铁调素调节与慢性丙型肝炎

铁调素（hepcidin）已经成为人们公认的铁的负性调节激素,调控十二指肠铁吸收和巨噬细胞铁释放的水平,在机体铁储存和铁循环中发挥着重要作用。实验和临床研究表明,慢性丙型肝炎（CHC）患者中经常出现轻度至中度铁超负荷,铁过载是促进肝损伤进展的一个危险因子,也是促进肝纤维化、肝硬化和肝细胞癌的危险因素。现就铁调素功能、铁调素的调节机制、在慢性丙型肝炎中铁调素表达的抑制等方面论述铁调素调节与慢性丙型肝炎的关系。     

聚乙二醇干扰素α-2a治疗慢性丙型肝炎病毒／乙型肝炎病毒共感染临床疗效

目的研究慢性丙型肝炎（CHC）与丙型肝炎病毒/乙型肝炎病毒（HCV/HBV）共感染者用聚乙二醇干扰素α-2a（PEG-IFNα-2a）抗病毒治疗疗效的观察。方法治疗前后定期采集31例CHC、30例HCV/HBV共感染者的外周血,检测HCV RNA、HBV DNA和肝脏纤维化指标。结果治疗后CHC患者血清中HCV RNA含量51.6%〈102拷贝/ml,HCV/HBV共感染者HCV、HBV下降均不理想。结论 PEG-IFNα-2a抗病毒治疗HCV/HBV共感染者疗效较单纯丙型肝炎患者差,但对HBV、HCV有抑制作用,并部分改善机体免疫功能及肝功能。     

慢性丙型肝炎与糖尿病的相关性

慢性丙型肝炎(CHC)是由丙型肝炎病毒(HCV)感染引起的一种慢性感染性肝脏疾病[1].HCV是一种RNA病毒,与乙型肝炎病毒(HBV)这种DNA病毒的致病机制不同.目前已经积累的临床与研究资料表明,慢性HCV感染不仅引起CHC、肝硬化、肝细胞癌,而且还引起一系列的全身性的代谢疾病,我们曾经提出HCV感染引起的多代谢综合征(metabolicdisturbance syndrome))的概念[2].近年来的研究资料表明,HCV感染可以引起2型糖尿病(NIDDM)的发生[3].     

天津地区慢性丙型肝炎患者自身抗体的检测结果及临床分析

目的分析天津地区慢性丙型肝炎（CHC）患者血清中自身抗体阳性率及其临床意义。方法选择天津地区98例CHC患者,检测自身抗体（ANA、ASA、AMA、RF、LKM-I）阳性率,并比较自身抗体（＋）及自身抗体（-）群年龄、性别及病毒复制状况。结果 CHC患者血清中自身抗体至少一种阳性的32例,阳性率32.7%。ANA阳性率最高,为26.5%;其次为RF阳性率（8.1%）,再次为AMA阳性率（2.0%）,LC-1及LKM-1阳性率为1.0%。另外,自身抗体阳性组和阴性组有关因素比较发现,阳性组年龄较大（57.1岁vs 46.8岁）,女性多见（65.6%vs 47.0%）。肝脏功能差,免疫功能异常,病毒复制活跃。结论丙型肝炎病毒（HCV）感染者存在自身免疫反应。HCV感染使感染者体内产生多种自身抗体,自身抗体检出率与年龄关系密切且与病毒的复制有关。自身抗体可能是HCV感染后肝组织损伤的重要因素。     

氟西汀在慢性丙型肝炎抗病毒治疗中的作用

超过20%的慢性丙型肝炎(CHC)患者接受IFNα抗病毒治疗后出现抑郁症,氟西汀常用于缓解此症状。氟西汀具有抗炎特性,可改变肝脏脂质合成,但其对CHC抗病毒治疗的影响及机制仍未阐明。近期研究表明氟西汀可抑制HCV感染Huh7.5细胞,且缓解了胞内活性氧生成和脂质蓄积,并通过激活STAT1和JNK通路促进IFNα介导的抗病毒作用,降低患者HCV载量及ALT水平。此外,氟西汀增强了CHC患者过氧化物酶体增殖物激活受体(PPAR)反应元件活性,其对HCV感染和脂质蓄积的抑制效应可被PPARβ/γ等拮抗物一定程度逆转,表明氟西汀可能通过调节PPARβ/γ和JNK/STAT通路抑制HCV感染、活性氧生成及脂质蓄积。     

HCV感染与动脉粥样硬化的关系

慢性感染和炎症反应与动脉粥样硬化的发生相关,而HCV感染是较为常见的感染性疾病。回顾了HCV感染与动脉粥样硬化相关疾病发生关系的最新进展,研究表明更多的证据支持HCV感染会增加冠心病、卒中、颈动脉粥样硬化的发生率以及因心血管事件的死亡风险。HCV感染是动脉粥样硬化的危险因素,虽然背后的机制尚需更多研究,但在丙型肝炎患者人群中应注意预防与控制动脉粥样硬化性疾病。     

丙型肝炎与肝脏脂肪变的相关性

丙型肝炎病毒(HCV)感染,除了引起急性丙型肝炎(AHC)、慢性丙型肝炎(CHC),与肝纤维化(LF)、肝细胞癌(HCC)的发生发展密切相关之外,与肝脏脂肪变、冷球蛋白血症、B细胞淋巴瘤(BCL)等也有密切的关系。说明HCV感染的致病机理与其他类型的肝炎病毒截然不同。关于HCV感染与肝脏脂肪变之间的关系,近年来积累了丰富的临床     

慢性丙型肝炎患者伴发代谢综合征的危险因素

目的对慢性丙型肝炎(CHC)患者伴发代谢综合征(MS)的因素进行分析,并探讨其发生的危险因素。方法根据MS诊断标准将未接受过抗病毒治疗的40例CHC患者分为MS组(14例)和非MS组(26例)。比较两组间一般情况、HCV基因型、病毒载量、肝脏脂肪变性及严重程度、肝脏酶学指标、糖代谢相关指标、脂代谢相关指标等因素。结果两组人群在性别、年龄、BMI、腰臀比、CHO、FFA、瘦素、肝脏脂肪变性程度、HCV病毒载量及基因型等方面无显著性差异(P0.05)。MS组FPG、TG的水平明显高于非MS组(P0.05),而ALT、AST、FINS、HOMA-IR、HOMA-β、ADI则明显低于非MS组(P0.05)。结论 CHC患者伴发MS与胰岛素抵抗及糖类、脂类代谢因素密切相关,与病毒本身无明确相关性。胰岛素抵抗可能是CHC患者伴发MS发病机制的中心环节。     

铁死亡在肝脏疾病中的作用与机制研究进展

[摘要]?铁死亡是近年发现的一种非凋亡形式的程序性细胞死亡方式,其中心环节是铁代谢紊乱导致的胞内脂质过氧化与氧化应激失调。机体内部铁转运系统以及组织细胞的抗氧化系统抑制了铁死亡并维持了生理状态的铁稳态。目前,在多种肝脏疾病中均发现了以脂质过氧化物和活性氧的堆积为特征的铁死亡现象,而铁死亡抑制剂可以有效地抑制铁死亡所致的肝脏损伤。因此,调控铁死亡的发生、发展成为一种新的肝脏疾病潜在治疗策略。本文综述了铁死亡的发生机制以及各种肝脏疾病中铁死亡的研究进展,为探索肝脏疾病的新型治疗方法提供理论基础。     

慢性丙型肝炎治疗的新进展：从病毒到宿主

丙型肝炎病毒（HCV）感染一直是全球公共卫生上的重要课题。慢『生丙型肝炎（CHC）的治疗在近年来已经有了长足的进步,亚太地区在这个研究领域上也有许多深入的研究与新的发现,以下将针对这个主题分成四个部分来说明：首先将对目前全球HCV感染的状况做简单的概述。在第二部分中将对全球CHC治疗方式的演进作介绍,以及目前依据不同HCV基因型与病毒动力学的个人化治疗作较详尽的解说。第三部分将探讨宿主因素与HCV感染或治疗的关系,特别是目前研究上最热门有关于代谢因子及宿主基因变异对CHC治疗的可能影响。最后将针对未来CHC治疗的可能发展方向作讨论。     

Cardiac arrest and resuscitation: brain iron delocalization during reperfusion

We hypothesize that brain injury from cardiac arrest occurs during reperfusion and is in part mediated by iron-dependent lipid peroxidation. We conducted a study to examine the time course of brain iron delocalization and lipid peroxidation in an animal model of cardiac arrest and resuscitation. Assays for brain tissue iron in low-molecular-weight species (LMWS iron) used the o-phenanthroline test on an ultrafiltered (molecular weight less than 30,000) tissue sample; malondialdehyde (MDA), a product of lipid peroxidation, in brain tissue was assayed by the thiobarbituric acid test (TBA). Samples of the parietal cortex from 11 nonischemic control dogs (Group 1) had LMWS iron levels of 9.6 +/- 4.9 nmol/100 mg tissue and MDA levels of 7.7 +/- 2.0 nmol/100 mg tissue. Samples from the parietal cortex taken from five dogs after 15 minutes of cardiac arrest (Group 2) had LMWS iron levels of 9.3 +/- 3.1 nmol/100 mg tissue and MDA levels of 6.1 +/- 1.0 nmol/100 mg tissue. Samples from the parietal cortex taken from five dogs after 45 minutes of cardiac arrest (Group 3) had LMWS iron levels of 6.7 +/- 3.3 nmol/100 mg tissue and MDA levels of 5.6 +/- 0.4 nmol/100 mg tissue. There was no significant difference among the three groups for either LMWS iron or MDA. Five dogs were subjected to 15 minutes of cardiac arrest and definitive resuscitation by internal cardiac massage and defibrillation (Group 4). Following resuscitation the chest was closed and the dogs were given intensive care for two hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-related effects of dietary iron supplementation in producing hepatic iron overload in rats

The influence of varying the level of supplemental dietary iron on the development of hepatic iron overload was examined in rats. Two days after giving birth, Porton rats were fed a diet supplemented with 0, 0.5, 1 or 2% carbonyl iron, to institute dietary iron supplementation to the young via breast milk. After weaning, the offspring continued to receive the assigned diet until 32 weeks of age. Liver biopsies were taken from some rats at 8, 16 and 24 weeks of age and from all rats at 32 weeks of age, for assessment of iron overload. For both male and female rats, hepatic iron content was increased in a dose-related manner by feeding supplemented diet. Hepatic iron content of male rats tended to reach a plateau after 8–16 weeks of supplementation, while that of female rats continued to rise throughout the experimental period, such that the hepatic iron content of female rats was 2.8-fold that of similarly treated males at 32 weeks of age. Iron supplementation was associated with only moderate retardation of growth. By choosing an appropriate level of iron supplementation, good (grade III-IV) hepatic iron loading can be achieved with minimal adverse effects on the animals’ overall health.     

How the binding of human transferrin primes the transferrin receptor potentiating iron release at endosomal pH

Delivery of iron to cells requires binding of two iron-containing human transferrin (hTF) molecules to the specific homodimeric transferrin receptor (TFR) on the cell surface. Through receptor-mediated endocytosis involving lower pH, salt, and an unidentified chelator, iron is rapidly released from hTF within the endosome. The crystal structure of a monoferric N-lobe hTF/TFR complex (3.22-Å resolution) features two binding motifs in the N lobe and one in the C lobe of hTF. Binding of Fe_NhTF induces global and site-specific conformational changes within the TFR ectodomain. Specifically, movements at the TFR dimer interface appear to prime the TFR to undergo pH-induced movements that alter the hTF/TFR interaction. Iron release from each lobe then occurs by distinctly different mechanisms: Binding of His349 to the TFR (strengthened by protonation at low pH) controls iron release from the C lobe, whereas displacement of one N-lobe binding motif, in concert with the action of the dilysine trigger, elicits iron release from the N lobe. One binding motif in each lobe remains attached to the same α-helix in the TFR throughout the endocytic cycle. Collectively, the structure elucidates how the TFR accelerates iron release from the C lobe, slows it from the N lobe, and stabilizes binding of apohTF for return to the cell surface. Importantly, this structure provides new targets for mutagenesis studies to further understand and define this system.     

Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry

BACKGROUND & AIMS: Previous uncontrolled studies have suggested that patients with hepatic iron overload have a poor outcome after liver transplantation. We examined the effect of HFE mutations on posttransplantation survival in patients with hepatic iron overload. METHODS: Two hundred sixty patients with end-stage liver disease and hepatic iron overload were enrolled from 12 liver transplantation centers. Hepatic iron concentration (HIC), hepatic iron index (HII), HFE mutation status, and survival after liver transplantation were recorded. RESULTS: HFE-associated hemochromatosis (HH) defined as homozygosity for the C282Y (n = 14, 7.2%) mutation or compound heterozygosity for the C282Y/H63D (n = 11, 5.6%) mutation was identified in 12.8% of patients. Survival postliver transplantation was significantly lower among patients with HH (1-, 3-, and 5-year survival rates of 64%, 48%, 34%, respectively) compared with simple heterozygotes (C282Y/wt or H63D/wt) or wild-type patients. Patients with HH had a hazard ratio for death of 2.6 (P = .002) after adjustment for age, United Network for Organ Sharing status, year of transplantation, and either elevated HII or HIC. Non-HH patients with hepatic iron overload also had significantly decreased survival when compared with the overall population undergoing liver transplantation (OR = 1.4, 95% CI: 1.15-1.61, P < .001). CONCLUSIONS: One- and 5-year survivals after liver transplantation are significantly lower among patients with HFE-associated HH. Our data also suggest that hepatic iron overload may be associated with decreased survival after liver transplantation, even in patients without HH. Early diagnosis of hepatic iron overload using HFE gene testing and iron depletion prior to liver transplantation may improve posttransplantation survival, particularly among patients with HH.     

铁超负荷在大鼠酒精性肝病发病中的作用

目的探讨肝组织铁超负荷在酒精性肝病（ALD）发病中的作用。方法48只健康Wistar大鼠随机分为对照组（A组）和酒精灌胃组（B组）。A组和B组根据实验时间又分为5周和10周组（A5、A10、B5、B10）。分别测定各组大鼠血清ALT、AST,取肝组织行普鲁士兰染色观察铁颗粒沉积,并观察肝脏组织学改变。结果B5和B10组大鼠血清ALT和AST分别较A5和A10组升高,且B10组高于B5组;A组大鼠肝组织未见铁颗粒沉积,B组大鼠肝组织可见铁颗粒沉积,且B10组较B5组严重;B组大鼠肝组织可见脂肪变性和炎细胞浸润,且B10组更严重。结论铁超负荷在ALD的发病中起重要作用。     

Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload

Background

The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with β-thalassemia major in the cardiac sub-study of the EPIC trial.

Design and Methods

Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years.

Results

Baseline myocardial T2* was severe (>5 to <10 ms) in 39 patients, and moderate-to-mild (10 to <20 ms) in 62 patients. Mean deferasirox dose was 33.1±3.7 mg/kg/d in the one-year core study increasing to 36.1±7.7 mg/kg/d during the second year of treatment. Geometric mean myocardial T2* increased from a baseline of 11.2 to 14.8 ms at two years (P<0.001). In patients with moderate-to-mild baseline T2*, an increase was seen from 14.7 to 20.1 ms, with normalization (≥20 ms) in 56.7% of patients. In those with severe cardiac iron overload at baseline, 42.9% improved to the moderate-to-mild group. The incidence of drug-related adverse events did not increase during the extension relative to the core study and included (≥5%) increased serum creatinine, rash and increased alanine aminotransferase.

Conclusions

Continuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with β-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT 00171821","term_id":"NCT00171821"}}NCT 00171821)