Yale researchers have redefined a key metric for diagnosing non-alcoholic fatty liver (NAFL) in young, lean, healthy people. Too much liver fat can lead to insulin resistance, type 2 diabetes, hepatic steatohepatitis (NASH), and cirrhosis, as well as an increased risk of cardiovascular disease.
For the past 10 years, the diagnostic criterion for NAFL was liver fat content of more than 5.56%. However, after 20 years of studying people with NAFL, Yale researchers believed that number was too high. A recent study of 2,331 mostly young, lean, and healthy people found that the threshold indeed should be much lower, with liver fat concentrations of more than 1.85% being associated with insulin resistance, type 2 diabetes, and a greater chance of heart disease.
Their study was published April 8 in JCI Insight.
“Previous studies by our group have suggested that normal liver fat content in lean individuals is below 3%,” the authors said. “Given that NAFL is found in lean individuals, even at the current definition of HTG greater than 5.56%, the question remained of whether even lower liver fat content is associated with insulin resistance and increased cardiometabolic risks.” In the JCI Insight paper they compared the group with liver fat content between 1.85 and 5.56% to the group with less than 1.85% and found that liver fat content above 1.85% was associated with insulin resistance and risk for cardiovascular disease.
NAFL affects between 20 and 30% of the U.S. and European populations. People with NAFL are predisposed for type 2 diabetes, NASH, cirrhosis, and liver cancer.
Kitt Petersen, MD, professor of medicine (endocrinology) in the Department of Internal Medicine at Yale School of Medicine, has been studying young, lean, healthy people with insulin resistance for more than 20 years. “The main determinant for insulin resistance is really when we start to build up fat in the organs where it doesn’t belong such as liver and skeletal muscle,” said Petersen, co-director of the Translational Research Core at the Yale Diabetes Research Center and first author on the study. “In healthy young people, we find that the first place ectopic fat builds up is mainly in the muscles and is associated with muscle insulin resistance.” The second occurrence in some people is that fat also begins to build up in their liver. “This increase in liver fat content can then result in hepatic insulin resistance which in turn can lead to type 2 diabetes, NASH and cirhhosis,” Petersen said.
In a previous study by Petersen and colleagues, participants with type 2 diabetes were put on a caloric restriction diet of about 1,200 calories a day and their diabetes medications were stopped. “The idea was, will caloric restriction lead to reductions in liver fat, and if so, will this reduction in liver fat reverse their hepatic insulin resistance and diabetes?” Petersen said.
After eight to 12 weeks on this diet, most of the study’s participants lost about 10% of their body weight. “And the liver fat came down,” Petersen said. She and her team measured the liver fat using MR spectroscopy, a non-invasive chemical measurement that allows researchers to quantify the fat in a person’s liver and muscles. “The day they didn’t have any more liver fat, their blood sugars were normal, they were not insulin resistant, and their diabetes was gone,” Petersen said.
The good news for people with type 2 diabetes is that they “don’t really have to get back to their high school weight,” Petersen said. By losing about 10% of their body weight, they can significantly decrease or eliminate fat in the liver.
However, as most diets don’t work long-term, Petersen and her group are working on new oral medications that can help the liver speed up its burning of fat. “Many companies are now getting onto the idea that we started some 20 years ago, saying let's figure out how we can help the liver burn off this extra fat,” she said. A treatment that gets liver fat down to normal, to completely normalize liver glucose and fat metabolism and reverse insulin resistance, is the goal.
“We are currently performing an NIH-funded study to examine the effects of a new oral drug treatment that promotes increased hepatic fat oxidation and inhibits de novo lipogenesis, the conversion of glucose to fat, to see if this will be of potential benefit to patients with NAFLD and NASH,” she said. “At the same time, we are assessing rates of hepatic mitochondrial metabolism using a new stable isotope/NMR method that we have developed called PINTA.”
The current study in JCI Insight also looks at ethnic differences in insulin sensitivity. The Yale researchers found that, in line with their previous studies on ethnic differences in insulin sensitivity and ectopic fat content, they find that even normal weight men of Asian Indian descent have a much higher incidence of fatty liver and insulin resistance than other ethnic groups, which Petersen believes is likely to be due to genetic causes and is trying to track down the gene.
“In our previous study when we looked at just young people who were normal weight, there were no differences between ethnic groups, Hispanics, Asians, Blacks, Caucasians, everyone was the same, except for one group and that was in our Asian Indian volunteers,” Petersen said. “It didn't matter whether they were born in India or here in the U.S., a very high percentage of the lean Asian Indian men had fatty liver and were insulin resistant.”
The researchers also found that liver fat content was generally lower in women than men and that postmenopausal women had increased liver fat content compared to premenopausal women, suggesting a protective effect of estrogen on liver fat accumulation which is consistent with their preclinical studies.
The study was funded by grants from the National Institutes of Health/NIDDK and the Novo Nordisk Foundation.
In addition to Petersen, Yale investigators are Sylvie Dufour, PhD, from the Department of Internal Medicine, Fangyong Li, MPH, MS, of the Yale Center for Analytical Sciences, Douglas L. Rothman, PhD, of the Department of Radiology & Biomedical Imaging, and Gerald I. Shulman, MD, PhD, of the Departments of Internal Medicine and Cellular & Molecular Physiology.