Metabolic-associated steatotic liver disease (MASLD) has become the most common chronic liver disease, especially in people with type 2 diabetes mellitus (T2DM). Liver biopsy remains the gold standard method for diagnosis of MASLD subtypes, but prevalences may be under or overestimated when biopsy is performed with selection bias. The aims of this study were to define prevalence of MASLD subtypes by liver biopsy in T2DM participants not selected by abnormal exams, determine variables associated with metabolic-associated steatohepatitis (MASH), and analyze performance of aminotransferases and abdominal ultrasound in diagnosis.

T2DM participants from 18 to 70 years were considered for enrollment. Of the 396 participants, 85 were included and submitted to clinical, laboratory examinations, and ultrasound. Eighty-three performed liver biopsy evaluated by two independent pathologists. Factors independently associated to MASH and significant fibrosis were assessed by hierarchical multivariate logistic regression.

Prevalence of MASLD was 92% (50% simple steatosis, 42% MASH) and kappa = 0.78. Steatosis was mild in 76% of participants with simple steatosis and severe in 65% of MASH (P < 0.001). Presence of MASH or fibrosis was associated with BMI and alanine aminotransferase (ALT) [threshold of 33.5 mg/dl in predicting MASH (area under the curve = 0.82, P = 0.001)].

Prevalence of MASLD by liver biopsy in T2DM regardless of ultrasound or ALT elevation is almost 100%, with 42% of MASH. MASH was associated to severe steatosis on histology. BMI and ALT were independently associated with MASH and ALT close to the upper limit of normal gave the best cutoff point for MASH detection.

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.

Environmental factors are linked to aging and age-related diseases. Emerging evidence suggests that enhancing body's resistance to xenobiotics might be an anti-aging strategy. The constitutive androstane receptor (CAR) regulates drug-metabolizing enzymes and transporters, coordinating metabolism and immune responses to adapt to stress triggered by exogenous exposure. However, the impact of activating CAR on aging remains unknown. In this study, Caenorhabditis elegans (C. elegans), drug-induced premature aging mice, and senescence accelerated P8 (SAMP8) mice are used as models to explore the effects of CAR activation on lifespan and healthspan, along with the underlying mechanisms. The results showed that hCAR agonist CITCO and mCAR agonist TCPOBOP prolonged the lifespan and healthspan in model organism. The longevity effects of CITCO and TCPOBOP were attenuated in CAR homozygous nhr-8/daf-12 mutant C. elegans as well as CAR-/- mice. In C. elegans, CITCO activated both anti-stress and detoxification genes, and increased the resistance to environmental adversities. Additionally, the lifespan-extending and xenobiotic resistant effects of CITCO might be related to the regulation of age-related pathways. Furthermore, CITCO improved age-related neurodegeneration in C. elegans models. Taken together, the results suggest that the longevity effects of CAR agonists may be related to the enhancement of xenobiotic resistance of animals.

Children and young people living with severe obesity experience a range of complications of excess weight (CEW); however the prevalence of complications is not well defined. We have evaluated baseline characteristics and CEW of patients from two UK tier 3 paediatric weight management services.

All new patients aged 2-17 years seen from March 2022 to February 2023 were included. Baseline demographic data was collected, and patients screened for CEW. PedsQL-4.0 questionnaires were used to assess health-related quality of life (HRQL).

185 patients were included, median age 14.3 years (range 3.3-18.0), 50.8% were girls. Of the patients, 73.8% were white British, with a significant excess of patients living in the most deprived decile (41.4%). Median body mass index SD score was +3.55 (IQR 3.11-3.90) and median body fat was 49.3% (IQR 42.3%-55.1%). Autistic spectrum disorder, attention deficit hyperactivity disorder and learning difficulties were vastly over-represented.Dyslipidaemia was the most common (51.6%) complication, followed by hypertension (28.9%), metabolic dysfunction-associated steatotic liver disease (17.8%), obstructive sleep apnoea (9.0%) and idiopathic intracranial hypertension (4.3%). Mean glycated haemoglobin was 35.0 mmol/mol (IQR 33-38). 8.1% had type 2 diabetes mellitus. Many of these complications were detected through screening in CEW clinics.Both child-reported (mean 51.9/100) and parented-reported (47.8/100) HRQL scores were low. Mental health problems were common: 26.2% with anxiety and 7.7% with depression.

This study demonstrates the significant and profound mental and organ-specific pathology resulting from severe obesity in childhood, highlighting the clinical necessity for CEW clinics. A rigorous approach to identify complications at an early stage is essential to improve long-term health outcomes.

Steatotic liver disease is prevalent among people with hepatitis C virus (HCV). The new definition of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasises the metabolic drivers of steatosis and recognises its frequent coexistence with other chronic liver diseases, including HCV. We aimed to evaluate the association of coexisting MASLD and HCV with liver fibrosis. Individuals with HCV who underwent transient elastography (TE) with associated controlled attenuation parameter (CAP) were included from two clinical centres. MASLD and significant liver fibrosis were defined as the presence of steatosis (CAP ≥ 275 dB/m) with at least one cardiometabolic risk factor, and liver stiffness measurement (LSM) ≥ 7.1 kPa measured by TE, respectively. Associated cofactors of significant liver fibrosis were determined using stepwise regression and cross-validation by LASSO models to select confounders. Among 590 participants, 31% were diagnosed with MASLD. The prevalence of significant liver fibrosis was the highest among people with MASLD (58%) followed by HCV-related steatosis (45%) and the non-steatosis group (39%). After adjusting for potential confounders, MASLD was associated with significant liver fibrosis (adjusted odds ratio [aOR] 2.29, 95% confidence interval [CI] 1.07-4.87). Furthermore, specific MASLD phenotypes including diabetes, hypertension and overweight were associated with significant liver fibrosis, with aORs of 4.76 (95% CI 2.16-10.49), 3.44 (95% CI 1.77-6.68) and 2.54 (95% CI 1.27-5.07), respectively. In conclusion, MASLD is associated with liver fibrosis in people with HCV, specifically the diabetes, overweight and hypertensive phenotypes. Beyond pursuing a virological cure, healthcare providers should prioritise managing metabolic conditions, particularly diabetes, hypertension and obesity.

Severity of fibrosis is the driver of liver-related outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD), and non-invasive testing such as fibrosis-4 (FIB-4) score is utilized for risk stratification. We aimed to determine if primary care patients at risk for MASLD and advanced fibrosis were evaluated with subsequent testing. A secondary aim was to determine if at-risk patients with normal aminotransferases had advanced fibrosis.

Primary care patients at increased risk for MASLD with advanced fibrosis (n = 91,914) were identified using previously established criteria. Patients with known alternative/concomitant etiology of liver disease or cirrhosis were excluded. The study cohort included patients with calculated FIB-4 score in 2020 (n = 52,006), and stratified into low, indeterminate, and high likelihood of advanced fibrosis. Among those at indeterminate/high risk, rates of subsequent testing were measured.

Risk stratification with FIB-4 characterized 77% (n = 40,026) as low risk, 17% (n = 8847) as indeterminate, and 6% (n = 3133) as high risk. Among indeterminate/high-risk patients (n = 11,980), 78.7% (n = 9433) had aminotransferases within normal limits, 0.95% (n = 114) had elastography, and 8.2% (n = 984) were referred for subspecialty evaluation.

In this cohort of primary care patients at risk for MASLD with fibrosis, the FIB-4 score identified a substantial proportion of indeterminate/high-risk patients, the majority of which had normal aminotransferase levels. Low rates of subsequent testing were observed. These data suggest that a majority of patients at increased risk for liver-related outcomes remain unrecognized and highlight opportunities to facilitate their identification.

Initial analysis of liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population.

We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers.

The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities.

Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.

Patients with diabetes are at a high risk for perioperative ischemic stroke (PIS). The use of biomarkers to identify high-risk patients and predict PIS may provide considerable reference value in clinical decision-making. The aspartate transaminase/alanine transaminase ratio (De Ritis ratio) has been proven to be associated with specific diabetic complications. However, the association between the De Ritis ratio and PIS has not been evaluated in this population. This retrospective cohort study aimed to evaluate the association between the preoperative De Ritis ratio and PIS in patients with type 2 diabetes undergoing noncardiovascular surgery.

Data from surgical patients were collected from January 2008 to August 2019. A total of 27,643 patients with type 2 diabetes mellitus (DM) undergoing noncardiovascular surgery under general anesthesia were screened. The optimal De Ritis ratio cutoff value was identified using the receiver operating characteristic (ROC) curve. Logistic regression models were used to evaluate the association between the preoperative De Ritis ratio and PIS. Propensity score matching (PSM), sensitivity analyses, and subgroup analyses were performed to further validate the robustness of this association.

A total of 151 patients experienced PIS. A De Ritis ratio ≥ 1.04 was associated with an elevated risk of PIS after adjusting for baseline characteristics (OR [95% CI]: 2.25 [1.59-3.21]; p < 0.001), intraoperative parameters (2.50 [1.80-3.49]; p < 0.001), and all confounding variables (2.29 [1.61-3.29]; p < 0.001). In the propensity score-matched cohort, the association between the De Ritis ratio and PIS remained significant (2.04 [1.38-3.05]; p < 0.001). These associations were also consistently maintained in the sensitivity and subgroup analyses.

An elevated De Ritis ratio is strongly associated with a higher risk of PIS in patients with type 2 DM undergoing noncardiovascular surgery. This may provide additional information on PIS risk assessment in patients with type 2 DM undergoing noncardiovascular surgery.

Background: Liver diseases are a global health concern. Many in vitro liver models utilize cryopreserved primary human hepatocytes (PHHs), which commonly undergo post-thaw processing through colloidal silica gradients to remove debris and enrich for a viable PHH population. Post-thaw processing effects on healthy PHHs are partially understood, but the consequences of applying disease-origin PHHs to post-thaw density gradient separation have not been described. Methods: Using the TruVivo® system, diseased, type 2 diabetes mellitus (T2DM), and fibrotic PHHs were cultured for 14 days after initially being subjected to either low-density (permissive) or high-density (selective) gradients using Percoll-based thawing medium. Results: Changes in functionality, including albumin and urea secretion and CYP3A4 activity, were measured in diseased, T2DM, and fibrotic PHHs enriched in low Percoll compared to PHHs enriched in high Percoll. Lipogenesis increased in the PHHs enriched in low Percoll. Higher expression of CK18 and TGF-β, two fibrotic markers, and changes in expression of the macrophage markers CD68 and CD163 were also measured. Conclusions: The use of Percoll for the enrichment of PHHs post-thaw results in differences in attachment and functionality, along with changes in diseased phenotypes, in the TruVivo® system.

Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the Phkg2-/- mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers - the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications.

Liver cirrhosis is a chronic disease caused by long-term inflammation and fibrosis of the liver. Early identification and intervention in liver cirrhosis have become an important goal for researchers to explore the influence of some metabolic factors on the risk of liver cirrhosis in terms of genetic susceptibility. Data from genome-wide association studies (GWASs) of fourteen metabolic factors and liver cirrhosis were obtained from publicly available databases. To make the results more credible, we selected 2 GWASs for liver cirrhosis to be validated separately. The causal effect of metabolic factors on liver cirrhosis was assessed separately using 2-sample Mendelian Randomization (MR). The inverse variance weighted (IVW) method was used as the main analysis method. The present MR analysis confirmed that fasting insulin level (IVW-OR = 2.89, 95% CI: 1.36-6.15, P = .006) and ALT (IVW-OR = 1.42, 95% CI: 1.11-1.80, P = .004) were positively causally associated with the risk of liver cirrhosis, and there was a negative causal relationship between hypertension and the risk of liver cirrhosis (IVW-OR = 0.40, 95% CI: 0.23-0.72, P = .002) in 1 liver cirrhosis GWAS. In replication analysis, our MR proved the positive causal effect between ALT (IVW-OR = 2.09, 95% CI: 1.61-2.72, P < .001) and BMI (IVW-OR = 1.44, 95% CI: 1.17-1.77, P < .001) and the risk of liver cirrhosis. A causal relationship between other metabolic factors and the risk of liver cirrhosis could not be established in the current selection of data. Our MR study revealed a causal and positive association between ALT and the risk of liver cirrhosis, suggesting an important role of effective control of ALT in liver cirrhosis prevention. The causal relationship between thirteen other metabolic factors and the risk of liver cirrhosis remains to be further verified.

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem worldwide, ranging from non-alcoholic fatty liver (NAFL) to the more severe metabolic non-alcoholic steatohepatitis (NASH). Although many studies have elucidated the pathogenesis of NAFLD, the epigenetic regulatory mechanism from NAFL to NASH remains incompletely understood. The histone H3 lysine 4 methyltransferase, MLL4 (also called KMT2D), is a critical epigenetic transcriptional coactivator that mediates overnutrition-induced steatosis in mice, but its potential role in the progression of NASH remains largely unknown. Here, we show that mice lacking the one allele of the Mll4 gene are resistant to hepatic steatosis, inflammation, and fibrosis in NASH conditions compared to wild-type controls. Transcriptome analysis of the livers of control and Mll4+/- mice identified pro-inflammatory genes regulated by the nuclear factor kappa B (NF-κB) signaling pathway as major target genes of MLL4. We show that MLL4 binds to p65 and that MLL4 is required for NF-κB transactivation. Myeloid-specific Mll4 knockout mice showed an almost complete block of NASH, while hepatocyte-specific Mll4 knockout mice showed mild inhibition of steatosis. Pro-inflammatory M1 polarization is decreased and anti-inflammatory M2 polarization is increased in liver macrophages from myeloid-specific Mll4 knockout mice. Importantly, we show that histone H3-lysine 4 methylation mediated by the MLL4-complex plays a critical role in promoting the expression of Ccl2 in hepatocytes and M1 marker genes in macrophages. Our results demonstrate that MLL4, through the NF-κB-MLL4 regulatory axis, exacerbates steatohepatitis in the context of an inflammatory response and represents a potential therapeutic target for NASH.

Nonalcoholic fatty liver disease (NAFLD) is a common metabolism-related disease worldwide. Although studies have shown that some medications may be effective for treating NAFLD, they do not satisfy the medical requirements, and lifestyle changes are the most basic strategy. Thus, early detection of NAFLD and timely lifestyle interventions are highly important.

The traditional diagnostic methods for NAFLD are limited by accuracy, cost, and security issues. Cytokeratin 18 (CK18), which is a marker of apoptosis and overall cell death, is an excellent biomarker for NAFLD. Liver fat accumulation in NAFLD triggers the activation of caspases, which increases the CK18 cleavage and its release into the blood. CK18 can help diagnose different stages of NAFLD, especially the nonalcoholic steatohepatitis (NASH) stage. In evaluating the efficacy of the NAFLD treatment and predicting the risk of NAFLD-related diseases, CK18 plays a significant role.

CK18 can non-invasively monitor the pathological conditions of NAFLD patients and provide new hope for the early diagnosis of NAFLD. Adding CK18 to the NAFLD diagnostic criteria that are widely used in clinical settings may be efficient for the detection of NAFLD and early effective intervention.

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.

Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.

The steatosis-associated fibrosis estimator (SAFE) score has been developed to distinguish clinically significant fibrosis in patients with steatotic liver disease (SLD). However, validation of its performance in Asian subjects is limited. This study aimed to evaluate the performance of the SAFE score in Asian subjects with biopsy-proven SLD and in different subgroups according to age, sex, and body mass index.

We retrospectively analyzed 6383 living liver donors who underwent a liver biopsy between 2005 and 2023. Of these, 1551 subjects with biopsy-proven SLD were included. The performance of the SAFE score was evaluated using areas under the curve and compared with those of the nonalcoholic fatty liver disease fibrosis score (NFS) and fibrosis-4 index (FIB-4).

The prevalence of clinically significant fibrosis in the cohort was 2.2%. The proportion of subjects with a "low-risk" SAFE score was the highest (91.0%), followed by those with "intermediate-risk" (7.8%) and "high-risk" (1.2%) scores. The prevalence of fibrosis in subjects with low-risk, intermediate-risk, and high-risk scores was 1.6%, 6.6%, and 21.1%, respectively. The SAFE outperformed FIB-4 and NFS (area under the curve: 0.70 vs 0.64 for both NFS and FIB-4). However, it showed low diagnostic accuracy and sensitivity (27%) at the low cutoff (SAFE < 0) in subjects aged 30-39 years (fibrosis: 1.2%), despite having a high negative predictive value (0.99).

While the SAFE score demonstrates superior performance compared with other noninvasive tests in Asian subjects with SLD, its performance varies across age groups. In younger subjects, particularly, its performance may be more limited.

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both facets of the metabolic syndrome, associated with obesity and insulin resistance. MASLD, a term that replaces non-alcoholic fatty liver disease (NAFLD), occurs in up to 70% of people with T2D. Not only do T2D and MASLD commonly co-occur, but there is a synergistic, bidirectional relationship between these conditions, meaning that each affects the natural disease course of the other. As such, it is important for those caring for people with T2D to recognize the importance of this co-diagnosis. In this summary, we detail the synergistic relationship between T2D and MASLD, explain the current challenges in recognizing this common co-diagnosis and suggest practical approaches for those caring for people with T2D to improve the diagnosis and treatment of MASLD.

The most common chronic liver illness worldwide is metabolic dysfunction linked to fatty liver disease (MAFLD), which is poorly understood by doctors and patients. Many people with this disease develop steatohepatitis, cirrhosis and its consequences, as well as extrahepatic manifestations; these conditions are particularly common if they are linked to diabetes mellitus or obesity. A breakthrough with numerous benefits is the switch from NAFLD to MAFLD in terms of terminology and methodology. The diagnosis of MAFLD is based on affirmative criteria; unlike NAFLD, it is no longer based on exclusion. The diagnosis of MAFLD and the evaluation of steatosis and fibrosis is achieved using liver biopsy and non-invasive laboratory or radiographic techniques. We briefly address the most recent developments in MAFLD epidemiology and diagnosis.

Given the substantial burden of metabolic dysfunction-associated steatotic liver disease (MASLD), there is an urgent need to assess knowledge and awareness levels among physicians. We assessed MASLD knowledge among healthcare providers from Saudi Arabia, Egypt, and Türkiye.

Two global surveys containing 54-59 items assessed awareness and knowledge of MASLD/NAFLD- one was for hepatologists and gastroenterologists, and the second was for non-specialists (e.g. endocrinologists, primary care providers [PCPs], and other healthcare professionals). Data were collected using an electronic data collection form. Knowledge scores and variables associated with higher knowledge scores were compared across all specialties.

A total of 584 physicians completed the survey (126 hepatologists, 178 gastroenterologists (GEs), 38 endocrinologists, 242 PCPs/others). Practice guidelines were the primary source for knowledge across all specialties (43-51%), then conferences (24-31%) except PCPs/others who selected the internet as the second common source (25%). Adherence to societal guidelines varied by specialty (81-84% of specialists vs 38-51% of non-specialists). Hepatologists and GEs showed similar mean knowledge scores (51-72% correct answers across three knowledge domains, p > 0.05); endocrinologists outperformed PCPs/others in knowledge scores in all knowledge domains, including Epidemiology/Pathogenesis (72% vs. 60%), Diagnostics (73% vs. 67%), and Treatment (78% vs. 67%) (all p < 0.01). Hospital-based practice and seeing a greater number of patients with MASLD/NAFLD were identified as independent predictors of higher knowledge scores among specialists (both p < 0.05).

A knowledge gap in the identification, diagnosis, and management of MASLD/NAFLD was found despite the growing burden of MASLD/NAFLD in Saudi Arabia, Egypt, and Türkiye. Education to increase awareness is needed.

Nonalcoholic fatty liver disease (NAFLD) is a global health challenge, with a rising rate in line with other metabolic diseases. We aimed to assess the global prevalence of NAFLD in adult and pediatric populations.

PubMed, Scopus and Web of Science databases were systematically searched up to May 2023. Heterogeneity was assessed using Cochran's Q test and I2 statistics, and random-effects model was used for meta-analysis. Analyses were performed using STATA version 18.

A total of 479 studies with 78,001,755 participants from 38 countries were finally included. The global prevalence of NAFLD was estimated to be 30.2% (95% CI: 28.7-31.7%). Regionally, the prevalence of NAFLD was as follows: Asia 30.9% (95% CI: 29.2-32.6%), Australia 16.1% (95% CI: 9.0-24.8%), Europe 30.2% (95% CI: 25.6-35.0%), North America 29% (95% CI: 25.8-32.3%), and South America 34% (95% CI: 16.9-53.5%). Countries with a higher human development index (HDI) had significantly lower prevalence of NAFLD (coefficient = -0.523, p = 0.005). Globally, the prevalence of NAFLD in men and women was 36.6% (95% CI: 34.7-38.4%) and 25.5% (95% CI: 23.9-27.1%), respectively. The prevalence of NAFLD in adults, adults with obesity, children, and children with obesity was 30.2% (95% CI: 28.8-31.7%), 57.5% (95% CI: 43.6-70.9%), 14.3% (95% CI: 10.3-18.8%), and 38.0% (95% CI: 31.5-44.7%), respectively.

The prevalence of NAFLD is remarkably high, particularly in countries with lower HDI. This substantial prevalence in both adults and children underscores the need for disease management protocols to reduce the burden.

There has been a rise in the prevalence of non-alcoholic steatohepatitis (NASH), a subset of non-alcoholic fatty liver disease (NAFLD) with an ongoing increase in the prevalence of linked conditions such as obesity, type II diabetes mellitus, and metabolic syndrome. To date, there are no specific drugs that are approved for the treatment of NAFLD/NASH. With the recent discovery of association between subclinical hypothyroidism and NASH, various trials exploring treatment options for NASH using thyroid hormone derivatives led to the discovery of resmetirom (MGL-316) with high affinity to thyroid hormone receptors (THRs) targeting the liver. Following standardized guidelines, a systematic review was performed on the safety, efficacy, and other practical aspects of resmetirom in the treatment of NASH. Advanced search was carried out using the MeSH search strategy and appropriate keywords in major databases using various inclusion and exclusion criteria. The search was narrowed down to seven high-quality articles: four randomized control trials (RCTs), and three reviews to be included in the current study. The online database search yielded 62 articles, out of which six high-quality articles were selected to be included in the current systematic review after deleting duplicates and screening for irrelevant titles, and articles. Out of the three RCTs, two of them assessed the safety and efficacy of resmetirom, while the remaining RCT assessed the impact on health-related quality of life with resmetirom on patients with NASH. resmetirom (MGL-316) is a thyroid hormone derivative with high affinity to THRs targeting the liver and acts by improving mitochondrial oxidation, and lipophagy in the hepatic cell line. All the trials suggested in favor of resmetirom with a decrease in NASH fibrosis score by at least two points, along with reduction in hepatic fat content (minimum relative reduction of 20%), liver volume by 61%, improving secondary outcomes such as low-density lipoprotein-C, apolipoprotein-B, triglycerides, and hepatic enzymes with greater reduction in the study groups treated with higher doses of resmetirom with no significant increase in adverse events. Resmetirom was found to improve patient-reported outcomes, and thereby quality-adjusted life years (QALYs) in 12 weeks while being cost-effective compared to placebo at a willingness-to-pay threshold of US$100,000 up to a daily threshold of US$72.00, and an effective incremental cost-effectiveness ratio of US$53,925 per QALY gained. After carefully analyzing the available data by our team members, it could be concluded that resmetirom holds a strong potential to be implemented as a drug of choice in treating NAFLD/NASH in the coming years with proven efficacy, safety while being cost-effective, and also reducing secondary co-morbidities by improving cardiovascular risk factors. The results can be best achieved when combined with conventional approaches such as weight loss and dietary modifications. Long-term safety and sustainability of the achieved results are yet to be confirmed with large-scale clinical trials. However, resmetirom is still an investigational drug and could be expected to be available for clinical practice in the near future.

Several genetic and metabolic variables, most notably the variation in the adipokine gene rs1501298, have been linked to metabolic-associated fatty liver disease etiopathogenesis (MAFLD). Liver biopsy, the gold standard for diagnosing MAFLD, is an invasive procedure; therefore, alternative diagnostic methods are required. Consequently, the integration of these metabolic variables with some of the patients' characteristics may facilitate the development of noninvasive diagnostic methods that aid in the early detection of MAFLD, identification of at-risk individuals and planning of management strategies.

This study included 224 Egyptians (107 healthy individuals and 117 MAFLD patients). Age, sex, BMI, clinical and laboratory characteristics, and rs1501299 adipokine gene polymorphisms were examined. The rs1501299 variant, insulin resistance, hypertension, obesity, blood pressure, lipid profile, hemoglobin A1C level, and hepatic fibrosis predictors were evaluated for MAFLD risk. The feasibility and effectiveness of developing non-invasive MAFLD diagnostic models will be investigated.

The +276G/T (rs1501299) polymorphism (GG vs GT/TT) was linked with MAFLD (OR: 0.43, CI: 0.26-0.69, P = 0.002). The GG variants had lower MAFLD rates than those of the GT and TT variants. In addition to altered lipid profiles, patients with MAFLD showed increased gamma-glutamyl transferase levels (GGT: 56 IU/L vs. 36 IU/L). Genetic diversity also affects the accuracy of hepatic fibrosis and steatosis prediction. Hepatic fibrosis and steatosis predictors had receiver operating characteristic (ROC) AUCs of 0.529%, 0.846%, and 0.700-0.825%, respectively. We examined a diagnostic model based on these variables and demonstrated its effectiveness.

The Adipokine variant rs1501299 increased the risk of MAFLD. Identifying and genotyping this variation and other metabolic variables allow for a noninvasive diagnostic model for early MAFLD diagnosis and identification of those at risk. This study illuminates the prevention and management of MAFLD. Further research with more participants is needed to verify these models and to prove their MAFLD diagnostic efficacy.

This study aims to evaluate the association of beverage consumption with cardiometabolic risk factors and alanine transaminase (ALT) levels in children and adolescents.

This nationwide study is a part of the fifth survey of a national surveillance program in Iran. Overall, 4200 students, aged 7-18 years, were selected from 30 provinces by multi-stage cluster sampling. In addition to filling in questionnaires, blood sampling and biochemical tests were done. The weekly use of six different beverage types including milk, juice, tea, coffee, soda, and non-alcoholic beer, was documented by interview.

The participation rate was 91.5% (n = 3843), and data of 3733 students were complete for the current study. Beverages containing high levels of sugar such as soda and non-alcoholic beer were significantly associated with higher levels of ALT. Model coefficient of regression (SD) was 0.66 (0.31) (P value: 0.034). Healthy beverages such as milk and fresh juice and also beverages containing high levels of caffeine did not have significant association with ALT levels (P value = 0.32, P value = 0.60). Healthy beverages had a significant and inverse relationship with triglycerides (TG) (P value = 0.029), total cholesterol (TC) (P value = 0.008) and low-density lipoprotein (LDL) (P value = 0.008) levels.

This study showed that consuming sugar-sweetened beverages is significantly associated with higher levels of ALT, whereas healthy beverages are associated with a better cardiometabolic profile meaning that consuming healthy beverages leads to lower TG, TC, and LDL levels. The effects of beverages on children's health should be emphasized in health recommendations.

In this editorial, we comment on the article by Chen et al. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a global public health burden whose incidence has risen concurrently with overweight and obesity. Given its detrimental health impact, early identification of at-risk individuals is crucial. MAFLD diagnosis is based on evidence of hepatic steatosis indicated by liver biopsy, imaging, or blood biomarkers, and one of the following conditions: Overweight/ obesity, type 2 diabetes mellitus, or metabolic dysregulation. However, in large-scale epidemiological studies, liver biopsies are not feasible. The application of techniques such as ultrasonography, computed tomography, magnetic resonance imaging, and magnetic resonance spectroscopy is restricted by their limited sensitivity, low effectiveness, high costs, and need for specialized software. Blood biomarkers offer several advantages, particularly in large-scale epidemiological studies or clinical scenarios where traditional imaging techniques are impractical. Analysis of cumulative effects of excess high-normal blood alanine aminotransferase (ALT) levels of blood ALT levels could facilitate identification of at-risk patients who might not be detected through conventional imaging methods. Accordingly, investigating the utility of blood biomarkers in MAFLD should enhance early detection and monitoring, enabling timely intervention and management and improving patient outcomes.

Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.

In community pathways for detection of liver disease the most common reason for referral is fibrosis assessment. We investigated the impact of adding the Enhanced Liver Fibrosis (ELF) score as a second-line test (subsequent to an indeterminate or high Fibrosis-4 index [FIB-4] and/or non-alcoholic fatty liver disease fibrosis score) to guide referral and prognostication in our multi-aetiology pathway.

Patients with ELF results from the intelligent Liver Function Testing (iLFT) pathway were recruited. Case note review was undertaken to compare ELF with endpoints of cirrhosis, hepatic decompensation, and mortality (liver-related and all-cause death).

In total, 1,327 individuals were included with a median follow-up of 859 days and median ELF score of 10.2. Overall sensitivity for cirrhosis at the 9.8 threshold was 94% (100% for metabolic-associated steatotic liver disease, 89% for alcohol-related liver disease). Determination of the ELF score as a second-line test reduced the referral rate by 34%. ELF scores predicted hepatic outcomes; each unit change was associated with increased decompensation (adjusted Hazard Ratio [aHR] 2.215, 95% CI: 1.934-2.537) and liver-related mortality (aHR 2.024, 95% CI: 1.674-2.446). ELF outperformed FIB-4 for risk of liver-related mortality, particularly in the short-term (area under the curve [AUC] 94.3% vs. 82.8% at six months). Where FIB-4 was indeterminate, ELF had higher AUC for all outcomes within at least 2 years. ELF ≥13 was associated with particularly high rates of decompensation (26% within 90 days) and all-cause mortality (38% at 1 year).

The addition of ELF reduced the number of individuals referred for fibrosis assessment following iLFT pathway testing and provided useful prognostic information. Individuals with ELF scores ≥13 were considered at high-risk of negative outcomes warranting urgent clinical assessment.

Primary care pathways for suspected liver disease are increasingly common and often lead to increased specialist hepatology referrals for fibrosis assessment. This study, using clinical follow-up for liver-related outcomes, provides further evidence supporting ELF testing to safely reduce referrals in a two-step approach when combined with other simple fibrosis markers. Additionally, ELF scores predict liver-related morbidity and mortality, with ELF scores ≥13 indicating particularly high-risk patients. This study may help inform the implementation of diagnostic pathways for early detection of liver disease and highlights the need for urgent review of individuals with very high ELF scores.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. Accumulating evidence in animal models suggests that loss of interleukin-10 (IL-10) anti-inflammatory actions might contribute to lobular inflammation, considered one of the first steps toward NASH development. However, the role of IL-10 in lobular inflammation remains poorly explored in humans. We examined mRNA and protein levels of IL-10 in liver biopsies and serum samples from morbidly obese patients, investigating the relationship between IL-10 and lobular inflammation degree. Materials and Methods: We prospectively enrolled morbidly obese patients of both sexes, assessing the lobular inflammation grade by the Brunt scoring system to categorize participants into mild (n = 7), moderate (n = 19), or severe (n = 13) lobular inflammation groups. We quantified the hepatic mRNA expression of IL-10 by quantitative polymerase chain reaction and protein IL-10 levels in liver and serum samples by Luminex Assay. We estimated statistical differences by one-way analysis of variance (ANOVA) and Tukey's multiple comparison test. Results: The hepatic expression of IL-10 significantly diminished in patients with severe lobular inflammation compared with the moderate lobular inflammation group (p = 0.01). The hepatic IL-10 protein levels decreased in patients with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.008 and p = 0.0008, respectively). In circulation, IL-10 also significantly decreased in subjects with moderate or severe lobular inflammation compared with the mild lobular inflammation group (p = 0.005 and p < 0.0001, respectively). Conclusions: In liver biopsies and serum samples of morbidly obese patients, the protein levels of IL-10 progressively decrease as lobular inflammation increases, supporting the hypothesis that lobular inflammation develops because of the loss of the IL-10-mediated anti-inflammatory counterbalance.

Insulin resistance is a common pathophysiology in patients with type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Thus, screening for the risk of insulin resistance is important to prevent disease progression. We evaluated the alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio to predict insulin resistance in the general population, regardless of comorbidities. Datasets from the 2015, 2019, and 2020 Korea National Health and Nutrition Examination Surveys were used, and the following four indices were implemented to indicate insulin resistance: fasting serum glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and β-cell function. We analyzed the degree of association between the liver enzyme profile and insulin resistance indices using Pearson's correlation coefficient and determined the associations using linear or logistic regression analysis. Accordingly, ALT levels in both sexes were positively and consistently correlated with the four aforementioned insulin resistance indices in stratification analyses based on diabetes, dyslipidemia, alcohol consumption, and obesity status. In multivariate linear regression, when comparing with ALT levels, the ALT/AST ratio exhibited superior predictive performance for fasting serum glucose and HOMA-β in Korean men and improved outcomes for all insulin resistance indices in Korean women. In this analysis that included a large community-based population, the ALT/AST ratio was a more useful predictive marker than the HOMA-IR. Regarding the predicted presence or absence of insulin resistance, the ALT/AST ratio could better predict HOMA-IR than the ALT level alone in Koreans. A simple, precise marker that represents the ALT/AST ratio could be a practical method to screen for insulin resistance in the general population, regardless of diabetes mellitus, alcohol intake, and sex.

Excess adipose tissue, particularly of the visceral type, triggering chronic low-grade inflammation and altering its secretory profile, is a contributing factor to the initiation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to compare the levels of selected adipokines and cytokines in individuals with normal weight and obesity, assessing their potential for diagnosing MASLD and establishing a cutoff point for body fat content associated with hepatic steatosis development. The research involved 99 participants categorized by body mass index and MASLD presence, undergoing body composition analysis, liver elastography, biochemical tests, and evaluation of adipokines and cytokines in serum. The results indicated elevated IL-6 (interleukin 6) serum levels in individuals with obesity with MASLD compared to the normal-weight group without MASLD. The multivariate regression analysis demonstrated a connection between hepatic steatosis and total adipose tissue content, VAT (visceral adipose tissue), VAT/SAT (subcutaneous adipose tissue) ratio, HOMA-IR (homeostasis model assessment of insulin resistance), IL-6, Il-1β (interleukin 1β), and MMP-2 (matrix metalloproteinase 2). Among the adipokines and cytokines examined in this study, interleukin 6 was the strongest predictor of MASLD regardless of gender. In addition, an association between the development of hepatic steatosis and higher serum IL-1β levels and higher adipose tissue was observed in women. However, further studies on a larger group of patients are needed to consider the use of these cytokines as markers of MASLD. The HOMA-IR index demonstrated potential diagnostic utility in identifying hepatic steatosis.

There is increasing appreciation of the complex interaction between nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D) and insulin resistance. Not only is the prevalence of NAFLD disease high among patients with T2D, the liver disease is also more progressive. Currently, the global prevalence of NAFLD in the general population (2016-2019) is 38 %. The prevalence of T2D among those with NAFLD is approximately 23 % while the prevalence of NAFLD among those with T2D can be as high as 70 %. The prevalence of nonalcoholic steatohepatitis (NASH) is approximately 7 % in the general population and 37 % among patients with T2D. Globally, the MENA and Latin America regions of the world appear to have the highest burden of both NAFLD and T2D. Compared to those with NAFLD but without T2D, those with NAFLD and T2D are at a much higher risk for disease progression to cirrhosis and for decompensated cirrhosis, hepatocellular carcinoma, and all-cause mortality. Given that highly effective new treatments are available for T2D, high risk NAFLD with T2D should be considered for these regimens. This requires implementation of risk stratification algorithms in the primary care and endocrinology practices to identify those patients at highest risk for adverse outcomes.

We examined midlife (1990-1992, mean age 57) and late-life (2011-2013, mean age 75) nonalcoholic fatty liver disease (NAFLD) and aminotransferase with incident dementia risk through 2019 in the Atherosclerosis Risk in Communities (ARIC) Study.

We characterized NAFLD using the fatty liver index and fibrosis-4, and we categorized aminotransferase using the optimal equal-hazard ratio (HR) approach. We estimated HRs for incident dementia ascertained from multiple data sources.

Adjusted for demographics, alcohol consumption, and kidney function, individuals with low, intermediate, and high liver fibrosis in midlife (HRs: 1.45, 1.40, and 2.25, respectively), but not at older age, had higher dementia risks than individuals without fatty liver. A U-shaped association was observed for alanine aminotransferase with dementia risk, which was more pronounced in late-life assessment.

Our findings highlight dementia burden in high-prevalent NAFLD and the important feature of late-life aminotransaminase as a surrogate biomarker linking liver hypometabolism to dementia. Highlights Although evidence of liver involvement in dementia development has been documented in animal studies, the evidence in humans is limited. Midlife NAFLD raised dementia risk proportionate to severity. Late-life NAFLD was not associated with a high risk of dementia. Low alanine aminotransferase was associated with an elevated dementia risk, especially when measured in late life.

To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors.

A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms.

The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples.

Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.