Lower Serum Alanine Aminotransferase Research Articles

Dietary restriction in moderately obese rats improves body size and glucose handling without the renal and hepatic alterations observed with a high-protein diet.

Obesity is increasing worldwide, and high-protein (HP) diets are widely used for weight loss. However, the overall safety of HP diets is not well established in obese individuals, who make up a significant proportion of the population. To evaluate the health effects of an HP diet in obesity, obesity-prone (OP) Sprague-Dawley rats were given high-fat diets for 12 weeks to induce obesity. Following this, for 8 more weeks, these rats were given either a normal-protein (NP) (15% of energy) or an HP (35% of energy) diet ad libitum, or the NP diet at a restricted level to achieve body weights similar to those of the HP group (pair-weighted (PW) group). Obesity-resistant (OR) control rats were also given the NP diet throughout the feeding period. The HP-OP group had higher food intake but lower body weight, improved glucose handling, and lowered serum haptoglobin compared with the NP-OP group. These benefits were also observed in PW-OP rats. In addition, PW-OP rats had less fat accumulation when compared with NP-OP rats, and an improved Lee index, lower liver size, and lower serum alanine aminotransferase when compared with HP-OP rats. On the other hand, kidney size, proteinuria, and serum homocysteine were increased in HP-OP rats compared with NP-OP rats, whereas PW-OP rats did not experience these effects. These results indicate that in obese rats, more benefits are obtained via dietary restriction with an NP diet and without some of the potentially detrimental effects of an HP diet.

Therapeutic efficacy of splenectomy is attenuated by necroinflammation of the liver in patients with liver cirrhosis.

Splenectomy is a therapy for thrombocytopenia caused by hypersplenism with liver cirrhosis. However, the determinant of therapeutic outcomes for this complication has not yet been fully clarified. We studied the laboratory findings of 55 patients who underwent splenectomy for hypersplenism with liver cirrhosis. In addition, we examined the histopathological findings of hepatosplenic tissues of nine patients who underwent hepatectomy for hepatocellular carcinoma and splenectomy for hypersplenism with liver cirrhosis on one stage surgery. The locations of platelets in hepatosplenic tissues were identified by immunohistochemistry. We used monoclonal antibody against CD41. Among 55 patients, 40 patients had high serum alanine aminotransferase (ALT) level (≧38 IU/l). Blood platelet count after splenectomy of patients with high serum ALT level were significantly lower than those of patients with low serum ALT level (P = 0.02). Histopathologically, platelet area of the liver tissues was positively correlated with hepatic inflammation (P = 0.02). Platelet area of the liver tissues was negatively correlated with blood platelet count after splenectomy (P = 0.03). Hepatic inflammation contributes to the accumulation of platelets in liver; therefore, in patients with high serum ALT level, improvement of thrombocytopenia by the elimination of hypersplenism was limited.

Glucagon-Like Peptide 2 Improves Cholestasis in Parenteral Nutrition--Associated Liver Disease.

Parenteral nutrition-associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon-like peptide-2 (GLP-2) is being advanced as therapy, the effect of GLP-2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP-2 administration on hepatic function in a neonatal piglet model of PNALD. Neonatal piglets (aged 2-6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP-2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age-matched sow-reared control piglets (group 3, n = 8) were used for comparison. Both groups 1 and 2 receiving PN developed cholestasis relative to sow-reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 µL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 µmol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens. The exogenous administration of GLP-2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP-2 in improving PNALD in the setting of prolonged PN duration.

A new model for predicting liver cirrhosis in chronic hepatitis B virus carriers with low serum alanine transaminase activity

To develop a cirrhosis-predicted model in chronic hepatitis B virus carriers with alanine transarninase (ALT) less than two times the upper limit of normal (ULN). Treatment-naive patients (n=278), who had undergone liver biopsies, were randomly divided into two groups - a training group and a validation group. Thirteen bio-clinical parameters were analyzed. A liver cirrhosis-predicting model (PPT model) was constructed using multivariate analysis. The diagnostic value of the model was analyzed by the receiving operating characteristics (ROC) method and compared with other available models. A PPT model to predict liver cirrhosis was derived from three independent predictors of liver fibrosis [platelet count (PLT), prothrombin time (PT) and total bile acid (TBA)]. PPT model predicted cirrhosis with an area under the ROC (AUROC) curve of 0.83, a positive predictive value of 86.7% and a negative predictive value of 95.2%. Compared with APRI, FIB-4, age-AST model, AP index and APGA model, PPT model had the highest correlation coefficient (r=0.49) and greater predictive performance (AUROC of 0.83). The PPT model was accurate in predicting cirrhosis and may reduce the need for liver biopsy in chronic hepatitis B virus carriers with ALT less than two times ULN.

Distribution and clinical correlates of viral and host genotypes in Chinese patients with chronic hepatitis C virus infection

Background and AimChronic hepatitis C virus (HCV) infection is relatively frequent in China. This study investigated the clinical, demographic, and viral and host genetic characteristics that may influence disease manifestations and clinical management.MethodsIn this cross-sectional observational study, treatment-naïve Han ethnic adults with recently confirmed chronic HCV infection were enrolled at 28 hospitals across China. HCV genotype and host interleukin 28B (IL28B) genotypes were determined and compared with patient demographic parameters and medical status.ResultsAmong the 997 HCV-positive patients analyzed, 56.8% were infected with HCV genotype 1b, followed in prevalence by genotypes 2, 3, and 6, with substantial regional variation. Overall, 84.1% of patients were IL28B genotype CC (rs12979860), with little regional variation. Cirrhosis was reported in 10.1% of patients and was significantly associated with hepatitis B virus coinfection, low HCV viral load, low serum alanine aminotransferase, high serum aspartate aminotransferase, diabetes, and high pickled food consumption. Medical procedures were common transmission risk factors; however, lifestyle-associated risk factors, including intravenous drug abuse and tattoos or piercings, were more common in patients with HCV genotype 3 or 6.ConclusionsMost HCV-infected Han Chinese patients were IL28B genotype CC (rs12979860). HCV genotypes varied by geographic region, and disease characteristics differed according to HCV genotype. Relatively frequent detection of advanced liver disease may reflect limitations on access to antiviral therapy, and suggests that greater awareness of factors that influence HCV-associated disease may help avoid clinical complications and improve patient outcomes.

Effects of Antibacterial Peptide Extracted from Bacillus subtilis fmbJ on the Growth, Physiological Response and Disease Resistance of Megalobrama amblycephala

The effects of an antibacterial peptide obtained from Bacillus subtilis fmbJ on growth, serum lysozyme complements 3 and 4, total protein content, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total antioxidative capacity, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and disease resistance of Wuchang bream (Megalobrama amblycephala) were examined. Fish were randomly divided into five groups: a control group which was fed a basic diet, and four groups fed the basic diet supplemented with 0.1%, 0.2%, 0.4%, or 0.8% antibacterial peptide. At eight weeks, M. amblycephala fed the diet containing 0.2% antibacterial peptide had higher serum lysozyme activity, complement 3 and 4 contents, and SOD activity than the control fish, but lower serum MDA content and AST activity. Fish fed the 0.4% diet had higher weight gain rate, serum lysozyme activity, complement 4 content, total antioxidative capacity, and total protein than the control, and lower serum ALT activity. Feed conversion ratios of fish fed the 0.2% or 0.4% diets were lower than those of control fish. Artificial infection with Aeromonas hydrophila resulted in 93% cumulative mortality in the control group, and 61-84% in the groups fed the 0.2% or 0.4% diets. The present study suggests that feed supplementation with 0.2-0.4% antibacterial peptides can stimulate immunity, increase resistance to pathogenic infection, and promote growth in M. amblycephala.

Role of interleukin 28-B in the spontaneous and treatment-related clearance of HCV infection in patients with chronic HBV/HCV dual infection

The purpose of this investigation was to evaluate the role of IL28-B polymorphism in the clearance of hepatitis C virus (HCV) in chronic hepatitis B virus (HBV)/HCV coinfection during a long-term follow-up. Thirty-four consecutive patients with HBV surface antigen (HBsAg)-positive/anti-HCV-positive chronic hepatitis were retrospectively enrolled at their first liver biopsy (LB). For all patients, a documented clinical, serological and virological follow-up of at least 3 years (range 3-16 years) after LB and a sample of whole blood for genetic evaluation were available. Of the 24 patients with detectable serum HBV-DNA and HCV-RNA at their first observation, three cleared both HBV-DNA and HCV-RNA, 12 HCV-RNA and five HBV-DNA. Of the seven HBV DNA-positive/HCV RNA-negative patients at enrolment, three cleared HBV-DNA and one remained HBV DNA-positive and became HCV RNA-positive. All three HBV DNA-negative/HCV RNA-positive patients remained unchanged. Compared with the 12 patients with HCV persistence, the 15 patients who cleared HCV were younger, had lower serum alanine aminotransferase (ALT), HCV load, and histological activity index (HAI) and fibrosis score, more frequently had IL28-B CC variant, had been receiving an interferon-based treatment and less frequently cleared serum HBV-DNA. To investigate the relationship between the IL28-B variants and clearance of HCV, excluding the confounding effect of interferon-based treatment, the Mantel-Haenszel test was used, which indicated an association between HCV clearance and IL28-B variants (p = 0.009). In chronic HBV/HCV coinfection, a long-term follow-up showed a frequent spontaneous or treatment-related clearance of active replication of one or both viruses and identified the IL28-B CC genotype as an independent predictor of HCV clearance.

The association of low serum alanine aminotransferase activity with mortality in the US population.

Elevated alanine aminotransferase (ALT) activity, an important marker of liver injury, has been associated inconsistently with higher mortality. We evaluated whether persons with nonelevated ALT levels are the most appropriate comparison group by examining the relationships of low ALT with mortality and body composition in the US National Health and Nutrition Examination Survey (NHANES). In NHANES 1988-1994, the mortality risk of persons in ALT deciles 1, 2, 3, and 10 was compared with that of persons in deciles 4-9 (mortality was relatively flat across these deciles) over an 18-year period (through 2006) among 14,950 viral-hepatitis-negative adults. In NHANES 1999-2006, low ALT was evaluated in association with dual-energy x-ray absorptiometry body composition measures among 15,028 adults. Multivariate-adjusted mortality was higher for decile 1 (hazard ratio (HR) = 1.42, 95% confidence interval (CI): 1.24, 1.63), decile 2 (HR = 1.27, 95% CI: 1.06, 1.53), and decile 3 (HR = 1.25, 95% CI: 1.04, 1.50) and nonsignificantly higher for decile 10 (HR = 1.21, 95% CI: 0.91, 1.61) than for deciles 4-9. Adjusted appendicular lean mass was decreased among the lowest ALT deciles. In the US population, low ALT was associated with higher mortality risk, possibly attributable to decreased appendicular lean mass. For mortality studies of elevated ALT levels, the most appropriate comparison group is persons in the middle range of ALT rather than all persons with nonelevated ALT.

The Effect of Aging on Acetaminophen Pharmacokinetics, Toxicity and Nrf2 in Fischer 344 Rats

We investigated the effect of aging on hepatic pharmacokinetics and the degree of hepatotoxicity following a toxic dose of acetaminophen. Young and old male Fischer 344 rats were treated with 800 mg/kg acetaminophen (young n = 8, old n = 5) or saline (young n = 9, old n = 9). Serum measurements showed old rats treated with acetaminophen had significantly lower serum alanine aminotransferase and higher acetaminophen and acetaminophen glucuronide levels and creatinine, compared with acetaminophen treated young rats (p < .05). Immunoblotting and activity assays showed old saline-treated rats had twofold lower cytochrome P450 2E1 activity and threefold higher NAD(P)H quinone oxireductase 1 protein expression and activity than young saline-treated rats (p < .05), although Nrf2, glutathione cysteine ligase-modulatory subunit, glutathione cysteine ligase-catalytic subunit, and cytochrome P450 2E1 protein expressions were unchanged. Primary hepatocytes isolated from young rats treated with 10 mM acetaminophen had lower survival than those from old rats (52.4% ± 5.8%, young; 83.6% ± 1.7%, old, p < .05). The pharmacokinetic changes described may decrease susceptibility to acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age.

IL-33 induces nuocytes and modulates liver injury in viral hepatitis (P6112)

Abstract Our aim was to investigate the role of IL-33, the damage-associated molecular pattern (DAMP) molecule, in acute viral hepatitis. C57BL/6 mice were i.v. infected with a recombinant adenovirus. IL-33 and its receptor ST2 expression increased steadily in the liver in the first week of the infection. Treatment of exogenous IL-33 resulted in a great decrease in the serum alanine aminotransferase (ALT) levels and the number of Councilman bodies. Attenuated liver injury by IL-33 correlated with an increase in T regulatory (Treg) cells but with a decrease in macrophages, dendritic cells and NK cells in the liver. IL-33 enhanced both type 1 (IL-2, IFN-γ) and type 2 (IL-5, IL-13) immune responses in infected mice. However, IL-33 inhibited TNF-α in hepatic T cells and macrophages, and significantly reduced TNF-α levels in the liver. In addition to direct effects of IL-33, we found that IL-33 strongly induced nuocytes in the liver and spleen of infected mice. When co-cultured with nuocytes, hepatic T cells and macrophages expressed lower levels of TNF-α. In addition, the adoptive transfer of nuocytes led to lower serum ALT levels in the Ad-infected recipient mice. In conclusion, this study reveals that IL-33 acts as a potent immune stimulator and a hepatoprotective cytokine in acute viral hepatitis. Its direct immunoregulatory functions and ability to induce nuocytes further suggest to us that it may be a potentially promising therapeutic candidate for the management of viral hepatitis.

805 Knockout of SULF2 Significantly Ameliorates Hypercholesterolemia, Steatohepatitis and Liver Fibrosis in Obese Mice Fed a Fast Food Diet

Background: Nonalcoholic fatty liver disease (NAFLD), an important consequence of metabolic disorders such as obesity and type 2 diabetes (T2DM), has become highly prevalent in the US, and is now an important public health concern. Recent reports have identified the heparan sulfate degrading endosulfatase sulfatase 2 (Sulf2) as a suppressor of triglyceriderich lipoprotein (TRL) remnant clearance by hepatocytes in T2DM mice, thus enhancing postprandial hypertriglyceridemia. Further, inhibition of Sulf2 normalized the VLDL-binding capacity of hepatocytes from T2DM mice and abolished postprandial hypertriglyceridemia. We hypothesized that an increase in hepatic Sulf2 occurring during insulin resistance states such as obesity and T2DM decreases hepatic clearance of TRL remnants and contributes to the development of NAFLD, which can be characterized by non-alcoholic steatohepatitis (NASH) and liver fibrosis. Aims: To investigate (1) whether a fast food diet high in saturated fats, cholesterol, and fructose can produce insulin resistance and overexpression of Sulf2; and (2) whether depletion of Sulf2 can protect against NASH and liver fibrosis in obese mice on a fast food diet. Methods: Sulf2 knockout and wild-type mice (n=12 each) were fed a fast food diet rich in saturated fats and cholesterol along with fructose in their drinking water or normal rodent chow with tap water, beginning at 6-8 weeks of age. At 9 months, mice were sacrificed, blood was obtained for assessment of insulin resistance, alanine transaminase (ALT) and serum lipids, and the livers were harvested and examined for steatosis, steatohepatitis, and fibrosis. Results: The fast food diet produced obesity and insulin resistance. Sulf2 knockout mice fed the fast food diet had significantly less weight gain and lower serum ALT, total cholesterol and LDL-cholesterol than wild-type mice (p,0.05). The fast food diet also induced histopathological features of NASH, including hepatic microvesicular steatosis, inflammation and fibrosis. Hepatic fibrosis was significantly decreased in Sulf2 knockout mice compared to controls (p,0.05). Conclusions: Depletion of Sulf2 improves hypercholesterolemia, steatohepatitis and hepatic fibrosis in a mouse model of NASH induced by a fast food diet. Inhibition of SULF2 may be a potential preventive and therapeutic strategy for NASH with progressive fibrosis.

Effects of high isoflavone soy diet vs casein or arginine‐supplemented casein diet on liver steatosis

Non‐alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function, is often associated with obesity. Arginine (Arg) plays a role in reducing body fat, but there is limited data as to the role that Arg may play in soy protein's ability to protect from fatty liver. The objective of this study was to find the role of native Arg in soy to protect from fatty liver in male obese Zucker rats (N=49; 6 weeks old). Rats had ad libitum access to water and were randomly assigned to one of 3 diets for 8 or 16 weeks: Casein (CAS) diet as control (0.6% Arg) or a casein diet supplemented to contain 1.3% Arg (ARG) or a soy protein isolate diet with high isoflavones (SPI) (1.3% Arg). SPI and ARG rats gained more weight (P&lt;0.05) than CAS rats after 16 weeks only. The SPI rats had lower liver steatosis after 8 and 16 weeks (P&lt;0.05 and P&lt;0.001, respectively) compared to CAS &amp; ARG rats. SPI rats had lower serum alanine amino transferase (ALT) &amp; aminotransferase (AST) levels (P&lt;0.05) compared to CAS after 16 weeks and AST was lower (P&lt;0.05) compared to ARG rats. After 16 weeks the SPI rats had lower (P&lt;0.05) serum ALT and AST levels than SPI rats at 8 weeks. Our results suggest that longer period of SPI feeding results in lower liver steatosis and serum ALT and AST levels while ARG diet had no effect on steatosis or ALT and AST levels. The protective effect of soy protein to reduce fatty liver does not appear to be due to its arginine content. Supported by ABI to RH

Hepatoprotective effects of Juglans regia extract against CCl4-induced oxidative damage in rats

Context: Different parts of the walnut [Juglans regia L. (Juglandaceae)] have been used in folk medicine for protection against liver injury, although its actual efficacy remains uncertain.Objective: The present study investigated the protective effect of walnut leaf extract against carbon tetrachloride (CCl4)-induced liver damage in rats.Materials and methods: The rats were randomly divided into seven groups: control, CCl4 (i.p., 0.5 mL/kg b.w., 50% CCl4 in olive oil), walnut extract (at dose level of 0.2 g/kg b.w.) alone, walnut extract (at dose levels of 0.05, 0.1, 0.2 and 0.4 g/kg b.w.) with CCl4, and treatment was carried out accordingly. On the 28th day, rats were sacrificed and blood was withdrawn by cardiac puncture. Liver damage was assessed by serum biochemical parameters (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and albumin), antioxidant enzymes (superoxide dismutase and catalase) and histopathological observation.Results: Administration of walnut leaf extract (ranging from 0.2 to 0.4 g/kg b.w.) significantly lowered serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in CCl4-treated rats. Walnut leaf extract increased antioxidant enzymes, including superoxide dismutase and catalase. Histopathological examination of livers showed that walnut leaves extract reduced fatty degeneration, cytoplasmic vacuolization and necrosis in CCl4-treated rats.Discussion and conclusion: These results suggest that walnut extract has a protective effect over CCl4-induced oxidative damage in rat liver. These results demonstrate that walnut extract acts as a good hepatoprotective and antioxidant agent in attenuating hepatocellular damage.

English

The study was conducted to determine the phytochemical constituents and also to assess the toxicity of the aqueous extract of&nbsp;Boswellia dalzielli&nbsp;stem bark on the liver and kidney of male mice. Healthy male mice weighing between 45 to 50 g were used. The mice were grouped into four different groups, each containing four mice, respectively. Different concentrations (200, 400 and 600 mg/kg) of the aqueous extract of&nbsp;B. dalzielli&nbsp;stem bark were orally administered, respectively according to group, at the interval of 12 h per day, whereas the other group was not given any treatment and this served as the normal control, providing a baseline data. The experiment lasted for two weeks after which the animals were sacrificed by human decapitation. The serum was obtained and used for the analysis of the parameters of hepatic and renal functions, respectively. The results of the phytochemical screening revealed the presence of alkaloid, flavonoid, tannins, saponins, balsam, cardiac glycoside, terpenes, steroids, resins, and phenols. All the treatment groups showed an elevated serum&nbsp;aspartate transaminase&nbsp;(AST) and a low serum&nbsp;alanine transaminase&nbsp;(ALT), and ALP was (p &lt; 0.05), indicating possibly a damage to the liver. Also, the treatments showed a low serum urea and a normal creatinine level (p &lt; 0.05). Therefore, it was concluded that the extract had some toxic effects on the liver but had no toxic effect on the kidney of the mice. &nbsp; Key words:&nbsp;Boswellia dalzielli, phytochemical constituents, toxicity, hepatic and renal functions.

Potential antioxidant properties and hepatoprotective effects of an aqueous extract formula derived from three Chinese medicinal herbs against CCl4-induced liver injury in rats

The hepatoprotective effects of an aqueous extract formula (AEF) derived from Artemisia capillaris, Lonicera japonica and Silybum marianum (ratio 1:1:1) were evaluated by its antioxidant properties and its attenuation of carbon tetrachloride (CCl4)-induced liver damage in rats. The antioxidant analyses revealed that the AEF showed higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and superoxide anion radical scavenging activities as well as ferric reducing antioxidant potential (FRAP) and Trolox equivalent antioxidant capacity (TEAC) compared with the individual herbs, suggesting a synergism in antioxidation between the three herbs. The animal experiments showed that the CCl4 treatment increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, but decreased triglyceride (TG) and glutathione (GSH) levels as well as glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities. However, AEF administration can successfully lower serum ALT and AST activities, restore the GSH level, ameliorate or restore GPx and CAT activities as well as improve SOD action depending on AEF dosage. Histological examination of liver showed that CCl4 increased the extent of bile duct proliferation, necrosis, fibrosis and fatty vacuolation throughout the liver, but AEF can improve bile duct proliferation, vacuolation and fibrosis, and restore necrosis. The present study demonstrated the hepatoprotective potential of AEF as an alternative to the traditional silymarin.

Hepatoprotective effect of Origanum vulgare in Wistar rats against carbon tetrachloride-induced hepatotoxicity

The effect of an aqueous extract of Origanum vulgare (OV) leaves extract on CCl4-induced hepatotoxicity was investigated in normal and hepatotoxic rats. To evaluate the hepatoprotective activity of OV, rats were divided into six groups: control group, O. vulgare group, carbon tetrachloride (CCl4; 2ml/kg body weight) group, and three treatment groups that received CCl4 and OV at doses of 50, 100, 150mg/kg body weight orally for 15days. Alanine amino transferase (ALT), alkaline phosphatase (ALP), and aspartate amino transferase (AST) in serum, lipid peroxide (LPO), GST, CAT, SOD, GPx, GR, and GSH in liver tissue were estimated to assess liver function. CCl4 administration led to pathological and biochemical evidence of liver injury as compared to controls. OV administration led to significant protection against CCl4-induced hepatotoxicity in dose-dependent manner, maximum activity was found in CCl4 + OV3 (150mg/kg body weight) groups and changes in the hepatocytes were confirmed through histopathological analysis of liver tissues. It was also associated with significantly lower serum ALT, ALP, and AST levels, higher GST, CAT, SOD, GPx, GR, and GSH level in liver tissue. The level of LPO also decreases significantly after the administration of OV leaves extract. The biochemical observations were supplemented with histopathological examination of rat liver sections. Thus, the study suggests O. vulgare showed protective activity against CCl4-induced hepatotoxicity in Wistar rats and might be beneficial for the liver toxicity.

Nrf2 activation prevents cadmium-induced acute liver injury

Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5mg Cd/kg, i.p.). Blood and liver samples were collected 8h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H2DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd.

Co-infections with torque teno viruses in HCV infection

Background/Aim: The potential role of co-infections with novel hepatitisviruses such as torque teno viruses (SENV and TTV) is not clear in HCVinfection. We determined the prevalence and clinical significance of theseagents in different forms of HCV infection. Patients: a total of 365 HCVinfected individuals have been studied. Out of them 33 were symptomfree HCV carriers with persistently normal alanine aminotransferase (ALT), 97suffered from chronic hepatitis C not treated with interferon (IFN)-basedtherapy, 48 patients (pts) had chronic hepatitis C and treated with IFN+ ribavirin (RBV) for one year, 76 pts previously treated with IFN+RBVand achieved sustained virological response (SVR) and 111 were non-responders to IFN +RBV. One hundred and eight healthy volunters served as controls for TTV studies and 40 for SENV investigations. Methods: HCVRNA was detected using Roche Cobas Amplicor Monitor 2.0 test, TTV DNA, SENV-D and SENV-H DNA by PCR method. Results: Prevalance of both SENV-D, SENV-H and TTV was higher in HCV pts than in healthy controls (SENV-D: 43.7% vs. 7.5%; SENV-H 66.6% vs. 35.0% and TTV: 77.7% vs. 18.5%, respectively). Both SENV and TTV carriers have lower serum ALT and higher HCV RNA levels than SENV negative and TTV negative pts. IFN+RBV treated pts with SVR, after the therapy showed lower frequency of SENV-D (10.5%) and TTV (3.9%) than not treated ones. HCV pts with SENV-D achieved lower SVR (33%) than SENV-D negative pts (45%). Conclusion: Torque teno viruses can be accidental tourists in HCV infection, and though they may interfere with HCV, their pathogenetic role in liver injury is questionable. They may be IFN (+RBV?) sensitive agents.

Sa1102 Refractory Anemia Due to Pyridoxine Deficiency in Patients With Crohn's Disease or Cirrhosis

Background/Aims: Pyridoxine or vitamin B6 deficiency is an established cause of sideroblastic anemia through the inhibition of heme synthesis. Reduced levels of this micronutrient has also been implicated in sickle cell anemia and anemia of pregnancy. In 1984, Diehl et al demonstrated an association between low serum alanine transaminase (ALT) and pyridoxine deficiency. The correlation between decreased pyridoxine and serum ALT level can therefore serve as a tool to identify patients with microcytic anemia associated with pyridoxine deficiency. Malabsorption is a prominent cause of pyridoxine deficiency, which is frequent in patients with IBD. Similarly, patients with cirrhosis suffer from defects in vitamin metabolism and thus are also susceptible to pyridoxine deficiency. We conducted a prospective study to identify pyridoxine deficiency in these patients using low ALT values as a marker of B6 deficiency. We theorize that supplementation with pyridoxine will correct the anemia. Methods: Patients with anemia who had either cirrhosis or Crohn's disease at Albany Medical Center and some from Johns Hopkins Hospital were identified. Of the 203 patients with Crohn's disease and 202 patients with cirrhosis, 29 and 33 patients, respectively, met the inclusion criteria and were incorporated into this study. Inclusion criteria were hematocrit < 36 g/dL, mean corpuscular volume (MCV) < 80, total iron < 30 ug/dL, and ALT < 25 IU/ L. Patients with folate deficiency or vitamin B12 deficiency were excluded from the study. Results: All eligible patients were contacted by letters or telephone calls. Preliminary results from the first 8 patients with microcytic anemia refractory to iron supplementation revealed low serum ALT and lower than normal plasma pyridoxine levels. These patients were prescribed 50 mg of oral pyridoxine to be taken daily. A repeat pyridoxine level, complete blood count, and iron studies were redrawn at the end of 2 months of treatment to evaluate for improvement in anemia. Of those 8 patients, six patients have completed treatment with improvement in hematocrit, ALT and pyridoxine levels. The remainig patients from both groups continue to be investigated. Conclusions: Persistent anemia unresponsive to iron supplementation associated with low ALT level may be due to pyridoxine deficiency in malnourished patients with chronic gastrointestinal or liver disease.

Sa1103 The use of Irrigation Pumps During Colonoscopy Improves the Quality of the Exam and Decreases the Likelihood of Repeating the Procedure at a Short Interval

Background/Aims: Pyridoxine or vitamin B6 deficiency is an established cause of sideroblastic anemia through the inhibition of heme synthesis. Reduced levels of this micronutrient has also been implicated in sickle cell anemia and anemia of pregnancy. In 1984, Diehl et al demonstrated an association between low serum alanine transaminase (ALT) and pyridoxine deficiency. The correlation between decreased pyridoxine and serum ALT level can therefore serve as a tool to identify patients with microcytic anemia associated with pyridoxine deficiency. Malabsorption is a prominent cause of pyridoxine deficiency, which is frequent in patients with IBD. Similarly, patients with cirrhosis suffer from defects in vitamin metabolism and thus are also susceptible to pyridoxine deficiency. We conducted a prospective study to identify pyridoxine deficiency in these patients using low ALT values as a marker of B6 deficiency. We theorize that supplementation with pyridoxine will correct the anemia. Methods: Patients with anemia who had either cirrhosis or Crohn's disease at Albany Medical Center and some from Johns Hopkins Hospital were identified. Of the 203 patients with Crohn's disease and 202 patients with cirrhosis, 29 and 33 patients, respectively, met the inclusion criteria and were incorporated into this study. Inclusion criteria were hematocrit < 36 g/dL, mean corpuscular volume (MCV) < 80, total iron < 30 ug/dL, and ALT < 25 IU/ L. Patients with folate deficiency or vitamin B12 deficiency were excluded from the study. Results: All eligible patients were contacted by letters or telephone calls. Preliminary results from the first 8 patients with microcytic anemia refractory to iron supplementation revealed low serum ALT and lower than normal plasma pyridoxine levels. These patients were prescribed 50 mg of oral pyridoxine to be taken daily. A repeat pyridoxine level, complete blood count, and iron studies were redrawn at the end of 2 months of treatment to evaluate for improvement in anemia. Of those 8 patients, six patients have completed treatment with improvement in hematocrit, ALT and pyridoxine levels. The remainig patients from both groups continue to be investigated. Conclusions: Persistent anemia unresponsive to iron supplementation associated with low ALT level may be due to pyridoxine deficiency in malnourished patients with chronic gastrointestinal or liver disease.