People with nonalcoholic fatty liver disease (NAFLD) and a lean or healthy body mass index are at increased risk for peripheral vascular disease, stroke, and cardiovascular disease, a surprise finding from a new study reveals.
“Our team had expected to see that those with a normal BMI would have a lower prevalence of any metabolic or cardiovascular conditions,” lead researcher Karn Wijarnpreecha, MD, MPH, said during a media briefing that previewed select research for Digestive Disease Week® (DDW) 2022. “So, we were very surprised to find this link to cardiovascular disease.”
The investigators saw this increased risk of cardiovascular disease despite this group having a lower prevalence of atherosclerotic risk factors and metabolic disease.
This first study of its kind suggests physicians should consider the risk of cardiovascular disease in all patients with NAFLD, not just in those who are overweight or living with obesity – groups traditionally thought to carry more risk.
NAFLD in lean individuals is not a benign disease.
“NAFLD patients with a normal BMI are often overlooked because we assume that the risk for more serious conditions is lower than for those who are overweight or obese. But this way of thinking may be putting these patients at risk,” added Dr. Wijarnpreecha, who is a transplant hepatology fellow at the University of Michigan, Ann Arbor.
Approximately 25% of U.S. adults live with NAFLD, an umbrella term for liver conditions in people who drink little to no alcohol. It is characterized by too much fat stored in the liver. Although most people have no symptoms, the condition can lead to other dangerous conditions, such as diabetes, cardiovascular disease, and cirrhosis of the liver, Dr. Wijarnpreecha said.
The investigators retrospectively studied a cohort of 18,793 adults diagnosed with NAFLD at the University of Michigan Hospital from 2012-2021. One aim was to compare the prevalence of cirrhosis, cardiovascular disease, metabolic diseases, and chronic kidney disease in relation to BMI.
They also classified people into four BMI categories: lean, overweight, obesity class 1, and obesity class 2-3.
Compared with non-lean patients, lean patients had a higher prevalence of peripheral arterial disease and stroke and a similar rate of cardiovascular disease based on identification of ICD codes.
Almost 6% of lean patients had peripheral arterial disease, compared with rates of approximately 4%-5% in overweight people and people with obesity. Similarly, more than 6% of the lean group experienced a stroke compared with 5% or less of the other BMI groups.
“We found that lean patients with NAFLD also had a significant higher prevalence of cardiovascular disease, independent of age, sex, race, smoking status, diabetes, hypertension, and dyslipidemia,” Dr. Wijarnpreecha said.
At the same time, compared with non-lean patients, lean patients had a lower prevalence of cirrhosis, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease in an analysis that adjusted for confounders.
Exploring the unknown
Researchers now have a mystery on their hands: What is causing this unexpected higher risk of cardiovascular disease in lean people with NAFLD?
Loren Laine, MD, chief of the section of digestive diseases at Yale University School of Medicine, New Haven, Conn., and moderator of the media briefing, asked Wijarnpreecha for his leading theory behind this connection.
“We think that could be from a difference in lifestyle, diet, exercise, genetics, or even gut microbiota,” Dr. Wijarnpreecha replied. “But these are factors that we did not capture from this current study.”
“We are preparing to conduct additional research with longitudinal data to better understand NAFLD in lean patients,” Dr. Wijarnpreecha added.
“It’s an interesting finding, but there are some questions from this retrospective study,” said Arun J. Sanyal, MD, when asked to comment on the study.
Identifying and quantifying any alcohol use, smoking, or hypertension that could also have contributed to increased cardiovascular risk would be useful. Another question relates to how the population with NAFLD was identified. Was NAFLD an incidental finding in their diagnosis, asked Dr. Sanyal, director of the Stravitz-Sanyal Institute for Liver Disease & Metabolic Health at Virginia Commonwealth University, Richmond.
“I’m not dissing the study,” he said, “But like all the observations like this, I think we have to kick the tires.”
It’s an “important new observation” that requires further study to fully understand what it means and what the therapeutic implications might be. It is also important to assess any possible confounders and any causal relationship among these factors, Dr. Sanyal added.
“There’s no question it is important to continue to do these types of studies,” he added. “Through this kind of research we find new things that lead to the science that can then significantly change how we approach these issues.”
A version of this article first appeared on. This article was updated on May 18, 2022.