Spotlight on lean NAFLD

Recent studies looked at the increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in patients without overweight or obesity and compared clinical characteristics of these patients with both healthy controls and patients with obesity and NAFLD.


Before presenting the latest research on nonalcoholic fatty liver disease (NAFLD), it is worth noting that this term is falling out of favor.

An international consensus panel of experts recently suggested metabolic dysfunction-associated fatty liver disease (MAFLD) as a term that more accurately reflects pathogenesis and can help in patient stratification for management. Two policy papers by the panel were published in the May Gastroenterology and in the July Journal of Hepatology. An article published in the July Nature Reviews Gastroenterology & Hepatology noted, “A new name for this disease affecting nearly one billion people globally is overdue, as knowledge gained from the past decades has assuringly demonstrated that MAFLD is a purely metabolic disorder.”

However, the suggested name change has not yet pervaded the literature. Thus, several recent studies focused on NAFLD in individuals with a normal body mass index (BMI).

A systematic review and meta-analysis, published in the August The Lancet Gastroenterology & Hepatology, included 93 studies with more than 10.5 million participants from 24 countries or areas. Primary outcomes included the prevalence of nonobese or lean people within the NAFLD group and the prevalence of nonobese or lean NAFLD in the general, nonobese, and lean populations. The researchers also characterized clinical characteristics of those with nonobese NAFLD.

Among NAFLD patients, 19.2% (95% CI, 15.9% to 23.0%) of people were lean and 40.8% (95% CI, 36.6% to 45.1%) were nonobese. The prevalence of nonobese NAFLD in the general population varied from 25% or lower in some countries (e.g., Malaysia and Pakistan) to higher than 50% in others (e.g., Austria, Mexico, and Sweden), although these figures were based on limited data. In the general population, 12.1% (95% CI, 9.3% to 15.6%) of people had nonobese NAFLD and 5.1% (95% CI, 3.7% to 7.0%) had lean NAFLD. Among other limitations, most analyses were characterized by high heterogeneity, the study authors noted. In addition, the authors defined lean and nonobese on the basis of primary studies, rather than using ethnicity-specific BMI cutoffs, which may have contributed to disparity between regions, an accompanying comment said. “An immediate implication of these findings is the need for new criteria for diagnosis of fatty liver disease associated with metabolic dysfunction that take into consideration the importance of metabolic health,” the commentators wrote.

A second systematic review and meta-analysis looked at data comparing lean with obese NAFLD or with healthy subjects regarding prevalence, comorbidities, liver chemistry and histology, and metabolic/inflammatory markers. Lean NAFLD was defined as a BMI less than 25 kg/m2 in Western studies and less than 23 kg/m2 in most studies from Asia. Overall, 53 studies on 65,029 participants with NAFLD (38,084 lean) and 249,544 healthy participants were included in the analysis. Forty-six studies were of good quality, and most were from Asia. Results were published in the July Hepatology Communications.

Pooled data from 30 studies showed a prevalence of lean NAFLD in the general population of 11.2% (95% CI, 9.6% to 13.0%) and, from 15 studies with 1,000 or more participants, a prevalence of 9.2% (95% CI, 7.4% to 11.3%). Based on geographic location, the prevalence of lean NAFLD was 12.0% (95% CI, 10.2% to 14.2%) in Asia from 23 studies, 10.2% (95% CI, 6.3% to 16.0%) in the Middle East from four studies, and 9.2% (95% CI, 8.4% to 10.2%) on the Western continent from three studies. Compared to healthy adults, patients with lean NAFLD were more likely to have central obesity with increased waist circumference, other components of metabolic syndrome, insulin resistance, and higher levels of inflammatory markers. However, lean NAFLD had a less severe and more favorable metabolic and inflammatory profile than obese NAFLD, with patients having less advanced histologic findings. “Although limited data suggest better clinical outcomes and natural history for lean versus obese NAFLD, larger multicenter prospective studies with long-term follow-up are needed,” the study authors concluded.

A third systematic review and meta-analysis looked 33 studies of 205,307 individuals from 14 countries. The global prevalence of lean NAFLD was 4.1% (95% CI, 3.4% to 4.8%) and showed an upward trend between 1988 and 2017, according to results published online on June 22 by the Journal of Gastroenterology and Hepatology. In lean subjects, the prevalence of NAFLD was 9.7% (95% CI, 7.7% to 11.8%). In those with lean NAFLD, the prevalence of diabetes, hypertension, metabolic syndrome, dyslipidemia, and central obesity was 0.6% (95% CI, 0.4% to 0.9%), 1.8% (95% CI, 1.2% to 2.5%), 1.4% (95% CI, 1.0% to 1.9%), 2.8% (95% CI, 1.9% to 3.7%), and 2.0% (95% CI, 1.6% to 2.4%), respectively. Asian individuals (4.8%; 95% CI, 4.0% to 5.6%) and people ages 45 to 59 years (4.4%; 95% CI, 3.2% to 5.5%) had the highest prevalence of lean NAFLD. Among other limitations, there was significant heterogeneity between studies, the study authors noted.

Finally, an analysis of the industry-funded TARGET-NASH study looked at the odds ratios of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities in 3,386 U.S. participants with NAFLD and a normal BMI. Based on standard BMI cutoff values, 12.8% of participants were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean NAFLD patients, and proportions decreased as BMI categories increased (P<0.0001), according to results published online on July 3 by Clinical Gastroenterology and Hepatology. Lower proportions of lean participants versus nonlean participants had cirrhosis (22.6% vs. 40.2%), history of CVD (9.0% vs. 14.8%), diabetes (32.6% vs. 53.5%), hypertension (47.8% vs. 67.4%), or dyslipidemia (54.0% vs. 64.1%). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After adjustment for age, sex, and center type and site, the odds of associated cirrhosis among lean NAFLD patients was halved in Asian patients compared to non-Asians (odds ratio, 0.47; 95% CI, 0.29 to 0.77).

Limitations of the study include the fact that rates of NAFLD-associated cirrhosis were mostly based on clinical diagnosis, with histologic confirmation available in only 21% of participants, the study authors noted. “More research is needed to provide a better understanding of the mechanisms responsible for the development of NAFLD in people who are lean, the reasons for the differences in prevalence of NAFLD among lean individuals of different races/ethnicities; and the long-term clinical implications of NAFLD in lean persons,” they concluded.