Liver histology is the classic method for staging the severity of liver fibrosis, which in turn is an important predictor of clinical outcome. Here, we have hypothesized that the susceptibility to develop fibrosis varies among racial groups.

We examined the histology of all patients over 18 years of age who underwent liver biopsy at the Medical University of South Carolina from 1/1/2013 to 7/1/2021. Patients with malignancy, liver metastases, or missing data were excluded. Fibrosis was quantified using the Batts-Ludwig system (F0 = no fibrosis to F4 = histological cirrhosis). Racial groups were propensity matched based on age, gender, diabetes, alcohol consumption, and CDC/ATSDR Social Vulnerability Index Themes to mitigate the risk of selection bias.

We identified 1101 patients with liver biopsy histological fibrosis scores. The cohort included 23% Black patients. After propensity matching, Black patients were significantly more likely to have Hepatitis C (73/228 (32%) vs 45/228 (20%), p < 0.001) and autoimmune hepatitis (34/228 (15%) vs 6/228 (3%), p < 0.001) than White patients, while White patients were significantly more likely to have metabolic dysfunction associated steatotic liver disease (71/228 (31%) vs 18/228 (8%), p < 0.001). White patients were significantly more likely to have cirrhosis than Black patients (White - 89/228 (39%) vs Black - 68/228 (30%), p < 0.05).

White patients had a greater overall burden of advanced fibrosis (F4/cirrhosis) than Black patients, independent of etiology. The data suggest that fibrosis risk and/or progression may be worse in White than Black patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases, which encompasses a spectrum of diseases, from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may ultimately progress to MASH-related cirrhosis and hepatocellular carcinoma (HCC). MASLD is a complex disease that is influenced by genetic and environmental factors. Dysregulation of hepatic lipid metabolism plays a crucial role in the development and progression of MASLD. Therefore, the focus of this review is to discuss the links between the genetic variants and DNA methylation of lipid metabolism-related genes and MASLD pathogenesis. We first summarize the interplay between MASLD and the disturbance of hepatic lipid metabolism. Next, we focus on reviewing the role of hepatic lipid related gene loci in the onset and progression of MASLD. We summarize the existing literature around the single nucleotide polymorphisms (SNPs) associated with MASLD identified by genome-wide association studies (GWAS) and candidate gene analyses. Moreover, based on recent evidence from human and animal studies, we further discussed the regulatory function and associated mechanisms of changes in DNA methylation levels in the occurrence and progression of MASLD, with a particular emphasis on its regulatory role of lipid metabolism-related genes in MASLD and MASH. Furthermore, we review the alterations of hepatic DNA and blood DNA methylation levels associated with lipid metabolism-related genes in MASLD and MASH patients. Finally, we introduce potential value of the genetic variants and DNA methylation profiles of lipid metabolism-related genes in developing novel prognostic biomarkers and therapeutic targets for MASLD, intending to provide references for the future studies of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, represents a prevalent condition ranging from simple steatosis to advanced stages associated with liver cancer. Asymptomatic presentation in the majority of cases underscores the need for non-invasive, cost-effective methods to stratify degree of hepatic steatosis. This cross-sectional study aimed to assess the association between obesity and lipid-related indices with the degree of hepatic steatosis in MASLD patients. 150 individuals recently diagnosed with metabolic dysfunction-associated steatotic liver disease were recruited. Anthropometric measurements, including weight, height, and waist circumference (WC), were taken, alongside biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides (TG), high-density lipoprotein, low-density lipoprotein, and fasting plasma glucose, following a 12-h fasting period. Various indicators of obesity and lipid metabolism, including body mass index, waist-to-height ratio (WHtR), a body shape index, lipid accumulation product (LAP), triglyceride-glucose index (TyG), visceral adiposity index, and hepatic steatosis index (HSI), were calculated. The diagnosis of MASLD and degree of hepatic steatosis were established through abdominal ultrasound examination. Data analysis was performed utilizing SPSS version 22. All the investigated indices displayed an area under the curve (AUC) surpassing 0.5, implying a correlation with the degree of hepatic steatosis. Notably, TyG-WC, TyG-WHtR, LAP, and a cardiometabolic obesity index showed the highest AUC values (> 0.7), indicating a relatively strong association with degree of hepatic steatosis. Specifically, in females, TyG-WC (AUC = 0.797, 95% CI 0.712-0.882, threshold = 865.991), while in males, LAP (AUC = 0.746, 95% CI 0.593-0.899, threshold = 74.290), demonstrated the highest AUC values. TyG-WHtR, TyG-WC, and LAP exhibited significant correlations with the degree of hepatic steatosis. Given their non-invasive nature and easy measurement, they hold promise for potential clinical utility, pending validation in additional studies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 30% of Western populations. While obesity is a recognized risk factor, MASLD does not develop in all obese individuals, highlighting the need to understand genetic and environmental interactions. The PNPLA3 I148M variant has been identified as a key genetic risk factor, significantly increasing the likelihood of MASLD development and progression.

We reviewed current literature on the role of PNPLA3 I148M in MASLD, focusing on gene-environment interactions involving diet, physical activity, obesity, and insulin resistance. We included studies analysing ethnic differences in PNPLA3 I148M prevalence and its association with MASLD. Additionally, we reviewed data on how PNPLA3 I148M influences the response to therapies, including lipid-lowering medications and GLP-1 agonists.

The PNPLA3 I148M variant markedly heightens MASLD risk, particularly in Hispanic populations, where a higher prevalence of MASLD is observed. Lifestyle factors such as high sugar intake, alcohol consumption, and physical inactivity exacerbate MASLD risk among I148M carriers. Evidence shows that insulin resistance amplifies MASLD risk associated with the I148M variant, especially in non-diabetic individuals. Moreover, the PNPLA3 I148M variant interacts with other genetic loci, further modifying MASLD risk and disease course. The variant also influences treatment response, with variability observed in effectiveness of lipid-lowering therapies and GLP-1 agonists among carriers.

The interplay between PNPLA3 I148M and environmental factors underscores the need for personalized MASLD prevention and treatment strategies. Targeting both genetic and lifestyle contributors may enhance MASLD management, offering a tailored approach to reducing disease burden.

Ectopic fat is reduced by effective weight management, but difficult to assess clinically.

We evaluated paired data on 42 participants in the intervention group of the Diabetes Remission Clinical Trial (DiRECT) at baseline, 12 and 24 months after weight loss as indicators of liver fat content measured by 3-point Dixon MRI.

Baseline liver fat was elevated at 13.0 [7.8-23.3]% with fasting plasma glucose 7.9 [7.1-10.1] mmol/L. Prevalence of baseline MASLD was 86.4%. After weight loss of 11.9 ± 1.2 kg (0-37 kg) at 12 months, remission of MASLD occurred in 74% and liver fat normalised for many (1.8 [1.2-5.2]%; p < 0.0001) as did fasting glucose (5.9 [5.5-7.2] mmol/L; p < 0.0001). Alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) decreased at 12 months by 38 [19-60]% (p < 0·0001) and 38 [16-53]% (p < 0.0001) respectively. The positive predictive value for decrease in liver fat, with baseline values of >40 IU/L, was 100% for ALT and 87.5% for GGT. As expected, change in liver fat correlated with change in ALT (r = 0.64; p < 0.0001), GGT (r = 0.38; p = 0.013), AST (r = 0.36; p = 0.018), fatty liver index (r = 0.50; p < 0.0001) and hepatic steatosis index (r = 0.44; p < 0.0001).

Metabolic dysfunction-associated steatotic liver disease, an important marker of ill-health is improved by intentional weight loss. If enzyme levels are raised at baseline, following weight loss, changes in ALT and GGT usefully reflect change in liver fat content, with high positive predictive value. Monitoring liver enzymes can provide a simple way to assess change in liver fat following weight loss in day-to-day clinical practice.

Data regarding the prevalence of hepatic fibrotic burden across the spectrum of hypothyroidism are scarce. Hence, we aimed to evaluate the prevalence of liver fibrotic burden across the spectrum of hypothyroidism.

30,091 individuals who attended a Health Management Centre between 2019 and 2021 were cross-sectionally analyzed. Participants were categorized as having strict-normal thyroid function, low-normal thyroid function, subclinical hypothyroidism, and overt hypothyroidism. Hepatic fibrosis was assessed by vibration-controlled transient elastography (VCTE). Significant and advanced fibrosis were defined as liver stiffness measurement in VCTE of 8.1-9.6 and 9.7-13.5 kPa, respectively.

Among both men and women, low-normal thyroid function group, subclinical hypothyroidism group, and overt hypothyroidism group all have more liver fibrosis present, including mild fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis, than the strict-normal thyroid function group. The low-normal thyroid function group have the similar liver fibrotic burden to the subclinical hypothyroidism group. The highest liver fibrotic burden was noted in the overt hypothyroidism group. Both significant and advanced liver fibrosis were significantly associated with low-normal thyroid function, subclinical hypothyroidism, and overt hypothyroidism in both men and women.

Liver fibrotic burden are highly prevalent in subjects with overt hypothyroidism. Moreover, fibrotic burden increased across the spectrum of hypothyroidism even within the low normal thyroid function. These results suggested that screening for liver fibrosis in patients with hypothyroidism is necessary.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver-related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors. PNPLA3 I148M (rs738409 C>G) is the variant with the greatest impact on the risk of developing progressive MASLD and likely other forms of steatotic liver disease. This variant is prevalent across the globe, with the risk allele (G) frequency exhibiting considerable variation. Here, we review the contribution of PNPLA3 I148M to global burden and regional differences in MASLD prevalence, focusing on recent evidence emerging from population-based sequencing studies and prevalence assessments. We calculated the population attributable fraction (PAF) as a means of quantifying the impact of the variant on MASLD. Furthermore, we employ quantitative trait locus (QTL) analysis to ascertain the associations between rs738409 and a range of phenotypic traits. This analysis suggests that these QTLs may underpin pleiotropic effects on extrahepatic traits. Finally, we outline potential avenues for further research and identify key areas for investigation in future studies.

Identifying patients with steatotic liver disease who are at a high risk of developing HCC remains challenging. We present a deep learning (DL) model to predict HCC development using hematoxylin and eosin-stained whole-slide images of biopsy-proven steatotic liver disease.

We included 639 patients who did not develop HCC for ≥7 years after biopsy (non-HCC class) and 46 patients who developed HCC <7 years after biopsy (HCC class). Paired cases of the HCC and non-HCC classes matched by biopsy date and institution were used for training, and the remaining nonpaired cases were used for validation. The DL model was trained using deep convolutional neural networks with 28,000 image tiles cropped from whole-slide images of the paired cases, with an accuracy of 81.0% and an AUC of 0.80 for predicting HCC development. Validation using the nonpaired cases also demonstrated a good accuracy of 82.3% and an AUC of 0.84. These results were comparable to the predictive ability of logistic regression model using fibrosis stage. Notably, the DL model also detected the cases of HCC development in patients with mild fibrosis. The saliency maps generated by the DL model highlighted various pathological features associated with HCC development, including nuclear atypia, hepatocytes with a high nuclear-cytoplasmic ratio, immune cell infiltration, fibrosis, and a lack of large fat droplets.

The ability of the DL model to capture subtle pathological features beyond fibrosis suggests its potential for identifying early signs of hepatocarcinogenesis in patients with steatotic liver disease.

The investigation of prevalence trends of metabolic cardiovascular risk factors is important for appropriate planning of future health programs aiming to prevent cardiovascular morbidity and mortality. In a previous study, we demonstrated an increase in the prevalence of type 2 diabetes (T2D) between 2000 and 2010 in Northeast Germany. The purpose of this study is to investigate prevalence trends of T2D treatment, dyslipidemia and hepatic steatosis in Northeast Germany.

The baseline examinations of the first Study of Health in Pomerania (SHIP) project were carried out from 1997 to 2001 (SHIP-START-0, 4308 subjects). A second, independent random sample of the same region was enrolled between 2008 and 2012 (SHIP-TREND-0, 4420 subjects). All data were standardized with post-stratification weighting derived from the adult population of the German federal state of Mecklenburg-West Pomerania.

The prevalence of metformin intake increased from 2.1% to 4.1% and insulin use from 2.0% to 2.8%. While the prevalence of statin intake increased from 6.8% to 12.2%, the prevalence of dyslipidemia decreased slightly from 49.0% in SHIP-START-0 to 45.5% in SHIP-TREND-0. The prevalence of hepatic steatosis increased from 29.7% to 37.3%. This increase was most prominently observed in women and younger age groups.

T2D, dyslipidemia and hepatic steatosis are common and increasing health problems among adults in Northeast Germany. Reassuring healthy diet and controlling obesity may result in prevention of above-mentioned health problems.

Metabolic dysfunction associated steatotic liver disease (MASLD) is prevalent in up to 60% of patients with type 2 diabetes mellitus (T2DM). T2DM accelerates the risk of hepatic fibrosis and hepatocellular carcinoma in patients with MASLD. Our goal in this study was to identify patients with suspected MASLD and hepatic fibrosis in a large T2DM clinic by using noninvasive fibrosis scoring systems.

We conducted a retrospective study of patients with T2DM seen by our endocrinologists at the Medical Faculty Associates (MFA) Diabetes Center in Washington, DC, from November 1, 2021, until November 1, 2022. We included all subjects who were over 18 years old with a hemoglobin A1c (HbA1c) of 6.5 or higher. Patients with a history of significant alcohol consumption, decompensated cirrhosis, previous bariatric surgery, or prior chronic liver disease were excluded from the study. We identified patients at risk for hepatic fibrosis by using the Fibrosis-4 (FIB-4) Index, NAFLD Fibrosis Score (NFS) and AST to Platelet Ratio Index (APRI) when lab values were available.

A total of 1,411 patients were evaluated for T2DM by an endocrinology provider during the one-year period. Out of these, 336 patients met one or more of the exclusion criteria, leaving a total of 1075 patients included in the analysis. The majority were African American (n = 582, 54%), 261 were Caucasian (24.3%), and 85 were Hispanic (7.9%). Most patients were females (n = 675, 62.7%). The mean HbA1c was 8.1 ± 2.3. 643 patients (59.8%) were insulin dependent. Based on FIB-4 scores, we found that 35 (3.9%) patients had a score of > 2.67 associated with advanced fibrosis and 257 (29%) patients with scores of 1.3-2.67 had moderate fibrosis. Using the NFS calculator, there were 281 (28%) patients with values of > 0.675 consistent with F3-F4 disease. 715 (71.8%) patients with values of < 0.675 consistent with F0-F2 fibrosis. A total of 6(< 1%) patients met criteria for advanced fibrosis by APRI scoring.

In our urban Diabetes Center, utilizing the NFS calculator may detect many patients with advanced liver disease. Further research is needed to ensure the internal validity of the non-invasive tests in predicting liver fibrosis and to correlate these findings with transient elastography and other imaging evidence of fatty liver disease.

Non-applicable.

The role of peridroplet mitochondria (PDM) in diseased liver, such as during the progression of metabolic dysfunction-associated steatohepatitis (MASH), remains unknown. We isolated hepatic cytoplasmic mitochondria (CM) and PDM from a mouse model of diet-induced MASLD/MASH to characterize their functions from simple steatosis to advanced MASH, using chow-fed mice as controls. Our findings show an inverse relationship between hepatic CM and PDM levels from healthy to steatosis to advanced MASH. Proteomics analysis revealed these two mitochondrial populations are compositionally and functionally distinct. We found that hepatic PDM are more bioenergetically active than CM, with higher pyruvate oxidation capacity in both healthy and diseased liver. Higher respiration capacity of PDM was associated with elevated OXPHOS protein complexes and increased TCA cycle flux. In contrast, CM showed higher fatty acid oxidation capacity with MASH progression. Transmission electron microscopy revealed larger and elongated mitochondria during healthy and early steatosis, which appeared small and fragmented during MASH progression. These changes coincided with higher MFN2 protein levels in hepatic PDM and higher DRP1 protein levels in hepatic CM. These findings highlight the distinct roles of hepatic CM and PDM in MASLD progression towards MASH.

Vitamin E is an effective treatment for metabolic dysfunction-associated steatohepatitis (MASH) but associated with hemorrhagic complications when used for other indications. We aimed to determine the risk of developing iron deficiency during treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) with vitamin E. Iron status was monitored prospectively in 20 people with MASLD treated with 200 - 800 IU/d vitamin E (https://clinicaltrials.gov/study/NCT01792115). To gain mechanistic insights liver histology, hepatic gene expression, hepatic 4-hydroxynonenal, haptoglobin genotype and plasma vitamin E levels were assessed. We found iron deficiency to occur in 11/20 subjects (55%) after a median 11 weeks (range 4-13) of vitamin E treatment, and anemia to occur in 6 of the 11 (30% of study population) after 23 weeks (16-36). Ferritin (84.5 ± 85.2 to 47.8 ± 54.9μg/L, p < 0.001) and mean corpuscular volume (MCV, 86.2 ± 4.9 to 84.3±4.3fL, p = 0.003) significantly decreased, with a concomitant rise in red-cell distribution width (RDW, 13.4 ± 1.3 to 14.4 ± 1.9%, p = 0.003). A gastrointestinal bleeding source was found in 75% of subjects with complete work-up. Iron deficiency occurred in all diabetics vs. 47% of non-diabetics (p 0.007). Iron deficiency risk was not associated with cirrhosis, platelet count, prothrombin time, haptoglobin genotype, or plasma vitamin E level. Changes in hepatic gene expression and oxidative stress were suggestive of an extrahepatic effect. Iron deficiency resolved with appropriate care even with continued vitamin E treatment. We conclude that occult gastrointestinal bleeding and iron deficiency were frequently observed during vitamin E treatment, possibly reflecting an effect on platelet function. Close monitoring is warranted during the first months of treatment, especially in diabetics and subjects with risk factors for gastrointestinal bleeding.

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most prevalent liver disorder globally, linked to obesity, type 2 diabetes, and cardiovascular risk. Understanding its potential progression from simple steatosis to cirrhosis and hepatocellular carcinoma (HCC) is crucial for patient management and treatment strategies. The disease's complexity requires innovative approaches for early detection and personalized care. Omics technologies-such as genomics, transcriptomics, proteomics, metabolomics, and exposomics-are revolutionizing the study of MASLD. These high-throughput techniques allow for a deeper exploration of the molecular mechanisms driving disease progression. Genomics can identify genetic predispositions, whilst transcriptomics and proteomics reveal changes in gene expression and protein profiles during disease evolution. Metabolomics offers insights into the metabolic alterations associated with MASLD, while exposomics links environmental exposures to MASLD progression and pathology. By integrating data from various omics platforms, researchers can map out the intricate biochemical pathways involved in liver disease progression. This review discusses the roles of omics technologies in enhancing the understanding of disease progression and highlights potential diagnostic and therapeutic targets within the MASLD spectrum, emphasizing the need for non-invasive tools in disease staging and treatment development.

Non-alcoholic Fatty Liver Disease (NAFLD) - whose terminology was recently replaced by metabolic liver disease (MAFLD) - is an accumulation of triglycerides in the liver of >5 % of its weight. Epidemiological studies indicated an association between NAFLD and reduced physical activity. In addition, exercise has been shown to improve NAFLD independently of weight loss. In this paper, we aim to systematically review molecular changes in sedentary experimental NAFLD models vs. those subjected to exercise. We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and standard review techniques. Studies were considered for inclusion if they addressed the primary question: the mechanisms by which exercise influenced NAFLD. This review summarized experimental evidence of improvements in NAFLD with exercise in the absence of weight loss. The pathways involved appeared to have AMPK as a common denominator. See also the graphical abstract(Fig. 1).

Hepatic steatosis (HS) and 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 7.5% are associated with increased risk for cardiovascular events.

To assess underlying coronary artery disease (CAD) and major adverse cardiovascular event (MACE) among those with and without HS at different ASCVD risk.

We evaluated stable chest pain patients receiving coronary computed tomography (CT) in the PROMISE trial. HS and CAD endpoints were defined on coronary CT. MACE was defined as unstable angina, non-fatal myocardial infarction, and all-cause death. Multivariable Cox regression, adjusting for CAD characteristics, assessed the association of HS with MACE for ASCVD < 7.5%.

One thousand two hundred and four of 3702 (32.5%) patients were at ASCVD < 7.5% and 20.3% (244/1204) of them had HS. Individuals with HS were younger (54.3 ± 5.2 vs. 55.8 ± 5.2; p < 0.001), more often males (40.2% [98/244] vs. 27.1% [260/960]; p < 0.001), had more risk factors/person (2.06 ± 0.89 vs. 1.93 ± 0.91; p = 0.047). CAD characteristics were similar between HS vs. non-HS patients at ASCVD < 7.5% and ASCVD ≥ 7.5% (all p > 0.05). Patients with HS had greater MACE rate compared to non-HS patients (ASCVD < 7.5%: 3.75%[9/244] vs. 1.5% [14/960]; p = 0.027 and ASCVD ≥ 7.5%: 4.7% [33/696] vs. 3.1% [56/1802]; p = 0.043). In patients without HS, MACE rate was higher in the ASCVD ≥ 7.5% vs. < 7.5% (3.1% [56/1802] vs. 1.5% [14/960]; p = 0.011). In patients with HS, MACE rates were not significantly different between ASCVD ≥ 7.5% vs. < 7.5% (4.7% [33/696] vs. 3.7% [9/244]; p = 0.484). In ASCVD < 7.5%, HS predicted MACE (aHR:2.34, 95%CI:1.01-5.43; p = 0.048), independent of CAD characteristics.

Individuals with HS at ASCVD < 7.5% risk had similar CAD characteristics as patients without HS at < 7.5% ASCVD risk, yet experienced comparable MACE rates as those at ASCVD ≥ 7.5%.

Cirrhosis prevalence is increasing, yet costs associated with its chronic, complex care are poorly understood. The aim was to characterize the costs of care for patients with cirrhosis and compare them to other chronic diseases such as heart failure (HF) and chronic obstructive pulmonary disease (COPD), for which the public health burden is better recognized.

Patients enrolled in Medicare Advantage plans from a large national insurer between 2011 and 2020 with cirrhosis, HF, and COPD were identified by ICD-9/-10 codes. Costs (USD) of care were calculated per patient-month and included inpatient medical, emergency medical, pharmacy, and other costs. In all, 93,308 patients with cirrhosis, 355,520 patients with HF, and 318,949 patients with COPD were analyzed. Patients with cirrhosis, HF, and COPD had a mean (SD) age of 69.6 (9.5), 75.9 (9.7), and 72.9 (9.8) years, respectively. The most frequent etiologies were metabolic dysfunction-associated steatohepatitis (37.7%) and alcohol-associated cirrhosis (22.1%). The total monthly cost of care for patients with cirrhosis, HF, and COPD was $3032.00, $2491.60, and $1955.60 respectively. The cost for patients with cirrhosis exceeded that for HF by $540.40 (21.7% higher) and COPD by $1076.30 (55.0% higher). The monthly cost of care for decompensated cirrhosis was $3969.30, which was 59.3% ($1477.70) higher than for HF and 103.0% ($1,955.60) higher than for COPD.

The cost of care for cirrhosis is high, significantly higher than HF and COPD. Interventions directed at optimizing care to prevent progression to cirrhosis and decompensation are likely to alleviate this public health burden.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common pediatric liver disease and can progress to liver fibrosis. Latino adolescents have increased MASLD and fibrosis risk. While fibrosis is diagnosed by biopsy or imaging, more accessible, noninvasive, and economical screening methods are needed. We aimed to use plasma metabolomics/lipidomics to identify potential fibrosis biomarkers in Latino adolescents with obesity.

Liver stiffness (LS) was measured in 93 Latino adolescents with obesity using magnetic resonance elastography. Metabolites and lipids were extracted from plasma and identified on Compound Discoverer. Associations between metabolites/lipids and fibrosis (LS > 2.73 kPa) were determined using linear regression models after covariate adjustment. False discovery rate (FDR) adjusted Pearson's correlations were performed. Analytes yielding significant FDR-adjusted correlations were examined further by receiver operator curve analysis.

Mean (±standard deviation) alanine transaminase (ALT) was 45.7(±65.2) IU/L, hepatic fat fraction was 12.7(±9.1)%, and LS was 2.4(±0.3) kPa. We identified 795 metabolites and 413 lipids in plasma, but only one single metabolite, dihydroxyacetone phosphate (DHAP), a marker of triglyceride synthesis, was significantly associated with fibrosis after FDR adjustment (p < 0.05). In terms of predicting fibrosis, ALT had an area under the curve (AUC) of 0.79, and DHAP had an AUC of 0.79. When combined, ALT + DHAP had an AUC of 0.89.

The combination of ALT + DHAP may have the potential as an accurate, noninvasive test for liver fibrosis. Our data are limited to Latino children with obesity, and a larger cohort should be examined to further validate this novel biomarker.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a leading cause of morbidity and mortality, and health disparities have been shown to influence disease burden.

In this review, we aim to characterize disparities in prevalence, diagnosis, treatment, and outcomes of MASLD, and to make recommendations for next steps to minimize these disparities.

Literature search on PubMed and Scopus databases was conducted to identify relevant articles published before September 2, 2024.

Relative to women and White populations, MASLD is more common in men and Hispanic populations and less common in Black populations. It is also more prevalent among those with lower SES. Noninvasive clinical scores may perform differently across groups, and screening practices vary both for initial disease and for progression to metabolic dysfunctionassociated steatohepatitis (MASH), formerly called non-alcoholic steatohepatitis (NASH). Women and Black and Hispanic patients suffer worse outcomes including rates of progression to MASH and mortality.

Health disparities related to race, ethnicity, gender, and socioeconomic factors impact multiple stages of care for patients with MASLD.

Liver fibrosis represents a common sequela of nonalcoholic fatty liver disease (NAFLD) and other chronic liver diseases. Noninvasive liver fibrosis scores (LFSs) aim to evaluate the severity of liver fibrosis. Whether LFSs can predict the risk of future cardiovascular events (CVEs) remains unclear. This systematic review aimed to clarify the association between liver fibrosis and CVEs by studying the value of LFSs, namely the Fibrosis-4 (FIB-4) Index for Liver Fibrosis score and the NAFLD Fibrosis Score (NFS), for predicting CVEs.

PubMed, Scopus, Web of Science, and Cochrane Library were searched for relevant prospective studies. Retrieved articles were screened to confirm their eligibility for the systematic review. We evaluated the quality of the included studies using the National Institutes of Health tool.

Twelve studies of high to fair quality were included in this systematic review. Of note, 10/12 studies reported an independent association between high LFSs and the risk of CVEs, cardiovascular mortality, and all-cause mortality (all P < 0.05). In addition, an advanced histological grade of liver fibrosis (grade 3 or 4) was suggestive of CVE occurrence. NAFLD also appeared to be associated with a higher risk of CVEs at any severity of fibrosis (all P < 0.05).

The findings of this review suggest that liver fibrosis in patients with NAFLD is an independent predictor of future adverse CVEs, cardiovascular mortality, and all-cause mortality. Noninvasive and easy-to-perform LFSs, including FIB-4 score and the NFS, appear useful in predicting such events in patients with a spectrum of cardiovascular diseases and the general population without known cardiovascular disease.

Type 2 diabetes mellitus (T2DM) is not just a local health issue but a significant global health burden, affecting patient outcomes and clinical management worldwide. Despite the wealth of studies reporting T2DM biomarkers, there is an urgent need for a comparative review. This review aims to provide a comprehensive analysis based on the reported T2DM biomarkers and how these are linked with other conditions, such as inflammation and wound healing. A comparative review was conducted on 24 001 study participants, including 10 024 T2DM patients and 13 977 controls (CTL; age 30-90 years). Four main profiles were extracted and analysed from the clinical reports over the past 11 years: haematological (1084 cases vs. 1458 CTL), protein (6753 cases vs. 9613 CTL), cytokine (975 cases vs. 1350 CTL) and lipid (1212 cases vs. 1556 CTL). This review provides a detailed analysis of the haematological profile in T2DM patients, highlighting fundamental changes such as increased white blood cells and platelet counts, accompanied by decreases in red blood cell counts and iron absorption. In the serum protein profile, a reduction in albumin and anti-inflammatory cytokines was noted along with an increase in globulin levels and pro-inflammatory cytokines. Furthermore, changes in lipid profiles were discussed, specifically the decreases in high-density lipoprotein (HDL) and the increases in low-density lipoprotein (LDL) and triglycerides. Understanding the changes in these four biomarker profiles is essential for developing innovative strategies to create diagnostic and prognostic tools for diabetes management.

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver. These transcripts are differentially expressed across areas of steatosis in spatial transcriptomics, and several are dynamic during stages of steatosis. Circulating multi-protein signatures of steatosis strongly associate with fatty liver disease and multi-system metabolic outcomes. Using a humanized "liver-on-a-chip" model, we induce hepatic steatosis, confirming cell-specific expression of prioritized targets. These results underscore the utility of this approach to identify a prognostic, functional, dynamic "liquid biopsy" of human liver, relevant to biomarker discovery and mechanistic research applications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC). Recent studies have highlighted the bidirectional impacts between host genetics/epigenetics and the gut microbial community. Host genetics influence the composition of gut microbiome, while the gut microbiota and their derived metabolites can induce host epigenetic modifications to affect the development of MASLD. The exploration of the intricate relationship between the gut microbiome and the genetic/epigenetic makeup of the host is anticipated to yield promising avenues for therapeutic interventions targeting MASLD and its associated conditions. In this review, we summarise the effects of gut microbiome, host genetics and epigenetic alterations in MASLD and MASLD-HCC. We further discuss research findings demonstrating the bidirectional impacts between gut microbiome and host genetics/epigenetics, emphasising the significance of this interconnection in MASLD prevention and treatment.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, coinciding with aging population. However, limited studies have evaluated its incidence and progression to advanced fibrosis in the elderly population. Therefore, our study aimed to investigate the incidence of MASLD and advanced fibrosis in this age group.

We included 878 686 individuals aged ≥60 years from the Korea National Health Insurance Service-Senior cohort. After excluding participants with preexisting MASLD, 329 388 individuals were finally analyzed. Participants were categorized into four groups based on the presence of overweight/obesity and additional risk factors (aRF) included in the cardiometabolic diagnostic criteria of MASLD.

The overall incidence of MASLD was 1.94 per 100 person-years, and the incidence of advanced fibrosis in MASLD patients was 1.78 per 100 person-years. MASLD development was significantly higher in overweight/obese patients (2.65 per 100 person-years) compared to lean patients (1.09 per 100 person-years), and this trend persisted after stratification by the presence of aRF. Similarly, the incidence of advanced fibrosis among MASLD patients was higher in overweight/obese individuals (2.06 per 100 person-years) compared to lean counterparts (0.87 per 100 person-years), irrespective of aRF.

The lower incidence of MASLD in the elderly population compared to the general population underscores the importance of identifying age-specific risk factors. Overweight/obesity emerged as a robust predictor of MASLD development and advanced fibrosis. Additionally, the presence of additional cardiometabolic risk factors further increased the risk of incident MASLD and advanced fibrosis among the elderly.

Provide a concise update on metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as a practical approach to screening and initial evaluation.

Nomenclature changes have placed a greater focus on cardiometabolic risk factors in the definition of MASLD. Screening for MASLD is by stepwise noninvasive serum and imaging tests which can identify patients at risk for advanced fibrosis and liver-related complications. MASLD has been increasing in prevalence and disease burden but is underrecognized in primary care and endocrinology clinics. Multiple society guidelines, synthesized here, provide a framework for the initial approach in the diagnosis and evaluation of MASLD. Recent advances in pharmacologic treatment underline the importance of screening for patients who are at risk for advanced fibrosis as they are most likely to benefit from new drug classes, such as the liver-directed thyroid receptor agonist resmiterom.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders, from benign steatosis to more severe conditions like non-alcoholic steatohepatitis, with risks of progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) indicates lipid metabolic dysregulation and is associated with increased risks of various diseases. This study examines the relationship between NHHR and NAFLD to evaluate NHHR as a potential predictive biomarker for NAFLD.

Data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES) were used for cross-sectional analysis. After excluding individuals with incomplete data, hepatitis infections, heavy alcohol use, and those under 18, the study included 2,757 adults. The relationship between NHHR and NAFLD was analyzed using multivariable logistic regression, including subgroup analysis and interaction testing.

Among the 2,757 participants (mean age 49.91 years), 44.9% had NAFLD. NHHR showed a significant positive association with NAFLD, with an unadjusted odds ratio (OR) of 1.71 and a fully adjusted OR of 1.45. Quartile analysis revealed a 228% higher prevalence of NAFLD in the highest NHHR quartile, with an OR of 3.28. This positive association was consistent across various subgroups.

Our findings suggest that elevated NHHR is positively correlated with the prevalence of NAFLD and possesses predictive value. We recommend that future research validate the clinical utility of NHHR, particularly for early detection of high-risk individuals and guiding personalized interventions.

Approximately 25% of the world's population and more than 60% of patients with type 2 diabetes (T2D) have metabolic-dysfunction-associated steatotic liver disease (MASLD). The association between these pathologies is an important cause of morbidity and mortality in Brazil and worldwide due to the high frequency of advanced fibrosis and cirrhosis. The objective of this study was to determine the epidemiologic and clinical-laboratory profile of patients with T2D and MASLD treated at an endocrinology reference service in a state in northeastern Brazil, and to investigate the association of liver fibrosis with anthropometric and laboratory measurements.

A cross-sectional study was performed in a specialized outpatient clinic with 240 patients evaluated from July 2022 to February 2024, using a questionnaire, physical examination, laboratory tests, and liver elastography with FibroScan®.

Estimates showed that women (adjusted OR = 2.69, 95% CI = 1.35-5.35, p = 0.005), obesity (adjusted OR = 2.23, 95% CI = 1.22-4.07, p = 0.009), high GGT (adjusted OR = 3.78, 95% CI = 2.01-7.14, p < 0. 001), high AST (adjusted OR = 6.07, 95% CI = 2.27-16.2, p < 0.001), and high ALT (adjusted OR = 3.83, 95% CI = 1.80-8.11, p < 0.001) were associated with the risk of liver fibrosis even after adjusted analysis.

The study findings suggested that female sex and BMI were associated with an increased risk of liver fibrosis, highlighting the importance of comprehensive evaluation of these patients. In addition, FIB-4 and MAF-5 provided a good estimate of liver fibrosis in our population and may serve as a useful tool in a public health setting with limited resources.

To examine the hypothesis that there would be ethnic differences in the relationship between ectopic fat and tissue-specific insulin resistance (IR) across a spectrum of glucose tolerance in Black African (BA) and White European (WE) men.

Fifty-three WE men (23/10/20 normal glucose tolerance [NGT]/impaired glucose tolerance [IGT]/type 2 diabetes [T2D]) and 48 BA men (20/10/18, respectively) underwent a two-step hyperinsulinaemic-euglycaemic clamp with infusion of D-[6,6-2H2]-glucose and [2H5]-glycerol to assess hepatic, peripheral and adipose tissue IR. Magnetic resonance imaging was used to measure subcutaneous adipose tissue, visceral adipose tissue (VAT) and intrahepatic lipid (IHL). Associations between ectopic fat and IR were assessed using linear regression models.

There were no differences in tissue-specific IR between ethnic groups at any stage of glucose tolerance. VAT level was consistently lower in the BA population; NGT (p = 0.013), IGT (p = 0.006) and T2D (p = 0.015). IHL was also lower in the BA compared with the WE men (p = 0.013). VAT and IHL levels were significantly associated with hepatic IR in the BA population (p = 0.001) and with peripheral IR in the WE population (p = 0.027).

The present study suggests that BA and WE men exhibit the same degree of IR across a glucose tolerance continuum, but with lower VAT and IHL levels in the BA population, suggesting that IR may be driven by a mechanism other than increased ectopic fat accumulation in BA men.

Background CT plays an important role in the opportunistic identification of hepatic steatosis. CT performance for steatosis detection has been inconsistent across various studies, and no clear guidelines on optimum thresholds have been established. Purpose To conduct a systematic review and meta-analysis to assess CT diagnostic accuracy in hepatic steatosis detection and to determine reliable cutoffs for the commonly mentioned measures in the literature. Materials and Methods A systematic search of the PubMed, Embase, and Scopus databases (English-language studies published from September 1977 to January 2024) was performed. Studies evaluating the diagnostic accuracy of noncontrast CT (NCCT), contrast-enhanced (CECT), and dual-energy CT (DECT) for hepatic steatosis detection were included. Reference standards included biopsy, MRI proton density fat fraction (PDFF), or NCCT. In several CECT and DECT studies, NCCT was used as the reference standard, necessitating subgroup analysis. Statistical analysis included a random-effects meta-analysis, assessment of heterogeneity with use of the I2 statistic, and meta-regression to explore potential sources of heterogeneity. When available, mean liver attenuation, liver-spleen attenuation difference, liver to spleen attenuation ratio, and the DECT-derived fat fraction for hepatic steatosis diagnosis were assessed. Results Forty-two studies (14 186 participants) were included. NCCT had a sensitivity and specificity of 72% and 88%, respectively, for steatosis (>5% fat at biopsy) detection and 82% and 94% for at least moderate steatosis (over 20%-33% fat at biopsy) detection. CECT had a sensitivity and specificity of 66% and 90% for steatosis detection and 68% and 93% for at least moderate steatosis detection. DECT had a sensitivity and specificity of 85% and 88% for steatosis detection. In the subgroup analysis, the sensitivity and specificity for detecting steatosis were 80% and 99% for CECT and 84% and 93% for DECT. There was heterogeneity among studies focusing on CECT and DECT. Liver attenuation less than 40-45 HU, liver-spleen attenuation difference less than -5 to 0 HU, and liver to spleen attenuation ratio less than 0.9-1 achieved high specificity for detection of at least moderate steatosis. Conclusion NCCT showed high performance for detection of at least moderate steatosis. © RSNA, 2024 Supplemental material is available for this article.

Previous studies reported inconsistent results of the association between Helicobacter pylori infection and nonalcoholic fatty liver disease (NAFLD).

A cohort study of 2,063 adults without NAFLD at baseline, who participated in a repeated health checkup including a 13C-urea breath test and abdominal ultrasonography, was conducted to evaluate the link between H. pylori infection and NAFLD development.

During a mean follow-up period of 1.7 years, we did not find a significant association between H. pylori infection and NAFLD (hazard ratio = 1.10 (0.86, 1.40), p = 0.4689). We also found that higher age, body mass index (BMI), systolic blood pressure (systolic BP), diastolic blood pressure (diastolic BP), fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were risk factors, and high-density lipoprotein cholesterol (HDL-C) was a protective factor for NAFLD development.

H. pylori infection might not be positively related to NAFLD development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease. Identifying MASLD risk factors could help early intervention and reduce the burden of the disease. Previous studies investigated the association between sarcopenia and NAFLD. Several trials were published after the last meta-analysis with indecisive results. This is an updated meta-analysis which aims to assess the association between sarcopenia, MASLD, and MASLD-related fibrosis.

Relevant trials published on PubMed, Web of Science, Scopus, and Cochrane Library databases until October 2022 were included. We included studies in which skeletal mass index (SMI) or sarcopenia was compared between patients with and without NAFLD now MASLD. Also, studies comparing fibrosis between MASLD patients with and without sarcopenia were included. Data were pooled as odds ratios (ORs) and 95 % confidence intervals (CIs) using Review Manager Software.

A total of 25 studies were included. The incidence of sarcopenia was significantly higher in MASLD than controls (OR, 1.25; 95 % CI, 1.08-1.44; P = 0.003). SMI odds showed no significant difference between MASLD patients and controls (OR, 1.02; 95 % CI, 0.91-1.15; P = 0.7). MASLD patients with sarcopenia had higher odds of fibrosis than MASLD patients without sarcopenia (OR, 1.49; 95 % CI, 1.03-2.14; P = 0.03).

Sarcopenia increased MASLD's probability and was associated with a higher probability of liver fibrosis in MASLD patients. However, SMI had no predictive value of MASLD occurrence.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing in prevalence, impacting over a third of the global population. The advanced form of MASLD, Metabolic dysfunction-associated steatohepatitis (MASH), is on track to become the number one indication for liver transplant. FDA-approved pharmacological agents are limited for MASH, despite over 400 ongoing clinical trials, with only a single drug (resmetirom) currently on the market. This is likely due to the heterogeneous nature of disease pathophysiology, which involves interactions between highly individualized genetic and environmental factors. To apply precision medicine approaches that overcome interpersonal variability, in-depth insights into interactions between genetics, nutrition, and the gut microbiome are needed, given that each have emerged as dynamic contributors to MASLD and MASH pathogenesis. Here, we discuss the associations and molecular underpinnings of several of these factors individually and outline their interactions in the context of both patient-based studies and preclinical animal model systems. Finally, we highlight gaps in knowledge that will require further investigation to aid in successfully implementing precision medicine to prevent and alleviate MASLD and MASH.

To investigate the renal fat deposition on Dixon-based magnetic resonance imaging (MRI) and to explore the predictive value of renal fat biomarkers of magnetic resonance (MR-RFBs) for early kidney damage in obesity.

This prospective study included 56 obese volunteers and 47 non-obese healthy volunteers. All volunteers underwent renal magnetic resonance examinations. The differences in MR-RFBs [including renal proton density fat fraction (PDFF), renal sinus fat volume (RSFV), and perirenal fat thickness (PRFT)] measured on Dixon-based MRI between the obese and non-obese volunteers were analyzed using a general linear model, taking sex, age, diabetes, and hypertension as covariates. The relationship between estimated glomerular filtration rate (eGFR) and demographic, laboratory, and imaging parameters in obese volunteers was examined by correlation analysis.

Obese volunteers had higher MR-RFBs than non-obese volunteers after controlling for confounders (all p < 0.001). Renal PDFF (r = - 0.383; p = 0.004), RSFV (r = - 0.368; p = 0.005), and PRFT (r = - 0.451; p < 0.001) were significantly negatively correlated with eGFR in obesity. After adjusting for age, sex, body mass index, diabetes, hypertension, visceral adipose tissue, subcutaneous adipose tissue, renal PDFF, and RSFV, PRFT remained independently negatively associated with eGFR (β = - 0.587; p = 0.003).

All MR-RFBs are negatively correlated with eGFR in obesity. The MR-RFBs, especially PRFT, may have predictive value for early kidney damage in obesity.

We have previously demonstrated that dietary saturated fatty acids (SFA), when compared to polyunsaturated fatty acids (PUFA), are preferentially partitioned into oxidation pathways. However, it remains unclear if this preferential handling is maintained when hepatocellular metabolism is shifted toward fatty acid (FA) esterification and away from oxidation, such as when hepatic de novo lipogenesis (DNL) is upregulated.

To investigate whether an acute upregulation of hepatic DNL influences dietary FA partitioning into oxidation pathways.

20 healthy volunteers (11 females) underwent a fasting baseline visit followed by two study days, 2-weeks apart. Prior to each study day, participants consumed an isocaloric high-carbohydrate diet (to upregulate hepatic DNL) for 3-days. On the two study days, participants consumed an identical standardised test meal that contained either [U13C]palmitate or [U13C]linoleate, in random order, to trace the fate of dietary FA. Blood and breath samples were collected over a 6h postprandial period and 13C enrichment in breath CO2 and plasma lipid fractions were measured using gas-chromatography-combustion-isotope ratio mass spectrometry.

Compared to the baseline visit, fasting plasma triglyceride concentrations and markers of hepatic DNL, the lipogenic and stearyl-CoA desaturase indices, were significantly (p < 0.05) increased after consumption of the high-carbohydrate diet. Appearance of 13C in expired CO2 and tracer recovery were significantly (p < 0.05) higher after consumption of the meal containing [U13C]linoleate compared to [U13C]palmitate (5.1 ± 0.5% vs. 3.7 ± 0.4%), respectively. Incorporation of 13C into the plasma triglyceride and non-esterified fatty acid pool was significantly (p < 0.001) greater for [U13C]palmitate compared to [U13C]linoleate.

Dietary PUFA compared to SFA appear to be preferentially partitioned into oxidation pathways during an acute upregulation of hepatic DNL, thus consumption of a PUFA-enriched diet may help mitigate intrahepatic triglyceride accumulation in individuals at risk of cardiometabolic disease.