Metabolism and Target Organ Damage

Primary sclerosing cholangitis (PSC) is a rare but devastating disease affecting the intra- and extrahepatic bile ducts, frequently progressing to end-stage liver disease. Patients develop peribiliary inflammation and fibrosis, leading to multifocal biliary strictures that evolve to biliary cirrhosis. PSC is frequently associated with inflammatory bowel disease and a high risk of cholangiocarcinoma development. The pathogenesis of this disease is not completely understood, and currently, there are no effective therapies beyond liver transplantation. The available experimental models of PSC do not fully reproduce the phenotype of the disease, and this is a major limitation for unraveling its pathogenic mechanisms and evaluating novel therapies. A recent study by Lukasova et al. proposed a new hypothesis on the pathogenesis of PSC. The relevance of their work is two-fold: (1) the authors provide preliminary evidence suggesting that the disruption of tight junctions in mouse biliary epithelium leads to a PSC-like phenotype; and (2) they provide the research community with a novel transgenic mouse model of the disease. Follow-up studies on this new mouse model are eagerly awaited.

The global prevalence of obesity and type 2 diabetes has increased, contributing to an increased worldwide prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Currently, one in three adults is affected by MASLD and/or its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), making this liver disease a significant public health challenge. Along with MASH-related cirrhosis, these conditions are poised to become the leading causes of chronic liver disease and liver transplants in the near future. Given the growing burden of MASLD and MASH, it is crucial to understand their impact from the patients’ perspective. One way to do this is by assessing patient-reported outcomes (PROs), including health-related quality of life (HRQL). HRQL can be assessed using generic instruments like the short form 36 version (SF-36) and the European quality of life-5 dimensions questionnaire (EQ-5D), or disease-specific tools such as the chronic liver disease questionnaire for nonalcoholic steatohepatitis (CLDQ-NASH). Given the limitations of each instrument, the best approach generally involves using both generic and disease-specific instruments. Evidence indicates that HRQL scores are significantly lower in individuals with MASLD, especially in areas assessing physical activity and the ability to perform daily living tasks. Fatigue and impaired work productivity are also important PROs for those with MASLD/MASH. These decrements in PROs worsen with disease progression but appear to improve with disease regression, including improvements linked to treatment. In this context, measuring PROs enhances the assessment of other patient-centric outcomes and provides insights for the healthcare community to develop interventions that could improve both clinical and humanistic outcomes for individuals living with MASLD/MASH.

This review article proposes the theory that liver fibrosis, the abnormal accumulation of excessive extracellular matrix, is not just an indicator of liver disease but also a negative reflection of overall systemic health. Liver fibrosis poses a heavy financial burden on healthcare systems worldwide and can develop due to chronic liver disease from various causes, often due to sustained inflammation. Liver fibrosis may not generate symptoms and become apparent only when it reaches the stage of cirrhosis and is associated with clinically significant portal hypertension and leads to decompensation events or promotes the development of hepatocellular carcinoma. While chronic viral hepatitis and excessive alcohol consumption were once the primary causes of chronic liver disease featuring fibrosis, this role is now increasingly taken over by metabolic dysfunction-associated steatotic liver disease (MASLD). In MASLD, endothelial dysfunction is an essential component in pathogenesis, promoting the development of liver fibrosis, but it is also present in endothelial cells of other organs such as the heart, lungs, and kidneys. Accordingly, liver fibrosis is a significant predictor of liver-related outcomes, as well as all-cause mortality, cardiovascular risk, and extrahepatic cancer. Physicians should be aware that individuals seeking medical attention for reasons unrelated to liver health may also have advanced fibrosis. Early identification of these at-risk individuals can lead to a more comprehensive assessment and the use of various treatment options, both approved and investigational, to slow or reverse the progression of liver fibrosis.

The conceptual evolution of non-alcoholic fatty liver disease (NAFLD) to what, since 2023, is called metabolic dysfunction-associated steatotic liver disease (MASLD) not only represents a change in the classification and definition of the disease but also reflects a broader understanding of this heterogeneous condition, which still with many aspects to refine. Although the definition of NAFLD can be interchanged to a high percentage with the new MASLD concept in different aspects, MASLD has been proposed as a relevant factor that influences the response to new immunotherapeutic treatments in the management of MASLD-related hepatocellular carcinoma (HCC), compared to HCC of other etiologies. This indicates that the etiology of HCC plays a relevant role in the prognosis, highlighting the urgency of evaluating treatment regimens for this subgroup of patients in upcoming clinical trials. A better understanding of the pathophysiology of MASLD generates strategies that not only aid in its management but also provide strategies to directly intervene in the carcinogenesis of HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive hepatic lipid accumulation and can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is manifested with persistent liver injury, inflammation, and fibrosis, increasing the risk for cirrhosis and hepatocellular carcinoma. Aberrant epigenetic reprogramming and epitranscriptomic remodeling emerge to be a driving force for MASLD and MASH. SNAIL1 and SLUG, two related transcriptional regulators, regulate de novo lipogenesis and liver steatosis by opposing epigenetic mechanisms. RNA m6A modification regulates not only liver steatosis but also liver injury and regeneration. MASLD is associated with changes in the expression of m6A writers, erasers, and readers, which significantly influence its progression.

Aim: Primary sclerosing cholangitis (PSC) and ulcerative colitis are often associated. In ulcerative colitis, a tight junction defect can be detected, resulting in impaired secretion of hydrophobic phosphatidylcholine to the intestinal mucus. This defect causes a vulnerable mucus shield, allowing the microbiota to attack and leading to mucosal inflammation. A similar pathomechanism may be present in PSC. Methods: To study biliary deletion of tight junctions, mice carrying a Cre/loxP system sensitive to tamoxifen were used to delete kindlin-2, a tight junction adapter protein. The Cre-preceded promoter was derived from hepatocyte nuclear factor-1β (Hnf1β), which is specific for biliary and pancreatic epithelium operative in embryonic life until adolescence. Cre-negative kindlin-2flox/flox mice treated with tamoxifen served as controls. Results: After tamoxifen induction, alterations in the biliary epithelium were detectable. As a hallmark feature of PSC, an onion-skin type of fibrosis around the bile ducts was present. However, levels of alkaline phosphatase, bilirubin, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in the serum were not yet elevated in these young mice. Conclusion: Genetic deletion of cholangiocyte kindlin-2 impairs tight junctions, revealing a PSC-like phenotype. This supports the hypothesis that an impaired phosphatidylcholine content of biliary mucus allows luminal bile acids to attack the biliary epithelium, leading to cholangitis.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disorder in which the immune system attacks insulin-producing β cells in the pancreas, leading to insulin deficiency and hyperglycemia. Despite advancements in treatment, managing T1D remains challenging, with patients experiencing diabetes distress and reduced life expectancy. Immunotherapy offers promising strategies for modifying the course of T1D by targeting the immune system’s attack on β cells. A recent highlight is teplizumab, an anti-CD3 monoclonal antibody, which delays the progression of T1D in patients with recent onset by preserving endogenous insulin production. Clinical trials have shown that teplizumab can improve glycemic control and delay the onset of stage 3 T1D for up to two years in at-risk individuals. Other immunotherapies, including targeting B cells with rituximab, have shown potential to preserve β cell function and reduce insulin requirements in recent-onset T1D. Additionally, T cell modulation therapies such as abatacept have been shown to slow the decline in β cell function. Cytokine-directed therapies targeting inflammation have also demonstrated potential in preserving β cell function and improving glycemic control. Combination therapies, such as the use of anti-interleukin (IL)-21 antibodies with liraglutide, may offer synergistic benefits and preserve endogenous insulin secretion. While immunotherapies offer the potential for short-term protection of β cells, ongoing research is needed to refine treatment strategies and identify optimal timing and combinations of therapies. This could lead to safer and more effective management of T1D, potentially reducing reliance on insulin therapy and providing long-term benefits for patients.

The prevalence of obesity is increasing worldwide, leading to a rise in several comorbidities, and is itself an important risk factor for heart failure. Patients with end-stage heart failure and obesity are often not eligible for heart transplantation (HT) and instead receive cardiac support from left ventricular assist devices (LVAD). In the absence of other contraindications, patients with obesity who are on LVAD support can lose enough weight to later qualify for HT. Bariatric surgery had been explored as an approach for weight loss in this patient population and was found to be a safe and effective option. One recent systematic review and meta-analysis has shown 67.4% of patients with LVAD support are able to be listed for transplantation after bariatric surgery and subsequent weight loss (95%CI: 0.477-0.871). Of these, 32.5% would go on to receive a heart transplant (95%CI: 0.201-0.448). There were also numerous cases of patients whose cardiac function improved after bariatric surgery such that they were delisted for HT and some had subsequent removal of their LVAD. There are many perioperative considerations when evaluating patients with LVADs for bariatric surgery. However, with careful patient selection by a multidisciplinary team and mindful preparation, patients with obesity and end-stage heart failure have an opportunity for longer years of life.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) together represent the majority of individuals with steatotic liver disease (SLD). MASLD and ALD prevalence continues to rise globally, which is driven by several factors including an aging population, increasing prevalence of cardiometabolic risk factors such as obesity and diabetes mellitus, and the increasing trends in high-risk unhealthy alcohol use which surged during the COVID-19 pandemic. As a result, MASLD, as well as ALD-related cirrhosis and hepatocellular carcinoma, is also on the rise, becoming major etiologies contributing to end-stage liver disease among adults awaiting liver transplantation. Accurately understanding MASLD and ALD epidemiology is critical to guide healthcare resource planning and health policy. Accurate estimates of MASLD and ALD epidemiology are particularly important to understand in the context of recent updates in nomenclature terminology. This review provides an updated assessment of existing literature describing the epidemiology of MASLD and ALD.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. The disease is a constellation of a broad range of metabolic and histopathologic abnormalities. It begins with hepatic steatosis and progresses to metabolic dysfunction-associated steatohepatitis (MASH), including hepatic fibrosis, apoptosis, and cell injury. Despite ample research effort, the pathogenesis of the disease has not been fully delineated. Whereas insulin resistance is implicated in the early stages of the disease, its role in hepatic fibrosis remains controversial. We have focused our studies on the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hepatocytes and endothelial cells in the metabolic and histopathological dysregulation in MASH. Patients with MASH exhibit lower hepatic CEACAM1 with a progressive decline in hepatocytes and endothelial cells as the fibrosis stage advances. In mice, conditional deletion of CEACAM1 in hepatocytes impairs insulin clearance to cause hyperinsulinemia-driven insulin resistance with steatohepatitis and hepatic fibrosis even when mice are fed a regular chow diet. In contrast, its conditional deletion in endothelial cells causes inflammation-driven hepatic fibrosis without adversely affecting metabolism (mice remain insulin-sensitive and do not develop hepatic steatosis). Thus, this review provides in vivo evidence that supports or discards the role of insulin resistance in liver injury and hepatic fibrosis.

Copper is a trace metal whose absence or deficiency can cause structural and functional alterations that can be corrected by copper administration. Copper excess is associated with significant liver toxicity, such as that seen in Wilson’s disease, which often exhibits liver steatosis and can be managed by copper sequestrants. Copper, due to its ability to either accept or donate electrons, is a cofactor in many physiological redox reactions, playing an essential role in cell energy homeostasis, detoxification of reactive oxygen species, and hepatic immunometabolism. Given these facts, it is reasonable to speculate that copper might be involved in the pathogenesis of liver fibrosis in the setting of metabolic dysfunction-associated fatty liver disease (MASLD). To address this research question, a narrative review of published studies was conducted, spanning from the needs, sources, and toxicity of copper to Menkes and Wilson’s disease. Most epidemiological studies have demonstrated that MASLD is associated with copper deficiency. However, several studies show that MASLD is associated with copper excess and very few conclude that copper is not associated with MASLD. Therefore, the putative pathomechanisms associating both copper excess and deficiency with MASLD development and progression are reviewed. In conclusion, epidemiological and pathogenic data support the notion that well-balanced copper homeostasis is a prerequisite for liver health. Accordingly, both copper excess and deficiency may potentially predispose to liver fibrosis via the development of MASLD. Therefore, studies aimed at restoring normal bodily stores of copper should be tailored according to precision medicine approaches based on the specific features of copper metabolism in individual MASLD patients.

Topical drugs have gained a lot of interest with their massive market growth and are available in various dosage forms. Prodrug compounds of transdermal delivery systems can be very different and designed to convert into the form of active pharmaceutical ingredients (APIs) through enzymatic action once they enter the body. The skin, as an interfacial barrier between the body and surroundings, has demonstrated critical roles in metabolizing, filtering, and detoxifying to minimize certain side effects and improve the medication benefits of topically administered products. It is well recognized that the drug pharmacokinetics can be altered by the presence of skin enzymes driven by biotransformation reactions. To evaluate the effectiveness of a topical generic drug product, its safety, and bioequivalence with the reference one, models assessing enzyme metabolic activity are highly required for testing the amount of drugs that are metabolized or can potentially be metabolized in both healthy and compromised skin. Thus, knowledge of skin composition and enzyme expression levels is of paramount importance in mapping the relevant metabolism that may have occurred. Regulatory authorities have also been making efforts to develop efficient and harmonizable protocols to evaluate the metabolism of transdermal products. This review is a compilation of reported skin metabolizing enzymes, including their role in both drug metabolism and homeostasis regulation, along with their localization and quantification in skin equivalents (and/or membrane layers). Various aspects that potentially affect the skin enzyme metabolism study were also discussed with respect to drug development considerations.

The dysregulation of sphingolipid metabolism emerges as a pivotal factor in the development and progression of liver fibrosis, a condition marked by the overproduction and buildup of extracellular matrix proteins that can lead to liver cirrhosis and failure. Sphingolipids, a diverse class of lipids essential for cellular structure and signaling, are integral to numerous biological functions such as cellular proliferation, morphological differentiation, and programmed cell death. In the context of liver fibrosis, changes in sphingolipid metabolism have been associated with the activation of hepatic stellate cells, the primary cells responsible for fibrogenesis in the liver. These metabolic disruptions lead to an imbalance between profibrotic and antifibrotic sphingolipids, notably sphingosine-1-phosphate and ceramide, contributing to the pathophysiological mechanisms that drive fibrosis. The intricate relationship between sphingolipid metabolism and fibrotic pathways underscores the potential of targeting sphingolipid metabolic enzymes and receptors as therapeutic strategies to mitigate liver fibrosis. The core of this review delves into how disruptions in sphingolipid metabolism contribute to liver fibrosis, exploring biomarkers and potential therapeutic targets. Challenges in research and future directions for comprehensively understanding sphingolipid roles in liver fibrosis are discussed, aiming to open new pathways for therapeutic intervention.

Liver steatosis is a frequent finding in clinical practice and it is estimated to affect 30% of the general adult population worldwide. It became one of the leading causes of end-stage liver disease and hepatocellular carcinoma. From its first description, a diagnosis of nonalcoholic fatty liver disease (NAFLD) required the exclusion of excessive alcohol consumption and concomitant chronic liver diseases of different origins, making it a diagnosis of exclusion. In recent years, the need to stress the strict association between liver steatosis and metabolic dysfunction (i.e., insulin resistance, overweight/obesity, type 2 diabetes, and metabolic syndrome), as well as the desire to define a condition in a positive rather than negative way, led to new definitions and new diagnostic criteria. Metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed by Eslam et al. in 2020. More recently, a Delphi consensus endorsed by several international hepatologic societies proposed a new terminology [metabolic dysfunction-associated steatotic liver disease (MASLD)] and a new set of diagnostic criteria. The MAFLD and MASLD definitions have a good degree of concordance. They mainly differ in the number of metabolic derangements needed to define “metabolic dysfunction” in normal-weight individuals and in alcohol consumption. Indeed, while MAFLD does not exclude patients with significant alcohol consumption, the recent Delphi consensus included the metabolic dysfunction and alcohol-related liver disease (MetALD) disease entity, a condition in which steatosis, metabolic dysfunction, and moderate alcohol intake coexist. In the present narrative review, we underline the strengths and possible limitations of each definition and summarize available evidence from epidemiologic studies evaluating the clinical usefulness of each set of diagnostic criteria.

Metabolic dysfunction-associated steatotic liver disease (MASLD) [previously termed nonalcoholic fatty liver disease (NAFLD)] is estimated to be the most common chronic liver disease worldwide, affecting 25% of the world’s population and becoming the leading cause of liver transplant in the US. The progression of MASLD from simple hepatic steatosis to the more severe metabolic dysfunction-associated steatohepatitis (MASH) [previously nonalcoholic steatohepatitis (NASH)] has critically important impacts on clinical outcomes. Early detection and staging of disease severity, along with lifestyle modifications and treatment of comorbid conditions, is the best way to prevent the progression or reverse the course of the disease. Although noninvasive imaging and predictive indices are available for the evaluation of hepatic fibrosis, the only way to diagnose MASH remains liver biopsy despite the risk for complications and being less desired by patients. Hence, there is a need to develop noninvasive tests to aid in both the diagnosis and monitoring of MASH, especially with the recent emergence of liver-directed therapy for “at risk” MASH (MASH with NAS ≥ 4 and Stage ≥ F2 Fibrosis). The goal of the current review is to cover the most recent pathophysiology, current diagnostic methods, and recent advances to aid in the diagnosis of MASH.

Aim: Obesity is a chronic disease that can lead to many consequences and is directly related to the development of other non-communicable chronic diseases. Since medical treatment for this comorbidity does not always yield satisfactory results, bariatric surgery ends up being the best option for many cases. Thus, the present study aims to analyze long-term weight loss in patients undergoing bariatric surgery, compare weight loss according to the surgical technique performed, and assess the quality of life of patients in the long-term postoperative period. Methods: This is a descriptive and cross-sectional study analyzing a pre-existing database along with new data collected through telephone interviews according to the modified Bariatric Analysis and Reporting Outcome System (BAROS) questionnaire. Medical records for those who underwent the procedure within the specified period were analyzed. Results: Records for a total of 208 patients were analyzed, of whom 181 underwent the Bypass surgical technique and 27 underwent the Sleeve technique. Based on the BAROS score, the majority of patients (64.9%) had a "good" or "very good" outcome. Regarding weight loss, 70.68% of the interviewed patients lost over 50% of weight, with this loss occurring in 74.58% of those who underwent Bypass and 44.44% of those who underwent Sleeve. Additionally, 95.2% of respondents reported feeling “better” or “much better” after surgery. Conclusion: Our results indicate that bariatric surgery is effective both in long-term weight loss and in improving the quality of life of patients. Meanwhile, our study suggests that the BAROS questionnaire may be insufficient to assess long-term quality of life.

Aim: To neurophysiologically characterize the innervation of the sole and assess the diagnostic efficacy of whole plantar nerve (WPN) conduction study in type 2 diabetes mellitus (T2DM) patients and healthy control subjects. Methods: This single-center prospective observational case-control study involved 51 individuals with T2DM and 34 healthy controls. All subjects underwent validated screening tests for peripheral neuropathy (PN), including proximal and distal sural nerve conduction study and WPN. Results: The median amplitude of the compound nerve action potentials (CNAPs) and the sensory conduction velocity (SCV) recorded by WPN conduction were significantly lower in patients with T2DM as compared to healthy controls. Sural nerve conduction revealed that both proximal and distal sensory nerve action potentials amplitude and SCV were significantly lower in subjects with diabetes, as compared to healthy controls. As compared with sural nerve conduction, WPN shows a Sensitivity of 77% and a negative predictive value (NPV) of 77%. Conclusions: WPN conduction study is helpful in characterizing the most distal nerve fibers in patients with T2DM and healthy controls. WPN may represent a useful tool in the diagnosis of length-dependent diabetic polyneuropathy.

Steatotic liver disease (SLD), including metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), is the primary cause of illness and mortality. In particular, MASLD affects more than 30% of the global population, while ALD accounts for 5.1% of all diseases and injuries worldwide. The SLD spectrum includes a variety of clinical conditions, from mild fatty liver and inflammation to different stages of liver fibrosis. Additionally, both conditions (MASLD and ALD) can be complicated by hepatocellular carcinoma (HCC), while around one-third of ALD patients can also develop at least one alcohol‐associated hepatitis (AH) episode. Both of these diseases are also associated with multiple extrahepatic complications, such as cardiovascular disease, chronic kidney disease, and malignancies. In MASLD, the rapid rise in global obesity and type 2 diabetes mellitus (T2DM) prevalence due to Westernized lifestyles has led to an increase in the prevalence of MASLD. Thus, the prevention and control of cardiometabolic risk factors (CMRFs) are the cornerstone of its treatment. Hypertension and atherogenic dyslipidemia are also important CMRFs associated with MASLD. Susceptible individuals with MASLD are adversely affected by even a small amount of alcohol consumption (though there is no agreed definition of a small amount), increasing the risk of severe outcomes and a faster progression of liver disease. This review explores factors that play a role in the development of SLD, especially focusing on the management of CMRFs and levels of alcohol use to prevent liver disease progression.

Metabolic dysfunction-associated steatotic liver disease (MASLD) stands as an independent risk factor for cardiovascular disease (CVD), which is the leading cause of mortality among MASLD patients. The diverse spectrum of cardio-nephro-metabolic and vascular manifestations inherent in MASLD highlights the complex profile of CVD risk associated with this condition. However, current approaches to assessing CVD risk in MASLD lack specificity, predominantly relying on traditional markers. Although it is widely accepted that patients with advanced fibrosis are more prone to CVD risk, recent evidence suggests that this isolated focus may overlook the remarkable phenotypic variability of this CVD risk across the entire MASLD population. Emerging data indicate a progressive escalation of CVD risk in parallel with the severity of MASLD, highlighting the need for precise disease staging to inform accurate risk assessment. To address this challenge, we propose a novel sequential approach to CVD risk assessment in MASLD. While traditional CVD risk factors remain essential, incorporating liver-specific parameters enhances risk stratification and guides targeted interventions to mitigate the substantial burden of cardiovascular disease in this vulnerable population. This approach involves initial screening using FIB-4 and NAFLD fibrosis score, followed by assessment of liver fibrosis with imaging-based non-invasive techniques in individuals at intermediate-high risk for advanced fibrosis and liver fat quantification in low-risk individuals. Future prospective investigations should focus on the simultaneous use of liver biomarkers and imaging modalities to evaluate, in a sex-specific manner, the efficacy of the proposed approach and to determine optimal thresholds of liver fibrosis and steatosis for optimal CVD risk assessment.

Heart disease remains a major health threat in women. Cardiometabolic risk factors such as obesity and diabetes differentially and adversely impact heart disease risk. Although obstructive coronary artery disease is an important cause of ischemic heart disease in women and is prognostic, women are more likely to have angina and myocardial ischemia without obstructive atherosclerosis, which has been attributed to coronary microvascular dysfunction (CMD). Heart failure with preserved ejection fraction (HFpEF) is another condition that predominates in women. CMD and HFpEF are both associated with cardiometabolic risk factors that are prevalent in women. Women are also more likely to have additional risk-enhancing conditions such as autoimmune dysfunction, chronic inflammation, and sex-specific hormonal factors that adversely influence risk. In this review, we focus on cardiometabolic risk factors of obesity and diabetes in heart disease in women, including ischemic heart disease from CMD, HFpEF, and arrythmias. Team-based care to focus on cardiometabolic risk reduction is needed to alter adverse heart disease outcomes in women. Identification, education, treatment, and active surveillance of these dysmetabolic risk factors are imperative in the primary and secondary prevention of heart disease in women.

Aim: Hepatic homocysteine (Hcy) accumulation promotes inflammation and fibrosis in experimental nonalcoholic fatty liver disease (NAFLD), while vitamin B12 and folate reduce hepatic Hcy and protect animals from nonalcoholic steatohepatitis. This suggests clinical implications for preventing/treating patients with NAFLD. Given the known sex-specific regulation of one-carbon metabolism (OCM), the response to various OCM cofactors may vary by sex and reproductive status. We aimed to strategize an effective Hcy-lowering treatment in broader NAFLD patients while discerning disparities in treatment responses. Methods: We analyzed existing hepatic microarray data relevant to Hcy metabolism with clinical and histologic data from patients with NAFLD (N = 82), while considering potential age/sex disparities. Additionally, we performed computer simulation analyses using a mathematical model of OCM to predict hepatic Hcy-lowering effects of OCM cofactors by sex. Results: Of 82 patients with NAFLD, 98% had at least one metabolic feature [i.e., metabolic dysfunction-associated steatotic liver disease (MASLD)]. Lower hepatic gene expressions of cystathionine-beta synthase (CBS) and phosphatidyl- ethanolamine N-methyltransferase (PEMT) were associated with more severe fibrosis in NAFLD, while sub-analysis suggested possible variations by age and sex. The simulation analysis demonstrated sex differences in the Hcy-lowering effects of the OCM cofactors (vitamins B6 and B12, folate, and betaine), with the combination of these cofactors consistently showing the maximum Hcy-lowering effect in both sexes. Conclusion: We theorize that the combination of OCM cofactors would maximize Hcy-lowering effects in the broader MASLD population. Our findings also underscore the importance of considering sex and age in designing future studies on homocysteine metabolism.

The term “democratization of science” describes the process of more evenly allocating epistemic authority between scientists, members of dominant civilizations, and the academic community at large, or members of less dominant societies. This means that it includes initiatives aimed at democratizing the decision-making process by acknowledging the presence of diverse types of “wisdom of crowd” and so reducing the barriers between the various stakeholders. Our purpose is to separate influence from involvement that contributes to the breakdown of conventional closed-circuit authority structures and to prevent future abuses of power by academic institutions, scientific societies, and even individual opinion leaders. A conceptual framework for comprehending the idea of the democratization of science is presented in this perspective piece. Our considerations are pertinent to the politics of widespread academic engagement in scientific decision-making, even though they were spurred by the discussion surrounding the definitions of fatty liver disease.