Non-Alcoholic Fatty Liver Disease Rapidly Increasing in Children; Harold Hamm Diabetes Center Researchers Earn $2.3 Million Grant for Study

Non-alcoholic fatty liver disease (NAFLD), which doctors historically have diagnosed in adults, is rapidly increasing in children, driven by the obesity epidemic, and the condition appears to develop more quickly in young people than adults. That troublesome reality has spurred researchers at the OU Health Sciences Center and OU Health Harold Hamm Diabetes Center to intensify their studies on pediatric NAFLD.

With the support of a four-year, $2.3 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases, a research team led by Kevin Short, Ph.D., has launched a study that aims to better understand the characteristics that drive the development of NAFLD in young people and to identify biomarkers that could one day be used to monitor treatments.

NAFLD, a buildup of excess fat in the liver not related to alcohol use, leads to inflammation and fibrosis in the liver. It is the most common liver disease worldwide, affecting nearly 40% of youth with obesity and 10% of the general pediatric population, and it is especially prevalent in Oklahoma. Diabetes is often diagnosed along with NAFLD.

“NAFLD in children is paralleling what we see with Type 2 diabetes — they are diseases formerly observed almost exclusively in adults. It is concerning that children are developing these diseases because they’ll have a lifetime burden of care. With NAFLD in children, the condition not only worsens at a faster pace than it does in adults, but an increasing number of young people are requiring liver transplants by the time they reach young adulthood. In order to develop new treatments, we need to distinguish how kids may be different than adults who have the same disease,” said Short, an associate professor in the Department of Pediatrics at the OU College of Medicine.

Although improved nutrition and exercise can reduce the liver fat that causes NAFLD, such behavior changes can be difficult for children to maintain, and no other treatments currently exist for children. Pediatric gastroenterologist Sirish Palle, M.D., who specializes in liver diseases, is collaborating with Short for the study, conducting liver biopsies to confirm NAFLD and enrolling patients and families. As a physician, he often sees patients only after NAFLD has progressed to a more severe stage.

“NAFLD does not have any symptoms,” said Palle, an associate professor in the Department of Pediatrics at the OU College of Medicine. “Normally when you think about liver disease, you think of someone being jaundiced or not feeling well, but that’s not the case with this disease. Unless a pediatrician checks a patient’s liver enzymes, NAFLD won’t be discovered until it is more advanced. Right now in our clinic, we spend a lot of time counseling patients, working with a nutritionist and a psychologist. But it’s getting more challenging and complicated with no medications and no treatments available.”

The study has three components. In the first, children will drink a liquid that contains a harmless tracer that will allow researchers to measure the metabolism of glucose and lipids, done through a blood draw. Previous research in adults with NAFLD has shown they have higher rates of fat production in the liver throughout the day, Short said. The same may be true in children, but this has not yet been studied. Researchers also will analyze patients’ ability to make new glucose molecules, another underlying problem in adults with NAFLD that has not yet been established in children, as well as insulin sensitivity — how well they are controlling their blood glucose and how much insulin it takes to do so.

“The kids have to drink these special drinks, which is a pretty non-invasive way for us to make comparisons between kids who have been diagnosed with NAFLD, kids who are obese but don’t have NAFLD, and kids who are normal weight,” Short said. “This is a key part of our study design — we can measure molecules in blood that will help us determine metabolic differences among those groups.”

In the second part of the study, researchers will use blood samples to analyze the concentration of microRNAs, a class of molecules involved in regulating gene expression. They hope this analysis will help them better diagnose and stage NAFLD.

“The reason this is important is because we don’t have many definitive tests for fatty liver disease,” Short said. “The gold standard continues to be a biopsy, but that’s pretty invasive and you can’t repeat it frequently. Liver enzymes can be measured, but they don’t always confirm the disease and they’re not a good gauge of its severity. We hope our work allows us to develop a panel of things to measure so that we can better understand whether a child has fatty liver disease and whether it’s getting worse or improving.” The team is particularly focused on two microRNAs that preliminary data show to be increased in children with NAFLD.

Finally, researchers will use advanced imaging tools to analyze tissue from liver biopsies. The sophistication of today’s imaging equipment provides a greatly enhanced picture of the amount and location of lipids, inflammation and fibrosis in the liver, which could shed light on why youth with NAFLD get worse more quickly.

Jed Friedman, Ph.D., director of Harold Hamm Diabetes Center and Associate Vice Provost for Diabetes Programs, is co-leading the work of the grant and contributing his expertise on the molecular pathways of NAFLD. He said the study is an example of the importance of team-based science and will provide much-needed new information about the pediatric version of the disease.

“NAFLD is a multifactorial disease. At present, it remains unclear what the molecular pathways are that lead to childhood NAFLD,” Friedman said. “This study, the first of its kind, will play a significant role in setting the research agenda for pathways to prevention.”

For more information about the study, call (405) 271-6549 or email kevin-short@ouhsc.edu.

Research reported in this news release is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the National Institutes of Health, under the award number 1R01DK129656-01A1. The research also has been funded by Presbyterian Health Foundation in Oklahoma City.

###