Does an Aspirin a Day Take the MASLD Away?

Although aspirin is deeply rooted in the most ancient history of medicine, the mechanism of action of this drug was only identified a few decades ago. Aspirin has several indications ranging from its long-known analgesic and antipyretic properties to the more recently discovered antithrombotic, chemopreventive and anti-eclampsia actions. In addition, a recent line of research has identified aspirin as a drug with potential hepatologic indications. This article specifically focuses on the nonalcoholic fatty liver disease/nonalcoholic metabolic dysfunction fatty liver disease/metabolic dysfunction-associated steatotic liver disease (NAFLD/MAFLD/MASLD) field. To this end, the most recently published randomized controlled trial on aspirin for non-cirrhotic MASLD is summarized and discussed. Moreover, previous epidemiologic evidence supporting the notion that aspirin exerts antisteatotic and antifibrotic hepatic effects, which may result in the primary prevention of hepatocellular carcinoma, is also addressed. Next, the putative mechanisms involved are examined, with reference to the effects on adipose tissue and liver and sex differences in the action of aspirin. It is concluded that these novel findings on aspirin as a "hepatologic drug" deserve additional in-depth evaluation.

Although aspirin is part of the history of medicine, its mechanism of action was only discovered a few decades ago. Aspirin can be used to treat pain, fever, inflammation and conditions where the blood tends to clot excessively (hypercoagulate) as well as for the prevention of certain types of cancer. Additionally, recent research has identified potential hepatologic indications and beneficial actions of aspirin among the so-called fatty liver disorders owing to conditions which disrupt the body's regular metabolic functions and disorders (such as obesity and diabetes). This article discusses a recently published study while also addressing previous studies supporting the notion that aspirin might have pharmacologic action against fatty liver and its progression to scarring tissue (liver fibrosis and hepatic cirrhosis) and prevent the most common type of primary liver cancer. Aspirin not only acts on the blood cells that protect against hemorrhage (i.e., the platelets) but also targets other tissues such as adipose tissue and the liver. Importantly, biologic sex may affect the pharmacologic action of aspirin. Collectively, the discoveries summarized in our article justify additional investigations into aspirin as a "novel" drug in the hepatologic field.

Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular-kidney-metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

The heterogeneity of metabolic syndrome presentation and challenges this causes in its pharmacological management: a narrative review focusing on principal risk modifiers.

INTRODUCTION: Metabolic syndrome (MetS), i.e. the cluster of cardiometabolic risk factors comprising visceral obesity, impaired glucose metabolism, arterial hypertension and atherogenic dyslipidemia, is prevalent globally and exacts a heavy toll on health care expenditures. AREAS COVERED: The pathophenotypes of individual traits of the MetS in adults are discussed first, with strong emphasis on nonalcoholic fatty liver disease (NAFLD) and sex differences. Next, I discuss recent studies on phenotypic and outcome heterogeneity of the MetS, highlighting the role of NAFLD, sex, reproductive status, and depressive disorders. In the second half of the article, the therapeutic implications of the variable MetS types and features are analyzed, focusing on the most recent developments, and guidelines. EXPERT OPINION: I have identified physiological, pathological, social and medical sources of phenotypical heterogeneity in the MetS and its constitutive traits. Improved understanding of these variables may be utilized in the setting of future precision medicine approaches in the field of metabolic disorders and target organ damage.

Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications.

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD.

Effect of cofactors on NAFLD/NASH and MAFLD. A paradigm illustrating the pathomechanics of organ dysfunction.

Primary nonalcoholic fatty liver disease (NAFLD) is bi-directionally associated with the metabolic syndrome and its constitutive features ("factors": impaired glucose disposal, visceral obesity, arterial hypertension, and dyslipidemia). Secondary NAFLD occurs due to endocrinologic disturbances or other cofactors. This nosography tends to be outdated by the novel definition of metabolic associated fatty liver disease (MAFLD). Irrespective of nomenclature, this condition exhibits a remarkable pathogenic heterogeneity with unpredictable clinical outcomes which are heavily influenced by liver histology changes. Genetics and epigenetics, lifestyle habits [including diet and physical (in)activity] and immunity/infection appear to be major cofactors that modulate NAFLD/MAFLD outcomes, including organ dysfunction owing to liver cirrhosis and hepatocellular carcinoma, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. The identification of cofactors for organ dysfunction that may help understand disease heterogeneity and reliably support inherently personalized medicine approaches is a research priority, thus paving the way for innovative treatment strategies.

Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis.

OBJECTIVE: Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD. DESIGN: We systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling. RESULTS: 13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2, with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; I2 =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias. CONCLUSION: This large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.

Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management.

Precision medicine defines the attempt to identify the most effective approaches for specific subsets of patients based on their genetic background, clinical features, and environmental factors. Nonalcoholic fatty liver disease (NAFLD) encompasses the alcohol-like spectrum of liver disorders (steatosis, steatohepatitis with/without fibrosis, and cirrhosis and hepatocellular carcinoma) in the nonalcoholic patient. Recently, disease renaming to MAFLD [metabolic (dysfunction)-associated fatty liver disease] and positive criteria for diagnosis have been proposed. This review article is specifically devoted to envisaging some clues that may be useful to implementing a precision medicine-oriented approach in research and clinical practice. To this end, we focus on how sex and reproductive status, genetics, intestinal microbiota diversity, endocrine and metabolic status, as well as physical activity may interact in determining NAFLD/MAFLD heterogeneity. All these factors should be considered in the individual patient with the aim of implementing an individualized therapeutic plan. The impact of considering NAFLD heterogeneity on the development of targeted therapies for NAFLD subgroups is also extensively discussed.

Renaming NAFLD to MAFLD: Could the LDE System Assist in This Transition?

Our understanding of fatty liver syndromes and their relationship with the metabolic syndrome has improved over recent decades and, paralleling this, we are now at the dawn of the NAFLD (nonalcoholic fatty liver disease) to MAFLD (metabolic-associated fatty liver disease) transition. The pitfalls of NAFLD diagnosis, together with disappointing results in therapeutic trials, and the inconsistencies and risks inherent in a "negative" definition (such as "nonalcoholic") as opposed to a "positive" one (i.e., "metabolic") are predicted to facilitate the proposed renaming of NAFLD to MAFLD. However, a premature change of terminology would not necessarily address major unmet needs in this area, and may even become counterproductive. As an aid to selecting more homogeneous cohorts of patients, I propose the LDE (Liver, Determinants, Extra-hepatic) classification system which, in principle, may help to assess the natural course of disease as well as the efficacy of novel drugs in patients with NAFLD/MAFLD.

Liver Fibrosis Biomarkers Accurately Exclude Advanced Fibrosis and Are Associated with Higher Cardiovascular Risk Scores in Patients with NAFLD or Viral Chronic Liver Disease.

Liver fibrosis predicts liver-related and cardiovascular outcomes in chronic liver disease patients. We compared the diagnostic performance of various liver fibrosis biomarkers for identifying histological significant/advanced fibrosis. Additionally, the correlations of such liver fibrosis biomarkers with cardiovascular risk (CVR) scores were evaluated. 173 patients with viral hepatitis (157 HCV and 16 HBV) and 107 with a non-alcoholic fatty liver disease (NAFLD) were consecutively enrolled. Various liver fibrosis biomarkers: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (ARR), AST to Platelet Ratio Index (APRI), Fibrosis-4 (FiB-4), Forns index, NAFLD fibrosis score (NFS), BARD (body mass index (BMI), AAR, Diabetes) score, and Hepamet fibrosis score (HFS), were used to identify significant/advanced fibrosis. CVR was assessed by using the SCORE, the Progetto CUORE, or the Framingham risk scoring systems. Liver fibrosis biomarkers performed better in predicting advanced rather than significant liver fibrosis in all patients, regardless of chronic liver disease aetiology. Forns index and HFS performed best in predicting advanced fibrosis in patients with viral chronic liver disease and NAFLD. Lower cut-offs of these liver fibrosis biomarkers had high negative predictive values for advanced fibrosis overall, as well as in patients with NAFLD or viral chronic liver disease. FIB-4, Forns index, NFS, and HFS were positively correlated with SCORE and Framingham risk scores. In conclusion, liver fibrosis biomarkers accurately exclude advanced fibrosis and positively correlate with CVR scores in patients with chronic liver disease.

Glucagon-Like Peptide-1 Receptor Agonists for Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: An Updated Meta-Analysis of Randomized Controlled Trials.

To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for treatment of nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH), we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Three large electronic databases were systematically searched (up to 15 December 2020) to identify placebo-controlled or active-controlled RCTs using different GLP-1 RAs. We included eleven placebo-controlled or active-controlled phase-2 RCTs (involving a total of 936 middle-aged individuals) that used liraglutide (n = 6 RCTs), exenatide (n = 3 RCTs), dulaglutide (n = 1 RCT) or semaglutide (n = 1 RCT) to specifically treat NAFLD or NASH, detected by liver biopsy (n = 2 RCTs) or imaging techniques (n = 9 RCTs). Compared to placebo or reference therapy, treatment with GLP-1 RAs for a median of 26 weeks was associated with significant reductions in the absolute percentage of liver fat content on magnetic resonance-based techniques (pooled weighted mean difference: -3.92%, 95% confidence intervals (CI) -6.27% to -1.56%) and serum liver enzyme levels, as well as with greater histological resolution of NASH without worsening of liver fibrosis (pooled random-effects odds ratio 4.06, 95% CI 2.52-6.55; for liraglutide and semaglutide only). In conclusion, treatment with GLP-1 RAs (mostly liraglutide and semaglutide) is a promising treatment option for NAFLD or NASH that warrants further investigation.

History of Nonalcoholic Fatty Liver Disease.

Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig's seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of "NAFLD as a manifestation of the Metabolic Syndrome", to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.

Sexual Dimorphism of NAFLD in Adults. Focus on Clinical Aspects and Implications for Practice and Translational Research.

Nonalcoholic fatty liver disease (NAFLD) embraces the clinico-pathological consequences of hepatic lipotoxicity and is a major public health problem globally. Sexual dimorphism is a definite feature of most human diseases but, under this aspect, NAFLD lags behind other medical fields. Here, we aim at summarizing and critically discussing the most prominent sex differences and gaps in NAFLD in humans, with emphasis on those aspects which are relevant for clinical practice and translational research. Sexual dimorphism of NAFLD is covered with references to the following areas: disease prevalence and risk factors, pathophysiology, comorbidities, natural course and complications. Finally, we also discuss selected gender differences and whether sex-specific lifestyle changes should be adopted to contrast NAFLD in men and women.

Semi-Quantitative Ultrasonographic Evaluation of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) embraces histopathological entities ranging from the relatively benign simple steatosis to the progressive form nonalcoholic steatohepatitis (NASH), which is associated with fibrosis and an increased risk of progression to cirrhosis and hepatocellular carcinoma. NAFLD is the most common liver disease and is associated with extrahepatic comorbidities including a major cardiovascular disease burden. The non-invasive diagnosis of NAFLD and the identification of subjects at risk of progressive liver disease and cardio-metabolic complications are key in implementing personalized treatment schedules and follow-up strategies. In this review, we highlight the potential role of ultrasound semiquantitative scores for detecting and assessing steatosis severity, progression of NAFLD, and cardio-metabolic risk. Ultrasonographic scores of fatty liver severity act as sensors of cardio-metabolic health and may assist in selecting patients to submit to second-line non-invasive imaging techniques and/or liver biopsy.

Extra-hepatic manifestations and complications of nonalcoholic fatty liver disease.

This review article aims to synthesize the evidence regarding nonalcoholic fatty liver disease (NAFLD) as a systemic disorder. We critically discuss the metabolic syndrome and its components; the cardiovascular and the endocrine system; chronic respiratory disorders; the musculoskeletal system; the skin; and extra-hepatic tumors. We conclude that, while some of these extra-hepatic conditions clearly predispose to the development of secondary forms of NAFLD (typically hypothyroidism-induced NAFLD), others result from pre-existent NAFLD (e.g., certain extra-hepatic tumors) and others (such as Type 2 Diabetes) have, with NAFLD, mutual and bidirectional associations. Analyzed data imply that NAFLD is not merely a hepatic disease. It is also and possibly more importantly, a systemic disorder requiring a special awareness, a multidisciplinary approach and a multidimensional vision.

NAFLD in Some Common Endocrine Diseases: Prevalence, Pathophysiology, and Principles of Diagnosis and Management.

Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, or growth hormones (GH) may cause secondary forms of NAFLD, which exhibit specific pathophysiologic features and, in theory, the possibility to receive an effective treatment. Here, we critically discuss epidemiological and pathophysiological features, as well as principles of diagnosis and management of some common endocrine diseases, such as polycystic ovary syndrome (PCOS), hypothyroidism, hypogonadism, and GH deficiency. Collectively, these forms of NAFLD secondary to specific endocrine derangements may be envisaged as a naturally occurring disease model of NAFLD in humans. Improved understanding of such endocrine secondary forms of NAFLD promises to disclose novel clinical associations and innovative therapeutic approaches, which may potentially be applied also to selected cases of primary NAFLD.

Association between Helicobacter pylori infection and risk of nonalcoholic fatty liver disease: An updated meta-analysis.

BACKGROUND: Recent studies that have examined the association between Helicobacter pylori infection and risk of nonalcoholic fatty liver disease (NAFLD) have produced conflicting data. We have performed a systematic review and meta-analysis to assess the association between H. pylori infection and risk of NAFLD. METHODS: We searched PubMed, Web of Science and Scopus databases using predefined keywords to identify observational studies (published up to November 2018), in which NAFLD was diagnosed by histology, imaging or biochemistry. Data from selected studies were extracted and meta-analysis was performed using random-effects modeling. The statistical heterogeneity among studies (I2-index), subgroup analyses and the possibility of publication bias were assessed. RESULTS: Thirteen observational (11 cross-sectional/case-control and 2 longitudinal) studies involving a total of 81,162 middle-aged individuals of predominantly Asian ethnicity (47.5% of whom had H. pylori infection diagnosed by urea breath test, faecal or serological tests) were included in the final analysis. Meta-analysis of data from cross-sectional and case-control studies showed that H. pylori infection was associated with increased risk of prevalent NAFLD (n = 11 studies; random-effects odds ratio [OR] 1.20, 95% CI 1.07-1.35; I2 = 59.6%); this risk remained significant in those studies where analysis was fully adjusted for age, sex, smoking, adiposity measures, diabetes or dyslipidemia (random-effects OR 1.19, 95% CI 1.07-1.32, I2 = 0%). Meta-analysis of data from longitudinal studies showed that H. pylori infection was also associated with increased NAFLD incidence (n = 2 studies; random-effects hazard ratio 1.14, 95% CI 1.05-1.23; I2 = 0%). Sensitivity analyses did not alter these findings. Funnel plot did not reveal significant publication bias. CONCLUSIONS: H. pylori infection is associated with mildly increased risk of both prevalent and incident NAFLD in middle-aged individuals. More prospective studies, particularly in non-Asian populations, and mechanistic studies are required to better elucidate the link between chronic H. pylori infection and NAFLD.