Lean Non-alcoholic Fatty Liver Disease Research Articles

Impact of PNPLA3 in Lean Individuals and in Cryptogenic Steatotic Liver Disease.

Although metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity, around 20% of individuals with hepatic steatosis may nonetheless have normal body mass index, a condition often referred to as lean nonalcoholic fatty liver disease (NAFLD). Under the new nomenclature and definition of MASLD, lean NAFLD can be further divided into lean MASLD (when there is one or more cardiometabolic risk factors) and cryptogenic steatotic liver disease (when there is no cardiometabolic risk factor). Current studies suggest that the at-risk PNPLA3 rs738409 variant is more common among individuals with lean NAFLD than their overweight and obese counterparts. However, even in this group, cardiometabolic risk factors are often required for the development of hepatic steatosis and liver injury. In the general population, PNPLA3 gene polymorphism is associated with an increased risk of MASLD, more severe liver histology (i.e., the presence of steatohepatitis and fibrosis) and future development of hepatocellular carcinoma and cirrhotic complications. Emerging data also suggest that individuals carrying the PNPLA3 GG genotype might have a greater reduction in hepatic steatosis and liver enzymes with lifestyle intervention and metabolic treatments, such as glucagon-like peptide-1 receptor agonists. Studies have not specifically examined the impact of PNPLA3 in lean individuals.

Liver and cardiovascular outcomes in lean non-alcoholic fatty liver disease: an updated systematic review and meta-analysis of about 1 million individuals.

Non-alcoholic fatty liver disease (NAFLD) is present in lean people. However, the magnitude of the prognostic hepatic and cardiovascular risk in these patients compared to non-lean counterparts remains unclear. We aimed to investigate this topic, and to explore whether these risks change based on factors related to NAFLD severity. PubMed and Embase databases were searched for cohort studies (published through April 2024) that evaluated liver and cardiovascular (CV) outcomes in lean and non-lean individuals with NAFLD and reported unadjusted or adjusted data. We pooled risk ratios (RRs) or hazard ratios (HRs) using a random-effects modeling and performed subgroup and meta-regressions analyses. We identified 22 studies with over 1 million NAFLD patients (13.0% were lean). Lean NAFLD showed a similar risk of liver-related events in unadjusted analysis (RR 1.08, 95% CI 0.79-1.49, I2 = 31%), but a higher risk in adjusted analysis (HR 1.66, 95% CI 1.17-2.36, I2 = 83%) compared to non-lean NAFLD. Lean NAFLD had a higher risk of liver-related mortality (RR 2.22, 95% CI 1.57-3.15, I2 = 0%; HR 2.26, 95% CI 1.14-4.51, I2 = 0%). For CV outcomes, lean NAFLD had a lower risk of any cardiovascular disease in unadjusted analysis (RR = 0.82, 95% CI 0.70-0.95, I2 = 88%), but similar risk in adjusted analysis (HR 0.89, 95% CI 0.77-1.02, I2 = 78%), and similar risk of cardiovascular mortality (RR 1.09, 95% CI 0.71-1.66, I2 = 85%; HR 1.26, 95% CI 0.89-1.78, I2 = 46%) compared to non-lean NAFLD. Lean NAFLD patients have worse liver outcomes, but similar CV outcomes compared to non-lean NAFLD patients, highlighting the importance of monitoring both groups closely.

Exploring Fibrosis Pathophysiology in Lean and Obese Metabolic-Associated Fatty Liver Disease: An In-Depth Comparison.

While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl4), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-β, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients.

Factors Predictive of Non-Alcoholic Fatty Liver Disease in Non-Obese Pakistani Population

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide, with a rising incidence in developing countries. In Pakistan, the estimated prevalence ranges from 14-47%. Studies have shown that NAFLD is also not uncommon among the non-obese lean population. Objective: The aim of this study was to evaluate the factors predictive of non-alcoholic fatty liver disease in a non-obese Pakistani population, defined by a body mass index (BMI) of less than 23 kg/m². Methods: This cross-sectional study was conducted at the Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation from November 1, 2020, to October 31, 2021. A total of 194 patients with BMI < 23 kg/m² presenting with abdominal pain were included. Exclusion criteria were viral hepatitis, significant alcohol intake, hepatocellular carcinoma, or other malignancies. Data collection involved recording demographic information, medical history, and clinical parameters. Ultrasound abdomen examinations were performed after 8-10 hours of fasting to diagnose NAFLD. Clinical assessments included history of hypertension and smoking, and laboratory tests such as liver function tests, fasting blood sugar levels, and lipid profiles. The primary outcome was the presence of fatty liver on ultrasound. Statistical analysis was conducted using SPSS version 25.0. Continuous variables were analyzed using the Student t-test and categorical variables using the Chi-square test. Significant variables in univariate analysis underwent multivariate logistic regression to identify independent predictors of lean NAFLD. A p-value ≤ 0.05 was considered significant. Results: Out of the 194 patients, 107 (55.2%) were females. The mean age was 36.1 ± 9.6 years, and the mean BMI was 21 ± 1.7 kg/m². NAFLD was detected in 48 (24.7%) patients. Among the study population, 78 (40.2%) were hypertensive, 40 (20.6%) were diabetic, 49 (25.3%) were smokers, and 54 (27.8%) had increased triglyceride levels. Decreased HDL-C levels were observed in 72 (37.1%) patients. Univariate analysis identified hypertension (p ≤ 0.001), diabetes (p ≤ 0.001), smoking (p ≤ 0.001), hypertriglyceridemia (p ≤ 0.001), and decreased HDL-C levels (p ≤ 0.001) as significant factors. Multivariate logistic regression showed that diabetes (OR: 9.4, p = 0.037), smoking (OR: 46.4, p ≤ 0.001), hypertriglyceridemia (OR: 4.75, p = 0.016), and decreased HDL-C levels (OR: 36.8, p ≤ 0.001) were independently associated with lean NAFLD. Conclusion: Non-obese individuals with a BMI less than 23 kg/m² can develop NAFLD and related complications. The study identified diabetes, smoking, hypertriglyceridemia, and decreased HDL-C levels as significant predictors of lean NAFLD. Further studies are needed to enhance the understanding of the disease's risk factors and behavior in this population.

To compare the HOMA-IR and metabolic profile in lean and obese subjects with non-alcoholic fatty liver disease

Background and objectiveNon-alcoholic fatty liver disease (NAFLD) is primarily perceived as a condition prevalent among obese individuals. Its pathogenesis is closely intertwined with metabolic syndrome components. However, the association between insulin resistance and NAFLD in nonobese individuals remains ambiguous. Observational studies have scrutinized the prevalence of insulin resistance and metabolic syndrome in lean NAFLD patients.Materials and methodsThis is an observational study, and NAFLD screening was carried out among inpatient and outpatient attendees at SRM Medical College’s General Medicine Department. Out of 200 screened patients meeting inclusion and exclusion criteria, 80 were diagnosed with non-alcoholic fatty liver disease (NAFLD). The assessment of metabolic syndrome was performed using the NCEP-ATP III criteria, allowing for comparison between groups concerning insulin resistance and metabolic parameters.ResultsAmong NAFLD patients, those in the obese age group exhibited a higher prevalence of hypertension (57.8%; p < 0.001) and metabolic syndrome (75.6%; p < 0.0001). The lean NAFLD group showed elevated HOMA-IR levels (4.16) compared to obese NAFLD patients (2.92), with a significant statistical disparity (p < 0.0001). Additionally, the HSI value significantly increased in obese NAFLD patients (p < 0.00001).ConclusionInsulin resistance, a key factor in metabolic syndrome, is prevalent in lean individuals with non-alcoholic fatty liver disease (NAFLD), playing a pivotal role in its development. This resistance, linked to metabolic syndrome, promotes hepatic triglyceride and fatty acid accumulation, leading to NAFLD. Moreover, insulin resistance correlates significantly with weight gain in NAFLD patients.

A New Genetic Mouse Model of Lean NAFLD Uncovers a Sexual Dimorphism for Hepatic Damages and Cardiometabolic Impairments

Background: The prevalence of non alcoholic fatty liver disease (NAFLD) is ~30% higher in the obese population. However, among patients living with NAFLD, 40% are not obese and half of them are lean. Although being mostly studied in obese individuals, the progression of NAFLD in lean patients may involve cardiac manifestations as well. Our hypothesis states that lean NAFLD patients also develop cardiac complications, independently of pre-existent metabolic disruptions, mechanisms of which remain to be fully understood, especially when considering the sexual dimorphism of the disease. Method: To address the underlying mechanisms of the progression of NAFLD independently of obesity, we used a murine model of hepatic mitochondrial deficiency, achieved through a hepato-specific knockout (KO) of Lrpprc. KO mice thus develop microvesicular steatosis without obesity in both sexes which was extensively characterized at the molecular and metabolic level in liver, plasma and heart. Our results unveiled a sex-dependent hepatic and cardiac phenotypic remodeling. KO male mice, to a greater extent than females, showed sustained fasting hypoglycemia and increased insulin sensitivity. Males also showed a more inflammatory hepatic profile characterized by a significant increase of F4/80 staining in immunohistological analyses (3-fold). Furthermore, only males exhibited an increase in the circulating hepatokine FGF21 (1.74-fold) and an increase in VLDLs lipoproteins while HDLs lipoproteins were decreased. In contrast, KO females showed a modest and global decrease of the lipoprotein profile. As such, sex differences occurred also in the heart since only males showed diastolic dysfunction while females’ cardiac function remained unaffected despite mitochondrial defects such as impairments in mitochondrial biogenesis, dynamics and oxidative capacities. Noteworthy, we also observed a significant and inverse correlation between glycemia and an index for cardiac relaxation only in males. Conclusion: Overall, this study underscores the value of this model for NAFLD without obesity where sex-dependent damage in the liver, the plasma and the heart are highlighted. Canadian Institutes of Health Research (CIHR), Montreal Heart Institute Foundation, Heart and Stroke Foundation of Canada, Cardiometabolic Health, Diabetes and Obesity Research Network. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Ganjianglingzhu Decoction on Lean Non-Alcoholic Fatty Liver Disease in Mice Based on Untargeted Metabolomics.

Non-alcoholic fatty liver disease (NAFLD) is usually associated with obesity. However, it is crucial to recognize that NAFLD can also occur in lean individuals, which is frequently overlooked. Without an approved pharmacological therapy for lean NAFLD, we aimed to investigate whether the Ganjianglingzhu (GJLZ) decoction, a representative traditional Chinese medicine (TCM), protects against lean NAFLD and explore the potential mechanism underlying these protective effects. The mouse model of lean NAFLD was established with a methionine-choline-deficient (MCD) diet in male C57BL/6 mice to be compared with the control group fed the methionine-choline-sufficient (MCS) diet. After four weeks, physiological saline, a low dose of GJLZ decoction (GL), or a high dose of GJLZ decoction (GH) was administered daily by gavage to the MCD group; the MCS group was given physiological saline by gavage. Untargeted metabolomics techniques were used to explore further the potential mechanism of the effects of GJLZ on lean NAFLD. Different doses of GJLZ decoction were able to ameliorate steatosis, inflammation, fibrosis, and oxidative stress in the liver; GL performed a better effect on lean NAFLD. In addition, 78 candidate differential metabolites were screened and identified. Combined with metabolite pathway enrichment analysis, GL was capable of regulating the glucose and lipid metabolite pathway in lean NAFLD and regulating the glycerophospholipid metabolism by altering the levels of sn-3-O-(geranylgeranyl)glycerol 1-phosphate and lysoPC(P-18:0/0:0). GJLZ may protect against the development of lean NAFLD by regulating glucose and lipid metabolism, inhibiting the levels of sn-3-O-(geranylgeranyl)glycerol 1-phosphate and lysoPC(P-18:0/0:0) in glycerophospholipid metabolism.

Update in lean metabolic dysfunction-associated steatotic liver disease.

A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). They are now defined as metabolic dysfunction-associated steatotic liver disease (MASLD), which includes cardiometabolic criteria in adults. This condition, extensively studied in obese or overweight patients, constitutes around 30% of the population, with a steady increase worldwide. Lean patients account for approximately 10%-15% of the MASLD population. However, the pathogenesis is complex and is not well understood. To systematically review the literature on the diagnosis, pathogenesis, characteristics, and prognosis in lean MASLD patients and provide an interpretation of these new criteria. We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023, specifically focusing on lean NAFLD, MAFLD, or MASLD patients. We include original articles with patients aged 18 years or older, with a lean body mass index categorized according to the World Health Organization criteria, using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population. We include 85 studies in our analysis. Our findings revealed that, for lean NAFLD patients, the prevalence rate varied widely, ranging from 3.8% to 34.1%. The precise pathogenesis mechanism remained elusive, with associations found in genetic variants, epigenetic modifications, and adaptative metabolic response. Common risk factors included metabolic syndrome, hypertension, and type 2 diabetes mellitus, but their prevalence varied based on the comparison group involving lean patients. Regarding non-invasive tools, Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients. Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles, with some medications showing efficacy to a lesser extent. However, lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart. MASLD is a complex disease comprising epigenetic, genetic, and metabolic factors in its pathogenesis. Results vary across populations, gender, and age. Limited data exists on clinical practice guidelines for lean patients. Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

Effects of Interventions for Improving Awareness and Knowledge of Nonalcoholic Fatty Liver Disease Among Chinese Young Adults for Prevention of Liver Cancer-A Randomized Controlled Trial.

Chinese young adults (CYA), who are at an increasing risk of developing nonalcoholic fatty liver disease (NAFLD), which in turn increases the risk of liver cancer, are an ideal target population to deliver educational interventions to improve their awareness and knowledge of NAFLD and consequently reduce their risk of developing NAFLD. The purpose of this study was to determine the efficacy of two interventions to improve awareness and knowledge of NAFLD among CYA for the prevention of liver cancer. Between May and July 2021, 1373 undergraduate students aged 18 to 25years in one university in China completed a web-based, self-administered survey distributed through WeChat app. One week after completion of the baseline survey, all eligible participants were randomly assigned to a pamphlet, a video intervention, or no intervention (control group), with follow-up assessments immediately and 1-month post-intervention. The 7-page pamphlet or 6.5-min video had information on NAFLD. Self-assessments included NAFLD awareness, lean NAFLD awareness, and knowledge scores of NAFLD. About 26% of participants had NAFLD awareness at baseline. Compared with controls, participants in both interventions showed significant improvement of awareness of NAFLD (pamphlet, + 46.0%; video, + 44.3%; control, + 18.7%; OR [95% CI], 3.13 [2.19-4.47] and 2.84 [1.98-4.08]), awareness of lean NAFLD (pamphlet, + 41.2%; video, + 43.0%; control, + 14.5%; OR [95% CI], 2.84 [1.62-4.99] and 2.61 [1.50-4.54]), and knowledge score of NAFLD (pamphlet, + 64.2%; video, + 68.9%; control, - 1.0%; OR [95% CI], 1.62 [1.47-1.80] and 1.67 [1.50-1.86]) at immediately post-intervention. Delivering NAFLD education through a pamphlet or video intervention was effective in improving the awareness and knowledge of NAFLD among CYA.

Association between TyG index trajectory and new-onset lean NAFLD: a longitudinal study.

The purpose of this manuscript is to identify longitudinal trajectories of changes in triglyceride glucose (TyG) index and investigate the association of TyG index trajectories with risk of lean nonalcoholic fatty liver disease (NAFLD). Using data from 1,109 participants in the Health Management Cohort longitudinal study, we used Latent Class Growth Modeling (LCGM) to develop TyG index trajectories. Using a Cox proportional hazard model, the relationship between TyG index trajectories and incident lean NAFLD was analyzed. Restricted cubic splines (RCS) were used to visually display the dose-response association between TyG index and lean NAFLD. We also deployed machine learning (ML) via Light Gradient Boosting Machine (LightGBM) to predict lean NAFLD, validated by receiver operating characteristic curves (ROCs). The LightGBM model was used to create an online tool for medical use. In addition, NAFLD was assessed by abdominal ultrasound after excluding other liver fat causes. The median age of the population was 46.6 years, and 440 (39.68%) of the participants were men. Three distinct TyG index trajectories were identified: "low stable" (TyG index ranged from 7.66 to 7.71, n=206, 18.5%), "moderate stable" (TyG index ranged from 8.11 to 8.15, n=542, 48.8%), and "high stable" (TyG index ranged from 8.61 to 8.67, n=363, 32.7%). Using a "low stable" trajectory as a reference, a "high stable" trajectory was associated with an increased risk of lean-NAFLD (HR: 2.668, 95% CI: 1.098-6.484). After adjusting for baseline age, WC, SBP, BMI, and ALT, HR increased slightly in "moderate stable" and "high stable" trajectories to 1.767 (95% CI:0.730-4.275) and 2.668 (95% CI:1.098-6.484), respectively. RCS analysis showed a significant nonlinear dose-response relationship between TyG index and lean NAFLD risk (χ2=11.5, P=0.003). The LightGBM model demonstrated high accuracy (Train AUC 0.870, Test AUC 0.766). An online tool based on our model was developed to assist clinicians in assessing lean NAFLD risk. The TyG index serves as a promising noninvasive marker for lean NAFLD, with significant implications for clinical practice and public health policy.

Gut Microbiota in Patients with Non-Alcoholic Fatty Liver Disease without Type 2 Diabetes: Stratified by Body Mass Index.

The relationship between gut dysbiosis and body mass index (BMI) in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD) is not adequately characterized. This study aimed to assess gut microbiota's signature in non-diabetic individuals with NAFLD stratified by BMI. The 16S ribosomal RNA sequencing was performed for gut microbiota composition in 100 patients with NAFLD and 16 healthy individuals. The differential abundance of bacterial composition between groups was analyzed using the DESeq2 method. The alpha diversity (Chao1, Shannon, and observed feature) and beta diversity of gut microbiota significantly differed between patients with NAFLD and healthy controls. However, significant differences in their diversities were not observed among subgroups of NAFLD. At the phylum level, there was no trend of an elevated Firmicutes/Bacteroidetes ratio according to BMI. At the genus level, patients with lean NAFLD displayed a significant enrichment of Escherichia-Shigella and the depletion of Lachnospira and Subdoligranulum compared to the non-lean subgroups. Combining these bacterial genera could discriminate lean from non-lean NAFLD with high diagnostic accuracy (AUC of 0.82). Non-diabetic patients with lean NAFLD had a significant difference in bacterial composition compared to non-lean individuals. Our results might provide evidence of gut microbiota signatures associated with the pathophysiology and potential targeting therapy in patients with lean NAFLD.

Diagnostic Utility of Triglyceride-Glucose Index in Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study on Lean Population.

Approximately 10-20% of individuals with non-alcoholic fatty liver disease (NAFLD) are lean, and the underlying pathophysiology is not yet understood. This study aims to explore the characteristics and the diagnostic value of triglyceride-glucose index (TyG) in early diagnosis of lean NAFLD. 99 patients with lean NAFLD and 1891healthy controls were included in thehealthexamination. The characteristics were compared between groups. Restricted cubic spline was utilized to analyze the relationship between TyG index and the risk of lean NAFLD. Logistic regression and receiver operating curve (ROC) were applied to explore the diagnostic value of TyG index for lean NAFLD. Overall, 99 (4.97%) patients had lean NAFLD. Patients with lean NAFLD have significant abnormal glycolipid metabolism and higher TyG index. Restriction cube spline analysis showed a significant dose-response relationship between the TyG index and risk of lean NAFLD. After adjusting for confounders, the relationship remained and the risk of developing lean NAFLD increased 2.99 times for per unit increase of TyG index (95% CI: 1.94, 4.67, P<0.001). The areas under the ROC of the TyG index for lean NAFLD detection were 0.851 (0.815 to 0.886). The TyG index is positively associated with the risk of developing lean NAFLD and could be a useful marker for early diagnosis of lean NAFLD.

Vitamin D3 exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in Sod1 knockout mice: a comparative study of two forms of vitamin D.

The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.

Triglycerides Mediate the Influence of Body Mass Index on Non-Alcoholic Fatty Liver Disease in a Non-Obese Chinese Population with Normal Low-Density Lipoprotein Cholesterol Levels.

Over 25% of the world's population has non-obese or lean non-alcoholic fatty liver disease (NAFLD), and the prevalence is higher than average in Asia. The present study focused on the relationship between body mass index (BMI) and non-obese NAFLD in non-overweight people in China, particularly the influence of triglycerides (TG) in the pathogenesis of non-obese NAFLD. The findings suggest new treatments for NAFLD patients with normal BMI, as well as provide an early warning system for the understanding and prevention of NAFLD in non-obese patients. This cross-sectional study enrolled 159,959 Chinese subjects with BMI &lt;24 kg/m2 and normal levels of low-density lipoprotein cholesterol (LDL-c). The average age was 40.21 ± 13.88 years, and males accounted for 45.7%. A total of 15,907 (9.94%) patients with NAFLD were diagnosed by ultrasonography. Biochemical indicators were measured using an automated analyzer (Abbott AxSYM). The BMI (kg/m2) was calculated from the weight (kg)/height in square meters (m2). The BMI quartile was used as the column-stratified variable to determine the baseline distribution, and logistic regression analysis was used to assess the relationship between NAFLD and its risk factors, with multiple logistic regression used to assess the relationships between BMI or TG and NAFLD and multivariate linear regression used to analyze the association between BMI and TG, while mediation analysis was used to assess the mediation effect of TG. After adjustment of all covariates, the odds ratios were 1.788 (95% CI: 1.749-1.829; p &lt; 0.00001) and 1.491 (95% CI: 1.451-1.532; p &lt; 0.00001) for the association between BMI and TG with NAFLD incidence. The multivariate linear regression coefficient of BMI and TG was β = 0.027 (95% CI: 0.023-0.030; p &lt; 0.00001). Mediation analysis showed that BMI contributed to 10.81% of lean NAFLD with a mediation effect of 2.98%. In a Chinese population with BMI &lt;24 kg/m2 and normal LDL-c levels, BMI and TG were found to be independent predictors of NAFLD. The direct effect of BMI on non-obese NAFLD was 10.41%. The TG level was found to partially mediate the association.

Impact of nonalcoholic fatty liver disease on the risk of gallbladder polyps in lean and non-obese individuals: A cohort study

BackgroundThe association between non-obese or lean nonalcoholic fatty liver disease (NAFLD) and gallbladder polyps (GBPs) has not yet been evaluated. We aimed to determine whether NAFLD is an independent risk factor for the development of GBPs, even in non-obese and lean individuals. MethodsWe analyzed a cohort of 331 208 asymptomatic adults who underwent abdominal ultrasonography (US). The risk of GBP development was evaluated according to the obesity and NAFLD status. ResultsThe overall prevalence of NAFLD and GBPs ≥ 5 mm was 28.5% and 2.9%, respectively. The prevalence of NAFLD among 160 276 lean, 77 676 overweight and 93 256 obese participants was 8.2%, 31.2%, and 61.1%, respectively. Individuals with NAFLD had a significantly higher incidence of GBPs with a size of ≥ 5 mm [adjusted odds ratio (OR) = 1.18; 95% confidence interval (CI): 1.11–1.25]. A higher body mass index and its categories were also significantly associated with an increased risk of GBPs ≥ 5 mm. Moreover, risk of GBPs ≥ 5 mm was significantly increased even in NAFLD individuals who are not obese (lean: adjusted OR = 1.36, 95% CI: 1.19-1.54; overweight: adjusted OR = 1.14, 95% CI: 1.03–1.26, respectively). ConclusionsNon-obese/lean NAFLD is an independent risk factor for GBP development, suggesting that NAFLD may play an important role in the pathogenesis of GBPs regardless of the obesity status. Therefore, a more thorough evaluation for GBPs may be necessary when hepatic steatosis is detected on abdominal US, even in non-obese or lean individuals.

Differential Mortality Outcomes in Real-world Patients with Lean, Nonobese, and Obese Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is commonly associated with obesity but can develop in normal-weight people (lean NAFLD). We compared outcomes in lean, overweight, and obese NAFLD. This retrospective chart review included patients at Stanford University Medical Center with NAFLD confirmed by imaging between March 1995 and December 2021. Lean, overweight, and obese patients had body mass index of <25.0, >25.0 and <29.9, and ≥30.0 kg/m2 for non-Asian and >23.0 and ≥27.5 for overweight and obese Asian patients. A total of 9061 lean (10.2%), overweight (31.7%), and obese (58.1%) patients were included. Lean patients were 5 years older than obese patients (53±17.4 vs. 48.7±15.1 years), more were female (59.6% vs. 55.2%), white (49.1% vs. 46.5%), had NASH (29.2% vs. 22.5%), cirrhosis (25.3% vs.19.2%), or nonliver cancer (25.3% vs. 18.3%). Fewer had diabetes (21.7% vs. 35.8%) or metabolic comorbidities (all p<0.0001). Lean NAFLD patients had liver-related mortality similar to other groups but higher overall (p=0.01) and nonliver-related (p=0.02) mortality. After multivariable model adjustment for covariates, differences between lean and obese NAFLD in liver-related, nonliver-related, and overall mortality (adjusted hazard ratios of 1.34, 1.00, and 1.32; p=0.66, 0.99, and 0.20, respectively) were not significant. Lean NAFLD had fewer metabolic comorbidities but similar adverse or worse outcomes, suggesting that it is not benign. Healthcare providers should provide the same level of care and intervention as for overweight and obese NAFLD.

Clinical characterization and proteomic profiling of lean nonalcoholic fatty liver disease.

Obesity has been historically associated with nonalcoholic fatty liver disease (NAFLD), but it can also occur in lean individuals. However, limited data is available on this special group. To investigate the clinical and proteomic characteristics of lean subjects with NAFLD, and to identify potential clinical variables and plasma proteins for diagnosing NAFLD in lean individuals, we collected clinical data from a large cohort of 2,236 subjects. Diagnosis of NAFLD relied on detecting pronounced hepatic steatosis through abdominal ultrasonography. Participants were categorized into four groups based on body mass index: overweight NAFLD, overweight control, lean NAFLD, and lean control. Plasma proteomic profiling was performed on samples from 20 subjects in each group. The lean NAFLD group was compared to both lean healthy and obese NAFLD groups across all data. The results indicated that the lean NAFLD group exhibited intermediate metabolic profiles, falling between those of the lean healthy and overweight NAFLD groups. Proteomic profiling of plasma in lean subjects with or without NAFLD revealed 45 statistically significant changes in proteins, of which 37 showed high diagnostic value (AUC > 0.7) for lean NAFLD. These potential biomarkers primarily involved lipid metabolism, the immune and complement systems, and platelet degranulation. Furthermore, AFM, GSN, CFH, HGFAC, MMP2, and MMP9 have been previously associated with NAFLD or NAFLD-related factors such as liver damage, insulin resistance, metabolic syndromes, and extracellular homeostasis. Overall, lean individuals with NAFLD exhibit distinct clinical profiles compared to overweight individuals with NAFLD. Despite having worse metabolic profiles than their healthy counterparts, lean NAFLD patients generally experience milder systemic metabolic disturbances compared to obese NAFLD patients. Additionally, the plasma proteomic profile is significantly altered in lean NAFLD, highlighting the potential of differentially expressed proteins as valuable biomarkers or therapeutic targets for diagnosing and treating NAFLD in this population.

Gastrointestinal cancers in lean individuals with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Obesity and non-alcoholic fatty liver disease (NAFLD) are known risk factors for gastrointestinal (GI) cancers. However, GI carcinogenesis in lean NAFLD patients remains unclear. This systematic review and meta-analysis aims to investigate the association between lean NAFLD and GI cancer risk. PubMed, Embase and Cochrane Library databases were systematically searched (from inception date to April 2023) for cohort studies assessing GI cancers in lean (body mass index [BMI] < 25 kg/m2 or < 23 kg/m2 in Asians) and non-lean (BMI ≥25 kg/m2 or ≥ 23 kg/m2 in Asians) NAFLD individuals. Data from eligible studies were extracted, and meta-analysis was carried out using a random effects model to obtain risk ratios (RRs) with 95% confidence intervals (CIs). Subgroup analyses, meta-regressions and sensitivity analyses were also performed. This study was registered in PROSPERO (CRD42023420902). Eight studies with 56,745 NAFLD individuals (11% were lean) and 704 cases of incident GI cancers were included. Lean NAFLD was associated with higher risk of hepatic (RR 1.77, 95% CI 1.15-2.73), pancreatic (RR 1.97, 95% CI 1.01-3.86) and colorectal cancers (RR 1.53, 95% CI 1.12-2.09), compared to non-lean NAFLD. No significant differences were observed for oesophagus, gastric, biliary and small intestine cancers. This study shows that lean NAFLD patients have an increased risk of liver, pancreatic and colorectal cancers compared to non-lean NAFLD patients, emphasizing the need to explore tailored cancer prevention strategies for this specific patient group. Further research is required to explore the mechanisms underlying the association between lean NAFLD and specific GI cancers.

Familial clustering of nonalcoholic fatty liver disease in first-degree relatives of adults with lean nonalcoholic fatty liver disease.

The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD. This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms. The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD. Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.

HOMA-IR is an effective biomarker of non-alcoholic fatty liver disease in non-diabetic population.

This study aimed to investigate the correlation between homeostasis model assessment of insulin resistance (HOMA-IR) and non-alcoholic fatty liver disease (NAFLD) in the non-diabetic population and establish its diagnostic efficacy. This observational study involved participants divided into NAFLD and non-NAFLD groups, and baseline data were analyzed. Univariate and multivariate logistic regression analyses were used to correlate HOMA-IR with the risk of NAFLD. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic efficacy of HOMA-IR for NAFLD. Subgroup analyses of non-obese individuals were performed. Overall, 2234 non-diabetic participants were included. The HOMA-IR was significantly higher in the NAFLD group than in the non-NAFLD group. Multivariate logistic regression analysis showed that HOMA-IR was a strong and independent risk factor for NAFLD after correcting for confounding factors. The area under the ROC curve (AUC) value of HOMA-IR for predicting NAFLD was 0.792. In the non-obese non-diabetic population, HOMA-IR was an independent risk factor for increased risk of lean NAFLD after correcting for confounding factors. The AUC value of HOMA-IR for predicting lean NAFLD was 0.770. HOMA-IR is independently associated with the risk of NAFLD in the non-diabetic and non-obese non-diabetic populations and has good diagnostic value.