Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma (liver cancer)
Journal of Hepatology Volume 42, Issue 2, Pages 218-224 (February 2005)
Jorge A. Marrero*email address, Robert J. Fontana, Sherry Fu, Hari S. Conjeevaram, Grace L. Su, Anna S. Lok
Division of Gastroenterology, University of Michigan, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA
We conducted a prospective case-control study of 210 subjects enrolled from the Liver or General Medicine Clinics at our hospital. Treatment-naïve HCC patients were recruited between June 2002 and August 2003.
"....alcohol consumption, tobacco smoking and obesity are independent risk factors of HCC.....We also showed that an exposure of <1500gram-years (of alcohol) was protective for development of HCC. It is unclear why, but likely there is a threshold of alcohol exposure that leads to cirrhosis, recently demonstrated to be >50g a day 31, and another one for HCC (>80g of ethanol). Therefore, if the alcohol threshold for developing HCC is not exceeded then it might not increase the risk of HCC or be protective as seen in coronary artery disease...... Our results indicate an important role of tobacco in the development of HCC in our patient population..... We also showed that obesity at the time of diagnosis is an independent risk factor for HCC......The relative risk of death from liver cancer among adults with BMI >35 was 5.2 compared to those with BMI <30, the risk may be higher if weights prior to diagnosis of HCC were available..... We showed a synergistic interaction between heavy alcohol consumption, heavy tobacco smoking and obesity on the risk of HCC.... these three risk factors appear to act synergistically in increasing the risk of HCC when compared with cirrhotic controls indicating that these factors may in part explain why some cirrhotics develop HCC and others do not. Our data need to be validated in large multicenter prospective studies...." See Author Discussion below
Background/Aims: Alcohol has been shown to be an important risk factor for hepatocellular carcinoma (HCC). The role of tobacco as a risk factor for HCC is controversial. Recently, obesity has been reported to be a risk factor for HCC. We investigated whether these factors increase the risk of HCC in American patients.
Methods: Consecutive patients with HCC, cirrhosis without HCC and, control patients without liver disease were enrolled and exposure to risk factors was assessed.
Results: When HCC cases were compared to cirrhotic controls, the risk of HCC increased 6-fold for alcohol (OR 5.7; 95% CI: 2.4--13.7), 5-fold for tobacco (OR 4.9; 95% CI: 2.2--10.6), and 4-fold with obesity (OR 4.3; 95% CI: 2.1--8.4). Using spline regression, a dose-dependent relationship between alcohol and tobacco exposure with risk of HCC was noted. There was significant interaction between alcohol, tobacco and obesity, with synergistic indices greater than 1.
Conclusions: Alcohol, tobacco and obesity are independent risk factors for HCC in our patient population, and they interact synergistically to increase the risk of HCC. Data from this study may allow us to stratify cirrhotics into low- and high-risk groups for the development of HCC surveillance strategies.
In the recent 2001 Annual Report to the Nation on the Status of Cancer in the USA, primary liver cancer had the highest increase in incidence of all tumors during the past decade 1. It is projected that the incidence of HCC in the US will continue to increase over the next 2 decades partially as a result of the hepatitis C (HCV) epidemic 2. The most important and consistently identified risk factor for HCC is cirrhosis 3. Worldwide, chronic HCV and hepatitis B (HBV) infection are the most important etiologic factors for the development of HCC 4. It has been estimated that the lifetime risk of patients with HCV and HBV cirrhosis is between 10 and 37% [5,6]. Therefore, not all cirrhotics and not all patients with chronic HCV or HBV infection will develop HCC. It is possible that environmental factors may play a role in determining which patients with cirrhosis develop HCC.
Alcohol has been previously studied as a risk factor for HCC. Heavy alcohol consumption has been shown to increase the risk of HCC compared to controls without liver disease 7. The results of studies on tobacco as a risk factor for HCC have been conflicting, varying from no significant risk to a 3-fold increase compared to non-smokers [8,9]. Obesity has been recently shown to be an important risk factor for liver cancer 10. Diabetes has also been reported to be associated with an increase in risk of HCC 11.
There are significant limitations with available literature on the effects of alcohol and tobacco on the risk of HCC. First, the choice of controls is critical and should include individuals at risk of developing HCC 12. Most studies evaluating risk factors for HCC employed controls without liver disease, who are at extremely low risk of developing HCC, and may have overestimated the impact of the risk factors studied. Secondly, most studies have been performed outside the US in which the cultural acceptance of tobacco and alcohol intake and the predominant etiology of the underlying liver disease may differ. Therefore, we performed a case-controlled study to test the hypothesis that tobacco, alcohol, and obesity independently increase the risk of HCC among Americans with cirrhosis.
In this case-control study, we showed that alcohol consumption, tobacco smoking and obesity are independent risk factors of HCC. Compared to normal controls with no liver disease, alcohol, tobacco and obesity were associated with a 24-, 64-, and 48-fold increase in risk of HCC, respectively. The effects of these risk factors were less dramatic when HCC patients were compared to cirrhotic controls, but a statistically significant effect persisted indicating that these factors may play a role in determining which patients with chronic liver disease will develop HCC.
Our study confirmed that alcohol consumption had a dose-dependent effect on the risk of HCC, the risk increased after >1500gram-years of alcohol exposure. The risk of HCC was not different when alcohol consumption was classified as none, former or active, because many of our patients had stopped drinking prior to or at the time of diagnosis. Our results are consistent with other studies indicating an estimated risk of HCC ranging from an odds ratio of 1.7--34 [26--30]. Most published studies expressed alcohol exposure as average daily consumption; we found that 72% of our patients drank intermittently, with a wide range in average daily consumption throughout their lifetime (data not shown). By measuring alcohol consumption in gram-years, we took into account average daily consumption as well as duration of regular drinking giving us a better estimate of lifetime alcohol exposure. We also showed that an exposure of <1500gram-years was protective for development of HCC. It is unclear why, but likely there is a threshold of alcohol exposure that leads to cirrhosis, recently demonstrated to be >50g a day 31, and another one for HCC (>80g of ethanol) 29. Therefore, if the alcohol threshold for developing HCC is not exceeded then it might not increase the risk of HCC or be protective as seen in coronary artery disease 32.
Tobacco exposure is the leading carcinogen associated with multiple solid tumors 33. Our results indicate an important role of tobacco in the development of HCC in our patient population. Several investigators have previously reported an association between tobacco and HCC with odds ratios ranging from 1.5 to 6.8 [28,34,35]. However, other studies found no association between tobacco and HCC [13,36]. An effect of tobacco in the development of HCC is biologically plausible, due to the carcinogenic potential of several of the ingredients in tobacco that are metabolized in the liver 37.
We also showed that obesity at the time of diagnosis is an independent risk factor for HCC. Evidence indicating that obesity is an important risk factor for liver cancer came from a prospectively followed adult cohort in the US 38. That study showed that obesity was associated with increased death rates for multiple solid tumors; the greatest impact of obesity was on liver cancer. The relative risk of death from liver cancer among adults with BMI >35 was 5.2 compared to those with BMI <30, the risk may be higher if weights prior to diagnosis of HCC were available. The mechanism by which obesity leads to cancer is unclear, though insulin growth factor-1 and estrogen have been implicated 39.
We showed a synergistic interaction between heavy alcohol consumption, heavy tobacco smoking and obesity on the risk of HCC. There have been no prior studies evaluating all three factors simultaneously. Three previous studies evaluating alcohol and tobacco as risk factors for HCC did not show tobacco exposure as an important risk factor [8,16,26], but 2 others showed that tobacco and alcohol had synergistic effect on the risk of HCC [9,28]. A case-control study from Japan evaluated tobacco and alcohol as risk factors for HCC compared to controls with chronic liver disease found that the estimated risk of developing HCC in subjects with exposure to both alcohol and tobacco was 17.9 40. The biological mechanism for the synergy between tobacco, alcohol and obesity is unknown. However, a similar synergistic effect has been observed in patients with esophageal and stomach cancer 41.
Our study is the first to simultaneously evaluate the relationship of alcohol, tobacco and obesity with HCC, but there are several limitations. Recruitment from a single tertiary center limits generalizability of results. We minimized selection bias by selecting cases and controls from clinics in the same institution to decrease potential differences such as access to care, referral patterns and socioeconomic status. Furthermore, lifetime assessment of exposure to alcohol and tobacco may be inaccurate due to recall bias, but we tried to address these concerns by using validated questionnaires administered by a trained interviewer. The interviewer was not blinded to case-control status; we do not eliminate the possibility that HCC patients may have been probed more thoroughly than the controls leading to recall bias. BMI was determined at the time of enrollment and may not reflect the usual weight of the HCC patients thus under-estimating the impact of obesity on the risk of HCC. Cirrhotic controls may harbor small HCC that are not detected at enrollment, however, all the cirrhotic controls had at least 6 months of follow up (with ultrasound and AFP) with no evidence of HCC. Our cirrhotic controls were age-matched to the HCC patients, indicating that they had less alcohol and tobacco exposure up to the same age. We did not find an association between HCC and diabetes likely due to the high prevalence of diabetics in the control groups (23% in cirrhotics and 21% in controls without liver disease) 42.
In conclusion, we have shown that alcohol, tobacco and obesity are independent risk factors for HCC with a dose-dependent effect. Moreover, these three risk factors appear to act synergistically in increasing the risk of HCC when compared with cirrhotic controls indicating that these factors may in part explain why some cirrhotics develop HCC and others do not. Our data need to be validated in large multicenter prospective studies. If confirmed, our data may help stratify patients with chronic liver disease into high and low risk groups and to design HCC surveillance algorithms tailored to the risk.
We conducted a prospective case-control study of 210 subjects enrolled from the Liver or General Medicine Clinics at our hospital. This study was approved by the University of Michigan Institutional Review Board, and informed consent was obtained from all participants. Treatment-naïve HCC patients were recruited between June 2002 and August 2003, only 7 HCC patients seen during this period refused enrollment. The diagnosis of HCC was made by histopathology (n=57), and if histopathology was not available by two imaging modalities (ultrasound [US], magnetic resonance imaging [MRI], or computed tomography [CT]) showing a vascular enhancing mass >2cm (n=10); or an alpha-fetoprotein (AFP) >400ng/ml plus one imaging modality showing a vascular mass in the liver (n=3) 13. For each HCC patient enrolled, 2 controls matched for age (±5 years) and gender were recruited (1 matched control with cirrhosis and 1 matched control with no liver disease were randomly selected for each case). Diagnosis of cirrhosis in the first group of controls was based on liver histology (n=56) or clinical, laboratory and imaging evidence of hepatic decompensation or portal hypertension (n=14) 14; all but 5 of the eligible cirrhotic controls were enrolled. All cirrhotics had no evidence of HCC based on normal AFP and ultrasound or other imaging within 3 months of enrollment. All cirrhotic controls had at least one normal AFP and hepatic imaging 6 months after enrollment. The cirrhotic controls have been followed for a median of 12 months (range 7--18 months) after enrollment, and no one has developed HCC. The control group of patients without liver disease had normal liver chemistry tests consecutively seen at the primary care clinics of our hospital, and 91% of the eligible patients approached were enrolled.
Measurement of exposure to tobacco, alcohol and obesity
To obtain data on lifetime exposures to tobacco and alcohol, all patients were interviewed using validated questionnaires at the time of enrollment by a single trained interviewer. For alcohol, we utilized the Skinner Alcohol Use Inventory 15. This instrument divides the patient's lifetime into different periods for easier recall, and the average daily intake of alcohol (beer, wine or hard liquor) during each period was recorded. Patients were classified as none, former and current drinkers. Former drinkers were defined as those who have not had a drink for more than 6 months before the interview. Because the duration and amount of alcohol consumption varies from person to person and in a single person's lifetime, lifetime alcohol exposure was expressed in gram-years: average daily consumption (grams) times the total duration of alcohol exposure (years). For example, a person who drank an average of 40g a day between ages 20 and 30, 20g a day between ages 30 and 40, and 80g a day between ages 40 and 50, would have a total lifetime alcohol consumption of [(0.04×365×10)+(0.02×365×10)+(0.08×365×10)] 511kg. The total gram-years would be [(40×10)+(20×10)+(80×10)] 1400gram-years and the average daily alcohol consumption would be [(40+20+80)/3] 47g/day. We categorized alcohol exposure as none (defined as a patient who consumed <100 servings of alcohol during his/her lifetime 16), <1500gram-years (mild-to-moderate) or ≧1500gram-years (heavy), which is equivalent to > or <60g/day over a 25 year period 17.
Lifetime tobacco exposure was determined by a validated instrument similar to the Skinner alcohol inventory in that it divides a person's lifetime into different periods 18. Only inhaled cigarette exposure was recorded. Patients were classified as none, former and current smokers. Smokers were classified as former smokers if their last cigarette was more than 6 months before the interview. Lifetime tobacco exposure was expressed as pack-years because it takes into account duration and quantity 19. Tobacco exposure was characterized as none (<100 cigarettes during their lifetime 16), <20 pack years or ≧20 pack-years. 20 pack-years were selected as the cutoff of tobacco exposure because 1 pack (20 cigarettes)/day has been shown to be a risk for HCC 20 over a 20-year period 21.
Height and weight were measured by a clinic nurse at the time of enrollment. Each patient was classified as lean (BMI <25kg/m2), overweight (BMI 25.1--30kg/m2) or obese (BMI >30kg/m2) 22. Diabetes mellitus was defined by use of insulin or oral diabetic medication.
There was no difference in age or gender among the three groups. In addition, the patients with cirrhosis and HCC were comparable with regards to etiology of underlying liver disease and race. All HCC patients had cirrhosis based on histological (n=54) or laboratory and radiological (n=16) criteria. The mean Child-Turcotte-Pugh (CTP) and Model for Endstage Liver Disease (MELD) scores were similar among HCC and cirrhotic patients. There was no difference in the presence of ascites between patients with cirrhosis (8%) and HCC (6%) (P=0.842).
Table 2 summarizes data on the various HCC risk factors across the three groups. HCC patients had a significantly longer total duration of alcohol consumption, higher average daily consumption and greater lifetime alcohol exposure compared to controls (P<0.05). A total of 33 patients with HCC and 23 controls (20 cirrhotics and 3 without liver disease) had an alcohol exposure of >1500gram-years. Patients with HCC had significantly longer duration of tobacco smoking and lifetime tobacco exposure compared to both control groups (P<0.05). A total of 38 patients with HCC and 24 controls (19 cirrhotics and 5 without liver disease) had a tobacco exposure of >20 pack-years. Twenty-one HCC patients (15%) had an exposure to alcohol of >1500gram-years and tobacco of >20 pack-years. Patients with HCC also had significantly higher BMI compared to both control groups (P<0.001).
Risk of hepatocellular carcinoma
Conditional regression analysis controlling for the etiology of the underlying liver disease (presence or absence of Hepatitis C) and race (non-Hispanic white vs. others) showed that tobacco and alcohol exposure were independent risk factors for HCC, with a dose-dependent increase in the risk. When HCC patients were compared to cirrhotic controls, the spline regression plots confirmed the dose-dependent effect of alcohol and tobacco exposure on the risk of HCC. The risk of HCC increased 6-fold for patients with lifetime alcohol exposure >1500gram-years, 5-fold with >20 pack-years of smoking, and 4-fold with BMI >30. The effects of alcohol, tobacco and obesity on the risk of HCC were elevated when the HCC patients were compared to normal controls with no liver disease.
Interactions of risk factors
After evaluating the independent effects of each of the risk factors, the interactions of alcohol consumption, tobacco smoking, and obesity on the risk of HCC were evaluated by comparing the HCC patients with the cirrhotic controls. Pairs of risk factors were analyzed with adjustment for the third risk factor. Table 4 shows that compared to patients with exposure to tobacco or alcohol only, the risk of HCC was higher when both risk factors were present (OR 7.2; 95% CI: 2.2--14.1). An increase in risk of HCC was also observed when exposure to tobacco or alcohol was present with obesity.
To determine if the interactions between alcohol, tobacco and obesity on the risk of HCC were synergistic or additive, the synergistic indices were determined based on the estimated odds ratio. The synergistic indices for the interaction between alcohol and tobacco, tobacco and obesity, and alcohol and obesity were 3.3, 2.9 and 2.5, respectively. When all three variables were analyzed together, the synergistic index was 1.6. Thus, there is synergism between the effects of alcohol, tobacco and obesity on the risk of HCC in our cohort.
This study was planned to identify a difference alcohol exposure. We identified a proportion of patients with alcohol exposure >1500gram-years (48% cases and 32% controls), the minimal detectable odds ratio is 0.61 (95% CI: 0.3--1.2). A sample size of 70 patients per group will have greater than 80% power when using McNemar's test at 5% level of significance. Continuous variables were transformed by taking the square root before analysis. The data were analyzed using a repeated measures analysis of variance, where the repeated factor was the matching and the grouping factor was the disease group. Categorical variables were compared by Fisher's exact test.
Conditional logistic regression modeling was used to generate odds ratio (OR) with 95% confidence intervals (CI) to estimate the risk of HCC. The maximum likelihood ratio test was used to assess the significance of alcohol, tobacco and obesity in the model 23. To depict the dose--response relation of alcohol and tobacco and the risk of HCC, we used a multivariable restricted regression spline analysis 24. A spline analysis fits separate curves for segments of the dose distribution, which allows the overall curve to reflect more accurately the shape of a dose--response trend. The interactions between risk factors comparing cirrhotics and HCC patients were evaluated by including them in the additive regression model using an interaction term with levels of exposure as present or absent. To assess whether the interactions between the risk factors were additive or synergistic, the Synergism index and its 95% CI was calculated to assess deviation from an additive model. Synergism (S)=[OR1+2-1]/[OR1+OR2] 25. OR1 is the estimated odds ratio for the presence of one risk factor, OR2 the odds ratio for the presence of another risk factor, and OR1+2 is the combined estimated odds ratio for the 2 risk factors. A value greater than the reference unit (1.0) suggests that the effect of the joint exposures of 2 risk factors is greater than the sum of the separate effects. All analysis was performed using SAS 8.2 (Cary, NC, USA).
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