Alpaslan Kilicarslan

Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid‐induced liver injury in superobese patients with nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)‐induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high‐affinity Na+/taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha‐hydroxylase (CYP7A1) were significantly up‐regulated in obese patients and hepatoma cells exposed to FFA. Up‐regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. Conclusion: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP‐mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin‐receptor agonists might prevent NASH. (HEPATOLOGY 2013;57:1394–1406)

Fetuin-A mRNA expression is elevated in NASH compared with NAFL patients

Fetuin-A is a pro-inflammatory protein expressed by hepatocytes. Its course in morbidly obese patients with NAFLD (non-alcoholic fatty liver disease) following weight loss by BAS (bariatric surgery) has not been fully elucidated yet. In the present study, we prospectively examined the effects of weight loss on various metabolic factors at 4 weeks and 6 months after surgery. Blood and liver tissues were retrieved from 108 morbidly obese NAFLD patients before/during BAS, and 50 of these individuals met the criteria for NASH (non-alcoholic steatohepatitis). Fetuin-A expression was measured by qPCR (quantitative real-time PCR), Western blotting and immunohistochemistry. Hepatocyte apoptosis was quantified via M30 (caspase-cleaved cytokeratin-18 fragments). Plasma concentrations of adiponectin and fetuin-A were determined by ELISA. Serum-derived parameters were additionally taken at 4 weeks and 6 months post-operatively. In addition, primary human hepatocytes were treated with NEFA (non-esterified fatty acid) to investigate changes in fetuin-A. BMI (body mass index) decreased significantly from 53.0±1.1 to 36.4±1.9 kg/m2 in the NAFL group and from 53.3±1.1 to 37.6±1.2 kg/m2 in the NASH group (P<0.0001) at 6 months post-surgery. This was associated with diminishing M30 and M65 (total cytokeratin-18) levels over 6 months after surgery. Adiponectin levels increased continuously in NASH patients, whereas NAFL patients plateaued at 4 weeks post-operatively. Hepatic fetuin-A mRNA and protein expression was elevated before surgery-induced weight loss. However, plasma concentrations of fetuin-A increased signficantly in NASH patients 4 weeks post-operatively. Treatment of hepatocytes with NEFA led to up-regulation of fetuin-A expression. BAS probably has a beneficial effect on NAFLD, as indicated by reduced hepatocyte apoptosis and improved adipokine profiles. In addition, fetuin-A expression is more prominent in NASH.

Pregnancy- and lactation-associated osteoporosis with severe vertebral deformities: can strontium ranelate be a new alternative for the treatment?

BACKGROUND CONTEXT Pregnancy- and lactation-associated osteoporosis is an uncommon condition that may be a consequence of preexisting low bone density, loss of bone mineral content during pregnancy, and increased bone turnover. PURPOSE To present a case of severe osteoporosis associated with pregnancy and lactation and its treatment protocol. STUDY DESIGN/SETTING A tertiary care hospital. PATIENT SAMPLE A young female after twin pregnancy presenting with severe osteoporosis. METHODS The diagnosis was done on the basis of bone mineral density (BMD) measurement. The patient was treated with first alendronate and then strontium ranelate. She was considered as a candidate for kyphoplasty. RESULTS A dramatic increase in the BMD and palliation of back pain were observed. CONCLUSIONS Strontium ranelate may be a new alternative in the treatment of pregnancy- and lactation-associated osteoporosis.

Hip fractures in a developing country: osteoporosis frequency, predisposing factors and treatment costs.

Hip fractures are a burden to both society and the individual. The aim of this study was to describe the frequency of osteoporosis and the in-hospital treatment costs of patients with hip fractures admitted to Hacettepe University Faculty of Medicine Hospital. Patients with a hip fracture who were admitted to the Orthopedics and Traumatology wards between April 2003 and December 2006 were interviewed and 50 of them were enrolled prospectively in the study protocol. Patient characteristics, predisposing factors for fractures and hospital costs were recorded as well as laboratory test results and bone mineral density measurements. The mean age was 74.2 years and 72% of the patients were women. Sixty-four percent of them presented with an intertrochanteric fracture. The patient population was significantly debilitated with a high prevalence of vitamin D insufficiency and secondary hyperparathyroidism. No association was shown with T scores and dietary habits and lifestyle characteristics of patients. In 34% of patients in whom measurements were available, no osteoporosis could be documented. The mean hospital expenditure was

Fenofibrate improves endothelial function and decreases thrombin-activatable fibrinolysis inhibitor concentration in metabolic syndrome

5983. Factors affecting the total cost were age and functional status of the patient and the duration of hospital stay, independent of the type of fracture and surgical procedure used.

Effect of Atorvastatin on CYP2C9 Metabolic Activity as Measured by the Formation Rate of Losartan Metabolite in Hypercholesterolaemic Patients

Procoagulant state, inflammation, and endothelial dysfunction have been documented in metabolic syndrome. Endothelial dysfunction is a strong predictor of cardiovascular events. Studies on the association of thrombin-activatable fibrinolysis inhibitor and thrombosis are still controversial, but substantial evidence suggests that increased thrombin-activatable fibrinolysis inhibitor or thrombin-activatable fibrinolysis inhibits or protects against arterial thrombosis. This study aimed to assess concomitantly the effects of fenofibrate therapy on thrombin-activatable fibrinolysis inhibitor concentrations and endothelial functions in patients with metabolic syndrome. Twenty-five patients (16 women; mean age 50.4 ± 7.0) were enrolled in the study. Plasma thrombin-activatable fibrinolysis inhibitor, C-reactive protein, and fibrinogen levels were measured before fenofibrate administration and after 8 weeks of fenofibrate treatment. Endothelial function was assessed by endothelial-dependent flow-mediated dilatation from brachial artery. Pretreatment (baseline) thrombin-activatable fibrinolysis inhibitor level was 52.3 (1.2–119.7) decreasing to 7.7 (0.9–51.2; P < 0.001) after 8 weeks of fibrate treatment. Endothelial functions, which were measured with flow-mediated dilatation, were significantly improved after treatment (mean flow-mediated dilatation was 6.76 ± 2.21 at baseline and 10.66 ± 1.17% after 8 week of fenofibrate treatment, P < 0.001). Fenofibrate decreases thrombin-activatable fibrinolysis inhibitor levels and improves endothelial function in metabolic syndrome and, thus, suggests a potential for protection against cardiovascular effects. Further studies are warranted to confirm the effects of fibrates on thrombin-activatable fibrinolysis inhibitor and for conclusive evidence on the association between thrombin-activatable fibrinolysis inhibitor and thrombosis.

Evaluation of bone metabolism and bone mass in patients with type-2 diabetes mellitus.

HMG-CoA reductase inhibitors (statins) have a potential to interact with substrates of the drug-metabolizing enzyme cytochrome P450 2C9 (CYP2C9). This may lead to concentration-dependent toxicity such as skeletal muscle side effects. Atorvastatin, a widely used statin, is presently inadequately investigated in vivo with regard to effects on CYP2C9 activity in human beings. The aim of this study was to determine the effect of atorvastatin on the activity of CYP2C9 in a group of Turkish hypercholesterolaemic patients. We prospectively investigated the atorvastatin effect on CYP2C9 activity in a sample of Turkish hypercholesterolaemia patients (11 women, 7 men) who commenced atorvastatin (10 mg/day). Losartan was used as a probe drug to determine CYP2C9 metabolic activity. A single 25-mg oral dose of losartan was given to the patients before, on the first day and after the fourth week of the atorvastatin treatment. Urinary concentrations of losartan and its metabolite, E3174, were measured by high-pressure liquid chromatography (HPLC). Urinary losartan/E3174 ratios were used as an index of CYP2C9 activity. As the baseline enzyme activity may influence the extent of drug-drug interactions, the CYP2C9*2 and 2C9*3 alleles were identified by using PCR-RFLP. In the patients with the CYP2C9*1*1 genotype (n = 12), atorvastatin treatment did not cause a significant change in losartan/E3174 ratios (medians; 95% CI) neither after the first day (0.73; 0.34-1.61) nor at the fourth week (0.71; 0.36-1.77) of the treatment as compared with the baseline activity (0.92; 0.57-1.74, p = 0.38). Similarly, no significant change in the baseline CYP2C9 activity (0.91; 0.30-1.60) was observed in patients with the CYP2C9*1*2 genotype as compared with those of the first day (1.08; 0.08-2.72) and fourth week (0.64; 0.0-3.82) of the atorvastatin treatment (n = 4, p = 0.86). These observations in a hypercholesterolaemic patient sample suggest that atorvastatin does not have a significant effect on enzymes encoded by the CYP2C9*1*1 and CYP2C9*1*2 genotypes when co-administered with a CYP2C9 substrate, losartan.