Cirrhosis Research Articles

Extracellular matrix protein 1 binds to connective tissue growth factor against liver fibrosis and ductular reaction.

Extracellular matrix protein 1 (ECM1) can inhibit TGFβ activation, but its antifibrotic action remains largely unknown. This study aims to investigate ECM1 function and its physical interaction with the profibrotic connective tissue growth factor (CTGF) in fibrosis and ductular reaction (DR). Ecm1 knockouts or animals that ectopically expressed this gene were subjected to induction of liver fibrosis and DR by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or α-naphthyl-isothiocyanate (ANIT). ECM1 and CTGF were also examined in the livers of patients with alcohol-associated liver disease (ALD) or ethanol-exposed animals that were fed the western diet for 4 months in the WDA model with liver pathology resembing ALD in patients. ECM1 bound to CTGF in yeast two-hybrid systems, cultured liver cells, and cholestatic livers damaged by DDC or α-naphthyl-isothiocyanate. This interaction blocked integrin αvβ6-mediated TGFβ activation, thereby reducing fibrotic responses in vitro. ECM1 downregulation was associated with biliary CTGF induction during human ALD progression. In experimental models, Ecm1 loss enhanced susceptibility to DDC-induced cholestasis with upregulation of Ctgf, αvβ6, alpha-smooth muscle actin, procollagen type I, serum transaminase, and total bilirubin levels in germline knockouts, whereas forced expression of this gene significantly attenuated DR and biliary fibrosis after the feeding of DDC or α-naphthyl-isothiocyanate containing diets. Moreover, ectopic Ecm1 inhibited not only alcohol-associated fibrosis but also TGFβ-mediated deregulation of hepatocyte nuclear factor 4α, preventing the production of the fetal p2 promoter-driven isoforms in the WDA model. We uncover a novel antifibrotic action by ECM1 that binds CTGF and inhibits integrin αvβ6-mediated TGFβ activation. Targeting its loss has therapeutic potential for the treatment of DR and liver fibrosis in chronic conditions, such as cholangiopathy and ALD.

USP9X-enriched MSC-sEV inhibits LSEC angiogenesis in MASH mice by downregulating the IκBα/NF-κB/Ang-2 pathway.

Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway.

Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study

Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms. We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP)≥263dB/m) and -fibrosis (liver stiffness measurement (LSM)≥7.0kPa). Plasma protein concentrations (n=2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics wereassessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins werecompared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26kg/m2. Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV. Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories. The 2000HIV study is funded by ViiV Healthcare.

The antisickling agent, 5-hydroxymethyl-2-furfural: Other potential pharmacological applications.

For the last two decades, the aromatic aldehyde 5-hydroxymethyl-furfural (5-HMF) has been the subject of several investigations for its pharmacologic potential. In 2004, the Safo group reported that 5-HMF has potent antisickling activity by targeting and ameliorating the primary pathophysiology of hypoxia-induced sickling of erythrocytes (red blood cells [RBC]). Following the encouraging outcome of the preclinical and phase I/II clinical studies of 5-HMF for the treatment of sickle cell disease (SCD), there have been multiple studies suggesting 5-HMF has several other biological or pharmacologic activities, including anti-allergic, antioxidant, anti-hypoxic, anti-ischemic, cognitive improvement, anti-tyrosinase, anti-proliferation, cytoprotective, and anti-inflammatory activities. The wide range of its effects makes 5-HMF a potential candidate for treating a variety of diseases including cognitive disorders, gout, allergic disorders, anemia, hypoxia, cancers, ischemia, hemorrhagic shock, liver fibrosis, and oxidative injury. Several of these therapeutic claims are currently under investigation and, while promising, vary in terms of the strength of their evidence. This review presents the research regarding the therapeutic potential of 5-HMF in addition to its sources, physicochemical properties, safety, absorption, distribution, metabolism, and excretion (ADME) profiles.

Transforming steatotic liver disease management: The emerging role of GLP-1 receptor agonists.

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

Rosehip (Rosa rugosa Thunb.) ethanol extract ameliorates liver fibrosis through upregulation of the PPAR signaling pathway

The objective of this study was to examine the effect of rosehip (Rosa rugosa Thunb.) ethanol extract (RRE) on liver fibrosis in mice and the underlying molecular mechanisms. RRE has no acute oral toxicity, and the MTD in mice is 46.14 g/kg. Histopathological analysis showed that RRE significantly ameliorated inflammation, necrosis, and apoptosis of hepatocytes and collagen deposition caused by CCl4. Further assays indicated that RRE significantly suppressed the production of MDA while markedly increasing the levels of SOD and GSH in the liver. The AST, ALT, IL-6, IL-1β, TNF-α, HA, LN, PCIII, and IVC levels in serum were decreased by RRE. Transcriptome analysis shows that RRE significantly upregulates the PPAR signaling pathway. The RT-q PCR results further confirmed the RRE up-regulating Pparγ, Rxrα, and Plin5 in the PPAR signaling pathway. The Western blot and immunohistochemical results indicate that RRE upregulated PPARγ, RXRα, and Perilipin 5 while downregulating α-SMA and COL1A1 expression. The results indicate that RRE can ameliorate liver fibrosis in mice by upregulating the PPAR signaling pathway.

Precision-cut liver slices as an ex vivo model to evaluate antifibrotic therapies for liver fibrosis and cirrhosis.

Considering the lack of successful treatment options and poor prognosis for cirrhosis and cirrhosis-induced HCC, new platforms to investigate antifibrotic therapies are urgently needed. Precision-cut liver slice (PCLS) is a powerful ex vivo culture model that can supplement and potentially replace the traditional models. PCLS were prepared from 4 different murine cirrhotic models (choline-deficient, l-amino acid-defined, high-fat diet, thioacetamide, diethylnitrosamine, and carbon tetrachloride) and compared with in vivo murine experiments, in vitro hepatic stellate cells, and human cirrhotic PCLS. PCLS viability in culture was stable for 72 hours. Treatment of erlotinib, an EGF receptor inhibitor, significantly inhibited profibrogenic gene expressions in PCLS from choline-deficient, l-amino acid-defined, high-fat diet or thioacetamide-induced cirrhotic rats. Erlotinib treatment of PCLS from diethylnitrosamine or carbon tetrachloride-induced cirrhotic rats inhibited the expression of profibrogenic genes, which was consistent with the impact of erlotinib on these genes in in vivo diethylnitrosamine or carbon tetrachloride-induced cirrhosis. In addition, in hepatic stellate cells at PCLS from normal mice, erlotinib treatment inhibited TGF-β1-upregulated expression of Acta2. Similar expression results were observed in in vitro hepatic stellate cells. Expression of key regulators of fibrosis progression and regression were also significantly altered. Changes in profibrogenic gene expression under erlotinib treatment were also corroborated with human cirrhotic PCLS. Responses to antifibrotic interventions can be detected and quantified with PCLS at the gene expression level. The antifibrotic effects of erlotinib are consistent between PCLS models of murine cirrhosis and those observed in vivo and in vitro. These results were verified in human cirrhotic PCLS. PCLS is an excellent model for assessing antifibrotic therapies that are aligned with the principles of replacement, reduction, and refinement (3Rs), and it will benefit preclinical and clinical research for human fibrosis and cirrhosis.

FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis.

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.

Christensenella minuta Mitigates Behavioral and Cardiometabolic Hallmarks of Social Defeat Stress

Psychological stress during early development and adolescence may increase the risk of psychiatric and cardiometabolic comorbidities in adulthood. The gut microbiota has been associated with mental health problems such as depression and anxiety and with cardiometabolic disease, but the potential role of the gut microbiota in their comorbidity is not well understood. We investigated the effects and mode of action of the intestinal bacterium Christensenella minuta DSM 32891 on stress-induced mental health and cardiometabolic disturbances in a mouse model of social defeat stress. We demonstrate that administered C. minuta alleviates chronic stress-induced depressive, anxiogenic and antisocial behavior. These effects are attributed to the bacterium’s ability to modulate the hypothalamic-pituitary-adrenal axis, which mediates the stress response. This included the oversecretion of corticosterone and the overexpression of its receptors, as well as the metabolism of dopamine (DA) and the expression of its receptors (D1, D2L and D2S). Additionally, C. minuta administration reduced chronically induced inflammation in plasma, spleen and some brain areas, which likely contribute to the recovery of physical and behavioral function. Furthermore, C. minuta administration prevented chronic stress-induced cardiovascular damage by regulating key enzymes mediating liver fibrosis and oxidative stress. Finally, C. minuta increased the abundance of bacteria associated with mental health. Overall, our study highlights the potential of microbiota-directed interventions to alleviate both the physical and mental effects of chronic stress.

Exercise training ameliorates carbon tetrachloride-induced liver fibrosis and anxiety-like behaviors.

Chronic liver diseases and cirrhosis are associated with mood disorders. Regular exercise has various beneficial effects on multiple organs, including the liver and brain. However, the therapeutic effect of exercise on liver fibrosis concomitant with mood disorders, such as anxiety, has not been evaluated. In this study, the effects of exercise training on liver fibrosis-related anxiety-like behaviors were evaluated. Male C57/BL6 mice were divided into four groups: vehicle-sedentary, vehicle-exercise, carbon tetrachloride (CCl4)-sedentary, and CCl4-exercise. Liver fibrosis was induced by CCl4 administration for 8 weeks, exercise was applied in the form of voluntary wheel running. After intervention, anxiety-like behavior was assessed using the elevated plus maze. CCl4 increased liver and serum fibrotic markers, as measured by blood analysis, histochemistry, and qRT-PCR, and these changes were attenuated by exercise training. CCl4 induced anxiety-like behavior, which was ameliorated by exercise training. In the hippocampus, CCl4-induced changes in mRNA and protein levels of factors related to anxiety, including BDNF and nNOS, were reversed by exercise. These results suggested that hepatic fibrosis-related anxiety-like behaviors are induced by excess hippocampal nNOS, and the beneficial effects of exercise were mediated by increases in BDNF and reductions in nNOS. The percentage of fibrotic area was negatively correlated with anti-anxiety behavior and positively associated with hippocampal nNOS protein levels. Liver fibrosis-related anxiety-like behaviors could be alleviated through the regulation of hippocampal BDNF and nNOS via exercise training. These results support the therapeutic value of exercise by targeting the mechanisms underlying liver fibrosis and associated anxiety.

Combi-Elastography versus Transient Elastography for Assessing the Histological Severity of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Combi-elastography is a B-mode ultrasound-based method in which two elastography modalities are utilized simultaneously to assess metabolic dysfunction-associated steatotic liver disease (MASLD). However, the performance of combi-elastography for diagnosing metabolic dysfunction-associated steatohepatitis (MASH) and determining fibrosis severity is unclear. This study compared the diagnostic performances of combi-elastography and vibration-controlled transient elastography (VCTE) for identifying hepatic steatosis, fibrosis, and high-risk MASH. Participants who underwent combi-elastography, VCTE, and liver biopsy were selected from a prospective cohort of patients with clinically suspected MASLD. Combi-elastography-related parameters were acquired, and their performances were evaluated using area under the receiver-operating characteristic curve (AUROC) analysis. A total of 212 participants were included. The diagnostic performance for hepatic steatosis of the attenuation coefficient adjusted by covariates from combi-elastography was comparable to that of the controlled attenuation parameter measured by VCTE (AUROC, 0.85 vs 0.85; p=0.925). The performance of the combi-elastography-derived fibrosis index adjusted by covariates for diagnosing significant fibrosis was comparable to that of liver stiffness measured by VCTE (AUROC, 0.77 vs 0.80; p=0.573). The activity index from combi-elastography adjusted by covariates was equivalent to the FibroScan-aspartate aminotransferase score in diagnosing high-risk MASH among participants with MASLD (AUROC, 0.72 vs 0.74; p=0.792). The performance of combi-elastography is similar to that of VCTE when evaluating histology of MASLD.

Chronic Hepatitis D Virus Infection and Its Treatment: A Narrative Review

More than 12 million individuals worldwide are chronically infected with the hepatitis D virus (HDV). HDV infection is the most severe form of viral hepatitis since it requires hepatitis B virus co-infection and accelerates progression to cirrhosis and hepatocellular carcinoma. Therefore, treatment modalities to slow the progression of the disease are essential but not yet available. In addition, no antiviral treatment to date has been shown to reliably eradicate HDV. Pegylated interferon (PEG-IFN) is the only universally used treatment to suppress HDV RNA replication and improve liver inflammation and fibrosis. This treatment can be completed in 12–18 months, but cure rates remain low, and success does not reliably increase with the addition of a nucleos(t)ide analog. PEG-IFN therapy is also limited by poor tolerability and multiple adverse effects, including neutropenia, thrombocytopenia, and neuropsychiatric symptoms. Newer antiviral therapies in development target unique aspects of HDV viral replication and show promising results in combination with PEG-IFN for long-term HDV RNA suppression. These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation.

Prognostic significance of early and multiple recurrences after curative resection for hepatocellular carcinoma

BackgroundIn hepatocellular carcinoma (HCC), postoperative recurrence remains high. This study aimed to evaluate the recurrence patterns and prognosis of HCC after curative hepatectomy.MethodsAmong 352 patients with primary HCC who underwent initial hepatectomy between January 2002 and December 2022, 151 with recurrence were assessed for the relationship between recurrence pattern and prognosis.ResultsThe early recurrence group (within 6 months postoperatively; n = 38) had significantly higher serum alpha-fetoprotein (p = 0.002), des-γ-carboxyprothrombin (DCP; p = 0.004) levels and Barcelona Clinic Liver Cancer (BCLC) stage (p < 0.001), larger tumor size (p < 0.001), higher incidence of multiple tumors (p = 0.002) and lower overall survival (OS) (p < 0.001) than the late recurrence group (> 6 months postoperatively; n = 113). The tumor size (p = 0.013) and BCLC stage (p = 0.001) were independent risk factors for early recurrence within 6 months in multivariate analysis.The multiple recurrence group (intrahepatic multinodular recurrence or distant metastasis; n = 89) had significantly lower prognostic nutritional index (p = 0.026), larger tumor size (p = 0.017), lower incidence of liver cirrhosis (p = 0.03) than the single recurrence group (single nodule recurrence; n = 62). The multiple recurrence group, especially patients with ≥ three intrahepatic nodules and distant metastases, had lower postoperative OS (p < 0.001) and shorter time to recurrence (p < 0.001) than the single recurrence group.When the patients were classified into three groups: late recurrence with one or two tumors (Group A; n = 74), early recurrence or three or more tumors or distant metastasis (Group B; n = 54), and early recurrence with three or more tumors or distant metastasis (Group C; n = 23), OS was significantly lower in Groups B and C than Group A (p < 0.001).ConclusionsPatients with early recurrence within 6 months after surgery and three or more recurrence nodule or distant metastasis exhibited poor prognosis after initial recurrence, and they should be carefully followed up.

Early detection of liver fibrosis in patients with Fontan circulation using multiparametric magnetic resonance imaging

Abstract Introduction Fontan procedure (FP), serving as the palliative intervention for complex congenital heart diseases characterized by single-ventricle physiology, precipitates a spectrum of late-stage complications. Fontan-associated liver disease (FALD) encompassing liver fibrosis (LF) which may progress to liver cirrhosis (LC) and thereby hepatocellular carcinoma (HCC) is among the most serious. Despite its importance, optimal surveillance of FALD remains undefined. Multiparametric Liver Multiscan (LMS) with corrected T1 (cT1) value emerges as a novel magnetic resonance (MRI) based non-invasive quantitative tool for liver inflammation and fibrosis evaluation. Aim of this study was to ascertain prevalence and severity of LF utilizing LMS, alongside identifying contributory risk factors for LF in adults post-FP. Material and methods Our cohort included 29 adult patients after FP who underwent LMS. Median age was 25y (20-43y) 54% were females. Liver morphology was assessed by ultrasound (USG) and MRI-based LMS protocol. Hepatic scoring systems, including the Aspartate Aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 (FIB-4) Index, and Model for End-Stage Liver Disease (MELD), were computed. Additionally, presence of fenestrations in the Fontan circulation, hemoglobin levels (Hb), and blood oxygen saturation both at rest and during exercise (SatO2%) were evaluated. Results Median cT1 was 914 (±207) ms, in 87% exceeding normal threshold . In those with elevated cT1, LF was undetected by USG in 38%. LC was identified in 27% of the cohort by USG. LC group exhibited significantly higher cT1 values (P&amp;lt;0.001) compared to non-LC group. cT1 value &amp;gt;933ms was associated with a sensitivity of 89% and a specificity of 80% for diagnosing LC (AUC 0.92). Significant correlation was found between cT1 values and Hb (P=0.01) and desaturation (SatO2 &amp;lt;90%/ interventional closure of fenestration, P=0.004). Conventional liver tests and hepatic scoring systems (APRI/FIB-4/MELD) did not predict cT1 nor LC. Conclusion Our study confirmed that LF is almost widely prevalentamong adult patients with single-chamber circulation. Risk factors for LF are systemic desaturation (SatO2 &amp;lt;90% or interventional closure of fenestration) and polyglobulia. However, reliable FALD surveillance remains challenging. Conventional liver assessments and scoring algorithms fall short in delineating the full scope of LF or LC. Consequently, the integration of non-invasive LMS into routine follow-up regimens is advocated, given its pronounced sensitivity for detecting subclinical FALD manifestations and predicting LC. The LMS-derived cT1 value &amp;gt;933ms is a critical predictor for LC, underscoring its importance in guiding further patient monitoring, treatment, and facilitating early HCC detection.

Impaired right ventricular strain is associated with worse prognosis in patients with liver cirrhosis

Abstract Introduction Cirrhotic cardiomyopathy is a complication of liver cirrhosis accounting for significant morbidity and associated with reduced patient survival. It is characterized by reduced afterload, increased cardiac output, and diastolic dysfunction. However, there are limited data regarding the prognostic significance of right ventricular (RV) mechanics. Novel echocardiographic techniques such as speckle tracking echocardiography can detect subclinical myocardial dysfunction early in the course of non-ischemic myocardiopathies. Purpose To investigate the prognostic role of RV free wall strain (RVFWS) in patients with liver cirrhosis. Methods We prospectively enrolled 70 patients with liver cirrhosis in stable clinical condition. Patients with coronary artery disease, valvular heart disease, ongoing alcohol consumption or poor acoustic window were excluded from the study. Transthoracic echocardiography was performed and RVFWS was calculated from RV focused 4-chamber views using a dedicated software. Since RVFWS was as expected negative in all patients, absolute values were used for all calculations. Clinical and laboratory examination was also performed in all patients and the Model for End-Stage Liver Disease (MELD) score a widely used tool for assessing liver disease severity was calculated. All-cause mortality at 24 months was the primary endpoint and was available in all patients. Results Mean RVFWS in the cohort was 27.4±6.3% and using a lower normal limit of 20%, reduced RVFWS was detected in six patients. According to the Spearman coefficient analysis, RVFWS was correlated with MELD (rho=0.274, p=0.023) indicating increased values in patients with more advanced liver disease. According to the univariate Cox-regression proportion hazard models RVFWS as a continuous variable was not significantly correlated with worse two year survival (HR: 1.01 (0.95-1.08, p=0.658). Interestingly, among conventional echocardiographic parameters basal RV diameter (p=0.004) and right atrial end-systolic area (p=0.008) were associated with increased risk for the primary endpoint. The association of the primary endpoint with other parameters of RV systolic function was also not statistically significant. The Multivatiate Cox Regression survival analysis, which incorporated age, sex, MELD, hemoglobin, systolic blood pressure and cardiac output, showed that among echocardiographic parameters for the evaluation of the RV, only RVFWS showed a tendency to be associated with worse survival (p=0.062). When patients were stratified into tertiles according to RVFWS values, those in the first tertile (with lower absolute RVFWS values) had significantly increased hazard for the primary endpoint (HR: 5.82, 2.18-15.8, P&amp;lt;0.001) (figure 1). Conclusions RVFWS values are within normal limits in most patients with liver cirrhosis. When adjusted for the severity of the liver disease, reduced RVFWS values are associated with worse prognosis in cirrhotics.

Investigating the influence of possible liver fibrosis on mortality in patients with coronary artery disease - a post-hoc ISCHEMIA trial analysis

Abstract Background There is a plethora of studies demonstrating that comorbidities (e.g., diabetes and renal dysfunction) directly influence outcomes in patients undergoing PCI or CABG for coronary artery disease (CAD). Yet, liver dysfunction is not really included in current risk assessment beyond the presence of liver cirrhosis. Retrospective single center evidence now suggests that the presence of liver fibrosis may be an indicator of elevated risk. Using the FIB-4 score, where increasing values correlate with increaseing degrees of histological liver fibrosis, liver fibrosis could already be detected with all required laboratory values (AST, ALT, platelets) within normal range. In addition, the study suggests a beneficial effect of off-pump CABG when FIB-4 is elevated. This finding contradicts current randomized evidence, negating any difference between off and on-pump CABG. Since randomized trials always suffer from strong selection of low risk patients, it is conceivable that trial patients may primarily have low FIB-4 scores. Purpose To address the distribution of FIB-4 scores in a selected trial population with CAD (from the ISCHEMIA trial) and relate the degree of liver fibrosis reflected by the score to mortality. Methods The FIB-4 score was calculated for all patients. According to the standard classification, a value of greater than 1.2 reflects a 90% chance of the presence of histological liver fibrosis. The imapct of FIB-4 on late all-cause mortality was assessed as a continuous and categorical variable using maximally selected rank statistics determined FIB-4 cutoff. Cox regression model was peformed including the adjustment for the main CAD risk factors. Results Among 3735 included patients, 58.8% had a FIB-4 value above 1.2. Patients with higher FIB-4 score (cutoff= 1.64) were slighly older, presented higher prevalence of male sex, prior PCI and CABG, and prior history of atrial fibrillation and cerebrovascular disease. FIB-4 score was directly associated with higher risk of mortality when addressed as a continouos variable and as a categorical variable (Fig. 1). This relationship was evident in the overall population and in all subsets (PCI, CABG and no revascularization; Fig. 2). Conclusions The use of Fib-4 to determine the degree of liver fibrosis may be powerful to predict mortality in CAD populations which may not show any evident clinical signs of liver dysfunction. The Fib-4 distribution in this trial population, considered as selected and low risk, warrants investigating randomized trial populations having compared on- and off-pump CABG.Figure 1.Mortality: overall population.Figure 2.Mortality: by therapy subsets.

The burden of cirrhosis and other chronic liver disease in the middle east and North Africa (MENA) region over three decades

BackgroundCirrhosis comprises a significant health challenge in the Middle East and North African (MENA) region impacting healthcare systems and communities. This study sought to investigate trends in the burden of cirrhosis and other chronic liver disease, different etiologies, deaths, and the disability burden utilizing data from the Global Burden of Disease (GBD) database.MethodsAnalyzing epidemiological trends from 1990 to 2021 across 21 MENA countries, this research utilized data on age-standardized incidence rates (ASIR), age-standardized death rates, and age-standardized disability-adjusted life years (DALYs) to evaluate the burden of cirrhosis and other chronic liver disease. The study also examined national variations and sociodemographic relationships.ResultsThe study identified a 114.9% increase in cirrhosis and other chronic liver disease incidence within the MENA region between 1990 and 2021, with 7,344,030 incident cases reported in 2021. The ASIR showed a steeper rise in females (9.6%) compared to males (7.0%). Etiology-specific analysis revealed an increase in the ASIR for MASLD related cirrhosis and other chronic liver disease by 22.2%, while those due to alcohol as well as hepatitis B and C decreased by 28.1%, 59.3%, and 30%, respectively. Despite the rising incidence, overall age-standardized death rates across all etiologies decreased by 54.3%, with DALYs showing a 51.4% decrease during the same period. Country-specific trends varied significantly, with Oman recording the highest annual ASIR increase (0.64%), and Qatar observing the most substantial annual reduction in age-standardized death rates (-2.88%).ConclusionThe study highlights evolving trends in cirrhosis and other chronic liver disease within the MENA region, emphasizing the necessity for comprehensive, etiology, and gender-specific interventions. Despite an increasing incidence, the observed improvements in mortality rates and age-standardized disability burden indicate progress in public health efforts to mitigate cirrhosis’s impact. These findings point to the complex nature of cirrhosis outcomes and the urgent need for tailored strategies to manage its increasing burden effectively.

An Elevated FIB-4 Score is associated with the severity of heart failure

Abstract Background Liver disease and heart failure (HF) are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced liver fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. Purpose Thus, our goal was to evaluate the connection between the FIB-4 index, heart failure, associated comorbidities, and cardiological biomarkers that predict the risk of liver fibrosis in patients with heart failure. Methods HF patients hospitalized in the cardiology department were divided into a group with an FIB-4 index &amp;lt;1.3 (indicating a low risk of liver fibrosis) (n=53) and a group with an FIB-4 index ≥1.3 (indicating intermediate and high risk of fibrosis) (n=59). Clinical examinations, laboratory results, echocardiography with Vivid E95-GE Healthcare, non-invasive body mass analysis with Body Composition Analyzer (Tanita Pro), and measurements of NT-proBNP, growth differentiation factor 15 (GDF-15), galectin-3, fatty acid-binding protein (FABP), copeptin, and vascular endothelial growth factor (VEGF) concentrations were performed. Results The patients with an FIB-4 index ≥1.3 had significantly higher: left ventricular volume index (LAVI) (p=0.004), E/E’ ratio (p=0.004) and lower left ventricular ejection fraction (p=0.003) compared to group with low risk of liver fibrosis. There were no differences in body mass compartments between groups except for ECW/TBW (%) - an index of body water distribution, which was lower in low-risk liver fibrosis group (p=0.0002). Patients with an FIB-4 index ≥1.3 had also lower: GFR MDRD (median 59.95 vs 85.1 mL/min/1.73 m²; p&amp;lt;0.001), total cholesterol (116.5 vs 15 mg/dL; p=0.002), LDL cholesterol (median 56 vs 93 mg/dL; p&amp;lt;0.0001) and HDL cholesterol (median 39 vs 47 mg/dL; p=0.03). Regarding heart failure biochemical biomarkers, patients with low risk of liver fibrosis had significantly lower level of NT-proBNP (median 37 vs 161 pg/ml; p&amp;lt;0.0001), GDF-15 (median 399.6 vs 898.9 pg/ml; p&amp;lt;0.0001) and FABP (median 101 vs 264,7 pg/ml; p=0.04). In a multiple logistic regression model the factors that were independently associated with the risk of liver fibrosis in HF patients based on an FIB-4 index were GDF-15 &amp;gt;724 pg/ml (OR 33.7, 95%CI: 6.5-174.2; p=0.0001), and NT-proBNP &amp;gt;129 pg/ml (OR 19.9, 95% CI: 3.8-103; p=0.0001) (Figure 1) Conclusion Our study suggests association between an elevated FIB-4 score and heart functions, and kidney impairment with fluid overload but not with higher total and low density cholesterols fractions or percentage of fat. Higher GDF-15 and NT-proBNP levels are independently associated with the risk of liver fibrosis based on an FIB-4 index. FIB-4 index in HF patients is an easy method to monitor the risk of liver fibrosis and might help to predict the HF progression and CVD complications.

A direct comparison of non-invasive blood markers of liver fibrosis as associates of cardiovascular risk. The Athens cardiometabolic registry

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD). This risk increases further with advanced liver fibrosis. To date, non-invasive tests (NIT) for liver fibrosis risk have not been established as diagnostic or prognostic biomarkers of CVD. Purpose The purpose of the study was to compare NIT of liver fibrosis with respect to their associations with vascular injury and cardiovascular (CV) events. Methods Individuals without clinically overt CVD and patients with CVD (total n=1,692), consecutively recruited in the Athens Cardiometabolic Registry, were analysed in this study. We retrospectively evaluated the association of NIT (i.e. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), BARD score) with indices of subclinical arterial injury (i.e. carotid wall thickness and atherosclerotic plaque for subclinical atherosclerosis, pulse wave velocity (PWV), for arterial stiffness) and the incidence of CV events. Patients were followed-up for CV events for a median time of 39 months. Results Elevated FIB-4 (&amp;gt;2.67) was associated with vascular damage [adjusted odds ratio (aOR)=2.97, 95% confidence intervals (CI)= 1.71-5.78 for maximal wall thickness (maxWT) and aOR=4.58, 95% CI=2.44-8.60 for PWV] across the entire study population, including those with or without clinically overt CVD. NFS&amp;gt; 0.675 showed similar associations but lacked significant correlation with arterial stiffness in coronary artery disease patients. FIB-4&amp;gt; 2.67 and BARD&amp;gt; 2 were associated with increased risk of the composite endpoint of CV death, acute myocardial infarction, or coronary revascularization [adjusted hazard ratio, (aHR)=2.00, 95% CI= 1.12-3.55 and aHR=3.36, 95% CI=1.03-11.0 for FIB-4 (n=842) and BARD (n=887) respectively]. FIB-4 and BARD as continuous variables confered incremental prognostic value compared to European Systematic Coronary Risk Evaluation 2 (SCORE2). Conclusion In a population with a wide range of cardiometabolic risk, FIB-4 was associated with both markers of atherosclerotic disease and arterial stiffness as well as with adverse CV events. These data support further investigation of FIB-4 as a biomarker of CV risk.

Effects of sodium-glucose contrasporter-2 inhibitors and glucagon-like peptide-1 receptor agonists on arterial stiffness, coronary flow reserve and liver steatosis in diabetes

Abstract Background Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) present an increased risk of cardiovascular disease. Sodium-glucose contrasporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to significantly decrease the risk of cardiovascular complications. Purpose The aim of the study was to investigate the effect of treatment with SGLT-2i or GLP-1RA on cardiovascular function and liver steatosis and fibrosis in patients with T2DM and NAFLD. Methods Forty patients with T2DM and NAFLD (mean age: 58 ± 11 years) were randomized to receive SGLT-2i (dapagliflozin; n = 20) or GLP-1RA (dulaglutide; n = 20). At baseline and after 6 and 12 months of treatment, we measured: (1) perfused boundary region (PBR) of the sublingual microvessels with a diameter 5-25μm using Sidestream Dark Field camera (Microscan, Glycocheck). Increased PBR indicates reduced glycocalyx thickness. (2) Pulse wave velocity (PWV) using Complior (ALAM Medical), (3) coronary flow reserve (CFR) using Doppler echocardiography, (4) LV global longitudinal strain (GLS) using speckle-tracking echocardiography, (5) controlled attenuation parameter (CAP) score to assess steatosis grade and liver stiffness (E) to evaluate fibrosis score using liver elastography (FibroScan, Echosens), and (6) NAFLD fibrosis score (NFS). Results At baseline, patients between the two groups had similar age, sex, HbA1c, steatosis grade, fibrosis score and markers of cardiovascular function (p &amp;gt; 0.05). Compared with baseline, all patients had reduced PBR, PWV, CAP, E and NFS and increased CFR and GLS (p &amp;lt; 0.01) after 12-month treatment. In the whole study population, the percentage reduction of CAP and NFS was correlated with the corresponding decrease of PBR (r = 0.248 and r = 0.387), PWV (r = 0.290 and r = 0.281) and with the increase of GLS (r = -0.320 and r = -0.295) after 12-month treatment (p &amp;lt; 0.05 for all correlations). Both treatments with SGLT-2i and GLP-1RA reduced markers of liver steatosis and fibrosis (Table). Conclusion Both treatments with SGLT-2i and GLP-1RA improve cardiovascular function and reduce liver steatosis in patients with T2DM and NAFLD after 12 months.