姜政;黄爱龙;陶小红;王丕龙摘要 幽门螺杆菌是人类最常见的致病菌,也是人类第一类致癌原,他的感染不但与胃肠道疾病有直接关系,而且与肠外疾病的发生也有重要的关系.Hp感染是一种慢性、持续性感染,通过慢性炎症免疫反应、毒素的释放、炎症递质的增多以及自由基的生成,引起感染局部和远处损害,从而导致或加重了除胃肠疾病外其他系统疾病.近年来,随着对Hp致病机制进一步认识,Hp与胃外疾病关系引起了广泛的关注,如Hp的感染增加了心脑疾病的危险因素,引起心肌缺血、坏死、以及脑卒中的发生;Hp的感染导致了胃泌素的增高,刺激了肺癌的发生敕⒄梗豹獺p的感染还增加了支气管炎的发生;硬皮病、酒渣鼻患者,Hp感染率显著地增高,根治Hp之后,上述症状得到了明显地改善等.综述近年来Hp与胃外疾病关联的研究报道,为临床诊断、鉴别诊断以及治疗提供理论依据.0 引言幽门螺杆菌(Helicobacter pylori ,Hp)是上消化道疾病的主要致病菌,他的感染不但与B型胃炎和消化性溃疡的发生有密切关系[1-6],而且与非溃疡性消化不良,MALT淋巴瘤和胃癌也有重要关系[7-14],并已被世界卫生组织列为胃癌等肿瘤发生的相关致病菌[15,16].Hp在我国普通人群的感染率较高达到50~80%,并仍以每年1~2%速度增加[17].近年来,随着对Hp的深入认识,Hp感染与胃外疾病的关联也引起广泛的关注.局部炎症伴随系统的损害-持续的感染能诱发慢性炎症和免疫反应,引起感染的局部和远处器官的损害.现将Hp感染与胃外疾病的关联及机制的研究进展作一综述.1 Hp感染与心血管系统疾病在发现Hp以前,有关消化性溃疡与心血管疾病的关系时有报道.1976年,Sternby报道了一组5万例的尸检报告,其中40-59岁之间消化性溃疡患者左冠状动脉阻塞发生率是无溃疡者的5倍;1998年Pasceri报道了88例缺血性心脏病患者Hp感染,检出率明显高于年龄、性别、饮食习惯等配比因素相似的对照组;Xu et al[18]研究发现冠状动脉疾病患者Hp感染率显著高于健康人.Hishiki et al[19]对消化性溃疡进行了Hp根治前后心脑血管疾病危险因子的检测,提示根除了Hp之后,可以延缓心脑血管疾病的进程.De-Luis et al[20]在糖尿病患者中研究了Hp的感染与心血管疾病和脑血管疾病的关系.他们检测了127例糖尿病患者微血管的并发症、心血管疾病的危险因子、急性期反应物等,发现Hp阳性的糖尿病患者更容易并发冠心病,而且脑栓塞也常发生,与Hp阴性的糖尿病患者存在显著的差异.据文献[21-25]报道,心脑疾病除了古典的危险因子外,还与持续的慢性的感染有重要关系,特别提到Hp的感染.这与毒力Hp感染通过少量、持续的炎症刺激引起动脉粥样硬化有关.有实验证明[26],用Hp热休克蛋白喂养动物,已能够导致冠状动脉粥样硬化.但 Tsai et al[27]在探讨Hp感染与心脑血管疾病的关系时,对165例冠心病患者和127名健康者就心脑血管危险因子、社会经济状况等进行了检测,结果发现Hp的感染与心脑血管疾病无直接联系.尽管目前多数观点认为Hp感染与冠心病关联密切,但Hp感染是否为冠心病的独立危险因素,目前尚有较大争议,且迄今为止尚无报道证明动脉粥样硬化斑块中有Hp的存在.2 Hp感染与呼吸系统疾病90%以上的支气管肺癌都归因于吸烟、石棉、以及空气污染等.而对肺癌的发展与浸润的内在因素而知之甚少.肺泡与消化道内皮细胞都起源于胚胎时期的内胚层,消化道内皮细胞在胃泌素的刺激下增生,而Hp感染的患者胃泌素分泌增多.不难假设,肺癌的发生、发展是否也与胃泌素的刺激有关?近来研究发现证明了此观点,其依据是[28]:(1)肺癌患者的Hp阳性率,特别是表达CagA基因者, 显著高于同性别同年龄健康对照组;(2)胃泌素以及胆囊收缩素受体在肺癌组织以及癌旁组织中高度表达,而在正常支气管黏膜中无发现;(3)免疫组化分析,胃泌素在肺癌组织以及癌旁组织中大量存在,从而推测肺癌的发生与Hp的感染存在一定的关系.Tsang et al[29]最近报道,对支气管扩张患者与健康志愿者从1min呼气量、最大呼气量、痰量以及呼吸道、消化道的症状进行了比较,发现支气管扩张患者,特别是表达CagA基因的Hp阳性患者发生了明显的改变.从而推论,Hp可能是导致支气管扩张的重要因素.Caselli et al[30]从流行病学的角度探讨了慢性支气管炎与Hp的关系.通过逻辑回归以及单因素等分析发现,Hp增加了慢性支气管炎发生的危险.从而提出对慢性支气管炎患者进行根除Hp之后进一步评估的建议.3 Hp感染与皮肤病慢性荨麻疹是最常见的皮肤损害之一,他的病因目前还不十分清楚.最近调查表明,上消化道Hp感染可能是慢性荨麻疹的病原菌[31-36]. Dauden et al[37]对Hp阳性的30例荨麻疹患者进行了一个疗程为14d的Hp治疗,并随访6mo,了解Hp根治情况和荨麻疹的缓解程度.其结果为,在根除Hp之后,有26.7%的患者得到了明显的改善蛳 Ojetti et al[38]对33例荨麻疹患者和25例消化不良患者进行血清/胃液嗜酸性阳离子蛋白(ECP)以及胃黏膜嗜酸性细胞浸润程度的检测,发现Hp阳性的荨麻疹患者,血清ECP和胃黏膜嗜酸性细胞浸润显著高于Hp阴性的荨麻疹患者和对照组,而且根除Hp之后,上述指征随之下降.有学者认为,上述症状是由于Hp持续感染,导致炎症递质的释放,引起皮肤血管通透性增加而形成的.近年来发现扁平苔癣患者常常伴有消化性溃疡的病史,而且Hp检出率与无扁平苔癣患者相比高出3倍[39].酒渣鼻是一个病因不清、常伴随消化道症状、抗菌素治疗有效的疾病.据报道,酒渣鼻患者Hp感染率比健康者高出许多.为了探讨Hp与酒渣鼻的关系,Utaset al[40]对25例酒渣鼻患者和87名健康者进行了Hp血清学检测,以及Hp根除之后,酒渣鼻的缓解情况.结果表明,Hp根除之后酒渣鼻得到了明显的改善.因此,作者得出了酒渣鼻的发生与Hp有一定的关系,并且根除Hp之后可控制或缓解酒渣鼻症状的结论.Szlachcic et al[41]对60例酒渣鼻患者进行了Hp、血清胃泌素、IL-8、TNF 等检测,其结果为:酒渣鼻患者Hp感染率、CagA阳性率分别为88%、67%,而对照组则为65%和32%,酒渣鼻伴随的胃炎及程度显著高于对照组,通过1wk抗溃疡治疗(克拉霉素500mg bid、奥美啦唑20mg bid、甲硝唑500mg bid),53例治疗者中,有51例Hp转为阴性;在2~4wk内,51例患者酒渣鼻症状得以消除,1例明显改善,1例无效,血清胃泌素、IL-8、以及五肽胃泌素诱导的最大胃酸分泌量都显著地下降.因此,酒渣鼻可能是Hp感染肠道外症状表现之一,这种症状可能与Hp细胞毒素和细胞因子有关.Vazquez et al[42]报道1例因排尿困难、酒渣鼻等皮肤损害,病史长达20a的52岁男性患者,通过根除Hp之后,上述症状得以消除.Avciet al[43]为了调查白塞病(Behcet’s disease,BD)与Hp的关系,研究了69例患者,虽然BD患者与健康者Hp感染率无显著差异,但根除Hp之后,BD症状显著地改善,因而提出了Hp参与了BD发生发展.Neri et al[44]研究了痒疹结节(Prurigo Nodularis ,NP)与Hp的关系, 对42例Hp阳性的门诊NP患者进行Hp根除,其中39例患者根除了Hp,其搔痒症状以及皮肤损害都得到了明显的改善.推测Hp可能诱发或加重了脉管炎,从而使临床症状、体征加重.Yazawa et al[45]为了探讨Hp与系统性硬皮病的关系,对124例硬皮病患者进行了Hp检测,结果发现硬皮病患者Hp感染率显著地增高,而且抗Hp血清滴度与硬皮病食管无动力呈正相关.因此,Hp在硬皮病食管无动力方面起了重要的作用.4 Hp感染与造血系统疾病最近报道,Hp与自身免疫性血小板减少性紫癜(ITP)有一定关系,Emilia et al[46]对30例ITP患者进行了Hp检测以及Hp根除.结果表明,ITP患者Hp感染率为43.33%,根除Hp之后,33.33%的患者获得了完全缓解,16.66%获得了部分的缓解.因此,作者认为,细菌的根除为ITP患者的治疗提供了一个全新的治疗方案.缺铁性贫血是最常见的一类贫血,最近研究表明,缺铁性贫血与Hp存在一定的关系[47-50],Parkinson et al[51]对Hp与缺铁性贫血的关系做了大量的研究,特别是20岁以下人群,缺铁性贫血与Hp感染呈正相关, 认为Hp是缺铁性贫血一个原因.Konno et al[52]报道了6例Hp阳性的缺铁性贫血患者,一旦停服铁剂,贫血就复发.在排除了其他导致贫血原因后,进行了Hp根治治疗,贫血也随之得以纠正.随访27~50mo,贫血不再复发.Annibale et al[53]对81例恶性贫血患者进行了一系列的检测,认为Hp对一部分恶性贫血起到一个诱发作用.Choe et al[54]为了调查体育运动员缺铁性贫血与Hp的关系,对440名在校学生和220名运动员进行了血红蛋白、血清铁、总铁结合能力、铁蛋白、IgG和抗Hp抗体等检测,结果发现,女性运动员缺铁性贫血发生率、Hp感染率、以及Hp阳性的缺铁性贫血发生率与对照组相比,差异显著.根除Hp之后, 血红蛋白、血清铁、总铁结合能力、铁蛋白得到了明显改善.Kaptan et al[55]研究了VitB12缺乏与Hp的关系以及根除Hp之后,VitB12缺乏改善的情况.对138例贫血和VitB12缺乏的患者进行了检测,Hp发生率为56%,根除Hp之后,40%的患者贫血和VitB12缺乏得到了显著地改善,从而认为根除Hp对纠正VitB12缺乏和改善贫血具有重要的意义.Annibale et al[56]对30例Hp感染的缺铁性贫血患者进行了Hp根治后对贫血的影响观察.随着Hp的根除,贫血也随之得到了纠正.Choe et al[57]对43例青少年患者就缺铁性贫血与Hp的关系进行了双盲、对照研究,发现补铁剂的同时辅以Hp根除治疗比单纯铁剂治疗起效更快、效果更显著,而且Hp根除治疗还可以增强铁剂的吸收.Cecchi et al[58]报道了1例过敏性紫癜患者,在根除了Hp后,过敏性紫癜也随之消除.作者认为Hp可能是过敏性紫癜病原之一.5 Hp感染与泌尿系统疾病血尿酸综合征主要表现为排尿困难、血尿、会阴疼痛等,手术后涉及到碱代谢、低氯血症、高胃泌素血症以及各种并发症. Celayir et al[59] 研究了Hp与上述症状的关系,对做了胃膀胱成形术的10例血尿酸综合征患者进行了检测,发现Hp的感染率为40%,这4例患者不同程度地出现了低pH尿液、高胃泌素血症、以及各种并发症.而其他6例Hp阴性患者则无上述表现.因此,作者建议对胃膀胱成形术后患者或即将行胃膀胱成形术患者进行Hp的检测,若Hp阳性,就需要Hp的根治,这样有利于减少术后的并发症.Celayir et al[60]报道1例膀胱外翻女孩,进行了胃膀胱成形术,近来出现会阴疼痛、排尿困难、血尿以及胃部症状.对她进行了膀胱中胃黏膜组织Hp检测和血清胃泌素检测,结果发现:血清胃泌素增高,Hp阳性.根除Hp之后,上述症状消除.因此,对胃膀胱成形术的患者出现上述症状就应考虑Hp感染的可能.肾功能不全的患者存在胃蛋白酶原增高的现象[61].Tamura et al[62]研究了血透析的患者胃蛋白酶原增高是否与Hp有关.对49例血透析的患者和48例对照者进行了胃镜检测、以及血清中胃蛋白酶原I和胃蛋白酶原II测定.结果发现透析患者胃蛋白酶原I和胃蛋白酶原II显著地增高.因此,作者提出,如果透析患者出现胃蛋白酶原I和胃蛋白酶原II增高,就要考虑Hp感染的可能,至于Hp如何导致透析患者胃蛋白酶原I和胃蛋白酶原II增高,目前还不清楚.据文献[63,64]报道,Hp还可使血透患者出现高胃泌素血症,根除Hp后,胃泌素随之下降.Nagashimaet al[65]研究了膜性肾病与Hp的关系,检测了16例膜性肾病,与糖尿病肾病、IgG肾病、以及正常肾脏进行对比.通过抗Hp多克隆、单克隆抗体进行免疫组织化学标记检测,在膜性肾病患者肾脏组织标本中,肾小球毛细血管壁上发现了有颗粒状沉积,而且与多克隆抗体起反应,从而证实Hp参与了膜性肾病的发生.6 Hp感染与骨骼系统疾病Zentilin et al[66]探讨了Hp与类风湿性关节炎的关系, 对15例Hp阳性患者和16例Hp阴性患者进行了一系列检测,除了抗类风湿性关节炎药物之外,对15例Hp阳性患者还加入了根治Hp的药物.结果发现,根除Hp之后,15例Hp阳性患者临床症状得到了全面的缓解,而Hp阴性患者则无丝毫地改变.因此,作者提出Hp可能参与了类风湿性关节炎的发生,同时对Hp感染的类风湿性关节炎建议进行Hp根除,有利于症状的控制.Hp热休克蛋白(HSP)与人类热休克蛋白高度同源性常是发生自身免疫性紊乱的机制.Aragona et al[67]研究了Hp及其HSP与斯耶格伦综合征的关系,对34例原发性和19例继发性斯耶格伦综合征,22例其他自身免疫性疾病以及43名健康者进行了检测,结果发现Hp及其HSP在原发性和继发性斯耶格伦综合征中显著高于其他患者,从而得出了HSP在原发性和继发性斯耶格伦综合征的免疫反应中与Hp的感染有一定关系.7 Hp感染与神经系统疾病慢性感染可增加缺血性脑中风的可能性,Grau et al[68]研究了缺血性脑中风与Hp的关系,对109例急性脑缺血和82名健康者进行了抗Hp血清学检测,以及多因素分析,结果发现:缺血性脑中风Hp感染率与健康者相比,差异显著.作者提出Hp可能是缺血性脑中风一个独立危险因子.Suto et al[69]报道,Hp能够使实验性肝硬化动物血氨增高,诱导肝性脑病的发生.最近研究表明,表达CagA的Hp与头疼具有一定的关系.Gasbarrini et al[70]探讨了头疼患者CagA阳性的Hp发生率.对175例头疼患者和152名健康者进行了研究,头疼患者与健康者Hp发生率差异不显著,但CagA阳性的发生率在两者之间差异显著,特别是先兆头疼,CagA阳性的Hp发生率显著性地增高.因此,作者推论头疼可能与Hp感染导致炎症递质的释放而引起血管扩张有关.帕金森病与消化性溃疡有关系,多巴胺拮抗剂可以引起实验性溃疡的发生,而多巴胺能神经激动剂则起保护作用[71].Dobbs et al[72]对105例特发性帕金森病患者和210名健康者进行了Hp检测,其结果特发性帕金森病患者Hp感染率显著性增高,与健康者存在显著性差异.Hp感染可降低多巴胺能的反应性.从而出现Hp感染可加重帕金森病症状8 Hp感染与自身免疫性疾病据推测Hp与自身免疫性甲状腺疾病(ATD)有一定关系,并在其发生发展中起着重要作用.Figura et al[73] 对41例ATD患者以及33例健康者进行了研究,78.0%ATD患者感染Hp,对照组为 48.4%,而CagA阳性的ATD患者为56.0%,对照组为24.2%,两者存在显著性差异.因而作者提出CagA阳性Hp感染者增加了患ATD的危险性.对于1型糖尿病患者来讲,Hp感染不但增加了并发症的发生,而且增加了胰岛素的用量[74].根除Hp后,1型糖尿病患者的血脂以及止血功能都得到了明显改善[75].Hp致自身免疫性疾病的机制可能是Hp感染引起致炎物质缓慢释放激活机体潜在的自身免疫反应,也可能Hp与机体有组织相容性抗原的存在. 总之,有关Hp感染与胃外疾病关联的报道日益增多,但多数机制目前尚属假定或推测阶段.因此有必要制备Hp单克隆抗体,进行免疫组织化学检测,进一步探讨Hp与胃外疾病的关系.姜政,陶小红,王丕龙,重庆医科大学第一附属医院消化科 重庆 400016黄爱龙,重庆医科大学肝炎研究所 重庆 400010参考文献1 Vandenplas Y. 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