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

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.

Open Issues in the Transition from NAFLD to MAFLD: The Experience of the Plinio Study

Metabolic associated fatty liver diseases (MAFLD) definition was proposed to identify fatty liver condition associated to metabolic disorders and to replace non-alcoholic fatty liver disease (NAFLD). We aimed to explore the effect of the application of the new MAFLD criteria on a pre-existing cohort of NAFLD patients. The consequences of the reclassification were investigated by applying the MAFLD criteria to a prospective cohort (The Plinio Study) of dysmetabolic patients examined for the presence of NAFLD. In the Plinio cohort, 795 patients had NAFLD and 767 of them (96.5%) were reclassified as MAFLD patients. Out of these, 94.9% had overweight/obesity or diabetes, while the remaining were lean and had metabolic dysregulation defined by the presence of at least two metabolic risk abnormalities. By contrast, 3.5% of the NAFLD patients were reclassified as no-MAFLD due to the absence of overweight/obesity, diabetes, or metabolic risk abnormalities. The only significant difference between the NAFLD and MAFLD groups was the higher prevalence of subjects with BMI ≥ 25 kg/m2 in the latter (88.6% vs. 92%; p = 0.018). In the cohort, 68 subjects were defined as “lean NAFLD”. Of these, 40 were reclassified as MAFLD and 28 as no-MAFLD. In conclusion, when applying MAFLD criteria to the Plinio cohort, there is a substantial overlap between NAFLD and MAFLD diagnosis. However, some specific subgroups of patients, such as those currently defined as lean NAFLD, were excluded by the new MAFLD definition.

Independent Dose–Response Associations between Fetuin-A and Lean Nonalcoholic Fatty Liver Disease

Patients with lean NAFLD make up an increasing subset of liver disease patients. The association between lean NAFLD and feutin-A, which serves as a hepatokine and adipokine, has never been examined. Our study aimed to explore the association of serum fetuin-A among lean and non-lean patients. The study comprised 606 adults from the community, stratified into lean or non-lean (BMI </≥ 24 kg/m2) and NAFLD or non-NAFLD (scoring of ultrasonographic fatty liver indicator, US-FLI ≥ 2/<2). Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD among the tertiles of fetuin-A after adjustment. The least square means were computed by general linear models to estimate marginal means of the serum fetuin-A concentrations in relation to the NAFLD groups. The odds ratio (OR) of having NAFLD for the highest versus the lowest tertile of fetuin-A was 2.62 (95% CI: 1.72–3.98; p for trend < 0.001). Stratifying by BMI, the OR of having lean NAFLD for the highest versus the lowest tertile of fetuin-A was 2.09 (95% CI: 1.09–3.98; p for trend 0.026), while non-lean NAFLD had no significant association with the fetuin-A gradient after adjustments. Fetuin-A was positively associated with lean NAFLD after adjusting for central obesity and insulin resistance.

Relationship between Dietary Macronutrient Composition and Nonalcoholic Fatty Liver Disease in Lean and Non-Lean Populations: A Cross-Sectional Study

Objective: This study aimed to customize dietary changes for lean patients with nonalcoholic fatty liver disease (NAFLD). Design: This study was done with a population-based cross-sectional design. The Food Frequency Questionnaire (FFQ) was used to analyze dietary macronutrient intake and ultrasonography results for NAFLD diagnosis. The study subjects were divided into the lean and non-lean groups based on their body mass index (< 25 and ≥ 25). Multivariable logistic regression was used to evaluate the relationship between dietary macronutrients and NAFLD. Substitution analyses were also performed. Setting: Amol and its suburban areas in Iran. Participants: Adults in the age range of 18 to <65 with full relevant data. Results: Among the total study subjects (2308), 46.7% had fatty liver. The substitution of polysaccharides for animal protein and saturated fatty acids (SFA) in the lean group resulted in a significant NAFLD reduction; whereas, the substitution of SFA for all types of macronutrients, except for w-6 and mono-disaccharides, led to a significant increase in NAFLD (p<0.05). In non-lean participants, the substitution of monounsaturated fatty acids (MUFA) for mono-disaccharides resulted in a significant reduction of NAFLD (p<0.05). In this group, the substitution of SFA and mono-disaccharides for MUFA, and w-6 for all macronutrients, except vegetable protein and SFA, were significantly related to an increase in NAFLD (p<0.05). Conclusions: Lower lean NAFLD is correlated with increasing polysaccharides in exchange for SFA and animal protein intake; whereas, lower non-lean NAFLD is correlated with increasing MUFA in exchange for mono-disaccharides and reducing w-6 and SFA.

Low serum vitamin D concentrations are associated with obese but not lean NAFLD: a cross-sectional study

Background A low serum vitamin D concentration has been reported to be associated with an increased risk of non-alcoholic fatty liver disease (NAFLD); however, whether lean or obese individuals show a similar association between vitamin D and NAFLD remains speculative. This study aimed to explore the relationship between serum vitamin D concentration and NAFLD in lean and obese Chinese adults. Methods This cross-sectional study included 2538 participants (1360 men and 1178 women) who underwent health checkups at the First Affiliated Hospital, Zhejiang University School of Medicine in 2019. NAFLD was diagnosed by liver ultrasound excluding other causes. The association of serum vitamin D concentration with NAFLD was analyzed in lean and obese participants. Results The overall prevalence of NAFLD was 33.61% (13.10% in lean and 53.32% in obese) in this study population. The serum vitamin D levels of obese NAFLD patients were lower than those of obese NAFLD-free controls. However, the serum vitamin D levels of lean NAFLD patients were comparable to those of lean NAFLD-free controls. Serum vitamin D level was negatively correlated with the prevalence of NAFLD in obese but not lean participants. Serum vitamin D level was independently associated with the risk of NAFLD in obese participants, with an adjusted odds ratio (95% CI) of 0.987 (0.981–0.993). However, serum vitamin D level was not related to the risk of NAFLD in lean participants. Conclusions A low serum vitamin D level is associated with NAFLD in obese but not lean participants.

Low serum vitamin D concentrations are associated with obese but not lean NAFLD: a cross-sectional study

Background: A low serum vitamin D concentration has been reported to be associated with an increased risk of non-alcoholic fatty liver disease (NAFLD); however, whether lean or obese individuals show a similar association between vitamin D and NAFLD remains speculative. This study aimed to explore the relationship between serum vitamin D concentration and NAFLD in lean and obese Chinese adults.Methods: This cross-sectional study included 2538 participants (1360 men and 1178 women) who underwent health checkups at the First Affiliated Hospital, Zhejiang University School of Medicine in 2019. NAFLD was diagnosed by liver ultrasound excluding other causes. The association of serum vitamin D concentration with NAFLD was analyzed in lean and obese participants.Results: The overall prevalence of NAFLD was 33.61% (13.10% in lean and 53.32% in obese) in this study population. The serum vitamin D levels of obese NAFLD patients were lower than those of obese NAFLD-free controls. However, the serum vitamin D levels of lean NAFLD patients were comparable to those of lean NAFLD-free controls. Serum vitamin D level was negatively correlated with the prevalence of NAFLD in obese but not lean participants. Serum vitamin D level was independently associated with the risk of NAFLD in obese participants, with an adjusted odds ratio (95% CI) of 0.987 (0.981–0.993). However, serum vitamin D level was not related to the risk of NAFLD in lean participants.Conclusions: A low serum vitamin D level is associated with NAFLD in obese but not lean participants.

In vivo magnetic resonance spectroscopy of hyperpolarized [1-13C] pyruvate in a male guinea pig model of life-long Western diet consumption and non-alcoholic fatty liver disease development

BACKGROUNDAlterations in glycolysis and oxidative pathways are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations in lean NAFLD.PURPOSE/HYPOTHESISTo use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) MRI techniques to investigate effects of a chronic, life-long exposure to the Western Diet (WD) in a model of NAFLD and identify cellular metabolite changes and correlations related to enzyme activity. It is hypothesized that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism.STUDY TYPEProspective POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: 28 male guinea pigs were weaned onto a control diet or WD.FIELD STRENGTH/SEQUENCE3T; T1, T2, IDEAL, broadband PRESS MRS.ASSESSMENTMedian PDFF was calculated in the liver and hind limbs. [1-13C]pyruvate dynamic MRS in the liver was quantified by the time to peak (TTP), calculated as the time from pyruvate peak to metabolite peak. After a recovery period, animals were euthanized, and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity.STATISTICAL TESTSUnpaired Student’s t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements.RESULTSLife-long WD consumption resulted in significantly higher liver PDFF correlated with elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. DATA CONCLUSION: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD, corresponding with increased liver triglyceride levels characteristic of lean NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD livers.