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Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis
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Article in Press, Corrected Proof
Journal of Hepatology Jan 2013
Chih-Wen Lin1,2, Chih-Che Lin3, Lein-Ray Mo1, Chi-Yang Chang1, Daw-Shyong Perng1,
Chia-Chang Hsu1, Gin-Ho Lo1, Yaw-Sen Chen4, Yung-Chieh Yen5, Jui-Ting Hu7,8, Ming-Lung Yu2,6,
Po-Huang Lee4,9, Jaw-Town Lin1,7, Sien-Sing Yang7,8,
"alcoholic cirrhotic patients with concomitant HBV infection have significantly higher incidence of HCC than those with HBV infection alone or alcoholism alone"......"Elevated HBV DNA levels were a strong risk predictor of HCC in alcoholic cirrhotic patients with concomitant HBV infection. Antiviral NUCs therapy significantly reduces the incidence of HCC in alcoholic cirrhotic patients with concomitant HBV infection. Aggressive antiviral NUCs therapy should be considered in alcoholic cirrhosis with detectable serum HBV DNA in order to reduce the incidence of HCC......Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively.....The 5-year cumulative incidence of HCC was up to 36.8% in the patients with concomitant HBV infection and alcoholism".....We retrospectively reviewed 966 consecutive, documented cirrhotic patients (132 with heavy alcoholism and HBV infection, 632 with HBV infection, and 202 with heavy alcoholism) at the Cathay General Hospital, Taipei, North Taiwan, and E-DA Hospital/I-SHOU University, Kaohsiung, South Taiwan, between 2000 and 2009.....For the study, heavy alcoholism was defined as consuming more than 80g of ethanol each day for at least 5years....http://www.cdc.gov/alcohol/faqs.htm -- A standard drink is equal to 14.0 grams (0.6 ounces) of pure alcohol. Generally, this amount of pure alcohol is found in
· 12-ounces of beer.
· 8-ounces of malt liquor.
· 5-ounces of wine.
· 1.5-ounces or a "shot" of 80-proof distilled spirits or liquor (e.g., gin, rum, vodka, or whiskey).
moderate alcohol consumption is defined as having up to 1 drink per day for women and up to 2 drinks per day for men
"Our data showed that the 5-year cumulative incidence of HCC is 10.7% in alcoholic cirrhotic patients. Our data also showed that alcoholic cirrhotic patients with concomitant HBV infection have significantly higher incidence of HCC than those with HBV infection alone or alcoholism alone. The 5-year cumulative incidence of HCC was up to 36.8% in the patients with concomitant HBV infection and alcoholism."
"Our study showed that antiviral NUCs therapy significantly reduces the incidence of HCC in alcoholic cirrhotic patients with concomitant HBV infection. ......Therefore, aggressive antiviral NUCs therapy should be considered in alcoholic cirrhosis with detectable serum HBV DNA, in order to reduce the incidence of HCC. To the best of our knowledge, the use of antiviral NUCs therapy to reduce the incidence of HCC in alcoholic cirrhosis with concomitant HBV infection has not been previously reported."
"Newly developed HCC in all cirrhotic patients -----
........The 10-year cumulative incidence of HCC was higher in patients with concomitant HBV infection and alcoholism than in those with HBV infection alone or alcoholism alone (52.8% vs. 39.8% vs. 25.6%, p <0.001).
.......Our data showed that alcoholic cirrhotic patients with higher serum HBV DNA levels had higher incidence of HCC than those with lower serum HBV DNA levels at the study entry......Our findings confirm that increasing HBV DNA levels precipitate the progression of liver cirrhosis to HCC. Therefore, baseline serum HBV DNA level is a risk predictor of HCC in cirrhosis with concomitant HBV infection and alcoholism. To the best of our knowledge, this finding has not previously been reported in the literature.
..........The annual incidence of HCC was 9.9%, 4.1%, and 2.1% for the patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively
.....Thirty-eight (28.8%), 100 (15.8%), and 21 (10.4%) patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively, were found to have newly developed HCC after 6months of follow-up
.....The 1-, 3-, 5-, and 10-year cumulative incidence of HCC was 3.1%, 28.7%, 36.8%, and 52.8%, respectively, for the patients with concomitant HBV infection and alcoholism; 1.2%, 9.4%, 18.4% and 39.8%, respectively, for the patients with HBV infection alone; and 1.1%, 6.1%, 10.7% and 25.6%, respectively, for the patients with alcoholism alone"
Abstract
Background & Aims
Taiwan has a high prevalence of hepatitis B viral (HBV) infection and hepatocellular carcinoma (HCC) with increasing consumption of alcohol. We investigated the impact of heavy alcohol consumption and HBV infection on HCC in cirrhotic patients.
Methods
966 cirrhotic patients (132 with HBV infection and alcoholism, 632 with HBV infection, and patients with alcoholism) were enrolled between 2000 and 2009 and followed until 2011. The primary end point was newly developed HCC.
Results
Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively. The 10-year cumulative (52.8% vs. 39.8% vs. 25.6%, p <0.001) and annual incidences (9.9%, 4.1%, and 2.1%) of HCC were significantly higher in cirrhotic patients with HBV infection and alcoholism than those in patients with HBV infection or alcoholism alone. For patients with HBV infection and alcoholism, baseline serum HBV DNA (OR=16.8, p=0.025), antiviral nucleos(t)ides analogues (NUCs) therapy (OR=0.01, p=0.035), and serum α-fetoprotein (OR=1.18, p=0.045) were risk predictors of HCC by multivariate logistic regression models. The cumulative incidence of HCC was higher in patients with higher baseline serum HBV DNA. Antiviral NUCs therapy reduced the incidence of HCC.
Conclusions
Heavy alcohol consumption significantly increased the risk of HCC in HBV-related cirrhotic patients. Elevated baseline serum HBV DNA was a strong risk predictor of HCC and antiviral NUCs therapy reduced the incidence of HCC in cirrhotic patients with HBV infection and alcoholism.
Introduction
Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer and the third most common cause of cancer-related death worldwide [1], [2], [3]. In Western countries, chronic alcohol use of greater than 80g per day for more than 5years increases the risk of HCC, and alcoholic cirrhosis is also a definite risk factor for HCC [4], [5], [6], [7]. Taiwan is a region of high prevalence of chronic hepatitis B (CHB) with increasing alcoholic liver disease [8], [9], [10]. Hepatitis B virus (HBV) infection has also been recognized as a major risk factor for cirrhosis and HCC [11], [12]. Serum HBV DNA level is a marker of viral replication and elevated serum HBV DNA level is a strong risk predictor of HCC in CHB patients [13], [14], [15], [16], [17]. Antiviral nucleos(t)ide analogues (NUCs) have been widely used to reduce the development of HCC in CHB patients with fibrosis or cirrhosis [18], [19], [20].
The synergism and interaction between HBV infection and alcohol consumption, in the pathogenesis of chronic liver disease and clinical outcomes, have been reported [4], [5], [6], [21]. However, the role of heavy alcohol consumption and HBV infection on the development of HCC remains uncertain and needs to be explored. We investigated the impact of heavy alcohol consumption and HBV infection on the development of HCC in cirrhotic patients.
Results
Baseline characteristics
The baseline characteristics of cirrhotic patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone are presented in Table 1. The rate was 13.7%, 65.4%, and 20.9% in cirrhotic patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively. The cirrhotic patients were found to be predominantly male. The mean age of patients with concomitant HBV infection and alcoholism was significantly younger than that in patients with HBV infection alone or alcoholism alone (43.9 vs. 47.8 vs. 49.3years, p=0.03). The rate of Child-Pugh class A with concomitant HBV infection and alcoholism was significantly less than that in patients with HBV infection alone or alcoholism alone (46% vs. 57% vs. 54%, p=0.04).
Newly developed HCC in all cirrhotic patients
Thirty-eight (28.8%), 100 (15.8%), and 21 (10.4%) patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively, were found to have newly developed HCC after 6months of follow-up (Table 1). Three, 8, and 2 patients in the each group, respectively, had newly developed HCC within six months. The 1-, 3-, 5-, and 10-year cumulative incidence of HCC was 3.1%, 28.7%, 36.8%, and 52.8%, respectively, for the patients with concomitant HBV infection and alcoholism; 1.2%, 9.4%, 18.4% and 39.8%, respectively, for the patients with HBV infection alone; and 1.1%, 6.1%, 10.7% and 25.6%, respectively, for the patients with alcoholism alone (Fig. 1). The 10-year cumulative incidence of HCC was higher in patients with concomitant HBV infection and alcoholism than in those with HBV infection alone or alcoholism alone (52.8% vs. 39.8% vs. 25.6%, p <0.001). The mean follow-up period was 2.9, 3.9, and 5.2years for the patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively. The annual incidence of HCC was 9.9%, 4.1%, and 2.1% for the patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively (Table 1).
Newly developed HCC in cirrhotic patients by Child-Pugh class
Among compensated cirrhotic patients, 20 (32.3%), 62 (17.2%), and 13 (11.8%) patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively, were found to have newly developed HCC after 6months of follow-up. The 1-, 3-, 5-, and 10-year cumulative incidence of HCC was 3.2%, 24.5%, 32.9% and 51.5%, respectively, for the patients with concomitant HBV infection and alcoholism; 0.6%, 7.8%, 15.3% and 33.8%, respectively, for the patients with HBV infection alone; and 0%, 4.8%, 8.9% and 21.4%, respectively, for the patients with alcoholism alone (Fig. 2). The 10-year cumulative incidence of HCC was higher in the patients with concomitant HBV infection and alcoholism than those with HBV infection alone or alcoholism alone (51.5% vs. 33.8% vs. 21.4%, p <0.001). The annual incidence of HCC was 7.8%, 3.7%, and 1.9% for the patients with concomitant HBV infection and alcoholism, HBV infection alone, and alcoholism alone, respectively. For cirrhotic patients with Child-Pugh class B and C, the cumulative incidence of HCC did not show a statistical significance.
Risk predictors of HCC
In cirrhotic patients with concomitant HBV infection and alcoholism, baseline serum HBV DNA level, antiviral NUCs therapy, serum α-fetoprotein, daily amount of alcohol intake, and years of alcohol intake were significantly associated with the incidence of HCC by univariate analyses (Table 2). Furthermore, in a series of multivariate logistic regression models (Table 2), there was not a significant association between gender, age, and incidence of HCC in Model 1. In Model 2, baseline serum HBV DNA levels [odds ratio (OR)=11.6; 95% confidence interval (CI): 3.42-39.6, p <0.001], antiviral NUCs therapy (OR=0.15; 95% CI: 0.01-0.15, p <0.001), and years of alcohol intake (OR=1.04; 95% CI: 1.01-1.12, p=0.043) were significantly associated with the incidence of HCC. The influence of daily amount of alcohol intake on the incidence of HCC was attenuated when age, gender, HBeAg positive, baseline serum HBV DNA, HBV genotype B vs. C, antiviral NUCs therapy, and years of alcohol intake were included in Model 2. In Model 3, baseline serum HBV DNA levels (OR=12.7; 95% CI: 3.38-47.8, p <0.001), antiviral NUCs therapy (OR=0.14; 95% CI: 0.21-0.71, p=0.001), and years of alcohol intake (OR=1.03; 95% CI: 1.01-1.09, p=0.049) remained significantly associated with the incidence of HCC. The influence of daily amount of alcohol intake on the incidence of HCC was attenuated when age, gender, HBeAg positive, baseline serum HBV DNA, HBV genotype B vs. C, antiviral NUCs therapy, years of alcohol intake, Child-Pugh class B vs. A, and Child-Pugh C vs. A were included in Model 3. In Model 4, baseline serum HBV DNA levels (OR=16.8; 95% CI: 1.94-104, p=0.025), and antiviral NUCs therapy (OR=0.01; 95% CI: 0.01-0.62, p=0.035) were still significantly associated with the incidence of HCC. Moreover, serum α-fetoprotein (OR=1.18; 95% CI: 1.01-1.38, p=0.045) was significantly associated with the incidence of HCC. The influence of daily amount of alcohol intake and years of alcohol intake on the incidence of HCC was attenuated when age, gender, HBeAg positive, baseline serum HBV DNA, HBV genotype B vs. C, antiviral NUCs therapy, Child-Pugh class B vs. A, Child-Pugh C vs. A, serum AST, serum ALT, serum total bilirubin, serum alkaline phosphatase, serum albumin, and serum α-fetoprotein were included in Model 4. In addition, the cumulative incidence of HCC during the follow-up period was significantly higher in those patients with higher baseline serum HBV DNA levels than those with lower baseline serum HBV DNA levels (Fig. 3). For patients with HBV viremia, the cumulative incidence of HCC was reduced by antiviral NUCs therapy (Fig. 4).
Discussion
Our data showed that the 5-year cumulative incidence of HCC is 10.7% in alcoholic cirrhotic patients. Our data also showed that alcoholic cirrhotic patients with concomitant HBV infection have significantly higher incidence of HCC than those with HBV infection alone or alcoholism alone. The 5-year cumulative incidence of HCC was up to 36.8% in the patients with concomitant HBV infection and alcoholism. Our findings are consistent with earlier studies that found the synergism between severe alcohol abuse and viral hepatitis infection increases the incidence of HCC [4], [5], [6], [7], [24], [25].
Our data also confirmed that HCC occurred at younger age in patients with concomitant HBV infection and alcoholism than those with HBV infection alone or alcoholism alone (43.9 vs. 47.8 vs. 49.3years, p=0.03). Moreover, the rate of Child-Pugh class A with concomitant HBV infection and alcoholism was significantly less than that with HBV infection alone or alcoholism alone (46% vs. 57% vs. 54%, p=0.04). The synergism between alcoholism and HBV infection leads to more severe liver disease and earlier occurrence of HCC. Therefore, alcoholic cirrhotic patients with concomitant HBV infection should be closely screened for HCC.
Our data showed that alcoholic cirrhotic patients with higher serum HBV DNA levels had higher incidence of HCC than those with lower serum HBV DNA levels at the study entry. Our findings confirm that increasing HBV DNA levels precipitate the progression of liver cirrhosis to HCC. Our data are compatible with the large nationwide REVEAL-HBV study in Taiwan [13], [14], [15] for CHB without alcoholism, which showed serum HBV DNA at study entry is a significant risk predictor of HCC. Therefore, baseline serum HBV DNA level is a risk predictor of HCC in cirrhosis with concomitant HBV infection and alcoholism. To the best of our knowledge, this finding has not previously been reported in the literature.
Antiviral NUCs therapy has been widely used for the treatment of HBV-related cirrhosis [19], [20]. Our study showed that antiviral NUCs therapy significantly reduces the incidence of HCC in alcoholic cirrhotic patients with concomitant HBV infection. Our findings are consistent with recent large-population, international studies, which showed antiviral NUCs therapy reduced the incidence of HCC in CHB patients without alcoholism [18], [26], [27], [28], [29]. Therefore, aggressive antiviral NUCs therapy should be considered in alcoholic cirrhosis with detectable serum HBV DNA, in order to reduce the incidence of HCC. To the best of our knowledge, the use of antiviral NUCs therapy to reduce the incidence of HCC in alcoholic cirrhosis with concomitant HBV infection has not been previously reported.
The limitations of the study include the following: the retrospective study might have resulted in unintended bias; in addition, 45% of patients did not have a liver biopsy to confirm the diagnosis of cirrhosis because of hepatic failure with coagulopathy, and massive ascites. Although these patients had upper endoscopies to confirm the presentation of esophageal varices, the lack of a biopsy might lead to an underestimation of cirrhosis in the patient population.
In conclusion, alcoholic cirrhotic patients with concomitant HBV infection have significantly higher incidence of HCC than those with HBV infection alone or alcoholism alone. The occurrence of HCC was at younger ages in patients with concomitant HBV infection and alcoholism than those with HBV infection alone or alcoholism alone. Elevated HBV DNA levels were a strong risk predictor of HCC in alcoholic cirrhotic patients with concomitant HBV infection. Antiviral NUCs therapy significantly reduces the incidence of HCC in alcoholic cirrhotic patients with concomitant HBV infection. Aggressive antiviral NUCs therapy should be considered in alcoholic cirrhosis with detectable serum HBV DNA in order to reduce the incidence of HCC.
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