Serum leptin levels are associated with tamoxifen -induced hepatic steatosis

Summary

Purpose: Tamoxifen, used in breast cancer treatment, may induce hepatic steatosis. It has been suggested that leptin, which has a relationship with body fat stores, may be involved in the pathogenesis of hepatic steatosis. In this study, we compared serum leptin levels in tamoxifen-treated patients with and without hepatic steatosis.

Methods: Thirty-four women with breast cancer receiving tamoxifen were included in the study. Serum samples were obtained from the patients before and 3 months after tamoxifen therapy.

Results: Increased hepatic steatosis was detected in 15 of 34 (44%) patients after 3 months of tamoxifen therapy. Serum leptin levels were found to be significantly elevated in patients with increased hepatic steatosis (37.3?±?17.7 to 50.5?±?22.4?ng/ml, p?=?0.023) compared to patients without or stable hepatic steatosis (48.2?±?20.2 to 42.6?±?14.9?ng/ml, p?>?0.05) after tamoxifen treatment.

Conclusion: Leptin may play a role in tamoxifen-induced hepatic steatosis. The exact mechanism involved should be investigated in further studies.     

Circulating leptin levels are associated with increased craving to smoke in abstinent smokers

The adipocyte hormone leptin regulates satiety and energy expenditure. Recent evidence suggests that leptin is associated with increased craving for alcohol and with shorter length of abstinence during alcohol treatment. This study examined leptin's associations with craving for cigarettes and smoking relapse among smokers interested in cessation. Participants (32 smokers; 14 women) attended a laboratory session 24 h following their designated quit day where circulating leptin levels and craving for smoking were assessed. Other measures of withdrawal symptoms, affect, physical symptoms, as well as neuroendocrine and cardiovascular measures were collected before and after performing two stress tasks (public speaking and cognitive tasks). High circulating leptin levels were associated with increased craving, withdrawal symptoms, negative affect, physical symptoms, and reduced positive affect. Circulating leptin levels were not related to cardiovascular and neuroendocrine measures, responses to acute stressors, or to smoking relapse. These results indicate that circulating leptin is a promising biological marker of craving for smoking and warrant further investigation of the links between appetite regulation and nicotine dependence.     

Serum levels of BDNF are associated with craving in opiate-dependent patients

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are involved in the modulation of addictive behaviour. We investigated alterations in serum levels of BDNF and GDNF in opiate-dependent patients (28 males) who received diacetylmorphine treatment within a structured opiate maintenance programme. BDNF (T = 2.735, p = 0.009) serum levels were significantly increased in the opiate-dependent patients as compared with healthy controls (21 males), whereas GDNF serum levels (T = 1.425, p = 0.162) did not differ significantly from GDNF serum levels of the healthy controls. BDNF serum levels were significantly associated with craving for heroin (measured by the Heroin Craving Questionnaire (r = 0.420, p = 0.029) and by the General Craving Scale (r = 0.457, p = 0.016), whereas GDNF serum levels were not associated with psychometric dimensions of heroin craving. In conclusion, our results show a positive association between BDNF serum levels and opiate craving in opiate-dependent patients.     

Blood oxidative stress markers are unreliable markers of hepatic steatosis

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and viral hepatitis are associated with hepatic oxidative stress, which is partially dependent on the amount of hepatic fat. AIM: To determine whether the circulating lipid and oxidative stress parameters could be non-invasive markers of hepatic steatosis. METHODS: Sixty-four patients with NAFLD or viral hepatitis were tested for lipid peroxidation products and antioxidant defence systems, lipid parameters and liver function tests. RESULTS: Hepatic steatosis was correlated with lipids, gamma-glutamyltranspeptidase, thiobarbituric acid-reactive substances, superoxide dismutase and superoxide dismutase/erythrocyte glutathione peroxidase ratio. gamma-Glutamyltranspeptidase, triglycerides and low-density lipoprotein cholesterol were significantly higher in the presence of steatosis. No difference in blood oxidative stress markers was observed according to the presence or absence of steatosis except for the superoxide dismutase/erythrocyte glutathione peroxidase ratio. Total cholesterol, triglycerides and low-density lipoprotein cholesterol were significantly higher in the NAFLD group (n = 17, 60% mean steatosis grade) than in the viral hepatitis group (n = 20, 13% mean steatosis grade). Only superoxide dismutase was lower and vitamin E higher in NAFLD than in viral hepatitis patients. CONCLUSIONS: Standard blood oxidative stress markers do not predict the extent of hepatic steatosis as they probably do not accurately reflect intrahepatic oxidative stress. Serum lipid levels were best correlated with hepatic steatosis.     

阻塞性睡眠呼吸暂停低通气综合征患者血清瘦素水平的变化

目的 观察阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea hypopnea syndrome,OSAHS)患者血清瘦素(leptin)水平的变化.方法 对20例OSAHS患者和20例健康成人进行多导睡眠监测(Polysomnography,PSG),用ELISA双抗体夹心法测定患者血清leptin水平.结果 OSAHS患者组与健康对照组血清leptin比较明显升高,差异有统计学意义(P<0.01),并且leptin水平与OSAHS患者睡眠暂停低通气指数(AHI)呈正相关.结论 患者血清leptin水平与OSAHS患者病情严重程度呈正相关.     

HIE新生儿血清食欲素、生长激素及瘦素水平变化

目的：探讨缺氧缺血性脑病（HIE）新生儿食欲素、生长激素及瘦素水平变化。方法选择HIE患儿58例为研究对象,其中轻度28例,中度22例,重度8例。另设对照组30例。检测各新生儿出生后24h食欲素、生长激素以及瘦素水平,分析HIE对患儿食欲素、生长激素以及瘦素的影响。结果轻度HIE患儿食欲素较对照组轻度升高,生长激素和瘦素较对照组轻度下降,无显著性差异（P＞0.05）。随着病情加重,中度HIE患儿和重度HIE患儿食欲素显著升高,生长激素和瘦素显著下降,与对照组比较,有显著性差异（P＜0.01）。结论 HIE患儿血清食欲素水平显著升高,瘦素和生长激素水平显著下降。     

肝炎后肝硬化患者血清瘦素水平变化的临床意义

目的测定肝炎后肝硬化患者血清瘦素水平，并探讨其异常变化的临床意义。方法采用放射免疫法测定64例肝炎后肝硬化患者和40例对照者血清瘦素水平，同时测定肝功能、身高、体重，根据体重（kg）／身高^2（m^2）计算体重指数。分析肝硬化患者血清瘦素变化与肝功能、体重指数及肝性脑病的关系。结果肝硬化患者的血清瘦素水平显著高于对照组，按Child-Pugh分级，血清瘦素水平逐渐升高。ChildA级血清瘦素水平较对照组升高，但差异无统计学意义；ChildB和ChildC级的血清瘦素水平均显著高于对照组。经相关分析发现瘦素水平与Child-Pugh分级有相关性，与体重指数、总蛋白、白蛋白水平无关。结论肝炎后肝硬化患者的血清瘦素水平明显升高，与肝功能密切相关。     

血清钙镁与急性脑出血病情及预后的相关性研究

探讨血清钙（Ca2+）和镁（Mg2+）浓度与急性脑出血患者的病情轻重和远期预后的相关性。选择我院首次发病的急性脑出血患者96例,入院24 h检测血清Ca2+、Mg2+浓度,依据入院时神经功能缺损评分（NIHSS）分为轻度组、中度组、重度组,对患者进行90 d随访,采用改良Rankin量表（mRS）评价患者远期预后,并将预后分为预后良好组和预后不佳组,分析比较组间指标差异。轻度组、中度组的Ca2+、Mg2+水平均显著高于重度组,轻度组又显著高于中度组（均P＜0.05）;预后良好组Ca2+、Mg2+水平显著高于预后不佳组（P＜0.05）;相关性分析显示,Ca2+、Mg2+水平与NIHSS评分和mRS评分均呈显著负相关（均P＜0.05）。急性脑出血患者血清Ca2+、Mg2+含量与病情严重程度和远期预后均呈负相关,Ca2+、Mg2+可能作为评估病情和预测患者预后的临床指标。     

The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

The development of adverse outcome pathways (AOPs) is becoming a key component of twenty-first century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organized toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands, there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This article reviews and summarizes the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome.     

Resistance to antidepressant treatment is associated with polymorphisms in the leptin gene,decreased leptin mRNA expression,and decreased leptin serum levels

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10^?5) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR^?D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.     

Serum cyclosporin levels, hepatic drug metabolism and renal tubulotoxicity

The present study was designed to examine inter-relationships between serum cyclosporin (CsA) levels, hepatic drug metabolising enzyme activity and CsA induced nephrotoxicity. CsA (25 mg/kg p.o.) was administered daily to male Sprague-Dawley rats: groups of animals were killed on days 0, 4, 7, 10 and 14 and thereafter at weekly intervals over the 7-week course of the experiment. Nephrotoxicity was evaluated by measuring tubular enzymuria and by light microscopy and serum CsA levels (parent drug plus certain metabolites) were determined by radioimmunoassay. The hepatic microsomal mono-oxygenase enzyme system was monitored by measurement of cytochrome P-450, aminopyrine N-demethylase and NADPH-cytochrome c reductase. Nephrotoxicity appeared within 4 days of starting treatment and continued for 4 weeks. Between weeks 4 and 6 there was a period of complete remission followed by the return of renal damage. Aminopyrine N-demethylase activity fell during the first 4 weeks. During the period of remission, however, N-demethylase activity rose to a point significantly higher than pretreatment values and serum CsA levels fell to their lowest concentration. With relapse, hepatic N-demethylase activity again fell below normal and serum drug levels rose to their pre-remission values. From the third week onward, changes in NADPH-cytochrome c reductase activity paralleled those in N-demethylase activity. The hepatic microsomal concentration of cytochrome P-450 did not, however, change significantly during the 7-week period of CsA treatment. Our results suggest that the spontaneous remission of CsA-induced nephrotoxicity is due to a reduction in circulating drug levels caused by increased hepatic CsA metabolism.     

妊娠期血清瘦素水平及其对该期和产后体重的影响

目的　为探讨孕妇血清瘦素水平变化及瘦素对孕期体重增加及产后体重保留的影响。方法　应用酶联免疫法 (ELISA)检测 80例孕产妇 (观察组 )及 2 0名正常非妊娠妇女 (对照组 )血清瘦素 ,并根据早期瘦素水平分成 3组观察比较孕期体重总增加值、净增加值及产后体重保留值。结果　观察组分娩期血清瘦素水平为 (19 9± 6 .7) μg/L ,对照组为 (7 1± 5 1) μg/L ,两组比较有极显著性差异 (P <0 .0 0 1) ,孕 17～ 2 0周瘦素水平为 (14.7± 6 .7) μg/L ,2 8周为 (17.3± 6 .6 ) μg/L ,分娩期为 (19.3± 6 .7)μg/L ,产后 6周为 (8.0 3± 3.4) μg/L ,随着妊娠进展 ,瘦素水平升高 ,产后下降 ,妊娠各阶段瘦素水平均高于非妊娠期。妊娠早期平均瘦素水平高的妊娠期体重增加明显 ,且产后体重保留值高。结论　测量瘦素水平对了解孕期体重增加及产后体重保留 ,防止孕期体重过度增加及肥胖可能有一定的意义。     

The clinical associations with hepatic steatosis: a retrospective study.

Hepatic steatosis is a common liver biopsy finding. As a preamble to a study of nonA, nonB hepatitis we aimed to determine the clinical associations in patients who had hepatic steatosis on biopsy. All liver biopsies performed in the gastroenterology department at Auckland Hospital between 1986 and 1989 were reviewed for evidence of steatosis and the clinical associations analysed. Steatosis was present in 69 (43.7%) of 158 liver biopsy specimens with 35 being mild (47%), 29 moderate (45%) and five severe (7%). Excess alcohol intake was the probable aetiological association in 28 (45%), obesity in 17 (27%) and diabetes mellitus in seven (11%). No causal association could be identified in 17 (24%) and included three of the five cases with severe steatosis. There were no significant differences in clinical presentation, biochemistry or hepatic histopathology between alcoholic and nonalcoholic steatosis. Nonalcoholic steatosis appeared to be more benign with only one case of cirrhosis but further follow up is required to determine true prognosis.     

Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection

BACKGROUND: Steatosis in chronic hepatitis C is associated with inflammation and accelerated fibrogenesis. AIM: To assess the contribution of peroxisome proliferator-activated receptor-alpha and -gamma to the pathogenesis of hepatitis C virus associated steatosis is unknown. METHODS: We measured peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma mRNA by quantitative polymerase chain reaction in liver biopsies of 35 genotype 1 and 22 genotype 3 infected patients and in Huh7 cells expressing hepatitis C virus 1b or 3a core protein. RESULTS: PPAR-alpha mRNA was significantly reduced in livers of patients with genotype 3 compared with genotype 1. Steatosis was associated to a decreased expression of PPAR-alpha in genotype 1, but not in genotype 3. PPAR-gamma expression was significantly lower in genotype 3 compared with genotype 1 and steatosis was associated to decreased levels of PPAR-gamma, but only in genotype 1. There was no significant relationship between PPARs mRNA levels and liver activity or fibrosis. Expression of the hepatitis C virus 3a core protein was associated with an increase in triglyceride accumulation and with a significant reduction of PPAR-gamma mRNA compared with hepatitis C virus 1b. CONCLUSIONS: The presence of steatosis and hepatitis C virus genotype 3 are both associated with a significant down-regulation of PPARs. These receptors, and also additional factors, seem to play a role in the pathogenesis of hepatitis C virus-associated steatosis.     

Pyrethroid insecticide metabolites are associated with serum hormone levels in adult men

Experimental studies have reported that pyrethroid insecticides affect male endocrine and reproductive function, but human data are limited. We recruited 161 men from an infertility clinic between years 2000–2003 and measured serum reproductive and thyroid hormone levels, as well as the pyrethroid metabolites 3-phenoxybenzoic acid (3PBA) and cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA and trans-DCCA) in spot urine samples. When adjusting for potential confounders, categories for all three metabolites, as well as their summed values, were positively associated with FSH (all p-values for trend <0.05). Statistically significant or suggestive positive relationships with LH were also found. In addition, cis-DCCA and trans-DCCA were inversely associated with inhibin B (p for trend = 0.03 and 0.02, respectively). Finally, there was evidence that trans-DCCA was inversely associated with testosterone and free androgen index (the ratio of testosterone to sex hormone binding globulin; p for trend = 0.09 and 0.05, respectively). The observed relationships were consistent with previous findings, but further research is needed for a better understanding of the potential association between pyrethroid insecticides and male reproduction.     

Identification of early proteomic markers for hepatic steatosis

The identification of biomarkers for disease state, drug efficacy, and toxicity is becoming increasingly important for drug discovery and development. We have used two-dimensional differential in-gel electrophoresis and mass spectrometry to identify proteomic markers associated with hepatocellular steatosis in rats after dosing with a compound (CDA) in preclinical development. Rats were dosed daily for up to 5 days with CDA for measurement of blood biochemical parameters, histological, and proteomic analysis. Alterations in plasma glucose and liver transaminases were detected from dosing day 3 onward, and livers showed trace levels of hepatocellular vacuolation from 6 h which increased in extent and severity over the 5 day time course. The number of significantly altered protein spots increased over the 5 day time course, and Ingenuity Pathway Analysis showed that the predominant functions altered by CDA treatment were cell death and cellular assembly and organization. This included alterations in secreted proteins, endoplasmic reticulum and mitochondrial chaperones, antioxidant proteins, and enzymes involved in fatty acid biosynthesis. Comparative in vitro dosing studies showed similar alterations to the proteome, neutral lipid accumulation, and mitochondrial dehydrogenase activity in response to CDA treatment of cultured rat hepatocytes. The finding that several proteins showed significant changes in abundance before the onset of overt toxicity in vivo suggested that these could serve as predictive biomarkers of compounds with a propensity to induce liver steatosis. These markers underwent further direct analysis in the in vitro hepatocyte toxicity model to determine their utility in the development of high throughput assays for drug-induced steatosis.     

Serum levels of leptin,adiponectin and resistin in patients with ankylosing spondylitis: A systematic review and meta-analysis

ObjectivesVarious studies have researched the serum levels of leptin, adiponectin and resistin in patients with ankylosing spondylitis (AS), but the results were inconclusive. The purpose of this study was to systematically evaluate the correlations between serum levels of these adipokines and AS.MethodsElectronic databases were retrieved to search relevant publications. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Cochrane Q test and I² statistic were used to test heterogeneity. Subgroup analysis and meta-regression were applied to assess possible sources of heterogeneity.ResultsA total of sixteen articles were included. Meta-analysis results indicated no statistical differences between AS patients and normal controls in serum leptin and adiponectin levels (leptin, SMD = 0.829, 95% CI = − 0.116 to 1.774, p = 0.085; adiponectin, SMD = 0.460, 95% CI = − 0.004 to 0.924, p = 0.052). However, AS patients had higher serum resistin levels than controls (SMD = 1.413, 95% CI = 0.294 to 2.531, p = 0.013). Subgroup analyses suggested that Asian and African AS patients as well as patients aged < 40 years had higher serum leptin and resistin levels when compared to controls. Serum adiponectin levels were higher in AS patients compared to controls in subgroup of age ≥ 40, and serum resistin levels in subgroup of BMI ≥ 25. Measurement method was a source of heterogeneity for resistin. Publication bias was not observed and the robustness of study results was confirmed by sensitivity analysis.ConclusionSerum resistin, but not leptin or adiponectin levels may be closely associated with the development of AS.