原发性血色病临床病理诊断研究进展

原发性血色病(hereditary haemochromatosis,HH)是一种常染色体隐性遗传病,由于基因突变导致小肠铁吸收增加,进而使铁在组织内沉积,导致组织损伤,肝脏是受影响的主要器官。最常见的类型是HFE相关原发性血色病,非HFE相关原发性血色病较少见。HH最初的临床表现是非特异性的,临床诊断时多是晚期,常见的临床并发症包括肝硬化、糖尿病、皮肤色素沉着和肝细胞癌等。当HH患者肝功能异常或血清铁蛋白高于1000μg/L时应进行肝组织活检,这有助于鉴定铁沉积的程度和纤维化分期。本文对HH的临床表现和病理诊断进行综述,包括铁沉积引起的组织学改变、肝铁浓度测量和治疗后病理改变。     

美国肝病学会2011年血色病诊疗指南要点

铁过度沉积综合征按照病因可分为遗传性血色病（HH,即狭义的血色病,HFE或非-HFE基因缺陷）、继发性铁过度沉积（最常见的病因为无效红细胞造血、胃肠外铁超负荷和慢性肝病等）和混合性,其中HH是白种人常见的遗传病,     

我国人群遗传性血色病基因突变特点分析

目的分析我国人群遗传性血色病(HH)的基因突变特点。方法选取2013年1月-2015年12月就诊于首都医科大学附属北京友谊医院的9例HH患者,提取基因组DNA,对4种类型HH基因HFE(Ⅰ型)、HJV(ⅡA型)、HAMP(ⅡB型)、TFR2(Ⅲ型)及SLC40A1(Ⅳ型)所有外显子进行PCR扩增和Sanger测序,分析基因突变情况;另选取50例健康人群作为对照组,分析已鉴定的基因突变在健康人群中的表达情况。结果 9例HH患者中,存在Ⅰ型HFE基因H63D突变2例、ⅡA型HJV基因E3D突变1例、Ⅲ型TFR2基因I238M突变2例,Ⅳ型SLC40A1基因IVS 3+10 del GTT剪切突变1例,未检出欧美人群常见的Ⅰ型HFE C282Y突变。5例患者未检测出任何错义或剪切突变。此外,在一个遗传家系中发现HH患者同时存在HFE H63D、HJV E3D及TFR2I238M突变,但携带其中2个突变的健康兄妹没有出现HH表型。结论 HH基因突变在不同种族患者中存在较大的差异,我国可能以非HFE型HH为主,推测可能存在与目前已知基因不同的HH相关基因,需进一步研究证实。     

Ⅳ型遗传性血色病一例家系的临床研究

遗传性血色病(hereditary hemochromatosis,HH)是欧美常见的遗传病,发病机制是以小肠铁吸收增加造成多种组织和器官进行性铁沉积并逐渐导致脏器功能损害为特点的铁代谢异常,通常在40～50岁发病,我国罕见.近年发现由肝脏合成的hepcidin是血清铁的负性调节激素,对于维持机体铁稳态发挥重要作用[1].目前研究证实存在多个HH相关突变基因,并据此将HH分为4型[2],Ⅰ～Ⅲ型均为常染色体隐性遗传病,Ⅳ型HH为常染色体显性遗传病.     

1例携带HFE基因剪切突变的遗传性血色病患者家系调查

目的探讨1例新型的遗传性血色病(HH)患者家系HFE基因突变形式。方法对确诊的1例HH患者分析其与5位相关亲属的血色病基因,提取血液基因组DNA,采用PCR扩增相关基因HFE、HJV、HAMP、转铁蛋白受体(TfR)2、SLC40A1的外显子、内含子剪切序列,琼脂糖凝胶电泳、纯化后,双向直接测序检测突变位点。结果先证者肝功能异常,血清铁(SI)、总铁结合力(TIBC)、铁蛋白(SF)、转铁蛋白饱和度(TS)均升高,HFE基因外显子EXON2的区间序列2号内含子第4个碱基出现T→C纯合突变(IVs 2+4T→C,C/C纯合,splicing,异常),HJV、HAMP、TfR2、SLC40A1未见异常,患者儿子出现与其相同纯合突变,3位亲属存在杂合突变,1位亲属无异常突变。结论基因检测在血色病诊断中起着重要作用,HFE基因IVs 2+4T→C突变可能是新型的中国HH的致病遗传基因突变类型。     

Comprehensive analysis of HFE gene in hereditary hemochromatosis and in diseases associated with acquired iron overload

BACKGROUND Patients with hepatitis C virus(HCV) and hepatocellular carcinoma(HCC) may or not develop iron overload(IO),which is associated with worst prognosis,because can cause serious damage to organs.HFE gene controls the iron uptake from gut,particularly in patients with hereditary hemochromatosis(HH).AIM To identify associations between HFE coding region in patients exhibiting hereditary hemochromatosis and in diseases associated with acquired IO.METHODS We sequenced exons 2 to 5 and boundary introns of HFE gene,evaluating all polymorphic sites in patients presenting hereditary(hemochromatosis) or acquired iron overload HCV and HCC) and in healthy controls,using Sanger sequencing.We also determined the ensemble of extended haplotype in healthy control individuals,including several major histocompatibility complex loci,using sequence specific probes.Haplotype reconstruction was performed using the Arlequin and Phase softwares,and linkage disequilibrium(LD) between histocompatibility loci and HFE gene was performed using the Haploview software.RESULTS The HFE*003 allele was overrepresented(f = 71%) and HFE*001 allele was underrepresented(f = 14%) in HH patients compared to all groups.A strong linkage disequilibrium was observed among the H63 D-G,IVS2(+4)-C and C282 YG gene variants,particularly in HH;however,the mutation IVS2(+4)TC was not directly associated with HH susceptibility.The HFE*001/HFE*002 genotype conferred susceptibility to HCC in HCV patients exhibiting IO(P = 0.02,OR =14.14).Although HFE is telomeric to other histocompatibility genes,the H63 DG/IVS2(+4)-C(P ≤ 0.00001/P ≤ 0.0057) combination was in LD with HLA-B*44 allele group in healthy controls.No LD was observed between HFE alleles and other major histocompatibility loci.CONCLUSION A differential HFE association was observed for HH and for diseases associated with acquired IO(HCV,HCC).Since HFE is very distant from other histocompatibility loci,only weak associations were observed with these alleles.     

Function of the hemochromatosis protein HFE： Lessons from animal models

Hereditary hemochromatosis （HH） is caused by chronic hyperabsorption of dietary iron. Progressive accumulation of excess iron within tissue parenchymal cells may lead to severe organ damage. The most prevalent type of HH is linked to mutations in the HFE gene, encoding an atypical major histocompatibility complex class I molecule. Shortly after its discovery in 1996, the hemochromatosis protein HFE was shown to physically interact with transferrin receptor 1 （TfR1） and impair the uptake of transferrin-bound iron in cells. However, these findings provided no clue why HFE mutations associate with systemic iron overload. It was later established that all forms of HH result from misregulation of hepcidin expression. This liverderived circulating peptide hormone controls iron efflux from duodenal enterocytes and reticuloendothelial macrophages by promoting the degradation of the iron exporter ferroportin. Recent studies with animal models of HH uncover a crucial role of HFE as a hepatocyte iron sensor and upstream regulator of hepcidin. Thus, hepatocyte HFE is indispensable for signaling to hepcidin, presumably as a constituent of a larger ironsensing complex. A working model postulates that the signaling activity of HFE is silenced when the protein is bound to TfR1. An increase in the iron saturation of plasma transferrin leads to displacement of TfR1 from HFE and assembly of the putative iron-sensing complex. In this way, iron uptake by the hepatocyte is translated into upregulation of hepcidin, reinforcing the concept that the liver is the major regulatory site for systemic iron homeostasis, and not merely an iron storage depot.     

遗传性血色病分子机制的研究进展

遗传性血色病是由于基因变异引起铁代谢异常,进而造成多器官铁沉积.目前认为铁代谢转运主要由hepcidin-转铁蛋白(FPN)轴控制,血色病蛋白编码基因(HFE)、FPN受体2(TfR2)、血幼素(HJV)、HAMP(hepcidin的编码基因)基因突变都可以影响hepcidin水平.FPN突变也可引起铁超负荷,但机制有所不同.各调节蛋白的基因突变可引起不同的疾病表型.     

《2019年美国胃肠病学院临床实践指南:遗传性血色素沉着症》摘译

遗传性血色素沉着症(hereditary hemochromatosis,HH)是北欧人群最常见的遗传疾病之一。最近HH在诊断、管理及治疗方面有了新的进展。大部分HH患者已通过分子诊断检测得以诊断。一些基因型-表型相关性的研究证实C282Y纯合基因型和其他HFE突变模式的患者之间的临床特征存在差异。越来越多的非侵入性检查(如MRIT2*)使肝脏铁沉积的定量测定更简便,并降低了患者肝活组织的检查率。诊断时血清铁蛋白(SF)<1000 ng/ml仍然是鉴别晚期肝纤维化低风险患者的重要诊断试验,应常规作为初步诊断评估的一部分。对其他类型的HH进行基因检测是可行的,但价格昂贵,通常不适用于大多数临床实际情况。血清SF在非酒精性脂肪性肝病(NAFLD)和酒精性肝病患者中可能会升高,在非C282Y纯合子或C282Y/H63D复合杂合子且血清SF升高的HH患者中,更为常见。在疑似铁超载的非C282Y纯合子患者中,应排除肝脏疾病的继发原因。静脉切开术仍然是主要的治疗方法,但新兴的新型治疗方法,如新的螯合剂可能对一些特定患者有一定的治疗作用。     

国人原发性血色病的临床特点—1例报告及17例综述

原发性血色病(Hereditary Hemochromatosis,HH)是一种与HLA关联的常染色体隐性遗传病,表现为纯合子的铁代谢紊乱,即肝脏和其他器官的实质细胞铁的渐进沉积.铁在实质器官的逐渐沉积可导致肝硬化、肝癌、充血性心力衰竭、性腺功能低下、糖尿病和皮肤色素沉着.有证据表明一旦铁浓度(Hepatic iron conce tration.HIC)>400μmol/gm则有出现肝硬化及进展性肝功能衰竭的危险.对与HH患者小肠吸收铁功能增强有关的血色病基因仍未明了.愈来愈多的证据表明在遗传状态下遗传因素在疾病表达中起重要作用.