Early Fibrosis (early + fibrosis)

Distribution by Scientific Domains


Selected Abstracts


CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis,

HEPATOLOGY, Issue 4 2010
Mirko Moreno Zaldivar
Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4,/, and wild-type mice were subjected to two models of chronic liver injury (CCl4 and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus,induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl4 and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf -, [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4,/, mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8+ T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. Conclusion: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies. (HEPATOLOGY 2010.) [source]


Rating of CCl4 -induced rat liver fibrosis by blood serum glycomics

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2007
Liesbeth Desmyter
Abstract Background:, Non-invasive staging of human liver fibrosis is a desirable objective that remains under extensive evaluation. Animal model systems are often used for studying human liver disease and screening antifibrotic compounds. The aim of the present study was to investigate the potential use of serum N-glycan profiles to evaluate liver fibrosis in a rat model. Methods:, Liver fibrosis and cirrhosis were induced in rats by oral administration of CCl4. Liver injury was assessed biochemically (alanine aminotransferase [ALT] activity, aspartate aminotransferase [AST] activity and total bilirubin) and histologically. The N-glycan profile (GlycoTest) was performed using DNA sequencer-assisted,fluorophore-assisted carbohydrate electrophoresis technology. In parallel, the effect of cotreatment with antifibrotic interferon-, (IFN-,) was studied. Results:, The biopsy scoring system showed that CCl4 induced early fibrosis (F < 1,2) in rats after 3 weeks of treatment, and cirrhosis (F4) after 12 weeks. Significant increases in ALT activity, AST activity and total bilirubin levels were detected only after 12 weeks of CCl4 treatment. GlycoTest showed three glycans were significantly altered in the CCl4 -goup. Peak 3 started at week 6, at an early stage in fibrosis development (F < 1,2), whereas peaks 4 and 5 occurred at week 9, at which time mild liver fibrosis (F = 1,2) had developed. The changes in the CCl4 -IFN-, group were intermediate between the CCl4 - and the control groups. Conclusion:, The GlycoTest is much more sensitive than biochemical tests for evaluating liver fibrosis/cirrhosis in the rat model. The test can also be used as a non-invasive marker for screening and monitoring the antifibrotic activity of potential therapeutic compounds. [source]


13C-methacetin breath test as liver function test in patients with chronic hepatitis C virus infection

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2005
B. Braden
Summary Background :,The 13C-methacetin breath test enables the quantitative evaluation of the cytochrome P450-dependent liver function. Aim :,To find out whether this breath test is sensitive in noncirrhotic patients also with chronic hepatitis C in early stages of fibrosis. Methods :,Sixty-one healthy controls and 81 patients with chronic hepatitis C underwent a 13C-methacetin breath test. In all patients, a liver biopsy was performed. The liver histology was classified according to the histology activity index,Knodell score. Results :,Delta over baseline values of the patients at 15 min significantly differed from controls (19.2 ± 9.2, vs. 24.1 ± 5.7,; P < 0.003). The cumulative recovery after 30 min in patients was 11.4 ± 4.8% and in healthy controls 13.8 ± 2.8% (P < 0.002). However, patients with early fibrosis (histology activity index IVB) did not differ in delta over baseline values of the patients at 15 min (23.2 ± 7.9, vs. 22.6 ± 7.2,; P = 0.61) or cumulative recovery (13.6 ± 3.7% vs. 13.2 ± 3.8%; P = 0.45) from patients with more advanced fibrosis (histology activity index IVC). Patients with clinically nonsymptomatic cirrhosis (histology activity index IVD; Child A) metabolized 13C-methacetin to a significantly lesser extent (delta over baseline values of the patients at 15 min: 8.3 ± 4.9,; P < 0.005 and cumulative recovery after 30 min: 5.6 ± 3.2%; P < 0.003). The 13C-methacetin breath test identified cirrhotic patients with 95.0% sensitivity and 96.7% specificity. Conclusion :,The non-invasive 13C-methacetin breath test reliably distinguishes between early cirrhotic (Child A) and noncirrhotic patients, but fails to detect early stages of fibrosis in patients with chronic hepatitis C. [source]


Dialysis Reduces Portal Pressure in Patients With Chronic Hepatitis C

ARTIFICIAL ORGANS, Issue 7 2010
Sandeep Khurana
Abstract The purpose of this study was to characterize changes in hepatic venous pressures in patients with chronic hepatitis C. The histology and laboratory data from patients with chronic hepatitis C who underwent a transjugular liver biopsy (TJLB) and hepatic venous pressure gradient measurement were analyzed. Portal hypertension was defined as hepatic venous pressure gradient ,6 mm Hg. A single pathologist masked to hepatic venous pressure gradient scored liver sections for inflammation and fibrosis. The patients with high-grade inflammation (relative risk [RR] 2.82, P = 0.027, multivariate analysis) and late-stage fibrosis (RR 2.81, P = 0.022) were more likely to have a hepatic venous pressure gradient ,6 mm Hg, while the patients on dialysis (RR 0.32, P = 0.01) were less likely to have a hepatic venous pressure gradient ,6 mm Hg. The patients on dialysis (n = 58) had an elevated serum blood urea nitrogen and creatinine when compared with those who were not (n = 75) (47.6 ± 3.3 and 7.98 ± 0.4 vs. 25.9 ± 2.0 and 1.66 ± 0.22 mg/dL, respectively; P < 0.001). While the hepatic venous pressure gradient increased with the rising levels of liver fibrosis in the latter group (P < 0.01), it did not change in the patients on dialysis (P = 0.41). The median hepatic venous pressure gradient was especially low in late-stage fibrosis patients on dialysis when compared with the latter group (5 vs. 10 mm Hg, P = 0.017). In patients on dialysis, serum transaminases were low across all levels of fibrosis. Twenty-three of the 92 patients with early fibrosis had a hepatic venous pressure gradient ,6 mm Hg. In patients with chronic hepatitis C, concomitant TJLB and hepatic venous pressure gradient measurement identify those who have early fibrosis and portal hypertension. Long-term hemodialysis may reduce portal pressure in these patients. [source]


Impact of human herpesvirus-6 on the frequency and severity of recurrent hepatitis C virus hepatitis in liver transplant recipients

CLINICAL TRANSPLANTATION, Issue 2 2002
Nina Singh
A role of tumor necrosis factor-alpha (TNF-,) In the immunopathogenesis of hepatitis C virus (HCV) infection has been proposed. The novel herpes virus, human herpes virus-6 (HHV-6), is amongst the most potent inducers of cytokines, including TNF-,. The impact of HHV-6 viremia on the progression of recurrent HCV hepatitis was assessed in 51 HCV-positive liver transplant recipients. The frequency of recurrent HCV hepatitis did not differ between patients with HCV viremia (47.6%, 10/21) as compared with those without HCV viremia (46.7%, 14/30, p=0.9). However, the patients with HHV-6 viremia had a significantly higher fibrosis score upon HCV recurrence than those without HHV-6 viremia (mean 1.5 vs. 0.3, p=0.01). An association between cytomegalovirus (CMV) viremia and HCV recurrence was not documented; 50% (15/30) of the patients with CMV viremia and 42.8% (9/21) of those without CMV viremia had recurrent HCV hepatitis (p > 0.5). Receipt of ganciclovir (administered upon the detection of CMV viremia) was associated with lower total Knodell score (mean 5.2 vs. 6.9, p=0.05) and a trend towards lower fibrosis score (mean 0.44 vs. 1.00, p=0.12) in patients with recurrent HCV hepatitis. Thus, HHV-6 viremia in HCV-positive liver transplant recipients identified a subgroup of patients at increased risk for early fibrosis upon HCV recurrence. [source]