Hepatic Scarring Research Articles

Association between Major Adverse Cardiovascular Events and the Liver Fibrosis Score in Patients with and without Coronary Artery Disease: From the FU-CCTA Registry.

The liver fibrosis score reflects the degree of hepatic scarring and has been reported to be associated with cardiovascular disease. Using a coronary artery computed tomography angiography registry at the Fukuoka University Hospital (FU-CCTA registry), we investigated the association between major adverse cardiovascular events (MACEs) and the liver fibrosis score (fibrosis-4 index (FIB-4I)) in 612 patients who underwent CCTA to screen for coronary artery disease and performed a prognosis survey for up to 5 years. The primary endpoint was MACEs (all-cause mortality, acute myocardial infarction, ischemic stroke, coronary revascularization). FIB-4I in all patients and in patients with hypertension (HTN) was significantly higher in the MACE group than in the non-MACE group. The event-free survival rate of MACEs targeting only patients with HTN was significantly lower in patients with a high risk of liver fibrosis (FIB-4I values of 2.67 or higher) than in those with a low or intermediate risk (less than 2.67). However, no significant difference was observed in all patients or in patients without HTN. Finally, FIB-4I and body mass index were independent factors associated with MACEs in patients with HTN. In conclusion, the liver fibrosis score may be an independent predictor of MACEs in hypertensive patients undergoing CCTA.

Investigating the Association between Coronary Artery Disease and the Liver Fibrosis-4 Index in Patients Who Underwent Coronary Computed Tomography Angiography: A Cross-Sectional Study.

Liver fibrosis scores, indicative of hepatic scarring, have recently been linked to coronary artery disease (CAD). We investigated the association between CAD and the fibrosis-4 index (FIB-4I) in patients who underwent coronary computed tomography angiography (CCTA). This study included 1244 patients who were clinically suspected of having CAD. The presence or absence of CAD was the primary endpoint. FIB-4I was higher in the CAD group than in the non-CAD group (1.95 ± 1.21 versus [vs.] 1.65 ± 1.22, p < 0.001). FIB-4I was also higher in the hypertension (HTN) group than in the non-HTN group (1.90 ± 1.32 vs. 1.60 ± 0.98, p < 0.001). In all patients, high FIB-4I (≥2.67) was a predictor of presence of CAD (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.30-2.83, p = 0.001), and low FIB-4I (≤1.29) was proven to be a predictor of absence of CAD (OR: 0.65, 95% CI: 0.48-0.88, p = 0.006). In the HTN group, high and low FIB-4I levels, were found to be predictors for CAD (OR: 2.01, 95% CI: 1.26-3.21, p < 0.001 and OR: 0.65, 95% CI: 0.45-0.94, p < 0.022, respectively), in particular. FIB-4I may serve as a diagnostic indicator of the presence or absence of CAD in hypertensive patients undergoing CCTA.

Therapeutic modulation of the liver immune microenvironment.

Inflammation is a hallmark of progressive liver diseases such as chronic viral or immune-mediated hepatitis, alcohol-associated liver disease, and NAFLD. Preclinical and clinical studies have provided robust evidence that cytokines and related cellular stress sensors in innate and adaptive immunity orchestrate hepatic disease processes. Unresolved inflammation and liver injury result in hepatic scarring, fibrosis, and cirrhosis, which may culminate in HCC. Liver diseases are accompanied by gut dysbiosis and a bloom of pathobionts, fueling hepatic inflammation. Anti-inflammatory strategies are extensively used to treat human immune-mediated conditions beyond the liver, while evidence for immunomodulatory therapies and cell therapy-based strategies in liver diseases is only emerging. The development and establishment of novel immunomodulatory therapies for chronic liver diseases has been dampened by several clinical challenges, such as invasive monitoring of therapeutic efficacy with liver biopsy in clinical trials and risk of DILI in several studies. Such aspects prevented advancements of novel medical therapies for chronic inflammatory liver diseases. New concepts modulating the liver immune environment are studied and eagerly awaited to improve the management of chronic liver diseases in the future.

Apigenin role against thioacetamide-triggered liver fibrosis: Deciphering the PPARγ/TGF-β1/NF-κB and the HIF/FAK/AKT pathways

Introduction: Liver tissue malfunction is a severe worldwide health concern that arises from various chronic liver conditions. The goal of this investigation was to look into the anti-fibrotic effect of apigenin (APG), an antioxidant found in various plants, versus thioacetamide (TAA)-triggered hepatic scarring in rats and the potential mechanisms behind it. Methods: TAA was administered thrice weekly (100 mg/kg, i.p.) for two weeks to produce hepatic scarring. APG was administered after TAA for 14 days (5 or 10 mg/kg, orally). Thereafter, hepatic liver enzymes, inflammatory markers, fibrotic indicators, and histopathological changes were evaluated. Results: TAA increased the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), reduced albumin and total protein, elevated hepatic level of lipid peroxidation, focal adhesion kinase (FAK), hypoxia-inducible factor-1α (HIF-1α), and inflammatory cytokines, decreased interleukin-10 (IL-10), reduced hepatic expression of peroxisome proliferator-activated receptor gamma (PPARγ) and nuclear factor-erythroid factor 2-related factor 2 (Nrf2), and elevated serine-threonine protein kinase (AKT) expression. Furthermore, TAA increased hepatic contents of collagen I, connective tissue growth factor (CTGF), hydroxyproline, and alpha-smooth muscle actin. On the other hand, APG evaded these changes and mitigated the harmful effects of TAA in a dose-dependent way. Histopathological and immunohistochemical observations reinforced these biochemical outcomes. Conclusion: APG can potentially alleviate liver fibrosis mediated via FAK and HIF1 inhibiting signaling pathways.

Hepatic Stellate Cell Activation and Inactivation in NASH-Fibrosis-Roles as Putative Treatment Targets?

Hepatic fibrosis is the primary predictor of mortality in patients with non-alcoholic steatohepatitis (NASH). In this process, the activated hepatic stellate cells (HSCs) constitute the principal cells responsible for the deposition of a fibrous extracellular matrix, thereby driving the hepatic scarring. HSC activation, migration, and proliferation are controlled by a complex signaling network involving growth factors, lipotoxicity, inflammation, and cellular stress. Conversely, the clearance of activated HSCs is a prerequisite for the resolution of the extracellular fibrosis. Hence, pathways regulating the fate of the HSCs may represent attractive therapeutic targets for the treatment and prevention of NASH-associated hepatic fibrosis. However, the development of anti-fibrotic drugs for NASH patients has not yet resulted in clinically approved therapeutics, underscoring the complex biology and challenges involved when targeting the intricate cellular signaling mechanisms. This narrative review investigated the mechanisms of activation and inactivation of HSCs with a focus on NASH-associated hepatic fibrosis. Presenting an updated overview, this review highlights key cellular pathways with potential value for the development of future treatment modalities.

NATURALLY DERIVED COMPOUNDS USED FOR PREVENTION OR REGRESSION OF EXPERIMENTALLY INDUCED LIVER FIBROSIS

Liver fibrosis is a common health problem that is associated with mortality and morbidity worldwide. The inappropriate tissue repair of damaged liver results in over-synthesis and deposition of fibrillar collagen. It is usually associated with progressive pathological and biochemical changes that ultimately lead to structural and metabolic abnormalities and hepatic scarring. If not properly treated, liver fibrosis may develop to cirrhosis and hepatocellular carcinoma within few years. Blocking this progression, therefore, could be an effective and potential strategy for survival. The only effective approach to treating advanced liver fibrosis is transplantation. Understanding its etiology and pathophysiology, however, could help to investigate therapeutic pathophysiology based treatment of liver fibrogenesis. Recently several promising natural based treatment methods interfering with cytokines signaling pathway involved in fibrogenesis have been investigated offering new potential therapeutic intervention. The aim of the present updated review is to identify the natural antifibrotic options that have been studied in animal models with liver fibrosis for the treatment of this pathological conditions enabling prevention or at least regression of its progression.

The Janus-like Face of IL-4Rα in Macrophages during Liver Fibrosis

The Janus-like Face of IL-4Rα in Macrophages during Liver Fibrosis

Q-T Interval Prolongation in Patients with Liver Cirrhosis.

Liver cirrhosis (LC) is the end stage of chronic liver disease characterized by the appearance of extensive fibrosis and regeneration nodes associated with hepatocyte necrosis in liver but also by the reshuffling of hepatic architecture. The triad consisting of hepatic parenchymal necrosis, regeneration and scarring is always present regardless of the type of clinical manifestation. The Child-Pugh-Turcotte classification dates back more than 30 years and has been widely used in diagnosing and assessing the severity of liver cirrhosis. This is preferred due to a low degree of complexity and a good predictive value. Prolongation of the QT interval on the electrocardiogram is common, with a prevalence exceeding 60% in patients with advanced stage of cirrhosis. In these cases, beta blockers and antiarrhythmics should be avoided or used with caution and with close QT interval monitoring. Changes in heart rate and Q-T interval are new entities in cirrhosis complications. A prolonged Q-T interval in chronic liver disease could lead to ventricular arrhythmias and sudden death. There is no report on heart rate and Q-T interval disorders in our area.

Histopathological Findings in Cholesteryl Ester Storage Disease: A Report of Three Cases

: Cholesteryl ester storage disease (CESD) is a disorder in which cholesteryl esters (CE) and triglycerides (TG) are preserved particularly in hepatocytes. The exact clinical manifestation is not known due to a lack of sufficient data. The current study presents 3 new cases of CESD with 2 of them being siblings. All had perturbed serum low-density lipoprotein (LDL), lactate dehydrogenase (LDH), triglyceride, and cholesterol. Hepatosplenomegaly was seen in all the patients. Liver biopsy showed fat storage in hepatocytes. Adrenomegaly or adrenal calcification, portal hypertension, esophageal varices, and hepatic scarring were not observed in any of the patients. Histopathologic features of CESD, including fat storage in hepatocytes, could characterize these patients.

Injection of embryonic stem cell derived macrophages ameliorates fibrosis in a murine model of liver injury

Chronic liver injury can be caused by viral hepatitis, alcohol, obesity, and metabolic disorders resulting in fibrosis, hepatic scarring, and cirrhosis. Novel therapies are urgently required and previous work has demonstrated that treatment with bone marrow derived macrophages can improve liver regeneration and reduce fibrosis in a murine model of hepatic injury and fibrosis. Here, we describe a protocol whereby pure populations of therapeutic macrophages can be produced in vitro from murine embryonic stem cells on a large scale. Embryonic stem cell derived macrophages display comparable morphology and cell surface markers to bone marrow derived macrophages but our novel imaging technique revealed that their phagocytic index was significantly lower. Differences were also observed in their response to classical induction protocols with embryonic stem cell derived macrophages having a reduced response to lipopolysaccharide and interferon gamma and an enhanced response to IL4 compared to bone marrow derived macrophages. When their therapeutic potential was assessed in a murine, carbon tetrachloride-induced injury and fibrosis model, embryonic stem cell derived macrophages significantly reduced the amount of hepatic fibrosis to 50% of controls, down-regulated the number of fibrogenic myofibroblasts and activated liver progenitor cells. To our knowledge, this is the first study that demonstrates a therapeutic effect of macrophages derived in vitro from pluripotent stem cells in a model of liver injury. We also found that embryonic stem cell derived macrophages repopulated the Kupffer cell compartment of clodronate-treated mice more efficiently than bone marrow derived macrophages, and expressed comparatively lower levels of Myb and Ccr2, indicating that their phenotype is more comparable to tissue-resident rather than monocyte-derived macrophages.

Revisiting Epithelial-to-Mesenchymal Transition in Liver Fibrosis: Clues for a Better Understanding of the "Reactive" Biliary Epithelial Phenotype.

Whether liver epithelial cells contribute to the development of hepatic scarring by undergoing epithelial-to-mesenchymal transition (EMT) is a controversial issue. Herein, we revisit the concept of EMT in cholangiopathies, a group of severe hepatic disorders primarily targeting the bile duct epithelial cell (cholangiocyte), leading to progressive portal fibrosis, the main determinant of liver disease progression. Unfortunately, therapies able to halt this process are currently lacking. In cholangiopathies, fibrogenesis is part of ductular reaction, a reparative complex involving epithelial, mesenchymal, and inflammatory cells. Ductular reactive cells (DRC) are cholangiocytes derived from the activation of the hepatic progenitor cell compartment. These cells are arranged into irregular strings and express a “reactive” phenotype, which enables them to extensively crosstalk with the other components of ductular reaction. We will first discuss EMT in liver morphogenesis and then highlight how some of these developmental programs are partly reactivated in DRC. Evidence for “bona fide” EMT changes in cholangiocytes is lacking, but expression of some mesenchymal markers represents a fundamental repair mechanism in response to chronic biliary damage with potential harmful fibrogenetic effects. Understanding microenvironmental cues and signaling perturbations promoting these changes in DRC may help to identify potential targets for new antifibrotic therapies in cholangiopathies.

Identifying associations between pig pathologies using a multi-dimensional machine learning methodology

BackgroundAbattoir detected pathologies are of crucial importance to both pig production and food safety. Usually, more than one pathology coexist in a pig herd although it often remains unknown how these different pathologies interrelate to each other. Identification of the associations between different pathologies may facilitate an improved understanding of their underlying biological linkage, and support the veterinarians in encouraging control strategies aimed at reducing the prevalence of not just one, but two or more conditions simultaneously.ResultsMulti-dimensional machine learning methodology was used to identify associations between ten typical pathologies in 6485 batches of slaughtered finishing pigs, assisting the comprehension of their biological association. Pathologies potentially associated with septicaemia (e.g. pericarditis, peritonitis) appear interrelated, suggesting on-going bacterial challenges by pathogens such as Haemophilus parasuis and Streptococcus suis. Furthermore, hepatic scarring appears interrelated with both milk spot livers (Ascaris suum) and bacteria-related pathologies, suggesting a potential multi-pathogen nature for this pathology.ConclusionsThe application of novel multi-dimensional machine learning methodology provided new insights into how typical pig pathologies are potentially interrelated at batch level. The methodology presented is a powerful exploratory tool to generate hypotheses, applicable to a wide range of studies in veterinary research.

Lectin–Like Ubiquitin Ligases Degrade Alpha‐1 Antitrypsin‐Z

Alpha‐1 antitrypsin deficiency is the leading cause of childhood liver failure, is responsible for two percent of all cases of emphysema in adults, and is one of the three most common lethal genetic diseases in Caucasians. The term A1AT‐Z deficiency is a misleading term; mutant A1AT‐Z fails to fold correctly and accumulates in the endoplasmic reticulum of the liver resulting in hepatic scarring, fibrosis, and carcinoma. The failure to correctly process the A1AT‐Z results in systemic deficiency leading to emphysema. The following study used cotransfection of mutant human A1At‐Z and ubiqtuin ligases into a variety of tissue culture cell lines. We identified three novel lectin‐like E3 ubiquitin ligases FBG1, FBG2, and FBG4 that participate in the clearance of A1AT‐Z. We demonstrate that both FBG1 and 2, but not FBG4, bind and pulldown A1AT‐Z. Only FBG1 and FBG2, are found in the liver, the location of A1AZ‐Z production. Furthermore, we show that soluble A1AT‐Z is degraded by the ubiquitin proteasome system and by autophagy while the insoluble form of A1AT‐Z is predominately degraded by autophagy. Overexpression of FBG1 and FBG2 decreases the half‐life of A1AT‐Z from 13 hours to 4 hours and 10 hours respectively. Finally, we show that FBG1 may increase A1AT‐Z secretion, suggesting that FBG1 may be used to treat both lung and liver disease in A1AT‐Z deficient patients.

Novel Serum Biomarker Candidates for Liver Fibrosis in Hepatitis C Patients

Liver biopsy is currently the gold standard for assessing liver fibrosis, and no reliable noninvasive diagnostic approach is available. Therefore a suitable serologic biomarker of liver fibrosis is urgently needed. We used a proteomics method based on 2-dimensional gel electrophoresis to identify potential fibrosis biomarkers. Serum samples from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) were analyzed and compared with serum from healthy controls. We observed the most prominent differences when we compared serum samples from cirrhotic patients with healthy control serum. Inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) fragments, alpha1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin, albumin, paraoxonase/arylesterase 1, and zinc-alpha2-glycoprotein were decreased in cirrhotic serum, whereas CD5 antigen-like protein (CD5L) and beta2 glycoprotein I (beta2GPI) were increased. In general, alpha2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis, whereas haptoglobin and complement components (C3, C4, and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis included ITIH4 fragments, complement factor H-related protein 1, CD5L, Apo L1, beta2GPI, and thioester-cleaved products of a2M. Assessment of hepatic scarring may be performed with a combination of these novel fibrosis biomarkers, thus eliminating the need for liver biopsy. Further evaluation of these candidate markers needs to be performed in larger patient populations. Diagnosis of fibrosis during early stages will allow early treatment, thereby preventing fibrosis progression.

Stellate Cell Activation in Alcoholic Fibrosi—An Overview

There has been remarkable progress in our understanding of how chronic alcohol ingestion may lead to hepatic injury and scarring, or fibrosis. Hepatic fibrosis represents the liver's wound healing response and is characterized by accumulation of interstitial matrix, or scar. Fibrosis in the liver results from the activation of stellate cells, or resident mesenchymal cells. Stellate cell activation is a dramatic phenotype transition whose net effect is the replacement of normal liver matrix by scar. Features of stellate cell activation include increased cell accumulation from proliferation and directed migration, increased matrix production, enhanced contractility, accelerated degradation of the normal liver matrix, release of profibrogenic cytokines, and loss of cellular vitamin A. Alcohol may enhance fibrogenesis through stimulation of stellate cells by hypoxia, generation of lipid peroxides from damaged hepatocytes, production of acetaldehyde that may have direct fibrogenic activity, and through activation of Kupffer cells or resident macrophages. Unanswered questions remain to be studied, but the clarification of underlying mechanisms of fibrosis portends continued progress in our ability to treat alcoholic liver fibrosis.

Outcome of hepatic amebic abscesses managed with three different therapeutic strategies

Three different approaches to hepatic abscesses due to Entamoeba histolytica were compared in 51 patients. The three modes of therapy utilized were: medical therapy with nitroimidazoles (N = 11 patients), open surgical drainage (N = 9 patients), and percutaneous drainage using ultrasound guidance followed by intralesional nitroimidazole administration (N = 31 patients). The results with each form of therapy were assessed clinically and by abdominal ultrasound. Patients receiving combined US-guided drainage and intralesional chemotherapy experienced a faster and overall better clinical response, which was confirmed also by sonographic follow-up of the hepatic lesions. This better response was associated with faster resolution, fewer relapses, and less residual hepatic scarring than either with medical therapy alone or open surgical drainage combined with medical therapy.

Hepatic Foci of Cellular and Enzymatic Alteration and Nodules in Rats Treated With Clofibrate or Diethylnitrosamine Followed by Phenobarbital: Their Rate of Onset and Their Reversibility

The histologic appearance and cytochemical characteristics of foci of hepatic cellular alteration, hepatic nodules, and hepatocellular carcinomas occurring in male Sprague-Dawley rats treated with the hypolipidemic agent clofibrate (CAS: 637-07-0), with phenobarbital (CAS: 50-06-6), or with diethylnitrosamine [(DENA) CAS: 55-18-5] followed by phenobarbital were studied after treatment periods from 1 month to 2 years. Rats treated with clofibrate revealed foci of cellular alteration that were more often basophilic and occurred slightly sooner (wk 42) than those in untreated controls (wk 60). Of 36 rats that had received 68 or more weeks of continuous clofibrate, 19 had hepatic nodules. Of the 11 nodules examined cytochemically, none was gamma-glutamyltransferase (gamma-GT) positive and 2 were positive to glucose-6-phosphate dehydrogenase (G-6-PD) under oxygen. In rats withdrawn from clofibrate for 16-18 weeks after 68-95 weeks of clofibrate, 0 of 14 had nodules. In several of these rats zones of hepatic scarring were observed, suggesting the reversibility of the nodules. Phenobarbital alone had little effect on the incidence of foci of cellular alteration, although the number of gamma-GT-positive foci was increased. DENA followed by phenobarbital led to the early appearance of foci of cellular alteration (from wk 4), of nodules (from wk 13), and of hepatocellular carcinomas (from wk 26). gamma-GT activity was raised in most of these nodules and carcinomas, while G-6-PD activity was raised in only 3 of 9 nodules but in all 9 carcinomas examined. DENA-phenobarbital given for 13 or 26 weeks followed by withdrawal of phenobarbital for 28 and 26 weeks, respectively, produced an essentially similar pattern of lesions. In view of the growing recognition of the nonspecificity gamma-GT as a marker of carcinogen-initiated foci, the value of G-6-PD (under oxygen) as a marker merits further investigation.

Cholesterol ester storage disease: Clinical, biochemical, and pathological studies

Of three siblings affected with cholesterol ester storage disease, two died at ages 7 and 9 years, respectively, with hepatic scarring and portal hypertension. Lipid storage was documented in both patients, as were esophageal varices and aortic plaques in the older child. The third affected sibling, followed to 13 years of age, has hepatomegaly, hyperlipidemia, short stature, adrenal calcification, and acid lipase deficiency. Leukocyte extracts demonstrated deficiency of acid lipase in this patient. This autosomal recessive condition may be allelic with Wolman disease with a more malignant course in this family than in most reported cases.

Reassessment of operative procedures for portal hypertension in infants and children

Experience with the surgical management of portal hypertension in nineteen children treated at the UCLA Hospital has been analyzed. On the basis of this clinical experience certain observations have been made. 1. 1. Patients with portal vein thrombosis (PVT) who survive through childhood may live until late adulthood with decreasing frequency and severity of variceal bleeding. None of the eight patients with PVT in the present series has died. 2. 2. Splenectomy alone does not prevent variceal hemorrhage and may make it difficult to visualize or shunt the portal venous system later. 3. 3. Gastrectomy may delay but not prevent bleeding and may be a cause of morbidity in itself. 4. 4. Medical therapy will control hemorrhage in most small children with PVT until they are of sufficient size to undergo a shunt operation. 5. 5. Variceal bleeding is not without risk in children with PVT and emergency variceal ligation may be necessary. 6. 6. End to side mesocaval, splenorenal, or portacaval shunts are preferred when feasible in children with PVT. Makeshift shunts are unsatisfactory. Distal splenorenal anastomosis is recommended when the splenic vein is thrombosed. 7. 7. Many children with intrahepatic portal venous obstruction have mild hepatocellular disease and may experience a good prognosis if variceal hemorrhage is controlled by a shunt. An aggressive approach is recommended in these children who frequently do not tolerate variceal hemorrhage well. 8. 8. Long-term chemotherapy with hepatotoxic drugs may produce hepatic scarring and portal hypertension which is amenable to shunt procedures. 9. 9. Side to side or end to side portacaval anastomoses are preferred in children with intrahepatic portal obstruction and may be performed successfully even in young children.

Hepatic Telangiectases and Portosystemic Encephalopathy in Osler-Weber-Rendu Disease

Summary A patient suffering from hereditary hemorrhagic telangiectases presented with an epigastric bruit and experienced, for 6 months prior to her death, repeated episodes of portosystemic encephalopathy. Angiography demonstrated tremendous dilation of the hepatic arteries and extensive portacaval shunting of blood through telangiectatic channels in the liver parenchyma. The latter were confirmed by biopsy and, later, at autopsy, which also revealed the absence of hepatic scarring. The occurrence of portosystemic encephalopathy due to hepatic telangiectases represents a new aspect of Osler-Weber-Rendu disease.