BACKGROUNDAlterations in circulating metabolites have been described in obese metabolic dysfunction-associated steatotic liver disease (MASLD), but data on lean MASLD are lacking. We investigated serum metabolites, including microbial bile acids and short-chain fatty acids (SCFAs), and their association with lean and obese MASLD.METHODSSerum samples from 204 people of European descent were allocated to groups: lean healthy, lean MASLD, obese healthy, and obese MASLD (n = 47). Liquid chromatography-mass spectrometry-based metabolomics and linear model analysis were performed. MASLD prediction was assessed based on least absolute shrinkage and selection operator regression. Functional effects of altered molecules were verified in organotypic 3D primary human liver cultures.RESULTSLean MASLD was characterized by elevated isobutyrate, methionine sulfoxide, propionate, and phosphatidylcholines. Patients with obese MASLD had increased sarcosine and decreased lysine and asymmetric dimethylarginine. Using metabolites, sex, and BMI, MASLD versus healthy could be predicted with a median AUC of 86.5% and 85.6% in the lean and obese subgroups, respectively. Functional experiments in organotypic 3D primary human liver cultures showed propionate and isobutyrate induced lipid accumulation and altered expression of genes involved in lipid and glucose metabolism.CONCLUSIONLean MASLD is characterized by a distinct metabolite pattern related to amino acid metabolism, lipids, and SCFAs, while metabolic pathways of lipid accumulation are differentially activated by microbial metabolites. We highlight an important role of microbial metabolites in MASLD, with implications for predictive and mechanistic assessment of liver disease across weight categories.FUNDINGRobert Bosch Stiftung, Swedish Research Council (2021-02801, 2023-03015, 2024-03401), ERC Consolidator Grant 3DMASH (101170408), Ruth and Richard Julin Foundation for Gastroenterology (2021-00158), SciLifeLab and Wallenberg National Program for Data-Driven Life Science (WASPDDLS22:006), Novo Nordisk Foundation (NNF23OC0085944, NNF23OC0084420), PMU-FFF (E-18/28/148-FEL).

Metabolic-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, is prevalent worldwide and is highly associated with cardiovascular disease (CVD). Lean MASLD is defined by hepatic steatosis and cardiometabolic risk factors in individuals with a body mass index below 25 in Western populations or below 23 in Asian populations. Paradoxically, some studies indicate that lean MASLD is associated with an elevated risk of cardiovascular (CV) disease and CV mortality compared with nonlean MASLD. Lean MASLD patients exhibit distinctive metabolic, genetic, and microbiome profiles contributing to increased visceral adiposity, sarcopenia, hepatic fibrosis, systemic inflammation, and endothelial dysfunction. This review examines the epidemiology, pathophysiology, and CV outcomes associated with lean MASLD, addressing discrepancies in the literature. Furthermore, it highlights current clinical guidelines, emphasizes lifestyle modifications, and discusses emerging pharmacotherapies as potential treatment options.

The present work aimed to examine the primary mechanisms of liver damage, namely the impact of gut-derived endotoxins along the gut-liver axis and adipose-derived free fatty acids along the adipose-liver axis. These processes are known to play a significant role in the development of hepatic inflammation and steatosis. Although possible overlapping in the pathogenesis was expected, these processes have unique pathophysiological consequences. Therefore, we used HepG2 cells as a model system to investigate the impact of lipopolysaccharides (LPS) and free fatty acid (FFA; albumin conjugated palmitic acid) on the intracellular metabolome. Although both LPS and FFA triggered the expression of nuclear factor κB (NFκB)-dependent inflammation, only LPS treatment was able to trigger a Toll-like receptor 4 (TLR4) dependent response. The intracellular cytoprotective enzymatic levels (catalase, peroxidase, glutathione) were increased due to FFA but lowered due to LPS. The free-radical neutralizing efficacies of cell-free metabolites of FFA-treated cells were better than those of the LPS-treated ones. The use of untargeted metabolomics allowed for the identification of distinct metabolic pathway enrichments, providing further insights into the differential effects of LPS and FFA on the metabolism of hepatocytes. Collectively, the current study highlights the distinct impacts of endotoxemia and lipotoxicity on the metabolome of hepatocytes, hence offering valuable insights into hepatocellular function.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

As the rates of obesity and type 2 diabetes (T2D) continue to increase globally, so does the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Currently, 38% of all adults and 7-14% of children and adolescents have MASLD. By 2040, the MASLD prevalence rate for adults is projected to increase to more than 55%. Although MASLD does not always develop into progressive liver disease, it has become the top indication for liver transplant in the United States for women and those with hepatocellular carcinoma (HCC). Nonetheless, the most common cause of mortality among patients with MASLD remains cardiovascular disease. In addition to liver outcomes (cirrhosis and HCC), MASLD is associated with an increased risk of developing de novo T2D, chronic kidney disease, sarcopenia, and extrahepatic cancers. Furthermore, MASLD is associated with decreased health-related quality of life, decreased work productivity, fatigue, increased healthcare resource utilization, and a substantial economic burden. Similar to other metabolic diseases, lifestyle interventions such as a heathy diet and increased physical activity remain the cornerstone of managing these patients. Although several obesity and T2D drugs are available to treat co-morbid disease, resmetirom is the only MASH-targeted medication for patients with stage 2-3 fibrosis that has approved by the Food and Drug Administration for use in the United States. This review discusses MASLD epidemiology and its related risk factors and outcomes and demonstrates that without further global initiatives, MASLD incidence could continue to increase.

The prevalence, health and socioeconomic burden of metabolic dysfunction-associated fatty liver disease (MAFLD) is growing, increasing the need for novel evidence-based lifestyle approaches. Lifestyle is the cornerstone for MAFLD management and co-existing cardiometabolic dysfunction. The aim of this review was to evaluate the evidence for lifestyle management of MAFLD, with a specific lens on 24-hour integrated behaviour and provide practical recommendations for implementation of the evidence.

Weight loss ≥ 7-10% is central to lifestyle management; however, liver and cardiometabolic benefits are attainable with improved diet quality and exercise even without weight loss. Lifestyle intervention for MAFLD should consider an integrated '24-h' approach that is cognisant of diet, physical activity/exercise, sedentary behavior, smoking, alcohol intake and sleep. Dietary management emphasises energy deficit and improved diet quality, especially the Mediterranean diet, although sociocultural adaptations to meet preferences should be considered. Increasing physical activity and reducing sedentary behavior can prevent MAFLD, with strongest evidence in MAFLD supporting regular structured moderate-vigorous aerobic exercise for 150-240 min/week. Resistance training in addition to aerobic exercise should be considered and prioritised for those who are losing body mass via diet and/or pharmacological approaches and those with sarcopenia, to minimise bone and lean mass loss. Limited evidence suggests that sleep is important for MAFLD prevention. Emerging novel approaches to diet and exercise may address some of the key barriers to behaviour change (e.g. lack of time, access to resources and social support).

Large-scale multidisciplinary trials in people with MAFLD with long-term follow-up, that can be scaled up into mainstream healthcare, are required. Future management guidelines should consider the heterogeneity of MAFLD and specialised models of care that coordinate the health workforce to manage the increased and growing MAFLD population.

Plasma bile acid (BA) has been widely studied as pathophysiological factors in chronic liver disease. But the changes of plasma BA level in lean metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. Here, we clarified the BA metabolic characteristics of lean MAFLD and explored its significance and mechanism as a marker.

We employed ultra-performance liquid chromatography tandem mass spectrometry based on BA metabonomics to characterize circulating bile acid in lean MAFLD patients. Explore its significance as serum biomarkers by further cluster analysis, functional enrichment analysis, and serum concentration change analysis of differential BAs. Evaluation of diagnostic value of differential BAs by ROC analysis.

A total of 65 BAs were detected and 17 BAs were identified which showed different expression in the lean-MAFLD group compared with the normal group. Functional annotation and enrichment analysis of KEGG and HMDB showed that differential BAs were mainly related to bile acid biosynthesis, bile secretion, cholesterol metabolism, and familial hypercholangitis, involving diseases including but not limited to cirrhosis, hepatocellular carcinoma, chronic active hepatitis, colorectal cancer, acute liver failure, and portal vein obstruction. ROC analysis displayed that the 6 BA metabolites (GCDCA-3S, GUDCA-3S, CDCA-3S, NCA, TCDCA, and HDCA) exhibited well differential diagnostic ability in discriminating between lean MAFLD patients and normal individuals with an area under the curve (AUC) ⩾0.85.

We delineated the characteristics of BA level in patients with lean MAFLD, and identified 6 potential plasma BA biomarkers of lean MAFLD.

Approximately 10-20% of individuals with non-alcoholic fatty liver disease (NAFLD) are lean, and the underlying pathophysiology is not yet understood. This study aims to explore the characteristics and the diagnostic value of triglyceride-glucose index (TyG) in early diagnosis of lean NAFLD.

99 patients with lean NAFLD and 1891 healthy controls were included in the health examination. The characteristics were compared between groups. Restricted cubic spline was utilized to analyze the relationship between TyG index and the risk of lean NAFLD. Logistic regression and receiver operating curve (ROC) were applied to explore the diagnostic value of TyG index for lean NAFLD.

Overall, 99 (4.97%) patients had lean NAFLD. Patients with lean NAFLD have significant abnormal glycolipid metabolism and higher TyG index. Restriction cube spline analysis showed a significant dose-response relationship between the TyG index and risk of lean NAFLD. After adjusting for confounders, the relationship remained and the risk of developing lean NAFLD increased 2.99 times for per unit increase of TyG index (95% CI: 1.94, 4.67, P<0.001). The areas under the ROC of the TyG index for lean NAFLD detection were 0.851 (0.815 to 0.886).

The TyG index is positively associated with the risk of developing lean NAFLD and could be a useful marker for early diagnosis of lean NAFLD.

There is an international consensus among experts advocating for the classification of fatty liver disease as a metabolic condition. However, some authors have raised concerns that this metabolic-centric framing may result in the underdiagnosis of metabolicdysfunction-associated steatotic liver disease (MASLD) in lean individuals. The present study was carried out with the objective of describing metabolic characteristics in MASLD and the prevalence of lean MASLD in the general population.

We carried out a hospital-based cross-sectional study. A pre-tested proforma was used to collect data on socio-demographic factors, lifestyle factors, and medical history. Transient elastography and blood investigations were carried out in all patients. The identification of independent predictors for MASLD and liver fibrosis was carried out using multivariable logistic regression. A test of interaction was conducted for studying effect modification in the association of diabetes and MASLD by subgroups of body mass index (BMI).

A total of 1,243 participants were interviewed and screened for MASLD. The overall prevalence of MASLD was 43.7% (n = 543), with the prevalence of lean MASLD being 4.3% (n = 53). The prevalence of MASLD in lean vs non-lean subjects differed (21.3 vs 66.7%, p < 0.001). Of the total MASLD cases, lean MASLD constituted 9.7% of cases. The association of diabetes and MASLD did not differ in subgroups by BMI. The test for interaction to detect effect modification was not statistically significant (p = 0.673).

The results support laying emphasis on metabolic dysfunction as a key criterion when defining fatty liver disease. The findings emphasize the shared metabolic underpinnings between lean and non-lean MASLD and advocate for inclusive approaches in diagnosis, management, and public health initiatives.

Prasad M, Bhardwaj N, Gupta E, et al. Prevalence and Predictors for Lean Fatty Liver Disease in General Population Attending a COVID-19 Vaccination Center in a Tertiary Care Hospital in India. Euroasian J Hepato-Gastroenterol 2024;14(2):145-150.

Fat accumulation in the liver is affecting 38% of the global population. It can also occur in normal-weight individuals, termed lean non-alcoholic fatty liver disease (NAFLD). This study examines Asian and Western body mass index (BMI) criteria, as well as metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) diagnostic guidelines, in lean fatty liver cases within a healthcare setting.

This study was cross-sectional included 111 lean patients diagnosed with NAFLD using either ultrasound or VCTE from January 2023 to March 2024. Anthropometric, laboratory and non-invasive liver fibrosis evaluation parameters were used. The study assessed clinical characteristics and metabolic risk factors of patients with BMI ≤ 23 kg/m2 and BMI between 23 and ≤ 25 kg/m2 using MASLD and MAFLD diagnostic criteria.

The cohort included NAFLD patients with a mean age of 43.3 years (±13.2 years). Of the participants, 33% were diagnosed through ultrasonography, whereas 67% diagnosis were made via Fibro scan. Majority were male 92 (83%), while females were 19 (17%) of the entire group. The lean NAFLD criteria for Asia and the West were satisfied by 43 (39%) persons with a BMI ≤ 23 kg/m2 and 68 (61%) individuals with a BMI between 23 and ≤ 25 kg/m2, respectively. The average body mass index (BMI) was 23.0 ± 1.5 kg/m2. Diabetes was observed in 16%, hypertension 11%, and ischemic heart disease in 2%. Out of the total individuals, 92 satisfied the MASLD-MAFLD criteria, whereas 18 did not qualify the MAFLD criteria for diagnosis and were classed as MASLD-Alone. Elevated triglycerides, insulin resistance (HOMA-IR ≥ 2), and three or more cardiometabolic risk factors (CMRF) were significant in the MASLD-MAFLD group compared to the MASLD-Alone group (p < 0.05). Comparing BMI criteria, no significant differences were found in terms of fibrosis between the Western and Asian lean NAFLD BMI criteria's (p = 0.243).

Lean NAFLD is a major global health concern. Applying non-Asian BMI criteria (BMI ≤ 25 kg/m2) for lean Asians improves early detection and intervention for at-risk individuals. Accurate use of MAFLD and MASLD criteria is essential to prevent confusion in diagnosing lean NAFLD. Further multicenter investigations with larger sample numbers are required to corroborate these results in our community.

Nazir S, Abbas Z, Gazder DP, et al. Characterizing Nonalcoholic Fatty Liver Disease (NAFLD) in Lean Individuals at a Tertiary Care Hospital: A Cross-sectional Study. Euroasian J Hepato-Gastroenterol 2024;14(2):198-204.

In this editorial, we commented on a recently released manuscript by Zeng et al in the World Journal of Gastroenterology. We focused specifically on lifestyle changes in patients with non-alcoholic fatty liver disease (NAFLD). NAFLD is a hepatic manifestation of the metabolic syndrome, which ultimately leads to advanced hepatic fibrosis, cirrhosis, and hepatocellular carcinoma and affects more than 25% of the population globally. Existing therapeutic strategies against NAFLD such as pharmacologic therapies focus on liver protection, anti-inflammation, and regulating disease-related metabolic disorder symptoms. Although several drugs are in late-stage development, potent drugs against the diseases are lacking. Additionally, existing surgical approaches such as bariatric surgery are not routinely used to treat NAFLD. Intervening in patients' unhealthy lifestyles, such as weight loss through dietary changes and exercises to ameliorate patient-associated metabolic disorders and metabolic syndrome, is the first-line treatment for patients with NAFLD. With sufficient intrinsic motivation and adherence, the management of unhealthy lifestyles can reduce the severity of the disease, improve the quality of life, and increase the survival expectancy of patients with NAFLD.

The metabolically-based liver disease, nonalcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease currently affecting 38% of the world's adult population. NAFLD can be progressive leading to nonalcoholic steatohepatitis (NASH), liver transplantation, liver cancer, liver-related mortality and is associated with decreased quality of life from impaired physical functioning and increased healthcare resource utilisation. However, screening for NAFLD is cost-prohibitive but screening for high risk NAFLD (NAFLD with F2 fibrosis or greater) is imperative.

To review the global perspective on NAFLD and NASH METHODS: We retrieved articles from PubMed using search terms NAFLD, prevalence, clinical burden, economic burden and management strategies.

NAFLD/NASH shows geographical variation across the globe. Highest prevalence rates are in South America and the Middle East and North Africa; lowest prevalence is in Africa. NAFLD's economic impact is from direct and indirect medical costs and loss in worker productivity. It is projected that, over the next two decades, the total cost of NAFLD and diabetes will exceed $1.5 trillion (USD). Risk stratification algorithms identifying "high risk NAFLD" were made following non-invasive tests for NAFLD identification and fibrosis development. These algorithms should be used in primary care and endocrinology settings so timely and appropriate interventions (lifestyle and cardiometabolic risk factor management) can be initiated.

To reduce the burgeoning burden of NAFLD/NASH, management should include risk stratification algorithms for accurate identification of patients, linkage to appropriate settings, and initiation of effective treatment regimens.

Introduction: Tuberous sclerosis complex (TSC) is a genetic disease caused by pathogenetic variants in either the TSC1 or TSC2 genes. Consequently, the mechanistic target of the rapamycin complex 1 (mTORC1) pathway, a regulator of cell growth, metabolism, and survival, becomes inappropriately activated, leading to the development of benign tumors in multiple organs. The role of mTORC1 in lipid metabolism and liver steatosis in TSC patients has not been well-studied, and clinical data on liver involvement in this population are scarce. Methods: We conducted a retrospective, cross-sectional study to compare liver steatosis in TSC patients with age-, sex-, BMI-, and diabetes status-matched controls. Participants with a definite diagnosis of TSC were recruited from the TSC clinic at UZ Brussel. Liver steatosis was quantified using the fat signal fraction from in-phase and out-of-phase MRI, with a threshold of ≥5% defining the presence of steatosis. We also evaluated the prevalence of liver angiomyolipomata in the TSC group and analyzed risk factors for both liver steatosis and angiomyolipomata. Results: The study included 59 TSC patients and 59 matched controls. The mean fat signal fraction was 4.0% in the TSC group and 3.9% in the controls, showing no significant difference (two-tailed Wilcoxon signed ranks test, p = 0.950). Liver steatosis was observed in 15.3% of TSC patients compared to 23.7% of the controls, which was not statistically significant (two-tailed McNemar test, p = 0.267). Liver angiomyolipomata were identified in 13.6% of the TSC cohort. Conclusions: Our study, describing in detail the liver phenotype of TSC patients, did not reveal a significant difference in the prevalence of MRI-assessed liver steatosis in a large cohort of TSC patients compared to a closely matched control group.

The prevalence of metabolic-associated fatty liver disease (MAFLD) has increased substantially in recent years because of the global obesity pandemic. MAFLD, now recognized as the number one cause of chronic liver disease in the world, not only increases liver-related morbidity and mortality among sufferers but also worsens the complications associated with other comorbid conditions such as cardiovascular disease, type 2 diabetes mellitus, obstructive sleep apnoea, lipid disorders and sarcopenia. Understanding the interplay between MAFLD and these comorbidities is important to design optimal therapeutic strategies. Sarcopenia can be either part of the disease process that results in MAFLD (e.g., obesity or adiposity) or a consequence of MAFLD, especially in the advanced stages such as fibrosis and cirrhosis. Sarcopenia can also worsen MAFLD by reducing exercise capacity and by the production of various muscle-related chemical factors. Therefore, it is crucial to thoroughly understand how we deal with these diseases, especially when they coexist. We explore the pathobiological interlinks between MAFLD and sarcopenia in this comprehensive clinical update review article and propose evidence-based therapeutic strategies to enhance patient care.

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.

Nonalcoholic fatty liver disease, renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of chronic liver disease with an estimated worldwide prevalence of 30.1% while clinical practice observations reflect a disproportionately lower prevalence of 1.9%, indicating a condition that is underrecognized in clinical care settings. Screening for MASLD is rarely performed, and little is known about the prevalence in Hawai'i.

This pilot aims to develop an understanding of the prevalence and factors associated with MASLD in Hawai'i's adolescent and young adult (AYA) population.

Cross-sectional observational pilot study: We used Fibroscan®-liver ultrasonographic vibration-controlled transient elastography (VCTE) to identify MASLD based on controlled attenuation parameter (CAP) scores ≥238 (dB/m) and collected biometric, anthropometric, and Beverage Intake Questionnaire (sugar-sweetened beverage) survey data.

The study took place at community clinics in Hawai'i on the island of O'ahu.

One hundred individuals were evaluated, age 14 to 34 years.

We used VCTE Fibroscan® with CAP scoring to identify the presence of hepatocyte steatosis (fatty liver).

Overall MASLD prevalence in the sample was 44% (95% confidence interval: 34.1%-54.3%). In participants with MASLD, obese Native Hawaiian and other Pacific Islanders (62%) and nonobese Asians (43%) had the highest rates of MASLD.

This pilot evaluation of the AYA NHOPI and Asian MASLD population in Hawai'i shows a higher rate of MASLD than those reported in other parts of the United States. Larger population health studies are indicated to expand our knowledge of MASLD in the Hawaiian Islands.

The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥  - 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients-lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p < 0.0001). Ten phenotypes were significant in the PheWAS, including chronic kidney disease, renal failure, and cardiovascular disease. Hepatic steatosis was found to be associated with cardiovascular, kidney, and metabolic conditions, separate from overweight BMI.

The relationship between obesity and nonalcoholic fatty liver disease (NAFLD) has long been established, and the prevalence of both conditions has grown together. Recent interest in NAFLD in nonobese individuals has led to an increasing number of studies, especially in Asia. Despite the fact that the prevalence of NAFLD in Latin America is one of the highest in the world, there is a lack of information on lean NAFLD populations from the region. The aim of the present study was to assess the risk of metabolic comorbidities across the whole body mass index spectrum when nonalcoholic steatohepatitis (NASH) was first diagnosed in a Latin American population.

A single-center, cross-sectional study on Colombian patients newly diagnosed with NAFLD, within the time frame of 2010-2020, compared their metabolic biochemical profile, liver enzymes, risk of prevalent metabolic abnormalities, and liver disease.

Data from 300 patients were collected. Ninety-two percent of the patients were men and the median patient age was 47 (IQR 20) years. We found no significant differences in the biochemical, metabolic profile, or liver enzyme plasma concentration between lean, overweight, and obese individuals. Obese patients had significantly higher LDL cholesterol, and a higher risk of dyslipidemia (OR 1.86, 95% CI 1.14-3.05). Every 1kg increase in body weight increased the risk of having NASH by 2% (95% CI 2-4).

We evaluated the metabolic risk across the entire body mass index spectrum in a Colombian cohort with NAFLD and presented the characteristics of what we believe is the first Latin American lean NAFLD population to be described.

Remnant cholesterol (remnant-C) mediates the progression of major adverse cardiovascular events. It is unclear whether remnant-C, and particularly cumulative exposure to remnant-C, is associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether remnant-C, not only baseline but cumulative exposure, can be used to independently evaluate the risk of NAFLD.

This study included 1 cohort totaling 21,958 subjects without NAFLD at baseline who underwent at least 2 repeated health checkups and 1 sub-cohort totaling 2,649 subjects restricted to those individuals with at least 4 examinations and no history of NAFLD until Exam 3. Cumulative remnant-C was calculated as a timeweighted model for each examination multiplied by the time between the 2 examinations divided the whole duration. Cox regression models were performed to estimate the association between baseline and cumulative exposure to remnant-C and incident NAFLD.

After multivariable adjustment, compared with the quintile 1 of baseline remnant-C, individuals with higher quintiles demonstrated significantly higher risks for NAFLD (hazard ratio [HR] 1.48, 95%CI 1.31-1.67 for quintile 2; HR 2.07, 95%CI 1.85-2.33 for quintile 3; HR 2.55, 95%CI 2.27-2.88 for quintile 4). Similarly, high cumulative remnant-C quintiles were significantly associated with higher risks for NAFLD (HR 3.43, 95%CI 1.95-6.05 for quintile 2; HR 4.25, 95%CI 2.44-7.40 for quintile 3; HR 6.29, 95%CI 3.59-10.99 for quintile 4), compared with the quintile 1.

Elevated levels of baseline and cumulative remnant-C were independently associated with incident NAFLD. Monitoring immediate levels and longitudinal trends of remnant-C may need to be emphasized in adults as part of NAFLD prevention strategy.

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.

The incidence and remission of nonalcoholic fatty liver disease (NAFLD) are sparsely studied outside Asia.

This prospective study aimed to investigate NAFLD incidence and remission, and their predictors among a general Finnish population.

The applied cohort included 1260 repeatedly studied middle-aged participants with data on liver ultrasound and no excessive alcohol intake. Hepatic steatosis was assessed by liver ultrasound with a 7.2-year study interval. Comprehensive data on health parameters and lifestyle factors were available.

At baseline, 1079 participants did not have NAFLD, and during the study period 198 of them developed NAFLD. Of the 181 participants with NAFLD at baseline, 40 achieved NAFLD remission. Taking multicollinearity into account, key predictors for incident NAFLD were baseline age (odds ratio 1.07; 95% CI, 1.02-1.13; P = .009), waist circumference (WC) (2.77, 1.91-4.01 per 1 SD; P < .001), and triglycerides (2.31, 1.53-3.51 per 1 SD; P < .001) and alanine aminotransferase (ALAT) (1.90, 1.20-3.00 per 1 SD; P = .006) concentrations as well as body mass index (BMI) change (4.12, 3.02-5.63 per 1 SD; P < .001). Predictors of NAFLD remission were baseline aspartate aminotransferase (ASAT) concentration (0.23, 0.08-0.67 per 1 SD; P = .007) and WC change (0.38, 0.25-0.59 per 1 SD; P < .001).

During follow-up, NAFLD developed for every fifth participant without NAFLD at baseline, and one-fifth of those with NAFLD at baseline had achieved NAFLD remission. NAFLD became more prevalent during the follow-up period. From a clinical perspective, key factors predicting NAFLD incidence and remission were BMI and WC change independent of their baseline level.

Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants.

REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis.

Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/μl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence.

In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors.

Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the adult population worldwide. This pathology can progress into end-stage liver disease with life-threatening complications, and yet no pharmacologic therapy has been approved. NAFLD is commonly characterized by excessive fat accumulation in the liver and is in closely associated with insulin resistance and metabolic disorders, which suggests that NAFLD is the hepatic manifestation of metabolic syndrome. Regarding treatment options, the current validated strategy relies on lifestyle modifications (exercise and diet restrictions). Although there are no approved drug-based treatments, several clinical trials are ongoing. Novel targets are being discovered, and the repurposing of drugs that show promising effects in NAFLD is starting to gain more interest. The field of nanotechnology has been growing at an increasing rate, with new and more efficient drug delivery strategies being developed for NAFLD treatment. Nanocarriers can easily encapsulate drugs that need to be better protected from the organism to exert their effect or that need help at reaching their target, thereby helping achieve a better bioavailability. Drug delivery systems can also be designed to target the site of the disease, in this case, the liver. In this review, we focus on the current knowledge of NAFLD pathology, the targets being considered for clinical trials, and the current guidelines and ongoing clinical trials, with a specific focus on potential oral treatments for NAFLD using promising drug delivery strategies.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and type 2 diabetes and independently contributes to long-term complications. Being often asymptomatic but reversible, it would require population-wide screening, but direct diagnostics are either too invasive (liver biopsy), costly (MRI) or depending on the examiner's expertise (ultrasonography). Hepatosteatosis is usually accommodated by features of the metabolic syndrome (e.g. obesity, disturbances in triglyceride and glucose metabolism), and signs of hepatocellular damage, all of which are reflected by biomarkers, which poorly predict NAFLD as single item, but provide a cheap diagnostic alternative when integrated into composite liver fat indices. Fatty liver index, NAFLD LFS, and hepatic steatosis index are common and accurate indices for NAFLD prediction, but show limited accuracy for liver fat quantification. Other indices are rarely used. Hepatic fibrosis scores are commonly used in clinical practice, but their mandatory reflection of fibrotic reorganization, hepatic injury or systemic sequelae reduces sensitivity for the diagnosis of simple steatosis. Diet-induced liver fat changes are poorly reflected by liver fat indices, depending on the intervention and its specific impact of weight loss on NAFLD. This limited validity in longitudinal settings stimulates research for new equations. Adipokines, hepatokines, markers of cellular integrity, genetic variants but also simple and inexpensive routine parameters might be potential components. Currently, liver fat indices lack precision for NAFLD prediction or monitoring in individual patients, but in large cohorts they may substitute nonexistent imaging data and serve as a compound biomarker of metabolic syndrome and its cardiometabolic sequelae.

Nonalcoholic fatty liver disease (NAFLD) represents a significant health threat worldwide. The aging population and a rise in metabolic syndrome in Asia might influence the epidemiology of NAFLD among the elderly. However, there is a lack of understanding of the burden and recommendations for NAFLD in this group. Our study sought to investigate the trends in the NAFLD burden among the elderly in the Asia-Pacific region. We employed data from the Global Burden of Disease 2019 study for an in-depth analysis of the prevalence and disability-adjusted life years (DALYs) along with age-standardized rate (ASR) associated with NAFLD in elderly populations (age 65-89 years) across the Asia-Pacific region, including the Southeast Asia (SEA) and Western Pacific (WP) regions, from 2010 to 2019. This study also examined the trends and disparities in NAFLD burden across different nations and sexes. In 2019, there were over 120 million cases of NAFLD in the elderly in the Asia-Pacific region. The ASR of prevalence was higher in SEA compared to WP (36,995.37 vs. 32,821.78 per 100,000). ASR of prevalence increased with annual percentage change (APC) +0.95% in the WP while it increased by +0.87% in SEA. During the study period, the ASR of DALYs decreased in SEA (APC -0.41%) but remained stable in the WP region. The burden of NAFLD in the elderly population in Asia-Pacific has increased, underscoring the timely intervention to tackle this high and rising burden.

Non-alcoholic fatty liver disease (NAFLD), especially lean NAFLD is associated with an increased risk of atherosclerotic cardiovascular disease (CVD). It is not currently known which clinical phenotypes of NAFLD contribute most to individual subclinical atherosclerosis risk. We examined the relationship between body mass index (BMI), the metabolically healthy status, and subclinical atherosclerosis in the NAFLD population.

Data from asymptomatic NAFLD subjects who participated in a routine health check-up examination were collected. Participants were stratified by BMI (cutoff values: 24.0-27.9 kg/m2 for overweight and ≥28.0 kg/m2 for obesity) and metabolic status, which was defined by Adult Treatment Panel III criteria. Subclinical atherosclerosis was evaluated by brachial-ankle pulse wave velocity (baPWV) in 27,738 participants and by carotid plaque in 14,323 participants.

Within each BMI strata, metabolically unhealthy subjects had a significantly higher prevalence of subclinical atherosclerosis than metabolically healthy subjects, whereas fewer differences were observed across subjects within the same metabolic category. When BMI and metabolic status were assessed together, a metabolically unhealthy status was the main contributor to the association of clinical phenotypes with the subclinical atherosclerosis burden (all p < 0.001). When BMI and metabolic abnormalities were assessed separately, the incidence of subclinical disease did not increase across BMI categories; however, it increased with an increase in the number of metabolic abnormalities (0, 1, 2 and ≥3).

A metabolically healthy status in NAFLD patients was closely correlated with subclinical atherosclerosis, beyond that of the BMI-based obesity phenotype. The application of metabolic phenotyping strategies could enable more precise classification in evaluating cardiovascular risk in NAFLD.

Non-alcoholic fatty liver disease is a sexual dimorphic disease, with adipose tissue playing an essential role. Our previous work showed that female rats fed a high-fat high-fructose diet devoid of cholesterol (HFHFr) developed simple hepatic steatosis dissociated from obesity. This study assessed the impact of the HFHFr diet on the male rat metabolism compared with data obtained for female rats. A total of 16 Sprague Dawley (SD) male rats were fed either a control (standard rodent chow and water) or HFHFr (high-fat diet devoid of cholesterol, plus 10% fructose in drinking water) diet for 3 months. Unlike female rats, and despite similar increases in energy consumption, HFHFr males showed increased adiposity and hyperleptinemia. The expression of hormone-sensitive lipase in the subcutaneous white adipose tissue was enhanced, leading to high free fatty acid and glycerol serum levels. HFHFr males presented hypertriglyceridemia, but not hepatic steatosis, partially due to enhanced liver PPARα-related fatty acid β-oxidation and the VLDL-promoting effect of leptin. In conclusion, the SD rats showed a sex-related dimorphic response to the HFHFr diet. Contrary to previous results for HFHFr female rats, the male rats were able to expand the adipose tissue, increase fatty acid catabolism, or export it as VLDL, avoiding liver lipid deposition.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by fatty lesions and fat accumulation in hepatic parenchymal cells, which is in the absence of excessive alcohol consumption or definite liver damage factors. The exact pathogenesis of NAFLD is not fully understood, but it is now recognized that oxidative stress, insulin resistance, and inflammation are essential mechanisms involved in the development and treatment of NAFLD. NAFLD therapy aims to stop, delay or reverse disease progressions, as well as improve the quality of life and clinical outcomes of patients with NAFLD. Gasotransmitters are produced by enzymatic reactions, regulated through metabolic pathways in vivo, which can freely penetrate cell membranes with specific physiological functions and targets. Three gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide have been discovered. Gasotransmitters exhibit the effects of anti-inflammatory, anti-oxidant, vasodilatory, and cardioprotective agents. Gasotransmitters and their donors can be used as new gas-derived drugs and provide new approaches to the clinical treatment of NAFLD. Gasotransmitters can modulate inflammation, oxidative stress, and numerous signaling pathways to protect against NAFLD. In this paper, we mainly review the status of gasotransmitters research on NAFLD. It provides clinical applications for the future use of exogenous and endogenous gasotransmitters for the treatment of NAFLD.

Nonalcoholic fatty liver disease (NAFLD), the most prominent cause of chronic liver disease worldwide, is a rapidly growing epidemic. It consists of a wide range of liver diseases, from steatosis to nonalcoholic steatohepatitis, and predisposes patients to liver fibrosis, cirrhosis, and even hepatocellular carcinoma. NAFLD is strongly correlated with obesity; however, it has been extensively reported among lean/nonobese individuals in recent years. Although lean patients demonstrate a lower prevalence of diabetes mellitus, central obesity, dyslipidemia, hypertension, and metabolic syndrome, a percentage of these patients may develop steatohepatitis, advanced liver fibrosis, and cardiovascular disease, and have increased all-cause mortality. The pathophysiological mechanisms of lean NAFLD remain vague. Studies have reported that lean NAFLD demonstrates a close association with environmental factors, genetic predisposition, and epigenetic modifications. In this review, we aim to discuss and summarize the epigenetic mechanisms involved in lean NAFLD and to introduce the interaction between epigenetic patterns and genetic or non genetic factors. Several epigenetic mechanisms have been implicated in the regulation of lean NAFLD. These include DNA methylation, histone modifications, and noncoding-RNA-mediated gene regulation. Epigenetics is an area of special interest in the setting of lean NAFLD as it could provide new insights into the therapeutic options and noninvasive biomarkers that target this under-recognized and challenging disorder.

Despite the increasing prevalence of lean nonalcoholic fatty liver disease (NAFLD), its risk factors are not well established. We examined the association between long working hours and incident NAFLD in lean Korean workers with emphasis on sex-based effect modification. This cohort study involved 46,113 non-overweight (BMI < 23 kg/m²) and NAFLD-free Korean workers (mean age, 35.5 years). Working hours were categorized into 35-40 (reference), 41-52, and ≥ 53 h. The presence of fatty liver and its severity were determined using ultrasonography and NAFLD fibrosis score (NFS), respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using parametric proportional hazards models. Incident cases of 5901 lean NAFLD developed over a median follow-up of 3.8 years. The incidence of lean NAFLD increased with increasing working hours with a stronger association in men than in women (P for interaction < 0.001). For men, multivariable-adjusted HRs (95% CIs) for lean NAFLD in time-dependent models comparing working hours of 41-52 and ≥ 53 h compared to the reference category were 1.17 (1.07-1.28) and 1.25 (1.12-1.39), respectively. The excess relative risk of developing lean NAFLD with intermediate/high NFS was observed in working hours of 41-52 and ≥ 53 h with a corresponding HR of 1.66 (1.13-2.43) and 1.54 (0.94-2.51), respectively. Conversely, no significant associations were found between working hours and incidence of lean NAFLD in women. In conclusion, long working hours were significantly associated with an increased incidence of lean NAFLD and its severe form in men but not in women.

We aimed to explore the metabolic features of lean nonalcoholic fatty liver disease (Lean-NAFLD) and its association with the risk of incident type 2 diabetes in young and middle-aged people.

We conducted a retrospective cohort study of 3001 participants who were enrolled in a health check-up program from January 2018 to December 2020 in the Health Management Center of Karamay People's Hospital. The age, sex, height, weight, body mass index (BMI), blood pressure, waist circumference (WC), fasting plasma glucose (FPG), lipid profiles, serum uric acid and alanine aminotransferase (ALT) of the subjects were collected. The cutoff point of BMI for lean nonalcoholic fatty liver disease is <25 kg/m². A COX proportional hazard regression model was used to analyze the risk ratio of lean nonalcoholic fatty liver disease to type 2 diabetes mellitus.

Lean NAFLD participants had many metabolic abnormalities, such as overweight and obesity with nonalcoholic fatty liver disease. Compared with lean participants without nonalcoholic fatty liver disease, the fully adjusted hazard ratio (HR) for lean participants with nonalcoholic fatty liver disease was 3.83 (95% CI 2.02-7.24, p<0.01). In the normal waist circumference group (man<90cm, woman<80 cm), compared with lean participants without NAFLD, the adjusted hazard ratios (HRs) of incident type 2 diabetes for lean participants with NAFLD and overweight or obese participants with NAFLD were 1.93 (95% CI 0.70-5.35, p>0.05) and 4.20 (95% CI 1.44-12.22, p<0.05), respectively. For excess waist circumference (man≥90 cm, woman ≥80 cm) compared with lean participants without NAFLD, the adjusted hazard ratios (HRs) of incident type 2 diabetes for lean participants with NAFLD and overweight or obese participants with NAFLD were 3.88 (95% CI 1.56-9.66, p<0.05) and 3.30 (95% CI 1.52-7.14, p<0.05), respectively.

Abdominal obesity is the strongest risk factor for type 2 diabetes in lean nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity but around 10% to 20% of patients with NAFLD have normal body mass index, a condition referred to as lean or nonobese NAFLD. Although lean patients more often have milder liver disease, a proportion may nonetheless develop steatohepatitis and advanced liver fibrosis. Both genetic and environmental factors contribute to the development of NAFLD. Noninvasive tests have similarly good accuracy as initial assessments for lean NAFLD. Future studies should determine the most appropriate treatment in this special population.

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.

Air pollution is increasingly recognized as an important environmental risk factor for non-alcoholic fatty liver disease (NAFLD). However, epidemiologic evidence on long-term exposure to high air pollution concentrations with incident NAFLD is still very limited. Here, we constructed a population-based dynamic cohort involving 17,106 subjects who were enrolled between 2005 and 2013 and subsequently followed until 2017, combined with a high-resolution ambient fine particulate matter ≤2.5 μm (PM_2.5) dataset, to investigate the association of long-term PM_2.5 exposure (cumulative annual average levels ranged from 36.67 to 111.16 μg/m³) with NAFLD incidence (N = 4,640). We estimated the adjusted hazard ratio (HR) for incident NAFLD among those exposed to the highest quartile of PM_2.5 was 2.04 [95% confidence interval (CI), 1.80-2.30] compared with individuals exposed to the lowest quartile of PM_2.5. The dose-response relationships for PM_2.5 are non-linear for NAFLD across the exposure distribution. Further stratified analyses revealed that lean (<23 kg/m²), younger (<40-year-old), and women individuals appeared more vulnerable to the harmful effects of PM_2.5 exposure. Our study suggests a greater long-term high ambient PM_2.5 exposure is associated with an increased risk of NAFLD in Chinese adults, particularly in specific groups, including lean, women, and younger people.

Liver disease is a leading cause of death in the United States and is often initially detected incidentally on lab tests ordered by general practitioners. Alanine transaminase (ALT), a marker of liver inflammation, is commonly ordered and may be abnormal in the setting of elevated body mass index, diabetes and dyslipidemia. Data regarding ALT testing within vulnerable populations are limited. Therefore, the prevalence of ALT testing and abnormal ALT in the absence of known chronic liver disease (CLD) among a safety-net population were assessed and factors associated with these outcomes were identified.

In this retrospective longitudinal study of 92,997 patients seen between 01/2017-01/2019 within San Francisco's Safety-Net Healthcare System, electronic medical records were used to abstract data back to 04/1997. Descriptive analyses and multivariable modeling were performed.

Overall, 59,323 (69%) without known CLD received an ALT test. Age, Black race, Latinx ethnicity, and metabolic factors were associated with higher odds of ALT testing, (p < 0.01). Among those with an abnormal ALT (44%) without known CLD: median age 53 years, 41% male, 19% White, 11% Black, 40% Latinx, 29% Asian/Pacific Islander (API), and 84% overweight/obese. On multivariable analysis, female sex (OR 2.7), Latinx ethnicity (OR 2.6), API race (OR 1.3), overweight/obesity (OR 1.8, OR 2.6), and dyslipidemia (OR 1.3) were associated with abnormal ALT, (p ≤ 0.001).

In the absence of known CLD, women, Latinx, API and persons with excess body weight were associated with greater odds of abnormal ALT. Future longitudinal studies are needed to confirm these differences and to determine if adequate work up for CLD is performed for abnormal ALT levels among at-risk populations.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and in India. The already high burden of NAFLD in India is expected to further increase in the future in parallel with the ongoing epidemics of obesity and type 2 diabetes mellitus. Given the high prevalence of NAFLD in the community, it is crucial to identify those at risk of progressive liver disease to streamline referral and guide proper management. Existing guidelines on NAFLD by various international societies fail to capture the entire landscape of NAFLD in India and are often difficult to incorporate in clinical practice due to fundamental differences in sociocultural aspects and health infrastructure available in India. A lot of progress has been made in the field of NAFLD in the 7 years since the initial position paper by the Indian National Association for the Study of Liver on NAFLD in 2015. Further, the ongoing debate on the nomenclature of NAFLD is creating undue confusion among clinical practitioners. The ensuing comprehensive review provides consensus-based, guidance statements on the nomenclature, diagnosis, and treatment of NAFLD that are practically implementable in the Indian setting.