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Heart failure (HF) is a clinical syndrome due to heart dysfunction, but in which other organs are also involved, resulting in a complex multisystemic disease, burdened with high mortality and morbidity. This article focuses on the mutual relationship between the heart and liver in HF patients. Any cause of right heart failure can cause hepatic congestion, with important prognostic significance. We have analyzed the pathophysiology underlying this double interaction. Moreover, we have explored several biomarkers and non-invasive tests (i.e., liver stiffness measurement, LSM) potentially able to provide important support in the management of this complex disease. Cardiac biomarkers have been studied extensively in cardiology as a non-invasive diagnostic and monitoring tool for HF. However, their usefulness in assessing liver congestion in HF patients is still being researched. On the other hand, several prognostic scores based on liver biomarkers in patients with HF have been proposed in recent years, recognizing the important burden that liver involvement has in HF. We also discuss the usefulness of a liver stiffness measurement (LSM), which has been recently proposed as a reliable and non-invasive method for assessing liver congestion in HF patients, with therapeutic and prognostic intentions. Lastly, the relationship between LSM and biomarkers of liver congestion is not clearly defined; more research is necessary to establish the clinical value of biomarkers in assessing liver congestion in HF patients and their relationship with LSM.

In the natural history of SARS-CoV-2 infection, liver injury is frequent but quite mild and it is defined as any liver damage occurring during disease progression and treatment of infection in patients with or without pre-existing liver diseases. The underlying mechanisms for hepatic injury in patients with COVID-19 are still unclear but the liver damage in SARS-CoV-2 infection seems to be directly caused by virus-induced cytopathic effects. In this review, we will summarize all data of updated literature, regarding the relationship between SARS-CoV-2 infection, acute response and liver involvement. An overview will be given on liver injury, liver transplant and the possible consequences of COVID-19 in patients with pre-existing liver diseases., (© 2020 The Scandinavian Foundation for Immunology.)

A prerequisite for establishment of mutualism between the host and the microbial community that inhabits the large intestine is the stringent mucosal compartmentalization of microorganisms. Microbe-loaded dendritic cells trafficking through lymphatics are arrested at the mesenteric lymph nodes, which constitute the firewall of the intestinal lymphatic circulation. We show in different mouse models that the liver, which receives the intestinal venous blood circulation, forms a vascular firewall that captures gut commensal bacteria entering the bloodstream during intestinal pathology. Phagocytic Kupffer cells in the liver of mice clear commensals from the systemic vasculature independently of the spleen through the liver's own arterial supply. Damage to the liver firewall in mice impairs functional clearance of commensals from blood, despite heightened innate immunity, resulting in spontaneous priming of nonmucosal immune responses through increased systemic exposure to gut commensals. Systemic immune responses consistent with increased extraintestinal commensal exposure were found in humans with liver disease (nonalcoholic steatohepatitis). The liver may act as a functional vascular firewall that clears commensals that have penetrated either intestinal or systemic vascular circuits., (Copyright © 2014, American Association for the Advancement of Science.)

Aims: Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints. Methods: Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable. Results: Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance. Conclusions: This study developed a series of ML models of accuracy ranging from 71.9—99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means. [ABSTRACT FROM AUTHOR]

Metabolic diseases are associated with a higher risk of a severer coronavirus disease 2019 (COVID‐19) course, since fatty liver is commonly associated with metabolic disorders, fatty liver itself is considered as a major contributor to low‐grade inflammation in obesity and diabetes. Recently a comprehensive term, metabolic (dysfunction) associated fatty liver disease (MAFLD), has been proposed. The hepatic inflammatory status observed in MAFLD patients is amplified in presence of severe acute respiratory syndrome coronavirus 2 infection. Intestinal dysbiosis is a powerful activator of inflammatory mediator production of liver macrophages. The intestinal microbiome plays a key role in MAFLD progression, which results in non‐alcoholic steatohepatitis and liver fibrosis. Therefore, patients with metabolic disorders and COVID‐19 can have a worse outcome of COVID‐19. This literature review attempts to disentangle the mechanistic link of MAFLD from COVID‐19 complexity and to improve knowledge on its pathophysiology. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. Methods: Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. Results: Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between 'HCCs + HGDNs' versus LGDNs ( p < 0.05); sensitivity, specificity, and accuracy for the diagnosis of 'HCCs + HGDNs' were 96.8 %, 100 %, 97.4 % respectively when combining hyperintensity on DWI and hypointensity on DPI, and 90.9 %, 81.0 %, 83.6 % respectively when lesion-to-liver ratio was <0.95. Conclusions: Hyperintensity on DWI, especially in association with hypointensity on DPI, and low lesion-to-liver ratios should raise the suspicion of HCC, or at least of HGDN, thus helping the characterization of atypically enhancing lesions. Key points: • Usefulness of DWI and ADC is shown in differential diagnosis of cirrhotic nodules. • Correlation of DWI with DPI improves differential diagnosis of cirrhotic nodules. • Characterization of atypically enhancing lesions becomes more confident. [ABSTRACT FROM AUTHOR]

Background and Aims: Variant in glucokinase regulatory protein (GCKR), associated with lipid and glucose traits, has been suggested to affect fatty liver infiltration. We aimed to assess whether GCKR rs780094 C→T SNP influences the expression of steatosis, lobular inflammation and fibrosis in NAFLD patients, after correction for PNPLA3 genotype. Methods: In 366 consecutive NAFLD patients (197 from Sicily, and 169 from center/northern Italy), we assessed anthropometric, biochemical and metabolic features; liver biopsy was scored according to Kleiner. PNPLA3 rs738409 C>G and GCKR rs780094 C>T single nucleotide polymorphisms were also assessed. Results: At multivariate logistic regression analysis in the entire NAFLD cohort, the presence of significant liver fibrosis (>F1) was independently linked to high HOMA (OR 1.12, 95% CI 1.01–1.23, p = 0.02), NAFLD activity score ≥5 (OR 4.09, 95% CI 2.45–6.81, p<0.001), and GCKR C>T SNP (OR 2.06, 95% CI 1.43–2.98, p<0.001). Similar results were observed considering separately the two different NAFLD cohorts. GCKR C>T SNP was also associated with higher serum triglycerides (ANOVA, p = 0.02) in the entire cohort. Conclusions: In patients with NAFLD, GCKR rs780094 C>T is associated with the severity of liver fibrosis and with higher serum triglyceride levels. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are both highly prevalent in the general population and associated with obesity and insulin resistance. We aimed to evaluate the prevalence of GD in a cross sectional study of NAFLD patients and to define whether the presence of GD is associated with diabetes and predicts more severe liver disease. Methodology/Principal Findings: We merged databases of four Liver Units, comprising 524 consecutive biopsy-proven NAFLD (373 males) observed between January 2003 and June 2010. GD was diagnosed in 108 (20%), and 313 cases (60%) were classified by liver biopsy as nonalcoholic steatohepatitis (NASH). The GD subgroup was characterized by a significantly higher prevalence of females, prediabetes/diabetes, abdominal obesity and metabolic syndrome, older age, higher BMI, fasting glucose, HOMA-IR and lower ALT. The prevalence of GD progressively increased with advancing fibrosis and with the severity of necroinflammatory activity (p for trend = 0.0001 and = 0.01, respectively), without differences in the severity of steatosis. At multivariate analysis GD was associated with female gender (OR 1.37, 95% CI 1.04-1.8), age (OR 1.027, 95% CI1.003-1.05), fasting glucose (OR 1.21, 95% CI 1.10-1.33) and NASH (OR 1.40,95% CI 1.06-1.89), whereas ALT levels were associated with a lower GD risk (OR 0.98, 95% CI 0.97-0.99). When subjects with cirrhosis were excluded from analysis, the association between GD and fasting glucose, female gender, and NASH was maintained. Conclusion: Patients with NAFLD have a high prevalence of GD, which characterizes subjects with altered glucose regulation and more advanced liver disease. [ABSTRACT FROM AUTHOR]

Background & Aims: Although nonalcoholic fatty liver disease (NAFLD) is increasingly common, only a minority of affected individuals develop fibrotic liver disease. Based on its role in liver growth and repair, we explored whether Kruppel-like factor 6 (KLF6) plays a role in NAFLD progression. Methods: KLF6 expression in 31 fibrosis scored NAFLD liver biopsy specimens was assessed by real-time polymerase chain reaction. Transfected minigene constructs were used to study the effect of a polymorphism, KLF6-IVS1-27G>A, that promotes KLF6 alternative splicing in vitro. We genotyped KLF6-IVS1-27G>A in 3 groups of patients (UK group 1, n = 306; Italian group 2, n = 109; trio group 3, n = 61 children and parents). Results: KLF6 expression was increased in association with increased steatosis, inflammation, and fibrosis in NAFLD livers. KLF6-IVS1-27G>A promoted alternative splicing of KLF6 and abrogated the up-regulation of both α-smooth muscle actin and collagen 1 in LX-2 cells. Group 1 genotyping identified KLF6-IVS1-27G>A in 44 of 306 (14.4%) patients. Notably, KLF6-IVS1-27G>A was associated significantly with milder NAFLD, with only 25% having more advanced fibrosis compared with 45% of wild-type (wt) individuals. This trend was confirmed in group 2. A linear regression analysis including all 415 patients, adjusted for age, sex, body mass index, and blood glucose level, confirmed that presence of the wt KLF6 allele was an independent predictor of fibrotic NAFLD. Furthermore, we have shown preferential transmission of the wt allele to children with fibrotic NAFLD. Conclusions: We report a functional polymorphism in the KLF6 gene associated with advanced NAFLD and believe further study of KLF6 may enhance our understanding of this disease process. [Copyright &y& Elsevier]

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries and is also predicted to become the most frequent indication for liver transplantation by 2030. In the last decade, it has become evident that the clinical burden of NAFLD is not restricted to liver-related morbidity or mortality, but there is now compelling evidence that NAFLD is a multisystem disease, affecting many extra-hepatic organs. In this article, we discuss the evidence linking NAFLD with important cardiometabolic complications (mainly Type 2 diabetes and cardiovascular disease) and the putative underlying mechanisms by which NAFLD may contribute to the development of these complications. [ABSTRACT FROM PUBLISHER]

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and represent a common finding in highly prevalent metabolic disorders (i.e. type 2 diabetes, metabolic syndrome, obesity). Non-alcoholic steatohepatitis (NASH) requires liver biopsy for grading and staging the liver damage by the assessment of steatosis, inflammation and fibrosis. In parallel with the development of numerous 'liquid' biomarkers and algorithms that combine anthropometric and laboratory parameters, innovative hepatic imaging techniques have increasingly been developed to attempt to overcome the need for biopsy, both in diagnosis and staging of NAFLD, and in possible use in the follow-up of the disease. In this review, we focused on the different imaging techniques trying to highlight the strengths and disadvantages of different approaches, particularly for ultrasound techniques, in stratifying liver injury and fibrosis in patients with NAFLD / NASH. • NAFLD is the most common cause of chronic liver disease and may progress to cirrhosis and liver cancer. • The diagnosis of steatohepatitis is based on liver histology. • Non invasive biomarkers are still a medical need for identify subjects with steatosis and fibrosis. • Ultrasound (US) based techniques are growing in order to evaluate steatosis and fibrosis in a non-invasive way. • Elastography and MRE are able to support the clinician for clinical decision in NAFLD subjects. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7) , which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p < 0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p < 0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation. [Display omitted] • NAFLD is the leading cause of liver disorders and has a strong heritable component. • Rare loss-of-function ATG7 gene mutations increase the risk of severe liver disease in patients with NAFLD. • ATG7 mutations cause altered protein function and impairment of autophagy, leading to hepatocellular ballooning and inflammation. • The most frequent variant is responsible for a meaningful fraction of predisposition to ballooning and hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated the longitudinal impact of antinuclear antibody (ANA) on clinical outcomes and survival in nonalcoholic fatty liver disease (NAFLD). METHODS: ANA were found in 16.9% of 923 biopsy-proven NAFLD patients, but none of them had histologic autoimmune hepatitis (AIH) or developed AIH after a mean follow-up of 106650 months. RESULTS: Although ANA-positive cases had a higher prevalence of nonalcoholic steatohepatitis at baseline, the occurrence of liver-related events, hepatocellula carcinoma, cardiovascular events, extrahepatic malignancy, and overall survival were similar to ANA-negative. DISCUSSION: Once AIH has been ruled out, the long-term outcomes and survival are unaffected by the presence of ANA in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: Increased visceral adiposity is considered the hallmark of the metabolic syndrome, whose hepatic manifestation is nonalcoholic fatty liver disease (NAFLD), although a subset of patients does not have visceral obesity. Our study aimed to compare metabolic alterations and liver damage in patients with NAFLD with and without visceral obesity. Methods: Four hundred and thirty one consecutive patients with liver biopsy-confirmed NAFLD were divided in three groups according to waist circumference, the simplest surrogate marker of visceral obesity. One hundred and thirty three patients (31%) had a waist circumference⩽94 (males) and⩽80cm (females) (group A), 157 (36%) between 94 and 102, and 80 and 88 (B), and the remaining 141 (33%) had values higher than 102 and 88cm (C). Results: Significant trends for older age, higher prevalence of female gender, lower HDL, higher triglycerides, altered glucose metabolism, hypertension, and metabolic syndrome were observed with increasing visceral adiposity. In contrast, non-alcoholic steatohepatitis (NASH) detected in 55% and 72% of patients with normal and increased waist circumference, respectively, and the presence of fibrosis⩾2 were not associated with visceral adiposity. Alanine aminotransferase (ALT), ferritin, HOMA-IR>4, and severe steatosis were independently associated with NASH, whereas ferritin and impaired glucose tolerance were associated with fibrosis⩾2. Conclusions: Patients with normal waist circumference, despite milder metabolic alterations, may have NASH and are at risk of developing fibrosis, suggesting that once NAFLD is present, visceral obesity is not a major determinant of liver damage severity. [ABSTRACT FROM AUTHOR]