Ebubekir Senates

SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease

Summary Sirtuins are members of the silent information regulator 2 (Sir2) family, a group of Class III histone/protein deacetylases. There are 7 different sirtuins in mammals (SIRT1-7), of which SIRT1 is the best known and most studied. SIRT1 is responsible for the regulation of protein activation by means of deacetylating a variety of proteins that play important roles in the pathophysiology of metabolic diseases. Recently, it has been shown that SIRT1 plays key roles in the regulation of lipid and glucose homeostasis, control of insulin secretion and sensitivity, antiinflammatory effects, control of oxidative stress and the improvements in endothelial function that result due to increased mitochondrial biogenesis and β-oxidation capacity. Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease, and it has been accepted as the hepatic component of metabolic syndrome. Recent studies have shown that SIRT expression in the liver is significantly decreased in an NAFLD model of rats fed a high-fat diet, and moderate SIRT1 overexpression protects mice from developing NAFLD. In addition to resveratrol, a natural SIRT1 activator, small-molecule pharmacologic SIRT1 activators have positive effects on metabolic diseases. These effects are particularly promising in the case of diabetes mellitus, for which phase studies are currently being performed. With this information, we hypothesized that the pharmacologic activation of SIRT1, which has been implicated in the pathogenesis of NAFLD, will be a potential therapeutic target for treating NAFLD. In this paper, we review the metabolic effects of SIRT1 and its association with the pathophysiology of NAFLD.

Circulating vaspin levels and epicardial adipose tissue thickness are associated with impaired coronary flow reserve in patients with nonalcoholic fatty liver disease

BACKGROUND Patients with nonalcoholic fatty liver disease (NAFLD) have a reduced coronary flow reserve (CFR) and an increased risk of cardiovascular disease. The fat cells that surround coronary arteries may play a central and underrecognized role in development of cardiovascular disease through the systemic secretion of adipokines. We therefore evaluated the relation of epicardial fat thickness, serum levels of epicardial fat-related adipokines (chemerin and vaspin), and CFR in patients with NAFLD. METHODS We investigated 54 patients with biopsy-proven NAFLD and 56 age- and sex-matched controls. CFR and epicardial fat thickness (EFT) were measured by transthoracic echocardiography. Serum levels of chemerin and vaspin were measured by ELISA. RESULTS EFT was significantly higher (0.64 ± 0.13 vs. 0.54 ± 0.10 cm, P<0.001) and CFR significantly lower (2.11 ± 0.45 vs. 2.52 ± 0.62, P < 0.001) in patients with NAFLD than in controls. Serum levels of vaspin and chemerin were both significantly increased in patients with NAFLD compared with controls. Stepwise regression analysis showed that EFT (β=-0.53, t=-3.7, P<0.001), serum vaspin levels (β=-0.30, t=-2.5, P=0.014), and liver fibrosis (β=-0.31, t=-2.11, P=0.041), in the order they entered into the model, were independent predictors of CFR in NAFLD patients. CONCLUSION Our data suggest the presence of a complex interplay between EFT, serum vaspin, and liver histology in promoting an impaired hyperemic stimulation of coronary blood flow in patients with NAFLD.

Characterization of nonalcoholic fatty liver disease unrelated to the metabolic syndrome

Eur J Clin Invest 2012; 42 (4): 411–418

Relation of epicardial adipose tissue and carotid intima-media thickness in patients with nonalcoholic fatty liver disease.

Objective Currently, nonalcoholic fatty liver disease (NAFLD) itself has been accepted as an atherosclerotic risk factor and related to increased cardiovascular disease risk. In this study, we aimed to investigate the relationship of epicardial fat thickness (EFT), a parameter associated with atherosclerosis in recent years, with carotid artery intima-media thickness (C-IMT), another parameter of subclinical atherosclerosis. Design and methods We investigated 57 patients with biopsy-proven NAFLD and 30 age-matched and sex-matched controls. EFT was obtained by transthoracic echocardiography and C-IMT was evaluated by an ultrasonographic measurement using a linear type B-mode probe. Results EFT and C-IMT were significantly higher in NAFLD patients compared with the controls (EFT: 0.58±0.18 vs. 0.36±0.17 cm, P<0.001 and C-IMT: 0.64±0.1 vs. 0.52±0.1 mm, P<0.001, respectively). We found a statistically significant correlation between EFT and BMI, C-IMT, waist circumference, homeostasis model assessment of insulin resistance, and nonalcoholic steatohepatitis scores in both groups. Stepwise regression analysis showed that C-IMT (&bgr;=0.36, t=2.86, P=0.006) and waist circumference (&bgr;=0.3, t=2.44, P=0.018), in the order they entered into the model, were independent predictors of EFT in patients with NAFLD. Conclusion Our findings indicate that EFT and C-IMT were significantly higher in patients with NAFLD compared with the controls and waist circumference and C-IMT are independent predictors for EFT in patients with NAFLD.

Serum Levels of Hepcidin in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease

BACKGROUND Research suggests the presence of mild-to-moderate iron overload in patients with nonalcoholic fatty liver disease (NAFLD). The role played by hepcidin, the master regulatory hormone of systemic iron metabolism, in the pathogenesis of NAFLD remains controversial. The aims of this study were to: (1) Evaluate serum hepcidin levels in patients with biopsy-proven NAFLD and age- and sex-matched controls and (2) identify the potential associations of hepcidin with the clinical and biochemical characteristics of the study participants. METHODS Serum levels of hepcidin were measured by enzyme-linked immunosorbent assay and compared in 88 patients with NAFLD (56 males and 32 females; mean age, 44 ± 11 years) and 88 controls (51 males and 37 females; mean age, 43 ± 12 years). Moreover, concentrations of hepcidin were assessed in relation to the general characteristics of the study participants and the results of liver biopsy. RESULTS Serum levels of hepcidin were significantly higher in patients with NAFLD (63.5 ± 19.5 ng/mL, P<0.001) compared with controls (32.7 ± 8.3 ng/mL). Multivariable regression analyses in patients with NAFLD showed that hepcidin levels were positively associated with total cholesterol (β=6.9, t=3.3, P<0.01) and triglycerides (β=1.4, t=2.4, P<0.05), but not with iron parameters, histological staging, and pathological characteristics of NAFLD. CONCLUSIONS Although subject to future confirmation, our data suggest that hepcidin levels are elevated in NAFLD and could be associated with lipid parameters in this setting.

Levofloxacin based sequential and triple therapy compared with standard plus probiotic combination for Helicobacter pylori eradication.

BACKGROUND/AIMS Development of resistance to standard therapy for Helicobacter pylori (H. pylori) eradication is rapid. The aim of this study is to compare the efficacy of alternative treatment modalities for H. pylori. Compared treatments were standard triple treatment plus probiotic, sequential therapy with levofloxacin, and a 14-day regimen of PPI (proton pump inhibitor) and levofloxacin/amoxicillin combination. METHODOLOGY Overall 285 patients were enrolled in the study and allocated into three groups. Group I (n=98) received lansoprazole, clarithromycin, amoxicillin and saccharomyces boulardii (probiotic) and group II (n=95) received esomeprazole, levofloxacin and amoxicillin for 14 days. Finally, group III (n=92) received esomeprazole and amoxicillin for five days, followed by esomeprazole, levofloxacin and metronidazole for seven days. Testing for H. pylori infection post-treatment was done using a stool antigen test five weeks after the completion of therapy. RESULTS Patients in all three groups were treatment-naive. Response to treatment (Per Protocol/ITT analysis) was 77.1/72.4% in Group I, 89.1/86.3% in Group II, and 95.5% in Group III. Response to treatment was significantly higher in Groups II and III compared to Group I (p=0.03 and p<0.001, respectively). There was no difference between Groups II and III in terms of response to treatment (p=0.1). CONCLUSIONS Levofloxacin-based sequential therapy and levofloxacin based triple therapy were significantly superior to standard triple therapy plus probiotic.

Comparison of the efficacy of entecavir and tenofovir in chronic hepatitis B.

BACKGROUND/AIMS This study aimed to compare the efficacy of entecavir and tenofovir in nucleos(t)ide-naive chronic hepatitis B patients after 48 weeks of therapy. METHODOLOGY We retrospectively reviewed our data of chronic hepatitis B patients. Nucleos(t)ide-naive patients who had received entecavir or tenofovir for at least 48 weeks were included. We compared entecavir and tenofovir after 48 weeks of therapy with respect to virological, biochemical, serological and histological responses. RESULTS Of the 44 patients, 24 received entecavir and 20 received tenofovir. Pretreatment characteristics of the patients were similar. After 48 weeks, serum HBV DNA levels decreased by 6.93±1.54log copy/ mL in the entecavir group and 6.89±1.22log copy/mL in the tenofovir group (p=0.65). A similar proportion of patients in entecavir and tenofovir groups achieved undetectable serum HBV DNA (87.5% vs. 95%, p=0.39) and serum ALT normalization (79.2% vs. 85%, p=0.62). The mean histological activity index score improved by 3.83±3.51 points in the entecavir group and 2.20±1.91 points in the tenofovir group (p=0.07), and the mean fibrosis scores improved by 0.38±1.61 points in the entecavir group and 0.70±1.17 points in the tenofovir group after 48 weeks (p=0.44). CONCLUSIONS Entecavir and tenofovir are similarly effective in nucleos(t)ide-naive chronic hepatitis B patients with high viral load and/or high fibrosis scores after 48 weeks of therapy.

A new model using platelet indices to predict liver fibrosis in patients with chronic hepatitis B infection

SummaryBackgroundWe aimed to investigate whether mean platelet volume (MPV) and platelet distribution width (PDW) are variables determining the severity of liver fibrosis in patients with chronic HBV infection.MethodsPatients were divided into two groups with fibrosis scores of 0–2 and 3–6 (according to Ishac scoring system). Whether MPV and PDW were independent variables determining the severity of liver fibrosis score or not was investigated by comparing these groups.ResultsOf the 111 cases, 74 (66.7 %) were male (mean age 37.7 ± 11.6 years). Twenty-two of the cases (19.8 %) were HBeAg-positive. Fibrosis scores of 42 cases (37.8 %) were ≥ 3 and the remaining 69 cases had fibrosis scores < 3 (62.2 %). Independent variables determining the severity of fibrosis score were low levels of albumin and mean platelet volume, and high levels of prothrombin time and PDW (Odds ratio (95 % confidence interval) and p values were 0.105 (0.018–0.605) and 0.012 for albumin, 0.402 (0.234–0.692) and 0.001 for mean platelet volume, 1.529 (1.183–1.975) and 0.001 for PDW, and 0.924 (0.875–0.976) and 0.005 for prothrombin time, respectively). The sensitivity, specificity, positive predictive value and negative predictive value of regression model that is established using above mentioned parameters were 88.1, 75.3, 68.5, and 91.7 %, respectively (AUC = 0.886, p = 0.0001).ConclusionsMPV and PDW are independent variables determining the severity of liver fibrosis, and the regression model that is established using these parameters along with other markers, may give more information about the severity of liver fibrosis.ZusammenfassungHintergrundWir untersuchten, ob das mittlere Thrombozytenvolumen und die Verteilung der Thrombozytenbreite Variable sind, die den Schweregrad der Leberfibrose bei Patienten mit chronischer Hepatitis B (HBV) Infektion bestimmen.MethodenDie Patienten (n = 111, davon waren 74 (66,7 %) männlich, mittleres Alter: 37,7 ± 11,6 Jahre) wurden in 2 Gruppen je nach Fibrose Score (0–2 und 3–6) eingeteilt. Verwendet wurde das Ishac Score System. Ob das mittlere Thrombozytenvolumen und die Breitenverteilung der Thrombozyten unabhängige, den Schweregrad der Leberfibrose bestimmende Variable sind, wurde durch Vergleich dieser Gruppen geprüft.ErgebnisseZweiundzwanzig (19,8 %) Patienten waren HbeAg positiv. Die Fibrose Scores waren bei 42 Patienten (37,8 %) ≥ 3 und bei den restlichen 69 (62,2 %) Patienten < 3. Folgende Parameter stellten sich als unabhängige, den Schweregrad der Leberfibrose bestimmende Variable heraus: niedrige Albumin- und niedrige mittlere Thrombozytenvolumen-Werte, sowie hohe Werte der Prothromin Zeit und der Breite der Thrombozyten (Odds ratio (95 % Konfidenz Intervalle) und p Werte waren respektive: 0,105 (0,018–0,605) und 0,012 für Albumin, 0,402 (0,234–0,692) sowie 0,001 für das mittlere Thrombozytenvolumen, 1,529 (1,183–1,975) and 0,001 für die Verteilung der Thromzytenbreite, und 0,924 (0,875–0,976) and 0,005 für die Prothrombin Zeit). Die Sensitivität, Spezifität, der positive und der negative Vorhersagewert des Regressionsmodells, das unter Verwendung der oben erwähnten Parameter etabliert wurde waren: 88,1, 75,3, 68,5, and 91.7 %, respektive (AUC = 0,886, p = 0,0001).SchlussfolgerungenDas mittlere Thrombozytenvolumen und die Verteilung der Thrombozytenbreite sind unabhängige Variable, die den Schweregrad der Leberfibrose bestimmen. Das auf Basis dieser und anderer Parameter etablierte Regressionsmodell könnte mehr Information über den Schweregrad der Leberfibrose geben.

TLR4 gene polymorphism in patients with nonalcoholic fatty liver disease in comparison to healthy controls.

OBJECTIVES Recent studies have suggested that bacterial overgrowth and endotoxemia along with its receptor, Toll-like receptor 4 (TLR-4), play a role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The present study was designed to test and evaluate the TLR4 gene polymorphism in patients with NAFLD in comparison to healthy controls. METHODS A total of 119 patients [mean (standard deviation, SD) age 43.4 (11.5) years, 55.5% were males] with NAFLD and 80 healthy controls [mean (SD) age 40.9 (8.1) years, 67.5% were females)] were evaluated in terms of patient demographics, anthropometrics, blood biochemistry, liver histology, and ultrasonographic (USG) findings. Histological evaluation was performed in 111 patients, and blood samples were collected from 119 patients with NAFLD and 80 healthy persons. Allelic variants of TLR4 (Asp299Gly and Thr399Ile) were assayed by real-time PCR. Genomic DNA was amplified using FAM/VIC primers specific for allelic variants of TLR4 Asp299Gly and Thr399Ile with real-time PCR. Amplicons were analyzed with high-resolution melting on a Light Cycler 480 for detecting different melting patterns of polymorphic and wild-type alleles. RESULTS The number of the subjects with heterozygous mutation at genotype 299 (Asp299Gly) was significantly lower in the NAFLD than in the control group (23.8 vs. 10.9%, P=0.027). Logistic regression analysis revealed that female gender [odds ratio (OR)=2.984, 95% confidence interval (CI) 1.561-5.360, P=0.001] and heterozygous (Asp299Gly) mutation at codon 299 (OR=2.998, 95% CI 1.325-6.783, P=0.008) were the significant predictors of higher likelihood of TRL4 gene polymorphism-related prevention of NAFLD. CONCLUSIONS As the first-time-in-humans controlled study related to investigation of TLR4 gene polymorphism in NAFLD, our findings contribute to the available data that TLR-4 signaling is pivotal for the pathogenesis of NASH and indicate that the TLR4 codon 299 heterozygous gene mutation (Asp299Gly) in humans may have a preventive role against the genesis of NAFLD.

First-line monotherapies of tenofovir and entecavir have comparable efficacies in hepatitis B treatment

Background Hepatitis B virus (HBV) infection is a health problem worldwide. Current treatment options for chronic hepatitis B (CHB) are nucleoside or nucleotide analogues and pegylated interferons. Tenofovir and entecavir are much more commonly used as they have better efficacy, tolerability, and high genetic barriers to resistance. Aim The aim of this study was to assess the efficacies of tenofovir and entecavir in previously untreated CHB patients in a treatment cohort. Patients and methods We included CHB patients in a cohort including previously untreated HBeAg-positive and HBeAg-negative patients from 10 centers in Istanbul, Turkey. The patients were compared in terms of baseline characteristics, decrease in alanine transaminase (ALT), decrease in HBV-DNA to undetectable levels, HBeAg loss and anti-HBe development (among baseline HBeAg-positive patients), interventions to therapy because of lack of efficacy, side effects, severe side effects, and side effects that required change in treatment. Results The study included 121 patients who were administered tenofovir and 130 patients who were administered entecavir. The majority of patients were men, with mild to moderate histology in both treatment groups. The mean duration of follow-up was 18 and 20 months for tenofovir and entecavir, respectively. Patients receiving both drugs showed comparable rates of HBeAg loss, rates of undetectable HBV-DNA levels, rates of ALT normalization, ALT decrease, and decrease in HBV-DNA. Both drugs were well tolerated. Conclusion This study shows that although the baseline characteristics did not match, tenofovir and entecavir sustained comparable virological efficacies. More patients discontinued entecavir during follow-up. Both drugs provided effective viral control, with few side effects.