Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients

BACKGROUNDMatrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans. AIMTo assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC).METHODSA prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest^®and/or FibroScan^®. Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTSSerum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 (P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 (P < 0.001). CONCLUSIONHigh concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.     

Further Validation of the IBS-QOL: Female Mexican IBS Patients Have Poorer Quality of Life Than Females from North Carolina

The Irritable Bowel Syndrome (IBS)-Quality of Life (QOL) is the most extensively validated health-related quality of life (HRQOL)-specific instrument for IBS with appropriate evidence for psychometric validity. Our aim was to linguistically validate the IBS-QOL for Mexico according to standard guidelines, to conduct further psychometric validation, and to compare the HRQOL between IBS patients from Mexico and North Carolina (University of North Carolina). Construct validity was tested by correlating scores from the Mexican Spanish IBS-QOL with those for anxiety and depression obtained by the Hospital Anxiety and Depression scale. Also, HRQOL from Rome I female IBS patients who consulted a tertiary referral center in Mexico was compared with that of female patients from UNC matched by age and bowel habit. A general univariate linear model was done to determine the most important variable over HRQOL, place of origin, or bowel habit. The majority of the IBS-QOL items had a negative correlation with depression as well as with anxiety. Compared to patients from UNC, the Mexican ones reported significant lower scores on Body Image and Health Worry and a trend in Interference with activities and in the Overall score. There were some differences in Dysphoria and Interference that were related to bowel habit, independently of the place of origin. In conclusion, the IBS-QOL validated in Mexican Spanish has shown construct validity. Using this instrument we found that female IBS patients who consulted a tertiary referral center in Mexico have lower HRQOL than those in North Carolina at least in factors such as Body Image and Health Worry.     

The impact of genetic variability on liver disease in the Hispanic/Latin-American population

Liver cirrhosis is within the top 10 causes of death in Latin-American countries and recent evidence suggests that Hispanics in the USA have a more aggressive course of many types of liver disease and show lower response to treatment of hepatitis C compared with other ethnic groups. Although environmental factors are very important, they do not appear to fully account for the observed ethnic differences in the incidence of cirrhosis and progression rates. Genome-wide association studies have been a powerful tool to identify genetic variants that directly confer susceptibility to liver disease. Here, we review the current knowledge on genetic variants associated with the most common types of liver disease that may contribute to ancestry-related differences in disease progression and mortality.     

Assessment of urinary TWEAK levels in Mexican patients with untreated lupus nephritis: An exploratory study

Objectives

Urinary levels of TWEAK (uTWEAK) may be correlated with the degree of lupus nephritis (LN) activity. Our objective was to determine the sensitivity and specificity of uTWEAK in Mexican patients with untreated active lupus nephritis.

Gene expression patterns in livers of Hispanic patients infected with hepatitis C virus

We report a gene expression study aimed at the identification of genes differentially expressed in the livers of Hispanic patients infected with hepatitis C virus (HCV). Six uninfected controls were compared with 14 HCV(+) patients in which the liver biopsies were obtained at the time of diagnosis. Among the latter, five patients were also analyzed 4 weeks after the onset of standard anti-HCV therapy (pegylated interferon-α +?ribavirin). We identified many genes up- or down-regulated by the infection with HCV in the human livers. When these genes were subjected to pathway analysis, several prominent pathways were revealed including many interferon (IFN)-inducible pathways as well as immune cell trafficking, inflammation, anti-microbial responses, and even cancer. We detected expression of many genes that have previously been associated with HCV infection, as well as several novel genes including CD47. The genes induced by HCV infection showed large expression changes, whereas the genes induced by the IFN-α combination therapy were relatively few (including MX2, ORMDL3, GPAM, KOPX18, TMEM56, and HBP1) and they reflected relatively small expression changes. This is the first study to identify changes in gene expression in livers of HCV(+) Hispanic patients and the first to identify genes induced by anti-HCV combination therapy in the human liver.     

Collagen matrix scaffolds: Future perspectives for the management of chronic liver diseases

Approximately 1.5 billion chronic liver disease(CLD) cases have been estimated worldwide, encompassing a wide range of liver damage severities. Moreover, liver disease causes approximately 1.75 million deaths per year. CLD is typically characterized by the silent and progressive deterioration of liver parenchyma due to an incessant inflammatory process, cell death, over deposition of extracellular matrix proteins, and dysregulated regeneration. Overall, these processes impair the correct functio...     

Liver fibrosis and chronic viral hepatitis

Liver fibrosis results from chronic damage to the liver in conjunction with the progressive accumulation of fibrillar extracellular matrix proteins. Fibrosis progression in patients with chronic viral hepatitis is a dynamic process where hepatic stellate cells, the most important contributor cell type, respond to a variety of host genetic factors and viral proteins. The abuse of alcohol, superimposed fatty liver disease, and age at the time of viral infection are some of the factors that accelerate liver fibrosis. Liver biopsy remains the gold standard to diagnose fibrosis and significant advances have been made to develop noninvasive markers for liver fibrosis.     

Management of alcoholic liver disease: an update

Treatment of alcoholic liver disease is for the most part based on the stage of the disease and the pathogenic event that is being targeted. The primary treatment modalities that are considered in the treatment of alcoholic liver disease include abstinence, agents that suppress inflammation, anticytokine therapy, nutritional support, modifiers of alcohol metabolism, anti-oxidants, and inhibitors of hepatic fibrosis. Future therapeutic options include exploration of new pathways such as the patatin-like phospholipase domain containing 3 protein (PNPLA-3).     

Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C

The cellular and humoral natural immune response induced by hepatitis C virus (HCV) is commonly unable to eradicate the virus. HCV is a highly mutable, hepatotropic RNA virus that causes acute and chronic hepatitis, an infection that involves the production of various cytokines. The aim of the study is to analyse the expression of pro-inflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma and the chemokine CXCL8 (IL-8) in liver tissue and their expression and secretion in PBMC of patients with chronic hepatitis C (CHC), in response to pentoxyfilline (PTX). We studied six CHC patients, naive to treatment. Patients received PTX 400 mg twice a day/8 weeks. Pentoxyfilline resulted in decreased expression of mRNA of liver IL-1beta, TNF-alpha and IFN-gamma: 144.2 versus 83.5 molecules of IL-1beta (P < 0.05), TNF-alpha 194.3 versus 17.6 molecules (P = 0.03) and IFN-gamma 26.1 versus 0.5 molecules (P = 0.04). Following PTX, PBMC exhibited a decrease in IFN-gamma mRNA 12.2 versus 1.5 molecules (P = 0.028) and CXCL8 4.2 versus 2.5 molecules (P = 0.027). In PBMC, only the secretion of TNF-alpha was decreased 1109 versus 933.5 pg/ml, P = 0.046. Production of cytokines both locally (within the liver) and systemically (PBMC) may serve as biomarkers of the infection with hepatitis C. PTX inhibits the expression of several pro-inflammatory cytokines in the liver. These results indicate that it is worth exploring PTX in hepatitis in future clinical trials in nonresponders to antiviral treatment.