Metabolic (dysfunction)-associated fatty liver disease metrics and contributions to liver research.

BACKGROUND: The international consensus to revise non-alcoholic fatty liver disease to metabolic (dysfunction)-associated fatty liver disease (MAFLD) in 2020 attracted significant attention. The impact of the MAFLD definition on the research community has not been objectively assessed. We conducted an analysis of systematically collected literature on MAFLD to understand its research impact. METHODS: From PubMed, Web of Science, and Scopus, the literature adopting MAFLD, written in English, and published from 2020 to 10 October 2023 was collected. The publication metrics, including publication counts, publishing journals, author countries, author keywords, and citation information, were analyzed to evaluate the research impact and key topics on MAFLD. RESULTS: 1469 MAFLD-related papers were published in 434 journals with a steady increase in the number. The intense publishing and citations activity on MAFLD indicates the large impact of the redefinition. Topic assessment with keyword and citation analysis revealed a transition from the proposal and discussion of the redefinition to clinical characterization of MAFLD with a focus on metabolic dysfunction. Moreover, the diagnostic criteria for MAFLD showed better performance in predicting hepatic and extrahepatic outcomes compared to NAFLD. The publications were from 99 countries with evidence of strong regional and global collaboration. Multiple international societies and stakeholders have endorsed MAFLD for its utility in clinical practice, improving patient management and promoting multidisciplinary care, while alleviating stigma. CONCLUSION: This survey provides a quantitative measure of the considerable international impact and contributions of the MAFLD definition towards liver research and as part of the spectrum of cardiometabolic disorders.

A literature review of genetics and epigenetics of HCV-related hepatocellular carcinoma: translational impact.

Background and Objective: Hepatocellular carcinoma (HCC) poses a significant global health burden and ranks as the fifth most prevalent cancer on a global scale. Hepatitis C virus (HCV) infection remains one of the major risk factors for HCC development. HCC is a heterogeneous disease, and the development of HCC caused by HCV is intricate and involves various factors, including genetic susceptibility, viral factors, immune response due to chronic inflammation, alcohol abuse, and metabolic dysfunction associated with fatty liver disease. In this review, we provide a comprehensive and updated review of research on the genetics and epigenetic mechanisms implicated in developing HCC associated with HCV infection. We also discuss the potential translational implications, including novel biomarkers and drugs for treatment. Methods: A comprehensive literature search was conducted in June 2023 in PubMed and Embase databases. Key Content and Findings: Recent findings indicate that a variety of genetic and epigenetic processes are involved in the pathogenesis and continue to exist even after the complete elimination of HCV. The deregulation of the epigenome has been identified as a significant factor in the deletrious effects of liver disease, especially during the initial stages when genetic alterations are uncommon. The enduring "epigenetic memory" of gene expression is believed to be regulated by epigenetic mechanisms, indicating that alterations caused by HCV infection continue to exist and are linked to the risk of development of liver cancer even after successful treatment. Systems biology analytical methods will be required to delineate the magnitude and significance of both genetic and epigenomic alterations in tumor evolution. Conclusions: By facilitating a more profound understanding of these aspects, this will ultimately foster the advancement of novel therapies and ultimately improve outcomes for patients.

Clinical features and mortality outcomes of patients with MASLD only compared to those with MAFLD and MASLD.

BACKGROUND AND AIMS: The applicability of the proposed metabolic dysfunction-associated steatotic liver disease (MASLD) definition has not been validated. We aimed to characterize the profiles and long-term survival of people meeting the criteria for MASLD, but not that of metabolic dysfunction-associated fatty liver disease (MAFLD), i.e. MASLD only. METHODS: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994, 7791 adult participants were included and categorized into four distinct groups: no SLD, non-MAFLD MASLD, MASLD-MAFLD, and cryptogenic SLD (steatosis without metabolic dysfunction). RESULTS: Participants in the MASLD-only group were younger and had better metabolic profiles and fibrosis degree compared to those with MASLD-MAFLD and those with no SLD. Their profiles were comparable to those with cryptogenic SLD. Similarly, the MASLD-only group tend to have lower cumulative incidence of all-cause and cardiovascular mortality. Clustering analysis showed that MASLD only clusters differently from individuals with MASLD-MAFLD. CONCLUSIONS: MASLD only is a distinct clinical group with substantial heterogeneity compared to those captured using the MAFLD criteria.

A Novel Model for Instance Segmentation and Quantification of Bridge Surface Cracks-The YOLOv8-AFPN-MPD-IoU.

Surface cracks are alluded to as one of the early signs of potential damage to infrastructures. In the same vein, their detection is an imperative task to preserve the structural health and safety of bridges. Human-based visual inspection is acknowledged as the most prevalent means of assessing infrastructures' performance conditions. Nonetheless, it is unreliable, tedious, hazardous, and labor-intensive. This state of affairs calls for the development of a novel YOLOv8-AFPN-MPD-IoU model for instance segmentation and quantification of bridge surface cracks. Firstly, YOLOv8s-Seg is selected as the backbone network to carry out instance segmentation. In addition, an asymptotic feature pyramid network (AFPN) is incorporated to ameliorate feature fusion and overall performance. Thirdly, the minimum point distance (MPD) is introduced as a loss function as a way to better explore the geometric features of surface cracks. Finally, the middle aisle transformation is amalgamated with Euclidean distance to compute the length and width of segmented cracks. Analytical comparisons reveal that this developed deep learning network surpasses several contemporary models, including YOLOv8n, YOLOv8s, YOLOv8m, YOLOv8l, and Mask-RCNN. The YOLOv8s + AFPN + MPDIoU model attains a precision rate of 90.7%, a recall of 70.4%, an F1-score of 79.27%, mAP50 of 75.3%, and mAP75 of 74.80%. In contrast to alternative models, our proposed approach exhibits enhancements across performance metrics, with the F1-score, mAP50, and mAP75 increasing by a minimum of 0.46%, 1.3%, and 1.4%, respectively. The margin of error in the measurement model calculations is maintained at or below 5%. Therefore, the developed model can serve as a useful tool for the accurate characterization and quantification of different types of bridge surface cracks.

Low dose insulin infusion versus the standard dose in children with diabetic ketoacidosis: a meta-analysis.

Aim: This systematic review aims to consolidate findings from current clinical trials that compare the effectiveness of insulin infusion at 0.05 IU/kg/h versus 0.1 IU/kg/h in managing pediatric diabetic ketoacidosis. Methods: We searched several databases, including PubMed, Embase, Scopus, Cochrane Central and Web of Science. Our primary outcomes were time to reach blood glucose ≤250 mg/dl and time to resolution of acidosis. Secondary outcomes included rate of blood glucose decrease per hour, incidence of hypoglycemia, hypokalemia, treatment failure, and cerebral edema. Results & conclusion: The present study establishes that a low insulin dose exhibits comparable efficacy to the standard dosage for managing pediatric patients suffering from diabetic ketoacidosis, with a lower incidence of complications.

When kids with type 1 Diabetes (T1DM) face a serious complication called Diabetic Ketoacidosis (DKA), it becomes a life-threatening situation. This condition, responsible for significant mortality, involves high blood sugar, ketone buildup and acidity. Our study delves into a critical aspect of DKA treatment-finding the right insulin dose. By pooling the studies on this point, we discovered that using a lower insulin dose is just as effective as the standard dose in managing DKA in children, with fewer complications. This insight is crucial for improving the care and outcomes for young patients dealing with this challenging condition.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

Telomere length and mortality in lean MAFLD: the other face of metabolic adaptation.

BACKGROUND AND AIMS: Healthy weight (lean) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) have a more favorable metabolic and histological profile in cross-sectional studies compared with their non-lean counterparts. Paradoxically, they also have higher overall mortality. The underpinning pathophysiology of this paradox is not understood. Telomere attrition is associated with increased mortality in various diseases. METHODS: We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy-proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H2O2 on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined. RESULTS: Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H2O2 induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people. CONCLUSION: Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy.

Exportin 4 DNA promoter methylation in liver fibrosis.

A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFß) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.

MERTK and Fibrosis: A New Target for Therapy.

Organ fibrosis is a devastating medical challenge that is collectively responsible for an estimated 45% of all deaths in developed countries and poses a substantial health and economic burden. The process of fibrosis has common characteristics that can occur in various organs, such as the liver, kidney, lung, and skin. Currently, there is a paucity of effective treatments available for fibrosis. Therefore, it is crucial to identify new approaches to find potential therapeutic targets. Genetic studies have shown great promise in advancing the drug development process. Mer tyrosine kinase (MERTK) was recently identified as a crucial regulator of fibrosis that specifically controls the activity of transforming growth factor beta (TGFß). In this brief review, we provide an overview of the potential role of MERTK as a targeted and valuable approach for treating organ fibrosis.

MAFLD identifies patients with significant hepatic fibrosis better than MASLD.

BACKGROUND AND AIMS: Diagnostic criteria for metabolic dysfunction-associated steatotic liver disease (MASLD) have been proposed but not yet validated. This study aimed to compare the diagnostic accuracy of the MASLD definition with the existing criteria for metabolic dysfunction-associated fatty liver disease (MAFLD) in identifying patients with significant fibrosis. METHODS: The analysis included a total of 8317 individuals who had complete biochemical and liver ultrasonography data from the National Health and Nutrition Examination Survey (2017-2020). In this study, significant fibrosis (≥ F2) was determined by a median liver stiffness of ≥ 8.0 kPa. To identify independent factors associated with significant fibrosis, multivariable logistic regression analyses were applied. RESULTS: MAFLD (OR 3.44; 95% CI 2.88-4.12; P < 0.0001) has a trend for stronger and independent association with significant fibrosis compared to MASLD (OR 2.63; 95% CI 2.22-3.11; P < 0.0001). Non-MASLD MAFLD is independently associated with a 14.28-fold higher odds of significant fibrosis compared to non-MAFLD MASLD. The sensitivity for detecting significant fibrosis for MAFLD and MASLD was 76.23% vs 69.94%, respectively. The performance of MAFLD remains consistent in a sub-analysis of patients with no or mild alcohol intake. CONCLUSIONS: The definition of MAFLD provides a more precise identification of individuals who have both fatty liver and significant fibrosis, assessed by non-invasive tests.

MAFLD: an ideal framework for understanding disease phenotype in individuals of normal weight.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significant, impacting almost one-third of the global population. MAFLD constitutes a primary cause of end-stage liver disease, liver cancer and the need for liver transplantation. Moreover, it has a strong association with increased mortality rates due to various extrahepatic complications, notably cardiometabolic diseases. While MAFLD is typically correlated with obesity, not all individuals with obesity develop the disease and a significant percentage of MAFLD occurs in patients without obesity, termed lean MAFLD. The clinical features, progression and underlying physiological mechanisms of patients with lean MAFLD remain inadequately characterized. The present review aims to provide a comprehensive summary of current knowledge on lean MAFLD and offer a perspective on defining MAFLD in individuals with normal weight. Key to this process is the concept of metabolic health and flexibility, which links states of dysmetabolism to the development of lean MAFLD. This perspective offers a more nuanced understanding of MAFLD and its underlying mechanisms and highlights the importance of considering the broader metabolic context in which the disease occurs. It also bridges the knowledge gap and offers insights that can inform clinical practice.

MAFLD criteria are better than MASLD criteria at predicting the risk of chronic kidney disease.

INTRODUCTION AND OBJECTIVES: Fatty liver disease is a multisystem disease. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a more accurate indicator of chronic kidney disease (CKD) than nonalcoholic fatty liver disease (NAFLD). However, the relationship between recently defined metabolic dysfunction-associated steatotic liver disease (MASLD) and CKD is currently unclear. The objective of this cross-sectional study was to investigate the prevalence of CKD and albuminuria among individuals diagnosed with either MAFLD or MASLD. PATIENTS AND METHODS: This study involved 5,492 participants who provided biochemical marker and liver ultrasound data from the U.S. National Health and Nutrition Examination Survey (2017-2020). Multiple logistic regression analyses were conducted to assess the independent associations of nonoverlapping MAFLD and MASLD with the presence of CKD or albuminuria (urinary albumin-to-creatinine ratio ≥ 3 mg/mmol). RESULTS: MAFLD and MASLD were identified in 47% and 44.5% of the participants, respectively. Individuals with MAFLD-only had a greater prevalence of CKD (24.7% vs. 8.3 %, P < 0.006) and albuminuria (18.6% vs. 5%, P < 0.01) than did those with MASLD-only. Importantly, after adjusting for factors such as sex, age, ethnicity, and alcohol use, it was demonstrated that individuals in the MAFLD-only group had a 4.73-fold greater likelihood of having prevalent CKD than those in the MASLD-only group (P < 0.03). CONCLUSIONS: The MAFLD criteria better identify patients with CKD than do the MASLD criteria. Therefore, it is suggested that the MASLD criteria be reconsidered, as currently, the justification for changing from MAFLD to MASLD criteria may not be appropriate.