Risk factors for hepatocellular carcinoma have undergone dramatic changesin recent years. Metabolic conditions such as obesity and diabetes, as well as associated nonalcoholic fatty liver disease, now sit at the top of the list. Alcohol use disorders also are on the increase, fueling alcoholic liver disease and alcoholic cirrhosis. At the same time, however, with more effective treatment and prevention, hepatitis C and hepatitis B infections have decreased in prevalence.
Fasiha Kanwal, MD
HOUSTON — Most cases of hepatocellular carcinoma (HCC), the most common form of primary liver cancer, occur in patients with cirrhosis. Yet cirrhosis, or scarring of the liver tissue, can develop for a number of reasons—and the most predominant risk factors have changed significantly in the United States over the past decade.
Metabolic conditions like obesity and diabetes, as well as nonalcoholic fatty liver disease (which is associated with these metabolic conditions), have become the top risk factors for cirrhosis. Rising rates of alcohol use disorders also have fueled an increase in alcoholic liver disease and alcoholic cirrhosis. Meanwhile, untreated hepatitis C and hepatitis B infections, which can lead to cirrhosis, have decreased in prevalence.
While experts expect that changes in cirrhosis risk factors could translate to shifts in the cirrhosis patients’ risk of HCC, a new study is among the first to analyze data related to these trends. The research, which was published in the journal Hepatology, looked at 2,733 cirrhosis patients, using data from two contemporary, multiethnic patient cohorts: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston VA Cirrhosis Surveillance Cohort. The study authors calculated the annual overall incidence rate for HCC and also examined how etiology, demographic, clinical and lifestyle factors affected patient risk.1
“The contributing risk factors for cirrhosis have changed,” said Fasiha Kanwal, MD, the study’s first author, an investigator at the VA Center for Innovations in Quality, Effectiveness and Safety at the Michael E. DeBakey VAMC and professor of medicine at Baylor College of Medicine, both in Houston. “This means that old estimates are no longer applicable, and we need new, relevant data to inform clinical decision making and policy.”
During the study period, 135 patients developed HCC at an annual incidence rate of 1.82%, which is lower than the rate reported in previous studies. (Earlier research, which has mostly included cirrhosis patients with untreated hepatitis B and hepatitis C, has found annual incidence rates between 2% and 8%.) These results show that the shift from hepatitis to non-alcoholic fatty liver disease as a dominant risk factor for cirrhosis has resulted in a subsequent reduction in HCC risk among cirrhosis patients.
Patients with active hepatitis C infections had a more than twofold higher risk of developing HCC compared to patients with nonalcoholic fatty liver disease. The annual HCC incidence rate was the highest in patients with active hepatitis C infections (3.36%), followed by patients with cured hepatitis C infections (1.71%), those with alcoholic liver disease (1.32%) and those with nonalcoholic fatty liver disease cirrhosis (1.24%). In total, 67 patients had hepatitis B infections, and only 32 of those did not have other risk factors (such as concurrent infection with hepatitis C virus). For that subgroup, the annual HCC incidence rate was 1.13%.
“We are seeing more and more patients who have cirrhosis from nonviral etiologies, such as nonalcoholic fatty liver disease,” Kanwal said. “Most of the patients with viral hepatitis-related cirrhosis have received treatment and have been cured of their infection. The risk of HCC in these patients is lower than the risk in patients with cirrhosis and active viral hepatitis.”
While the study did not find a significant difference in HCC risk among non-Hispanic whites, non-Hispanic Blacks and Hispanics, the risk of HCC was 2.2 times higher in men than in women. The risk of HCC also increased with age. Patients over age 65 had a 92% higher risk of HCC compared to those age 55 and younger.
Other factors that increased risk of HCC included smoking and overweight/obesity.However, dyslipidemia was associated with a lower risk of HCC.
“The risk factors for liver disease in veterans are now similar to the risk factors in nonveterans,” said Kanwal. “Hence, there will need to be a focus on managing overweight and smoking, if we were to continue to bend the curve within the VA.”
The study results also could guide future analyses of the effectiveness and cost-effectiveness of HCC surveillance among people with cirrhosis. The authors noted that current surveillance recommendations are based on older studies of patients with active hepatitis, with no direct evidence relating to newer cohorts of cirrhosis patients, most of whom have cured hepatitis infections or nonalcoholic fatty liver disease.
Still, “all subgroups of patients had HCC risk that was higher than the accepted thresholds for HCC surveillance—supporting the current recommendation to continue HCC surveillance in patients with cirrhosis,” Kanwal said.
The data also may be used to help inform measures to prevent HCC in cirrhosis patients. The researchers’ observed association of smoking with increased HCC risk supports recent guidance that cirrhosis patients should be counseled on abstaining from smoking. The study also provides evidence that obesity is associated with increased HCC risk among patients with cirrhosis, showing that the mechanisms of obesity-related hepatocarcinogenesis need to be further examined.
- Kanwal, F, Khaderi S, Singla, AG, Loo, N, Asrani, SK, et al. Risk factors for HCC in contemporary cohorts of patients with cirrhosis. Hepatology. Published March 1, 2022. DOI: 10.1002/hep.32434.
