Article(id=1211268934385406922, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211268928383348982, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.02.12, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1587398400000, receivedDateStr=2020-04-21, revisedDate=1602864000000, revisedDateStr=2020-10-17, acceptedDate=null, acceptedDateStr=null, onlineDate=1766718618246, onlineDateStr=2025-12-26, pubDate=1614441600000, pubDateStr=2021-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766718618246, onlineIssueDateStr=2025-12-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766718618246, creator=13701087609, updateTime=1766718618246, updator=13701087609, issue=Issue{id=1211268928383348982, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='2', pageStart='107', pageEnd='211', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766718616815, creator=13701087609, updateTime=1766718805938, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1211269721685627740, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211268928383348982, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1211269721685627741, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211268928383348982, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=181, endPage=185, ext={EN=ArticleExt(id=1211268934783865828, articleId=1211268934385406922, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress of relationship between serum ferritin and hepatic disease, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

As a crucial microelement of human body, iron is involved in many important physiological processes. Serum ferritin (SF) is the main form of protein for iron storage, and regulates the storage and metabolism of iron. Although detection of ferritin has been applied for clinical use for a long time, some biological properties of ferritin still remain controversial, including its tissue origin, secretory pathway, interactions with receptors and cellular effects. Although many researches paid attention to the relationship between the changes of ferritin and liver diseases, the cut-off points of ferritin used varies in different studies, which hinders the consistency analysis of the results of different studies. It is urgent to explore and establish uniform standard for the parameter of ferritin, so as to better elucidate the iron status in the body reflected by changes in ferritin. This paper reviews the in vivo metabolic process of iron, the structural composition and pathophysiological function of ferritin, and the relationship between SF and liver diseases for providing guidance for future research.

, correspAuthors=Guo-Shan Ding, authorNote=null, correspAuthorsNote=
*E-mail:
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铁作为人体内重要的微量元素之一,参与多种重要的生理过程。血清铁蛋白(SF)是铁的主要贮存蛋白,可调节铁的储存和代谢。尽管铁蛋白检测已在临床应用较长时间,但其部分生物学特性如组织来源、分泌途径、受体相互作用及细胞效应等仍存在争议。虽然许多研究关注铁蛋白变化与肝脏疾病的关系,但各研究采纳的铁蛋白过高/过低阈值不尽相同,阻碍了对不同研究结果的一致性分析,亟需研究和制定铁蛋白参数的统一标准,以更好地阐明铁蛋白变化所反映的机体内铁状态。该文就铁的体内代谢过程,铁蛋白的结构及病理生理功能,以及SF与肝脏疾病关系的研究进展进行综述,以期为未来的研究提供导向。

, correspAuthors=丁国善, authorNote=null, correspAuthorsNote=
丁国善,E-mail:
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沙治林,硕士研究生,主要从事肝脏疾病与肝移植方面的研究。E-mail:

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tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268934385406922, language=CN, orderNo=5, keyword=肝移植)], refs=[Reference(id=1211268939372433663, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211268934385406922, doi=null, pmid=null, pmcid=null, year=2020, volume=38, issue=1, pageStart=1, pageEnd=3, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=Jiang YG, Hong Y, Gao WN, journalName=Med J Chin PLA, refType=null, unstructuredReference=Jiang YG, Hong Y, Gao WN, et al. 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血清铁蛋白及其与肝脏疾病的关系研究进展
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沙治林 , 宋少华 , 丁国善 *
解放军医学杂志 | 综述 2021,46(2): 181-185
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解放军医学杂志 | 综述 2021, 46(2): 181-185
血清铁蛋白及其与肝脏疾病的关系研究进展
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沙治林 , 宋少华, 丁国善*
作者信息
  • 海军军医大学附属长征医院器官移植科,上海 200003
  • 沙治林,硕士研究生,主要从事肝脏疾病与肝移植方面的研究。E-mail:

通讯作者:

丁国善,E-mail:
Research progress of relationship between serum ferritin and hepatic disease
Zhi-Lin Sha , Shao-Hua Song, Guo-Shan Ding*
Affiliations
  • Department of Organ Transplantation, Changzheng Hospital Affiliated to Naval Military Medical University, Shanghai 200003, China
出版时间: 2021-02-28 doi: 10.11855/j.issn.0577-7402.2021.02.12
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铁作为人体内重要的微量元素之一,参与多种重要的生理过程。血清铁蛋白(SF)是铁的主要贮存蛋白,可调节铁的储存和代谢。尽管铁蛋白检测已在临床应用较长时间,但其部分生物学特性如组织来源、分泌途径、受体相互作用及细胞效应等仍存在争议。虽然许多研究关注铁蛋白变化与肝脏疾病的关系,但各研究采纳的铁蛋白过高/过低阈值不尽相同,阻碍了对不同研究结果的一致性分析,亟需研究和制定铁蛋白参数的统一标准,以更好地阐明铁蛋白变化所反映的机体内铁状态。该文就铁的体内代谢过程,铁蛋白的结构及病理生理功能,以及SF与肝脏疾病关系的研究进展进行综述,以期为未来的研究提供导向。

铁元素  /  铁蛋白  /  肝炎  /  肝硬化  /  肝移植

As a crucial microelement of human body, iron is involved in many important physiological processes. Serum ferritin (SF) is the main form of protein for iron storage, and regulates the storage and metabolism of iron. Although detection of ferritin has been applied for clinical use for a long time, some biological properties of ferritin still remain controversial, including its tissue origin, secretory pathway, interactions with receptors and cellular effects. Although many researches paid attention to the relationship between the changes of ferritin and liver diseases, the cut-off points of ferritin used varies in different studies, which hinders the consistency analysis of the results of different studies. It is urgent to explore and establish uniform standard for the parameter of ferritin, so as to better elucidate the iron status in the body reflected by changes in ferritin. This paper reviews the in vivo metabolic process of iron, the structural composition and pathophysiological function of ferritin, and the relationship between SF and liver diseases for providing guidance for future research.

iron  /  ferritin  /  hepatitis  /  liver cirrhosis  /  liver transplantation
沙治林, 宋少华, 丁国善. 血清铁蛋白及其与肝脏疾病的关系研究进展. 解放军医学杂志, 2021 , 46 (2) : 181 -185 . DOI: 10.11855/j.issn.0577-7402.2021.02.12
Zhi-Lin Sha, Shao-Hua Song, Guo-Shan Ding. Research progress of relationship between serum ferritin and hepatic disease[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (2) : 181 -185 . DOI: 10.11855/j.issn.0577-7402.2021.02.12
作为重要的微量元素之一,铁参与了人体内多种重要的生理过程。血清铁蛋白(serum ferritin,SF)是铁的主要贮存蛋白,调节铁的储存和代谢[1]。铁蛋白最早于1937年由法国科学家Laufberger发现并从马的脾脏中分离出来[2]。SF的精确测量依赖于铁蛋白和抗铁蛋白抗体的纯化,以及高敏感度免疫检测技术的研发。1972年,Addison等建立了血清铁蛋白的免疫放射分析法,成功地从人血清中检测出铁蛋白。尽管铁蛋白检测已在临床应用较长时间,但其部分生物学特性如组织来源、分泌途径、受体相互作用以及细胞效应等仍存在争议[2]。本文综述铁在体内代谢的过程,铁蛋白的结构及病理生理功能,以及SF与肝脏疾病关系的研究进展。
铁元素以二价铁的形式吸收入血后被氧化成三价铁,经转铁蛋白转运到组织或细胞内,而后在线粒体中合成血红素,血红素与珠蛋白结合形成血红蛋白。未结合的铁与蛋白质结合形成铁蛋白及含铁血黄素,贮存于肝、脾、骨髓等器官的单核巨噬细胞系统中[3-4]
铁蛋白由蛋白质外壳和铁核心组成,其中蛋白质外壳是由L和H两种亚单位构成的24亚基蛋白,铁核心含4500个铁原子,是体内储存铁的形式之一。L、H型亚基分别由人体肝脏、心脏分离而出,其中L型比重较低。铁蛋白的L型与H型亚基比例取决于不同的组织类型和发育阶段[5]。由于大量分离、纯化SF较难,研究者常使用外源性组织铁蛋白研究其对细胞的作用,以模拟体内细胞分泌铁蛋白的旁分泌作用,取得了一定的研究成果,包括铁蛋白受体的识别、铁蛋白的增殖和信号反应等[2,6]
细胞外铁蛋白可作为肝星状细胞的促炎信号分子。外源性给予铁蛋白处理细胞,可激活磷脂酰肌醇-3羟激酶(phosphatidylinositol 3-hydroxy kinase,PI3K)磷酸化,以及活化蛋白激酶Cζ(protein kinase Cζ,PKCζ)和丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK),从而导致核因子κB(nuclear factor kappa-B,NF-κB)激活,进而增强白细胞介素1β(interleukin-1β,IL-1β)、诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)等促炎介质的表达[7]
普遍认为SF是体内多种炎症的急性期反应物与标志物,可在多种炎症状态下非特异性升高,包括慢性肾脏病、类风湿性关节炎、其他自身免疫性疾病,以及急性感染和恶性肿瘤等[8-9]
研究表明,细胞外铁蛋白可作为向细胞内输送铁的载体。转铁蛋白最多可携带2个铁原子,而单个铁蛋白分子可螯合多达4500个铁原子,是潜在的非常有效的铁转运系统[2]。既往研究发现铁蛋白可与多种不同细胞进行饱和结合,且识别了铁蛋白在人类淋巴细胞表面饱和结合的位点,并证实该结合为H铁蛋白而非L铁蛋白的特异性结合[2]
多种恶性肿瘤患者均存在SF升高[10]。某些情况下,循环系统中铁蛋白水平增高与铁蛋白构成向富含H铁蛋白的形态转变相关。铁蛋白和含铁血黄素释放的三价铁被还原为二价铁,后者在超氧化物和过氧化氢的存在下催化羟自由基形成。羟自由基是一种强氧化剂,可引起脂质过氧化、基因突变、DNA双链断裂、原癌基因激活以及抑癌基因抑制[11]。铁过载可改变T淋巴细胞亚群的分布,抑制T辅助细胞的功能及巨噬细胞和单核细胞的肿瘤杀伤作用,增加抑制性T细胞的数量和活性,进而损伤免疫系统对肿瘤细胞的监视和杀伤作用[12]
肝脏能够合成铁代谢中的关键蛋白——铁调素。铁调素与细胞结合后,会通过内吞作用及配体-受体复合物的蛋白水解作用触发转铁蛋白降解,从而减少铁流入血浆并导致饮食中铁的吸收受阻[13]。肝脏发生病毒性肝炎等炎症时,此过程因肝细胞合成铁调素减少而受阻,导致铁超负荷,从而引起肝脏中铁沉积和SF水平升高[14-15]。沉积于肝脏的铁通过对肝细胞的氧化应激进一步损伤肝脏。
据统计,慢性乙型肝炎病毒(HBV)感染影响全球约2亿人,并可能导致包括慢性乙型肝炎(CHB)、肝硬化和肝细胞癌(hepatocellular carcinoma,HCC)在内的慢性肝病。尽管有疫苗和抗病毒药物,每年仍有880 000例患者死于HBV相关肝病[16]。有研究发现,与非HBV感染者相比,HBV感染患者血液中可检测到较高水平的SF和较低水平的血清铁调素,其机制可能是由于HBV复制,被破坏的肝细胞释放铁蛋白增多,从而加重了肝细胞铁沉积[17]
全球有超过1亿7千万人感染丙型肝炎病毒(HCV),占全球人口的2.8%~3.0%,对全球健康构成了沉重的负担[18]。在慢性HCV感染中,铁吸收增加,导致肝脏铁过载而损害肝细胞,释放出铁蛋白并最终导致肝纤维化[19]。中国台湾一项连续纳入738例慢性丙型肝炎患者的研究发现,40.8%的患者SF水平升高,高SF水平与慢性丙型肝炎患者肝细胞脂肪变性和纤维化密切相关,SF水平升高是慢性肝病严重程度的早期标志[18]。有研究发现,SF水平与肝炎相关肝硬化患者的预后密切相关,与SF水平较低的患者相比,SF水平升高的肝硬化患者病死率更高[20]。肝炎相关肝硬化患者的SF水平与肝脏疾病的严重程度相关,且与早期病死率相关[21]
酒精能够增加人体内铁的吸收,吸收的铁到达肝脏后发挥促氧化作用,刺激肝胶原和铁蛋白合成以及肝星状细胞活化,从而促进肝纤维化和炎症的发生,这种致病机制在理论上支持铁蛋白作为酒精性肝病过渡到肝硬化的标志,也支持铁蛋白作为一种反映不良预后的因素[22]。酒精和铁对肝细胞的持续性损伤加剧了酒精性肝病患者的肝损伤程度[23]。有研究发现,在铁蛋白升高的酒精性肝病人群中,患者的SF在戒酒期间迅速降低,于戒酒后1~6周达到正常水平,此外,在肝功能和肝纤维化严重程度相近的条件下,未戒酒的酒精性肝病患者铁超负荷显著高于戒酒患者[24]
除酒精性肝病外,非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)、Wilson病及遗传性血色素沉积症等其他疾病也可导致肝脏脂肪变性和铁超负荷。中国一项研究分析了2029名有/无NAFLD的成人,对血清谷丙转氨酶(ALT)和SF的水平进行logistic回归分析,以评估SF与NAFLD和ALT升高的相关性,结果表明,在正常体重的中国成人中,SF与NAFLD发病风险和ALT升高呈正相关[25]。另一项研究发现,4%~65%的NAFLD患者合并高铁蛋白血症,肝铁含量增加可达11%~52%,表明铁超载与氧化应激、晚期纤维化和存活率降低相关[26]。体内过量的铁可能参与胰岛素抵抗,其机制包括降低碳水化合物的燃烧能力和改变脂肪组织的功能,从而加重NAFLD[2]
肝纤维化是一种对持续性肝脏损伤产生过度活跃的修复反应所致的细胞外基质过多沉积的病理状态,是慢性肝病向肝硬化的进展过程。在一些未经治疗的慢性肝病如血色素沉积症、病毒性肝炎、酒精性肝病及NAFLD中经常可观察到肝纤维化[27]。铁水平升高是上述促纤维化疾病的共同特征,因此,铁超负荷可能是此类疾病进展的危险因素[28]。过量的铁会导致产生大量的氧自由基,引起严重的细胞和组织损伤,还可在细胞中诱导促纤维化信号,加速肝纤维化进程[29]。肝硬化是临床常见的慢性进行性肝病,病理特征为广泛的肝细胞坏死、残存肝细胞结节状再生以及纤维间隔形成导致假小叶形成,最终肝脏变硬形成肝硬化[30]。CTP(Child-Turcotte-Pugh)评分已用于预测肝硬化患者的严重程度及预后。有研究发现,高SF水平可能与肝硬化预后不良相关[13]。肝硬化患者的SF水平与CTP评分存在明显正相关关系,高铁蛋白血症患者CTP评分更高。铁过载可通过诱导促炎性细胞因子的分泌而加重肝细胞炎症和凋亡,进而加重肝脏损害,SF作为胞质蛋白从坏死的肝细胞中漏出进入血管系统,引起高铁蛋白血症,因此,SF水平升高与肝硬化的程度及预后相关[31]
HCC通常基于慢性肝病而发生,是全球与癌症相关死亡的重要原因[32]。有研究发现,肝癌患者的SF水平高于健康受试者或其他肝病患者[33],肿瘤引起的SF水平升高可归因于两个方面:一方面,肿瘤相关巨噬细胞可导致SF的合成增加;另一方面,部分肿瘤组织可直接分泌SF[34]。SF检测可用于早期肝癌的诊断,铁水平升高使患者更容易发生感染,并可诱发氧化应激,改变免疫系统,以及促进肿瘤细胞的生长。在肝癌预测方面,存在肝脏铁过载的患者,慢性肝病进展更重、HCC发病风险更高。有前瞻性队列研究发现,男性和女性患者中均存在SF水平与肝癌风险之间的关联,在甲胎蛋白值低的患者中尤为明显。甲胎蛋白是诊断肝癌公认的肿瘤标志物,但其对肝癌的预测准确率并不高,有研究发现,将SF纳入甲胎蛋白预测模型后,预测肝癌的准确率显著增高[33]。术前SF是接受根治性肝切除术的肝癌患者术后生存率的重要独立预测因素,SF预测肝癌术后生存率的最佳临界值为267 ng/ml,术前SF水平升高提示患者的预后较差[34]。韩国的一项研究发现,晚期肝癌患者的SF水平增高与不良生存结局明显相关,在接受相同治疗的情况下,SF较高的患者中位生存期较短,表明SF在预测晚期肝癌患者的生存预后中具有重要作用[35]。因此,可通过SF识别可能预后不良的患者,以便在术前进行相应的个体化治疗。SF是一种临床上可通过非侵袭性手段获取的生物标志物,因而也适用于随访过程中的实时检测和重复监测[36]
肝移植常作为不可逆肝损伤的最终治疗选择,目前主要通过终末期肝病模型评分(model for end-stage liver disease,MELD)评估需求,预测不同肝脏疾病的3个月病死率,以及决定肝脏供体分配的优先级。MELD包括国际标准化比值(international normalized ratio,INR)、血清肌酐和血清胆红素等指标,高MELD评分提示病死率和并发症发生率更高,即更换器官的需求更加迫切。为更好地改善MELD评分分配的准确性,研究者开始关注SF与肝移植术后存活率的关系[37]。一项使用365 μg/L作为临界值将328例肝移植患者分为低SF组与高SF组的研究发现,高SF组患者的3年、5年生存率降低,总生存期显著缩短,提示肝移植术前SF水平升高预示肝移植术后病死率增高,SF可作为肝移植术后生存的独立预测因素[38]
肝移植术中缺血再灌注损伤(ischemia-reperfusion injury,IRI)可影响术后多种器官的功能,因此,准确判定IRI的严重程度对预测术后其他器官的损伤程度十分必要。研究发现,供体高SF水平与受体IRI风险呈正相关,且SF的检测具有微创、简便和经济的优势,有利于评估IRI的严重程度[39]。此外,有研究表明,术中SF的峰值与术中急性肺损伤、术后早期感染以及ICU停留时间存在正相关关系[40]
虽然现有研究越来越多地关注铁蛋白变化与肝脏疾病的关系,但到目前为止,各研究中使用的铁蛋白过高/过低阈值不尽相同,阻碍了对不同研究结果的一致性分析。未来研究应针对不同基础疾病人群进行分层分析,进一步明确铁蛋白变化与肝脏疾病的关系,且亟需研究和制定铁蛋白参数的统一标准,以更好地阐明铁蛋白变化所反映的机体内铁状态。铁稳态对维持人体的正常功能至关重要。肝脏通过产生铁调素在铁水平的调节中起着关键作用,慢性肝病患者常因产生的铁调素较少而导致铁超负荷。根据与转铁蛋白相互作用的铁调素结构域设计合成的迷你铁调素不仅可发挥降解转铁蛋白、减少铁流入血浆、阻止铁吸收的作用,还可避免天然铁调素价格昂贵、吸收率低、半衰期短等问题。未来研究可侧重于迷你铁调素的临床研究及操纵各种代谢途径来增加铁调素的内源性生成。
  • 国家自然科学基金(81671576)
  • 上海市卫生和计划生育委员会课题(201640274)
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doi: 10.11855/j.issn.0577-7402.2021.02.12
  • 接收时间:2020-04-21
  • 首发时间:2025-12-26
  • 出版时间:2021-02-28
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  • 收稿日期:2020-04-21
  • 修回日期:2020-10-17
基金
National Natural Science Foundation of China(81671576)
国家自然科学基金(81671576)
Project of Shanghai Municipal Commission of Health and Family Planning(201640274)
上海市卫生和计划生育委员会课题(201640274)
作者信息
    海军军医大学附属长征医院器官移植科,上海 200003

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2种不同金属材料的力学参数

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genus
种数
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species
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Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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