Serum Alanine Aminotransaminase Levels Research Articles

Effect of Nutmeg on Transaminase Activities in Liver and Serum of Adult Wistar rats

This study examines the activities of alanine aminotransaminase (ALT) and aspartate aminotransferase (AST) in the liver of 30 adult Wistar rats exposed to nutmeg for 30 days. 1 g of nutmeg was administered to group A (n=10), 2 g of nutmeg to group B (n=10) and group C (n=10) was used as the control. Enzyme activities were assayed in both serum and liver (tissue homogenate) spectrophotometrically. Results obtained showed a significant increase (p < 0.05) in level of AST in serum of rats in group A and B (20.2±7.29 and 23.2 ± 3.27 U/L) when compared to the control group (14.8± 1.78 U/L) while serum ALT level was significantly reduced (5.2± 1.78 and 4.2 ± 0.04 U/L) compared to the control group (7.0 ± 2.6 U/L) but the differences based on dosage was statistically insignificant (p≥ 0.05). The enzyme activities in liver tissue homogenate showed a significant increase (p˂ 0.05) in AST levels (13.8 ± 1.14, 14.6 ± 1.78 and 12.8 ± 0.08 U/L) among test groups and between controls but ALT levels though lower in treated groups than control, was statistically insignificant (p≥ 0.05) among test and between control group (4.6 ± 1.34, 4.0 ± 0.08 and 5.8 ± 0.03 U/L). Differences in enzyme activities due to nutmeg administration may lead to hepatocellular injury as well as myocardial infarction. The results suggests that dosage and long-term consumption of nutmeg could have severe health implication as it affects liver function as well as other associated organ of the body.

The efficacy and tolerability of glecaprevir/pibrentasvir treatment in a real-world chronic hepatitis C patients cohort.

The aims of the present study were to evaluate the real-life efficacy and tolerability of glecaprevir (GLE)/pibrentasvir (PIB) in the treatment of patients with chronic hepatitis C (CHC). Between May 2019 and May 2022, 686 patients with CHC, treated with GLE/PIB combination from 21 participating centers in Turkiye, were enrolled in the study. All patients were Caucasian, and their median age was 56 years. At the start of GLE/PIB treatment, the median serum Hepatitis C virus RNA and serum alanine amino transaminase (ALT) levels were 6.74 log10 IU/mL and 47 U/L, respectively. Fifty-three percent of the patients were infected with genotype 1b, followed by genotype 3 (17%). Diabetes was the more common concomitant disease. The sustained virological response (SVR12) was 91.4% with intent-to-treat analysis and 98.5% with per protocol analysis. The SVR12 rates were statistically significant differences between the patients who were i.v. drug users and non-user (88.0% vs. 98.8%, p=0.025). From the baseline to SVR12, the serum ALT levels and Model for End-Stage Liver Disease score were significantly improved (p<0.001 and p=0.014, respectively). No severe adverse effect was observed. GLE/PIB is an effective and tolerable treatment in patients with CHC.

Association of Serum Cholinesterase and Liver Enzymes with Clinical Severity and Outcomes in Organophosphorus Poisoning

Abstract Background: Organophosphorus (OP) compound poisoning is a medico-toxic emergency that results in multiorgan failure. The primary mechanism of action is by inhibition of acetylcholinesterase, leading to disruption in processes of oxidative stress, apoptosis, and microsomal metabolism resulting in liver toxicity. The present study was conducted to explore the prognostic value of serum cholinesterase in predicting severity of organophosphorous compound poisoning and the need for ventilatory support; and to understand the role of aspartate aminotransaminase (AST), alanine aminotransaminase (ALT) and bilirubin in assessing the severity of acute organophosphate poisoning. Methodology: Hospital-based prospective observational study was conducted among OP poisoning cases at a tertiary hospital in Hubli. Clinical examination was done during the initial resuscitation and treatment of patients. Three milliliter of plain blood was collected on admission before administration of atropine and plasma cholinesterase level, and other biochemical parameters were estimated. Results: Sixty-five percent of poisoning cases had &gt;50% of cholinesterase activity with normal grade poisoning. Moderate and severe grade poisonings were present among 3% and 5% of poisoning cases, respectively. Patients with cholinesterase level activity of ≤50% had significantly higher proportions of respiratory failure (77%) and fatal outcomes (33%). Median levels of AST (Q2: 73.2 IU/mL) and ALT were significantly higher (Q2: 22.7 IU/L) among severe grade poisoning (Che: &lt;10%) compared to other grades of poisoning. Conclusion: The assessment of cholinesterase level activity in OP poisoning would be a useful guide to the physician for planning of intensive care, duration of hospital stay, and clinical prognosis. Serum AST and ALT levels can also contribute as supportive biomarkers to assess the severity, chances of respiratory failure, and clinical outcomes of OP poisoning.

Effect of dehydroepiandrosterone on the liver of perimenopausal rat: multiple doses study

ABSTRACTDehydroepiandrosterone (DHEA) is a widespread nutritional “anti-aging” supplement. Exogenous supplementation of DHEA is now being commonly used to augment ovarian stimulation in perimenopausal women with diminished ovarian reserve. Whether DHEA causes side effects in such age is, however, unknown. Thus, this study investigates the effects of pharmacological doses of DHEA supplementation on the liver of perimenopausal rats. DHEA supplementation to perimenopausal rats resulted in slight hepatomegaly and steatosis, hepatocytic hypertrophy, mitochondrial swelling, elevation in serum alanine aminotransaminase levels, in addition to the accumulation of lipid droplets and lipolysosomes in a dose-dependent manner. In conclusion, long-term administration of high doses of DHEA causes ultrastructural alterations and changes in the levels of cholesterol and triglyceride in hepatocytes of perimenopausal rats. DHEA at a dose of 50 mg/kg improves health and decreases the body weight, with the least side effects on the liver of perimenopausal rats.

Protective Effect of Hexane Extract ofTrachyspermum ammiLinn in Carbon Tetra Chloride-Induced Hepatitis in Rats

Objectives: To evaluate the hepatoprotective activity of hexanolic extract of leaves of Trachyspermum ammi linn were studied against Wister rats with liver damage induced by carbon tetrachloride (CCl4) Methods: The hepatoprotective effect of the hexanolic extract is measured against Wister rats with liver damage induced by carbon tetrachloride (CCl4) through measuring the serum levels of Aspartate aminotransaminase (AST), Alanine aminotransaminase (ALT) and alkaline phosphatase (ALP) and Bilirubin to a significant extent. The hexanolic extract was screened for toxicity by oral toxicity studies according to OECD guidelines 423. LD 50 was calculated for selection of dose. The liver samples were dissected out, blotted off blood, washed with saline and also stored it in 10% formalin and proceeded for histopathology to evaluate the details of hepatic architecture in each group microscopically. Results: Administration of Trachyspermum ammi Linn (Dose 250mg/kg, 500mg/kg s.c) significantly prevented carbon tetrachloride induced elevation of serum ALT, AST, ALP and bilirubin level. Histological examination of the liver section revealed hepatic regeneration, after administration of various doses of Trachyspermum ammi Linn. Conclusion: The hexanolic extracts of leaves of Trachyspermum ammi linn showed significant decrease in the levels of serum markers, indicating the protection of hepatic cells, the extract of root of the plant could afford significant dose-dependent protection against CCl4 induced hepatocellular injury.

Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation.

To assessed the clinical significance of protocol liver biopsy (PLB) in pediatric liver transplantation (LT). Between July 2008 and August 2012, 89 and 55 PLBs were performed in pediatric patients at two and five years after LT, respectively. We assessed the histopathological findings using the Metavir scoring system, including activity (A) and fibrosis (F), and we identified factors associated with scores of ≥ A1 and ≥ F1. Our results clarified the timing and effectiveness of PLB. The incidences of scores of ≥ A1 and ≥ F1 were 24.7% and 24.7%, respectively, at two years after LT and 42.3% and 34.5%, respectively, at five years. Independent risk factors in a multivariate analysis of a score of ≥ A1 at two years included ≥ 2 h of cold ischemic time, no acute cellular rejection and an alanine amino transaminase (ALT) level of ≥ 20 IU/L (P = 0.028, P = 0.033 and P = 0.012, respectively); however, no risk factors were identified for a score of ≥ F1. Furthermore, no independent risk factors associated with scores of ≥ A1 and ≥ F1 at five years were identified using multivariate analysis. A ROC curve analysis of ALT at two years for a score of ≥ A1 demonstrated the recommended cutoff value for diagnosing ≥ A1 histology to be 20 IU/L. The incidence of scores of ≥ A2 or ≥ F2 at two years after LT was 3.4% (three cases), and all patients had an absolute score of ≥ A2. In contrast to that observed for PLBs at five years after LT, the incidence of scores of ≥ A2 or ≥ F2 was 20.0% (11 cases), and all patients had an absolute score of ≥ F2. In all cases, the dose of immunosuppressants was increased after the PLB, and all ten patients who underwent a follow-up liver biopsy improved to scores of ≤ A1 or F1. PLB at two years after LT is an unnecessary examination, because the serum ALT level reflects portal inflammation. In addition, immunosuppressive therapy should be modulated to maintain the ALT concentration at a level less than 20 IU/L. PLB at five years is an excellent examination for the detection of early reversible graft fibrosis because no serum markers reflect this finding.

Virological Response and Muscular Adverse Events during Long-Term Clevudine Therapy in Chronic Hepatitis B Patients

BackgroundRecently, several reports issued clevudine induced myopathy in the long term use.ObjectivesThe aim of this study was to investigate antiviral effects and adverse events of clevudine monotherapy in patients with chronic hepatitis B (CHB).Patients and MethodsThe subjects were 110 treatment-naïve CHB patients. They were treated with 30 mg clevudine/day for more than six months. Virological and biochemical tests, including that for serum creatine kinase (CK), were monitored at baseline and at 3-month intervals during treatment period.ResultsIn HBeAg-positive patients, the cumulative rates of virological response were 74.0 %, 68.5 %, and 67.3 % after one, two, and three years of clevudine treatment, respectively. Cumulative rates of HBeAg loss or seroconversion were 17.8 %, 30 %, and 31.5 % after one, two and, three years of clevudine treatment, respectively. In HBeAg-negative patients, the cumulative rates of virological response were 97.3 %, 100 %, and 94.6 %, respectively. Virological breakthrough occurred in 27 patients. The rtM204I mutation in HBV polymerase was predominantly detected. Muscular adverse events were observed in 15 patients. All patients with myopathy recovered after the cessation of clevudine monotherapy. Fluctuations in CK level during the clevudine treatment period were frequently observed irrespective of development of myopathy. Multiple episodes of CK elevation were significantly related to the development of myopathy.ConclusionsLong-term clevudine monotherapy is effective for suppression of serum HBV DNA level and normalization of serum alanine amino transaminase levels, but associated with occurrence of rtM204I mutation. Clevudine-induced muscular adverse events are not uncommon, although they are totally reversible after cessation of the treatment. Muscular adverse events and serum CK level should be carefully monitored during long-term treatment with clevudine.

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

More than 350 million people are chronically infected with hepatitis B virus, and dysfunctional T cell responses contribute to persistent viral infection and immunopathogenesis in chronic hepatitis B (CHB). However, the underlying mechanisms of T cell hyporesponsiveness remain largely undefined. Given the important role of microRNA-146a (miR-146a) in diverse aspects of lymphocyte function, we investigated the potential role and mechanism of miR-146a in regulating T cell immune responses in CHB. We found that miR-146a expression in T cells is significantly upregulated in CHB compared with healthy controls, and miR-146a levels were correlated with serum alanine aminotransaminase levels. Both inflammatory cytokines and viral factors led to miR-146a upregulation in T cells. Stat1 was identified as a miR-146a target that is involved in antiviral cytokine production and the cytotoxicity of CD4(+) and CD8(+) T cells. In vitro blockage of miR-146a in T cells in CHB greatly enhanced virus-specific T cell activity. Therefore, our work demonstrates that miR-146a upregulation in CHB causes impaired T cell function, which may contribute to immune defects and immunopathogenesis during chronic viral infection.

Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C

Dysfunctional hepatitis C virus (HCV) specific CD4(+) T cells are known to contribute to inadequate adaptive immunity in chronic hepatitis C (CHC), although the underlying mechanisms remain largely undefined. In this study, OX40 ligand (OX40L) expression was investigated in 41 treatment-naïve CHC patients, 20 sustained virological responders and 36 healthy subjects. We observed that OX40L expression was significantly upregulated in peripheral monocytes in CHC patients compared with sustained virological responders and healthy subjects. OX40L upregulation correlated significantly with plasma viral load rather than serum alanine aminotransaminase levels. Furthermore, longitudinal analyses indicated that upregulated OX40L expression on monocytes is closely associated with rapid or early virological responses in patients receiving pegylated IFN-α/ribavirin treatment. In vitro, HCV core antigen strongly stimulated monocyte expression of OX40L and blockade of TLR2 signaling significantly downregulated OX40L expression. More importantly, elevated OX40L expression was also shown to be closely associated with elevation of the HCV-specific CD4(+) T-cell response and in vitro blockade of OX40L expressed on monocytes led to impaired CD4(+) T-cell function. These findings, therefore, implicate OX40L expression can be used as a marker to evaluate antiviral treatment efficacy and extend the notion that enhancement of OX40L expression could be a good way for immunotherapy in CHC patients.

First National Report on Aminotransaminases` Percentiles in Children of the Middle East and North Africa (MENA): the CASPIAN-III Study

BackgroundBy the current global obesogenic environment, non-alcoholic fatty liver disease is becoming an important health problem in the pediatric age group.ObjectivesThis study aimed to determine the first age-and gender-specific percentiles and upper limit normal limit (ULN) of alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) among a nationally-representative sample of children and adolescents in the Middle East and North Africa (MENA). The second objective was to determine the linear association of obesity indexes and age with serum ALT and AST levels.Patients and MethodsThis nationwide study was conducted among a representative sample of 4078 students aged 10-18 years, who were selected by multistage random cluster sampling from 27 provinces of Iran. ALT and AST were measured on fresh sera. Body mass index (BMI) was calculated as an index of generalized obesity, and waist- to- height ratio (WHtR) as an index of abdominal obesity. The age- and gender-specific percentiles of ALT and AST were constructed, and the 95th percentile of each enzyme was considered as the ULN. Gender-specific linear regression analysis was employed to examine the association of BMI or WHtR with the levels of ALT and AST.ResultsData of ALT and AST were available for 4078 (2038 girls) and 4150 (2061 girls),respectively. Participants had a mean (SD) age of 14.71 (2.41).The ULN of ALT for boys, girls,and the total individuals were 36.00; 38.00; and, 37.00 U/L, respectively. In both genders, ALT and AST had linear association with age. The association with BMI was significant for ALT in both genders and for AST only in boys, the association of ALT with WHtR was significant in both genders; the corresponding figures were not significant for AST.ConclusionsThe findings of the current study confirmed the current ULN value of 40 U/L commonly used for the pediatric age group. The linear association of indexes for generalized and abdominal obesity with ALT underscores the importance of timely prevention and control of childhood obesity.

Matrix metalloproteinase-9 contributes to parenchymal hemorrhage and necrosis in the remnant liver after extended hepatectomy in mice

To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse. Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor. We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver. Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.

L-Tryptophan-mediated Enhancement of Susceptibility to Nonalcoholic Fatty Liver Disease Is Dependent on the Mammalian Target of Rapamycin

Nonalcoholic fatty liver disease is one of the most common liver diseases. l-Tryptophan and its metabolite serotonin are involved in hepatic lipid metabolism and inflammation. However, it is unclear whether l-tryptophan promotes hepatic steatosis. To explore this issue, we examined the role of l-tryptophan in mouse hepatic steatosis by using a high fat and high fructose diet (HFHFD) model. l-Tryptophan treatment in combination with an HFHFD exacerbated hepatic steatosis, expression of HNE-modified proteins, hydroxyproline content, and serum alanine aminotransaminase levels, whereas l-tryptophan alone did not result in these effects. We also found that l-tryptophan treatment increases serum serotonin levels. The introduction of adenoviral aromatic amino acid decarboxylase, which stimulates the serotonin synthesis from l-tryptophan, aggravated hepatic steatosis induced by the HFHFD. The fatty acid-induced accumulation of lipid was further increased by serotonin treatment in cultured hepatocytes. These results suggest that l-tryptophan increases the sensitivity to hepatic steatosis through serotonin production. Furthermore, l-tryptophan treatment, adenoviral AADC introduction, and serotonin treatment induced phosphorylation of the mammalian target of rapamycin (mTOR), and a potent mTOR inhibitor rapamycin attenuated hepatocyte lipid accumulation induced by fatty acid with serotonin. These results suggest the importance of mTOR activation for the exacerbation of hepatic steatosis. In conclusion, l-tryptophan exacerbates hepatic steatosis induced by HFHFD through serotonin-mediated activation of mTOR.

Down-regulation of Z39Ig on macrophages by IFN-γ in patients with chronic HBV infection

Co-inhibitory signals from the B7 superfamily have been demonstrated to induce T cell dysfunction in chronic HBV infection (CHB). However, the expression and function of Z39Ig, a new inhibitor of the B7 superfamily, is still unclear in CHB. Here immunohistochemical staining showed that Z39Ig was restricted to macrophages and that its level was decreased significantly in CHB patients compared to healthy controls. Moreover, reduced Z39Ig expression was positively correlated with plasma HBV load but was inversely related to serum alanine aminotransaminase levels. Further, Z39Ig mRNA had a negative relation to IFN-gamma in vivo, and IFN-gamma also down-regulated Z39Ig expression on monocyte-derived macrophages (MDMs) in a time- and dose-dependent manner in vitro. Interestingly, Z39Ig expression on MDMs was restored when IFN-gamma neutralizing antibodies were added to the T cell/MDM co-culture system, indicating that the IFN-gamma derived from activated-T cells may contribute to the reduction of Z39Ig in the CHB environment. Our results suggest that T cells can opposite T cell hyporesponsiveness through dampening Z39Ig inhibitory signals from macrophages and thus maintain their anti-viral function in CHB. Therefore, decreasing Z39Ig signals from macrophages could contribute to CHB clinical therapy.

Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample

It is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these associations. The aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context. We analyzed data from the population-based Study of Health in Pomerania. We used data from 3863 subjects (1971 women) aged 20-79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays. Hyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption. Our data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.

Treatment of hepatitis B e antigen-negative patients

Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) occurs at the late phase in hepatitis B virus (HBV) infection's natural history. The disease is characterized by progressive liver damage due to variants with mutations in the precore/core promoter region that reduce or abolish HBeAg expression. Chronic HBeAg-negative disease's prognosis is poor, with only rare incidences of spontaneous remission. Recent studies in Europe, Asia, and the United States all have reported an increased prevalence of HBeAg-negative and a decreased prevalence of HBeAg-positive chronic hepatitis; this may be related to increased awareness, decrease in new HBV infections, and aging of existing carriers. The end point of therapy for HBeAg-negative CHB patients is difficult to assess. In most studies, HBV DNA suppression and normalization of serum alanine aminotransaminase levels have been used to indicate therapeutic response. Six drugs currently are licensed for the treatment of CHB infection. These are the immunomodulatory agents (conventional interferon-alpha-2b and pegylated interferon-alpha-2a) and the nucleoside/nucleotide analogues (lamivudine, adefovir dipivoxil, entecavir, and telbivudine). Sustained treatment response rates generally are poor due to the high probability of relapse, particularly following nucleoside/nucleotide analogue therapy. As not all patients can tolerate or will respond to interferon-based therapy, maintenance therapy with nucleoside/nucleotide therapy is the alternative. However, this latter approach can lead to development of viral resistance and long-term safety concerns.

Effects of granulocyte colony stimulating-factor in a rat model of acute liver injury

Background/aim Controversial experimental observations suggest that granulocyte colony stimulating-factor may promote hepatic regeneration after hepatectomy and chemical injury either by directly stimulating adult liver cells or facilitating the mobilization of bone marrow cells and their homing to the liver. We investigated whether different schedules of granulocyte colony stimulating-factor administration protect against experimental acute liver injury. Methods Acute liver injury was induced in Sprague-Dawley fed rats by injecting a single intraperitoneal dose of carbon tetrachloride. Recombinant human granulocyte colony stimulating-factor or vehicle was given daily after intoxication (4 days) or before (7 days) and after carbon tetrachloride administration. Liver injury and regeneration were assessed 2 and 4 days after damage. Bone marrow cells mobilization was evaluated by the white blood cell count and the assessment of circulating clonogenic haematopoietic progenitors (colony forming unit-cells). Results In this experimental model, although granulocyte colony stimulating-factor induced the significant mobilization of colony forming unit-cells, the study cytokine had no effect on liver injury (serum alanine amino transaminase level and necrotic index) and liver regeneration (mitotic index and bromodeoxyuridine incorporation), regardless of the administration schedule. Conclusions This study does not support the conclusion that: (1) granulocyte colony stimulating-factor exerts a protective effect against toxic-induced, non-lethal acute liver injury and (2) promotes hepatocyte regeneration.

B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B

Although dysfunctional dendritic cells contribute to inadequate adaptive immunity in chronic hepatitis B (CHB), underlying molecular mechanisms remain largely undefined. In this study, we examined B7-H1 expression on circulating myeloid dendritic cells (mDCs) in 46 CHB patients, 10 autoimmune hepatitis patients, and 10 healthy subjects as control. We found that B7-H1 expression is significantly up-regulated on circulating mDCs of CHB and autoimmune hepatitis patients compared with healthy individuals. The B7-H1 up-regulation was significantly correlated with an elevation of serum alanine aminotransaminase levels and plasma viral load. In addition, in vitro, both IFN-alpha and IFN-gamma could strongly stimulate mDCs to express B7-H1. More importantly, elevated B7-H1 expression is also closely associated with the suppression of T cell immune function. In vitro blockade of B7-H1 signaling could not only down-regulate IL-10 and up-regulate IL-12 production by mDCs, but also enhance mDC-mediated allostimulatory capacity and cytokine production of T cells. Blockade of B7-H1 signaling could improve hepatitis B c Ag-pulsed monocyte-derived DC-induced IFN-gamma production by autologous hepatitis B virus-specific T cells. These new findings suggested that chronic inflammation may contribute to B7-H1 up-regulation on mDCs in CHB patients, which potentially cause defective hepatitis B virus-specific T cell function and viral persistence. Our findings further support the notion that the blockade of B7-H1 may represent a novel therapeutic approach for this disease.

Kinetics and Risk of De Novo Hepatitis B Infection in HBsAg–Negative Patients Undergoing Cytotoxic Chemotherapy

De novo hepatitis B virus (HBV)-related hepatitis after chemotherapy results in high morbidity and mortality. We evaluate the clinical course of de novo HBV-related hepatitis after chemotherapy. Two hundred forty-four consecutive hepatitis B surface antigen (HBsAg)-negative lymphoma patients treated with chemotherapy were followed up for a median of 12.4 (range, 0.1-65.0) months. Serially collected serum samples were analyzed for hepatitis, serum HBV DNA, and HBsAg seroreversion. Eight of the 244 patients (3.3%) developed de novo HBV-related hepatitis. A 100-fold increase in serum HBV DNA preceded de novo HBV-related hepatitis by a median of 18.5 (range, 12-28) weeks. All 8 patients had normal serum alanine aminotransaminase level when the 100-fold increase in serum HBV DNA occurred. Patients with de novo HBV-related hepatitis were more likely to have occult HBV infection before chemotherapy. Direct sequencing results showed that these 8 patients had de novo HBV-related hepatitis from reactivation of occult HBV infection. Three of the 8 patients with de novo HBV-related hepatitis compared with 6 of the 236 patients without de novo HBV-related hepatitis developed fulminant hepatic failure (37.5% vs 2.5%, respectively, P < .001). On multivariate Cox analysis, de novo HBV-related hepatitis was independently associated with a higher risk of fulminant hepatic failure (relative risk, 29.854; 95% confidence interval: 4.844-183.980; P < .001). Close surveillance for a 100-fold increase in HBV DNA is recommended for HBsAg-negative patients treated with chemotherapy so that early commencement of antiviral therapy can be initiated before the occurrence of de novo HBV-related hepatitis.

ENOS Gene Therapy Exacerbates Hepatic Ischemia-Reperfusion Injury in Diabetes

Previous studies indicate that endothelial nitric oxide synthase (eNOS) function is impaired in diabetes as a result of increased vascular generation of reactive oxygen species. We hypothesized that eNOS gene therapy would augment NO. bioavailability and protect against hepatic ischemia-reperfusion (I-R) injury in type 2 diabetes mellitus. We developed a transgenic (Tg) diabetic mouse in which eNOS is systemically overexpressed. We also examined the effects of hepatic eNOS adenovirus therapy in diabetic mice. Diabetic (db/db) and nondiabetic mice were subjected to hepatic I-R injury. In nondiabetic mice, genetic overexpression of eNOS (both eNOS-Tg and eNOS adenovirus) resulted in hepatoprotection. In contrast, hepatic I-R injury was significantly increased in the db/db eNOS-Tg mouse, as serum alanine aminotransaminase (ALT) levels were increased by 3.3-fold compared with diabetic controls. Similarly, eNOS adenovirus treatment resulted in a 3.2-fold increase in serum ALT levels as compared with diabetic controls. We determined that hepatic eNOS was dysfunctional in the db/db mouse and increased genetic expression of eNOS resulted in greater production of peroxynitrite. Treatment with the eNOS cofactor tetrahydrobiopterin (BH4) or the BH4 precursor sepiapterin resulted in a significant decrease in serum ALT levels following I-R injury. We present clear examples of the protective and injurious nature of NO. therapy in I-R. Our data indicate that eNOS exists in an "uncoupled" state in the setting of diabetes and that "recoupling" of the eNOS enzyme with cofactor therapy is beneficial.

495 Viral load is a strong predictor of hepatocellular carcinoma risk in people chronically infected with hepatitis B virus and with normal serum alanine aminotransaminase level

495 Viral load is a strong predictor of hepatocellular carcinoma risk in people chronically infected with hepatitis B virus and with normal serum alanine aminotransaminase level