Accessible noninvasive screening tools for metabolic dysfunction-associated steatotic liver disease (MASLD) are needed. We aim to explore the performance of a deep learning-based artificial intelligence (AI) model in distinguishing the presence of MASLD using 12-lead electrocardiogram (ECG).

This is a retrospective study of adults diagnosed with MASLD in Olmsted County, Minnesota, between 1996 and 2019. Both cases and controls had ECGs performed within 6 years before and 1 year after study entry. An AI-based ECG model using a convolutional neural network was trained, validated, and tested in 70%, 10%, and 20% of the cohort, respectively. External validation was performed in an independent cohort from Mayo Clinic Enterprise. The primary outcome was the performance of ECG to identify MASLD, alone or when added to clinical parameters.

A total of 3468 MASLD cases and 25,407 controls were identified. The AI-ECG model predicted the presence of MASLD with an area under the curve (AUC) of 0.69 (original cohort) and 0.62 (validation cohort). The performance was similar or superior to age- and sex-adjusted models using body mass index (AUC, 0.71), presence of diabetes, hypertension or hyperlipidemia (AUC, 0.68), or diabetes alone (AUC, 0.66). The model combining ECG, age, sex, body mass index, diabetes, and alanine aminotransferase had the highest AUC: 0.76 (original) and 0.72 (validation).

This is a proof-of-concept study that an AI-based ECG model can detect MASLD with a comparable or superior performance as compared with the models using a single clinical parameter but not superior to the combination of clinical parameters. ECG can serve as another screening tool for MASLD in the nonhepatology space.

Cardiovascular disease morbidity and mortality rates are high in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). The objective of this study was to analyze the risk factors and differences between lean MAFLD and overweight MAFLD, and establish and validate a nomogram model for predicting lean MAFLD.

This retrospective cross-sectional study included 4363 participants who underwent annual health checkup at Yuyao from 2019 to 2022. The study population was stratified into three groups: non-MAFLD, lean MAFLD (defined as the presence of fatty liver changes as determined by ultrasound in individuals with a BMI < 25 kg/m2), and overweight MAFLD (BMI ≥ 25.0 kg/m2). Subsequent modeling analysis was conducted in a population that included healthy subjects with < 25 kg/m2 (n = 2104) and subjects with lean MAFLD (n = 849). The study population was randomly split (7:3 ratio) to a training vs. a validation cohort. Risk factors for lean MAFLD was identify by multivariate regression of the training cohort, and used to construct a nomogram to estimate the probability of lean MAFLD. Model performance was examined using the receiver operating characteristic (ROC) curve analysis and k-fold cross-validation (k = 5). Decision curve analysis (DCA) was applied to evaluate the clinical usefulness of the prediction model.

The multivariate regression analysis indicated that the triglycerides and glucose index (TyG) was the most significant risk factor for lean MAFLD (OR: 4.03, 95% CI 2.806-5.786). The restricted cubic spline curves (RCS) regression model demonstrated that the relationships between systolic pressure (SBP), alanine aminotransferase (ALT), serum urate (UA), total cholesterol (TCHO), triglyceride (TG), triglyceride glucose (TyG) index, high density lipoprotein cholesterol (HDLC), and MAFLD were nonlinear and the cutoff values for lean MAFLD and overweight MAFLD were different. The nomogram was constructed based on seven predictors: glycosylated hemoglobin A1c (HbA1c), serum ferritin (SF), ALT, UA, BMI, TyG index, and age. In the validation cohort, the area under the ROC curve was 0.866 (95% CI 0.842-0.891), with 83.8% sensitivity and 76.6% specificity at the optimal cutoff. The PPV and NPV was 63.3% and 90.8%, respectively. Furthermore, we used fivefold cross-validation and the average area under the ROC curve was 0.866 (Figure S3). The calibration curves for the model's predictions and the actual outcomes were in good agreement. The DCA findings demonstrated that the nomogram model was clinically useful throughout a broad threshold probability range.

Lean and overweight MAFLD exhibit distinct metabolic profiles. The nomogram model developed in this study is designed to assist clinicians in the early identification of high-risk individuals with lean MAFLD, including those with a normal BMI but at metabolic risk, as well as those with abnormal blood lipid, glucose, uric acid or transaminase levels. In addition, this model enhances screening efforts in communities and medical screening centers, ultimately ensuring more timely and effective medical services for patients.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease among adults. High uric acid (UA) increases the incidence of NAFLD in the general population. However, further exploration is warranted to determine the relationship between UA levels and NAFLD in various populations. We conducted a historical cohort study to investigate the causality between UA and NAFLD across different weight categories.

A historical cohort was established from the Jidong community cohort. All participants were enrolled and followed up from July 1st, 2013 to August 1st, 2018. The study participants were retrospectively assigned to four groups according to their UA levels (Q1, 69-210 μmol/L; Q2, 211-255 μmol/L; Q3, 256-310 μmol/L; Q4, 311-593 μmol/L). The NAFLD incidence was investigated in each group. We used the UA level determined by an automatic analyzer. NAFLD was diagnosed with abdominal ultrasonography examination. Demographic information, lifestyle history, clinical anthropometric data, and blood samples of participants were collected. Univariate analysis and multivariable Cox regression were applied to analyze the relationship between UA and NAFLD by stratification of participants' body mass index (BMI) categories (underweight, normal weight, overweight, and obese).

Two thousand nine hundred eighty four participants were enrolled. 740 (24.8%) were assigned to UA Q1 group, 755 (25.3%) to UA Q2, 743 (24.9%) to UA Q3, and 746 (25.0%) to UA Q4. The global incidence of NAFLD was 26.0% (777/2984). The risk of NAFLD significantly increased with elevated UA levels in underweight and normal-weight participants (HR = 3.498, 95% CI: 2.413-5.072, P < 0.05). In multivariable analysis, UA showed a positive association with NAFLD, independent of other risk factors in underweight and normal-weight participants (UA Q2: 1.152 (0.761-1.743), UA Q3: 2.168 (1.489-3.157), UA Q4: 3.075 (2.103-4.196), P < 0.05). In the absence of other risk factors, high UA levels independently explained 17% of NAFLD risk in underweight and normal-weight participants.

High UA levels serve as an independent risk factor for NAFLD in underweight and normal-weight individuals, highlighting the necessity of early NAFLD screening through monitoring liver function and UA levels, and personalized treatment plans for NAFLD patients with higher UA levels, which may include uric acid-lowering therapy and lifestyle modifications. However, the relationship between UA levels and NAFLD in overweight and obese individuals remains inconclusive.

One-third of adults across the globe exhibit metabolic dysfunction-associated steatotic liver disease (MASLD)-formerly known as nonalcoholic fatty liver disease (NAFLD). To date, MASLD is the fastest-growing etiology of chronic liver disease and hepatocellular carcinoma (HCC). Besides the population with obesity, MASLD can also be found in lean populations, accounting for 13% of the global population, especially Asians. Notably, individuals with lean MASLD face equal or higher overall mortality rates compared to their non-lean counterparts. Risk modifiers encompass advanced age, hepatic fibrosis, and type 2 diabetes mellitus (T2DM). Moreover, the population with lean MASLD is associated with an increased risk of HCC, while their non-lean counterparts are more prone to cardiovascular outcomes and T2DM. Existing evidence indicates a similar risk of liver-related events and extrahepatic cancer between the two groups. However, MASLD-related genetic variants, such as PNPLA3 and TM6SF2, did not significantly affect mortality between the two populations. Still, underreporting alcohol consumption and regional representation limits the study's comprehensiveness. Longitudinal studies and mechanistic explorations are needed to understand differences in lean versus non-lean MASLD populations. This review highlights the need for awareness and tailored interventions in managing MASLD, considering lean individuals' unique risks.

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.

Growing evidence suggests an increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). We aimed to clinically and mechanistically characterize steatotic liver disease (SLD) in a prospective cohort of patients with IMID compared to controls.

Cross-sectional, case-control study including a subset of patients with IMID. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched at a 1:2 ratio. SLD was established using controlled attenuation parameter. Liver biopsies were obtained when significant liver fibrosis was suspected. Total RNA was extracted from freshly frozen cases and analyzed by RNA-seq. Differential gene expression was performed with 'limma-voom'. Gene set-enrichment analysis was performed using the fgsea R package with a preranked "limma t-statistic" gene list.

A total of 1,456 patients with IMID and 2,945 controls were included. Advanced SLD (liver stiffness measurement ≥9.7 kPa) (13.46% vs. 3.79%; p <0.001) and advanced MASLD (12.8% vs. 2.8%; p <0.001) prevalence were significantly higher among patients with IMID than controls. In multivariate analysis, concomitant IMID was an independent, and the strongest, predictor of advanced SLD (adjusted odds ratio 3.318; 95% CI 2.225-4.947; p <0.001). Transcriptomic data was obtained in 109 patients and showed 87 significant genes differentially expressed between IMID-MASLD and control-MASLD. IMID-MASLD cases displayed an enriched expression of genes implicated in pro-tumoral activities or the control of the cell cycle concomitant with a negative expression of genes related to metabolism.

The prevalence of advanced SLD and MASLD is disproportionately elevated in IMID cohorts. Our findings suggest that IMIDs may catalyze a distinct MASLD pathway, divergent from classical metabolic routes, highlighting the need for tailored clinical management strategies.

The prevalence of steatotic liver disease with advanced fibrosis is increased in patients with immune-mediated inflammatory diseases, independent of classic metabolic risk factors or high-risk alcohol consumption. Transcriptomic analysis revealed a unique gene expression signature associated with cellular activities that are compatible with a liver condition leading to an accelerated and aggressive form of steatotic liver disease. Our findings underscore the importance of heightened screening for advanced liver disease risk across various medical disciplines overseeing patients with immune-mediated inflammatory diseases.

Lean metabolic dysfunction-associated steatotic liver disease (MASLD) defies traditional views of fatty liver diseases by manifesting in nonobese individuals. The renaming from nonalcoholic fatty liver disease to MASLD underscores a broader understanding of its pathophysiology, highlighting the complex interplay of metabolic factors beyond obesity. Despite its clinical importance, diagnosing and managing lean MASLD remains challenging due to its historical ties to obesity and a general lack of awareness about its unique characteristics. On December 4, 2023, a systematic literature search was conducted across six databases, focusing on peer-reviewed studies in English related to the diagnosis and management of lean MASLD. This study was registered with the International Prospective Register of Systematic Reviews (CRD42023489308). Out of 95 studies following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 43 addressed diagnosis and surveillance, whereas 52 explored management strategies. The results revealed the difficulties in diagnosing lean MASLD, pointing out the limitations of traditional markers and the potential of advanced imaging techniques. Management strategies discussed included lifestyle changes and possible pharmacological treatments tailored to the specific metabolic features of this patient group. The study highlights the necessity for increased clinical awareness, regular monitoring, and personalized therapeutic approaches for lean MASLD. It calls for further research to refine diagnostic criteria and develop targeted treatments, aiming to enhance care for individuals with lean MASLD.

The natural history of metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is complex and long. A minority of patients develop inflammation and risk progressive fibrosis that can result in cirrhosis. Progression to cirrhosis occurs in 3-5% of patients and often takes more than 20 years. This narrative review presents an update on the natural history of MASLD, discussing studies and risk estimates for progression to severe outcomes, such as decompensated cirrhosis or hepatocellular carcinoma. We highlight the dynamic progression of liver damage, how to identify patients whose disease progresses over time, and how risk factors might be mitigated to reduce the risk for disease progression.

Non-alcoholic fatty liver disease (NAFLD) is a common liver condition affecting 25%-40% of the worldwide population. NAFLD is traditionally related to obesity and metabolic disorders. NAFLD can also affect non-obese individuals, termed "lean NAFLD" (LN), who exhibit a paradoxical combination of physical leanness and metabolic obesity. Factors contributing to LN remain unclear, necessitating further research. This analysis aims to understand LN's prevalence and metabolic characteristics compared to obese NAFLD (ON) populations.

This meta-analysis searched various databases until August 1, 2023. Inclusion criteria involved observational studies comparing LN with overweight/obese NAFLD. Data extraction included baseline characteristics, disease occurrence, metabolic profile, and clinical parameters-statistical analysis employed calculating risk ratios (RR) and standard mean differences.

Twenty-five studies were analyzed. LN is associated with lower prevalence in both NAFLD (RR 0.27, 95% confidence interval (CI) 0.14-0.52, p = <0.0001) and total (RR 0.27, 95% CI 0.15-0.51, p < 0.0001) population. LN had lower diabetes mellitus (RR 0.78, 95% CI 0.71-0.87, p < 0.00001), dyslipidemia (RR 0.87, 95% CI 0.79-0.95, p = 0.002), hypertension (RR 0.80, 95% CI 0.74-0.87, p < 0.00001), and metabolic syndrome (RR 0.45, 95% CI 0.31-0.64, p < 0.00001) compared to those with ON. The LN group's lipid profile, blood pressure, and other clinical parameters were favorable compared to ON.

The prevalence of NAFLD among lean and non-lean individuals varies by region. Our analysis revealed that LN is associated with lower metabolic diseases, fasting blood sugar, blood pressure, and a more favorable lipid profile compared to ON.

This study estimated the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long-term impacts of MASLD on all-cause and cardiometabolic-specific mortality were evaluated.

We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self-reported medication use and clinical seromarkers. All-cause and cardiometabolic-specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020.

The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (Pfor trend < 0.001). After follow-up, patients with MASLD had a 9%-29% higher risk of all-cause, cardiovascular-related, or diabetes-related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate-adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05-1.25) and 1.10 (1.03-1.17), respectively, and those for diabetes deaths were 1.42 (1.05-1.93) and 1.24 (0.98-1.57), respectively, compared with those in the non-MASLD group (Pfor trend < 0.001).

Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all-cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications.

We aimed to investigate the correlation and to explore which MAFLD subtypes have the greatest influence on progression of arterial stiffness risk.

Using data from a health examination-based cohort, a total of 12,129 participants who underwent two repeated health examinations that included brachial-ankle pulse wave velocity (baPWV) from 2012 to 2020 were enrolled. Participants were separated into non-MAFLD, overweight/obese (OW-MAFLD), lean/normal weight (lean-MAFLD) and diabetes (DM-MAFLD) groups. Among the participants with a median follow-up of 2.17 years, 4511 (37.2%) participants had MAFLD at baseline, among which 3954 (87.7%), 123 (2.7%), and 434 (9.6%) were OW-, lean- and DM-MAFLD, respectively. Analyses using linear regression models confirmed that compared with the non-MAFLD group, the elevated baPWV change rates (cm/s/year) were 12.87 (8.81-16.94), 25.33 (7.84-42.83) and 38.49 (27.88-49.10) in OW, lean and DM-MAFLD, respectively, while the increased change proportions (%) were 1.53 (1.10-1.95), 3.56 (1.72-5.40) and 3.94 (2.82-5.05), respectively. Similar patterns were observed when these two baPWV parameters were transformed in the form of the greatest increase using Cox proportional hazards model analyses. Furthermore, the risk of arterial stiffness progression across MAFLD subtypes presented a significant, gradient, inverse relationship in the order of DM-, lean-, OW with metabolic abnormalities (MA)-, and OW without MA-MAFLD.

MAFLD, especially DM-MAFLD and lean-MAFLD, was significantly associated with arterial stiffness progression, providing evidence that stratification screening and surveillance strategies for CVD risk have important clinical implications.

Although nonalcoholic fatty liver disease (NAFLD) commonly occurs in overweight or obese individuals, it is increasingly being identified in the lean population. The association between lean and an increased risk of all-cause mortality among patients with NAFLD remains controversial. We aimed to perform a systematic review and meta-analysis of the literature to evaluate this association and compare the long-term outcomes of lean NAFLD patients and non-lean NAFLD patients.

For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, and Chinese Biomedical Literature Database (CBM) from inception to October 15, 2021, for relevant original research articles without any language restrictions. Our primary outcome was to compare the all-cause mortality in lean NAFLD patients and non-lean NAFLD patients by qualitative synthesis. Relative risks (RRs) and corresponding 95% confidential intervals (CIs) were pooled with a random effect model. Heterogeneity was evaluated using I-squared (I²) statistics while publication bias was determined using Egger's tests. Subgroup and sensitivity analyses were performed. As for secondary outcomes, we estimated total, cardiovascular, and liver-related mortality, as well as the incidence of diabetes, hypertension, cirrhosis, and cancer in lean and non-lean individuals with NAFLD by quantitative synthesis. Person-years of follow-up were used as the denominator to estimate the mortality and incidence.

We identified 12 studies (n = 26,329), 7 of which (n = 7924) were used to evaluate the risk of all-cause mortality between lean and non-lean NAFLD patients. Lean patients with NAFLD were found to be at an elevated risk of death compared to non-lean patients (RR = 1.39, 95% CI 1.08-1.82, heterogeneity: I² = 43%). Among the lean NAFLD population, all-cause mortality was 13.3 (95% CI: 6.7-26.1) per 1000 person-years, 3.6 (95% CI: 1.0-11.7) for liver-related mortality, and 7.7 (95% CI: 6.4-9.2) for cardiovascular-related mortality. The incidence of new-onset diabetes was 13.7 (95% CI 8·2-22.7) per 1000 person-years, new-onset hypertension was 56.1 (95% CI: 40.2-77.9), cirrhosis was 2.3 (95% CI: 1.0-5.0), and cancer was 25.7 (95% CI: 20.3-32.4).

Lean patients with NAFLD had a higher risk of all-cause death than non-lean patients. Body mass index (BMI) should not be used as a criterion to determine whether further observation and therapy of patients with NAFLD are warranted.

Lean metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by a BMI < 25 kg/m² (or < 23 kg/m² in Asians), presents a challenging prognosis compared to non-lean MASLD. This study examines cardiovascular outcomes in both lean and non-lean MASLD cohorts.

In this meta-analysis, pooled odds ratios (ORs) within 95 % confidence intervals (CIs) were calculated for primary outcomes (cardiovascular mortality and major adverse cardiovascular events [MACE]) and secondary outcomes (cardiovascular disease [CVD], all-cause mortality, hypertension, and dyslipidemia). Studies comparing lean and non-lean MASLD within the same cohorts were analyzed, prioritizing those with larger sample sizes or recent publication dates.

Twenty-one studies were identified, encompassing lean MASLD patients (n = 7153; mean age 52.9 ± 7.4; 56 % male) and non-lean MASLD patients (n = 23,514; mean age 53.2 ± 6.8; 63 % male). Lean MASLD exhibited a 50 % increase in cardiovascular mortality odds compared to non-lean MASLD (OR: 1.5, 95 % CI 1.2-1.8; p < 0.0001). MACE odds were 10 % lower in lean MASLD (OR: 0.9, 95 % CI 0.7-1.2; p = 0.7), while CVD odds were 40 % lower (p = 0.01). All-cause mortality showed a 40 % higher odds in lean MASLD versus non-lean MASLD (p = 0.06). Lean MASLD had 30 % lower odds for both hypertension (p = 0.01) and dyslipidemia (p = 0.02) compared to non-lean MASLD.

Despite a favorable cardiometabolic profile and comparable MACE rates, lean individuals with MASLD face elevated cardiovascular mortality risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease and 10%-20% occurs in lean individuals. There is little data in the literature regarding outcomes in an ethnically-diverse patient populations with MASLD. Thus, we aim to investigate the natural history and ethnic disparities of MASLD patients in a diverse population, and stratified by body mass index categories.

We conducted a retrospective multicenter study on patients with MASLD at the Banner Health System from 2012 to 2022. Main outcomes included mortality and incidence of cirrhosis, cardiovascular disease, diabetes mellitus (DM), liver-related events (LREs), and cancer. We used competing risk and Cox proportional hazard regression analysis for outcome modelling.

A total of 51 452 (cross-sectional cohort) and 37 027 (longitudinal cohort) patients were identified with 9.6% lean. The cohort was 63.33% European ancestry, 27.96% Hispanic ancestry, 3.45% African ancestry, and 2.31% Native American/Alaskan ancestry. Median follow-up was 45.8 months. After adjusting for confounders, compared to European individuals, Hispanic and Native American/Alaskan patients had higher prevalence of cirrhosis and DM, and individuals of Hispanic, African, and Native American/Alaskan ancestry had higher mortality and incidence of LREs and DM. Lean patients had higher mortality and incidence of LREs compared with non-lean patients.

Native American/Alaskan, Hispanic, and African patients had higher mortality and incidence of LREs and DM compared with European patients. Further studies to explore the underlying disparities and intervention to prevent LREs in lean patients, particularly several ethnic groups, may improve clinical outcomes.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significant, impacting almost one-third of the global population. MAFLD constitutes a primary cause of end-stage liver disease, liver cancer and the need for liver transplantation. Moreover, it has a strong association with increased mortality rates due to various extrahepatic complications, notably cardiometabolic diseases. While MAFLD is typically correlated with obesity, not all individuals with obesity develop the disease and a significant percentage of MAFLD occurs in patients without obesity, termed lean MAFLD. The clinical features, progression and underlying physiological mechanisms of patients with lean MAFLD remain inadequately characterized. The present review aims to provide a comprehensive summary of current knowledge on lean MAFLD and offer a perspective on defining MAFLD in individuals with normal weight. Key to this process is the concept of metabolic health and flexibility, which links states of dysmetabolism to the development of lean MAFLD. This perspective offers a more nuanced understanding of MAFLD and its underlying mechanisms and highlights the importance of considering the broader metabolic context in which the disease occurs. It also bridges the knowledge gap and offers insights that can inform clinical practice.

There is currently no available information on the correlation between abdominal obesity indices and the risk of liver fibrosis progression. We aimed to investigate the relationship between the body mass index (BMI), waist circumference (WC), and the visceral adiposity index (VAI) with the progression of liver fibrosis. The study also evaluated the association between these indices and the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis. A total of 1403 subjects participated in the cross-sectional and longitudinal population-based study. Liver stiffness was assessed via transient elastography, at baseline and follow-up (median: 4.2 years). The subgroup with dysglycemia was also analyzed. In the cross-sectional study, the highest quartile of VAI, BMI ≥ 30 kg/m2, and abdominal obesity showed significant associations with the prevalence of MASLD and liver fibrosis, as well as with fibrosis progression. However, VAI showed no association with MASLD incidence. Among the dysglycemic subjects, there was no observed association between VAI and the incidence of MASLD or the progression of fibrosis. In conclusion, the BMI, WC, and the VAI are associated with an increased risk of progression to moderate-to-advanced liver fibrosis in the general population. However, the VAI does not perform better than the BMI and WC measurement.

Disagreements about the risk of non-obese, non-alcoholic fatty liver disease for cardiometabolic outcomes occurred widely. This study aims to characterize the cardiometabolic and metabolic profile of lean/normal, overweight and obese patients with nonalcoholic fatty liver disease on a big sample.

Appeared healthy adults who participated in health examinations during the year of 2019-2022 were screened for fatty liver diagnosis. BMI classified fatty livers as lean, overweight and obese. Eleven cardiometabolic metrics (SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglycerides; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol) and metabolic metrics (GLU: blood glucose; GHB: glycated haemoglobin; UA: uric acid; AST: aspartate aminotransferase; ALT: alanine aminotransferase) were included, described and compared among BMI categories.

There were 56,496 fatty livers diagnosed by ultrasound in this study. In total, the lean fatty liver had lowest mean SBP, DBP, GLU, TG, UA, AST, and ALT but highest TC and HDL among BMI categories (all p < 0.001). The number of abnormal metrics in total was 2.5, 2.9 and 3.4 in lean, overweight, and obesity, respectively (p < 0.001, p_trend < 0.001). Visualized data showed that lean fatty liver was similar but milder in all metabolic metrics than overweight and obesity at the young ages. However, lean fatty liver had higher coefficients of age and risk of metabolic abnormality regression (p <0.001 for SBP, DBP, GLU, GHB, TC).

The lean type of fatty livers at a younger age has a relatively favourable cardiometabolic and metabolic profile compared to overweight and obese fatty livers. Due to the possible catch-up effect of metabolic dysfunctions in young lean fatty liver, lean fatty liver may have the same health outcomes as overweight/obesity fatty liver in long term. The evaluation and intervention may be critical for young lean fatty liver management to slowdown the rapid progress of metabolic dysfunction.

Cohort studies reported controversial results regarding the long-term prognosis of patients with lean non-alcoholic fatty liver disease (NAFLD) compared to non-lean NAFLD patients. This updated meta-analysis aimed to estimate the magnitude of the association between lean body mass index and all-cause mortality risk in NAFLD patients.

We systematically searched the EMBASE and MEDLINE databases from inception to March 2023 to identify observational studies that reported hazard ratio (HR) for all-cause mortality of patients with lean NAFLD versus those with non-lean, overweight, or obese NAFLD. Multivariable-adjusted hazard ratios (HRs) for all-cause mortality were pooled using a random effects model.

Fourteen studies with 94,181 NAFLD patients (11.3 % with lean NAFLD) and 7,443 fatal events over a median follow-up of 8.4 years (IQR, 6.6-17.4 years) were included. Patients with lean NAFLD had a higher risk of all-cause mortality than those with non-lean NAFLD (random-effects HR 1.61, 95 % CI 1.37-1.89; I2=77 %). The magnitude of this risk remained unchanged even after stratified analysis by measures of NAFLD diagnosis, study country, cohort setting, length of follow-up, adjustment with fibrosis stage/cirrhosis, and the Newcastle-Ottawa Scale. The risk was independent of age, sex, and cardiometabolic risk factors. Sensitivity analyses did not alter these findings. The funnel plot and Egger's test revealed no significant publication bias.

This meta-analysis revealed that lean NAFLD is associated with an approximately 1.6-fold increased mortality risk. Further studies are needed to unravel the existing but complex link between lean NAFLD and an increased risk of death.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Screening the general population for this may help to select appropriate diagnostic and preventive measures before disease progression.

We aimed to develop a screening method to identify patients with NAFLD in the general population.

We analyzed cross-sectional data from a large Japanese study of NAFLD. Principal component analysis was used to analyze the data. Candidate predictors were patients' demographic, clinical, and laboratory characteristics. The resulting model was externally validated using three data sets from different populations.

Of 15,464 (54.5% men) included patients, 2,741 (17.7%) had NAFLD as determined by ultrasonography. An index was calculated as the arithmetic mean of the scaled body mass index and serum triglyceride levels for both men and women. The area under the receiver operating characteristic curve, sensitivity, specificity, and false positive rate were 0.875, 0.824, 0.770, and 17.6%, respectively. The mean index values were significantly different between the patients with and without non-alcoholic fatty liver disease (p <0.001). The odds ratio of the index cutoff was 15.6 (95% confidence interval [CI]:14.05, 17.39). The model yielded areas under the curve of 0.828, 0.851, and 0.836 for a Chinese (N = 2,319), an Iranian (N = 2,160), and a Brazilian (N = 45,029) data set, respectively.

The proposed composite index demonstrated high performance and generalizability, suggesting its potential use as a screening tool for NAFLD in the general population.

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.

This study aims to investigate cardiovascular risk factors in nonobese patients with type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD) and to determine whether they might be used to predict high-risk individuals effectively.

This cross-sectional study included 245 nonobese patients with T2DM who underwent FibroTouch in the National Metabolic Management Center of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from January 2021 to December 2022. All individuals were divided into NAFLD and non-NAFLD groups. Patients with NAFLD were further grouped by UAP tertiles (T1, T2 and T3). We created a Cardiovascular Score (total scale: 0-5 points; ≥3 points was defined as high-risk individual) based on baPWV, carotid ultrasound, and urinary microalbumin creatinine ratio (UA/CR) to assess the risk of cardiovascular disease in non-obese T2DM patients with NAFLD. Risk factors were evaluated using univariate and multivariate analysis. The performance of risk factors was compared according to the area under the receiver operating characteristic (ROC) curve.

Atherogenic index of plasma (AIP), atherosclerosis index (AI), prevalence of hypertension, body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR) were higher in the NAFLD group compared to the non-NAFLD group. In T3 group, AIP, AI, BMI and HOMA-IR were higher than those of T1 group. Multivariate logistic regression showed that age, systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C) and AIP were risk factors for cardiovascular disease among nonobese patients with T2DM and NAFLD. The area under the ROC curve for age, systolic blood pressure, LDL-C and AIP were 0.705, 0.688, 0.738 and 0.642, respectively. The area under the ROC curve was 0.895 when combining them.

Age, systolic blood pressure, AIP and LDL-C are all independent risk factors for cardiovascular disease in non-obese individuals with T2DM and NAFLD, which can be combined to identify high-risk populations and carry out intervention.

Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared to the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. In this study we created a mouse model to mimic this condition. In this study involving seven-week-old C57BL/6J male mice, two dietary conditions were tested: a standard high-fat/high-cholesterol diet (STHD-01) and a combined diet of STHD-01 and ethanol. Over periods of 6 and 12 weeks, we analyzed the effects on liver and cardiac tissues using various staining techniques and PCR. Echocardiography and blood tests were also performed to assess cardiac function and liver damage. The results showed that mice on the ethanol-supplemented STHD-01 diet developed signs of steatohepatitis and cardiac dysfunction, along with increased sympathetic activity, as early as 6 weeks. At 12 weeks, more pronounced exacerbations accompanied with cardiac dilation, advanced liver fibrosis, and activated myocardial fibrosis with sympathetic activation were observed. This mouse model effectively replicated non-obese MASLD and cardiac dysfunction over a 12-week period using a combined diet of STHD-01 and ethanol. This dietary approach highlighted that both liver inflammation and fibrosis, as well as cardiac dysfunction, could be significantly worsened due to the activation of the sympathetic nervous system. Our results indicate that alcohol, even when completely metabolized on the day of drinking, exacerbates the progression of non-obese MASLD and cardiac dysfunction.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the world's adult population. While it is associated with obesity and metabolic syndrome, emerging evidence has shown that a substantial number of MASLD patients have a normal body mass index ("lean individuals with MASLD"). In this article, we provide an overview of the definition, epidemiology, pathogenesis, and clinical outcomes associated with lean individuals with MASLD and updates on current management.

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.

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.

Nonalcoholic fatty liver disease (NAFLD) is a growing public health concern worldwide. Early detection and management of modifiable risk factors are critical to mitigating its impact. This study aimed to investigate the prevalence and risk factors of NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis among lean adults in the United States (US), using the latest National Health and Nutrition Examination Survey (NHANES) dataset from 2017-2020.

Using controlled attenuation parameter scores of ≥285 dB/m, we assessed the age-adjusted prevalence of lean NAFLD. To determine the age-adjusted prevalence of high-risk NASH and significant fibrosis, we used the FibroScan-aspartate aminotransferase (FAST) score (cutoffs 0.35 and 0.67) and vibration-controlled transient elastography (liver stiffness measurement ≥8 kPa). Multivariate logistic regression was used to identify potential risk factors.

We found the age-adjusted prevalence of lean NAFLD to be 6.30%. Among lean US adults, the age-adjusted prevalence of high-risk NASH and significant fibrosis was 1.29% and 4.35%, respectively. Older age and metabolic comorbidities, such as hypertension, diabetes, and dyslipidemia were associated with NAFLD and its complications.

These findings suggest that the prevalence of NAFLD is of concern among lean individuals, particularly those aged 40 and older with metabolic comorbidities, while a targeted approach to screening and risk stratification for hepatic fibrosis upon lean NAFLD diagnosis is warranted.

Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method.

We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters.

The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3-4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2 ). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease.

Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

Although most patients with NAFLD are obese or overweight, some are lean with normal BMI. Our aim was to assess differences in clinicopathological profile and liver disease severity among lean and non-lean NAFLD.

Data of 1040 NAFLD patients over last 10 years was analysed. BMI < 23 kg/m2 categorised lean patients. Non-invasive assessment of steatosis was done by ultrasound and controlled attenuation parameter (CAP) while fibrosis was assessed with FIB-4 and liver stiffness measurement (LSM). FibroScan-AST (FAST) score was used for non-invasive prediction of NASH with significant fibrosis. Histology was reported using NASH-CRN system.

149 (14.3%) patients were lean while 891 (85.7%) patients were non-lean. Diabetes mellitus [25 (16.7%) vs 152 (17.05%), p > 0.99], elevated triglycerides [81 (54.3%) vs 525 (58.9%), p = 0.33] and low HDL [71(47.6%) vs 479(53.7%), p = 0.18] were observed in a similar proportion. Lean patients were less likely to have central obesity [72 (48.3%) vs 788 (88.4%), p < 0.001], hypertension [16 (10.7%) vs 239(26.8%), p < 0.001] and metabolic syndrome [21 (14.09%) vs 290 (32.5%), p < 0.001]. No difference in steatosis assessment was noted using ultrasound (p = 0.55) or CAP (0.11). FAST [0.38 (0.18-0.66) vs 0.39 (0.27-0.73), p = 0.53], FIB-4 [1.08 (0.65-1.91) vs 1.09 (0.66-1.94), p = 0.94] and LSM [6.1 (4.8-7.9) vs 6.2 (4.7-8.6), p = 0.19) were similar. Liver biopsy was available in 149 patients [lean: 19 (12.7%), non-lean: 130 (87.3%)]. There was no difference in the number of patients with NASH [4 (21.05%) vs 20 (15.3%), p = 0.51], significant fibrosis [2 (10.5%) vs 32 (24.6%), p = 0.25] or advanced fibrosis [1 (5.26%) vs 18 (13.84%), p = 0.47].

Although metabolic co-morbidities are less common, there is no difference in liver disease severity among both groups.

Although approximately 40% of patients with nonalcoholic fatty liver disease (NAFLD) are nonobese or lean, little is known about the long-term clinical outcomes of lean NAFLD. We aimed to estimate the risk of mortality and adverse liver-related events in patients with lean NAFLD compared with those with non-lean NAFLD.

We searched the PubMed, Embase, and Cochrane Library databases through May 2022 for articles reporting mortality and/or development of cirrhosis among lean and non-lean NAFLD patients. The relative risks (RRs) of all-cause mortality, cardiovascular mortality, liver-related mortality, and occurrence of decompensated cirrhosis or hepatocellular carcinoma were pooled using the random-effects model. We also performed subgroup analysis according to characteristics of the study population, methods of NAFLD diagnosis, study design, study region, and length of follow-up.

We analyzed 10 cohort studies involving 109,151 NAFLD patients. Patients with lean NAFLD had comparable risks for all-cause mortality (RR, 1.09; 95% confidence interval [CI], 0.66-1.90), cardiovascular mortality (RR, 1.12; 95% CI, 0.66-1.90), and adverse liver events including decompensated cirrhosis and hepatocellular carcinoma (RR, 0.81; 95% CI, 0.50-1.30). However, the risk of liver-related mortality was higher in patients with lean than non-lean NAFLD (RR, 1.88; 95% CI, 1.02-3.45).

This study highlights a higher risk of liver-related mortality in patients with lean NAFLD than those with non-lean NAFLD. This finding indicates that further understanding of the pathophysiology, risk factors of adverse outcomes, and genetic and ethnic variabilities of lean NAFLD phenotype is warranted for individualized treatment strategies in lean NAFLD patients.

Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach.

The severity of liver injury and clinical outcomes in lean individuals with NAFLD is a subject of debate and very few studies have been performed in the general population. The aim of this study was to compare subject characteristics and mortality between lean and nonlean NAFLD in a community setting.

The study population included 169,303 participants from the nationwide Constances cohort. Subjects with excessive alcohol consumption, viral hepatitis, or other liver diseases were excluded and 137,206 subjects were analyzed. The diagnosis of NAFLD and fibrosis was performed using the Fatty Liver Index and the Forns Index. The median follow-up was 3.58 years. The prevalence of NAFLD was 5.3% (95% CI: 5.2-5.4) in lean subjects, while 16.3% (95% CI: 15.7-16.8) of NAFLD subjects were lean. Despite their better metabolic profile, the prevalence of advanced fibrosis was significantly higher in lean than in nonlean NAFLD (3.7% vs. 1.7%, respectively, p < 0.01). Among NAFLD subjects and after adjustment for demographics, metabolic risk factors and lifestyle, lean status was associated with advanced fibrosis (OR=1.26, 95% CI: 1.20-1.65, p = 0.005), an increased risk of liver-related events (adjusted HR=5.84, 95% CI: 4.03-8.46), chronic kidney disease (adjusted HR=2.49, 95% CI: 1.49-4.16), and overall mortality (adjusted HR=3.01, 95% CI: 2.21-4.11). Liver-related events and overall mortality were related to the severity of fibrosis, both in lean and nonlean NAFLD subjects, whatever the usual risk factors.

This study in a large community-based cohort confirms that NAFLD in lean subjects is more severe for fibrosis, the progression of liver disease, chronic kidney disease, and overall mortality.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.

Hepatic steatosis can occur in lean individuals, while its metabolic and risk profiles remain unclear. We aimed to characterize the clinical and risk profiles of lean and non-lean steatosis. This cross-sectional study included 1610 patients with transient elastography-assessed steatosis. The metabolic and risk profiles were compared. Compared to their non-lean counterparts, lean subjects with steatosis had a lower degree of fibrosis (F0-F1: 91.9% vs. 80.9%), had a lower prevalence of diabetes (27.9% vs. 32.8%), dyslipidemia (54.7% vs. 60.2%) and hypertension (50.0% vs. 51.3%), and had higher levels of high-density lipoprotein cholesterol while lower fasting insulin and homeostatic model assessment for insulin resistance (all p < 0.05). Of the 16 potential risk factors, being Hispanic was associated with higher odds of non-lean steatosis but not with lean steatosis (odds ratio (OR): 2.07 vs. 0.93), while excessive alcohol consumption had a different trend in the ratio (OR: 1.47 vs.6.65). Higher waist-to-hip ratio (OR: 7.48 vs. 2.45), and higher waist circumference (OR: 1.14 vs. 1.07) showed a stronger positive association with lean steatosis than with non-lean steatosis (all P_{heterogeneity} < 0.05). Although lean individuals with steatosis presented a healthier metabolic profile, both lean and non-lean steatosis had a significant proportion of metabolic derangements. In addition, the etiological heterogeneity between lean and non-lean steatosis may exist.

Non-alcoholic fatty liver disease (NAFLD) can develop in individuals who are not overweight. Whether lean persons with NAFLD have lower mortality and lower incidence of cirrhosis, cardiovascular diseases (CVD), diabetes mellitus (DM) and cancer than overweight/obese persons with NAFLD remains inconclusive. We compared mortality and incidence of cirrhosis, CVD, DM and cancer between lean versus non-lean persons with NAFLD.

This is a retrospective study of adults with NAFLD in a single centre from 2012 to 2021. Primary outcomes were mortality and new diagnosis of cirrhosis, CVD, DM and cancer. Outcomes were modelled using competing risk analysis and Cox proportional hazards regression analysis.

A total of 18,594 and 13,420 patients were identified for cross-sectional and longitudinal analysis respectively: approximately 11% lean, 25% overweight, 28% class 1 obesity and 35% class 2-3 obesity. The median age was 51.0 years, 54.6% were women. The median follow-up was 49.3 months. Lean patients had lower prevalence of metabolic diseases at baseline and lower incidence of cirrhosis and DM than non-lean patients and no difference in CVD, any cancer or obesity-related cancer during follow-up. However, lean patients had significantly higher mortality with incidence per 1000 person-years of 16.67, 10.11, 7.37 and 8.99, respectively, in lean, overweight, obesity class 1 and obesity class 2-3 groups respectively.

Lean patients with NAFLD had higher mortality despite lower incidence of cirrhosis and DM, and similar incidence of CVD and cancer and merit similar if not more attention as non-lean patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but is also common in individuals with a normal body mass index (BMI), who also experience the hepatic inflammation, fibrosis, and decompensated cirrhosis associated with NAFLD progression. The clinical evaluation and treatment of NAFLD in this patient population are challenging for the gastroenterologist. A better understanding of the epidemiology, natural history, and outcomes of NAFLD in individuals with normal BMI is emerging. This review examines the relationship between metabolic dysfunction and clinical characteristics associated with NAFLD in normal-weight individuals.

Despite a more favorable metabolic profile, normal-weight NAFLD patients exhibit metabolic dysfunction. Visceral adiposity may be a critical risk factor for NAFLD in normal-weight individuals, and waist circumference may be better than BMI for assessing metabolic risk in these patients. Although screening for NAFLD is not presently recommended, recent guidelines may assist clinicians in the diagnosis, staging, and management of NAFLD in individuals with a normal BMI.

Individuals with a normal BMI likely develop NAFLD as a result of different etiologies. Subclinical metabolic dysfunction may be a key component of NAFLD in these patients, and efforts to better understand this relationship in this patient population are needed.

NAFLD is a multisystem condition and the leading cause of chronic liver disease globally. There are no approved NAFLD-specific dugs. To advance in the prevention and treatment of NAFLD, there is a clear need to better understand the pathophysiology and genetic and environmental risk factors, identify subphenotypes, and develop personalized and precision medicine. In this review, we discuss the main NAFLD research priorities, with a particular focus on socioeconomic factors, interindividual variations, limitations of current NAFLD clinical trials, multidisciplinary models of care, and novel approaches in the management of patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally. NAFLD is closely associated with metabolic syndrome, which are both becoming increasingly more common with increasing rates of insulin resistance, dyslipidemia, and hypertension. Although NAFLD is strongly associated with obesity, lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat. Currently, there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors, pathophysiology, and clinical outcomes. In this review, we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence, incidence, risk factors, genetic predisposition, and pathophysiology. Furthermore, we discuss and compare the clinical outcomes, such as insulin resistance, dyslipidemia, hypertension, coronary artery disease, mortality, and progression to nonalcoholic steatohepatitis, among lean/nonobese and obese NAFLD patients. Finally, we summarize the most up to date current management of NAFLD, including lifestyle interventions, pharmacologic therapies, and surgical options.

Non-alcoholic fatty liver disease (NAFLD) is associated with a greater risk of developing cardiovascular disease and have adverse impacts on the cardiac structure and function. Little is known about the effect of non-obese NAFLD upon cardiac function. We aimed to compare the echocardiographic parameters of left ventricle (LV) between non-obese NAFLD group and control group, and explore the correlation of non-obese NAFLD with LV diastolic dysfunction.

In this cross-sectional study, 316 non-obese inpatients were enrolled, including 72 participants with NAFLD (non-obese NAFLD group) and 244 participants without NAFLD (control group). LV structural and functional indices of two groups were comparatively analyzed. LV diastolic disfunction was diagnosed and graded using the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave and E value. Compared with control group, the non-obese NAFLD group had the lower E/A〔(0.80 ± 0.22) vs (0.88 ± 0.35), t = 2.528, p = 0.012〕and the smaller LV end-diastolic diameter〔(4.51 ± 0.42)cm vs (4.64 ± 0.43)cm, t = 2.182, p = 0.030〕. And the non-obese NAFLD group had a higher prevalence of E/A < 1 than control group (83.3% vs 68.9%, X² = 5.802, p = 0.016) while two groups had similar proportions of LV diastolic dysfunction (58.3% vs 53.7%, X² = 0.484, p = 0.487). Multivariate logistic regression analysis showed that non-obese NAFLD was associated with an increase in E/A < 1 (OR = 6.562, 95%CI 2.014, 21.373, p = 0.002).