Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The University of Toronto liver transplant program began in 1985 at a time when the procedure had already evolved from an experimental form of surgery to an accepted treatment for many forms of liver failure. The program was established not only to provide clinical care for patients but also to address academically the barriers which impeded success. The program brought together experts in medicine, surgery, pathology, and the basic sciences of immunology, virology and molecular biology. Our group has had a special interest in transplantation for viral hepatitis. We demonstrated the role of HBV DNA as a prospective factor in both viral recurrence and survival. We further studied a number of agents to prevent re-infection including PGE, HBIG and more recently lamivudine. Although the short-term results of transplantation for HCV appear excellent, reinfection of the graft and development of chronic hepatitis and cirrhosis may make long-term results problematic. Therefore, we have directed attention to studies of pathogenesis and treatment of HCV in liver transplantation. Our studies have demonstrated a unique role for ribavirin as an immunomodulatory agent which can benefit the course of posttransplant HCV. Future studies will examine combination therapy in an attempt to eradicate the virus. Our group also has been interested in PNF and FHF and have demonstrated a positive effect of PGE in this setting. As we look to the future, the greatest challenges facing transplantation are the shortage of organ donors and the toxic effects of long-term immunosuppression. Our group now has established research efforts both in tolerance induction and xenotransplantation which we feel are necessary to make transplantation an effective, universal treatment for end stage organ failure.
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PMID:The University of Toronto liver transplant program. 928 67

In chronic viral hepatitis, autoimmune hepatitis, and some chronic cholestatic liver diseases, T-lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix (ECM) components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp (RGD) sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic nonpeptidic analogues of RGD and of soluble receptor of tumor necrosis factor (TNF)-alpha in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and of RGD analogues in inhibiting the development of liver cirrhosis in rats. The concanavalin A-induced elevation of serum transaminases and TNF-alpha, and the infiltration of liver tissue by inflammatory cells, were inhibited by pretreatment of the mice with the synthetic RGD mimetics and soluble TNF receptor. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the coadministration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necroinflammation, cholestasis and fibrosis.
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PMID:The use of synthetic analogues of Arg-Gly-Asp (RGD) and soluble receptor of tumor necrosis factor to prevent acute and chronic experimental liver injury. 962 59

Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor alpha (TNF-alpha) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-alpha in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-alpha, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-alpha production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-alpha levels, and in vitro TNF-alpha production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-alpha, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-alpha and sTNFR levels. In vitro TNF-alpha production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-alpha levels were further increased and in vitro TNF-alpha production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-alpha and sTNFR levels in cirrhosis.
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PMID:Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. 1271 78

TR6/DcR3/M68 is a soluble receptor that belongs to the TNF receptor family. It is expressed in malignant cells of several tumor types and has been postulated to help tumor cells to gain survival advantage by inhibiting apoptosis and by interfering with immune surveillance. In our study, we assessed for the first time serum TR6 in tumor patients to explore its diagnostic and prognostic value. We examined serum TR6 levels with ELISA in 146 tumor patients, 19 patients with acute infection, 5 patients with liver cirrhosis and 29 healthy individuals. TR6 expression in tumor mass was studied with immunohistochemistry. TR6 gene copy number in tumor tissues was evaluated by real time PCR. Ninety-seven point nine percent (47 of 48 cases) of healthy individuals and patients with acute infection were serum TR6-negative. In contrast, 56.2% (82 of 146 cases) of the tumor patients were serum TR6-positive. Almost all serum TR6-positive individuals (98.8%, 82 out of 83 cases) had malignancy, excluding the cases of liver cirrhosis. In gastric carcinomas, serum TR6 levels were closely correlated with tumor differentiation status and TNM classification. Tumor mass was the source of serum TR6 because its levels decreased drastically after curative tumor resection. TR6 gene amplification occurred in about half of liver carcinomas, but not in gastric or pancreatic carcinomas, indicating plural mechanisms of TR6 upregulation. Our study demonstrated that serum TR6 should be considered as a novel parameter for the diagnosis, treatment and prognosis of malignancies.
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PMID:Clinical significance of detecting elevated serum DcR3/TR6/M68 in malignant tumor patients. 1274 Sep 25

Liver cirrhosis is a risk factor for osteoporosis. Nevertheless, little is known about the mechanisms of bone mass loss in patients with viral cirrhosis. TNFalpha is a potent bone-resorbing agent. Serum concentrations of soluble TNF receptor p55 (sTNFR-55) correlate with clinical activity in liver cirrhosis. Our aim was to evaluate the possible role of sTNFR-55 in the pathogenesis of osteoporosis in patients with viral cirrhosis and its relationship with bone turnover markers. We studied 40 consecutive patients with viral cirrhosis and no history of alcohol intake and 26 healthy volunteers. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in the lumbar spine (LS) and femoral neck (FN). Patients with viral cirrhosis had reduced BMD (expressed as the z-score) in all sites [LS, -1.5 +/- 0.22 (P < 0.001); FN, -0.37 +/- 0.15 (P < 0.01)]. Serum concentrations of sTNFR-55 and urinary deoxypyridinoline, a biochemical marker of bone resorption, were significantly higher in patients with osteoporosis than in patients without osteoporosis (P < 0.001 and P < 0.05, respectively). Serum levels of sTNFR-55 correlated inversely with BMD in LS (r = -0.62; P < 0.005) and FN (r = -0.47; P < 0.05) and positively with urinary deoxypyridinoline (r = 0.72, P < 0.001). Our findings show that high serum concentrations of sTNFR-55 play a role in the pathogenesis of viral cirrhosis-associated bone mass loss and provide evidence of increased bone resorption related to the high serum sTNFR-55 levels.
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PMID:Osteoporosis, mineral metabolism, and serum soluble tumor necrosis factor receptor p55 in viral cirrhosis. 1535 28

Unexplained chronic hepatitis (CH) in the adult liver allograft recipient is not uncommon, but its natural history and clinical significance is unknown. A retrospective study was undertaken of adult liver allograft recipients to determine the frequency and natural history of unexplained CH. We evaluated only those patients who had undergone >or=2 liver biopsies after 6 months and were grafted for indications where recurrent disease could be confidently excluded (alcoholic liver disease [ALD] in those who remained abstinent and fulminant hepatic failure [FHF] from drug reactions). Of 288 patients who were transplanted for ALD or FHF, 30 fulfilled the above criteria. CH was first diagnosed at a median of 15.25 months after transplantation. A total of 24 patients showed mild necroinflammatory changes, and 12 had mild or moderate fibrosis. Liver tests did not reflect the presence or degree of inflammation or fibrosis. After a median of 4 years, necroinflammatory scores were increased in 5; new or progressive fibrosis was noted in 13%; 3 had developed cirrhosis; and 5 developed clinical evidence of portal hypertension. Progressive fibrosis was associated with a high titer of anti-nuclear antibodies (>1:1600) and a portal tract plasma cell infiltrate. There was a trend for correlation between necroinflammatory activity and fibrosis stage, but this did not reach statistical significance (P = 0.06). Serum alkaline phosphatase (P = 0.012) and female gender of the donor (P = 0.033) were associated with progressive fibrosis. Unexplained CH is not uncommon in the liver allograft and may progress to established cirrhosis in a subgroup of patients transplanted for ALD or FHF. Standard liver tests do not reflect the extent of these changes, so protocol liver biopsies may be required to detect these changes. We recommend careful history and follow-up in these patients.
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PMID:Natural history of unexplained chronic hepatitis after liver transplantation. 1752 Jul 43

The liver performs multiple functions that are essential for life, the most crucial being its role in the body metabolism. Impairment of this function, because of liver insufficiency, can be partially restored by medical management but OLT remains the ultimate therapeutic treatment. Because not always indicated or available, other alternatives are proposed such as LCT. Compared to OLT, this procedure is less invasive, less expensive, and fully reversible. More than 50 patients have thus far benefited of this technique and are reviewed here. Indications were multiple including inborn errors of metabolism, FHF, acute on chronic diseases, and decompensated end-stage cirrhosis. Documented results were encouraging, especially for metabolic disorders, with medium-term efficacy up to two yr. Related complications were exceptional. On this basis, LCT has entered its phase of clinical application and current indications and protocols are detailed. Ongoing lines of research are discussed, including cell quality, stem cell field, and rejection prevention. Further improvement of the procedure is therefore expected and should lead to broader applications of LCT.
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PMID:Cell transplantation in the treatment of liver diseases. 1818 83

Chronic ethanol (EtOH) abuse results in the development of steatosis, alcoholic hepatitis, and cirrhosis. Augmented TNF-alpha production by macrophages and Kupffer cells and signaling via the p55 TNF receptor have been shown to be critical for these effects of chronic EtOH; however, the molecular mechanisms leading to augmented TNF-alpha production remain unclear. Using cell culture models and in vivo studies we demonstrate that chronic EtOH results in increased TNF-alpha transcription, which is independent of NF-kappaB. Using reporter assays and chromatin immunoprecipitation we found that this increased transcription is due to increased IRF-3 binding to and transactivation of the TNF promoter. As IRF-3 is downstream from the TLR4 adaptor TIR-domain-containing adapter-inducing IFN-beta (Trif), we demonstrate that macrophages from Trif-/- mice are resistant to this dysregulation of TNF-alpha transcription by EtOH in vitro as well as EtOH-induced steatosis and TNF dysregulation in vivo. These data demonstrate that the Trif/IRF-3 pathway is a target to ameliorate liver dysfunction associated with chronic EtOH.
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PMID:TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. 1871 75

Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease (ALD). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD, which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL-22/STAT3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide (LPS), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD. We further discuss the findings of recent translational studies and potential therapeutic targets.
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PMID:Alcoholic liver disease: pathogenesis, management, and novel targets for therapy. 2385

Bone marrow endothelial cells (BMECs) are important components of the hematopoietic microenvironment in bone marrow, and they can secrete several types of cytokines to regulate the functions of hematopoietic stem/progenitor cells. To date, it is unknown whether BMECs undergo functional changes and lead to hematopoietic abnormalities in cases of liver cirrhosis (LC). In the present study, whole genome microarray analysis was carried out to detect differentially expressed genes in human BMECs treated for 48 h with medium supplemented with 20% pooled sera from 26 patients with LC or 10 healthy volunteers as the control group. A total of 1,106 upregulated genes and 766 downregulated genes were identified. In Gene Ontology analysis, the most significant categories of genes were revealed. A large number of the upregulated genes were involved in processes, such as cell-cell adhesion, apoptosis and cellular response to stimuli and the downregulated genes were involved in the negative regulation of secretion, angiogenesis, blood vessel development and cell growth. Pathway analysis revealed that the upregulated genes were either cell adhesion molecules or parts of the apoptotic signaling pathway and the downregulated genes were involved in the Wnt signaling pathway and MAPK signaling pathway. These were the pathways with the highest enrichment scores. The results of apoptosis assays revealed that the humoral inhibitors in the sera of patients with LC induced the apoptosis of BMECs, which confirmed the accuracy of bioinformatic analysis. Moreover, we screened and verified 21 differentially expressed cytokine genes [transforming growth factor (TGF)B1, tumor necrosis factor (TNF)B, TNF receptor superfamily, member 11b (TNFRSF11B), TNF (ligand) superfamily, member 13b (TNFSF13B), interleukin (IL)1A, IL6, IL11, IL17C, IL24, family with sequence similarity 3, member B (FAM3B), Fas ligand (FASLG), matrix metallopeptidase (MMP)3, MMP15, vitronectin (VTN), insulin-like growth factor 1 (IGF1), fibroblast growth factor 22 (FGF22), slit homolog 2 (Drosophila) (SLIT2), thrombospondin (THBS)2, THBS3, chemokine (C-C motif) ligand 28 (CCL28) and macrophage stimulating 1 (MST1)] from 97 cytokine genes in BMECs treated with serum from patients with LC. The results from our study demonstrate that the humoral inhibitors in the sera of patients with LC induce the dysfunction and abnormal cytokine secretion by BMECs, which may be a novel mechanism responsible for hematological abnormalities in patients with LC.
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PMID:Whole genome expression profiling and screening for differentially expressed cytokine genes in human bone marrow endothelial cells treated with humoral inhibitors in liver cirrhosis. 2404 11


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