Elevated Serum Alanine Aminotransferase Activity Research Articles

Effects of graded levels of dietary pomegranate peel on methane and nitrogen losses, and metabolic and health indicators in dairy cows

This study aimed to quantify the effects of dietary inclusion of tannin-rich pomegranate peel (PP) on intake, methane and nitrogen (N) losses, and metabolic and health indicators in dairy cows. Four multiparous, late-lactating Brown Swiss dairy cows (796 kg body weight; 29 kg/d of energy corrected milk yield) were randomly allocated to 3 treatments in a randomized cyclic change-over design with 3 periods, each comprising 14 d of adaptation, 7 d of milk, urine, and feces collection, and 2 d of methane measurements. Treatments were formulated using PP that replaced on a dry matter (DM) basis 0% (control), 5%, and 10% of the basal mixed ration (BMR) consisting of corn and grass silage, alfalfa, and concentrate. Gaseous exchange of the cows was determined in open-circuit respiration chambers. Blood samples were collected on d 15 of each period. Individual feed intake as well as feces and urine excretion were quantified, and representative samples were collected for analyses of nutrients and phenol composition. Milk was analyzed for concentrations of fat, protein, lactose, milk urea N, and fatty acids. Total phenols and antioxidant capacity in milk and plasma were determined. In serum, the concentrations of urea and bilirubin as well as the activities of alanine aminotransferase (ALT), aspartate aminotransferase, glutamate dehydrogenase, alkaline phosphatase, and γ-glutamyl transferase were measured. The data were subjected to ANOVA with the Mixed procedure of SAS, with treatment and period as fixed and animal as random effects. The PP and BMR contained 218 and 3.5 g of total extractable tannins per kg DM, respectively, and thereof 203 and 3.3 g of hydrolyzable tannins. Total DM intake, energy corrected milk, and methane emission (total, yield, and intensity) were not affected by PP supplementation. The proportions of C18:2n-6 and C18:3n-3 in milk increased linearly as the amount of PP was increased in the diet. Milk urea N, blood urea N, and urinary N excretion decreased linearly with the increase in dietary PP content. Total phenols and antioxidant capacity in milk and plasma were not affected by the inclusion of PP. The activity of ALT increased in a linear manner with the inclusion of PP. In conclusion, replacing up to 10% of BMR with PP improved milk fatty acid composition and alleviated metabolic and environmental N load. However, the elevated serum ALT activity indicates an onset of liver stress even at 5% PP, requiring the development of adaptation protocols for safe inclusion of PP in ruminant diets.

Systemic histiocytic disorder in a jaguar (Panthera onca)

A 7-year-old captive female jaguar (Panthera onca) was presented with a 7-day history of dyspnoea and weight loss. Clinical examination revealed hepatomegaly and elevated serum alanine aminotransferase activity. Pulmonary ultrasonography revealed comet-tail images and an alveolar pattern was detected on thoracic radiography. Due to the poor prognosis, the jaguar was euthanized after 10 days. At necropsy, the main gross findings were hepatomegaly, splenomegaly and multifocal to coalescent, slightly elevated grey areas in the lungs. Histological examination revealed neoplastic proliferation of pleomorphic histiocytes arranged in cohesive sheets in the lungs, liver, spleen, kidneys and lymph nodes. Neoplastic cells had intense immunolabelling for vimentin and ionized calcium-binding adaptor molecule 1, and were immunonegative for pancytokeratin, E-cadherin, CD20, CD3 and CD79α. These findings were compatible with a systemic histiocytic disorder, distinct from any well-defined histiocytic proliferative disease in domestic animals.

Liver-adipose tissue crosstalk in alcohol-associated liver disease: The role of mTOR

BackgroundAlcohol-associated liver disease (ALD) is a major chronic liver disease around the world without successful treatment. Acute alcoholic hepatitis is one of the most severe forms of ALD with high mortality, which is often associated with binge drinking. Alcohol drinking dysregulates lipid metabolism, increases adipose tissue lipolysis, and induces liver steatosis and adipose tissue atrophy. Increasing evidence implicates that crosstalk of liver and adipose tissue in the pathogenesis of ALD. Mechanistic target of rapamycin (mTOR) is a phosphatidylinositol 3-kinase (PI3K)-like serine/threonine protein kinase that regulates lipid metabolism, cell proliferation and autophagy. However, the role of mTOR in regulating adipose-liver crosstalk in binge drinking-induced organ damage remains unclear. MethodsWe generated liver-specific and adipocyte-specific regulatory-associated protein of mTOR (Rptor) knockout (RptorLKO and RptorAKO) as well as Mtor knockout (MtorLKO and MtorAKO) mice, by crossing Rptorflox and Mtorflox mice with albumin Cre or adiponectin Cre mice, respectively. In addition, we generated liver and adipocyte double deletion of Rptor or Mtor (MtorLAKO and RptorLAKO) mice. The knockout mice with their matched wild-type littermates (RptorWT and MtorWT) were subjected to acute gavage of 7 g/kg ethanol. ResultsMice with adipocyte deletion of Rptor or Mtor developed hepatomegaly and adipose tissue atrophy. Alcohol gavage increased liver injury, hepatic steatosis and inflammation in mouse livers as demonstrated by elevated serum alanine aminotransferase activities, increased hepatic levels of triglyceride and increased hepatic numbers of CD68 positive macrophages in mouse livers after alcohol gavage. Liver injury was further exacerbated by deletion of adipocyte Rptor or Mtor. Serum adipokine array analysis revealed that increased levels of pro-inflammatory cytokines IL-6 and TNFα as well as chemokine MCP-1 following acute alcohol gavage in wild-type mice, which were further increased in adipocyte-specific Mtor or Rptor knockout mice. Conversely, levels of anti-inflammatory cytokine IL-10 decreased in adipocyte-specific Mtor or Rptor knockout mice. The levels of circulating fibroblast growth factor 21 (FGF21) increased whereas levels of circulating adiponectin and fetuin A decreased in wild-type mice after alcohol gavage. Intriguingly, adipocyte-specific Mtor or Rptor knockout mice already had decreased basal level of FGF21 which increased by alcohol gavage. Moreover, adipocyte-specific Mtor or Rptor knockout mice already had increased basal level of adiponectin and decreased fetuin A which were not further changed by alcohol gavage. ConclusionsAdipocyte but not hepatocyte ablation of Mtor pathway contributes to acute alcohol-induced liver injury with increased inflammation. Our results demonstrate the critical role of adipocyte mTOR in regulating the adipose-liver crosstalk in ALD.

Hepatitis A: Current view of an ancient disease

Hepatitis A: Current view of an ancient disease

Incidence of hepatopathies in dogs administered zonisamide orally: A retrospective study of 384 cases.

BackgroundAcute hepatopathy secondary to administration of zonisamide has been reported in 2 dogs, but overall incidence of hepatopathy is unknown.ObjectiveTo characterize the incidence of hepatopathy in dogs administered zonisamide PO.AnimalsThree hundred eighty‐four dogs administered zonisamide PO.MethodsMulticenter retrospective study. Medical records were searched for dogs prescribed zonisamide PO and which had follow‐up for at least 3 months (acute exposure) and >3 months (chronic exposure). Reported clinical signs, physical examination findings, and serum biochemical panels were reviewed for possible hepatotoxicosis. Serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity and albumin concentration were documented for all available cases.ResultsAcute clinical hepatopathy was found in 2 of 384 treated dogs (0.52%, 95% confidence interval [CI], 0.06‐1.9) after 13‐16 days of zonisamide treatment. One additional dog had elevated serum ALT activity with no clinical signs. Of these 3 dogs, 2 recovered after administration of zonisamide was stopped, and 1 was euthanized because of liver failure. Of the 117 cases chronically administered zonisamide, 10 had an increase in ALP, 6 had an increase in ALT, and 1 had hypoalbuminemia. No clinical signs of liver disease were noted in dogs chronically treated with zonisamide (median, 20 months; range, 5‐94 months).Conclusions and Clinical ImportanceAcute, potentially life‐threatening hepatopathy associated with oral administration of zonisamide to dogs is estimated to occur in less than 1% of dogs and was observed in the first 3 weeks of treatment. Subclinical abnormalities in ALT and ALP activity were noted in <10% of dogs during chronic administration of zonisamide, with no clinical signs of liver disease noted.

Inflammatory arthritis increases the susceptibility to acute immune-mediated hepatitis in mice through enhancing leptin expression in T cells

Liver function abnormalities are common in patients with inflammatory arthritis. However, the precise mechanism is still unclear. In this study, inflammatory arthritis was established in mice by subcutaneous injection of complete Freund’s adjuvant, and the intravenous injection of concanavalin A (Con A) was employed to induce acute immune-mediated hepatitis in mice. The result showed that the arthritis mice were more susceptible to ConA-induced hepatitis than the control mice, as evidenced by increased hepatic necrosis, elevated serum alanine aminotransferase activity, and raised inflammatory cytokines. Besides, the in vitro assay demonstrated that the T cells from arthritis mice were more sensitive to the Con A stimulation than those from control mice. Moreover, we determined that the level of leptin, a kind of adipokine, was significantly increased in the serum and hepatic T cells of arthritis mice. Interestingly, the data indicated that the enhanced expression of leptin in hepatic T cells is responsible for the hypersensitivity of arthritis mice-derived T cells to Con A challenge. Collectively, our findings demonstrate an unexpected role of leptin in the connection between inflammatory arthritis and acute immune-mediated hepatitis, thus providing new insight into the clinical therapy of arthritis-related liver dysfunction.

Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole-Protein Adducts.

Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole–protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of Crotalaria sessiliflora (containing one PA: monocrotaline) and Gynura japonica (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole–protein adducts formed in the rats’ livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole–protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole–protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole–protein adducts—which directly correlated with the elevation of serum ALT activity—was a common insult leading to PA-ILI, suggesting a potential for using pyrrole–protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.

Characterization of liver injury induced by a pyrrolizidine alkaloid in rats

BackgroundPyrrolizidine alkaloids (PAs) are common phytotoxins. PA intoxication is reported to cause severe acute liver damage, typically known as hepatic sinusoidal obstruction syndrome (HSOS), but it remains obscure whether the acute liver damage may progress into chronic liver disease characterized by hepatic fibrosis. PurposeThis study aims to characterize the biochemical markers of liver injury and histological features of regressive and progressive liver fibrosis, and to examine changes in hepatic gene expression that may underpin mechanisms of fibrogenesis in rats induced by retrorsine (RTS), a representative toxic PA. Study design/methodsRats were gavaged with RTS via two dosing regimens, i.e. a single dose of 40 mg/kg (Group 1) and two doses of 40 mg/kg and 20 mg/kg on day 0 and day 7 (Group 2), respectively. Rats receiving one (Group 3) or two (Group 4) doses of vehicle served as negative controls. The animals were followed for up to 16 weeks by serum biochemical analyses and histological examination, and gene expression assays of liver tissues. ResultsAcute liver injury on day 2 manifested as HSOS, characterized by sinusoidal dilation, endothelial cell damage, and elevated serum alanine aminotransferase activity and bilirubin levels. In Group 1, mild liver fibrosis developed at sinusoids and perisinusoidal space surrounding the central veins at week 1 and 2, and thereafter, all liver injury resolved gradually. In Group 2, liver fibrosis progressed within the 16-week observation period. No apparent liver injury was observed in Groups 3 and 4. Compared with negative control groups, RTS induced myofibroblastic activation, TGF-β1 signaling, and changes in expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). These dynamic changes differed in Groups 1 and 2, corresponding with the regression and progression of liver fibrosis, respectively, in these groups. ConclusionThis study has provided in-vivo proof of concept that “one hit” and “two hits” of RTS lead to acute resolving liver injury and chronic progressive liver fibrosis, respectively. These animal models may serve as powerful tools for studying RTS toxicology and related preventive and therapeutic strategies and as positive controls for studying other PA- and non-PA-induced liver injury.

Atypical hypoadrenocorticism in a dog with chronically elevated serum alanine aminotransferase (ALT) activity

A 10-year-old male, castrated, Beagle dog was presented for subclinical, chronic elevated serum alanine aminotransferase activity on serial serum biochemistry profiles. Additionally, mild hypocholesterolaemia, hypoalbuminaemia and hyperammonaemia were identified. Microhepatica...

Serum Alanine Aminotransferase (ALT) Activity among Diabetic Patients

Serum Alanine aminotransferase (ALT) activity is the most common screening test as a part of routine assessment of liver damage. Due to its low activity in extra hepatic tissues an increase in serum ALT is more specific for liver disease. The liver pathology among diabetics is similar to that of alcoholic liver disease, including fatty liver, steatohepatitis, fibrosis, and cirrhosis. Thus, elevated serum ALT activity which is a common sign of liver disease is also observed more frequently in diabetics. This study has been designed with the aim to determine the association of serum ALT activity with diabetes mellitus. The study included 208 subjects attending Nepal police hospital during the time frame 6th October 2009 to 4th January 2010.The ALT activity in serum was determined by kit method, fasting and post prandial sugar was tested by GOD-POD method.Among the total diabetic subjects 43.26% were found to have elevated serum ALT activity (&gt;40IU/L). Diabetic status was found to be significantly associated with ALT activity (p=0.04). In addition to diabetic status body mass index (BMI) was also significantly associated with ALT activity (p=0.02) and higher BMI increases the likelihood of elevated ALT. The association of ALT activity was found to be inverse and significant with age of the patient(r=-0.217, p=0.005). Physical activity was also found to be inversely associated with ALT activity(r=-0.149, p=0.03). Int J Appl Sci Biotechnol, Vol 4(3): 386-390

Accelerated Partial Hepatectomy–Induced Liver Cell Proliferation Is Associated with Liver Injury in Nur77 Knockout Mice

Nur77, encoded by Nr4a1 (alias Nur77), plays roles in cell death, survival, and inflammation. To study the role of Nur77 in liver regeneration, wild-type (WT) and Nur77 knockout (KO) mice were subjected to standard two-thirds partial hepatectomy (PH). Nur77 mRNA and protein levels were markedly induced at 1 hour after PH in WT livers, coinciding with ERK1/2 activation. Surprisingly, Nur77 KO mice exhibited a higher liver-to-body weight ratio than WT mice at 24, 48, and 72 hours after PH. Nur77 KO livers exhibited increase in Ki-67-positive hepatocytes at 24 hours, with early induction of cell-cycle genes. Despite accelerated regeneration, Nur77 KO livers paradoxically incurred necrosis, hepatocyte apoptosis, elevated serum alanine aminotransferase activity, and Kupffer cell accumulation. Microarray analysis revealed up-regulation of genes modulating inflammation, cell proliferation, and apoptosis but down-regulation (due to Nur77 deficiency) of glucose and lipid homeostasis genes. Levels of proinflammatory cytokines IL-6, IL-12, IL-23, and CCL2 were increased and levels of anti-inflammatory IL-10 were decreased, compared with WT. Activated NF-κB and STAT3 and mRNA levels of target genes Myc and Bcl2l1 were elevated in Nur77 KO livers. Overall, Nur77 appears essential for regulating early signaling of liver regeneration by modulating cytokine-mediated inflammatory, apoptotic, and energy mobilization processes. The accelerated liver regeneration observed in Nur77 KO mice is likely due to a compensatory effect caused by injury.

Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine.

Methimazole is the most convenient drug used in the management of hyperthyroid patients. However, associated with its clinical use is hepatotoxicity as a life threatening adverse effect. The exact mechanism of methimazole-induced hepatotoxicity is still far from clear and no protective agent has been developed for this toxicity. This study attempts to evaluate the hepatotoxicity induced by methimazole at different experimental conditions in a mice model. Methimazole-induced hepatotoxicity was investigated in different situations such as enzyme induced and/or glutathione depleted animals. Methimazole (100 mg/kg, i.p) administration caused hepatotoxicity as revealed by increase in serum alanine aminotransferase (ALT) activity as well as pathological changes of the liver. Furthermore, a significant reduction in hepatic glutathione content and an elevation in lipid peroxidation were observed in methimazole-treated mice. Combined administration of L-buthionine sulfoximine (BSO), as a glutathione depletory agent, caused a dramatic change in methimazole-induced hepatotoxicity characterized by hepatic necrosis and a severe elevation of serum ALT activity. Enzyme induction using phenobarbital and/or β-naphtoflavone beforehand, deteriorated methimazole-induced hepatotoxicity in mice. N-acetyl cysteine (300 mg/kg, i.p) administration effectively alleviated hepatotoxic effects of methimazole in both glutathione-depleted and/or enzyme induced animals. The severe hepatotoxic effects of methimazole in glutathione-depleted animals, reveals the crucial role of glutathione as a cellular defense mechanism against methimazole-induced hepatotoxicity. Furthermore, the more hepatotoxic properties of methimazole in enzyme-induced mice, indicates the role of reactive intermediates in the hepatotoxicity induced by this drug. The protective effects of N-acetylcysteine could be attributed to its radical/reactive metabolite scavenging, and/or antioxidant properties as well as glutathione replenishment activities.

Determination of enzymatic source of alanine aminotransferase activity in serum from dogs with liver injury

Introduction Increase of serum alanine aminotransferase (ALT) activity is widely used as a surrogate marker for tissue damage. Two ALT isoforms, ALT1 and ALT2, have been cloned recently in mammals. The study investigated the source of elevated ALT activity in serum of dogs treated with a hepatotoxic compound. Methods ALT activity was measured by enzyme assay. Immunoblot analysis was performed using generated specific peptide antibodies against dog ALTs. LC-MS/MS-based proteomics analysis was conducted to independently identify dog ALT peptides. Serum samples immunodepleted of major serum components by Seppro IgY-D11 microbead spin column were evaluated by the immunoblot analysis, and compared with those of the ALT activity. Results Involvement of ALT enzyme(s) is consistent with the following observations: 1) all the substrates ( l-alanine and α-ketoglutarate) were required for serum ALT activity as purified porcine ALT1 needed for activity, 2) serum ALT activity was inhibited by l-cycloserine, a known ALT inhibitor, and 3) apparent Km value for the ALT reaction catalyzed by the serum, liver, and skeletal muscle was roughly similar. Immunoblot analysis showed that ALT1 was detected in liver and both ALTs were detected in the skeletal muscle. The relative expression level of ALTs was —: liver ALT1 > skeletal muscle ALT1 > skeletal muscle ALT2. LC-MS/MS-based proteomics analysis gave similar results. Immunoblot analysis of the depleted serum samples revealed the presence of ALT1 in compound-treated dogs. Intensity of the ALT1 band detected in the sera correlated well with the ALT activity measured by the enzyme assay. Discussion Based on these findings, we conclude that the elevation of serum ALT activity in dogs with liver injury is attributed to elevation of ALT1 protein level in serum. The methodology to directly detect ALT proteins in serum could be a tool to facilitate our understanding of biological and toxicological significance of the ALT isoenzymes.

Metastatic Angioinvasive Lymphoma (Lymphomatoid Granulomatosis) in a Cat

A subcutaneous mass removed from the right rear leg of a 17-year-old, spayed, female Domestic Shorthair cat was characterized histopathologically by granulomatous inflammation, sheets of large atypical lymphoid cells, and necrosis. The walls of the small and medium caliber blood vessels were invaded transmurally by atypical lymphoid cells. A diagnosis of angioinvasive lymphoma (AIL), or lymphomatoid granulomatosis, was made based on histopathologic findings. The cat was euthanized 2 months later because of recurrence of the mass and elevated serum alanine aminotransferase activity, and a necropsy was performed. The histopathologic lesion of AIL was seen in the skin and subcutis of the right rear leg, and neoplastic cell infiltrates were seen in adjacent skeletal muscle, right superficial inguinal lymph node, liver, and spleen. By immunohistochemistry, variable numbers of neoplastic cells expressed B-lymphocyte antigen 36 (BLA36) or cluster of differentiation (CD)3 markers, indicative of B- and T-cell lineages, respectively. Neoplastic cells were uniformly positive for vimentin and uniformly negative for cytokeratins and myeloid/histiocytic antigen. Although the cat had received a Rabies virus vaccine subcutaneously in the right rear leg 6 months earlier, the AIL lesion was not typical of vaccine-induced sarcomas. The AIL in this cat was unusual because the extrapulmonary metastases involved the skin and subcutis.

Modest Inflammation Enhances Diclofenac Hepatotoxicity in Rats: Role of Neutrophils and Bacterial Translocation

Idiosyncratic adverse drug reactions (IADRs) represent an important human health problem, yet animal models for preclinical prediction of these reactions are lacking. Recent evidence in animals suggests that some IADRs arise from drug interaction with an inflammatory episode that renders the liver sensitive to injury. Diclofenac (DCLF) is one of those drugs for which the clinical use is limited by idiosyncratic liver injury. We tested the hypothesis that modest inflammation triggered in rats by a small dose of lipopolysaccharide (LPS) renders a nonhepatotoxic dose of DCLF injurious to liver. Cotreatment of rats with nonhepatotoxic doses of LPS and DCLF resulted in elevated serum alanine aminotransferase activity and liver histopathologic changes 6 h after DCLF administration. Neither LPS nor DCLF alone had such an effect. Gene array analysis of livers revealed a unique gene expression pattern in the LPS/DCLF-cotreated group compared with groups given either agent alone. Antiserum-induced neutrophil (PMN) depletion in LPS/DCLF-cotreated rats protected against liver injury, demonstrating a role for PMNs in the pathogenesis of this LPS/DCLF interaction. Gut sterilization of LPS/DCLF-treated rats did not protect against liver injury. In contrast, gut sterilization did attenuate liver injury caused by a large, hepatotoxic dose of DCLF, suggesting that hepatotoxicity induced by large doses of DCLF is caused in part by its ability to increase intestinal permeability to endotoxin or other bacterial products. These results demonstrate that inflammation-DCLF interaction precipitates hepatotoxicity in rats and raise the possibility of creating animal models that predict human IADRs.

Silymarin Protects Against Acute Ethanol‐Induced Hepatotoxicity in Mice

Accumulated evidence has demonstrated that both oxidative stress and abnormal cytokine production, especially tumor necrosis factor-alpha (TNF), play important etiological roles in the pathogenesis of alcoholic liver disease (ALD). Agents that have both antioxidant and anti-inflammation properties, particularly anti-TNF production, represent promising therapeutic interventions for ALD. We investigated the effects and the possible mechanism(s) of silymarin on liver injury induced by acute ethanol (EtOH) administration. Nine-week-old mice were divided into 4 groups, control, silymarin treatment, EtOH treatment, and silymarin/EtOH treatment, with 6 mice in each group. Because control and silymarin values were virtually identical, only control treatment is shown for ease of viewing. Ethanol-treated mice received EtOH [5 g/kg body weight (BW)] by gavage every 12 hours for a total of 3 doses. Control mice received an isocalorical maltose solution. In the silymarin/EtOH group, silymarin was dissolved in the EtOH and gavaged simultaneously with EtOH at a dose of 200 mg/kg BW. At 4 hours after the last dosing, the mice were anesthetized and subsequent serum alanine aminotransferase (ALT) level, hepatic lipid peroxidation, enzymatic activity of hepatic cytochrome P450 2E1, hepatic TNF-alpha, and glutathione (GSH) levels were measured. Histopathological change was assessed by hematoxylin and eosin staining. Acute EtOH administration caused prominent hepatic microvesicular steatosis with mild necrosis and an elevation of serum ALT activity, induced a significant decrease in hepatic GSH in conjunction with enhanced lipid peroxidation, and increased hepatic TNF production. Supplementation with a standardized silymarin attenuated these adverse changes induced by acute EtOH administration. Silymarin protects against the liver injury caused by acute EtOH administration. In view of its nontoxic nature, it may be developed as an effective therapeutic agent for alcohol-induced liver disease by its antioxidative stress and anti-inflammatory features.

Elevated serum alanine aminotransferase activity and calculated risk of coronary heart disease in the United States

In the United States, elevated serum alanine aminotransferase (ALT) activity in the absence of viral hepatitis or excessive alcohol consumption is most commonly attributed to nonalcoholic fatty liver disease (NAFLD). NAFLD is related to predictors of coronary heart disease (CHD) such as insulin resistance and central obesity. We examined the association between elevated serum ALT activity and the 10-year risk of CHD as estimated using the Framingham risk score (FRS). We performed a cross-sectional analysis comparing participants in the Third National Health and Nutrition Examination Survey with normal and elevated ALT activity (>43 IU/L), examining the mean levels of FRS. Among participants without viral hepatitis or excessive alcohol consumption, those with elevated ALT activity (n=267) had a higher FRS than those with normal ALT activity (n=7259), both among men (mean difference in FRS 0.25, 95% CI 0.07-0.4; hazard ratio for CHD 1.28, 95% CI 1.07-1.5) and women (mean difference in FRS 0.76, 95% CI 0.4-1.1; hazard ratio for CHD 2.14, 95% CI 1.5-3.0). The ALT threshold for increased risk of CHD was higher in men (>43 IU/L) than in women (>30 IU/L). Elevated ALT activity was not associated with higher FRS among nonobese participants with viral hepatitis or excessive alcohol consumption. In condusion, individuals with elevated serum ALT activity in the absence of viral hepatitis or excessive alcohol consumption, most of whom have NAFLD, have an increased calculated risk of CHD. This association is more prominent in women.

Expression and activity of inducible nitric oxide synthase and endothelial nitric oxide synthase correlate with ethanol-induced liver injury

To study the expression and activity of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in rats with ethanol-induced liver injury and their relation with liver damage, activation of nuclear factor-kappaB (NF-kappaB) and tumor necrosis factor-alpha (TNF-alpha) expression in the liver. Female Sprague-Dawley rats were given fish oil (0.5 mL) along with ethanol or isocaloric dextrose daily via gastrogavage for 4 or 6 wk. Liver injury was assessed using serum alanine aminotransferase (ALT) activity and pathological analysis. Liver malondialdehyde (MDA), nitric oxide contents, iNOS and eNOS activity were determined. NF-kappaB p65ìiNOS, eNOS and TNF-alpha protein or mRNA expression in the liver were detected by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR). Chronic ethanol gavage for 4 wk caused steatosis, inflammation and necrosis in the liver, and elevated serum ALT activity. Prolonged ethanol administration (6 wk) enhanced the liver damage. These responses were accompanied with increased lipid peroxidation, NO contents, iNOS activity and reduced eNOS activity. NF-kappaB p65, iNOS and TNF-alpha protein or mRNA expression were markedly induced after chronic ethanol gavage, whereas eNOS mRNA expression remained unchanged. The enhanced iNOS activity and expression were positively correlated with the liver damage, especially the necro-inflammation, activation of NF-kappaB, and TNF-alpha mRNA expression. iNOS expression and activity are induced in the liver after chronic ethanol exposure in rats, which are correlated with the liver damage, especially the necro-inflammation, activation of NF-kappaB and TNF-alpha expression. eNOS activity is reduced, but its mRNA expression is not affected.

Coffee and Tea Consumption Are Associated With a Lower Incidence of Chronic Liver Disease in the United States

Coffee drinking has been suggested to protect against liver injury, but it is uncertain whether this is of clinical significance. We examined the relationship of coffee and tea consumption with the incidence of hospitalization or death from chronic liver disease (CLD). Participants in the population-based, first National Health and Nutrition Examination Survey, 1971-1975, were asked about coffee and tea consumption, which was categorized as <1 cup (mean, 0.2 cups), 1 to 2 cups, and >2 cups per day (mean, 4.0 cups). A second analysis included persons who, in 1982-1984, were asked more detailed questions on coffee and tea drinking. Participants were followed through 1992-1993 for a hospital or death certificate diagnosis of CLD or cirrhosis (ICD-9-CM 571). Hazard rate ratios for CLD according to coffee and tea intake were calculated using Cox proportional hazards analysis. Among 9849 persons followed for a median of 19.0 years (range, 0.02-22.1), the cumulative incidence of CLD was 1.4%. In multivariate analysis, participants who drank >2 cups per day had less than half the rate of CLD as those who drank <1 cup per day (hazard ratio, 0.43, 95% confidence interval: 0.24-0.78). Protection by coffee and tea was limited to persons at higher risk for liver diseases from heavier alcohol intake, overweight, diabetes, or high iron saturation. Among 9650 participants who provided detailed drink information in 1982-1984, intake of regular ground coffee and of caffeine was associated with lower incidence of CLD. Coffee and tea drinking decreases the risk of clinically significant CLD.

Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice

The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 degrees C water bath immersion for 30 min). Hsp70i knockout mice were more susceptible to APAP-induced hepatotoxicity than controls, as indicated by elevated serum alanine aminotransferase activities 24 and 48 h after the APAP dose. Increased APAP hepatotoxicity in knockout mice was verified by morphological evaluation of liver sections. The difference in toxic response to APAP between knockout and control strain mice could not be attributed to differences in APAP bioactivation, assessed by measurement of CYP2E1 and glutathione S-transferase activities, hepatic nonprotein sulfhydryl content, or covalent binding of reactive APAP metabolites to proteins. Pretreatment with transient hyperthermia to produce a general upregulation of Hsps resulted in decreased APAP hepatotoxicity in both the knockout and control strains. Among thermally-pretreated mice, hepatotoxicity of APAP was greater in the knockouts compared with the control strain. These observations suggest that increased Hsp70i expression in response to APAP acts to limit the extent of tissue injury. Results further suggest that other factors related to heat stress can also contribute to protection against APAP toxicity.