IGF-1 and IGF-2 as Molecules Linked to Causes and Consequences of Obesity from Fetal Life to Adulthood: A Systematic Review.

This study examines the impact of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) on various aspects of children's health-from the realms of growth and puberty to the nuanced characteristics of metabolic syndrome, diabetes, liver pathology, carcinogenic potential, and cardiovascular disorders. A comprehensive literature review was conducted using PubMed, with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method employing specific keywords related to child health, obesity, and insulin-like growth factors. This study reveals associations between insulin-like growth factor 1 and birth weight, early growth, and adiposity. Moreover, insulin-like growth factors play a pivotal role in regulating bone development and height during childhood, with potential implications for puberty onset. This research uncovers insulin-like growth factor 1 and insulin-like growth factor 2 as potential biomarkers and therapeutic targets for metabolic dysfunction-associated liver disease and hepatocellular carcinoma, and it also highlights the association between insulin-like growth factors (IGFs) and cancer. Additionally, this research explores the impact of insulin-like growth factors on cardiovascular health, noting their role in cardiomyocyte hypertrophy. Insulin-like growth factors play vital roles in human physiology, influencing growth and development from fetal stages to adulthood. The impact of maternal obesity on children's IGF levels is complex, influencing growth and carrying potential metabolic consequences. Imbalances in IGF levels are linked to a range of health conditions (e.g., insulin resistance, glucose intolerance, metabolic syndrome, and diabetes), prompting researchers to seek novel therapies and preventive strategies, offering challenges and opportunities in healthcare.

Berberine Ameliorates Metabolic-Associated Fatty Liver Disease Mediated Metabolism Disorder and Redox Homeostasis by Upregulating Clock Genes: Clock and Bmal1 Expressions.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases, which in turn triggers mild inflammation, metabolic dysfunction, fibrosis, and even cancer. Accumulating evidence has suggested that Berberine (BBR) could significantly improve MAFLD progression. Clock and Bmal1 as heterodimer proteins highly participated in the development of MAFLD, but whether BBR targets Clock and Bmal1 in MAFLD remains poorly understood. The result suggested that the protein levels of Clock and Bmal1 were decreased in MAFLD mice, which was negatively correlated with elevated reactive oxygen species (ROS) accumulation, the H2O2 level, liver inflammation, metabolic dysfunction, and insulin resistance. The mRNA and protein levels of Clock and Bmal1 were also decreased in glucosamine-induced HepG2 cells, which were are negatively related to glucose uptake, the ROS level, and the H2O2 level. More importantly, Bmal1 siRNA could mimic the effect of glucosamine in HepG2 cells. Interestingly, Berberine (BBR) could rescue metabolism disorder and redox homeostasis through enhancing Clock and Bmal1 expression in vivo and in vitro. Therefore, BBR might be an effective natural compound for alleviating redox homeostasis, metabolism disorder, and liver pathological changes in MAFLD by activating Clock and Bmal1 expression.

Characterization of microbiome and metabolite analyses in patients with metabolic associated fatty liver disease and type II diabetes mellitus.

BACKGROUND: State-of-the-art renewal has indicated the improvement of diagnostics of patients with metabolic associated fatty liver disease (MAFLD) and/or type II diabetes mellitus (T2DM) by dissecting the clinical characteristics as well as genomic analysis. However, the deficiency of the characterization of microbial and metabolite signatures largely impedes the symptomatic treatment. METHODS: For the purpose, we retrospectively analyzed the clinical data of 20 patients with MAFLD (short for "M"), 20 cases with MAFLD and T2DM (short for "MD"), together with 19 healthy donors (short for "Ctr"). Microbial and metabolite analyses were further conducted to explore the similarities and differences among the aforementioned populations based on feces and blood samples, respectively. RESULTS: Compared with those in the Ctr group, patients with M or MD revealed multifaceted similarities (e.g., Age, ALP, LDL, BUN) and distinctions in clinical indicators of liver (e.g., BMI, ALT, PCHE, CAP). With the aid of microbial and metabolite analyses as well as bioinformatic analyses, we found that the characteristics of gut microbiota (e.g., abundance, hierarchical clustering, cladogram, species) and lipid metabolism (e.g., metabolite, correlation coefficient and scatter plot) were distinct among the indicated groups. CONCLUSIONS: The patients with MD revealed multifaceted similarities and distinctions in characteristics of microbiome and metabolites with those in the M and HD groups, and in particular, the significantly expressed microbes (e.g., Elusimicrobiota, Berkelbacteria, Cyanobacteria, Peregrinibacteria) and lipid metabolites (e.g., Lipid-Q-P-0765, Lipid-Q-P-0216, Lipid-Q-P-0034, Lipid-Q-P-0800), which would collectively benefit the clinical diagnosis of MAFLD and T2DM.

Follow-up evaluation of patients with liver test abnormalities detected during SARS-CoV2 infection.

Abnormal liver function tests (A-LFTs) during admission for coronavirus disease-19 (COVID-19) are frequent, but its evolution after COVID-19 resolution remains unexplored. We evaluated factors related to A-LFTs during COVID-19 and assessed the liver outcome after patients' discharge. This is a observational study including: (1) retrospective analysis of variables related to A-LFTs during COVID-19; and (2) follow-up evaluation with blood test, transient elastography and liver biopsy in those with persistent A-LFTs. A-LFTs were defined according to CTCAEv4.0. Among 595 patients, 366 (61.5%) showed A-LFTs. The ratio of partial pressure of oxygen and inspired oxygen fraction (P/F) below 200, ferritin ≥1000 ng/mL, male gender and antibiotic and immunomodulatory treatments were related to A-LFTs. Follow-up evaluation was performed in 153 individuals. Persistent A-LFTs at follow-up was similar in patients with/without A-LFTs during admission (14.1% vs. 4.9%, p = 0.104). Fifteen (93%) and 58 (39%) patients with/without A-LFTs at follow-up showed metabolic fatty liver disease criteria (p < 0.001), which were histologically confirmed. In conclusion, A-LFTs during COVID-19 were related to infection severity. Abnormalities remitted at follow-up in >80% of patients, and no correlation between A-LFTs at admission and at follow-up was found. Most patients with A-LFTs at follow-up had non-invasive and histologically proven fatty liver disease.

Applications of artificial intelligence (AI) in researches on non-alcoholic fatty liver disease(NAFLD) : A systematic review.

Non-alcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease in the world, it has been found that cardiovascular and renal risks and diseases are also highly prevalent in adults with NAFLD. Diagnosis and treatment of NAFLD face many challenges, although the medical science has been very developed. Efficiency, accuracy and individualization are the main goals to be solved. Evaluation of the severity of NAFLD involves a variety of clinical parameters, how to optimize non-invasive evaluation methods is a necessary issue that needs to be discussed in this field. Artificial intelligence (AI) has become increasingly widespread in healthcare applications, and it has been also brought many new insights into better analyzing chronic liver disease, including NAFLD. This paper reviewed AI related researches in NAFLD field published recently, summarized diagnostic models based on electronic health record and lab test, ultrasound and radio imaging, and liver histopathological data, described the application of therapeutic models in personalized lifestyle guidance and the development of drugs for NAFLD. In addition, we also analyzed present AI models in distinguishing healthy VS NAFLD/NASH, and fibrosis VS non-fibrosis in the evaluation of NAFLD progression. We hope to provide alternative directions for the future research.

Gender differences in the ideal cutoffs of visceral fat area for predicting MAFLD in China.

BACKGROUND: Since the discovery of metabolic-associated fatty liver disease (MAFLD) in 2020, no report on the connection between the visceral fat area (VFA) and MAFLD has been published in China, and the ideal cutoffs of VFA for predicting MAFLD has not been determined so far. Thus, the purpose of this research was to clarify the relationship between VFA and MAFLD and the ideal cutoffs of VFA to predict MAFLD in the Chinese population. METHODS: Five thousand three hundred forty subjects were included in this research, with 30% randomly selected for the validation set (n = 1602) and 70% for the Training set (n = 3738). The association between VFA and MAFLD was determined by multiple logistic regression. ROC curves were used to evaluate the prediction effect of VFA on MAFLD. RESULTS: Multiple logistic regression analysis revealed that the VFA ORs (95% CIs) were 1.25 (1.20, 1.29) for women and 1.15 (1.12, 1.17) for men. Meanwhile, the VFA quartile OR (95% CI) were 3.07 (1.64, 5.75), 7.22 (3.97, 13.14), 18.91 (10.30, 34.71) for women and 3.07 (1.64, 5.75), 7.22 (3.97, 13.14),18.91 (10.30, 34.71) for men in the Q2, Q3, and Q4 groups compared with Q1. The ROC curve showed the VFA, WC, WHR, and WHtR to predict MAFLD, the AUC value of VFA was the highest and the prediction effect was the best. The ideal cutoffs of VFA to predict MAFLD was 115.55 cm2 for women and 178.35 cm2 for men, and the AUC was 0.788 and 0.795, respectively. Finally, the AUC was 0.773 for women and 0.800 for men in the validation set. CONCLUSION: VFA was an independent predictive factor for MAFLD, and the ideal cutoff of VFA to predict MAFLD was 115.55 cm2 in women and 178.35 cm2 in men.

Plasma Calprotectin Levels Associate with Suspected Metabolic-Associated Fatty Liver Disease and All-Cause Mortality in the General Population.

Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured in subjects (n = 5446) participating in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort study. Suspected MAFLD was defined by the fatty liver index (FLI ≥ 60) and hepatic steatosis index (HSI ≥ 36) as proxies. Plasma calprotectin levels were significantly higher in subjects with FLI ≥ 60 (0.57 [IQR: 0.42−0.79] mg/L, n = 1592) (p < 0.001) compared to subjects with FLI < 60 (0.46 [0.34−0.65] mg/L, n = 3854). Multivariable logistic regression analyses revealed that plasma calprotectin levels were significantly associated with suspected MAFLD (FLI ≥ 60), even after adjustment for potential confounding factors, including current smoking, alcohol consumption, hypertension, diabetes, cardiovascular diseases, insulin resistance (HOMA-IR), hs-CRP, eGFR, and total cholesterol levels (OR 1.19 [95% CI: 1.06−1.33], p = 0.003). Interaction analyses revealed significant effect modifications for the association between plasma calprotectin and suspected MAFLD by BMI (p < 0.001) and hypertension (p = 0.003), with the strongest associations in subjects with normal BMI and without hypertension. Prospectively, plasma calprotectin levels were significantly associated with all-cause mortality after adjustment for potential confounding factors, particularly in subjects without suspected MAFLD (FLI < 60) (hazard ratio (HR) per doubling: 1.34 (1.05−1.72), p < 0.05). In conclusion, higher plasma calprotectin levels are associated with suspected MAFLD and with the risk of all-cause mortality, the latter especially in subjects without suspected MAFLD.

Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL).

Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.

Outcomes and potential surrogate markers for future clinical trials of non-alcoholic steatohepatitis cirrhosis.

Non-alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non-alcoholic steatohepatitis cirrhosis is projected to increase by 64%-156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non-alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non-alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non-alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology-specific pathways and/or at more general aetiology-agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non-alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non-alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients.

Infections at the nexus of metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that affects about a quarter of the world population. MAFLD encompasses different disease stadia ranging from isolated liver steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although MAFLD is considered as the hepatic manifestation of the metabolic syndrome, multiple concomitant disease-potentiating factors can accelerate disease progression. Among these risk factors are diet, lifestyle, genetic traits, intake of steatogenic drugs, male gender and particular infections. Although infections often outweigh the development of fatty liver disease, pre-existing MAFLD could be triggered to progress towards more severe disease stadia. These combined disease cases might be underreported because of the high prevalence of both MAFLD and infectious diseases that can promote or exacerbate fatty liver disease development. In this review, we portray the molecular and cellular mechanisms by which the most relevant viral, bacterial and parasitic infections influence the progression of fatty liver disease and steatohepatitis. We focus in particular on how infectious diseases, including coronavirus disease-19, hepatitis C, acquired immunodeficiency syndrome, peptic ulcer and periodontitis, exacerbate MAFLD. We specifically underscore the synergistic effects of these infections with other MAFLD-promoting factors.

[Risk analysis of serum chemical residues for metabolic associated fatty liver disease based on exposome-lipidome wide association study].

Metabolic associated fatty liver disease (MAFLD) is a common liver disease with a prevalence of up to 25%; it not only adversely affects human health but also aggravates the economic burden of society. An increasing number of studies have suggested that the occurrence of chronic noncommunicable diseases is affected by both environmental exposures and genetic factors. Research has also shown that environmental pollution may increase the risk of MAFLD and promote its occurrence and development. However, the relationship between these concepts, as well as the underlying exposure effects and mechanism, remains incompletely understood. Lipidomics, a branch of metabolomics that studies lipid disorders, can help researchers investigate abnormal lipid metabolites in various disease states. Lipidome-exposome wide association studies are a promising paradigm for investigating the health effects of cumulative environmental exposures on biological responses, and could provide new ideas for determining the associations between metabolic and lipid changes and disease risk caused by chemical-pollutant exposure. Hence, in this study, targeted exposomics and nontargeted lipidomics studies based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) were used to characterize exogenous chemical pollutants and endogenous lipid metabolites in the sera of patients with MAFLD and healthy subjects. The results demonstrated that fipronil sulfone, malathion dicarboxylic acid, and monocyclohexyl phthalate may be positively associated with the disease risk of patients diagnosed as simple fatty liver disease (hereafter referred to as MAFLD(0)). Moreover, fipronil sulfone, acesulfame potassium, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), 4-hydroxybenzophenone, and 3,5-di-tert-butyl-4-hydroxybenzoic acid (DBPOB) may be positively associated with the disease risk of patients diagnosed as fatty liver complicated by single or multiple metabolic disorders. Association analysis was carried out to explore the lipid metabolites induced by chemical residues. Triglyceride (TG) and diglyceride (DG) were significantly increased in MAFLD and MAFLD(0). The numbers of carbons of significantly changed DGs and TGs were mainly in the ranges of 32-40 and 35-60, respectively, and both were mainly characterized by changes in polyunsaturated lipids. Most of the lipid-effect markers were positively correlated with chemical residues and associated with increased disease risk. Our research provides a scientific basis for studies on the association and mechanism between serum chemical-pollutant residues and disease outcomes.

Comparative study of MAFLD as a predictor of metabolic disease treatment for NAFLD.

A novel concept of Metabolic Associated Fatty Liver Disease (MAFLD) was proposed, incorporating metabolic abnormalities such as obesity and diabetes, which are risk factors that affect the prognosis. Non-Alcoholic Fatty Liver Disease (NAFLD), entails fat accumulation in the liver without alcohol consumption and is often linked to obesity, insulin resistance, and metabolic syndrome. However, the broad nature of the disease concept has hindered prognosis accuracy. In this study, we assess the contribution of the impact of diagnostic criteria for MAFLD on metabolic disease progression compared to conventional diagnostic criteria for NAFLD. A total of 7159 patient who were presented to the health screening center in Tokai University Hospital both in 2015 and 2020 were included in the study. Fatty liver was diagnosed using abdominal ultrasonography. The diagnostic criteria for NAFLD were consistent with the global guidelines based on alcohol consumption. The diagnostic criteria for MAFLD were based on the International Consensus Panel. Medications (anti-hypertensive, diabetic, and dyslipidemia medications) were evaluated by self-administration in the submitted medical questionnaire. A total of 2500 (34.9%) participants were diagnosed with fatty liver (FL +), 1811 (72.4%) fit both NAFLD and MAFLD diagnostic criteria (overlap), 230 (9.2%) fit only the NAFLD diagnostic criteria (NAFLD group) and 404 (16.1%) fit the MAFLD diagnostic criteria (MAFLD group) at 2015. Over the next 5 years, medication rates increased in the NAFLD group for anti-hypertensive, + 17 (7.4%); diabetes, + 3 (1.3%); and dyslipidemia, + 32 (13.9%). In contrast, the only-MAFLD group showed a more significant increase with + 49 (12.1%), + 21 (5.2%), and + 49 (12.1%), for the respective medications, indicating a substantial rise in patients starting new medications. Our analysis of repeated health check-ups on participants revealed that the diagnostic criteria for MAFLD are more predictive of future treatment for metabolic disease than conventional diagnostic criteria for NAFLD.

Metabolic dysfunction-associated fatty liver disease: current therapeutic strategies.

The definition of "Metabolic Associated Fatty Liver Disease - MAFLD" has replaced the previous definition of Nonalcoholic Fatty Liver Disease (NAFLD), because cardiometabolic criteria have been added for the prevention of cardiological risk in these patients. This definition leads to an in-depth study of the bidirectional relationships between hepatic steatosis, Type 2 Diabetes Mellitus (T2DM), Cardiovascular Disease (CVD) and/or their complications. Lifestyle modification, which includes correct nutrition combined with regular physical activity, represents the therapeutic cornerstone of MAFLD. When therapy is required, there is not clear accord on how to proceed in an optimal way with nutraceutical or pharmacological therapy. Numerous studies have attempted to identify nutraceuticals with a significant benefit on metabolic alterations and which contribute to the improvement of hepatic steatosis. Several evidences are supporting the use of silymarin, berberine, curcumin, Nigella sativa, Ascophyllum nodosum, and Fucus vesiculosus, vitamin E, coenzyme Q10 and Omega-3. However, more evidence regarding the long-term efficacy and safety of these compounds are required. There is numerous evidence that highlights the use of therapies such as incretins or the use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors or other similar therapies which, by assisting existing therapies for pathologies such as diabetes, hypertension, insulin resistance, have given a breakthrough in prevention and the reduction of cardiometabolic risk. This review gave an overview of the current therapeutic strategies that are expected to aid in the treatment and prevention of MAFLD.

Lack of awareness and ethnic polarity is a major cause of metabolic associated fatty liver disease in high-risk diabetes population in South London.

Background: Metabolic associated fatty liver disease (MAFLD) stands as the leading cause of chronic liver disease globally. Notably, individuals with metabolic risk factors, such as diabetes and obesity, exhibit a staggering prevalence of MAFLD, with estimates reaching up to 70%. However, despite its widespread occurrence, there's a noticeable gap in understanding and awareness about MAFLD among these high-risk groups. Objectives: The main objective of this study was to assess the awareness and prevalence of MAFLD among diabetic patients who regularly receive secondary care focusing particularly on how multiethnic backgrounds and associated lifestyle preferences influence these health outcomes. Design: Cross-sectional study. Methods: Patients with type 2 diabetes (T2D) who regularly attend Lambeth Diabetes Intermediate Care Team clinics were invited to undergo MAFLD screening using FibroScan. Those who agreed to participate were provided with structured questionnaires on diet, physical activity, and MAFLD knowledge by a hepatologist. For each participant, anthropometric data, medical history, liver stiffness measurement, and controlled attenuation parameter (CAP) were documented. Steatosis was identified with a CAP value of ⩾275 dB/m, and advanced fibrosis was flagged at values of ⩾8 kPa. Results: The FibroScan data was valid in 96.4% (215), 53.5% (115/215) had steatosis and 26.2% (58/215) had liver fibrosis in this multiethnic high-risk group. Awareness of MAFLD was notably low at 30.9%. Alarmingly, 69% of patients diagnosed with liver fibrosis were unfamiliar with the condition. Additionally, understanding of MAFLD showed variation among different ethnic groups with highest levels were demonstrated in the Caucasian/White population (46%). Majority (96%) of these subjects were receiving specific lifestyle advice from healthcare professionals due to metabolic conditions and comorbidities. However, most patients preferred diets that were rich in carbohydrates (65.8%) and only 43% subjects performed moderate exercise daily highlighting lack of understanding regarding MAFLD and lifestyle management. Conclusion: There's a pressing need for increased awareness of MAFLD, especially in multiethnic high-risk groups. Additionally, the development of cost-effective strategies to stratify risk is essential to address this growing health concern.

Ethnic differences and lack of awareness increase fatty liver disease risk in South London diabetics Metabolic associated fatty liver disease (MAFLD) or more commonly fatty liver disease is the leading cause of chronic liver disease globally, particularly affecting individuals with diabetes and obesity. This study focuses on patients with type 2 diabetes in South London who regularly receive secondary care, examining the awareness and prevalence of MAFLD, especially across different ethnic groups. Participants, all with Type 2 Diabetes, attended clinics run by the Diabetes Intermediate Care Team where they underwent MAFLD screening using Fibroscan. This tool measures liver stiffness (fibrosis) and fat levels. In addition to the scans, participants answered questions about their diet, physical activity, and knowledge of MAFLD. Key findings include a low overall awareness of MAFLD, with only about 30.9% of patients aware of the disease. Among those diagnosed with liver fibrosis, 69% were unfamiliar with the condition, indicating a significant awareness gap. Interestingly, awareness levels varied among ethnic groups, with Caucasian/white patients showing the highest awareness at 46%. Despite receiving lifestyle advice from health professionals, many participants preferred carbohydrate-rich diets and only a minority engaged in daily moderate exercise. This behaviour highlights a general lack of understanding about MAFLD and its management through lifestyle changes. The study concludes that there is a critical need to raise awareness about MAFLD among high-risk, multi-ethnic groups in South London. It also highlights the necessity for developing cost-effective strategies to better identify and manage this growing health concern.

Treatment Options and Continuity of Care in Metabolic-associated Fatty Liver Disease: A Multidisciplinary Approach.

The terms non-alcoholic fatty liver disease and non-alcoholic steatohepatitis have some limitations as they use exclusionary confounder terms and the use of potentially stigmatising language. Recently, a study with content experts and patients has been set to change this nomenclature. The term chosen to replace non-alcoholic fatty liver disease was metabolic dysfunction-associated steatotic liver disease (MASLD), which avoids stigmatising and helps improve awareness and patient identification. MASLD is the most common cause of chronic liver disease with an increasing prevalence, accounting for 25% of the global population. It is considered the hepatic manifestation of the metabolic syndrome with lifestyle playing a fundamental role in its physiopathology. Diet change and physical activity are the cornerstones of treatment, encompassing weight loss and healthier behaviours and a holistic approach. In Europe, there is no approved drug for MASLD to date and there is a substantial unmet medical need for effective treatments for patients with MASLD. This review not only provides an update on advances in evidence for nutrition and physical activity interventions but also explores the different therapeutic options that are being investigated and whose development focuses on the restitution of metabolic derangements and halting inflammatory and fibrogenic pathways.

Non-alcoholic fatty liver disease in patients with morbid obesity: the gut microbiota axis as a potential pathophysiology mechanism.

BACKGROUND/AIM: Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy. SUBJECTS/METHODS: 110 patients with morbid obesity were evaluated by biopsy obtained during bariatric surgery for MAFLD. Stool samples were collected prior to surgery for microbiota analysis. RESULTS: Gut microbiota from patients with steatosis and non-alcoholic steatohepatitis (NASH) were characterized by an enrichment in Enterobacteriaceae (an ethanol-producing bacteria), Acidaminococcus and Megasphaera and the depletion of Eggerthellaceae and Ruminococcaceae (SCFA-producing bacteria). MAFLD was also associated with enrichment of pathways related to proteinogenic amino acid degradation, succinate production, menaquinol-7 (K2-vitamin) biosynthesis, and saccharolytic and proteolytic fermentation. Basic histological hepatic alterations (steatosis, necroinflammatory activity, or fibrosis) were associated with specific changes in microbiota patterns. Overall, the core microbiome related to basic histological alterations in MAFLD showed an increase in Enterobacteriaceae and a decrease in Ruminococcaceae. Specifically, Escherichia coli was associated with steatosis and necroinflammatory activity, whilst Escherichia-shigella was associated with fibrosis and necroinflammatory activity. CONCLUSIONS: We established a link between gut microbiota alterations and histological injury in liver diagnosis using biopsy. Harmful products such as ethanol or succinate may be involved in the pathogenesis and progression of MAFLD. Thus, these alterations in gut microbiota patterns and their possible metabolic pathways could add information to the classical predictors of MAFLD severity and suggest novel metabolic targets.

Elevated AIP is associated with the prevalence of MAFLD in the US adults: evidence from NHANES 2017-2018.

Background: Atherogenic Index of plasma (AIP) is closely related to metabolic abnormalities. But as of now, there is no definitive conclusion on the dose-response relationship pattern between AIP and metabolic associated fatty liver disease (MAFLD). Objective: The objective of this study was to provide a fresh insight for understanding the intrinsic link between AIP and the prevalence of MAFLD by exploring the dose-response pattern between AIP and MAFLD. Methods: A total of 9254 participants received the survey and 1090 participants were finally included according to the screening criteria. To evaluate the association between AIP and the prevalence of MAFLD based on weighted multivariate logistic regression. Sensitivity analysis of the association between AIP and MAFLD was performed using propensity score matching (PSM). Restrictive cubic splines (RCS) were used to identify patterns of dose-response relationships between AIP and MAFLD, and receiver operator characteristic (ROC) curves were used to evaluate the predictive ability of AIP and traditional lipid parameters for MAFLD. Results: In this study, a total of 563 participants were found to have MAFLD. The results of weighted multivariate logistic regression analysis demonstrated that, after adjusting for sex and age, participants in the highest quartile (Q4) of AIP had a significantly increased risk of developing MAFLD compared to those in the lowest quartile (Q1) (Model 2: OR = 9.03, 95% CI 4.75-17.17). A similar trend was observed in the fully adjusted model (Model 3: OR = 3.85, 95% CI 1.55-9.52). The RCS analysis revealed a linear dose-response association between AIP and MAFLD(P for crude non-linearity = 0.087). This association remained significant after accounting for potential confounding variables(P for adjusted non-linearity = 0.663). The ROC curve results suggest that AIP performs better than traditional lipid indicators in predicting MAFLD (AUC = 0.732, 95%CI 0.705-0.758). Conclusion: A linear dose-response relationship exists between AIP and MAFLD, suggesting that as AIP increases, so does the risk of developing MAFLD.

The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease.

Cardiometabolic disease (CMD), which encompasses metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD) and cardiovascular disease (CVD), has been increasing considerably in the past 50 years. CMD is a complex disease that can be influenced by genetics and environmental factors such as diet. With the increased reliance on processed foods containing saturated fats, fructose and cholesterol, a mechanistic understanding of how these molecules cause metabolic disease is required. A major pathway by which excessive nutrients contribute to CMD is through oxidative stress. In this review, we discuss how oxidative stress can drive CMD and the role of aberrant nutrient metabolism and genetic risk factors and how they potentially interact to promote progression of MAFLD, CVD and CKD. This review will focus on genetic mutations that are known to alter nutrient metabolism. We discuss the major genetic risk factors for MAFLD, which include Patatin-like phospholipase domain-containing protein 3 (PNPLA3), Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) and Transmembrane 6 Superfamily Member 2 (TM6SF2). In addition, mutations that prevent nutrient uptake cause hypercholesterolemia that contributes to CVD. We also discuss the mechanisms by which MAFLD, CKD and CVD are mutually associated with one another. In addition, some of the genetic risk factors which are associated with MAFLD and CVD are also associated with CKD, while some genetic risk factors seem to dissociate one disease from the other. Through a better understanding of the causative effect of genetic mutations in CMD and how aberrant nutrient metabolism intersects with our genetics, novel therapies and precision approaches can be developed for treating CMD.

Metabolic-associated fatty liver disease: a selective review of pathogenesis, diagnostic approaches, and therapeutic strategies.

Background: Metabolic associated fatty liver disease (MAFLD) is a novel terminology introduced in 2020 to provide a more accurate description of fatty liver disease associated with metabolic dysfunction. It replaces the outdated term nonalcoholic fatty liver disease (NAFLD) and aims to improve diagnostic criteria and tailored treatment strategies for the disease. NAFLD, the most prevalent liver disease in western industrialized nations, has been steadily increasing in prevalence and is associated with serious complications such as cirrhosis and hepatocellular carcinoma. It is also linked to insulin resistance syndrome and cardiovascular diseases. However, current studies on NAFLD have limitations in meeting necessary histological endpoints. Objective: This literature review aims to consolidate recent knowledge and discoveries concerning MAFLD, integrating the diverse aspects of the disease. Specifically, it focuses on analyzing the diagnostic criteria for MAFLD, differentiating it from NAFLD and alcoholic fatty liver disease (AFLD), and exploring the epidemiology, clinical manifestations, pathogenesis, and management approaches associated with MAFLD. The review also explores the associations between MAFLD and other conditions. It discusses the heightened mortality risk associated with MAFLD and its link to chronic kidney disease (CKD), showing that MAFLD exhibits enhanced diagnostic accuracy for identifying patients with CKD compared to NAFLD. The association between MAFLD and incident/prevalent CKD is supported by cohort studies and meta-analyses. Conclusion: This literature review highlights the importance of MAFLD as a distinct terminology for fatty liver disease associated with metabolic dysfunction. The review provides insights into the diagnostic criteria, associations with CKD, and management approaches for MAFLD. Further research is needed to develop more accurate diagnostic tools for advanced fibrosis in MAFLD and to explore the underlying mechanisms linking MAFLD with other conditions. This review serves as a valuable resource for researchers and healthcare professionals seeking a comprehensive understanding of MAFLD.

Maternal obesity and metabolic (dysfunction) associated fatty liver disease in pregnancy: a comprehensive narrative review.

INTRODUCTION: Obesity and metabolic-associated fatty liver disease (MAFLD) during pregnancy constitute significant problems for routine antenatal care, with increasing prevalence globally. Similar to obesity, MAFLD is associated with a higher risk for maternal complications (e.g. pre-eclampsia and gestational diabetes) and long-term adverse health outcomes for the offspring. However, MAFLD during pregnancy is often under-recognized, with limited management/treatment options. AREAS COVERED: PubMed/MEDLINE, EMBASE, and Scopus were searched based on a search strategy for obesity and/or MAFLD in pregnancy to identify relevant papers up to 2024. This review summarizes the pertinent evidence on the relationship between maternal obesity and MAFLD during pregnancy. Key mechanisms implicated in the underlying pathophysiology linking obesity and MAFLD during pregnancy (e.g. insulin resistance and dysregulated adipokine secretion) are highlighted. Moreover, a diagnostic approach for MAFLD diagnosis during pregnancy and its complications are presented. Finally, promising relevant areas for future research are covered. EXPERT OPINION: Research progress regarding maternal obesity, MAFLD, and their impact on maternal and fetal/offspring health is expected to improve the relevant diagnostic methods and lead to novel treatments. Thus, routine practice could apply more personalized management strategies, incorporating individualized algorithms with genetic and/or multi-biomarker profiling to guide prevention, early diagnosis, and treatment.