Pediatric Nonalcoholic Fatty Liver Disease Study

Principal Investigators: Jeffrey Schwimmer (University of California, San Diego) and Miriam Vos (Emory University)

Schwimmer JB, Ugalde-Nicalo P, Welsh JA, Angeles JE, Cordero M, Harlow KE, Alazraki A, Durelle J, Knight-Scott J, Newton KP, Cleeton R, Knott C, Konomi J, Middleton MS, Travers C, Sirlin CB, Hernandez A, Sekkarie A, McCracken C, Vos MB.  Effect of a Low Free Sugar Diet vs Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys: A Randomized Clinical Trial.  JAMA. 2019; 321:256-265.

Nonalcoholic fatty liver disease (NAFLD), characterized by an excess of fat in the liver, is the most common form of liver disease.  NAFLD can progress to a more serious inflammatory condition, nonalcoholic steatohepatitis (NASH), which can lead to liver cirrhosis, end-stage liver disease, and death. NAFLD also increases the risk for type 2 diabetes, liver cancer, and cardiovascular disease. NAFLD is typically associated with obesity, but also develops in lean individuals, who appear to have a poorer prognosis than those who are obese.

NAFLD is a global problem, affecting about 20% of the world’s population. In the US, 64 million people have NAFLD according to recent estimates.  This includes about 7 million children, which is particularly troubling as the likelihood that NAFLD will progress to NASH increases with time.

There is currently no approved drug treatment for NAFLD. Liver transplant is an option for those with more advanced disease, but with the prevalence and incidence of NAFLD and NASH growing rapidly, the demand for transplantable livers will easily overwhelm the limited supply. In short, NAFLD represents a staggering medical and public health challenge, made worse by the fact that few people have even heard of it.

With no established pharmaceutical solution and the impracticality of liver transplant for such a prevalent disease, treatment guidelines for NAFLD emphasize lifestyle modifications for weight loss, including exercise and diet. However, no consensus exists on what type of diet would be best to prevent or reverse NAFLD.

In this context, NuSI convened two meetings of leading physicians and researchers with interest and expertise in adult and pediatric NAFLD to discuss and design possible studies to identify potential dietary triggers and treatment of the disease. In particular, metabolic and epidemiologic data implicated dietary sugar in the occurrence and progression of NAFLD, but no controlled clinical trial data existed to support an evidence-based recommendation for patients to limit sugar intake.

As a result, with an eye toward impacting clinical practice, the group recommended conducting a preliminary, but well-controlled trial on the effects of reducing sugar intake in children. NuSI responded by funding a study led by Drs. Jeffrey Schwimmer and Miriam Vos that examined the effect of a diet low in free sugars (i.e., low in sugar or high fructose corn syrup, either added to food and beverages or from fruit juices) on liver fat content in children with NAFLD.

A total of 40 boys 11-16 years old with diagnosed and active NAFLD were randomly assigned to either a low free sugar diet (intervention diet) group or a usual diet group for 8 weeks. Before the intervention diet was instituted, study staff replaced all sugars or sugar-containing products in the intervention group’s households with no or low-sugar substitutes. For the duration of the study, families of the participants in the intervention group were then provided with all their food or food ingredients, tailored to their preferences and the participant’s habitual diet, but containing less than 3% free sugars. In addition to instructing participants in the intervention group to avoid sugar-containing foods and beverages, study staff contacted their families twice-weekly to assess satisfaction with the diet and address dietary issues regarding special events and holidays. Families of participants in the usual diet group were instructed to eat their usual diet and were given a weekly stipend with which to purchase food and beverages of their choice.

Liver fat content of participants was measured using magnetic resonance imaging (MRI) at the beginning and end of the 8-week trial. Liver fat content decreased more and was significantly lower after 8 weeks in the diet intervention group compared with the usual diet group.  These effects of the low free-sugar diet were observed after controlling for differences in body weight or body mass index (BMI) between the two groups, suggesting that the reduction in sugar intake, not weight or weight loss, was primarily responsible for the improvement in liver fat content. Blood concentration of ALT (alanine aminotransferase), a marker for liver function indicative of the degree of damage associated with NAFLD and NASH, also improved more in the diet intervention group.

These findings suggest that limiting sugar intake can be beneficial for children with NAFLD and therefore constitute evidence implicating excessive intake of sugars in the etiology of NAFLD. However, additional research is needed to establish a causal role for dietary sugars in NAFLD and to buttress a strategy of limiting intake of sugars in its prevention and treatment. In particular, it will be important to conduct longer duration controlled trials in a larger and more diverse population of patients, including with participants of both genders and a range of ethnicities, and under more realistic conditions in which participants and their families are responsible for selecting their own diets.