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.

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.

Liver fibrosis is critical for liver-related outcomes and mortality in chronic liver disease, irrespective of etiology, including nonalcoholic fatty liver disease (NAFLD). NAFLD has been viewed as an independent correlate of cardiovascular risk. This review article briefly describes the cellular and molecular pathomechanisms underlying hepatic fibrosis. We then address noninvasive assessment of liver fibrosis. Finally, we discuss published evidence supporting fibrosis biomarkers’ role in assessing cardiovascular risk among patients with NAFLD. While histological assessment is the diagnostic standard of hepatic fibrosis, we specifically address noninvasive techniques, including equations based on anthropometric parameters, laboratory indices, and elastometry obtained with imaging techniques. The former group includes AST: ALT ratio, the Forns Index, the AST-to-platelet ratio index score, BARD (BMI, AAR, Diabetes) score, the fibrosis-4 index (FIB-4), the NAFLD fibrosis score, the gamma-glutamyl transferase-to-platelet ratio, and the Hepamet fibrosis score. The latter comprises elastographic techniques associated with ultrasonography or magnetic resonance. Our literature review identified numerous studies demonstrating that biomarkers of fibrosis (the most common being FIB-4) and elastographic techniques predict overall mortality and major cardiovascular events among NAFLD patients. The mechanisms accounting for this association are briefly reviewed. In addition to assessing hepatic fibrosis at baseline, during follow-up, and after therapeutic interventions in NAFLD patients, noninvasive assessment of hepatic fibrosis may predict cardiovascular events and overall mortality in these patients.

Here, we comment on a recent article supporting the use of the ultrasonographic fatty liver indicator (US-FLI) as a point-of-care biomarker to be used in the community to rule out nonalcoholic steatohepatitis (NASH). To this end, we discuss definitions and characteristics of US-FLI, and we critically summarize the principal studies published from 2012 to 2023. We conclude that US-FLI exhibits high reproducibility. It finds utility across both the pediatric population and the point-of-care settings. Furthermore, it demonstrates a robust correlation with metabolic derangements, and also serves as a predictive tool for varying grades of hepatic steatosis and important liver histology endpoints. Notably, it excels in its capacity to differentiate between bland steatosis and true NASH. However, US-FLI reportedly exhibits limited accuracy among patient populations with obesity. Finally, we propose a detailed agenda to advance research on US-FLI.

Tick-borne encephalitis (TBE), a human viral infectious disease caused by the tick-borne encephalitis virus (TBEV), is emerging in Italy, especially in the north-eastern area. No human cases of autochthonous TBE have been reported in Italy's central regions (such as Emilia-Romagna, Italy). However, here we describe the first human case of TBEV infection in this region, pointing to endemic transmission of TBEV, supporting the concept of circulation of TBEV and of the presence of a possible hot spot in the Serramazzoni region in the Emilian Apennines.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a significant healthcare burden, and represent the main indications for anticoagulation. Direct oral anticoagulants (DOACs) are the first choice treatment of AF/VTE, and have become the most prescribed class of anticoagulants globally, overtaking vitamin K antagonists (VKAs). Compared to VKAs, DOACs have a similar or better efficacy/safety profile, with reduced risk of intracerebral hemorrhage (ICH), while the risk of major bleeding and other bleeding harms may vary depending on the type of DOAC. We have critically reviewed available evidence from randomized controlled trials and observational studies regarding the risk of bleeding complications of DOACs compared to VKAs in patients with AF and VTE. Special patient populations (e.g., elderly, extreme body weights, chronic kidney disease) have specifically been addressed. Management of bleeding complications and possible resumption of anticoagulation, in particular after ICH and gastrointestinal bleeding, are also discussed. Finally, some suggestions are provided to choose the optimal DOAC to minimize adverse events according to individual patient characteristics and bleeding risk.

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.

Aim: We examined the diagnostic accuracy of ultrasonography to detect any HS (defined as steatotic hepatocytes >= 5% on histology) and moderate-severe HS (defined as steatotic hepatocytes >= 30% on histology) by performing a systematic review and meta-analysis. Methods: We systematically searched PubMed, Web of Science, and Scopus databases, from January 2011 to February 2021, to identify studies conducted in adults investigating the diagnostic accuracy of ultrasonography vs. histology for detecting either >= 5% histologically defined HS or moderate-severe HS (>= 30%). Meta-analysis was performed using random-effects modeling. Results: Twelve studies were included involving a total of 2921 individuals, 1710 (58.5%) of whom had HS >= 5% by histology. The overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasonography for the detection of >= 5% histologically defined HS, compared to histology, were 82% (95% confidence interval 76%-86%), 80% (72%-86%), 4.0 (2.90-5.70), and 0.23 (0.18-0.30), respectively. Based on the pooled analysis of seven studies, the overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasonography for the detection of >= 30% histologically defined HS were 85% (72%-92%), 85% (73%-93%), 5.72 (3.06-10.7), and 0.18 (0.10-0.33) , respectively. Funnel plots did not reveal any significant publication bias. Conclusion: Conventional ultrasonography allows for reliable and accurate detection of >= 5% histologically defined HS compared to histology. These findings call for an extensive use of conventional ultrasonography in the clinical arena.

Metabolism and Target Organ Damage (M&TOD) is an international, peer-reviewed, open access scientific journal which provides an online platform for publication of clinical, basic and translational studies.

In 2006, we were first in proposing Fatty Liver Index (FLI) as a non-invasive biomarker which might assist in detecting those individuals to submit to liver ultrasonography for suspected nonalcoholic fatty liver disease (NAFLD). In the present review article, which conforms to the scale for the quality assessment of narrative review articles (SANRA) criteria, we evaluate the directions followed by publications on FLI over the last 15 years. Data have shown that FLI and NAFLD share the same risk factors, which indirectly supports the notion that, in epidemiological studies, FLI does identify NAFLD, and could be useful for a screening campaign in populations at risk. In the same setting, FLI identifies the risk of both subclinical and overt atherosclerosis and the risk of incident diabetes and chronic kidney disease. More limited studies suggest that FLI is also a useful predictor of the metabolic syndrome of some endocrine derangements, certain types of tumors and overall and cause-specific mortality. We conclude that FLI is a worldwide well validated non-invasive marker to identify Fatty Liver and NAFLD. Additional studies should evaluate whether specific modifiers may improve FLI equation, for example by taking in consideration also age, sex, reproductive status, and ethnicity.

: 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.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent and relevant healthcare issues. Direct oral anticoagulants (DOACs) are now the first-choice for anticoagulant treatment of these conditions displaying a better efficacy/safety profile than vitamin-K antagonists, mainly due to significantly reduced risk of major bleeding, especially of intracranial haemorrhage. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in developed countries showing a continuously growing prevalence. Nonalcoholic steatohepatitis (NASH), its evolutive form, will be the leading cause for liver transplantation by 2020. NAFLD is independently associated with an increased risk of abnormalities of cardiac structure and function, including cardiac rhythm disorders (mainly AF). Moreover, data suggest an increased risk of unprovoked VTE associated with NAFLD/NASH. Therefore, a growing number of patients with chronic liver disease (CLD) will be candidate for anticoagulant therapy in the near future. Cirrhosis of any etiology is characterized by an unstable thrombosis/bleeding haemostatic balance, making anticoagulant therapy particularly challenging in this condition. Given that patients with significant active liver disease and cirrhosis were excluded from all pivotal randomized controlled trials on DOACs, this comprehensive review aims at critically discussing real-world evidence, including the latest population studies, regarding the use of DOACs in patients with CLD/cirrhosis.

Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.

Nonalcoholic fatty liver disease (NAFLD) exhibits sexual dimorphism, with men being more exposed than women to the risk of simple steatosis, nonalcoholic steatohepatitis fibrosis, and hepatocellular carcinoma (HCC), while the protection conferred to women seemingly disappears with aging and reproductive senescence (i.e., menopause). HCC, the most common primary liver cancer, which carries an ominous prognosis, may result from various genetic and non-genetic risk factors. NAFLD is now projected to become the most common cause of HCC. HCC also exhibits a definite sexual dimorphism in as much as it has a worldwide high male-to-female ratio. In this review article, we focus on sex differences in the epidemiological features of HCC. Moreover, we discuss sex differences in the clinical outcome and molecular pathobiology of NAFLD-HCC. By highlighting the research gaps to be filled, the aim of this review is to prompt future research of sex differences in HCC and facilitate developing personalized cancer prevention strategies, detection, and treatments to achieve better patient outcomes in NAFLD-HCC, considering sex differences in HCC pathobiology. Received: First Decision: Revised: Accepted: Published: Science Editor: Copy Editor: Production Editor: Jing Yu Page 2 of 12 Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89

New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD-in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome-and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.

Introduction: Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD carries an increased risk of cardio-metabolic and liver-related events accounting for a substantial economic burden. Given that the natural history of NAFLD is critically dependent on the stage of fibrosis, non-invasively identifying the subgroup of patients at a higher risk of progressive disease is key. Areas covered: This review highlights the recent developments in the use of ultrasound-based techniques in NAFLD and their performance in predicting metabolic derangements, cardiovascular risk, and progression of liver disease, notably including diagnosis of fibrosing NASH, identification, and treatment of HCC. Expert opinion: Our ability to identify NAFLD patients and to estimate steatofibrosis with various ultrasound-based techniques has undergone tremendous progress over the last few years. However, it is more difficult to capture the inflammatory component of NASH with such ultrasound-assisted techniques. Moreover, semi-quantitative, quantitative, elastographic, and contrast-enhanced ultrasound techniques are increasingly being appreciated and made available but not all such techniques will gain success in the clinical and research area. Therefore, further research will precisely define the role of the most innovative ultrasonographic techniques, while reducing costs and increasing feasibility.

Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD.

Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.