By Jillian L Lokere, MS

February 4, 2005 — Alcohol, tobacco and obesity are not only independent risk factors for the development of hepatocellular carcinoma (HCC), they appear to act synergistically to further increase risk, according to a retrospective, case-control study.

Alcohol consumption and obesity have both been shown to be risk factors for HCC, while studies on tobacco usage have produced conflicting results. In the most recent examination of this issue, Marrero and colleagues pointed out that most case-control studies on HCC have used volunteers without liver disease as controls. These volunteers are at very low risk of developing HCC, which could inflate the risk in some studies.

To examine the role of alcohol consumption, obesity, tobacco, and diabetes on the development of HCC, the authors conducted a case-control study in which each patient with HCC was matched to 2 controls: a patient with cirrhosis but without HCC, and a volunteer without liver disease.

A total of 210 participants, 70 per study group, were enrolled from the liver or general medicine clinics at the University of Michigan hospital. Controls were matched to patients with HCC by age and gender. None of the patients with cirrhosis developed HCC during a median follow-up of 12 months.

Subjects' lifetime alcohol exposures were measured using the Skinner Alcohol Use Inventory, an interview-based questionnaire. Patients were classified as none, former, or current drinkers, with former drinkers being those who did not drink for more than 6 months before the interview. Lifetime alcohol exposure was calculated and expressed in gram-years. Those who had a lifetime total of less than 100 servings of alcohol were defined as having no exposure, those with less than 1500 gram-years as mild-to-moderate exposure, and those with over 1500 gram-years as heavy exposure.

Similarly, lifetime tobacco exposure was determined and expressed in pack-years. Patients were classified as none, former (no cigarettes in the past 6 months), or current smokers. Tobacco exposure was characterized as none for those exposed to less than 100 cigarettes during their lifetime, mild-to-moderate for those exposed to less than 20 pack-years, and heavy for those exposed to greater than 20 pack years.

Height and weight were measured at the time of enrollment, and patients were characterized as lean (BMI less than 25 kg/m2), overweight (BMI 25.1-30 kg/m2) or obese (BMI greater than 30 kg/m2). Diabetes mellitus was defined by use of insulin or oral diabetic medication.

HCC patients had a significantly longer total duration of alcohol consumption, higher average daily consumption, and greater lifetime exposure when compared with both control groups. Whereas 68% of HCC patients had an exposure of greater than 1500 gram-years, only 37% of the cirrhotic group and 4% of the healthy control group had this level of exposure. The data were similar for tobacco, with 70% of the HCC patients, 49% of the cirrhotic patients and 5% of the healthy controls having an exposure of greater than 20 pack-years. Patients in the HCC group also had a significantly higher BMI than did either control group. The percentage of diabetics in each group was not significantly different.

A conditional regression analysis that controlled for race and presence or absence of hepatitis C virus infection was conducted. When HCC cases were compared to cirrhotic controls, the risk of HCC increased 6-fold for heavy alcohol exposure, 5-fold for heavy tobacco exposure, and 4-fold for obesity. These risks were much higher (24-fold, 64-fold, and 48-fold) when HCC patients were compared with healthy controls.

The researchers then used to the data from the HCC patients and cirrhotic controls to calculate whether any 2 of the risk factors acted synergistically to increase the risk by 2- to 3-fold over what could be accounted for by additive effects. They found significant synergistic interaction between alcohol, tobacco, and obesity, with a 50% increase in risk over what could be accounted for additively.

"Our study is the first to simultaneously evaluate the relationship of alcohol, tobacco and obesity with HCC," wrote the authors. Although the mechanism is unknown, they note that "a similar synergistic effect has been observed in patients with esophageal and stomach cancer."

Bob Gish, M.D., from the California Pacific Medical Center, commented, "The development of liver cancer is clearly multifactorial. This provides further impetus to have our patients at risk modify their risk behavior."

Reference

Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol. 2005;42:218-224.