Lean Non-alcoholic Fatty Liver Disease Patients Research Articles

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.

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.

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.

Long-term outcomes in lean and non-lean NAFLD patients: a systematic review and meta-analysis.

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 nonalcoholic fatty liver disease: Age-dependent differences in pathology, prognosis, and liver-related events.

This study aimed to evaluate the age-specific characteristics, prognosis, and complications of patients with lean nonalcoholic fatty liver disease (NAFLD). Background factors (age, sex, diabetes, dyslipidemia, hypertension, and PNPLA3 gene polymorphism), blood test results, liver histology findings, muscle mass, and grip strength were investigated in 782 patients with NAFLD who underwent liver biopsy. Prognosis and complications were compared among 549 patients with nonlean or lean NAFLD who were followed up for 6.5years. Additionally, background factors, blood test results, liver histology findings, prognosis, and complications were compared according to age (≥60years vs. <60years) in patients with lean NAFLD. Lean NAFLD patients showed lower aspartate aminotransferase, alanine aminotransferase, homeostasis model assessment-insulin resistance, high-sensitivity C-reactive protein, ferritin, and leptin but higher adiponectin and hemoglobin A1c (HbA1c) levels than patients with nonlean NAFLD. Furthermore, lean NAFLD patients showed less liver fibrosis, inflammation, steatosis, and ballooning. Among lean NAFLD patients, those aged 60years and older were more frequently female, showed higher rates of hypertension, diabetes, and dyslipidemia, had higher HbA1c and type IV collagen 7S levels, lower platelet count, higher liver fibrosis and inflammation grades, and lower muscle mass and grip strength. Lean NAFLD was associated with a worse prognosis in patients aged 60years and over than in those younger than 60years of age and with a higher incidence of liver-related disease, cerebrocardiovascular events, and nonliver cancer. Age is an important consideration in patients with lean NAFLD. Compared with nonlean NAFLD, lean NAFLD was associated with a worse prognosis and higher risk of complications in patients aged 60years and older.

Adiponectin–leptin ratio for the early detection of lean non-alcoholic fatty liver disease independent of insulin resistance

Background Lean Non-alcoholic Fatty Liver Disease (NAFLD) shares a similar disease burden to those of their overweight counterparts and should be detected early. We hypothesized that the adiponectin–leptin ratio (AL ratio) could be a good marker for early detection of lean NAFLD independent of insulin resistance. Materials and methods A total of 575 adults without diabetes were enrolled in a community-based study. The subjects were stratified into the lean controls, lean NAFLD, simple overweight/obesity and overweight/obesity NAFLD groups according to body mass index (BMI) and ultrasonographic fatty liver indicators. Serum adiponectin and leptin levels were measured by enzyme-linked immunosorbent assay. Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD in relation to the tertiles of serum AL concentration after adjustment. Receiver operating characteristic (ROC) analyses were applied to evaluate the diagnostic performance of the AL ratio for NAFLD. Results The mean age of the participants was 42.8 ± 11.5 years. Comparing with the lean controls, the odds of having lean NAFLD for the highest versus the lowest tertile of AL ratio was 0.28(95%CI: 0.12–0.69) after adjustment. Putting AL ratio, BMI, triglyceride, AST/ALT ratio to the diagnosis performance of NAFLD, the ROC was 0.85 (95% CI: 0.82–0.88), 0.83 (95% CI 0.78–0.87) and 0.86 (95% CI 081–0.91) for all NAFLD, NAFLD in women and NAFLD in men, respectively. (p < .001). Conclusions The study revealed that the AL ratio could be a good biomarker to early distinguish lean NAFLD patients from lean controls independent of insulin resistance. [AQ3] Key messages The prevalence of non-alcoholic fatty liver disease (NAFLD) increases globally and is related to liver diseases and metabolic dysfunctions. Lean subset of NAFLD shares a similar disease burden to those of their overweight counterparts and should be detected early. Adiponectin–leptin ratio were associated with the severity of steatosis and was a predictor of obese NAFLD better than each single adipokine. To date, there is no investigation that explores specifically for the relationship between lean NAFLD and AL ratio. Our study found that adiponectin–leptin ratio is a sole independent marker regardless of insulin resistance in lean NAFLD. Having lean NAFLD for the highest versus the lowest tertile of adiponectin–leptin ratio was 0.28(95%CI: 0.12–0.69) after adjustment of age, sex, current smoking, exercise habits, HOMA-IR and AST/ALT. ROC for the NAFLD performance is good for the early detection (0.85; 95% CI: 0.82–0.88). Further rigorous investigation is necessary and should be promptly performed.

WITHDRAWN: Evidence Synthesis to Advance Clinical Practice and Scientific Research: A CGH Pillar

WITHDRAWN: Evidence Synthesis to Advance Clinical Practice and Scientific Research: A CGH Pillar

Serum miR-4488 as a potential biomarker of lean nonalcoholic fatty liver disease.

In lean individuals, nonalcoholic fatty liver disease (NAFLD) is not a benign disease, and these patients have long-term morbidity and mortality similar to those of their nonlean counterparts. Finding biomarkers for noninvasive and early detection is urgent and microRNAs (miRNAs) show potential. The aims of this study were to investigate the potential role of serum miRNAs in the detection of lean NAFLD and to explore the possible pathogenesis of lean NAFLD. A total of 498 patients with NAFLD and 98 healthy controls were included to compare the clinical characteristics of lean NAFLD patients [LNs: body mass index (BMI) <23 kg/m2], nonlean NAFLD patients (NLNs: BMI ≥23 kg/m2) and normal healthy individuals (HIs). A total of 14 serum samples were collected from 4 LNs, 6 NLNs and 4 HIs for high-throughput profiling to identify altered miRNA expression patterns in lean NAFLD. The candidate miRNA, miR-4488, was identified by filtering based on studies in a second independent cohort (31 LNs, 62 NLNs, 72 HIs) that included quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction network analyses were performed to investigate the potential molecular mechanism of miR-4488 in lean NAFLD. LNs were older and had a smaller waist circumference, lower levels of alanine aminotransferase, glutamyl transpeptidase, fasting insulin, and uric acid, lower HOMA-IR score, and higher levels of total cholesterol, high-density lipoprotein cholesterol, and hemoglobin (P<0.05). The serum level of miR-4488 was increased in LNs compared with HIs (P<0.0001) and NLNs (P=0.025). miR-4488 had acceptable performance in predicting [area under the curve (AUC) =0.794, 0.698] lean NAFLD. Moreover, GO and KEGG enrichment analyses revealed that the differentially expressed target genes were mainly involved in choline metabolism in cancer, the tumor-necrosis factor (TNF) signaling pathway and the p53 signaling pathway. PPI analysis identified ARHGAP1, SLC10A1 and SIX5 as the hub genes. Taken together, our findings indicate that serum miR-4488 is a potential biomarker for diagnosing and predicting the pathogenetic mechanisms of lean NAFLD.

Genetic variation in TBC1 domain family member 1 gene associates with the risk of lean NAFLD via high-density lipoprotein.

Objective: Non-alcoholic fatty liver disease (NAFLD) affects almost a quarter of the world's population. Although NAFLD often co-exists with obesity, a substantial proportion of NAFLD patients are lean which is relatively unexplored. This study aimed to examine the association between genetic variation in candidate genes, e.g., TBC1D1 and the risk of lean NAFLD in the elderly Chinese Han population. Methods: This is an extension of the research on physical examination in the Zhanjiang community center including 5387 residents, Shanghai, China, in 2017. According to the classification in adult Asian populations, participants were categorized into four groups: lean NAFLD (BMI <23, n = 106), non-lean NAFLD (BMI ≥23, n = 644), lean non-NAFLD (BMI <23, n = 216) and non-lean non-NAFLD (BMI ≥23, n = 253).116 NAFLD-related candidate genes, which cover 179 single nucleotide polymorphisms (SNPs) were included in the KEGG enrichment analysis. Independent samples t-test was adopted for the group comparison. The associations between genetic variations with the specific phenotype in five genetic models were analyzed with the "SNPassoc" R package and rechecked with logistic regression analysis. Mediation models were conducted to explore whether the certain phenotype can mediate the association between SNPs and the risk of lean NAFLD. Results: Compared with lean non-NAFLD individuals, lean NAFLD patients had higher BMI, low-density lipoprotein and triglyceride, and lower HDL. The AMPK signaling pathway, which includes TBC1D1 and ADIPOQ genes, was the most significant (p < .001). The A allele frequency of rs2279028 in TBC1D1 (p = .006) and G allele frequency of rs17366568 in ADIPOQ (p = .038) were significantly lower in lean NAFLD. The association between rs2279028 and the risk of lean NAFLD was mediated by HDL (p = .014). No significant mediation effect was found between rs17366568 and the risk of lean NAFLD. Conclusion: This study, for the first time, indicated that rs2279028 of TBC1D1 may contribute to the progression of lean NAFLD through HDL. This finding provides more evidence for exploring the mechanism of lean NAFLD and suggests practical solutions for the treatment of lean NAFLD.

Frequencies of Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome in Lean Individuals

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) prevalence has doubled in the last 20 years and is becoming a vital health concern due to its increasing prevalence. Lean patients having normal-weight central obesity with NAFLD may have increased morbidity and all-cause mortality and thus form an important target for lifestyle modifications and preventive strategies. Objective: To determine frequencies of NAFLD and Metabolic Syndrome in lean individuals. Methods: The present cross-sectional study was undertaken at the Medicine Department, Pakistan Ordinance Factories Hospital, Wah Cantonment Pakistan from July 2018 to June 2020 enrolling 230 patients aged 20 to 70 years, of both sex. Demographic information, co-morbid conditions, BMI, and waist circumference were recorded. An abdominal ultrasound was performed to determine hepatic fatty infiltration. Blood samples were collected for serum HDL-cholesterol (HDL-C) and serum triglyceride estimation. SPSS 22.0 was used for data entry and analysis. Results: Mean age was 45.7+12.5 years with male predominance at 130 (56.5%). Diabetes mellitus was present in 104 (45.2%) and 102 (44.3%) were hypertensive. The mean BMI was 23.4+3.6 kg/m2. The mean serum triglyceride level was 209+10.1 mg/dl and elevated at 141 (61.3%). The mean serum HDL-C level was 23.1+4.2 mg/dl and was reduced by 142 (61.8%). NAFLD was seen in 38 (16.5%) and 24 (10.4%) had Metabolic Syndrome. Among the 38 lean NAFLD patients, 21 (55.3%) had Metabolic Syndrome. Conclusion: NAFLD was seen in almost one-fifth of lean patients enrolled. Metabolic syndrome was reported in more than one-half of these lean NAFLD patients.

Predictive Risk Factors of Nonalcoholic Fatty Liver Disease in a Lean Chinese Population.

Although nonalcoholic fatty liver disease (NAFLD) is related to obesity, it may also affect lean individuals. Recent data suggest that lean NAFLD patients can develop the whole spectrum of NASH. However, the NAFLD predictive model for lean populations remains lacking. A total of 5037 lean individuals were included in this study, and the data were separated for training and validation. The logistic regression method was used, and a nomogram, a type of prediction model, was constructed according to the logistic regression analysis and the significant clinical factors. The performance of this model was evaluated based on its discrimination, calibration, and clinical utility. The individuals were divided into the training (n = 4068) or validation (n = 969) cohorts at a ratio of 8 to 2. The overall prevalence of NAFLD in the lean cohort was 6.43%. The nomogram was constructed based on seven predictors: alanine aminotransferase, total cholesterol, triglycerides, low-density lipoprotein cholesterol, creatinine, uric acid, and hemoglobin A1C. The model based on these factors showed good predictive accuracy in the training set and in the internal validation set, with areas under the curve (AUCs) of 0.870 and 0.887, respectively. The calibration curves and decision curve analysis (DCA) displayed good clinical utility. the nomogram model provides a simple and reliable ability to predict the risk of NAFLD in lean subjects. The model can predict lean NAFLD and can help physicians screen and identify lean subjects at a high risk of NAFLD.

Presence of sarcopenia identifies a special group of lean NAFLD in middle-aged and older people.

Sarcopenia, the age-related loss of muscle mass and function, is closely associated and frequently concomitant with non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the clinical features of the sarcopenic NAFLD patients from middle-aged and older people. A total of 1305 patients with NAFLD from the Shanghai Changfeng Study were included for analysis. Sarcopenia was diagnosed based on the height-adjusted appendicular skeletal muscle mass (ASM/height2). We comprehensively analyzed the metabolic phenotype, carotid artery condition, liver fibrosis score, and serum metabolomic profile of each participant. Among the middle-aged and older population, 68.1% of patients with sarcopenia and NAFLD were lean. Sarcopenia was independently associated with increased risk of carotid plaque (OR, 2.22; 95%CI 1.23-4.02) and liver fibrosis (OR, 2.07; 95%CI 1.24-3.44), and the sarcopenic lean NAFLD patients were characterized by a higher risk of carotid plaque (p = 0.008) and liver fibrosis (p = 0.001) than the non-sarcopenic lean NAFLD patients, despite their lower BMI and similar prevalence of metabolic syndrome and diabetes. Further serum metabolomic examination indicated that the sarcopenic lean NAFLD patients presented a distinct metabolomic profile prone to carotid plaque and liver fibrosis, with upregulated serum valine, N-acetylneuraminyl-glycoproteins, lactic acid, small LDL triglycerides and VLDL5 components, and reduced components of HDL4. A sarcopenic characterization score based on above metabolites was established and could also predict increased risk of carotid plaque and liver fibrosis. The presence of sarcopenia identifies a special subgroup of lean NAFLD with increased risk of cardiovascular disease and liver fibrosis clinically.

Fasting glucose mediates the influence of genetic variants of SOD2 gene on lean non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) imposes an enormous burden on public health, and a large proportion of NAFLD patients are lean with normal body weight, which is rarely mentioned. We conducted this study to determine the mediation effects of fasting glucose on the relationships between genetic variants of SOD2 and the susceptibility of lean NAFLD in the elderly Chinese Han population. Methods: Data in this manuscript were collected in a cross-sectional study among 5,387 residents (aged ≥60years) in the Zhangjiang community center, Shanghai, China, in 2017. Ten (single nucleotide polymorphisms) SNPs previously reported to be related to NAFLD and obesity, including rs9939609, rs1421085, rs9930506, rs626283, rs641738, rs4880, rs58542926, rs738409, rs2281135, and rs2294918 were genotyped. The associations between genetic variations in SOD2 and fasting glucose in five genetic models were analyzed with the SNPassoc R package and rechecked with regression analysis. Mediation models were conducted to explore whether fasting glucose can mediate the association between SNPs and the susceptibility of lean NAFLD. Results: In this study, lean NAFLD individuals had a higher waist circumference and waist-to-hip ratio, ALT, and fasting glucose than lean non-NAFLD individuals (p < 0.050). In comparison, the AA genotypic frequency of rs4880 in SOD2 gene was much lower in lean NAFLD patients (p = 0.005). And rs4800 had a significant indirect effect on lean NAFLD incidence mediated by fasting glucose (p < 0.001). Conclusion: For the first time, the mediation effect of fasting glucose on the association of rs4880 in SOD2 with the susceptibility of lean NAFLD was clarified in the elderly Chinese Han population. It emphasized the connection between glucose homeostasis and oxidative stress in the mechanisms of lean NAFLD.

The impact of body mass index on clinicopathological features of nonalcoholic fatty liver disease in Taiwan.

The aim of this study was to assess the impact of body mass index (BMI) on the clinical and histological characteristics of patients with nonalcoholic fatty liver disease (NAFLD). Patients with clinically diagnosed NAFLD who received liver biopsy were retrospectively enrolled from 2007 to 2019. For comparison, all of the patients were divided into lean body mass (<23kg/m2 ), overweight (23-24.9kg/m2 ), and obesity (BMI≧25kg/m2 ). A total of 572 patients with histologically confirmed NAFLD, including 40 (6.99%) lean body mass, 54 (9.44%) overweight, and 478 (83.57%) obese patients, were recruited. Obese NAFLD patients had significantly higher grade of steatosis (grade 3: 29.92% vs 22.22% vs 12.5%, P<0.0001) and hepatocyte ballooning (grade 2: 14.85% vs 12.96% vs 12.5%, P<0.0001) than overweight and lean NAFLD patients. The prevalence of nonalcoholic steatohepatitis (NASH) was 22.5%, 25.93%, and 36.19% in lean, overweight, and obese NAFLD patients, respectively. Obesity was significantly associated with fibrosis severity (P=0.03). The fibrosis index based on four factors (FIB-4) score can identify NAFLD patients without significant fibrosis or with cirrhosis. The areas under the receiver-operating characteristic curve of FIB-4 score to identify patients without significant fibrosis or with cirrhosis were 0.82 (95% confidence interval [CI]: 0.69-0.96) and 0.87 (95% CI: 0.76-0.99) in lean patients; 0.77 (95% CI: 0.61-0.93) and 0.81 (95% CI: 0.59-1.0) in overweight patients; and 0.77 (95% CI: 0.72-0.82) and 0.89 (95% CI: 0.85-0.92) in obese patients. The majority of NAFLD patients are obese, as defined by BMI. Obesity was significantly associated with NASH and hepatic fibrosis severity in patients with NAFLD.

Effect of Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease: A Randomized Clinical Trial

Background and AimsThe clinical efficacy of fecal microbiota transplantation (FMT) in patients with non-alcoholic fatty liver disease (NAFLD) and the variant effects of FMT on lean and obese NAFLD patients remain elusive. Our study aimed to determine the clinical efficacy and safety of FMT for patients with NAFLD, elucidating its different influences on lean and obese patients with NAFLD.MethodsWe performed a randomized and controlled clinical trial. Patients in the non-FMT group were administered oral probiotics. In the FMT group, patients were randomized to receive FMT with donor stool (heterologous) via colonoscopy, followed by three enemas over 3 days. Both groups were also required to maintain a healthy diet and keep regular exercise for more than 40 min every day. They returned to the hospital for reexamination 1 month after treatment.ResultsFMT can decrease the fat accumulation in the liver by improving the gut microbiota dysbiosis, thus attenuating fatty liver disease. Significant differences in the clinical features and gut microbiota between lean and obese NAFLD patients were unveiled. Moreover, FMT had better effects on gut microbiota reconstruction in lean NAFLD than in obese NAFLD patients.ConclusionsFMT could successfully improve the therapeutic effects on patients with NAFLD, and its clinical efficacy was higher in lean NAFLD than in obese NAFLD patients.

Association of Low Skeletal Muscle Mass with the Phenotype of Lean Non-Alcoholic Fatty Liver Disease.

Low skeletal muscle mass (LSMM) has emerged as a potential risk factor for non-alcoholic fatty liver disease (NAFLD). However, its clinical implications in patients with lean NAFLD have not yet been elucidated. We investigated the role of LSMM in patients with lean NAFLD. Lean NAFLD was defined as a body mass index of ≤23 kg/m2. Using bioelectrical impedance analysis, the appendicular skeletal muscle mass (ASM) was adjusted by height squared. The LSMM was based on 1 SD below the sex-specific mean for young, healthy Asian adults. Of the 8905 ultrasound-confirmed NAFLD patients, 3670 (41.2%) were diagnosed with lean NAFLD. The lean NAFLD group was younger (45.0 vs. 49.0 years, p < 0.001), and had a lower waist circumference (74.0 vs. 85.0 cm, p < 0.001), lower prevalence of diabetes (3.1 vs. 7.4%, p < 0.001) and hypertension (4.2 vs. 15.2%, p < 0.001), and a higher proportion of LSMM (28.0 vs. 2.2%, p < 0.001) than the non-lean NAFLD group. Stepwise adjusted models suggested that LSMM was associated with lean individuals with NAFLD (odds ratio = 7.02, p < 0.001). LSMM may be a novel risk factor for lean NAFLD patients more than non-lean NAFLD patients, independent of classic metabolic factors.

Association between the number of metabolic parameters and vibration controlled transient elastography in patients with lean and non-lean non alcoholic fatty liver disease

Background and Aim: Non-alcoholic fatty liver disease(NAFLD) is identified in normal body weight individuals also, termed lean-NAFLD. Lean and non-lean NAFLD patients have higher cardiovascular mortality risks. Liver fibrosis can be assessed using vibration-controlled transient elastography(VCTE) for the early identification of at-risk patients. We tried to evaluate the association between the presence of multiple metabolic syndrome components(MeTSc) as defined by NCEP ATP III criteria with VCTE values in lean and non-lean NAFLD patients. Methods: Cross-sectional observational study including 120 patients of lean NAFLD(BMI<23kg/m2) and 120 non-lean NAFLD(BMI‰¥23 kg/m2). Baseline demographic and clinical data were noted, including measurement of hemogram, liver biochemistry, lipid profile, and HOMA-IR. Liver fibrosis was assessed using VCTE. Data were compared between the two groups. One way ANOVA test was done to identify whether there was a significant association between the number of MeTSc and VCTE values. Results: Among the Lean-NAFLD patients 9.5% had no MeTSc with VCTE 8.5±2.66, 12.5% had 1 MeTSc with VCTE 8.79±2.73, 24.17% had 2 MeTSc with VCTE 7.6±1.97, and 55.85% had 3 MeTSc with VCTE 8.3±2.15. There was no significant difference in VCTE values between these groups(p=0.333). Among non-lean NAFLD patients 0% had no MeTSc, 6.67% had 1 MeTSc with VCTE 6.2±1.39, 12.5% had 2 MeTSc with VCTE 7.4±2.83 and 80.83% had ‰¥3 MeTSc with VCTE 8.18±2.58. The VCTE was higher in patients with higher number of MeTSc(p=0.036). Among lean NAFLD, 40% had significant fibrosis (VCTE >= 7 kpa) and 22% had advanced fibrosis (VCTE>= 9.9kpa). Among non lean NAFLD, 37% had significant fibrosis and 23% had advanced fibrosis. Conclusions: MeTSc are important in determining hepatic fibrosis in patients with non-lean NAFLD. This effect is not seen in patients with lean-NAFLD. Metabolic syndrome is significantly higher in non-lean NAFLD patients than lean NAFLD.

Correlation of waist circumference, hip circumference and waist-hip ratio with VCTE in lean and non-lean NAFLD

Background and Aim: Waist circumference (WC) is a measure of abdominal adiposity, an important predictor of Non alcoholic fatty liver disease (NAFLD). Waist-to-hip ratio (WHR) also has a strong correlation with development of NAFLD. Vibration-controlled transient elastography (VCTE) is a widely used noninvasive technique for assessment of liver fibrosis. We tried to compare the WC, Hip circumference (HC) and WHR in lean and non lean NAFLD and to assess the correlation between WHR and VCTE. Methods: Cross-sectional observational study including 120 lean (BMI<23kg/m2 ) and 120 non-lean (BMI>23kg/m2 ) NAFLD patients. Liver stiffness was determined using VCTE (Fibroscan 502, Echosens, Paris, France) in kilopascals (kPa). Comparison of categorical variables was done using Chi-square (Î2) test. Pearson’s correlation coefficient was used to test the strength of correlation. Univariate linear regression was used to predict the relation between WHR and VCTE. Results: 105(87.5%) of non-lean NAFLD and 59(49.17%) of lean NAFLD patients were found to have high WC (p<0.001), but the proportion of patients having high WHR was comparable in both the groups (p=0.551). Compared to the lean NAFLD population, WC and HC were significantly higher in the non-lean group (p<0.001 for both), but mean WHR were comparable between lean (0.93+0.14) and non-lean (0.94+0.14) groups (p=0.639). Mean VCTE was also comparable in lean NAFLD (8.18+2.23) and non-lean NAFLD (7.74+2.54), (p=0.162). Both HC and WC had poor correlation with VCTE. Mean WHR had a moderately strong correlation with VCTE in non-lean NAFLD (r=0.326) and a weak correlation in lean NAFLD (r=0.169). On univariate linear regression, the relationship between WHR and VCTE was significant in non-lean NAFLD (Î2=5.226, p=0.002), but not in lean NAFLD (Î2=2.665, p=0.064). Conclusions: High WHR has significant correlation with liver fibrosis in non-lean NAFLD, but not in lean NAFLD. Individually, WC and HC do not correlate significantly with VCTE.