Yücel Batur

Infliximab: a new therapeutic agent in acute pancreatitis?

Purpose Tumor necrosis factor alpha (TNF-alpha) has a central role in the pathogenesis of acute pancreatitis and related systemic complications. The aim of this study is to investigate the therapeutic effectiveness of monoclonal TNF antibody (infliximab) in acute edematous and severe necrotizing pancreatitis models in rats. Methods One hundred rats were randomly divided into 10 groups. Acute edematous pancreatitis (AEP) was induced by injection of cerulein 20 &mgr;g/kg 4 times subcutaneously at hourly intervals. Severe necrotizing pancreatitis (SNP) was induced by retrograde injection of 3% taurocholate into the common biliopancreatic duct. Infliximab 8 mg/kg was given via intravenous infusion. Serum amylase activity, pancreatic histopathology, myeloperoxidase enzyme activity (MPO), and pulmonary changes were assessed. Results Infliximab treatment significantly decreased serum amylase activity (11939 ± 1914 U/L versus 3458 ± 915 U/L, P < 0.001) and histopathologic score (4.1 ± 0.5 versus 1.5 ± 0.3, P < 0.001) in AEP. It also suppressed neutrophil infiltration and MPO activity of the pancreatic tissue. In SNP, infliximab treatment was found to decrease pathologic score (9.4 ± 1.2 versus 3.6 ± 0.8, P < 0.001) and serum amylase activity (20442 ± 2375 versus 8990 ± 1730, P < 0.01). It ameliorated both parenchymal and fatty tissue necrosis of the pancreas. Infliximab also alleviated alveolar edema and acute respiratory distress syndrome like pulmonary complications, but the difference was not significant. Conclusions Chimeric TNF antibody, infliximab, should be evaluated for treatment of acute pancreatitis.

Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease.

Aim To investigate the efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease (NAFLD) patients. Methods This is an open-label, randomized, a single-center study. Sixty-four patients, with impaired glucose metabolism and elevated alanine aminotransferase for at least 6 months before enrollment and NAFLD activity score at least 5 in liver biopsy, were randomized as group 1 and received metformin 1700 mg/day, group 2 received rosiglitazone 4 mg/day, and group 3 received a combination of metformin 1700 mg/day and rosiglitazone 4 mg/day for 12 months. Results Baseline demographic and laboratory findings were similar in all the three groups, except baseline insulin level that was significantly higher in group 1 and group 3 versus group 2 (P<0.05). Serum transaminase levels showed a significant decrease after treatment in both group 2 and group 3. Serum &ggr;-glutamyl transpeptidase levels decreased significantly only in the group 3. However, there was no significant change in liver tests of group 1. Postprandial glucose levels showed significant decrease in all of the three groups. Homeostasis model assessment-insulin resistance was reduced significantly in only group 2. NAFLD score was significantly decreased on follow-up biopsy of the patients in group 2 and group 3. Fibrosis did not change significantly after the treatment. Conclusion Rosiglitazone therapy seems to be more effective in metabolic control and histological improvement in NAFLD patients with impaired glucose metabolism.

EFFECTS OF TRIMETAZIDINE ON OXIDANT/ANTIOXIDANT STATUS IN TRINITROBENZENESULFONIC ACID-INDUCED CHRONIC COLITIS

Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male Swiss Albino rats with ethanol (50%) and trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) produced colitis as evidenced by histopathologic damage and inflammatory alterations, lipid peroxidation [increased malondialdehyde (MDA) levels], and enhanced neutrophil infiltration [increased myeloperoxidase (MPO) activity] without marked change in glutathione status. Administration of TMZ (5 mg/kg) to TNBS-treated rats failed to affect the TNBS-induced changes in histopathology and MPO activities. Unexpectedly, intrarectal (ir) administration of TMZ significantly elevated colonic MDA levels to a greater extent than TNBS alone. Intraperitoneal (ip) TMZ treatment seemed to increase total glutathione (tGSH), GSH, and GSH/GSSG values. In conclusion, our results demonstrated that (a) ir administration of ethanol and TNBS is an effective way of inducing a chronic colitis model, (b) inflammation and lipid peroxidation augment tissue damage in the chronic colitis model, (c) ip TMZ treatment significantly inhibits MDA production in the chronic colitis model, (d) TMZ treatment is more effective via the ip compared to ir route, and (e) TMZ seems to show its antioxidant effect via preserving the tissues GSH/GSSG ratios.Trimetazidine (TMZ), an anti-ischemic agent with proposed antioxidant properties, was used in a chronic colitis model in order to evaluate its effectiveness as a therapeutic agent in chronic colitis. Treatment of male Swiss Albino rats with ethanol (50%) and trinitrobenzenesulfonic acid (TNBS) (30 mg/kg) produced colitis as evidenced by histopathologic damage and inflammatory alterations, lipid peroxidation [increased malondialdehyde (MDA) levels], and enhanced neutrophil infiltration [increased myeloperoxidase (MPO) activity] without marked change in glutathione status. Administration of TMZ (5 mg/kg) to TNBS-treated rats failed to affect the TNBS-induced changes in histopathology and MPO activities. Unexpectedly, intrarectal (i.r.) administration of TMZ significantly elevated colonic MDA levels to a greater extent than TNBS alone. Intraperitoneal (i.p.) TMZ treatment seemed to increase total glutathione (tGSH), GSH, and GSH/GSSG values. In conclusion, our results demonstrated that (a) i.r. administration of ethanol and TNBS is an effective way of inducing a chronic colitis model, (b) inflammation and lipid peroxidation augment tissue damage in the chronic colitis model, (c) i.p. TMZ treatment significantly inhibits MDA production in the chronic colitis model, (d) TMZ treatment is more effective via the i.p. compared to i.r. route, and (e) TMZ seems to show its antioxidant effect via preserving the tissues GSH/GSSG ratios.

Liver Fibrosis Is Associated with Decreased Peripheral Platelet Count in Patients with Chronic Hepatitis B and C

Thrombocytopenia is a common complication of chronic liver diseases, but its pathogenesis is not clear. Although generally attributed to hypersplenism, other factors should also be considered. We investigated the relationship between the peripheral platelet count and the degree of fibrosis in patients with chronic viral hepatitis. In an effort to avoid the effects of hypersplenism, we excluded patients with splenomegaly and/or bi- or pan-cytopenia. Seven hundred eighty-four patients (265 chronic viral hepatitis C and 519 chronic viral hepatitis B) were included in the study. Univariate analysis showed that the peripheral platelet count had a negative correlation with fibrosis score, necroinflammatory activity, and age in both groups. In multivariate analysis, the peripheral platelet count had a similar correlation with the fibrosis score and age, but not with necroinflammatory activity, in both groups. The peripheral platelet count decreased more significantly in females with chronic hepatitis C but not in the chronic hepatitis B group. In conclusion, a decrease in peripheral platelet count may be a sign of an increase in the degree of fibrosis during the course of chronic viral hepatitis B and C and factors other than hypersplenism may play a role in this decrease in the peripheral platelet count.

Live donor liver transplantation for acute liver failure.

Background. Acute liver failure (ALF) carries a high mortality unless urgent orthotopic liver transplantation (OLT) is performed on time. Live donors are utilized to treat this irreversible condition first in pediatric cases and then in adults. Herein, we aimed to report our experience with live donors for ALF in a country of a deceased donor organ donation rate is only 1.5 per million people. Methods. Among the 245 live donor liver transplantations (LDLT) performed from June 1999 to December 2005, 14 of them (6%) were performed for ALF in 8 pediatric and 6 adult cases. Right lobes were harvested for the adult cases whereas left lateral segments were harvested for pediatric cases, except one child transplanted with a right lobe graft. The etiology of the disease was; acute hepatitis B in four cases, hepatitis A in three cases, Wilson disease two cases, autoimmune hepatitis in two cases, and was unknown in three cases. Results. Three-year graft and patient survival is 79% for these series. Five of the six adult patients and six of the eight pediatric cases survived after transplantation. There was not any donor mortality or major morbidity. Conclusions. LDLT offers a safe and effective modality of treatment for ALF for both pediatric and adult patients to overcome the problem of organ shortage especially in countries where the chance of receiving an organ from a deceased donor is low.

Serum procalcitonin and CRP levels in non-alcoholic fatty liver disease: a case control study

BackgroundBoth C reactive protein (CRP) and procalcitonin (PCT) are well known acute phase reactant proteins. CRP was reported to increase in metabolic syndrome and type-2 diabetes. Similarly altered level of serum PCT was found in chronic liver diseases and cirrhosis. The liver is considered the main source of CRP and a source of PCT, however, the serum PCT and CRP levels in non-alcoholic fatty liver disease (NAFLD) were not compared previously. Therefore we aimed to study the diagnostic and discriminative role of serum PCT and CRP in NAFLD.MethodsFifty NAFLD cases and 50 healthy controls were included to the study. Liver function tests were measured, body mass index was calculated, and insulin resistance was determined by using a homeostasis model assessment (HOMA-IR). Ultrasound evaluation was performed for each subject. Serum CRP was measured with nephalometric method. Serum PCT was measured with Kryptor based system.ResultsSerum PCT levels were similar in steatohepatitis (n 20) and simple steatosis (n 27) patients, and were not different than the control group (0.06 ± 0.01, 0.04 ± 0.01 versus 0.06 ± 0.01 ng/ml respectively). Serum CRP levels were significantly higher in simple steatosis, and steatohepatitis groups compared to healthy controls (7.5 ± 1.6 and 5.2 ± 2.5 versus 2.9 ± 0.5 mg/dl respectively p < 0.01). CRP could not differentiate steatohepatitis from simple steatosis. Beside, three patients with focal fatty liver disease had normal serum CRP levels.ConclusionSerum PCT was within normal ranges in patients with simple steatosis or steatohepatitis and has no diagnostic value. Serum CRP level was increased in NAFLD compared to controls. CRP can be used as an additional marker for diagnosis of NAFLD but it has no value in discrimination of steatohepatitis from simple steatosis.

Characterization of the Cellular Response During Apoptosis Induction in Cadmium-Treated Hep G2 Human Hepatoma Cells

Cadmium is a toxic transition heavy metal of continuing occupational and environmental concern, with a wide variety of adverse effects on regulation of gene expression and cellular signal transduction pathways. Injury to cells by cadmium leads to a complex series of events that can culminate in the death of the cell. It has been reported that cadmium induces apoptosis in many cell lines. However, the morphological characteristics leading to apoptosis or subsequent regeneration in cells exposed to cadmium have not been clarified.We evaluated whether human hepatoma cells maintained in culture undergo apoptosis when exposed to cadmium. Cytotoxic activity of cadmium on Hep G2 cells determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. A DNA ladder assay was performed by electrophoresis. Cell cycle analysis was quantified by flow cytometry. Nuclear morphology was studied by fluorescence microscopy after staining with propidium iodide and Hoechst 33342. Morphologic alterations in culture hepatocytes treated with CdCl2 were observed by transmission electron microscopy.We have demonstrated that apoptosis is a major mode of elimination of damaged HepG2 cells in cadmium toxicity and it precedes necrosis.

TT Virus Infection and Genotype Distribution in Blood Donors and a Group of Patients from Turkey

Abstract.Background: TT virus (TTV) DNA has been found in a large proportion of patients with different forms of non-A-G hepatitis, however the clinical importance is unclear. We aimed to determine the genotypes of TTV isolates foung in blood donors and different patient groups from the western part of Turkey. Materials and Methods: TT DNA was investigated in serum samples of 91 volunteer blood donors (BD), 105 thalassemia (TH) patients, ten patients with fulminant hepatitis (FH) and 16 hemodialysis (HD) patients by heminested PCR using primers NG059, NG061 and NG063 from the ORF1 region. 39 isolates were genotyped by analyzing the partial sequence of ORF1. Results: TTV DNA was found in 75% of HD, 80% of FH, 61% of TH patients and in 51.6% of BD. Among the sequenced isolates, 14 (35.9%) belonged to genotype 1 (G1) and 25 (64.1%) belonged to genotype 2 (G2). Among the G2 sequences, 22 were grouped as G2c. Conclusion: TTV infection was common in the population studied, even with moderately sensitive primers. G2 was the major genotype of the studied population without any significant differences in distribution between various patient groups and BD.

Possible role of glutathione in prevention of acetaminophen-induced hepatotoxicity enhanced by fish oil in male Wistar rats

It has been reported that fish oil protects the rat liver against acetaminophen (APAP) induced toxicity; however, this finding is controversial. The present study was undertaken to investigate the effects of fish oil-enriched diet on APAP-induced liver injury in Wistar rats. Rats were fed a diet supplemented with either 8% fish oil or 8% corn oil, or standard rat feed for 6 wk. After an overnight fast, rats in each group were given either 2 g/kg APAP or saline orally. Our findings showed that APAP increased serum alanine aminotransferase (ALT) and that this rise was potentiated in the presence of dietary fat. Further fish oil ingestion increased the glutathione (GSH) content in rat liver; however, this was not effective in protecting liver from APAP-induced toxicity. Data suggest that GSH may be necessary to detoxify APAP metabolites, which are known to induce hepatotoxicity but are increased by dietary fat.

Trace elements analysis of ascitic fluid in benign and malignant diseases

OBJECTIVES To evaluate differences in ascitic fluid trace element concentrations which might be useful in discrimination between benign and malignant ascites. DESIGN AND METHODS The concentrations of copper, zinc, magnesium and iron in ascitic fluid and venous blood in 17 patients were investigated. The relationship between these trace elements and type of disease were examined. Investigations were carried out in a group of 5 males and 5 females aged 54 to 77 yr who had cirrhosis ascites and in a group of 7 females aged 41 to 76 yr with ascites due to gynecologic neoplasms. RESULTS The mean ascitic fluid and serum concentrations of copper were significantly higher in neoplastic diseases compared to benign disease states (118,43 vs. 97,50, 91,14 vs. 26.90) (p < 0,05 and p < 0,01 respectively). The zinc levels in ascitic fluid and serum were significantly different between the groups (p < 0,01). Neoplastic patients had significantly higher ascitic fluid magnesium levels than the benign disease group (2,17 vs. 1,55, p < 0,001). The serum levels of iron were significantly lower in the neoplastic diseases group (92, 28 vs. 255, p < 0, 01). In benign diseases the concentration of zinc in ascitic fluid correlated positively with ascitic fluid copper concentrations. The concentrations of zinc and iron in malignant ascites correlate positively with the magnesium concentrations. Statistically significant negative correlations were found between ascites zinc and magnesium and magnesium and copper in cirrhotic patients and magnesium and copper in malignant diseases. CONCLUSIONS The results showed that zinc, magnesium and iron levels were significantly different between cirrhotic and neoplastic illness. Analysis of serum and ascitic fluid trace element composition may be helpful in identifying and distinguishing the malignant and nonmalignant ascites and provides useful information on processes regulating passage of blood components into the peritoneal cavity.