corresponding Author:
Liaw YP
Department of Public Health and Institute of Public Health
Chung Shan Medical University, No. 110
Section 1 Jianguo N. Road, Taichung City 40201, Taiwan
Tel: +886-4-24730022 ext. 11838
Fax: +886-4-23248179
E-mail: [email protected]

Received date: February 22, 2017; Accepted date: March 10, 2017; Published date: April 01, 2017

Citation: Liaw YP, Chen YL, Lung CC, et al. Association between Traditional Chinese Medicine Use and Liver Cancer in Patients with Liver Cirrhosis: A Population-based Study. J Cancer Epidemiol Prev. 2017, 2:1.

 
Visit for more related articles at Journal of Cancer Epidemiology and Prevention

Abstract

Background

The global incidence and mortality of liver diseases is increasing. One of the major risk factors for liver cancer is the presence of liver cirrhosis. Traditional Chinese medicines (TCM) are being sought as alternative medicines for liver diseases. This study evaluated the association between traditional Chinese herbal medicine and liver cancer in patients with liver cirrhosis.

Methods

The analytical data were collected from the Longitudinal Health Insurance Databases (LHID2005). Samples included patients with liver cirrhosis who sought Traditional Chinese medicine from 2001-2004. Diagnosis of liver cancer was from 2004-2010 using the ICD 9 codes 155 and A code A095. The Chi-square (χ2) test was used to test for associations while multivariate logistic regression was used to investigate the association between CM and liver cancer in cirrhotic patients. All statistics were analyzed using the SAS 9.2 software (Cary, NC, USA). Differences were considered significant at p-value< 0.05.

Results

From 2001-2004, a total of 8 145 individuals were identified with liver cirrhosis; 5 469 were men and 2 676 were women. Among the cirrhotic patients who sought TCM, 25.3% of men and 20.41% of women were identified with liver cancer. Multivariate logistic regression analysis showed a significant odds ratio (OR) of 0.880 (95% CI 0.787-0.984) for liver cancer. However, when analyzed by gender, significant odds existed only in men (OR: 0.872, 95% CI 0.764-0.955).

Conclusion

There was a significant association between traditional Chinese medicine and liver cancer in men with cirrhosis.

Keywords

Cirrhosis; Liver cancer; Chinese herbal medicine

Introduction

Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the third leading cause of cancer-related death worldwide [1]. Cirrhosis is the strongest predisposing factor for HCC. Approximately 80% of cases with HCC develop in cirrhotic liver [2]. The annual incidence of HCC in patients with and without cirrhosis is 2.0-6.6 and 0.4%, respectively [2]. Variceal bleeding is one of the commonest and most severe complications of liver cirrhosis. When cirrhosis is diagnosed, varices are present in about 30-40% of compensated patients and in 60% of those who present with ascites [3]. There is no effective medication to prevent the development of varices [4]. Liver transplantation (LT) may serve as the best treatment choice for varices [5,6]. However, shortage of donor organs is a serious well known limitation [7].

Because of the complexity and difficulty involved in the treatment of liver cirrhosis, many patients seek traditional Chinese Herbal medicine (an alternative treatment). A previous study has reported the therapeutic and beneficial effects of Chinese medicine on hepatic fibrosis [8]. Chinese Medicine has also been linked to hepatoprotective effect in cirrhotic patients [9]. However, studies to investigate the links between TCM and liver cancer among patients with liver cirrhosis using a large-scale database are limited. Therefore, this study was conducted to assess the relationship between traditional Chinese herbal medicine and liver cancer in patients with liver cirrhosis.

Methods

The study data were collected from the National Health Insurance Research Database (NHIRD) which contains detailed clinical records of every patient on each visit. It also includes primary and secondary diagnostic codes as well as prescription orders. A randomized sample of 1,00,0000 individuals were retrieved from the LHID2005. The database contained deidentified data hence, ethics approval was not required. Cirrhotic patients were either identified from the CD (ambulatory care expenditures by visit) or DD (inpatient expenditures by admission) datasets using codes 571.2, 571.5, 571.6 and A code A347. The study samples included a total of 8145 cirrhotic patients: 4,509 who sought and 3,636 who did not seek TCM from 2001-2004). Excluded were individuals who were diagnosed with liver cancer from 2001 to 2004 and those who sought TCM during 2005-2010. Liver cancer diagnosis was from 2004-2010 using the ICD 9 code 155 and Acode A095.

Information about demographic variables, insurance cost and geographical region is contained in the NHIRD. Household income was categorized into four groups: family dependent, s5,7$20,000, $20,000 to less than $40,000, and ≥ $40,000. Insurance has been categorized into mainly six regions according to geographic and administrative districts: Taipei (Taipei City, Taipei County, Keelung City, Yilan County, Kinmen County, Lianjiang County), Northern (Taoyuan County, Hsinchu City, Hsinchu County, Miaoli County), Central (Taichung City, Taichung County, Changhua County, Nantou County), Southern (Tainan City, Tainan County, Chiayi City, Chiayi County, Yunlin County), Kao-Ping (Kaohsiung City, Kaohsiung County, Pingtung County, Penghu County), and Eastern region (Hualien County, Taitung County). Adjustments were made for sociodemographic characteristics (Table 1) as well as other potential confounders (hepatitis B virus, hepatitis C virus, chronic hepatitis, alcoholic hepatitis).

Variable TCM from 2001-2004 No TCM from 2001-2004 P -value
(n=4,509) (n=3,636)
Number % Number %
Age (2005) 55.62 ± 15.47   56.53 ± 16.11   0.0095
Sex         <0.0001
Men 2.749 60.97 2.720 74.81  
Women 1.760 39.03 916 25.19  
Household income         <0.0001
Dependent 1.107 24.55 800 22  
< 20 000 2.303 51.08 2.107 57.95  
20 000-39 999 691 15.32 449 12.35  
= 40 000 408 9.05 280 7.7  
Geographic area         <0.0001
Taipei City 1.284 28.48 965 26.54  
North 544 12.06 504 13.86  
Central 932 20.67 527 14.49  
South 775 17.19 753 20.71  
Kaohsiung-Pingtung 785 17.41 696 19.14  
East 189 4.19 191 5.25  
Liver cancer         0.0267
Yes 1.042 23.11 917 25.55  
No 3.467 76.89 2 719 74.78  
Chronic hepatitis         <0.0001
Yes 2.864 63.52 1 973 54.26  
No 1.645 36.48 1 663 45.74  
Hepatitis B         0.0012
Yes 1.116 24.75 789 21.7  
No 3.393 75.25 2 847 78.3  
Hepatitis C         <.0001
Yes 954 21.16 624 17.16  
No 3 555 78.84 3 012 82.84  
Alcoholic hepatitis         0.9446
Yes 286 6.34 232 6.38  
No 4 223 93.66 3 404 93.62  

Table 1: Demographic characteristics of patients who sought TCM (age=30), age was mean ± S.E.

Statistical analysis

The study participants were categorized into ≥ 18, 18-40, and ≥ 40 age groups. T-test was used to analyze the age differences between individuals who received TCM and those who did not. Chi square test was used to assess the links between TCM and categorical variables while multivariate logistic regression was used to evaluate the relationship between TCM and liver cancer. All analyses were made using the SAS software (version 9.2, Cary, NC, USA). Differences were considered significant at p-value<0.05.

Results

A total of 8,145 cirrhotic individuals aged 30 years and older were enrolled in this study. The mean age of cirrhotic men who sought TCM treatment was significantly less than that of those who never sought any treatment (p<0.0001) as shown in Table 2.

Variable TCM from 2001-2004 No TCM from 2001-2004 P-value
(n=2,749) (n=2,720)
Number % Number %
Age (2005) 52.61 ± 15.06   54.55 ± 15.54   <0.0001
Household income          
Dependent 473 17.21 452 16.62 <0.0001
< 20,000 1.477 53.73 1.656 60.88  
 20,000-39,999 450 16.37 368 13.53  
 = 40,000 349 12.70 244 8.97  
Geographic area         <0.0001
Taipei City 789 28.70 715 26.29  
North 333 12.11 395 14.52  
Central 570 20.73 416 15.29  
South 428 15.57 533 19.6  
Kaohsiung-Pingtung 505 18.37 525 19.30  
East 124 4.51 136 5.00  
Liver cancer         0.1265
 Yes 688 25.03 730 26.84  
 No 2.061 74.97 1.990 73.16  
Chronic hepatitis         <0.0001
 Yes 1.745 63.48 1.469 54.01  
 No 1.004 36.52 1.251 45.99  
Hepatitis B         0.0069
 Yes 736 26.77 642 23.60  
 No 2.013 73.23 2.078 76.40  
Hepatitis C         0.0694
 Yes 467 16.99 413 15.18  
 No 2.282 83.01 2.307 84.82  
Alcoholic hepatitis         0.1311
 Yes 255 9.28 221 8.13  
 No 2.494 90.72 2.499 91.88  

Table 2: Demographic characteristics of cirrhotic men who soughtTCM (age=30), age was mean ± S.E.

About 25.03% of cirrhotic men who sought TCM and 26.78% of those who never sought TCM were diagnosed with liver cancer. As shown in Table 3, the mean age of cirrhotic women who sought TCM treatment was significantly lower than that of those who did not (p<0.0001).

Variable TCM from 2001-2004 No TCM from 2001-2004 P-value
(n=1.760) (n=916)
Number % Number %
Age (2005) 60.30 ± 14.93   62.42 ± 16.32   0.0011
Household income         0.0034
Dependent 634 36.02 348 37.99  
< 20 000 826 46.93 451 49.24  
20,000-39,999 241 13.69 81 8.84  
= 40 000 59 3.35 36 3.93  
Geographic area         <0.0001
Taipei City 495 28.13 250 27.29  
North 211 11.99 109 11.9  
Central 362 20.57 111 12.12  
South 347 19.75 220 24.02  
Kaohsiung-Pingtung 280 15.91 171 18.67  
East 65 3.69 55 6  
Liver cancer         0.8539
Yes 354 20.11 187 20.41  
No 1.406 79.89 729 79.59  
Chronic hepatitis         <0.0001
Yes 1.119 63.58 504 55.02  
No 641 36.42 412 44.98  
Hepatitis B         0.0006
Yes 380 21.59 147 16.05  
No 1.380 78.41 769 83.95  
Hepatitis C         0.0096
Yes 487 27.67 211 23.03  
No 1.273 72.33 705 76.97  
Alcoholic hepatitis         0.2684
Yes 31 1.76 11 1.2  
No 1.729 98.24 905 98.8  

Table 3: Demographic characteristics of cirrhotic women who soughtTCM (age>30), age was mean ± S.E.

About 20.11% of cirrhotic men who sought TCM and 20.41% of those who never sought TCM were diagnosed with liver cancer. Results of multivariate logistic regression models stratified by gender and adjusted for insurance cost, geographical region and related confounders (hepatitis B virus, hepatitis C virus, chronic hepatitis, alcoholic hepatitis) are shown in Table 4. In the first model, the odds ratio of developing liver cancer in cirrhotic patients who sought TCM was (OR 0.880, 95% CI 0.787-0.984). Further analysis showed significant odds ratio only in men (0.872, 95% CI 0.764-0.955).

Variable Total Men Women
OR 95% CI OR 95% CI OR 95%CI
TCM in 2001-2004            
 Yes 0.88 0.787-0.984 0.872 0.764-0.95555 0.893 0.722-1.104
 No 1 - 1 - 1 -
Age (2005) 1.027 1.022-0.031 1.028 1.023-1.033 1.022 1.013-1.031
Sex            
Male 1 -        
Female 1.937 1.705-2.200        
Household income            
Dependent 1.189 1.035-1.366 1.355 1.132-1.622 0.936 0.751-1.167
< 20 000 1 - 1 - 1 -
 20,000-39,999 1.184 0.999-1.403 1.308 1.077-1.589 0.839 0.585-1.203
 = 40 000 1.089 0.884-1.343 1.187 0.949-1.484 0.607 0.301-1.222
Geographic area            
Taipei City 1 - 1 - 1 -
North 0.89 0.740-1.070 0.96 0.772-1.194 0.719 0.506-1.022
Central 0.903 0.764-1.068 0.918 0.750-1.124 0.88 0.653-1.186
South 0.94 0.797-1.108 1.055 0.863-1.289 0.718 0.535-0.962
Kaohsiung-Pingtung 1.004 0.852-1.183 1.15 0.947-1.396 0.71 0.519-0.970
East 0.549 0.398-0.757 0.54 0.366-0.795 0.588 0.332-1.041
Co-morbidity            
Chronic hepatitis 1.173 1.041-1.322 1.085 0.942-1.250 1.417 1.131-1.776
Hepatitis B 2.696 2.386-3.046 3.111 2.692-3.595 1.802 1.424-2.282
Hepatitis C 2.491 2.186-2.839 2.384 2.018-2.817 2.642 2.138-3.265
Alcoholic hepatitis 0.431 0.317-0.585 0.475 0.348-0.649 <0.001 -

Table 4: Risk of liver cancer in cirrhotic patients who sought TCM, adjusted for age, sex, household income and region.

Discussion

To our knowledge, this is the first nationwide populationbased study to evaluate the relationship between liver cirrhosis, Chinese traditional medicine and liver cancer. Cirrhotic men who received TCM had a significantly lower risk of liver cancer. The risk was also lower but insignificant in their female counterparts. There may have been an interaction effect of TCM and hormones on liver cirrhosis. Future studies would help to clarify such interactions. In Taiwan, liver cancer accounts for more than 28% of total deaths [10]. The annual standardized mortality incidence increased from 22.7/1,00,000 in 1991 to 26.2/1,00,000 in 2009 [10]. The majority of patients with hepatocellular carcinoma (HCC) worldwide have underlying cirrhosis [11]. Hepatocellular carcinoma occurs at a rate of 1 to 4% per year after cirrhosis is established [12] while cirrhosis underlies HCC in approximately 80%-90% of cases worldwide [13]. Preventing the development of liver cancer in patients with liver cirrhosis is an important public health issue.

In Taiwan, chronic hepatitis B and C are the leading causes of liver cirrhosis [14-16]. About 95% of liver cirrhosis is caused by both B and C types of hepatitis viruses. Other causes include alcohol, chronic hepatitis, and persistence [14]. In this study, adjustments were made for potential confounders such as hepatitis B, C, alcohol and chronic hepatitis. HCC was significantly lower in cirrhotic patients who had received TCM. The mean age of cirrhotic men who were exposed to TCM was below that of their non-exposed counterparts. Significant association between traditional Chinese medicine and liver cancer was found only in men. More studies that take into account gender disparity are essential.

This study has some limitations. First, no specific Chinese medicine was included in the model. Second, there is a dearth of information about the stage of liver cirrhosis. Third, the NHIRD contain records of different scientifically processed Chinese herbal medications whose herbal preparations range from a single to multi-ingredient preparations. This makes it difficult to determine how frequently the patients were taking the medications. Finally, adjustments were not made for potential behavioral confounders such as smoking and drinking.

Conclusion

There was a significant association between traditional Chinese medicine and liver cancer in men with cirrhosis.

Conflict of Interest

Authors have no conflict of interest to disclose.

Acknowledgments

Authors express sincere thanks to Chung Shan Medical University and the entire team that assisted in realizing this work.

References

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