Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.

Genetic algorithms applied to translational strategy in metabolic-dysfunction associated steatohepatitis (MASH). Learning from mouse models.

BACKGROUND & AIMS: We previously identified subsets of patients with metabolic (dysfunction)-associated steatotic liver disease (MASLD) with different metabolic phenotypes. Here, we aimed to refine this classification based on genetic algorithms implemented in a Python package. The use of these genetic algorithms can help scientists to solve problems which cannot be solved with other methods. We present this package and its capabilities with specific problems. The name, PyGenMet, comes from its main goal, solving problems in Python with Genetic Algorithms and Metabolomics data. METHODS: We collected serum from methionine adenosyltransferase 1a knockout (Mat1a-KO) mice, which have chronically low level of hepatic S-adenosylmethionine (SAMe) and the metabolomes of all samples were determined. We also analyzed serum metabolomes of 541 patients with biopsy proven MASLD (182 with simple steatosis and 359 with metabolic (dysfunction)-associated steatohepatitis or MASH) and compared them with the serum metabolomes of this specific MASLD mouse model using Genetic Algorithms in order to select patients with a specific phenotype. RESULTS: By applying genetic algorithms, we have found a subgroup of patients with a lipid profile similar to that observed in the mouse model. When analyzing the two groups of patients, we have seen that patients with a lipid profile reflecting the mouse model characteristics show significant differences in lipoproteins, especially in LDL-4, LDL-5, and LDL-6 associated with atherogenic risk. CONCLUSION: The results show that the application of genetic algorithms to subclassify patients with MASLD (or other metabolic disease) give consistent results and are a good approximation for the treatment of large volumes of data such as those from omics sciences and patient classification.

Metabolic dysfunction-associated steatohepatitis exhibits sex differences in people with HIV.

OBJECTIVES: People with HIV are at increased risk for metabolic dysfunction-associated steatohepatitis (MASH). Although sex differences are documented in the general population, their role in the context of HIV is less understood. METHODS: This was a multicentre cohort study including people with HIV without viral hepatitis coinfection. A FibroScan-AST (FAST) score >0.35 was used to diagnose MASH with significant liver fibrosis (stage F2-F4). We investigated sex-based differences in MASH trends as a function of age using a segmented linear mixed-effects model. Random effects accounted for clustering by the four sites. Adjusted models included ethnicity, diabetes, hypertension, and detectable HIV viral load. RESULTS: We included 1472 people with HIV (25% women). At baseline, the prevalence of MASH with fibrosis by FAST score was lower in women than in men (4.8% vs. 9.2%, p = 0.008). Based on the adjusted model, male sex (+0.034; p = 0.04), age per year (+0.003; p = 0.05), detectable HIV viral load (+0.034; p = 0.02), and hypertension (+0.03; p = 0.01) were positively associated with MASH with fibrosis. Although men exhibited generally higher FAST scores, FAST scores increased in women during the critical biological age of presumed perimenopause to menopause (between 40 and 50 years), reaching levels similar to those in men by the age of 55 years. CONCLUSION: Despite women with HIV having a lower prevalence of MASH with fibrosis than men, they exhibit an acceleration in FAST score increase around the perimenopausal age. Future studies should target adequate consideration of sex differences in clinical investigation of metabolic dysfunction-associated steatotic liver disease to fill current gaps and implement precision medicine for people with HIV.

The interaction of genetics and physical activity in the pathogenesis of metabolic dysfunction associated liver disease.

Genetic variants associated with increased liver fat and volume have been reported, but whether physical activity (PA) can attenuate the impact of genetic susceptibility to these traits is poorly understood. We aimed to investigate whether higher PA modify genetic impact on liver-related traits in the UK Biobank cohort. PA was self-reported, while magnetic resonance images were used to estimate liver fat (n = 27,243) and liver volume (n = 24,752). Metabolic dysfunction-associated liver disease (MASLD) and chronic liver disease (CLD) were diagnosed using ICD-9 and ICD-10 codes. Ten liver fat and eleven liver volume-associated genetic variants were selected and unweighted genetic-risk scores for liver fat (GRSLF) and liver volume (GRSLV) were computed. Linear regression analyses were performed to explore interactions between GRSLF/ GRSLV and PA in relation to liver-related traits. Association between GRSLF and liver fat was not different among lower (ß = 0.063, 95% CI 0.041-0.084) versus higher PA individuals (ß = 0.065, 95% CI 0.054-0.077, pinteraction = 0.62). The association between the GRSLV and liver volume was not different across different PA groups (pinteraction = 0.71). Similarly, PA did not modify the effect of GRSLF and GRSLV on MASLD or CLD. Our findings show that physical activity and genetic susceptibility to liver-related phenotypes seem to act independently, benefiting all individuals regardless of genetic risk.

Metabolic dysfunction-associated steatotic liver disease (SLD) and alcohol-associated liver disease, but not SLD without metabolic dysfunction, are independently associated with new onset of chronic kidney disease during a 10-year follow-up period.

AIMS: The new nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We aimed to elucidate the relationship between each category of SLD and chronic kidney disease (CKD). METHODS: We investigated the effects of various SLDs on the development of CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or positive for urinary protein, during a 10-year period in 12 138 Japanese subjects (men / women, 7984/4154; mean age, 48 years) who received annual health examinations including abdominal ultrasonography. RESULTS: The prevalences of SLD without metabolic dysfunction (SLD-MD[-]), MASLD, MetALD, and ALD were 1.7%, 26.3%, 4.9%, and 1.9%, respectively. During the follow-up period, 1963 subjects (16.2%) (men / women, 1374 [17.2%]/589 [14.2%]) had new onset of CKD. Multivariable Cox proportional hazard model analyses after adjustment of age, sex, eGFR, current smoking habit, diabetes mellitus, hypertension, and dyslipidemia showed that the hazard ratios (HR [95% confidence interval]) for the development of CKD in subjects with MASLD (1.20 [1.08-1.33], p = 0.001) and those with ALD (1.41 [1.05-1.88], p = 0.022), but not those with MetALD (1.11 [0.90-1.36], p = 0.332), were significantly higher than the HR in subjects with non-SLD. Interestingly, subjects with SLD-MD[-] had a significantly lower HR (0.61 [0.39-0.96], p = 0.034) than that in subjects with non-SLD. The addition of the novel classification of SLDs into traditional risk factors for the development of CKD significantly improved the discriminatory capacity. CONCLUSIONS: MASLD and ALD, but not SLD-MD[-], are independently associated with the development of CKD.

Growth differentiation factor 15: Emerging role in liver diseases.

Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-ß (TGFß) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases.

Current and experimental pharmacotherapy for the management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with its incidence increasing in parallel with the global prevalence of obesity and type 2 diabetes mellitus. Despite our steadily increasing knowledge of its pathogenesis, there is as yet no available pharmacotherapy specifically tailored for NAFLD. To define the appropriate management, it is important to clarify the context in which the disease appears. In the case of concurrent metabolic comorbidities, NAFLD patients are treated by targeting these comorbidities, such as diabetes and obesity. Thus, GLP-1 analogs, PPAR, and SGLT2 inhibitors have recently become central to the treatment of NAFLD. In parallel, randomized trials are being conducted to explore new agents targeting known pathways involved in NAFLD progression. However, there is an imperative need to intensify the effort to design new, safe drugs with biopsy-proven efficacy. Of note, the main target of the pharmacotherapy should be directed to the regression of fibrotic NASH, as this histologic stage has been correlated with increased overall as well as liver-related morbidity and mortality. Herein we discuss the drugs currently at the forefront of NAFLD treatment.

Between-Visit Reproducibility of Shear Wave Viscoelastography in Volunteers and Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease.

OBJECTIVE: To assess the reproducibility of six ultrasound (US)-determined shear wave (SW) viscoelastography parameters for assessment of mechanical properties of the liver in volunteers and patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH). METHODS: This prospective, cross-sectional, institutional review board-approved study included 10 volunteers and 20 patients with MASLD or MASH who underwent liver US elastography twice, at least 2 weeks apart. SW speed (SWS), Young's modulus (E), shear modulus (G), SW attenuation (SWA), SW dispersion (SWD), and viscosity were computed from radiofrequency data recorded on a research US scanner. Linear mixed models were used to consider the sonographer on duty as a confounder. The reproducibility of measurements was assessed by intraclass correlation coefficient (ICC), coefficient of variation (CV), reproducibility coefficient (RDC), and Bland-Altman analyses. RESULTS: The sonographer performing the exam had no impact on viscoelastic parameters (P > .05). ICCs of SWS, E, G, SWA, SWD, and viscosity were, respectively, 0.89 (95% confidence intervals [CI]: 0.79-0.95), 0.81 (95% CI: 0.79-0.95), 0.90 (95% CI: 0.80-0.95), 0.96 (95% CI: 0.93-0.98), 0.78 (95% CI: 0.60-0.89), and 0.90 (95% CI: 0.80-0.95); CVs were 11.9, 23.3, 24.2, 10.1, 29.0, and 32.2%; RDCs were 33.0, 64.5, 66.9, 27.7, 80.3, and 89.2%, and Bland-Altman mean biases and 95% limits of agreement were -0.05 (-0.45, 0.35) m/s, -0.61 (-5.33, 4.10) kPa, -0.25 (-2.06, 1.56) kPa, -0.01 (-0.27, 0.26) Np/m/Hz, -0.09 (-7.09, 6.91) m/s/kHz, and -0.33 (-2.60, 1.94) Pa/s, between the two visits. CONCLUSION: US-determined viscoelastography parameters can be measured with high reproducibility and consistency between two visits 2 weeks apart on the same ultrasound machine.

Circulating miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p as potential predictive biomarkers for Metabolic Dysfunction-Associated Steatotic Liver Disease assessment.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a worldwide leading cause of liver-related associated morbidities and mortality. Currently, there is a lack of reliable non-invasive biomarkers for an accurate of MASLD. Hence, this study aimed to evidence the functional role of miRNAs as potential biomarkers for MASLD assessment. Data from 55 participants with steatosis (MASLD group) and 45 without steatosis (control group) from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. Anthropometrics and body composition, biochemical and inflammatory markers, lifestyle factors and liver status were evaluated. Circulating miRNA levels were measured by RT-PCR. Circulating levels of miR-122-5p, miR-151a-3p, miR-126-5p and miR-21-5p were significantly increased in the MASLD group. These miRNAs were significantly associated with steatosis, liver stiffness and hepatic fat content. Logistic regression analyses revealed that miR-151a-3p or miR-21-5p in combination with leptin showed a significant diagnostic accuracy for liver stiffness obtaining an area under the curve (AUC) of 0.76 as well as miR-151a-3p in combination with glucose for hepatic fat content an AUC of 0.81. The best predictor value for steatosis was obtained by combining miR-126-5p with leptin, presenting an AUC of 0.95. Circulating miRNAs could be used as a non-invasive biomarkers for evaluating steatosis, liver stiffness and hepatic fat content, which are crucial in determining MASLD. CLINICAL TRIAL REGISTRATION: • Trial registration number: NCT03183193 ( www.clinicaltrials.gov ). • Date of registration: 12/06/2017.

Elongation factor 1A1 inhibition elicits changes in lipid droplet size, the bulk transcriptome, and cell type-associated gene expression in MASLD mouse liver.

Eukaryotic elongation factor 1A1 (EEF1A1), originally identified for its role in protein synthesis, has additional functions in diverse cellular processes. Of note, we previously discovered a role for EEF1A1 in hepatocyte lipotoxicity. We also demonstrated that a two-week intervention with the EEF1A1 inhibitor didemnin B (DB) (50 µg/kg) decreased liver steatosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) (129S6/SvEvTac mice fed western diet (42% fat) for 26 weeks). Here, we further characterized hepatic changes occurring in these mice by assessing lipid droplet (LD) size, bulk differential expression, and cell type-associated alterations in gene expression. Consistent with the previously demonstrated decrease in hepatic steatosis, we observed decreased median LD size in response to DB. Bulk RNA-seq followed by gene set enrichment analysis revealed alterations in pathways related to energy metabolism and proteostasis in DB-treated mouse livers. Deconvolution of bulk data identified decreased cell-type association scores for cholangiocytes, mononuclear phagocytes, and mesenchymal cells in response to DB. Overrepresentation analyses of bulk data using cell type marker gene sets further identified hepatocytes and cholangiocytes as the primary contributors to bulk differential expression in response to DB. Thus, we show that chemical inhibition of EEF1A1 decreases hepatic LD size and decreases gene expression signatures associated with several liver cell types implicated in MASLD progression. Furthermore, changes in hepatic gene expression were primarily attributable to hepatocytes and cholangiocytes. This work demonstrates that EEF1A1 inhibition may be a viable strategy to target aspects of liver biology implicated in MASLD progression.

Manifestation and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease in a Predominately African American Population at a Multi-Specialty Healthcare Organization.

African Americans (AA) have a high incidence of risk factors associated with MASLD (metabolic dysfunction-associated steatotic liver disease); the AA population has a lower incidence of MASLD and MASH (metabolic-associated steatotic hepatitis) than Caucasian and Hispanic Americans (non-AA). We investigated if underlying risk factor variation between AA and non-AA individuals could provide a rationale for the racial diversity seen in MASLD/MASH. Using ICD-10 codes, patients from 2017 to 2020 with MASLD/MASH were identified and confirmed to have either MASLD or MASH. Despite the large (>80%) AA population in our clinics, only 54% of the MASLD/MASH patients were African American. When the non-invasive NAFLD Fibrosis Scores (NFS) evaluated at early diagnosis were compared to the most recent values, the only increase in fibrosis score by NFS over time was in non-AA MASH patients. The increase in fibrosis only in non-AA MASLD patients is consistent with racial disparity in the disease progression in non-AA as compared to AA patients. Even with the large proportion of AA patients in our study, there was no significant racial disparity in the earliest assessment of either risk factors, laboratory values, or fibrosis scores that would account for racial disparity in the development and progression of MASLD.

Immunology of bile acids regulated receptors.

Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.

Efficacy of Ultrasound for the Detection of Possible Fatty Liver Disease in Children.

Pediatric MASLD (previously referred to as NAFLD) incidence has continued to rise along with the obesity pandemic. Pediatric MASLD increases the risk of liver fibrosis and cirrhosis in adulthood. Early detection and intervention can prevent and reduce complications. Liver biopsy remains the gold standard for diagnosis, although imaging modalities are increasingly being used. We performed a retrospective study of 202 children seen in a pediatric gastroenterology clinic with a complaint of abdominal pain, elevated liver enzymes or MASLD, or a combination of the three to evaluate screening methods for MASLD. A total of 134 of the 202 patients included in the study underwent laboratory testing and abdominal ultrasound. Ultrasound images were reviewed with attention to liver size and echotexture by a fellowship-trained pediatric radiologist for liver size and echotexture. Overall, 76.2% of the initial radiology reports correctly identified hepatomegaly based on age and 75.4% of the initial radiology reports correctly described hepatic echogenicity that was consistent with increased hepatic fat deposition. Use of screening ultrasound in concert with other clinical evaluations can be helpful to identify children at risk of MASLD. Utilizing ranges for liver span according to age can help to diagnose hepatomegaly, and understanding how to identify hepatic echogenicity is important for identifying possible hepatic steatosis.

Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, against MASLD Progression.

Progression of metabolic dysfunction-associated steatites liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis, and MASH can lead to cirrhosis and hepatocellular carcinoma. Previously, we showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2-related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASH-linked liver fibrosis and tumorigenesis. Male and female mice with flox alleles for genes encoding Nrf1 (Nfe2l1), Nrf2 (Nfe2l2), or both were fed a MASH-inducing diet enriched with high fat, fructose, and cholesterol (HFFC) or a control diet for 24-52 weeks. During this period, hepatocyte Nrf1, Nrf2, or combined deficiency for ~7 days, ~7 weeks, and ~35 weeks was induced by administering mice hepatocyte-targeting adeno-associated virus (AAV) expressing Cre recombinase. The effects on MASH, markers of liver fibrosis and proliferation, and liver tumorigenesis were compared to control mice receiving AAV-expressing green fluorescent protein. Also, to assess the impact of Nrf1 and Nrf2 induction on liver fibrosis, HFFC diet-fed C57bl/6J mice received weekly injections of carbon tetrachloride, and from week 16 to 24, mice were treated with the Nrf2-activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and these groups were compared to control. Compared to the control diet, 24-week feeding with the HFFC diet increased bodyweight as well as liver weight, steatosis, and inflammation. It also increased hepatocyte proliferation and a marker of liver damage, p62. Hepatocyte Nrf1 and combined deficiency increased liver steatosis in control diet-fed but not HFFC diet-fed mice, and increased liver inflammation under both diet conditions. Hepatocyte Nrf1 deficiency also increased hepatocyte proliferation, whereas combined deficiency did not, and this also occurred for p62 level in control diet-fed conditions. In 52-week HFFC diet-fed mice, 35 weeks of hepatocyte Nrf1 deficiency, but not combined deficiency, resulted in more liver tumors in male mice, but not in female mice. In contrast, hepatocyte Nrf2 deficiency had no effect on any of these parameters. However, in the 15-week CCL4-exposed and 24-week HFFC diet-fed mice, Nrf2 induction with bardoxolone reduced liver steatosis, inflammation, fibrosis, and proliferation. Induction of hepatic Nrf1 activity with hNRF1 enhanced the effect of bardoxolone on steatosis and may have stimulated liver progenitor cells. Physiologic Nrf1 delays MASLD progression, Nrf2 induction alleviates MASH, and combined enhancement synergistically protects against steatosis and may facilitate liver repair.

NAFLD (MASLD)/NASH (MASH): Does It Bother to Label at All? A Comprehensive Narrative Review.

Nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated steatotic liver disease (MASLD), is a liver condition that is linked to overweight, obesity, diabetes mellitus, and metabolic syndrome. Nonalcoholic steatohepatitis (NASH), or metabolic dysfunction-associated steatohepatitis (MASH), is a form of NAFLD/MASLD that progresses over time. While steatosis is a prominent histological characteristic and recognizable grossly and microscopically, liver biopsies of individuals with NASH/MASH may exhibit several other abnormalities, such as mononuclear inflammation in the portal and lobular regions, hepatocellular damage characterized by ballooning and programmed cell death (apoptosis), misfolded hepatocytic protein inclusions (Mallory-Denk bodies, MDBs), megamitochondria as hyaline inclusions, and fibrosis. Ballooning hepatocellular damage remains the defining feature of NASH/MASH. The fibrosis pattern is characterized by the initial expression of perisinusoidal fibrosis ("chicken wire") and fibrosis surrounding the central veins. Children may have an alternative form of progressive NAFLD/MASLD characterized by steatosis, inflammation, and fibrosis, mainly in Rappaport zone 1 of the liver acinus. To identify, synthesize, and analyze the scientific knowledge produced regarding the implications of using a score for evaluating NAFLD/MASLD in a comprehensive narrative review. The search for articles was conducted between 1 January 2000 and 31 December 2023, on the PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases. This search was complemented by a gray search, including internet browsers (e.g., Google) and textbooks. The following research question guided the study: "What are the basic data on using a score for evaluating NAFLD/MASLD?" All stages of the selection process were carried out by the single author. Of the 1783 articles found, 75 were included in the sample for analysis, which was implemented with an additional 25 articles from references and gray literature. The studies analyzed indicated the beneficial effects of scoring liver biopsies. Although similarity between alcoholic steatohepatitis (ASH) and NASH/MASH occurs, some patterns of hepatocellular damage seen in alcoholic disease of the liver do not happen in NASH/MASH, including cholestatic featuring steatohepatitis, alcoholic foamy degeneration, and sclerosing predominant hyaline necrosis. Generally, neutrophilic-rich cellular infiltrates, prominent hyaline inclusions and MDBs, cholestasis, and obvious pericellular sinusoidal fibrosis should favor the diagnosis of alcohol-induced hepatocellular injury over NASH/MASH. Multiple grading and staging methods are available for implementation in investigations and clinical trials, each possessing merits and drawbacks. The systems primarily used are the Brunt, the NASH CRN (NASH Clinical Research Network), and the SAF (steatosis, activity, and fibrosis) systems. Clinical investigations have utilized several approaches to link laboratory and demographic observations with histology findings with optimal platforms for clinical trials of rapidly commercialized drugs. It is promising that machine learning procedures (artificial intelligence) may be critical for developing new platforms to evaluate the benefits of current and future drug formulations.

Regional gray matter changes in steatotic liver disease provide a neurobiological link to depression: A cross-sectional UK Biobank cohort study.

BACKGROUND: Steatotic liver disease (SLD) is characterized by excessive accumulation of lipids in the liver. It is associated with elevated risk of hepatic and cardiometabolic diseases, as well as mental disorders such as depression. Previous studies revealed global gray matter reduction in SLD. To investigate a possible shared neurobiology with depression, we examined liver fat-related regional gray matter alterations in SLD and its most significant clinical subgroup metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We analyzed regional cortical thickness and area obtained from brain MRI in 29,051 participants in UK Biobank. Liver fat amount was computed as proton density fat fraction (PDFF) from liver MRI scans. We examined the relationship between brain structure and PDFF, adjusting for sociodemographic, physical, lifestyle, and environmental factors, as well as alcohol intake and a spectrum of cardiometabolic covariates. Finally, we compared patterns of brain alterations in SLD/MASLD and major depressive disorder (MDD) using previously published results. RESULTS: PDFF-related gray matter alterations were region-specific, involving both increases and decreases in cortical thickness, and increased cortical area. In several regions, PDFF effects on gray matter could also be attributed to cardiometabolic covariates. However, PDFF was consistently associated with lower cortical thickness in middle and superior temporal regions and higher cortical thickness in pericalcarine and right frontal pole regions. PDFF-related alterations for the SLD and the MASLD group correlated with those observed in MDD (Pearson r = 0.45-0.54, p < 0.01). CONCLUSION: These findings suggest the presence of shared biological mechanisms linking MDD to SLD and MASLD. They might explain the well-known elevated risk of depression in these groups and support early lifestyle interventions and treatment of metabolic risk factors for the successful management of the interconnected diseases depression and SLD/MASLD.

Sex hormones differently regulate lipid metabolism genes in primary human hepatocytes.

BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is higher in men than in women. Hormonal and genetic causes may account for the sex differences in MASLD. Current human in vitro liver models do not sufficiently take the influence of biological sex and sex hormones into consideration. METHODS: Primary human hepatocytes (PHHs) were isolated from liver specimen of female and male donors and cultured with sex hormones (17ß-estradiol, testosterone and progesterone) for up to 72 h. mRNA expression levels of 8 hepatic lipid metabolism genes were analyzed by RT-qPCR. Sex hormones and their metabolites were determined in cell culture supernatants by LC-MS analyses. RESULTS: A sex-specific expression was observed for LDLR (low density lipoprotein receptor) with higher mRNA levels in male than female PHHs. All three sex hormones were metabolized by PHHs and the effects of hormones on gene expression levels varied depending on hepatocyte sex. Only in female PHHs, 17ß-estradiol treatment affected expression levels of PPARA (peroxisome proliferator-activated receptor alpha), LIPC (hepatic lipase) and APOL2 (apolipoprotein L2). Further changes in mRNA levels of female PHHs were observed for ABCA1 (ATP-binding cassette, sub-family A, member 1) after testosterone and for ABCA1, APOA5 (apolipoprotein A-V) and PPARA after progesterone treatment. Only the male PHHs showed changing mRNA levels for LDLR after 17ß-estradiol and for APOA5 after testosterone treatment. CONCLUSIONS: Male and female PHHs showed differences in their expression levels of hepatic lipid metabolism genes and their responsiveness towards sex hormones. Thus, cellular sex should be considered, especially when investigating the pathophysiological mechanisms of MASLD.

Precision medicine and nucleotide-based therapeutics to treat MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex multifactorial disease and becoming the leading cause of liver-related morbidity and mortality. MASLD spans from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), that may progress to cirrhosis and hepatocellular carcinoma (HCC). Genetic, metabolic, and environmental factors strongly contribute to the heterogeneity of MASLD. Lifestyle intervention and weight loss represent a viable treatment for MASLD. Moreover, Resmetirom, a thyroid hormone beta receptor agonist, has recently been approved for MASLD treatment. However, most individuals treated did not respond to this therapeutic suggesting the need for a more tailored approach to treat MASLD. Oligonucleotide-based therapies, namely small-interfering RNA (siRNA) and antisense oligonucleotide (ASO), have been recently developed to tackle MASLD by reducing the expression of genes influencing MASH progression, such as PNPLA3 and HSD17B13. Here, we review the latest progress made in the synthesis and development of oligonucleotide-based agents targeting genetic determinants of MASH.

Incorporating artificial intelligence in portable infrared thermal imaging for the diagnosis and staging of nonalcoholic fatty liver disease.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is one of the most prevalent chronic liver diseases worldwide. Thermal imaging combined with advanced image-processing and machine learning analysis accurately classified disease status in a study on mice; this study aimed to develop this tool for humans. This prospective study included 46 patients who underwent liver biopsy. Liver thermal imaging was performed on the same day as liver biopsy. We developed an image-processing algorithm that measured the relative spatial thermal variation across the skin covering the liver. The texture parameters obtained from the thermal images were input into the machine learning algorithm. Patients were diagnosed with MASLD and stratified according to nonalcoholic fatty liver disease activity score (NAS) and fibrosis stage using the METAVIR score. Twenty-one of 46 patients were diagnosed with MASLD. Using thermal imaging followed by processing, detection accuracy for patients with NAS >4 was 0.72.

Acute-on-chronic liver failure in metabolic dysfunction-associated fatty liver disease patients: a disease multiplier.

Acute-on-chronic liver failure (ACLF) is a syndrome of liver failure due to an acute hepatic insult leading to liver failure with or without extra-hepatic organ failure in a patient of chronic liver disease (CLD) with or without cirrhosis presenting for the first time. The definition is still with controversy; hence, homogeneity and clarity of the case is an unmet need. There is a paradigm shift noted as far as the etiology of CLD is concerned with rise in metabolic dysfunction-associated fatty liver disease (MAFLD) and ethanol as the dominant cause even in developing countries. MAFLD is the change in nomenclature from NAFLD to justify the metabolic derangement in these group of patients. The shift from an exclusion-based criteria to one that has evolved to a diagnosis that requires positive criteria has profound significance. Clearly there is a difference in terms of its prevalence, disease progression, and liver-related events, as well as management of metabolic risk factors and MAFLD itself which requires further understanding. In tandem with the global rise in MAFLD, the incidence of MAFLD-ACLF is increasing. Excessive alcohol consumption causes metabolic and toxic injury to the liver resulting in nearly similar pathway of fatty liver, hepatitis, and cirrhosis. The interaction of MAFLD as an additional underlying chronic liver injury in ACLF patients is complex due to the presence of metabolic risk factors that are unique to MAFLD. There is lack of clarity on how MAFLD affects the clinical course of ACLF due to scarcity of this specific data. This narrative review aims to understand the unique effects, consequences, and management of MAFLD as the chronic liver injury component in ACLF.