Alanine Transferase Levels Research Articles

Prevalence of Insulin Resistance in Subjects with Nonalcoholic Fatty Liver Disease and Its Predictors in a Chinese Population.

Insulin resistance (IR) is a key factor involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). However, the prevalence of IR in NAFLD patients and its risk factors have been rarely reported, especially in China. This prospective study was undertaken to clarify these issues in the Chinese population. A total of 600 NAFLD patients and 300 age- and sex-matched healthy controls were recruited between January 1, 2011, and December 31, 2013. Demographic information and clinical characteristics were collected, and the presence of IR was evaluated using the homeostasis model. Uni- and multivariate analyses were conducted, and receiver operating characteristic (ROC) curves were generated to identify IR predictors. NAFLD patients had a much higher prevalence of IR than healthy controls (37.8 vs. 2.3 %, P < 0.001). The rates of elevated alanine transferase (ALT) and aspartate transferase (AST) levels were much higher in NAFLD patients with IR than those without (53.7 vs. 41.6 % and 28.6 vs. 18.2 %, respectively, P < 0.001). Uni- and multivariate analyses revealed that female sex, general obesity, abdominal obesity, and hypertension were independent predictors for IR. The area under the ROC curve for fasting plasma insulin (FPI) detecting IR was 0.93 (P < 0.001), and the optimal cutoff was 11.3 μU/ml (sensitivity = 0.86, specificity = 0.92). Chinese NAFLD patients are susceptible to IR. Female sex, general and abdominal obesity, and hypertension were independent predictors for IR in NAFLD patients. FPI is an optimal predictor for IR.

Clinical Significance of Hepatitis B Virus Precore and Core Promoter Variants in Korean Patients With Chronic Hepatitis B

We aimed to clarify the clinical significance of precore (preC)/core promoter (CP) variants of hepatitis B virus (HBV) in chronic hepatitis B (CHB) patients. We assessed serum HBeAg, HBV DNA levels, alanine transferase (ALT) levels, and progression of liver fibrosis in 226 Korean CHB patients, presumed to be infected with genotype C HBV, to analyze HBV variants in the preC region (G1896A) and CP regions (A1762T, G1764A). CP and preC variants were more frequently found in HBeAg-negative patients than in HBeAg-positive patients (P<0.05). HBeAg-positive patients with CP variants had higher ALT levels and more advanced fibrosis scores (all P<0.01) than those without variants; those with preC variant had lower HBV DNA levels (P=0.009), with no significant difference in ALT levels and fibrosis scores. However, no significant correlation was found between HBV variants and clinicopathologic findings in HBeAg-negative patients. Furthermore, multivariate analysis revealed that (1) progression of liver fibrosis (≥F2) was associated with older age in both HBeAg-positive and HBeAg-negative patients (P<0.05) and with CP variants in the HBeAg-positive group (P=0.007), and (2) HBV DNA levels were positively correlated with ALT levels, irrespective of HBeAg (P<0.05), whereas they were negatively correlated with the presence of preC variant in the HBeAg-positive group (P=0.004). In HBeAg-positive CHB patients infected with genotype C HBV, preC variant was associated with enhanced host immune response with lower HBV DNA levels, whereas CP variants were associated with severe liver damage and liver fibrosis progression.

Association of the Nonalcoholic Hepatic Steatosis and Its Degrees With the Values of Liver Enzymes and Homeostasis Model Assessment-Insulin Resistance Index.

BackgroundNonalcoholic fatty liver disease (NAFLD) is among the most common chronic diseases of the modern world with a wide variety of factors including genetic, environmental and metabolic. The aim of this study was to verify the association between the degrees of hepatic steatosis at the abdominal ultrasound and the values of aminotransferases (aspartate aminotransferase (AST) and alanine transferase (ALT)), gamma glutamyl transpeptidase (GGT) and homeostasis model assessment-insulin resistance (HOMA-IR) index.MethodsA prospective, descriptive survey study, using a quantitative analytical examination, was conducted from July 2013 to July 2014. In the statistical analysis, values were expressed as median, first and third quartiles. We used the nonparametric Kruskal-Wallis test to compare the medians between the degrees of steatosis, adopted a statistical significance of 5% (P ≤ 0.05) and used the statistical program SPSS 22.0.ResultsWe diagnosed 233/800 (29.1%) patients with hepatic steatosis on routine ultrasound, and 65.7% were female. Regarding degrees, 119 had grade 1 (51.0%), 94 grade 2 (40.4%) and 20 grade 3 (8.6%). The median age of the patients with grade 1, 2 or 3 did not vary significantly (P > 0.05). The median body mass index (BMI), although clinically important because of its elevation, did not differ significantly (P > 0.05). ALT levels increased as the degree of hepatic steatosis has advanced as well as the levels of AST, GGT and HOMA-IR. AST values showed a greater association with the severity of fatty liver (P = 0.0001) than the ALT (P = 0.001).ConclusionsALT, AST, GGT and HOMA-IR are associated to the degrees of hepatic steatosis on ultrasound and can help in the selection of patients for the liver histological evaluation.

Abstract 2956: The role of apoptotic blebbing in tissue homeostasis and cancer

Abstract Efficient apoptotic cell clearance prevents the release of potentially immunogenic intracellular contents into the surrounding environment to maintain tissue homeostasis; however, the importance of membrane blebbing for apoptotic cell recognition and clearance has not been established. To address fundamental questions regarding the influence of ROCK1 cleavage and consequent apoptotic membrane blebbing in cellular corpse clearance and the maintenance of tissue homeostasis, mice were generated with a single amino acid substitution in the caspase cleavage site (D1113A) that converts ROCK1 to a non-cleavable (ROCK1nc) form. We previously showed that during apoptosis, caspase cleavage of ROCK1 removes an auto-inhibitory carboxy-terminal region to yield a constitutively active kinase fragment that leads to phosphorylation of downstream targets which promote contractile force generation leading to shrinkage, blebbing and nuclear disintegration. When apoptosis was induced in mouse embryonic fibroblasts, the biochemical apoptotic programme itself was unaffected, although cells had significantly impaired morphological alterations. Furthermore, by imaging apoptosis of GFP labelled melanoblasts in ex vivo embryonic skin explants, the effect of the ROCK1nc point mutation was to impair typical apoptotic morphological changes. To understand the biological role of membrane blebbing in the maintenance of tissue homeostasis, we used the liver-selective genotoxic compound diethylnitrosamine (DEN) to induce acute tissue damage. Following DEN treatment, we found that TUNEL positive apoptotic cells were inefficiently cleared in ROCK1nc mice, which resulted in increased neutrophil infiltration in response to the accumulating apoptotic debris. Histologically, the ROCK1nc livers appeared more damaged with evidence of steatohepatitis and perivenular damage, which was accompanied by higher serum alanine transferase levels. We then asked whether defects in tissue damage responses in ROCK1nc mice would affect tumor development in a model of DEN-induced hepatocellular carcinoma. Interestingly, ROCK1nc mice had reduced tumor volume and numbers, suggesting that defective blebbing may be beneficial for reducing tumor initiation and growth. Taken together, our results indicate that efficiency of phagocytic clearance may contribute to cancer susceptibility. Citation Format: Linda Julian, Michael F. Olson. The role of apoptotic blebbing in tissue homeostasis and cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2956. doi:10.1158/1538-7445.AM2014-2956

Su1028 The Tip of an Iceberg -Who Is Known to Have Hepatitis C?

BACKGROUND: Therapies that can slow the progression of liver fibrosis in chronic liver disease are needed. Mounting evidence suggests that statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, exert antiproliferative, antiangiogenic and anti-inflammatory effects on hepatic cells. Although animal models have demonstrated that statins effectively prevent progression of hepatic fibrosis, human data is lacking. AIM: We evaluated the effect of continuous statin use on histological liver fibrosis progression in the HALT-C Trial cohort. METHODS: Among the 1050 randomized subjects in the HALT-C cohort, 547 patients had non-cirrhotic hepatic fibrosis (Ishak Fibrosis Scores ≥3) and underwent serial liver biopsies at baseline, 1.5 years and 3.5 years after randomization. The primary histological outcome was defined as a 2-point or greater increase in Ishak fibrosis score on at least one of the two serial biopsies. We used complementary log-log regression analysis to assess the association between continuous statin use and time to histological progression. RESULTS: Thirty patients (5%) with non-cirrhotic hepatic fibrosis used statins continuously during the study observation period. Statin users were more likely to be African American, to have diabetes, and to have lower baseline alanine transferase (ALT) levels, when compared to non-users (Table 1). Continuous statin use was associated with a significantly decreased time to histological progression even after adjustment for body mass index, platelets, diabetes and hepatic steatosis score (HR 0.26, 95% CI 0.08 0.84; p = 0.023). The mean change in Ishak fibrosis score for statin users was -0.33 (SE 0.18) during the 3.5 year observation period, while the mean change in Ishak fibrosis score among non-users was +0.43 (SE 0.07), p= 0.005 after adjustment for baseline fibrosis score. CONCLUSION: Statin use is associated with a significant reduction in fibrosis progression in advanced chronic hepatitis C infection. Randomized HALTC patients with baseline non-cirrhotic fibrosis (N=547)

Su1026 Statin Use Reduces Risk of Progression of Liver Fibrosis, Among Patients With Chronic Hepatitis C: Analysis of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial

BACKGROUND: Therapies that can slow the progression of liver fibrosis in chronic liver disease are needed. Mounting evidence suggests that statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, exert antiproliferative, antiangiogenic and anti-inflammatory effects on hepatic cells. Although animal models have demonstrated that statins effectively prevent progression of hepatic fibrosis, human data is lacking. AIM: We evaluated the effect of continuous statin use on histological liver fibrosis progression in the HALT-C Trial cohort. METHODS: Among the 1050 randomized subjects in the HALT-C cohort, 547 patients had non-cirrhotic hepatic fibrosis (Ishak Fibrosis Scores ≥3) and underwent serial liver biopsies at baseline, 1.5 years and 3.5 years after randomization. The primary histological outcome was defined as a 2-point or greater increase in Ishak fibrosis score on at least one of the two serial biopsies. We used complementary log-log regression analysis to assess the association between continuous statin use and time to histological progression. RESULTS: Thirty patients (5%) with non-cirrhotic hepatic fibrosis used statins continuously during the study observation period. Statin users were more likely to be African American, to have diabetes, and to have lower baseline alanine transferase (ALT) levels, when compared to non-users (Table 1). Continuous statin use was associated with a significantly decreased time to histological progression even after adjustment for body mass index, platelets, diabetes and hepatic steatosis score (HR 0.26, 95% CI 0.08 0.84; p = 0.023). The mean change in Ishak fibrosis score for statin users was -0.33 (SE 0.18) during the 3.5 year observation period, while the mean change in Ishak fibrosis score among non-users was +0.43 (SE 0.07), p= 0.005 after adjustment for baseline fibrosis score. CONCLUSION: Statin use is associated with a significant reduction in fibrosis progression in advanced chronic hepatitis C infection. Randomized HALTC patients with baseline non-cirrhotic fibrosis (N=547)

Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome.

This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8 wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase-12, Bcl-2 and nuclear factor (NF)-κB. The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-κB were significantly elevated, in the HPS models. There were also close correlation between these proteins and GRP78. Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications.

Longitudinal Study on Liver Functions in Patients with Thalassemia Major before and after Deferasirox (DFX) Therapy.

By performing regular blood transfusion and iron chelation therapy, most patients with beta thalassemia major (BTM) now survive beyond the third decade of life. Liver disease is becoming an important cause of morbidity and mortality in these patients. Chronic hepatitis and/or severe iron overload are both important causes of liver pathology. Iron chelation with desferrioxamine (DFO) reduces excessive body iron, but its efficacy is limited by poor compliance and dose related toxicity. The recent use of Deferasirox ( DFX ), an oral single dose therapy, has improved the compliance to chelation.AimsTo study the long-term liver functions in BMT patients, seronegative for liver infections before versus after DFX treatment in relation to ferritin level.MethodsOnly BTM patients with hepatitis negative screening (checked every year) and on treatment with DFO for at least five years and with DFX for four years were enrolled. Liver function tests including serum bilirubin, alanine transferase (ALT), aspartate transferase (AST), albumin, insulin-like growth factor – I (IGF-I) and serum ferritin concentrations were followed every six months in 40 patients with BTM.ResultsDFX treatment (20 mg/kg/day) significantly decreased serum ferritin level in patients with BTM; this was associated with a significant decrease in serum ALT, AST, ALP and increase in IGF-I concentrations. Albumin concentrations did not change after DFX treatment. ALT and AST levels were correlated significantly with serum ferritin concentrations ( r = 0.45 and 0.33 respectively, p < 0.05). IGF-I concentrations were correlated significantly with serum ALT (r= 0.26, p = 0.05) but not with AST, ALP, bilirubin or albumin levels.The negative correlation between serum ferritin concentrations and ALT suggests that the impairment of hepatic function negatively affect IGF-I synthesis in these patients due to iron toxicity, even in the absence of hepatitis.ConclusionsSome impairment of liver function can occur in hepatitis negative thalassemic patients with iron overload. The use of DFX was associated with mild but significant reduction of ALT, AST and ALP and increase in IGF-I levels. The negative correlation between IGF-I and ALT concentrations suggest that preventing hepatic dysfunction may improve the growth potential in these patients.

Myeloid-Cell Protein Tyrosine Phosphatase-1B Deficiency in Mice Protects Against High-Fat Diet and Lipopolysaccharide-Induced Inflammation, Hyperinsulinemia, and Endotoxemia Through an IL-10 STAT3-Dependent Mechanism

Protein tyrosine phosphatase-1B (PTP1B) negatively regulates insulin and leptin signaling, rendering it an attractive drug target for treatment of obesity-induced insulin resistance. However, some studies suggest caution when targeting macrophage PTP1B, due to its potential anti-inflammatory role. We assessed the role of macrophage PTP1B in inflammation and whole-body metabolism using myeloid-cell (LysM) PTP1B knockout mice (LysM PTP1B). LysM PTP1B mice were protected against lipopolysaccharide (LPS)-induced endotoxemia and hepatic damage associated with decreased proinflammatory cytokine secretion in vivo. In vitro, LPS-treated LysM PTP1B bone marrow-derived macrophages (BMDMs) displayed increased interleukin (IL)-10 mRNA expression, with a concomitant decrease in TNF-α mRNA levels. These anti-inflammatory effects were associated with increased LPS- and IL-10-induced STAT3 phosphorylation in LysM PTP1B BMDMs. Chronic inflammation induced by high-fat (HF) feeding led to equally beneficial effects of macrophage PTP1B deficiency; LysM PTP1B mice exhibited improved glucose and insulin tolerance, protection against LPS-induced hyperinsulinemia, decreased macrophage infiltration into adipose tissue, and decreased liver damage. HF-fed LysM PTP1B mice had increased basal and LPS-induced IL-10 levels, associated with elevated STAT3 phosphorylation in splenic cells, IL-10 mRNA expression, and expansion of cells expressing myeloid markers. These increased IL-10 levels negatively correlated with circulating insulin and alanine transferase levels. Our studies implicate myeloid PTP1B in negative regulation of STAT3/IL-10-mediated signaling, highlighting its inhibition as a potential anti-inflammatory and antidiabetic target in obesity.

Protective Role of Onion Oil on Hepato- testicular Oxidative Damage Induced by Gamma Irradiation in Rats

Aim: Onions have potential antioxidant properties that lower the oxidative status. The Present study was aimed to investigate the antioxidant activity of onion oil in irradiated male albino rats. Study Design: Randomized controlled experiment. Place and Duration of Study: Experimental Animal Unit, Drug Radiation Research Department, National Center for Radiation Research and Technology, Cairo Egypt. Methodology: Animals were divided to the following groups each of eight rats. Control group, Onion oil group: Rats received 200 mg/kg b.wt onion oil orally for seven days. IRR group: Rats were exposed to γray as a fractionated dose of 9 Gy for 7 days, Onion oil + IRR group: Rats were administered with onion oil orally along with γray exposure. At the end of this study the animals were sacrificed and the effects of onion oil against hepatotesticular oxidative damages were monitored by assaying the levels of serum alanine transferase (ALT), aspartate aminotransferase (AST), alkaline phoshatase (ALP), as well as testosterone and DHEA level. In addition both liver and testis lipid peroxidation (MDA), superoxide dismutase (SOD), and catalase (CAT) were examined. Results: The results showed a significant increase in serum ACP, AST, and ALT activities (107.7%, 91.1% and 100.2% compared to control) with a decrease in testosterone (12% compared to control) and nonsignificant change in DHEA. The levels of SOD (59.31±10.67 & 0.21± 0.022), CAT (0.2081± 0.022 & 0.247±0.0453) and GSH (0.32±0.046 & 3.46± 0.476) were significantly decreased in irradiated group, Original Research Article European Journal of Medicinal Plants, 4(2): 135-144, 2014 136 accompanied by significant increase in both liver and testis MDA (171.2±13.69 202.2±49.34) respectively. The levels of reversal effects of irradiation were shown by Onion oil + IRR group in both liver and testis. Conclusion: Data concluded that onion oil showed the reversal effects of ionizing radiation induced hepatotesticular oxidative stress.

Hepatoprotective and Antioxidant Effects of &amp;lt;i&amp;gt;Salvia officinalis&amp;lt;/i&amp;gt; L. Hydroalcoholic Extract in Male Rats

The antioxidant effects of Salvia officinalis L. hydroalcoholic extract and also its hepatoprotective effects in male rats were evaluated. Salvia officinalis L. extract was administered intraperitoneally for 28 days. Serum levels of aspartate aminotransferase, alanine transferase and alkaline phosphates in rats coadministered with both isoniazid (INH) 50 mg/kg and Salvia officinalis L. extract at 250 mg/kg showed significant reduction when compared to INH group, but administration of Salvia officinalis L. extract 250 mg/kg alone and with INH has alleviated gamma-glutamyl transferase comparing to INH receiving rats. After treatment of rats with INH 50mg/kg, severe tissue necrosis, and inflammation of central vein in liver and lymphocyte proliferation were observed; in the experimental group receiving Salvia officinalis L. extract (250 mg/kg) mild dilution in central vein and sinusoids in liver were seen. In rats coadministered with Salvia officinalis L. extract 250 mg/kg and INH low sinusoids dilution was indicated. It seems that Salvia officinalis L. extract exhibited anti-oxidative and hepatoprotective effects.

Expression of the 78 kD glucose-regulated protein is induced by endoplasmic reticulum stress in the development of hepatopulmonary syndrome

ObjectiveThis study is to explore the role of 78kD glucose-regulated protein (GRP78) in the development of hepatopulmonary syndrome (HPS) in rats. MethodsThe rat model of liver cirrhosis and HPS were induced with multiple pathogenic factors. Hematoxylin and eosin (H & E) staining was performed to detect the pathological changes of the lung and liver tissues. The levels of alanine transferase (ALT), endotoxin, and tumor necrosis factor-α (TNF-α) in plasma and TNF-α and malondialdehyde (MDA) in lung tissues were detected. RT-PCR and Western blotting were conducted to detect the mRNA and protein expression levels of GRP78 in lungs. ResultsThe plasma endotoxin level was gradually increased as HPS developed, and the mRNA and protein expression levels of GRP78 in lungs were also increased as the disease progressed. The levels of ALT and TNF-α in plasma and the contents of TNF-α and MDA in lung tissues were gradually increased along with the disease progression, with a strong positive correlation. Compared with controls, the plasma TNF-α level and the mRNA and protein expression levels of GRP78 in lung tissues were significantly higher in rats with HPS. The levels of endotoxin and ALT in plasma and the level of MDA in lungs were significantly higher in rats with HPS than controls. ConclusionsThe increased GRP78 expression is indicative of endoplasmic reticulum stress response during HPS, which may play an important role in the disease pathogenesis.

Orthogonal design based optimization of a mouse model of acute liver failure induced by D-galactosamine and lipopolysaccharide

To apply an orthogonal design optimization strategy to a mouse model of acute liver failure induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) exposure. A four-level orthogonal array design (L16(45)) was constructed to test factors with potential impact on successful establishment of the model (D-GalN and LPS dosages, and dilution rate of the D-GalN/LPS mixture). The mortality rate of mice within 24 hours of D-GalN/LPS administration was determined by the Kaplan-Meier method. The model outcome was verified by changes in serum alanine transferase level, liver histology, and hepatocyte apoptosis. The orthogonal array identified the optimal model technique as intraperitoneal injection of a combination of D-GalN and LPS at dosages of 350 mg/kg and 30 mug/kg, respectively, and using a dilution rate of 3. The dosages tested had no effect on survival. The typical signs of liver failure appeared at 6 hrs after administration of the D-GalN/LPS combination. The orthogonal design optimization strategy provided a procedure for establishing a mouse model of acute liver failure induced by D-GalN and LPS that showed appropriate disease outcome and survival, and which will serve to improve future experimental research of acute liver failure.

Liver histopathological features influencing HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B responding to Peg-IFN treatment

To investigate the therapeutic efficiency of antiviral treatment with pegylated-interferon (Peg-IFN) for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) and to explore whether liver histopathological features or other factors influence the HBeAg seroconversion treatment response. Eighty HBeAg-positive CHB patients with diagnosis confirmed by liver puncture were treated with Peg-IFN(2a or 2b)body weight dose, once weekly). At treatment week 48, the rate of HBeAg seroconversion was determined and used to analyze the influence of liver histopathological features (liver biopsy assessment of: inflammation, graded G0 to G4; fibrosis stage, graded S0 to S4), sex, age, differential levels (pre-treatment baseline vs. week 48 post-treatment) of serum alanine transferase (ALT), and HBV DNA, by binary logistic analysis. At week 48, the overall rate of HBeAg seroconversion was 30.0%. The rate of HBeAg seroconversion gradually advanced with increased liver inflammation (X2 = 8.435, P = 0.015): 9.09% of the 22 patients with G1; 31.58% of the 38 patients with G2; 47.30% of the 19 patients with G3; the one patient with G4. In contrast, the rate of HBeAg seroconversion showed a much weaker association with liver fibrosis (X2 = 5.917, P = 0.116). Only baseline HBeAg level, and no other baseline index, was significantly different between the patients who achieved HBeAg seroconversion and those who did not. Liver inflammation and baseline HBeAg level were identified as influencing factors of HbeAg seroconversion in response to Peg-IFN treatment. Peg-IFN therapy induces a higher rate of HBeAg seroconversion in HBeAg-positive CHB patients with severe liver inflammation; histological analysis of pre-treatment liver biopsies may help to identify patients most likely to benefit from the antiviral regimen.

Asymptomatic EBV Infection may Uncover Ezetimibe Liver Alterations in a Hypercholesterolemic Child

The Epstein Barr viral (EBV) infection may be associated with liver side-effects from ezetimibe treatment in children. An 11-year-old child with familial hypercholesterolemia (FH) presented with a normal biochemical liver profile before ezetimibe treatment, with no significant alterations of liver enzymes. Three months after beginning treatment with ezetimibe 10 mg/day, he complained of constant weakness, and blood testing revealed marked transaminase elevations. Administration of ezetimibe was stopped. However 15 days later alanine transferase (ALT) levels showed a further increase, followed, 10 days later, by an improvement in all pathological levels. After a further 2 months, all values had returned to normal. Tests for antibodies to the EBV were positive, suggesting a recent but not acute EBV infection. It was thus decided to test ezetimibe 10 mg/day again, and after 1 month aspartate aminotransferase (AST) and ALT levels were in a normal range, together with a very satisfactory LDL-cholesterol (LDL-C) response. This is the first report of a child with significant liver side-effects from ezetimibe treatment. Ezetimibe treatment may not have been the direct cause of liver damage in this child, because a concomitant EBV infection. Association of the two should be a warning for possible liver complications. J Med Cases. 2013;4(2):66-68 doi: https://doi.org/10.4021/jmc903w

Effectiveness of Sirolimus in Combination with Cyclosporine against Chronic Rejection in a Pediatric Liver Transplant Patient

The patient is a 3-year-old boy who received living-donor liver transplantation (LDLT) for hepatoblastoma, with his mother as the donor. Oral tacrolimus was started at a dose of 0.3 mg every 12 h from day 1, with the dosage adjusted on the basis of trough concentrations. The levels of aspartate aminotransferase (AST), alanine transferase (ALT), and total bilirubin (T-bil) were 110 U/L, 182 U/L, and 12.6 mg/dL, respectively, when chronic rejection (CR) was pathologically diagnosed. Then, sirolimus at a dose of 1.0 mg/d was added to the tacrolimus-based regimen. The T-bil level rapidly decreased to 5.4 mg/dL, without changes in AST and ALT. Because the intracellular receptor of sirolimus and tacrolimus is FK506-binding protein 12, we switched tacrolimus to cyclosporine at a dose of 60 mg/d to avoid competitive inhibition between these 2 drugs. The target trough concentration of sirolimus and cyclosporine was set to around 15 ng/mL and 180 ng/mL, respectively. The concentration/dose ratio of sirolimus was significantly correlated with the blood cyclosporine level (r=0.5293, p<0.05), suggesting the pharmacokinetic interaction between these 2 drugs. Thereafter, the levels of AST and ALT as well as the T-bil were successfully decreased to 73 U/L, 83 U/L, and 3.0 mg/dL, respectively. These results suggest that sirolimus therapy in combination with cyclosporine may be an effective treatment against CR after liver transplantation.

Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy

To determine incidence of increased levels of alanine transferase (ALT) >2× upper limit of normal (ULN) in patients receiving methotrexate (MTX), treated according to a dynamic strategy, and to identify predictors of ALT of >2× ULN. Data of 508 recent-onset rheumatoid arthritis (RA) patients from the BeSt study, randomized to initial monotherapy or combination therapy, were used. Treatment was dynamic, aiming at a disease activity score = ≤ 2.4. ALT was measured every three months. With logistic regression analyses, baseline variables predictive of first ALT of >2× ULN were identified and the association between use of concomitant antirheumatic drugs, the actual and cumulative dose of MTX and ALT of >2× ULN was determined. In total, 498 patients ever initiated MTX, with a total duration on MTX of 1,416 patient-years. In 89 patients, a first incidence of ALT of >2× ULN occurred. Incidence rate was 6.3 per 100 patient-years and cumulative incidence 18 %. ACPA positivity and baseline ALT of >1× ULN were independent predictors of later ALT of >2× ULN (OR 1.8 (95 % CI, 1.1-3.1) and OR 3.1 (95 % CI, 1.6-6.2), respectively). Smoking showed a trend (OR 1.6 (95 % CI, 0.98-2.7)). Mean MTX dosage over time was higher in patients with an ALT of >2× ULN. Patients who did not have an ALT of >2× ULN used more concomitant disease-modifying antirheumatic drugs and longer. In RA patients treated with MTX according to a dynamic strategy resembling daily clinical practice, incidence of increased ALT of >2× ULN was lower than previously reported, and also without treatment adjustments, persistence was rare. The recommendations for ALT monitoring may be reevaluated.

Asymptomatic EBV Infection may Uncover Ezetimibe Liver Alterations in a Hypercholesterolemic Child

The Epstein Barr viral (EBV) infection may be associated with liver side-effects from ezetimibe treatment in children. An 11-year-old child with familial hypercholesterolemia (FH) presented with a normal biochemical liver profile before ezetimibe treatment, with no significant alterations of liver enzymes. Three months after beginning treatment with ezetimibe 10 mg/day, he complained of constant weakness, and blood testing revealed marked transaminase elevations. Administration of ezetimibe was stopped. However 15 days later alanine transferase (ALT) levels showed a further increase, followed, 10 days later, by an improvement in all pathological levels. After a further 2 months, all values had returned to normal. Tests for antibodies to the EBV were positive, suggesting a recent but not acute EBV infection. It was thus decided to test ezetimibe 10 mg/day again, and after 1 month aspartate aminotransferase (AST) and ALT levels were in a normal range, together with a very satisfactory LDL-cholesterol (LDL-C) response. This is the first report of a child with significant liver side-effects from ezetimibe treatment. Ezetimibe treatment may not have been the direct cause of liver damage in this child, because a concomitant EBV infection. Association of the two should be a warning for possible liver complications. doi: http://dx.doi.org/10.4021/jmc903w

Inflammatory status hepatic enzymes and serum creatinine in HIV-, HIV+ and HIV-TB co-infected adult Central Africans

Background and aimHuman immunodeficiency virus (HIV)/acquired immunodeficiency syndrome is a major public health issue in Africa. The objective of this study was to determine which of isolated HIV-infection, isolated naive pulmonary tuberculosis (PTB), or naive HIV-PTB coinfection was more harmful to inflammatory, hepatic, and renal functions.MethodsThis cross-sectional study was undertaken among ten patients with isolated HIV infection, ten patients with isolated naive HIV infection, ten patients with isolated PTB and 32 patients with HIV-PTB coinfection, with the aim of determining which group had the highest levels of oxidative stress and hepatic and renal dysfunction markers. Serum aminotransferase (AST), alanine transferase (ALT), gamma-glutamyl transferase (GGT), and creatinine measurements were compared across the three groups of patients, who were managed from admission in the pulmonology division of the Brazzaville Teaching Hospital, Congo.ResultsHIV patients had the highest levels of ALT, GGT, and creatinine before and after adjusting for age and sex. Adjusted levels of AST, ALT, GGT, and creatinine were higher in HIV-PTB coinfection patients than in sero-negative PTB patients.ConclusionThere is a significant association between HIV infection and increase in concentration of ALT, GGT, and creatinine.

A Novel In Vivo siRNA Delivery System Specifically Targeting Liver Cells for Protection of ConA-Induced Fulminant Hepatitis

BackgroundFulminant hepatitis progresses to acute liver failure (ALF) when the extent of hepatocyte death exceeds the liver's regenerative capacity. Although small interfering RNA (siRNA) appears promising in animal models of hepatitis, the approach is limited by drawbacks associated with systemic administration of siRNA. The aim of this study is to develop a hepatocyte-specific delivery system of siRNA for treatment of fulminant hepatitis.Methodology/Principal FindingsGalactose-conjugated liposome nano-particles (Gal-LipoNP) bearing siRNA was prepared, and the particle size and zeta potential of Gal-LipoNP/siRNA complexes were measured. The distribution, cytotoxicity and gene silence efficiency were studied in vivo in a concanavalin A (ConA)-induced hepatitis model. C57BL/6 mice were treated with Gal-LipoNP Fas siRNA by i.v. injection 72 h before ConA challenge, and hepatocyte injury was evaluated using serum alanine transferase (ALT) and aspartate transaminase (AST) levels, as well as liver histopathology and TUNEL-positive hepatocytes. The galactose-ligated liposomes were capable of encapsulating >96% siRNA and exhibited a higher stability than naked siRNA in plasma. Hepatocyte-specific targeting was confirmed by in vivo delivery experiment, in which the majority of Gal-LipoNP-siRNA evaded nuclease digestion and accumulated in the liver as soon as 6 h after administration. In vivo gene silencing was significant in the liver after treatment of Gal-Lipo-siRNA. In the ConA-induced hepatitis model, serum levels of ALT and AST were significantly reduced in mice treated with Gal-lipoNP-siRNA as compared with control mice. Additionally, tissue histopathology and apoptosis showed an overall reduction of injury in the Gal-LipoNP siRNA-treated mice.Conclusions/SignificanceThis study is the first to our knowledge to demonstrate reduction of hepatic injury by liver-specific induction of RNA interference using Gal-LipoNP Fas siRNA, highlighting a novel RNAi-based therapeutic potential in many liver diseases.