Understanding lean NAFLD: Results from a population-based study

Oct. 20, 2021

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and part of a spectrum of conditions that includes fatty infiltration of the liver, nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma and end-stage liver failure.

Commonly associated with excess weight and metabolic abnormalities such as diabetes mellitus, hypertension and dyslipidemia, NAFLD is known to increase overall mortality and risk of morbidity and mortality from cardiovascular diseases, malignancies and liver disease.

Although obesity is described in 50% to 90% of patients diagnosed with NAFLD, the condition can also affect individuals with a normal weight and body mass index. The natural history of NAFLD in these patients, a phenotype known as lean NAFLD, is not well understood. This knowledge gap limits the ability of clinicians to provide counseling and disease management for patients who fit this profile.

In an effort to address this lack of data, a group of Mayo Clinic researchers conducted a longitudinal study comparing the trajectory of NAFLD in lean, overweight and obese individuals from the United States. The results of this study were published in Clinical Gastroenterology and Hepatology in 2021.

Study methods

Using data from the Rochester Epidemiology Project, the researchers identified a total of 4,834 adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1996 and 2016, and a record of all subsequent medical events associated with these individuals. The researchers divided study subjects into three groups (normal, overweight and obese) using body mass index (BMI) at NAFLD diagnosis. Following the study subjects longitudinally, they estimated the probability of developing cirrhosis, decompensation, malignancies and cardiovascular events, and the probability of death among the three groups using the Aalen-Johansen method. And they calculated the impact of BMI categories on these outcomes using the Cox proportional hazards regression analysis.

Within the 4,834 study subjects identified, the study pool included 414 (8.6%) in the normal BMI group, 1,189 (24.6%) in the overweight group and 3,231 (66.8%) in the obese group. The researchers followed subjects from study entry date (first NAFLD diagnosis date) until death, last date of follow-up, or the study end date (May 31, 2019), for a median of 6.4 years (range, 0 to 20 years).


According to Alina M. Allen, M.D., analysis of study data yielded some interesting information about associated risks for the three study groups. Dr. Allen is a gastroenterologist and hepatologist at Mayo Clinic's campus in Rochester, Minnesota, who served as the corresponding author for the research team's publication in Clinical Gastroenterology and Hepatology.

Overall, the data suggests that a diagnosis of NAFLD with normal BMI is associated with a possibly lower risk of liver disease progression, a healthier metabolic profile, and a similar risk of cardiovascular disease and malignancy when compared with risks linked to a diagnosis of NAFLD with obesity.

Risk of cirrhosis

Subjects with a normal BMI showed a trend toward a lower risk of developing cirrhosis (hazard ratio, 0.33; 95% confidence interval, 0.10 to 1.05, P = 0.06), although the relative risk difference did not reach statistical significance.

Risk of decompensation, cardiovascular events and malignancies

No significant differences were observed in the risk of decompensation, cardiovascular events or malignancy between the three groups.

Risk of all-cause mortality

Subjects from the normal BMI group had a higher risk of death when compared with subjects from the obese group, even after controlling for main confounders (hazard ratio, 1.96; 95% confidence interval, 1.52 to 2.51), which persisted after adjusting for other covariates. Malignancy and cardiovascular disease were the most common causes of death in all groups. Liver-related deaths were highest in subjects from the obese group (10%) when compared with the normal BMI (1.4%) and overweight (2%) groups.

When asked to interpret the elevated risk of death among subjects from the normal BMI group, Dr. Allen says: "This finding was previously noted in some but not all publications, and it does require further examination. The top two causes of death in the normal BMI group were similar to those for the other groups, but there were less liver-related causes and a higher proportion of a mix of other causes of death."

Dr. Allen explains that the study suggests that lean NAFLD is likely underestimated in the general population, an idea that has implications for clinicians and future research.

"A normal BMI and healthier metabolic profile can give us fewer reasons to look for NAFLD," says Dr. Allen. "Because the risk of liver-related complications does not seem to be higher, as previously suggested in some studies, monitoring for liver disease progression should follow the general guidelines used in those with higher BMIs. Conducting further studies to disentangle the unique pathophysiological characteristics of lean NAFLD and how they impact patient outcomes will help guide the management of NAFLD in patients with normal BMI."

For more information

Ahmed OT, et al. Natural history of nonalcoholic fatty liver disease with normal body mass index: A population-based study. Clinical Gastroenterology and Hepatology. In press.