The epidemiology of the most common liver cancer, hepatocellular carcinoma, is changing, according to Evi Farazi, PhD. While the incidence and mortality for most other cancer types are decreasing, the trends for liver cancer are increasing.
“Now, one of the most common etiologies of HCC is the progressive form of non-alcoholic fatty liver disease, known as non-alcoholic steatohepatitis (NASH),” she said. “And some of the causes of NASH include obesity, diabetes, metabolic syndrome and so on.”
During a recently published, multiyear study, Dr. Farazi, the Tim Hawks Chair in Cancer Prevention and Population Science in the UNMC Department of Epidemiology in the College of Public Health, discovered that an unhealthy diet leads to the development of HCC irrespective of obesity status in male mice, whereas in female mice obesity was a prerequisite for HCC development.
“The danger there is, because people are lean, a doctor may not suspect that they have NASH. Hence, they may be diagnosed with HCC later and have poorer outcomes,” she said.
Dr. Farazi worked with mouse models, inducing the disease using an unhealthy diet that was high in fat, cholesterol and fructose. She found that mice who became obese under the unhealthy diet eventually developed NASH and hepatocellular carcinoma. But even the male mice who remained lean eventually developed NASH and hepatocellular carcinoma, with equal frequency, albeit had larger tumors.
“So, it seems the unhealthy diet is triggering disease progression,” she said. “The organismal effects of obesity are not a prerequisite for developing the disease in males.”
The study also provided another surprising result – none of the female lean mice developed hepatocellular carcinoma, while obese female mice did. Lean female mice only developed pre-malignant nodules that did not progress to cancer.
“It’s an interesting model to help us try to understand the gender differences in terms of developing hepatocellular carcinoma,” she said. “Especially when you ask the question ‘Are there gender differences in human HCC?’ – because yes, males develop HCC more commonly than females.”
Dr. Farazi is moving ahead with another study to further explore the disease pathways that might be responsible for the gender difference and the disease prevalence in lean and obese females, suggesting that there may be a hormonal element to the disease pathway.
“But the unhealthy diet is something we need to target,” she said. “Going forward, I see two angles – we’re interested in looking at gender differences and comparing the obese with the non-obese in terms of the mechanistic differences. We started looking at epigenetics and more specifically methylation changes to see how they may be different between the models so we can understand if we need to target different pathways in terms of treatment within the disease or even prevention.
“In the differences between obese and lean, can we have common disease pathway targets, or should we target the disease differently? And can the gender differences we saw in our animal models help us understand the gender difference in human HCC?”
Answering these questions will provide potential avenues that in the future may help physicians better diagnose, treat and prevent liver cancer that arises from non-alcoholic fatty liver disease.
Congratulations, Evi!