Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges

Abstract

Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world’s population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.

The Determinants of Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus

“…However, NAFLD in non-obese individuals has recently caught clinical physicians’ attention. The prevalence of lean/non-obese NAFLD varies widely, ranging from 3% to 30% globally [ 39 ]. Recent studies suggest that individuals with non-obese NAFLD exhibit substantial liver and non-liver comorbidities including advanced fibrosis, and cardiovascular- and liver-related mortality [ 39 , 40 , 41 ].…”

From MAFLD to hepatocellular carcinoma and everything in between

“…MAFLD is more prevalent in males than in females in the younger age groups, although the opposite trend is seen in the oldest age groups (≥65 years) [10] . It should be noted that up to a quarter of people with MAFLD have a BMI within the ethnic-specific health weight range [11] …”

“…[ 10 ] It should be noted that up to a quarter of people with MAFLD have a BMI within the ethnic-specific health weight range. [ 11 ]…”

“…[10] It should be noted that up to a quarter of people with MAFLD have a BMI within the ethnic-specific health weight range. [11] Race and genetics contribute to the development of MAFLD. A sequence variant (I148 allele) in the Patatinlike phospholipase domain-containing protein 3 (PNPLA3) is a well-known genetic risk factor for MAFLD [8] and is most prevalent in Hispanics [7] and lowest in African Americans.…”

Macrophage-Specific SCAP Promotes Liver and Adipose Tissue Damage in a Lean NAFLD Model: Lean, Mean, Proinflammatory Machine

“…The current consensus is that lean NAFLD is less severe than obese NAFLD; however, this concept has been challenged recently 10 and the utilization of a lean NAFLD model will be useful to evaluate pathogenesis and therapeutics. In an obese NAFLD model, the liver was shown to modulate obesity and white-to-brown fat conversion via paracrine signaling 11 ; therefore, studies evaluating eWAT in lean NAFLD are novel.…”