以消化道出血为主要表现的CREST综合征合并干燥综合征及原发性胆汁性肝硬化1例报道

2013-07-13 北京协和医院内科 卢杰 北京协和医院消化内科 李 姚方 杨爱 中国医学论坛报

    病史简介   患者女性,51岁,因“腹泻12年,反酸1年半,呕血1个月”于2009年3月5日被收入我院。   患者于1997年接受阑尾切除术后开始出现腹泻,4~5次/日

 

  病史简介

  患者女性,51岁,因“腹泻12年,反酸1年半,呕血1个月”于2009年3月5日被收入我院。

  患者于1997年接受阑尾切除术后开始出现腹泻,4~5次/日,为黄色稀糊样便,不伴腹痛、里急后重,在接受止泻等对症治疗后可减轻。

  2007年底,患者开始出现反酸、胃灼热及胸骨后异物感,饱餐后及平卧位加重,间断服用埃索美拉唑等药物后症状可明显缓解。

  2009年2月初患者出现进硬食后反复呕吐咖啡色物,共3次,每次250~400 ml,伴有黑便、头晕、乏力,无腹痛。就诊于当地医院,血常规检查结果显示,白细胞为 2.3×109/L,血红蛋白为77 g/L,血小板为89×109/L;肝肾功能正常;胃镜检查显示食管溃疡、浅表性胃炎;腹部增强CT显示,肝硬化、门脉高压、脾大、腹水。患者在接受止血等对症支持治疗后症状缓解。

  2月28日,患者进硬食后呕鲜血,约100 ml,我院门诊就诊。检查结果显示,血红蛋白为69 g/L,平均红细胞体积为75.9 fl;便常规检查显示,红细胞、白细胞阴性,便潜血(+);肝功能检查未见异常;乙肝五项检查均为阴性;凝血功能正常;腹部B超检查显示,肝内弥漫性病变,脾大,脾静脉、门静脉增宽;胃镜检查显示,距门齿35 cm处见食管呈疝环样改变,其上食管右侧壁可见黏膜下毛细血管扩张,环下方可见溃疡覆少许白苔(图1~2)。患者呈贫血胃黏膜相。为进一步诊治收入院。

  患者既往史、个人史、月经婚育史及家族史均无特殊。

  查体显示,患者贫血貌,无黄疸,浅表淋巴结未触及肿大。颈静脉无怒张,肝颈回流征阴性。心肺未见明显异常。腹软,肝肋下未及,脾肋下5 cm可触及,质软。移动性浊音阳性。

  《北京协和医院消化疑难病剖析111例》是北京协和医院为了纪念我国医学泰斗张孝骞教授诞辰111周年而出版。张孝骞教授毕生治学严谨,重视实践,坚持用科学的态度对待每一个病例。这种精神和做法始终影响着协和,特别是协和消化科一代代医师的成长。该书汇集了协和医院在2004-2008年期间比较典型的疑难或特色病例,每一个病例均从初诊开始,一步步抽丝剥茧,明确诊断。阅读此书,对培养病例诊断的临床思维大有裨益。

  如何解释患者的临床表现?

  患者目前最突出的问题是“消化道出血”,这也是到我院就诊的原因。此外,患者同时存在的其他突出问题包括血常规三系降低,影像学提示肝硬化和门脉高压。三者间能否用一元论解释?

  患者表现为呕吐咖啡样物,伴有黑便,便常规正常,潜血阳性,因而出血部位考虑为上消化道,出血量中等。在出血原因方面,根据先后两次胃镜结果,基本可除外消化性溃疡或曲张静脉破裂出血。内镜下见到胃食管接合部溃疡及食管毛细血管扩张,二者皆有可能为出血病因。

  结合患者既往慢性腹泻及反酸病史,临床影像学检查提示肝硬化、门脉高压、脾大,实验室检查提示血常规三系降低等,病因方面需要考虑以下几方面。

  肝硬化、门脉高压、→上消化道出血

  不支持之处在于,患者临床肝硬化表现不典型,肝功能、血白蛋白、凝血功能基本正常,胃镜下未见食管胃底静脉曲张,不支持静脉曲张出血。肝硬化病因方面,患者乙肝五项阴性,不支持慢性乙型病毒性肝炎;患者为中年女性,须考虑自身免疫性肝病,尤其是原发性胆汁性肝硬化(PBC)的可能。

  胃食管反流病(GERD)

  患者有反酸、烧心,与饱餐及体位有关,质子泵抑制剂(PPI)治疗有效。胃镜检查可见食管胃接合部疝囊结构,故食管裂孔疝及GERD诊断明确。食管裂孔疝患者胃食管接合部可发生溃疡,多为线性溃疡,又名为卡梅伦(Cameron)溃疡,是上消化道出血的少见原因之一,存在于5%的食管裂孔疝患者。但食管裂孔疝、GERD合并溃疡出血不能解释患者慢性腹泻、毛细血管扩张及门脉高压等表现。

  遗传性毛细血管扩张症

  该病的毛细血管扩张可发生于全身任何部位的皮肤和黏膜。胃肠道最常受累的部位是胃和十二指肠,常表现为隐性消化道出血、缺铁性贫血。但该患者缺乏其他部位皮肤及黏膜毛细血管扩张或出血表现,且该病也无法解释患者的其他临床表现。

  系统性结缔组织病

  该患者为中年女性,慢性病程,前述疾病无法解释患者全貌,须警惕结缔组织病。

  结缔组织病可累及肝脏或合并自身免疫性肝病,硬皮病、干燥综合征(SS)、多发性肌炎/皮肌炎等都可致食管运动功能异常,并发食管炎,硬皮病中的特殊类型CREST综合征还可引起毛细血管扩张。

  须进一步追问相关病史,检测自身免疫相关血清学指标,寻找多系统受累证据。

  进一步检查发现自身免疫性疾病证据

  追问病史,患者有双手雷诺现象、口干、眼干表现,无反复口腔溃疡、外阴溃疡等。进一步查体发现患者双手指尖可疑“腊肠指”,指端皮肤可见毛细血管扩张。

  检查结果显示, 碱性磷酸酶为88 U/L,γ-谷氨酰转酞酶为30 U/L,红细胞沉降系数为6 mm/第1小时,C反应蛋白为2.4 mg/L,免疫球蛋白M为3.01 g/L,免疫球蛋白A、G、补体正常;ANA(+),为散点型1 ∶640;抗Sm、SSA、SSB、Scl-70、Jo-1、RNP、rRNP抗体均阴性;AMA(+),为1 ∶640,AMA-M2亚型>200 RU/ml;ACA(+),为1 ∶640;ACL及ANCA均阴性。

  全消化道造影显示,食管蠕动力差,食管下段管腔狭窄,右侧有小溃疡。

  腹盆增强CT显示,肝硬化伴门脉高压,门脉多发血栓形成(图3~4)。与既往外院CT片相比,门脉充盈缺损为新出现病变;食管胃底消化道管壁强化增加,侧支循环形成可能性大。腹平片显示,双髂骨重叠处皮下多发钙化影(图5)。结肠镜检查显示,结肠散在多发毛细血管扩张(图6)。

  骨穿检查显示,骨髓增生活跃,考虑脾亢。口腔科、眼科会诊结果为符合口干燥症、眼干燥症。唇腺活检检查显示,少许小涎腺组织,部分腺泡轻度萎缩,导管周围散在淋巴细胞浸润,导管扩张。

  CREST综合征合并其他两种自身免疫疾病诊断明确

  至此,结合患者存在食管动力异常、雷诺现象、内镜下食管与结肠黏膜多发毛细血管扩张、指端毛细血管扩张、腊肠指、皮下钙化及ACA高滴度阳性,CREST综合征[钙质沉着(calcinosis)、雷诺现象(Raynaud’s phenomenon)、食管运动功能异常(esophageal dysmotility)、肢端硬化(sclerodactyly)及 毛细血管扩张(telangiectasis)]诊断明确。

  CREST综合征的特征

  CREST综合征是硬皮病的特殊亚型,包括上述5种表现,该病并发消化道出血临床并不多见。

  但有研究者在总结其所在医院1985-1996年间144例系统性硬化(SSc)及CREST综合征患者的资料后发现,22例(15.3%) 有消化道出血(女性16例,男性 6例,平均59.4 岁),其中8例(36%)发生多次消化道出血。消化道黏膜毛细血管扩张是出血的最常见原因(40.9%,9/22例),其次为消化性溃疡 (31.8%,7/22例)及糜烂性胃炎(13.6%,3/22例)。该患者的消化道出血可能与毛细血管扩张有关。

  自身免疫性疾病常可重叠

  自身免疫性疾病往往可以相互重叠。患者AMA、AMA-M2高滴度阳性,AMA-M2亚型诊断PBC敏感性、特异性均超过90%。而PBC的病理机制为汇管区淋巴细胞浸润。

  根据以往的临床经验,这类患者容易早期发生门脉高压症候群(如静脉曲张、脾亢、腹水等),而临床缺乏典型肝硬化表现(如肝功能异常、肝脏缩小等),该患者特点与之相符,临床诊断PBC成立。

  患者有口眼干症状,口腔科、眼科会诊符合口干燥症、眼干燥症,尽管抗体检查阴性,结合唇腺活检结果,SS诊断明确。

  研究显示,PBC合并SS最为常见。在113例PBC患者中,66例合并SS(58%),有10例合并SSc(9%),其中SSc主要类型为CREST综合征。日本学者报告过26例PBC-CREST重叠综合征,其中16例(61.5%)合并SS。

  如何治疗?

  在治疗方面,针对免疫性疾病本身,无论是CREST综合征还是SS,患者无高球蛋白血症,红细胞沉降系数、C反应蛋白也正常,病情活动证据不足,无应用激素、免疫抑制剂治疗的指征。

  针对PBC,给予熊去氧胆酸15 mg/(kg·d)治疗。对于门静脉血栓,由于患者有反复消化道出血病史,存在抗凝治疗禁忌证。对于引起患者反复消化道出血的食管毛细血管扩张,目前尚缺乏有效的治疗手段。

  该类病例的相关文献很少,仅有几例接受内镜下氩离子束凝固术(APC)治疗的个案报告,远期疗效并不明确。

  手术解决患者消化道出血问题

  患者住院期间接受静脉补铁、抑酸、利尿及肠内营养等治疗,同时口服熊去氧胆酸。病情稳定后出院。

  半个月后,患者再次呕鲜血约400 ml。复查胃镜,结果显示,食管毛细血管扩张较前加重,未见明显静脉曲张。超声内镜检查显示,食管下段、贲门胃底黏膜下可见曲张静脉。

  经多科讨论,考虑患者有食管胃底黏膜下静脉曲张,APC治疗并发黏膜下曲张静脉出血风险大。遂对患者实施Phemister术(即脾切除+食管胃底周围血管离断+食管下段、胃底切除+食管胃底吻合术)。术中可见患者肝脏表面弥漫性结节样改变,质地偏硬。

  患者术后恢复良好。随访6个月,无呕血、黑便、腹胀等发生。复查血常规,白细胞为6.56×109/L,血红蛋白为125 g/L,血小板为329×109/L。便潜血阴性。复查胃镜,食管胃吻合口通畅,食管未见毛细血管扩张、曲张静脉及溃疡。患者继续口服熊去氧胆酸治疗,并定期到门诊接受随访。

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  总结

  该病例以消化科常见临床症状“上消化道出血”为主要表现,经过详尽检查及分析,其消化道出血病因却是非常少见的CREST综合征合并PBC及SS。CREST综合征消化道毛细血管扩张合并出血罕见,治疗经验缺乏。根据患者同时合并PBC、门脉高压、脾亢,出血部位集中于胃食管接合部,制定了Phemister手术治疗方案。

  该患者手术治疗成功。这为今后类似病例的治疗提供了可借鉴的经验。但对于原发病,包括CREST综合征、PBC、SS等自身免疫性疾病的治疗,目前尚有待开发新型的、疗效更佳、副作用更小的药物。[6040501]

  ■ 点评 北京协和医院消化内科 姚方

  该患者以消化科常见临床症状——“上消化道出血”入院。胃镜检查证实其有食管溃疡和毛细血管扩张,这两者都可以合并上消化道出血。

  但临床医师未满足已有的发现而轻易得出诊断,而是结合患者存在的不典型肝硬化、门脉高压表现,小心求证,针对性地进行深入检查,最终明确CREST综合征的诊断,同时也发现PBC及SS的证据,为患者制定个体化的治疗方案,并获得较好的疗效。

  CREST综合征患者以消化道出血表现而就诊的非常少见,但该类疾病可以有广泛的消化道毛细血管扩张,存在消化道出血的基础。另外,尽管患者的SS相关抗体阴性,但却符合SS诊断标准。这再次提醒临床医师,结缔组织病常常有重叠现象,须仔细检查分析,不能局限于血清学抗体结果,必要时进行相关的功能学、影像学或病理学的检查,以取得诊断依据。[6040502]

  ■ 自身抗体英文缩写注解

  ANA:抗核抗体

  抗Sm抗体:诊断红斑狼疮特异性抗体

  抗SSA、SSB抗体:抗干燥综合征特异性抗体

  抗Scl-70抗体:Scl特异性抗体

  抗Jo-1抗体:抗组氨酰tRNA合成酶抗体

  抗RNP抗体:抗核糖核蛋白抗体

  抗rRNP抗体:抗核糖体核糖核蛋白抗体

  AMA:抗线粒体抗体

  ACA:抗着丝点抗体

  ACL:抗心磷脂抗体

  ANCA:抗中性粒细胞胞浆抗体

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  1. [GetPortalCommentsPageByObjectIdResponse(id=1846442, encodeId=3c6f184644291, content=<a href='/topic/show?id=d3a33e0306d' target=_blank style='color:#2F92EE;'>#原发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37030, encryptionId=d3a33e0306d, topicName=原发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8e4c53, createdName=jiyangfei, createdTime=Wed Nov 27 23:56:00 CST 2013, time=2013-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1809358, encodeId=212f1809358f8, content=<a href='/topic/show?id=5eba834e876' target=_blank style='color:#2F92EE;'>#胆汁性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83478, encryptionId=5eba834e876, topicName=胆汁性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Wed Jan 01 11:56:00 CST 2014, time=2014-01-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2050357, encodeId=17b9205035ec3, content=<a href='/topic/show?id=95f8e042dd' target=_blank style='color:#2F92EE;'>#EST#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7042, encryptionId=95f8e042dd, topicName=EST)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e9a6357, createdName=xiangyuzhou971, createdTime=Sun Dec 01 11:56:00 CST 2013, time=2013-12-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1783802, encodeId=fad41e8380292, content=<a href='/topic/show?id=7c225202e5' target=_blank style='color:#2F92EE;'>#CREST综合征#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5202, encryptionId=7c225202e5, topicName=CREST综合征)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f634250, createdName=chentianping, createdTime=Sun Sep 01 20:56:00 CST 2013, time=2013-09-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1430394, encodeId=c2fb1430394db, content=<a href='/topic/show?id=f9b9e9124a8' target=_blank style='color:#2F92EE;'>#综合征#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79124, encryptionId=f9b9e9124a8, topicName=综合征)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1464484, encodeId=2993146448427, content=<a href='/topic/show?id=32e765e6591' target=_blank style='color:#2F92EE;'>#消化道#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65765, encryptionId=32e765e6591, topicName=消化道)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7b6e6676048, createdName=changhe715, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1579136, encodeId=f01d15e9136de, content=<a href='/topic/show?id=372b834e673' target=_blank style='color:#2F92EE;'>#胆汁#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83476, encryptionId=372b834e673, topicName=胆汁)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=2a0616505872, createdName=108807375_62823132, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1581446, encodeId=1165158144613, content=<a href='/topic/show?id=2bc1519579' target=_blank style='color:#2F92EE;'>#CRE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5195, encryptionId=2bc1519579, topicName=CRE)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4ca216802819, createdName=HinsMax, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=)]
  2. [GetPortalCommentsPageByObjectIdResponse(id=1846442, encodeId=3c6f184644291, content=<a href='/topic/show?id=d3a33e0306d' target=_blank style='color:#2F92EE;'>#原发性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37030, encryptionId=d3a33e0306d, topicName=原发性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=8e4c53, createdName=jiyangfei, createdTime=Wed Nov 27 23:56:00 CST 2013, time=2013-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1809358, encodeId=212f1809358f8, content=<a href='/topic/show?id=5eba834e876' target=_blank style='color:#2F92EE;'>#胆汁性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83478, encryptionId=5eba834e876, topicName=胆汁性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Wed Jan 01 11:56:00 CST 2014, time=2014-01-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2050357, encodeId=17b9205035ec3, content=<a href='/topic/show?id=95f8e042dd' target=_blank style='color:#2F92EE;'>#EST#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=7042, encryptionId=95f8e042dd, topicName=EST)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e9a6357, createdName=xiangyuzhou971, createdTime=Sun Dec 01 11:56:00 CST 2013, time=2013-12-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1783802, encodeId=fad41e8380292, content=<a href='/topic/show?id=7c225202e5' target=_blank style='color:#2F92EE;'>#CREST综合征#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5202, encryptionId=7c225202e5, topicName=CREST综合征)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f634250, createdName=chentianping, createdTime=Sun Sep 01 20:56:00 CST 2013, time=2013-09-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1430394, encodeId=c2fb1430394db, content=<a href='/topic/show?id=f9b9e9124a8' target=_blank style='color:#2F92EE;'>#综合征#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=79124, encryptionId=f9b9e9124a8, topicName=综合征)], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/aLGWoFXAyMbIu3qymFOyheQLjPSX3OUs5GmkyBlcCOwTPIeq3why9NGibxxUqYo6hcx8qZLHZFgNPnBK1yzWeOFpyg2OnWOt0/0, createdBy=fa4716, createdName=zhouqu_8, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1464484, encodeId=2993146448427, content=<a href='/topic/show?id=32e765e6591' target=_blank style='color:#2F92EE;'>#消化道#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=65765, encryptionId=32e765e6591, topicName=消化道)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7b6e6676048, createdName=changhe715, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1579136, encodeId=f01d15e9136de, content=<a href='/topic/show?id=372b834e673' target=_blank style='color:#2F92EE;'>#胆汁#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=83476, encryptionId=372b834e673, topicName=胆汁)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=2a0616505872, createdName=108807375_62823132, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1581446, encodeId=1165158144613, content=<a href='/topic/show?id=2bc1519579' target=_blank style='color:#2F92EE;'>#CRE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5195, encryptionId=2bc1519579, topicName=CRE)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4ca216802819, createdName=HinsMax, createdTime=Mon Jul 15 01:56:00 CST 2013, time=2013-07-15, status=1, ipAttribution=)]
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    2013-07-15 HinsMax

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