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    Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999-2016. Zou B,Yeo Y H,Nguyen V H,Cheung R,Ingelsson E,Nguyen M H Journal of internal medicine BACKGROUND:Updated prevalence and outcome data for nonobese NAFLD for the multi-ethnic US population is limited. OBJECTIVES:We aimed to investigate the prevalence, clinical characteristics and mortality of obese and nonobese individuals with NAFLD in the United Sates. METHODS:A retrospective study was conducted using the 1999-2016 NHANES databases. We determined hazard ratio stratified by obesity status in NAFLD individuals using Cox regression and log-rank test. RESULTS:Overall NAFLD prevalence was 32.3%: 22.7% were obese and 9.6% were nonobese, with increasing trend over time for obese NAFLD, but not nonobese NAFLD. Amongst those with NAFLD, 29.7% (95% CI: 27.8%-31.7%) were nonobese, of which 13.6% had lean NAFLD. Nonobese NAFLD was more common in older (40.9% if ≥ 65 vs. 24.2% if < 65 years), male (34.0% vs. 24.2%) and foreign-born Asian people (39.8% vs. 11.4%) and uncommon in black (11.5% vs 30-35% in other ethnicities, P < 0.001). Metabolic comorbidities were common in nonobese NAFLD individuals who also had more advanced fibrosis. Nonobese NAFLD individuals had higher 15-year cumulative all-cause mortality (51.7%) than obese NAFLD (27.2%) and non-NAFLD (20.7%) (P < 0.001). However, DM and fibrosis, but neither obese nor nonobese NAFLD compared to non-NAFLD was independently associated with higher mortality. CONCLUSION:Nonobese NAFLD makes up about one-third of the NAFLD in the United States (even higher in older, male and foreign-born individuals) and carries higher mortality than obese NAFLD. Screening for NAFLD should be considered in high-risk groups even in the absence of obesity. 10.1111/joim.13069
    Distinctive clinical and genetic features of lean vs overweight fatty liver disease using the UK Biobank. Hepatology international BACKGROUND:Lean NAFLD may differ from NAFLD found in overweight or obese patients. We used the UK biobank to conduct a cross-sectional study that examined features that distinguish lean NAFLD from overweight or obese NAFLD. METHODS:MRI-PDFF data were used to identify patients with NAFLD, with NAFLD defined as PDFF ≥ 5%. BMI patient cohorts were identified, with lean defined as a BMI < 25, and overweight or obese defined as a BMI ≥ 25. Variables of interest to fatty liver disease, including single nucleotide polymorphisms, were chosen from the UK biobank data portal. Logistic regression was used to generate models predictive of NAFLD in each cohort. RESULTS:1007 patients had NAFLD, and of these, 871 had BMI ≥ 25, and 136 BMI < 25. Factors associated with NAFLD in patients with BMI < 25 included male sex, white blood cell count, red blood cell count, triglycerides, ALT, creatinine, visceral adipose tissue, rs58542926 T, and rs738409 G. In contrast, factors associated with NAFLD in patients with BMI ≥ 25 included male sex, waist circumference, HDL cholesterol, triglycerides, serum glucose, ALT, creatinine, urate, visceral adipose tissue, rs1260326 T, rs1044498 C, rs58542926 T, and rs738409 G. For lean patients, our generated prediction score had an AUC of 0.92, sensitivity of 0.90 and specificity of 0.81. For overweight or obese patients, the prediction score had an AUC of 0.86, sensitivity of 0.87 and specificity of 0.70. CONCLUSIONS:Our analysis suggests that lean and overweight or obese NAFLD are distinct entities. We have developed a risk score incorporating both clinical and genetic factors that accurately classify lean patients with NAFLD, with the potential to serve as a tool for screening purposes. 10.1007/s12072-022-10304-z
    Laboratory parameters in lean NAFLD: comparison of subjects with lean NAFLD with obese subjects without hepatic steatosis. Bernhardt Philipp,Kratzer Wolfgang,Schmidberger Julian,Graeter Tilmann,Gruener Beate, BMC research notes OBJECTIVE:Search for meaningful laboratory and anthropometric parameters in lean non-alcoholic fatty liver disease (lean NAFLD) in the general population. Out of 2445 subjects in a random population sample, we compared those who had a body mass index (BMI) < 25 and a fatty liver [lean NAFLD (LN), n = 5] with obese subjects who had a BMI > 30 but no fatty liver [non-NAFLD (NN), n = 27] in a follow-up examination. Ultrasonic, anthropometric and laboratory parameters were collected. RESULTS:There were significant differences (p < 0.05) between the LN and the NN groups with respect to serum ferritin (199.2 ± 72.1 LN vs 106.0 ± 89.6 NN), haemoglobin (14.9 ± 0.8 LN vs 13.5 ± 1.2 NN), haematocrit (0.438 ± 0.019 LN vs 0.407 ± 0.035 NN) and Mean corpuscular haemoglobin concentration (34 ± 0.6 LN vs 33.2 ± 0.8 NN). Significantly lower values of soluble transferrin receptor were measured in the LN group (2.8 ± 0.4 LN vs 3.8 ± 1.5 NN). In both groups, the measured HOMA-IR index (homeostatic model assessment of insulin resistance index) (2.3; normal range ≤ 1) was abnormal. Mean cholesterol (6.2 ± 1.4 LN and 5.6 ± 1.1 NN) and low-density lipoprotein levels (3.8 ± 1.0 LN 3.4 ± 0.9 NN) were above the upper limit of normal in both groups, as was the mean triglycerides level in the LN group (2.6 ± 2.0). In summary, there are differences in parameters of iron and fat metabolism between subjects with LN and overweight subjects without fatty liver infiltration. 10.1186/s13104-018-3212-1
    Metabolic (dysfunction)-associated fatty liver disease in individuals of normal weight. Nature reviews. Gastroenterology & hepatology Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects up to a third of the global population; its burden has grown in parallel with rising rates of type 2 diabetes mellitus and obesity. MAFLD increases the risk of end-stage liver disease, hepatocellular carcinoma, death and liver transplantation and has extrahepatic consequences, including cardiometabolic disease and cancers. Although typically associated with obesity, there is accumulating evidence that not all people with overweight or obesity develop fatty liver disease. On the other hand, a considerable proportion of patients with MAFLD are of normal weight, indicating the importance of metabolic health in the pathogenesis of the disease regardless of body mass index. The clinical profile, natural history and pathophysiology of patients with so-called lean MAFLD are not well characterized. In this Review, we provide epidemiological data on this group of patients and consider overall metabolic health and metabolic adaptation as a framework to best explain the pathogenesis of MAFLD and its heterogeneity in individuals of normal weight and in those who are above normal weight. This framework provides a conceptual schema for interrogating the MAFLD phenotype in individuals of normal weight that can translate to novel approaches for diagnosis and patient care. 10.1038/s41575-022-00635-5
    Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease. Gastroenterology BACKGROUND AND AIMS:Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. METHODS:Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. RESULTS:Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. CONCLUSIONS:Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262). 10.1053/j.gastro.2021.05.008
    The metabolic profiles and body composition of lean metabolic associated fatty liver disease. Cheng Yu-Ming,Kao Jia-Horng,Wang Chia-Chi Hepatology international BACKGROUND/PURPOSE:Metabolic associated fatty liver disease (MAFLD) is the commonest cause of chronic liver disease, which is associated with obesity and diabetes. However, it also occurs in lean individuals especially in Asian populations. METHODS:The participants of Tzu Chi MAFLD cohort (TCMC) including health controls or MAFLD patients were enrolled. MAFLD was defined as fatty liver in imaging without hepatitis B virus, hepatitis C virus infection, drug, alcohol or other known causes of chronic liver disease. Lean MAFLD was defined as MAFLD in lean subjects (BMI < 23 kg/m). RESULTS:A total of 880 subjects were included for final analysis. Of 394 MAFLD patients, 65 (16.5%) patients were diagnosed as lean MAFLD. Lean MAFLD patients were elder, higher percentage of female gender, lower ALT, diastolic blood pressure, triglyceride, and waist circumference but higher HDL than non-lean MAFLD patients. Using binary regression analysis, elder age and lower waist circumference were associated with lean MAFLD. Compared with lean healthy controls, lean MAFLD patients had higher BMI, waist circumference, and percentage of hypertension. In body composition, fatty tissue index (FTI), lean tissue index (LTI) ,and total body water (TBW) were lower in lean MAFLD than non-lean MAFLD patients; but they were comparable with lean healthy controls. CONCLUSIONS:The prevalence of lean MAFLD was 16.5% in this study population and it was higher in elder age, especially of female subjects. Lean MAFLD patients had different metabolic profiles compared with lean healthy controls, but different body composition compared with non-lean MAFLD patients. 10.1007/s12072-021-10147-0
    Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis. Sumida Yoshio,Yoneda Masashi,Tokushige Katsutoshi,Kawanaka Miwa,Fujii Hideki,Yoneda Masato,Imajo Kento,Takahashi Hirokazu,Eguchi Yuichiro,Ono Masafumi,Nozaki Yuichi,Hyogo Hideyuki,Koseki Masahiro,Yoshida Yuichi,Kawaguchi Takumi,Kamada Yoshihiro,Okanoue Takeshi,Nakajima Atsushi,Jsg-Nafld Japan Study Group Of Nafld International journal of molecular sciences Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D. 10.3390/ijms21061907
    NAFLD in normal weight individuals. Diabetology & metabolic syndrome Nonalcoholic fatty liver disease (NAFLD) can develop in lean individuals. Despite a better metabolic profile, the risk of disease progression to hepatic inflammation, fibrosis, and decompensated cirrhosis in the lean is similar to that in obesity-related NAFLD and lean individuals may experience more severe hepatic consequences and higher mortality relative to those with a higher body mass index (BMI). In the absence of early symptoms and abnormal laboratory findings, lean individuals are not likely to be screened for NAFLD or related comorbidities; however, given the progressive nature of the disease and the increased risk of morbidity and mortality, a clearer understanding of the natural history of NAFLD in lean individuals, as well as efforts to raise awareness of the potential health risks of NAFLD in lean individuals, are warranted. In this review, we summarize available data on NAFLD prevalence, clinical characteristics, outcomes, and mortality in lean individuals and discuss factors that may contribute to the development of NAFLD in this population, including links between dietary and genetic factors, menopausal status, and ethnicity. We also highlight the need for greater representation of lean individuals in NAFLD-related clinical trials, as well as more studies to better characterize lean NAFLD, develop improved screening algorithms, and determine specific treatment strategies based on underlying etiology. 10.1186/s13098-022-00814-z
    Presence of sarcopenia identifies a special group of lean NAFLD in middle-aged and older people. Hepatology international BACKGROUND: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. METHODS: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/height). We comprehensively analyzed the metabolic phenotype, carotid artery condition, liver fibrosis score, and serum metabolomic profile of each participant. RESULTS: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. CONCLUSION:The presence of sarcopenia identifies a special subgroup of lean NAFLD with increased risk of cardiovascular disease and liver fibrosis clinically. 10.1007/s12072-022-10439-z
    What are the clinical settings and outcomes of lean NAFLD? Ren Tian-Yi,Fan Jian-Gao Nature reviews. Gastroenterology & hepatology 10.1038/s41575-021-00433-5
    AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review. Gastroenterology DESCRIPTION:Nonalcoholic fatty liver disease (NAFLD) is well recognized as a leading etiology for chronic liver disease, affecting >25% of the US and global populations. Up to 1 in 4 individuals with NAFLD have nonalcoholic steatohepatitis, which is associated with significant morbidity and mortality due to complications of liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although NAFLD is observed predominantly in persons with obesity and/or type 2 diabetes mellitus, an estimated 7%-20% of individuals with NAFLD have lean body habitus. Limited guidance is available to clinicians on appropriate clinical evaluation in lean individuals with NAFLD, such as for inherited/genetic disorders, lipodystrophy, drug-induced NAFLD, and inflammatory disorders. Emerging data now provide more robust evidence to define the epidemiology, natural history, prognosis, and mortality of lean individuals with NAFLD. Multiple studies have found that NAFLD among lean individuals is associated with increased cardiovascular, liver, and all-cause mortality relative to those without NAFLD. This American Gastroenterological Association Clinical Practice Update provides Best Practice Advice to assist clinicians in evidence-based approaches to the diagnosis, staging, and management of NAFLD in lean individuals. METHODS:This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Lean NAFLD should be diagnosed in individuals with NAFLD and body mass index <25 kg/m (non-Asian race) or body mass index <23 kg/m (Asian race). BEST PRACTICE ADVICE 2: Lean individuals with NAFLD should be evaluated routinely for comorbid conditions, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. BEST PRACTICE ADVICE 3: Lean individuals with NAFLD should be risk stratified for hepatic fibrosis to identify those with advanced fibrosis or cirrhosis. BEST PRACTICE ADVICE 4: Lean individuals in the general population should not undergo routine screening for NAFLD; however, screening should be considered for individuals older than 40 years with type 2 diabetes mellitus. BEST PRACTICE ADVICE 5: NAFLD should be considered in lean individuals with metabolic diseases (such as type 2 diabetes mellitus, dyslipidemia, and hypertension), elevated liver biochemical tests, or incidentally noted hepatic steatosis. BEST PRACTICE ADVICE 6: Clinicians should query patients routinely regarding alcohol consumption patterns in all patients with lean NAFLD. BEST PRACTICE ADVICE 7: In patients with lean NAFLD, other causes of liver disease should be ruled out, including other causes of fatty liver, such as HIV, lipodystrophy, lysosomal acid lipase deficiency, familial hypobetalipoproteinemia, and medication-induced hepatic steatosis (methotrexate, amiodarone, tamoxifen, and steroids). BEST PRACTICE ADVICE 8: Current evidence is inadequate to support routine testing for genetic variants in patients with lean NAFLD. BEST PRACTICE ADVICE 9: Liver biopsy, as the reference standard, should be considered if there is uncertainty regarding contributing causes of liver injury and/or the stage of liver fibrosis. BEST PRACTICE ADVICE 10: Serum indices (NAFLD fibrosis score and Fibrosis-4 score) and imaging techniques (transient elastography and magnetic resonance elastography) may be used as alternatives to liver biopsy for fibrosis staging and patient follow-up. These tests can be performed at the time of diagnosis and repeated at intervals of 6 months to 2 years, depending on fibrosis stage and the patient's response to intervention. BEST PRACTICE ADVICE 11: If noninvasive tests (eg, Fibrosis-4 and NAFLD fibrosis score) are indeterminate, a second noninvasive test (eg, transient elastography or magnetic resonance elastography) should be performed to confirm the stage and prognosis of NAFLD. BEST PRACTICE ADVICE 12: In lean patients with NAFLD, lifestyle intervention, including exercise, diet modification, and avoidance of fructose- and sugar-sweetened drinks, to target a modest weight loss of 3%-5% is suggested. BEST PRACTICE ADVICE 13: Administration of vitamin E may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis, but without type 2 diabetes mellitus or cirrhosis. Oral pioglitazone 30 mg daily may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis without cirrhosis. BEST PRACTICE ADVICE 14: The therapeutic role of glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors in the management of lean NAFLD is not fully defined and requires further investigation. BEST PRACTICE ADVICE 15: Hepatocellular carcinoma surveillance with abdominal ultrasound with or without serum α-fetoprotein twice per year is suggested in patients with lean NAFLD and clinical markers compatible with liver cirrhosis. 10.1053/j.gastro.2022.06.023
    NAFLD in lean individuals: not a benign disease. Gut 10.1136/gutjnl-2021-324162
    Emerging Role of Genomic Analysis in Clinical Evaluation of Lean Individuals With NAFLD. Hepatology (Baltimore, Md.) 10.1002/hep.32047