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Summary: Background: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. Aim: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. Methods: Serum samples were available from 138 large‐duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008‐2012 and 52 ulcerative colitis patients (controls). The median follow‐up time was 2.2 (range 0‐4.3) years. Specific biomarkers of type III and V collagen formation (PRO‐C3 and PRO‐C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N‐terminal peptide, tissue inhibitor of metalloproteinase‐1 and hyaluronic acid was assessed for comparison. Results: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO‐C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO‐C3 and PRO‐C5 the odds ratio for predicting transplant‐free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. Conclusions: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO‐C3 was identified as a potent prognostic marker and an independent predictor of transplant‐free survival in primary sclerosing cholangitis. [ABSTRACT FROM AUTHOR]

In the hepatic tissue repair mechanism, hepatic stellate cells (HSCs) are recruited at the site of injury and their changes reflect paracrine stimulation by all neighbourinç cell types, including sinusoidal endothelial cells, Kupffer cells, hepatocytes, platelets and leucocytes. Thrombin converts circulating fibrinogen to fibrin, promotes platele aggregation, is a potent activator of endothelial cells, act as a chemoattractant for inflammatory cells and is a mitogen and chemoattractant for fibroblasts and vascul~ smooth muscle cells. Most of the cellular effects elicite by thrombin are mediated via a family of widely expresse G-protein-coupled receptors termed protease activated receptors (PARs). All known members of the PAR famil stimulate cell proliferation/activation in a rat HSC line. Thrombin receptors are constitutively expressed in the liver, and their expression increases in parallel with the severity and/or the duration of liver disease. In human studies, thrombotic risk factors were found to be independently associated with the extent of fibrosis; severity of hepatitis C virus (HCV(-associated liver diseas appears to be less in patients with haemoihilia when compared with those with HCV alone. Several studies, based mostly on rat models, demonstrate that anti- coagulants or antiplatelet agents prevent hepatic necrosi and fibrosis by acting on HSCs. These drugs could be therapeutic agents in patients with chronic liver diseasE and specific studies should be initiated. [ABSTRACT FROM AUTHOR]

Background: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease. Aim: To assess the value of TE for predicting the stage of fibrosis. Methods: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated. Results: The areas under the curve for the prediction of significant fibrosis (⩾F2), advanced fibrosis (⩾F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE <6 or ⩾12, <9 or ⩾12, and <12 or ⩾18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis. Conclusions: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis. [ABSTRACT FROM AUTHOR]

Background Chronic liver diseases are frequently complicated by portal hypertension, an important component of which is the increased intrahepatic vascular resistance, in part related to endothelial dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is an established mediator and marker of endothelial dysfunction. We therefore investigated the possible implication of ADMA in chronic liver diseases-induced portal hypertension. Materials and methods We studied 39 consecutive patients with compensated hepatitis C virus (HCV) related chronic liver diseases. All patients underwent hepatic venous pressure gradient (HVPG) measurement, and simultaneous blood sampling from the hepatic vein and the pulmonary artery, for ADMA and nitrite/nitrate (NOx) plasma level determinations. Results A positive correlation between HVPG and ADMA concentrations in hepatic veins (ADMA- h) was found ( r = 0·77, P < 0·0001). Moreover, a negative correlation between HVPG and NOx concentrations in the hepatic veins (NO- h) ( r = −0·50, P = 0·005), and between ADMA- h and NO- h was observed ( r = −0·40, P = 0·02). ADMA concentrations in pulmonary artery (ADMA- p) (0·55 ± 0·13 µmol L−1) were significantly higher than in hepatic veins (0·47 ± 0·09 µmol L−1) ( P < 0·0001). Conclusions These results suggest that ADMA may play a pathophysiological role in portal hypertension by contributing to the relative intrahepatic NO deficiency typical of endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background and aims: Myofibroblast-like cells, originating from activation of hepatic stellate cells (HSC/MFs), play a key role in liver fibrosis, a potentially reversible process that may rely on induction of HSC/MFs apoptosis. While this possibility has been shown in cultured rat HSC, very limited data are currently available for human HSC/MFs. Methods: Cultured human HSC/MFs were exposed to several proapoptotic stimuli, including those known to induce apoptosis in rat HSC/MFs, and induction of cell death and related mechanisms were investigated using morphology, molecular biology, and biochemical techniques. Results: In this study we report that fully activated human HSC/MFs did not undergo spontaneous apoptosis and survived to prolonged serum deprivation, Fas activation, or exposure to nerve growth factor, tumour necrosis factor α (TNF-α), oxidative stress mediators, doxorubicin, and etoposide. Induction of caspase dependent, mitochondria driven apoptosis in HSC/MFs was observed only when protein synthesis or transcription were inhibited. Importantly, the process of HSC activation was accompanied by changes in expression of a set of genes involved in apoptosis control. In particular, activated human HSC/MFs in culture overexpressed Bcl-2. The role of Bcl-2 was crucial as Bcl-2 silenced cells became susceptible to TNF-α induced apoptosis. Finally, Bcl-2 was markedly expressed in HSC/MFs present in liver tissue obtained from patients with hepatitis C virus related cirrhosis. Conclusions: Human activated HSC/MFs are resistant to most proapoptotic stimuli due to Bcl-2 overexpression and this feature may play a key role in the progression of fibrosis in chronic liver diseases. [ABSTRACT FROM AUTHOR]

Background and aim: Activated myofibroblast-like cells, originating from hepatic stellate cells (HSC/MFs) or other cellular sources, play a key profibrogenic role in chronic liver diseases (CLDs) that, as suggested by studies in animal models or rat HSC/MFs, may be modulated by reactive oxygen intermediates (ROI). In this study, human HSC/MFs, exposed to different levels of superoxide anion (O2...) and, for comparison, hydrogen peroxide (H2O2), were analysed in terms of cytotoxicity, proliferative response, and migration. Methods: Cultured human HSC/MFs were exposed to controlled O2... generation by hypoxanthine/xanthine oxidase systems or to a range of H2O2 concentrations. Induction of cell death, proliferation, and migration were investigated using morphology, molecular biology, and biochemical techniques. Results: Human HSC/MFs were shown to be extremely resistant to induction of cell death by O2... and only high rates of O2... generation induced either necrotic or apoptotic cell death. Non-cytotoxic low levels of O2..., able to upregulate procollagen type I expression (but not tissue inhibitor of metalloproteinase 1 and 2), stimulated migration of human HSC/MFs in a Ras/extracellular regulated kinase (ERK) dependent, antioxidant sensitive way, without affecting basal or platelet derived growth factor (PDGF) stimulated cell proliferation. Non-cytotoxic levels of H2O2 did not affect Ras/ERK or proliferative response. A high rate of O2... generation or elevated levels of H2O2 induced cytoskeletal alterations, block in motility, and inhibition of PDGF dependent DNA synthesis. Conclusions: Low non-cytotoxic levels of extracellularly generated O2... may stimulate selected profibrogenic responses in human HSC/MFs without affecting proliferation. [ABSTRACT FROM AUTHOR]

Background: Somatostatin analogues have been used with conflicting results to treat advanced hepatocellular carcinoma (HCC}. The aim of this study was to investigate expression of somatostatin receptor (SSTR) subtypes in human liver, and to examine the effect of selective SSTR agonists on proliferation, apoptosis, and migration of hepatoma cells (HepG2, HuH7) and hepatic stellate cells (HSCs). Methods: Expression of SSTRs in cell lines, normal and cirrhotic liver, and HCC was examined by immunohistochemistry and reverse transcription-polymerase chain reaction. Effects of SSTR agonists on proliferation and apoptosis of tumour cells and HSCs were assessed by the 5-bromo-2' deoxyuridine and TUNEL methods, respectively. The influence of SSTR agonists on migration was investigated using Boyden chambers. Results: In normal liver, both hepatocytes and HSCs were negative for all five SSTRs. Cirrhotic liver and HCC as well as cultured hepatoma cells and HSCs expressed all five SSTRs, both at the protein and mRNA levels, except for HuH7 cells which did not immunoreact with SSTR3. None of the agonists influenced proliferation or apoptosis. However, compared with untreated cells, L-797,591, an SSTR1 agonist, reduced migration of HepG2, HuE-U, and HSCs significantly to 88 (7)% (p<0.05), 83 (1 1)% (p<0.05), and 67 (13)% (p<0.01), respectively. Conclusions: Cirrhotic liver and HCC express SSTRs. Although the somatostatin analogues used in this study did not affect proliferation and apoptosis, stimulation of SSTR1 may decrease invasiveness of HCC by reducing migration of hepatoma cells and/or HSCs. Clinical trials evaluating somatostatin analogues for the treatment of HCC should take these findings into account. [ABSTRACT FROM AUTHOR]

Ordered array of dendritic cells and CD8+ lymphocytes in portal infiltrates in chronic hepatitis C Aims: Despite the importance of dendritic cells in stimulating primary and secondary immune responses by presenting antigens to T-lymphocytes in draining lymph nodes and peripheral tissues, respectively, very limited information is available on the presence and localization of these cells in hepatitis C virus (HCV)-related chronic active hepatitis. Therefore, we addressed the ultrastructure, immunophenotype, distribution and relationships to lymphatics of dendritic cells in portal infiltrates of this disease. Methods and results: Part of percutaneous diagnostic liver biopsies (Knodell’s histological assessment index: 9–13) was processed for electron microscopy and for immunohistochemical detection of immune system cell membrane antigens and of the lymphatic endothelium marker podoplanin. In portal infiltrates, cells with electron microscopical and cell marker features of dendritic cells and expressing the activation markers CD54, CD80, CD83 and CD86 were organized in a discontinuous network, that embedded CD8+ lymphocytes in close contact with dendritic cells and came in contact with hepatocytes, sometimes infiltrating beyond the limiting plate. Also, dendritic cells were found within newly formed lymphatic capillaries in thin, infiltrated septa among hepatocytes. Conclusions: This evidence strongly suggests a critical role of dendritic cells and newly formed lymphatics in the pathogenesis and organization of the immune infiltrate that characterizes HCV-related chronic active hepatitis. [ABSTRACT FROM AUTHOR]

The use of polytetrafluoroethylene (PTFE)-covered prostheses improves trans-jugular intrahepatic porto-systemic shunt (TIPS) patency and decreases the incidence of clinical relapses and re-interventions. Therefore, the improvement provided by covered stents might expand the currently accepted recommendations for TIPS use. Stent-related occlusion of the hepatic vein with consequent ischaemia of the corresponding liver parenchyma emerges as a novel complication reported in at least 5% of patients implanted with coated stents. However, this complication was reported to be mild, without signs or symptoms of liver failure, and self-limiting. We report a case of segmental liver ischaemia following PTFE-covered stent placement resulting in a marked impairment in liver function in a patient with hepatitis C virus cirrhosis implanted because of refractory oesophageal bleeding, thus expanding the severity range of this new procedural complication. Moreover, we discuss the possible involvement of additional pathogenetic mechanisms other than out-flow obstruction in the onset of coated-stent induced congestive liver ischaemia. [ABSTRACT FROM AUTHOR]

There is an increasing desire for non-invasive tests to assess both the stage of liver fibrosis and the rate of progression of fibrogenic chronic liver diseases and so reduce the need for repeated liver biopsies. However, higher quality non-invasive diagnostic procedures are still needed. [ABSTRACT FROM AUTHOR]

The article focuses on a research conducted on the pancreatic stellate cells (PSCs). PSCs play an important role in the cellular and molecular mechanisms of pancreatic fibrogenesis. Fibrosis in the pancreas takes place due to necrosis or apoptosis, inflammation or duct obstruction. The initial event that induces fibrogenesis in the pancreas is an injury that may involve the interstitial mesenchymal cells, duct cells and acinar cells. Damage occurring in any of these tissue compartments is associated with cytokine triggered transformation of resident fibroblasts or pancreatic stellate cells into myofibroblasts and the subsequent production and deposition of extracellular matrix.

A response by M. Pinzani and F. Vizzutti to a letter to the editor about his article "ADMA correlates with portal pressure in patients with compensated cirrhosis" in issue 509 is presented.

A quiz concerning a medical case study involving a 41 year old female with non-specific abdominal pain and intermittent hyperpyrexia is presented.

A response by M. Pinzani to a letter to the editor about his commentary on non-invasive evaluation of hepatic fibrogenesis is presented.