The mortality from hepatocellular carcinoma (HCC) in the United States has increased by an average of 2.7% from 2004 to 2013, according to data from the Surveillance, Epidemiology, and End Results Program, with a greater increase in incidence occurring in many southern states in the country.
“The predominant hypothesis for the southern state increase is the influence of NASH [nonalcoholic steatohepatitis] or NAFLD [non-alcoholic fatty liver disease] alone or in combination with viral hepatitis,” said Hashem B. El-Serag, MD, MPH, during Sunday’s Hepatobiliary Neoplasia SIG Program.
Dr. El-Serag, the Dan L. Duncan Professor of Medicine and Chief of Gastroenterology and Hepatology at Baylor College of Medicine, led off the program with a discussion of what is currently known about the relationship between NASH and HCC.
Among patients with NAFLD, about 20% to 25% will progress to NASH and about 11% over 15 years will progress from NASH to cirrhosis. This translates into about a 1% risk per year of developing HCC, a risk that is “high but lower than that of hepatitis B or C-related cirrhosis,” Dr. El-Serag said.
There are also some patients who will progress directly from NAFLD or NASH to HCC, but it comprises only about “3% to 10% of all HCC and no one knows the risks for progression,” Dr. El-Serag said.
The relative risk for HCC is modestly elevated in patients with metabolic syndrome, but the absolute risk is low. Abdominal obesity and diabetes are among the suspected factors influencing HCC risk. One study found that a high waist-to-hip ratio conferred a threefold higher HCC risk to patients in the upper tertile of waist-to-hip ratio compared with the lowest tertile. In a meta-analysis of 25 cohort studies of patients with diabetes, 18 showed that diabetes – mostly type 2 – was associated with an increased incidence of HCC.
However, currently, NASH-related HCC has not yet translated into a large burden. Temporal trends show that NAFLD-related HCC is now the second most leading etiology, increasing from 8% in 2002 to 13.5% in 2012, but hepatitis C remains the dominant risk factor for HCC, Dr. El-Serag said.
Following Dr. El-Serag’s overview, Tim F. Greten, MD, discussed emerging concepts in HCC pathogenesis in NASH. During his presentation he presented the results of an animal study that showed that NAFLD leads to the selective loss of CD4 T cells in the liver.
Dr. Greten and colleagues used a transgenic mouse model of HCC combined with a methionine and choline deficient diet to induce NASH. They found that, whenever the mice were put on the diet to induce fatty liver disease, which promoted tumor development, there was a loss of CD4 cells but no loss of CD8 cells.
The researchers studied tissue from the mice on this diet and found that linoleic acid was found in the local environment and caused selective loss of CD4 T cells by ROS production. Additionally, ROS blockage rescued CD4 T cells in the livers of mice with NAFLD, restored anti-tumor immunity, and slowed down tumor progression.
“This is the first study to demonstrate that a diet can control immunological effects in the tumor microenvironment leading to enhanced or diminished anti-tumor immune responses,” Dr. Greten said.