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Alanine Aminotransferase (alanine + aminotransferase)
Kinds of Alanine Aminotransferase Terms modified by Alanine Aminotransferase Selected AbstractsClinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver diseaseLIVER INTERNATIONAL, Issue 2 2006Nicole A. Palekar Abstract: Nonalcoholic fatty liver disease (NAFLD) encompasses both simple steatosis and nonalcoholic steatohepatitis (NASH). Differentiation of these two entities requires histopathologic evaluation. The aim of this study was to establish a reliable diagnostic model for differentiating steatosis from steatohepatitis utilizing both clinical characteristics and a panel of biochemical markers of lipid peroxidation and fibrosis. Eighty subjects with biopsy proven NAFLD were enrolled, 39 with simple steatosis and 41 with histopathologic evidence of NASH. Demographic and laboratory data to include serologic testing for 8-epi-PGF2,, transforming growth factor-, (TGF-,), adiponectin, and hyaluronic acid (HA) were obtained and compared between the two groups. There were significant differences between the two groups with respect to age (P=0.004), female gender (P=0.024), aspartate aminotransferase (AST) (P=0.028), body mass index (BMI) (P=0.003), fasting insulin (0.018), AST/alanine aminotransferase (ALT) ratio (AAR) (P=0.017), quantitative insulin sensitivity check index (QUICKI) (P=0.002), and HA (P=0.029). A composite index for distinguishing steatosis from NASH was calculated by summing the risk factors of age ,50 years, female gender, AST,45 IU/l, BMI ,30 mg/kg2, AAR,0.80, and HA,55 mcg/l, and its accuracy was determined by receiver operating characteristic (ROC) analysis to be 0.763 (95% CI: 0.650,0.876). The presence of three or more risk factors had a sensitivity, specificity, PPV, and NPV of 73.7%, 65.7%, 68.2%, and 71.4%, respectively. In addition, HA at a cutoff of 45.3 mcg/l was a good predictor of advanced fibrosis. In conclusion, we propose a noninvasive screening model for distinguishing simple steatosis from NASH. Identifying patients at risk for NASH will allow clinicians to more accurately determine who may benefit from liver biopsy. [source] Long-term follow-up after successful interferon therapy of acute hepatitis CHEPATOLOGY, Issue 1 2004Johannes Wiegand Early treatment of acute hepatitis C infection with interferon alfa-2b (IFN-,-2b) prevents chronicity in almost all patients. So far, no data are available on the long-term outcome after interferon (IFN) therapy of acute hepatitis C. The aim of this study was to assess the clinical, virological, and immunological long-term outcome of 31 successfully treated patients with acute hepatitis C infection who were followed for a median of 135 weeks (52-224 weeks) after end of therapy. None of the individuals had clinical evidence of liver disease. Alanine aminotransferase (ALT) levels were normal in all but 1 patient. Serum hepatitis C virus (HCV) RNA was negative throughout follow-up, even when investigated with the highly sensitive transcription-mediated amplification (TMA) assay (cutoff 5-10 IU/mL). In addition, no HCV RNA was detected in peripheral blood mononuclear cells (PBMC) of 15 cases tested. The patients' overall quality-of-life scores as determined by the SF-36 questionnaire did not differ from the German reference control cohort. Ex vivo interferon gamma (IFN-,) ELISPOT analysis detected HCV-specific CD4+ T-helper cell reactivity in only 35% of cases, whereas HCV-specific CD8+ T-cell responses were found in 4 of 5 HLA -A2,positive individuals. Anti-HCV antibody levels decreased significantly during and after therapy in all individuals. In conclusion, early treatment of symptomatic acute hepatitis C with IFN-,-2b leads to a long-term virological, biochemical, and clinical response. Waning of anti-HCV humoral immunity and presence of HCV-specific CD8+ (but not CD4+) T cells highlights the complexity of T-cell and B-cell memory to HCV, which might be significantly altered by IFN treatment. (HEPATOLOGY 2004;40:98,107.) [source] Efficacy of low dose long-term interferon monotherapy in aged patients with chronic hepatitis C genotype 1 and its relation to alpha-fetoprotein: A pilot studyHEPATOLOGY RESEARCH, Issue 7 2007Hideyuki Nomura Aim:, The objective of this study was to examine the efficacy and safety of low dose long-term interferon (IFN) therapy in aged patients with chronic hepatitis C genotype 1. Methods:, The IFN therapy was performed in Shin-Kokura Hospital on 44 patients aged 60 or older with chronic hepatitis C. All patients had high viral loads of genotype 1. Three million units of natural IFN-, was administered intramuscularly or intrasubcutaneously, three times a week for three years. A control group of 44 subjects not treated with IFN, matched for age, gender and hepatic histology, was formed. Results:, Two of the 44 patients showed a sustained virological response. Alanine aminotransferase was below the upper limit of normal in 59% (23/39) of the patients and alpha-fetoprotein was less than 40 ng/mL in 97% (38/39) on the completion of treatment. Sustained biochemical response was observed in 53% (19/36) of the patients. In the liver cirrhosis group, serum albumin values and platelet counts increased in 38% (6/16) and 33% (6/18) of patients, respectively. Hepatocellular carcinoma (HCC) appeared in three patients by 13 months after the start of treatment, but no cases were reported thereafter. The cumulative non-carcinogenesis rate of HCC in the liver cirrhosis group was significantly higher in the IFN treatment group compared to the control group (log,rank test, P = 0.046). Conclusion:, Low dose long-term interferon monotherapy to prevent carcinogenesis of HCC was considered useful in aged patients for whom peg-interferon and ribavirin combination therapy is difficult. [source] A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2005J. B. Schwimmer Summary Background :,Children with non-alcoholic steatohepatitis are insulin-resistant and metformin has been proposed as a potential therapy. However, paediatric safety and efficacy data are absent. Aim :,To test the hypothesis that metformin therapy will safely improve markers of liver disease in paediatric non-alcoholic steatohepatitis. Methods :,Single-arm open-label pilot study of metformin 500 mg twice daily for 24 weeks in non-diabetic children with biopsy-proven non-alcoholic steatohepatitis. Results :,Ten obese children (mean body mass index 30.4) enrolled and completed the trial. Mean alanine aminotransferase and aspartate aminotransferase (AST) improved significantly (P < 0.01) from baseline (184, 114 U/L) to end of treatment (98, 68 U/L). Alanine aminotransferase normalized in 40% and AST normalized in 50% of subjects. Children demonstrated significant improvements in liver fat measured by magnetic resonance spectroscopy (30,23%, P < 0.01); insulin sensitivity measured by quantitative insulin sensitivity check index (0.294,0.310, P < 0.05); and quality of life measured by pediatric quality of life inventory 4.0 (69,81, P < 0.01). Conclusion :,Open-label treatment with metformin for 24 weeks was notable for improvement in liver chemistry, liver fat, insulin sensitivity and quality of life. A large randomized-controlled trial is needed to definitively determine the efficacy of metformin for paediatric non-alcoholic steatohepatitis. [source] Short-term administration of (-)-epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic miceLIVER TRANSPLANTATION, Issue 3 2005Ryan N. Fiorini Hepatic steatosis increases the extent of cellular injury incurred during ischemia/reperfusion (I/R) injury. (-)-Epigallocatechin gallate (EGCG), the major flavonoid component of green tea (camellia sinensis) is a potent antioxidant that inhibits fatty acid synthase (FAS) in vitro. We investigated the effects of EGCG on hepatic steatosis and markers of cellular damage at baseline and after I/R injury in ob/ob mice. Animals were pretreated with 85 mg/kg EGCG via intraperitoneal (ip) injection for 2 days or oral consumption in the drinking water for 5 days before 15 minutes of warm ischemia and 24 hours of reperfusion. After EGCG administration, total baseline hepatic fat content decreased from baseline. Palmitic acid and linoleic acid levels also were reduced substantially in all ECGC-treated animals before I/R. Alanine aminotransferase (ALT) levels decreased in all EGCG-treated animals compared with control animals after I/R. Histologic analysis demonstrated an average decrease of 65% necrosis after EGCG administration. EGCG administration also increased resting hepatic energy stores as determined by an increase in cellular adenosine triphosphate (ATP) with a concomitant decrease in uncoupling protein 2 (UCP2) before I/R. Finally, there was an increased level of glutathione (GSH) in the EGCG-treated mice compared with the vehicle-treated mice both at baseline and after I/R. In conclusion, taken together, this study demonstrates that treatment with ECGC by either oral or ip administration, significantly protects the liver after I/R, possibly by reducing hepatic fat content, increasing hepatic energy status, and functioning as an antioxidant. (Liver Transpl 2005;11:298,308.) [source] Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis CLIVER TRANSPLANTATION, Issue 2 2004F. Xavier López-Labrador The association between the severity of chronic hepatitis C and the variability of the hepatitis C virus (HCV) genome remains controversial, but to our knowledge few data are available to date regarding T-cell epitope coding regions in transplant patients. In the current study, we identified 21 human leukocyte antigen (HLA)-A2-positive Spanish patients with chronic hepatitis C, 14 immunosuppressed liver transplant recipients, and 7 immunocompetent controls. Alanine aminotransferase, aspartate aminotransferase, viral load, and rate of fibrosis progression were determined. Genetic distances of HCV isolates and variations in epitopes of the HCV nonstructural 3 protein (NS3-1393 LIFCHSKKK and NS3-1406 KLVALGINAV) were compared between patients with slow or fast progression of fibrosis. Isolates from transplant patients with fast progression were found to be more divergent (P =.03), had a higher mean value of synonymous (dS) variations (P =.02), and some were differentiated in a phylogenetic tree, compared with isolates from patients with slow progression. The HLA-A2-restricted NS3-1406 epitope was found to be more variable (20 of 21 isolates differed from the prototype) compared with the A3-restricted NS3-1392 epitope (19% vs. 1.25% variation). A shift in the viral peptide was not detected in a subset of transplant patients, but was evident in two of three nontransplant patients with follow-up. There was no correlation noted between a particular amino acid variation and fibrosis progression (slow or fast) in either transplant or nontransplant patients. The results of the current study suggest that 1) there may be different HCV-1b strains in our geographic area, 2) immunosuppression appears to have little effect in amino acid variation at the HCV NS3-1406 epitope, and 3) variations over time might be more frequent in nonimmunosuppressed patients. (Liver Transpl 2004;10:217,227.) [source] A United States compassionate use study of lamivudine treatment in nontransplantation candidates with decompensated hepatitis B virus,related cirrhosisLIVER TRANSPLANTATION, Issue 1 2003Hie-Won L. Hann MD Patients with hepatitis B,related decompensated cirrhosis have limited treatment options. This prospective, multicenter study assessed lamivudine in 75 patients with decompensated cirrhosis, the majority of whom (93%) were not candidates for liver transplantation. At baseline, all 75 patients tested positive for hepatitis B surface antigen [HBsAg (+)] and 62% tested positive for hepatitis B e antigen [HBeAg (+)]. Hepatitis B virus (HBV) DNA levels were detectable in 64% of patients by the branched chain DNA (bDNA) assay. Patients received lamivudine 100 mg once daily (median duration, 12.7 months; range, 0.5 to 33 months). In patients with detectable HBV DNA pretreatment, the virus became undetectable by the bDNA assay in 69% of patients with , 6 months treatment and in 64% overall. Alanine aminotransferase (ALT) level improved in 90% and normalized in 55% of patients with , 6 months treatment and in 48% overall. Improvements in bilirubin and albumin levels occurred throughout treatment. The median Child-Pugh score improved from a baseline of 10 to 8 at last visit, with 31% (23/75) having an improved score of , 2 points, 57% (43/75) unchanged (< 2 points), and 12% (9/75) worsened (, 2 points). A virologic breakthrough developed in eight of 41 patients (18%) after a median of 13.1 months of treatment. Tyrosine-methionine-aspartate-aspartate (YMDD) variant HBV was detected in three of four patients tested. Nevertheless, at last visit, ALT, albumin, and bilirubin levels were similar for patients with and without breakthrough. Lamivudine treatment can lead to significant improvements in liver disease severity in nontransplantation candidates with advanced disease. Additional studies of lamivudine in combination with other antivirals are indicated for the large population of patients worldwide with advanced HBV-related cirrhosis and inadequate access to liver transplantation. [source] Growth and hepatopancreas performances of gibel carp fed diets containing low levels of aflatoxin B1AQUACULTURE NUTRITION, Issue 4 2010D. HAN Abstract The effects of aflatoxin B1 (AFB1) on growth, physiological responses and histological changes were investigated in juvenile gibel carp (Carassius auratus gibelio). Triplicate groups of gibel carp (3.53 ± 0.02 g) were fed seven semipurified diets (Diet 1 to 7) containing 3.20, 5.37, 7.08, 9.55, 12.70, 17.90 and 28.60 ,g AFB1 kg,1 diet for 3 months. The results showed fish weight gain fed Diet 6 was 112.6% of that of control group (Diet 1) after 3 months, but there was no significant difference of weight gain between fish fed Diet 7 and the control group. Alanine aminotransferase (ALT) of fish hepatopancreas fed Diet 7 was significantly higher than the control group (P < 0.05), but no significant difference was observed in ALT activities of the fish fed with more than 10 ,g AFB1 kg,1 (Diet 4, 5, 6 and 7). No significant histological lesions were identified between the control and increasing AFB1 treatments. AFB1 accumulated in hepatopancreas was logarithmically related to the dietary AFB1 levels, and AFB1 also accumulated in muscles and ovaries of gibel carp fed Diet 3 to Diet 7. The present results indicated that fish fed with more than 10 ,g AFB1 kg,1 diet showed impaired physiological responses and more AFB1 residue of muscles and ovaries above the safety limitation of European Union. [source] Psychosocial factors are independent risk factors for the development of Type 2 diabetes in Japanese workers with impaired fasting glucose and/or impaired glucose tolerance,DIABETIC MEDICINE, Issue 10 2008M. Toshihiro Abstract Aims, We prospectively studied Japanese workers with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and analysed possible risk factors for diabetes, including psychosocial factors such as stress. Methods, The participants were 128 male Japanese company employees (mean age, 49.3 ± 5.9 years) with IFG and/or IGT diagnosed by oral glucose tolerance test (OGTT). Participants were prospectively studied for 5 years with annual OGTTs. The Kaplan,Meier method and Cox's proportional hazard model were used to analyse the incidence of diabetes and the factors affecting glucose tolerance, including anthropometric, biochemical and social,psychological factors. Results, Of 128 participants, 36 (28.1%) developed diabetes and 39 (30.5%) returned to normal glucose tolerance (NGT) during a mean follow-up of 3.2 years. Independent risk factors for diabetes were night duty [hazard ratio (HR) = 5.48, P = 0.002], higher fasting plasma glucose (FPG) levels within 6.1,6.9 mmol/l (HR = 1.05, P = 0.031), stress (HR = 3.81, P = 0.037) and administrative position (HR = 12.70, P = 0.045), while independent factors associated with recovery were lower FPG levels (HR = 0.94, P = 0.017), being a white-collar worker (HR = 0.34, P = 0.033), non-smoking (HR = 0.31, P = 0.040) and lower serum alanine aminotransferase (ALT) levels (HR = 0.97, P = 0.042). Conclusions, In addition to FPG levels at baseline, psychosocial factors (night duty, stress and administrative position) are risk factors for Type 2 diabetes, while being a white-collar worker, a non-smoker and lower serum ALT levels are factors associated with return to NGT in Japanese workers with IFG and/or IGT. [source] Levels of transaminases, alkaline phosphatase, and protein in tissues of Clarias gariepienus fingerlings exposed to sublethal concentrations of cadmium chlorideENVIRONMENTAL TOXICOLOGY, Issue 6 2008Babu Velmurugan Abstract The freshwater fish, Clarias gariepienus fingerlings, were exposed to sublethal concentrations (1.7 and 3.4 mg/L) of cadmium chloride for 12 days. Aspartate aminotransferase (AAT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total protein levels were assayed in the gill, brain, and muscle of the fish at regular intervals of 6 and 12 days. The activities of AAT, ALT, and ALP of the treated fishes increased significantly in all the tissues compared with the control fish. Protein level in all the tissues showed a significant decrease in comparison to unexposed controls throughout the experimental periods. These results revealed that cadmium chloride effects the intermediary metabolism of C. gariepienus fingerlings and that the assayed enzymes can work as good biomarkers of contamination. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2008. [source] A gene duplication led to specialized ,-aminobutyrate and ,-alanine aminotransferase in yeastFEBS JOURNAL, Issue 7 2007Gorm Andersen In humans, ,-alanine (BAL) and the neurotransmitter ,-aminobutyrate (GABA) are transaminated by a single aminotransferase enzyme. Apparently, yeast originally also had a single enzyme, but the corresponding gene was duplicated in the Saccharomyces kluyveri lineage. SkUGA1 encodes a homologue of Saccharomyces cerevisiae GABA aminotransferase, and SkPYD4 encodes an enzyme involved in both BAL and GABA transamination. SkPYD4 and SkUGA1 as well as S. cerevisiaeUGA1 and Schizosaccharomyces pombeUGA1 were subcloned, over-expressed and purified. One discontinuous and two continuous coupled assays were used to characterize the substrate specificity and kinetic parameters of the four enzymes. It was found that the cofactor pyridoxal 5,-phosphate is needed for enzymatic activity and ,-ketoglutarate, and not pyruvate, as the amino group acceptor. SkPyd4p preferentially uses BAL as the amino group donor (Vmax/Km = 0.78 U·mg,1·mm,1), but can also use GABA (Vmax/Km = 0.42 U·mg,1·mm,1), while SkUga1p only uses GABA (Vmax/Km = 4.01 U·mg,1·mm,1). SpUga1p and ScUga1p transaminate only GABA and not BAL. While mammals degrade BAL and GABA with only one enzyme, but in different tissues, S. kluyveri and related yeasts have two different genes/enzymes to apparently ,distinguish' between the two reactions in a single cell. It is likely that upon duplication ,200 million years ago, a specialized Uga1p evolved into a ,novel' transaminase enzyme with broader substrate specificity. [source] An animal model of testicular toxicity by cyclosporine: evaluation and protectionFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2009Ridha Ben Ali Abstract CyclosporineA (CsA) improves the survival of patients who benefited from transplantation. However, its use is generally limited by its side effects. The aim of our study was to measure, in an experimental model, the changes of the testosterone plasma levels after 21 days of CsA treatment and to explain the mechanism of this modification. After treatment, the levels of CsA, testosterone, corticosterone, transaminases were measured. The cytotoxic effect of CsA was evaluated by microscopic observation. The experimental study showed that CsA had no effect on the plasmatic levels of hepatic enzymes - alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl-transferase , because their plasma concentrations in treated rats did not differ from those of the sham group. The plasma concentration of corticosterone was not modified, the plasma level of testosterone decreased when the dose of cyclosporine was increased to 4 mg/kg/day. The photonic microscope observation showed that the number of Leydig cells was increased and the electronic microscope observation showed mitochondria alteration. The treatment by CsA and trimetazidine did not correct the alteration caused by CsA. N-benzyl-N'-(2-hydrox-3, 4-dimethyloxybenzyl)-pipeazine did not protect the mitochondrial function but partially protected mitochondria structure from the deleterious effect induced by CsA. The decrease of the plasma level of testosterone induced by CsA was due to the inhibition of the mitochondrial 20,22 desmolase which blocked the formation of the testosterone precursor and the destruction of the mitochondria structure. [source] Efficiency of combined methotrexate/chloroquine therapy in adjuvant-induced arthritisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2005M.A.R.C.P. Silva Abstract The present study evaluates the effects of methotrexate (MTX) and chloroquine (CQ), and of combined MTX + CQ treatment, on the inflammatory response and on plasma and liver phosphatase and transaminase activities, employing an adjuvant-induced arthritis model in rats. Arthritis was induced by the intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil into the plantar surface of the hind paws. Development of the inflammatory response was assessed over a 21-day period. Animal groups received either: (i) MTX, administered i.p., weekly, in 0.15, 1.5, 3, 6 or 12 mg/kg doses; (ii) CQ, given intragastrically, in daily 25 or 50 mg/kg doses; or (iii) MTX + CQ, administered in two combinations (MTX1.5 mg/kg + CQ50 mg/kg, or MTX6 mg/kg + CQ50 mg/kg). At the end of the experimental period, the animals were anesthetized and killed, blood and liver samples were collected and prepared for measurement of acid and alkaline phosphatase (AP, ALP), and aspartate (AST) and alanine aminotransferase (ALT) activities. MTX at 6 and 12 mg/kg reduced the inflammatory response while CQ had no effect. MTX6 mg/kg + CQ50 mg/kg reduced the inflammatory response similar to MTX12 mg/kg, without affecting the bone marrow. Plasma AP and liver ALP activities were very elevated in the arthritic rats. While MTX treatment partially reduced both plasma AP and liver ALP activities at all doses used in the arthritic rats, CQ treatment reduced plasma AP, but increased liver AP activity. MTX + CQ treatment decreased plasma AP and liver ALP activities in the arthritic rats to control values. Plasma and liver AST activities were unaltered in the arthritic rats, and were unaffected by treatment. However, plasma and liver ALT activities were significantly reduced in the arthritic rats. While MTX or CQ treatment did not alter plasma transaminase activity in the arthritic rats, after MTX + CQ treatment, plasma ALT activity returned to normal values. In conclusion, the present data suggest that MTX + CQ treatment provides more effective anti-inflammatory protection against adjuvant-induced arthritis than does MTX alone, reverting the alterations in enzyme activities induced by this inflammatory disease in rats. [source] Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease,,HEPATOLOGY, Issue 5 2010Kausik Das There is a paucity of community-based epidemiological data on nonalcoholic fatty liver (NAFL) among nonaffluent populations in developing countries. Available studies are radiological and/or biochemical and lack histological assessment, limiting their strength. We conducted a prospective epidemiological study comprising a 1:3 subsample of all adult (>18 years) inhabitants of a rural administrative unit of West Bengal, India. Subjects positive for hepatitis B virus and/or hepatitis C virus infection and consuming any amount of alcohol were excluded. Diagnosis of NAFL was by dual radiological screening protocol consisting of ultrasonographic and computed tomographic examination of the liver. Transient elastographic examination and liver biopsy were performed in a subset to identify significant liver disease. The risk factors of having NAFL were analyzed. A total of 1,911 individuals were analyzed, 7% of whom were overweight and 11% of whom had abdominal obesity. The prevalence of NAFL, NAFL with elevated alanine aminotransferase, and cryptogenic cirrhosis was 8.7%, 2.3%, and 0.2%, respectively. Seventy-five percent of NAFL subjects had a body mass index (BMI) <25 kg/m2, and 54% were neither overweight nor had abdominal obesity. The subjects with the highest risk of having NAFL were those with a BMI >25 kg/m2 (odds ratio 4.3, 95% confidence interval 1.6-11.5). Abdominal obesity, dysglycemia (fasting plasma glucose >100 mg/dL or elevated homeostatic model assessment of insulin resistance), and higher income were the other risk factors. Even having a normal BMI (18.5-24.9 kg/m2) was associated with a 2-fold increased risk of NAFL versus those with a BMI <18.5 kg/m2. Conclusion: There is a significant prevalence of NAFL and potentially significant liver disease, including cryptogenic cirrhosis, in this predominantly nonobese, nonaffluent population in a developing country. NAFL will be a major determinant of future liver disease burden in countries of the developing world. (HEPATOLOGY 2010) [source] Variability in the upper limit of normal for serum alanine aminotransferase levels: A statewide study,HEPATOLOGY, Issue 6 2009Anand Dutta We conducted a study to characterize the variability in the upper limit of normal (ULN) for alanine aminotransferase (ALT) across different laboratories (labs) in Indiana and to understand factors leading to such variability. A survey was mailed to all eligible labs (n = 108) in Indiana, and the response rate was 62%. The survey queried for ALT ULN, the type of chemical analyzer used, five College of American Pathologists (CAP) sample results, and methods used to establish the reference interval. There was a wide variability in the ALT ULN for both men and women. Eighty-five percent of labs used chemical analyzers belonging to one of the four brands. For all five CAP samples, there was a statistically significant difference in ALT values measured by different analyzers (P < 0.0001), but these differences were not clinically significant. The majority of labs used the manufacturers' recommendations for establishing their ALT ULN rather than in-house healthy volunteer testing (only 17%). When healthy volunteers were tested, the process for testing was haphazard in terms of the number of individuals tested, frequency of testing, and criteria for choosing the reference population. After controlling for chemical analyzer type, there was no significant relationship between ALT ULN values and the method used for its establishment. Conclusion: Wide variability in ALT ULN across different labs is more likely due to variable reference intervals of different chemical analyzers. It may be possible to minimize variability in ALT ULN by (1) each lab solely following the manufacturers' recommendations and (2) manufacturers of different analyzers following consistent and rigorous methodology in establishing the reference range. Alternatively, studies should be undertaken to identify outcome-based reference intervals for ALT. (HEPATOLOGY 2009.) [source] Impact of pegylated interferon and ribavirin on morbidity and mortality in patients with chronic hepatitis C and normal aminotransferases in France,HEPATOLOGY, Issue 5 2009Sylvie Deuffic-Burban Clinicians continue to raise questions concerning the necessity of treating chronic hepatitis C virus (HCV)-infected patients with normal alanine aminotransferase (N-ALT), in light of their slower progression to cirrhosis than patients with elevated alanine aminotraferase (E-ALT). This study was undertaken to predict the impact of pegylated interferon (IFN) and ribavirin on HCV-related morbidity and mortality in patients with N-ALT. A previous Markov model was adapted to separately simulate patients with N-ALT (30%) and those with E-ALT (70%). The model estimates fibrosis progression rates according to age, sex, and whether ALT levels are normal or elevated, assuming that patients with E-ALT have a 2.6 times higher progression than those with N-ALT. It takes into account improvement in HCV screening and treatment and competitive mortality. We assumed that N-ALT patients were treated 80% less frequently between 2002 and 2004 and 70% less frequently from 2005 on, as obtained in real life from three multicentric cohorts (Hepatys, Adequation, Persee). Antiviral treatment of HCV-infected populations might reduce 2008-2025 HCV-related morbidity and mortality by 34,200 cases of cirrhosis (36%, 33,000-35,000), 22,400 complications (28%, 21,000-23,000) and 17,500 deaths (25%, 17,000-18,000), including 3000 cases of cirrhosis (22%, 2000-5000), 1200 complications (15%, 1000-1700), and 1000 deaths (14%, 900-1300) in the N-ALT population, despite a probability of receiving treatment that is three to five times less in this population. If N-ALT patients are treated at the same proportions as those with E-ALT, morbidity and mortality could be further reduced by 1400 cases of cirrhosis (13%, 1200-2200), 600 complications (9%, 600-1000), and 500 deaths (9%, 500-800). Conclusion: Treatment of N-ALT patients would decrease HCV morbidity and mortality. These patients should be considered candidates for treatment just as others are. (HEPATOLOGY 2009.) [source] Determinants of relapse after a short (12 weeks) course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection,HEPATOLOGY, Issue 2 2009Alessandra Mangia In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24-week course of therapy. RVR patients received pegylated interferon (Peg-IFN) alfa-2b (1.5 ,g/kg) and ribavirin (1000-1200 mg/day) for 12 weeks; those who relapsed were re-treated with the same drug doses but for the extended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (ALT), HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1-85.8) attained SVR, and 67 (14.1%, CI 10.4-16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm3 [odds ratio, 2.51; confidence interval (CI), 1.49-4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03-2.70) were independently associated with relapse. Forty-three of 67 patients with relapse agreed to be re-treated, and an SVR was achieved in 30 (70.0%) of them. Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI. (HEPATOLOGY 2008.) [source] Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy,HEPATOLOGY, Issue 2 2009Patrick Ingiliz Liver damage associated with chronic unexplained high serum transaminases in human immunodeficiency virus (HIV)-infected patients under combined antiretroviral therapy is unknown. Liver histology was prospectively investigated in patients presenting serum transaminase elevation for more than 6 months, after exclusion of alcohol abuse, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, autoimmune, and genetic liver diseases. In a subgroup of patients, liver mitochondrial activities were measured by spectrophotometry and mitochondrial DNA (mtDNA) by real-time polymerase chain reaction (PCR). Thirty patients were included with median values of alanine aminotransferase (ALT) levels: 80 U/L, age: 46 years, body mass index: 23 kg/m2, HIV RNA: 200 copies/mL, CD4 count: 365/mm3, duration of HIV infection: 13 years, and duration of treatment exposure: 118, 41, and 53 months for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Histological anomalies were found in 22 of 30 patients. Steatosis was present in 18 patients, severe in nine patients, and associated with inflammation in 16 patients with a diagnosis of non-alcoholic steatohepatitis (NASH). Fibrosis was found in 18 patients, severe in six patients and associated with steatosis in 13 patients. Significant liver respiratory complex I defect, contrasting with high complex IV activity and normal mitochondrial DNA content, was observed in the group of patients compared with controls. The presence of NASH was correlated with high fasting glycemia and insulin levels, not with liver mitochondrial function or mitochondrial DNA content. Conclusions: HIV-infected patients on combined antiretroviral therapy with chronic transaminase elevation of unknown origin have a high rate of liver lesions, mostly consistent with NASH related to insulin resistance. (HEPATOLOGY 2008.) [source] Treatment recommendations for chronic hepatitis B: An evaluation of current guidelines based on a natural history study in the United States,HEPATOLOGY, Issue 4 2008Myron John Tong Current guidelines for treatment of chronic hepatitis B include hepatitis B e antigen (HBeAg) status, levels of hepatitis B virus (HBV) DNA, and serum alanine aminotransferase (ALT) values in the setting of either chronic hepatitis or cirrhosis. Based on findings from a prospective study of hepatitis B surface antigen (HBsAg)-positive patients, we determined whether these guidelines included patients who developed hepatocellular carcinoma (HCC) and who died of non-HCC liver-related complications. The criteria for treatment from four published guidelines were matched to a cohort of 369 HBsAg-positive patients enrolled in the study. During a mean follow-up of 84 months, 30 patients developed HCC and 37 died of non-HCC liver-related deaths. Using criteria for antiviral therapy as stated by the four guidelines, only 20%-60% of the patients who developed HCC, and 27%-70% of patients who died of non-HCC liver-related deaths would have been identified for antiviral therapy according to current treatment recommendations. If baseline serum albumin levels of 3.5 mg/dL or less or platelet counts of 130,000 mm3 or less were added to criteria from the four treatment guidelines, then 89%-100% of patients who died of non-HCC liver-related complications, and 96%-100% of patients who developed HCC would have been identified for antiviral therapy. In addition, if basal core promoter T1762/A1764 mutants and precore A1896 mutants also were included, then 100% of patients who developed HCC would have been identified for treatment. Conclusion: This retrospective analysis showed that the current treatment guidelines for chronic hepatitis B excluded patients who developed serious liver-related complications. (HEPATOLOGY 2008.) [source] Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen,positive chronic hepatitis B,HEPATOLOGY, Issue 3 2008Patrick Marcellin Treatment of 171 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) with adefovir dipivoxil (ADV) 10 mg over 48 weeks resulted in significant histological, virological, serological, and biochemical improvement compared with placebo. The long-term efficacy and safety of ADV in a subset of these patients was investigated for up to 5 years. Sixty-five patients given ADV 10 mg in year 1 elected to continue in a long-term safety and efficacy study (LTSES). At enrollment, the 65 LTSES patients were a median 34 years old, 83% male, 74% Asian, 23% Caucasian, median baseline serum hepatitis B virus (HBV) DNA 8.45 log10 copies/mL, and median baseline alanine aminotransferase (ALT) 2.0 × upper limit of normal. At 5 years on study, the median changes from baseline in serum HBV DNA and ALT for the 41 patients still on ADV were 4.05 log10 copies/mL and ,50 U/L, respectively. HBeAg loss and seroconversion were observed in 58% and 48% of patients by end of study, respectively. Fifteen patients had baseline and end of follow-up liver biopsies; improvements in necroinflammation and fibrosis were seen in 67% and 60% of these patients, respectively. Adefovir resistance mutations A181V or N236T developed in 13 LTSES patients; the first observation was at study week 195. There were no serious adverse events related to ADV. Conclusion: Treatment with ADV beyond 48 weeks was well tolerated and produced long-term virological, biochemical, serological, and histological improvement. (HEPATOLOGY 2008;48:750,758.) [source] Serum aminotransferase activity and mortality risk in a United States community,HEPATOLOGY, Issue 3 2008Tae Hoon Lee Serum aminotransferase [such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] is commonly used as an indicator of liver disease. The aim of the study was to determine the degree to which aminotransferase results are associated with increased mortality at the population level. All adult residents of Olmsted County, Minnesota, who had a health care encounter at Mayo Clinic, Rochester, in 1995 were identified and their AST or ALT results extracted from a laboratory database. These subjects were followed forward from January 1995 to April 2006 and their survival determined. To exclude patients with abnormal results because of a terminal illness, deaths within the first 2 years were excluded. The main outcome measure was survival. Standardized mortality ratios (SMRs) were calculated, based on Minnesota White death rates. During 1995, AST was measured at least once in 18,401 community residents, of whom 2,350 (13%) had results greater than the upper limit of normal (ULN). Of 6,823 subjects who had their ALT measured, 911 (13%) had results higher than ULN. Abnormal AST was associated with a significantly increased SMR (1.32 for 1,2× ULN and 1.78 for >2× ULN). SMR was also higher for abnormal ALT (SMR = 1.21 for 1,2× ULN and 1.51 for >2× ULN). In contrast, normal AST or ALT was associated with a risk of death lower than expected (SMR 0.95 for AST, 0.61 for ALT). Conclusion: Serum levels of AST and ALT obtained in a routine medical care setting are associated with future mortality in community residents. (HEPATOLOGY 2008;47:880,887.) [source] Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis,HEPATOLOGY, Issue 5 2007Norio Akuta We showed previously that amino acid (aa) substitutions in hepatitis C virus core region (HCV-CR) are negative predictors of virologic response to pegylated interferon (IFN) plus ribavirin therapy. HCV-CR induces hepatocellular carcinoma in transgenic mice, but the clinical impact is still unclear. To evaluate the impact of aa substitutions in HCV-CR on hepatocarcinogenesis, we performed a follow-up study on 313 noncirrhotic consecutive naïve patients infected with HCV genotype 1b who received IFN monotherapy. The median follow-up was 14.7 years. A sustained virologic response (SVR) after the first IFN was achieved by 65 patients (20.8%) (group A). Of 248 patients (79.2%) of non-SVR after first IFN, 112 (35.8%) did not receive additional IFN (group B), and the remaining 136 (43.5%) received multicourse IFN monotherapy (group C). As a whole, cumulative hepatocarcinogenesis rates in double wild-type (arginine at aa 70/leucine at aa 91) of HCV-CR were significantly lower than those in nondouble wild-type. Multivariate analyses identified 3 parameters (fibrosis stage 3, nondouble wild-type of HCV-CR, and group B) that tended to or significantly influenced hepatocarcinogenesis independently. With regard to hepatocarcinogenesis rates in group C according to HCV-CR and the mean alanine aminotransferase (ALT) during IFN-free period, significantly higher rates were noted in patients of nondouble wild-type with ALT levels of more than 1.5 times the upper limit of normal (25.7%) compared with the others (2.4%). Conclusion: Amino acid substitutions in the HCV-CR are the important predictor of hepatocarcinogenesis. In multicourse IFN therapy to nondouble wild-type, we emphasize the importance of reducing the risk of hepatocarcinogenesis by mean ALT during an IFN-free period below 1.5 times the upper limit of normal. (HEPATOLOGY 2007.) [source] Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV,HEPATOLOGY, Issue 4 2006Renate G. van der Molen In patients with chronic hepatitis B virus (HBV), 2 predominant precursor dendritic cell (DC) subtypes, the myeloid dendritic cell (mDC) and the plasmacytoid dendritic cell (pDC), were recently found to be functionally impaired. HBV DNA was found to be present in the DC subtypes, but no viral replication could be detected. The question remains whether simply the presence of the virus and viral proteins causes this dysfunction of DCs. To address this issue, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the number and functionality of circulating DCs was studied during 6 months of treatment. Treatment resulted in a mean 5 log10 decrease in the viral load and normalization of alanine aminotransferase within 3 months. The number of mDCs, but not of pDCs, increased significantly over 6 months of treatment to a level comparable to that of uninfected healthy controls. The allostimulatory capacity of isolated and in vitro matured mDCs increased significantly after 3 months of treatment. Accordingly, mDCs exhibited an increased capacity to produce tumor necrosis factor alpha and interleukin-12 after 3-6 months of treatment. There was no change in interferon alpha production by pDCs during treatment. In conclusion, adefovir treatment results in an improvement in the number and functionality of mDCs, but not of pDCs. Our findings provide clues for the reasons why current antiviral therapy does not lead to consistently sustained viral eradication. (HEPATOLOGY 2006;44:907,914.) [source] Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta,,HEPATOLOGY, Issue 3 2006Grazia Anna Niro Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen- and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 ,g/kg) alone as monotherapy (n = 16) or in combination with ribavirin (n = 22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174 ± 53 to 86 ± 41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor. (HEPATOLOGY 2006;44:713,720.) [source] Adiponectin protects LPS-induced liver injury through modulation of TNF-, in KK-Ay obese miceHEPATOLOGY, Issue 1 2004Takayuki Masaki Adiponectin, an adipocytokine, has been identified in adipose tissue, and its receptors are widely distributed in many tissues, including the liver. The present study was performed to clarify the role of adiponectin in lipopolysaccharide (LPS)-induced liver injury using KK-Ay obese mice. We analyzed the effects of adiponectin pretreatment on liver injury induced by D -galactosamine/LPS (GalN/LPS) in KK-Ay obese mice. GalN/LPS treatment induced significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood, apoptotic and necrotic changes in hepatocytes, and/or showed a high degree of lethality. The GalN/LPS-induced liver injury was more pronounced in KK-Ay obese mice than in lean controls. Pretreatment with adiponectin ameliorated the GalN/LPS-induced elevation of serum AST and ALT levels and the apoptotic and necrotic changes in hepatocytes, resulting in a reduction in lethality. In addition, pretreatment with adiponectin attenuated the GalN/LPS-induced increases in serum and hepatic tumor necrosis factor , (TNF-,) levels and increased peroxisome proliferator-activated receptor (PPAR) , messenger RNA expression in the liver. Furthermore, abdominal macrophages from KK-Ay obese mice pretreated with adiponectin in vitro exhibited decreased LPS-induced TNF-, production compared with controls. Finally, adiponectin pretreatment also ameliorated TNF-,-induced liver injury. In conclusion, these findings suggest that adiponectin prevents LPS-induced hepatic injury by inhibiting the synthesis and/or release of TNF-, of KK-Ay obese mice. (HEPATOLOGY 2004;40:177,184.) [source] The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: Hype or hope?HEPATOLOGY, Issue 1 2004Michael Trauner M.D. Farnesoid X receptor (FXR) is a bile acid,activated transcription factor that is a member of the nuclear hormone receptor superfamily. FXR-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease. [source] Role of V, 14 NKT cells in the development of impaired liver regeneration in vivoHEPATOLOGY, Issue 5 2003Hiroyasu Ito Although we have previously demonstrated that IL-12 stimulation increases the number of hepatic natural killer (NK) T (NKT) cells and enhances liver injury during the early phase of liver regeneration, the role of NKT cells has remained unknown. We therefore evaluated the influence of NKT cells activated by IL-12 or by ,-galactosylceramide (,-GalCer) on murine liver regeneration using V, 14 NKT knockout (J, 281,/,) mice. Levels of serum alanine aminotransferase (sALT) 24 hours after partial hepatectomy were enhanced in J, 281+/+ but not in J, 281,/, mice by both procedures. Hepatic NKT cells expressed considerably more interferon (IFN) , and tumor necrosis factor , (TNF-,) messenger RNA (mRNA) after stimulation with both factors in J, 281+/+ mice. Either anti-IFN-, or TNF-, antibody inhibited the enhancement of liver injury. Furthermore, recombinant TNF-, injection similarly caused injury in hepatectomized livers of both J, 281+/+ and J, 281,/, mice; indeed, adoptively transferred TNF-,+/+ NKT cells enhanced liver injury after hepatectomy in TNF-, knockout mice. TNF receptor expressions on hepatocytes increased and peaked 24 hours after partial hepatectomy. In conclusion, simultaneous TNF-, synthesis and high levels of TNF receptor expression on hepatocytes cause severe liver damage by activated NKT cells during liver regeneration. [source] A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis CHEPATOLOGY, Issue 5 2003Frederik Nevens New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty-five chronic hepatitis C patients (genotype 1) were randomized to receive 20 ,g of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty-four patients (12 men, 12 women; mean age, 52 y; 18 interferon-based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV-RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1-specific T-cell response. The increase in anti-E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P , .01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study. [source] Induction of cellular resistance against Kupffer cell,derived oxidant stress: A novel concept of hepatoprotection by ischemic preconditioningHEPATOLOGY, Issue 2 2003Rolf J. Schauer Ischemic preconditioning (IP) triggers protection of the liver from prolonged subsequent ischemia. However, the underlying protective mechanisms are largely unknown. We investigated whether and how IP protects the liver against reperfusion injury caused by Kupffer cell (KC)-derived oxidants. IP before 90 minutes of warm ischemia of rat livers in vivo significantly reduced serum alanine aminotransferase (AST) levels and leukocyte adherence to sinusoids and postsinusoidal venules during reperfusion. This protective effect was mimicked by postischemic intravenous infusion of glutathione (GSH), an antioxidative strategy against KC-derived H2O2. Interestingly, no additional protection was achieved by infusion of GSH to preconditioned animals. These findings and several additional experiments strongly suggest IP mediated antioxidative effects: IP prevented oxidant cell injury in isolated perfused rat livers after selective KC activation by zymosan. Moreover, IP prevented cell injury and pertubations of the intracellular GSH/GSSG redox system caused by direct infusion of H2O2 (0.5 mmol/L). IP-mediated resistance against H2O2 could neither be blocked by the adenosine A2a antagonist DMPX nor mimicked by A2a agonist CGS21680. In contrast, H2O2 resistance was abolished by the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, but induced when p38 MAPK was directly activated by anisomycin. In conclusion, we propose a novel concept of hepatoprotection by IP: protection of liver cells by enhancing their resistance against KC-derived H2O2. Activation of p38 MAPK and preservation of the intracellular GSH/oxidized glutathione (GSSG) redox system, but not adenosine A2a receptor stimulation, seems to be pivotal for the development of H2O2 resistance in preconditioned livers. [source] Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotectionHEPATOLOGY, Issue 2 2003Xiu-Da Shen Ischemia/reperfusion (I/R) injury remains an important problem in clinical organ transplantation. There is growing evidence that T lymphocytes, and activated CD4+ T cells in particular, play a key role in hepatic I/R injury. This study analyzes the role of signal transducer and activator of transcription 4 (Stat4) and Stat6 signaling in liver I/R injury. Using a partial lobar warm ischemia model, groups of wild-type (WT), T cell,deficient, Stat4-/Stat6-deficient knockout (KO) mice were assessed for the extent/severity of I/R injury. Ninety minutes of warm ischemia followed by 6 hours of reperfusion induced a fulminant liver failure in WT and Stat6 KO mice, as assessed by hepatocellular damage (serum alanine aminotransferase [sALT] levels), neutrophil accumulation (myeloperoxidase [MPO] activity) and histology (Suzuki scores). In contrast, T cell deficiency (nu/nu mice) or disruption of Stat4 signaling (Stat4 KO mice) reduced I/R insult. Unlike adoptive transfer of WT or Stat6-deficient T cells, infusion of Stat4-deficient T cells failed to restore hepatic I/R injury and prevented tumor necrosis factor , (TNF-,) production in nu/nu mice. Diminished TNF-,/Th1-type cytokine messenger RNA (mRNA)/protein elaborations patterns, along with overexpression of heme oxygenase-1 (HO-1),accompanied hepatic cytoprotection in Stat4 KO recipients. In contrast, HO-1 depression restored hepatic injury in otherwise I/R resistant Stat4 KOs. In conclusion, Stat4 signaling is required for, whereas Stat4 disruption protects against, warm hepatic I/R injury in mice. The cytoprotection rendered by Stat4 disruption remains HO-1,dependent. [source] | ||||||||||||||||||||||||||||||||||||||||||||||