成都医学院第一附属医院-烟草依赖综合征-专家在线问诊-京东健康互联网医院

简介:

医院立足三甲医院和大学附属医院功能定位，按照建设“成北区域医疗中心”的发展总思路，开展新院区建设。新院区建设地址位于成都市新都区鸿运大道和绕城大道交汇处西侧地块，占地面积共计约273亩。以建设现代化、智慧化、园林式的区域医疗中心为目标，打造医教研综合医学平台，新院区规划总建筑面积约57.9万平方米，主体医疗建筑面积将近23.7万平方米，规划编制床位2000张。新院区整体完工并投入使用后，将促进成都北部地区整体医疗实力和服务效率进一步提升，在医联体建设、学科共建、设备共享、慢病管理体系建设、老年疾病诊疗、医养结合、联合科研等方面发挥引领作用，充分彰显医疗卫生、教育教学两方面公益性，更好地服务区域经济社会发展。社会公益职责认真贯彻落实党中央、国务院、四川省委省政府关于脱贫攻坚重大决策部署，根据四川省卫健委安排，切实组织实施精准帮扶凉山州普格县螺髻山镇德育村、凉山彝族自治州盐源县前所乡、马尔康市脚木足乡蒲市口村和广元市昭化区太公镇白头村，定点帮扶凉山州盐源县盐塘镇西沟村。以党建为抓手，产业帮扶为核心，卫生指导和教育支持为重点，共计选派扶贫干部6人、驻村干部2人，其中5人多次获得省级、市级荣誉奖项和称号。转制以来，我院累计选派323名专家对口支援马尔康市人民医院、松潘县人民医院、雅安市名山区人民医院等26家贫困地区和服务薄弱地区医疗机构，通过理论讲座、诊疗示范、手术示教、教学查房、案例分析，免费接收受援机构工作人员来院进修等方式，精准传帮带，切实帮助受援医院提高医疗技术水平和服务能力。医院历年来在处置重大突发性公共卫生事件，在援外医疗，在“5.12”汶川大地震、“4.20”芦山地震的抗震救灾、伤员转运、伤员救治等方面始终以高度的使命感和责任感不惧危险、冲锋在前，发挥着三级甲等综合医院、教学医院的重要作用，受到广大人民群众、政府和卫生行政部门的好评。新冠肺炎疫情爆发以来，我院累计选派33名医务人员驰援湖北、北京、新疆、云南等地，援鄂医疗队荣获四川省抗击新冠疫情先进集体、10人荣获四川省抗击新冠肺炎疫情先进个人及优秀党员、四川省先进工作者等称号。健康所系、性命相托。全体成医附院人继承和发扬着军队优良传统，秉承“崇道尚德自强不息”的医院精神，尊崇“精诚为术仁爱为医”的医院院训，坚持以病人中心，努力为广大群众提供更加优质的医疗服务。药物依赖是一组认知、行为和生理症状群,使用者尽管明白使用成瘾物质会带来问题,但还在继续使用，长期大量使用烟草，脑，脱毒治疗和脱毒后防止复吸及社会心理康复治疗，不确定，不确定，不确定，。

true 向宸辉主任医师

三级甲等成都医学院第一附属医院

好评率：99% 接诊量：799 平均响应：15分钟

从事泌尿外科临床工作27+年，任四川省泌尿外科、男科学委员；中国性学会手术学分会委员，亚太性学会委员，擅长泌尿系结石肿瘤，先天畸形矫正，女性尿失禁、女性盆底重建，私密整形，前列腺增生、前列腺疾病、泌尿系结石（肾，输尿管，膀胱结石，尿道结石等）输尿管镜钬激光碎石，输尿管软镜钬激光碎石，经皮肾镜碎石取石术，男科学，性功能障碍，早泄治疗（阴茎增粗延长术，阴茎起搏器等）阴茎弯曲矫正术。

true 陈琦主任医师

三级甲等成都医学院第一附属医院

好评率：99% 接诊量：317 平均响应：30分钟

口臭，牙龈出血，牙龈炎，牙周炎，牙齿松动，冠周炎，阻生牙，智齿，龋齿，蛀牙，根管治疗，牙缺损，牙外伤，牙齿变色，四环素牙，牙齿美白，牙齿不齐，牙齿矫正，箍牙，隐形矫正，牙套，烤瓷牙，全瓷牙，种植牙。

true 何杰主治医师

三级甲等成都医学院第一附属医院

好评率：100% 接诊量：2 平均响应：-

肺小结节诊断，结核，慢性阻塞性肺疾病

true 李书平副主任医师

三级甲等成都医学院第一附属医院

好评率：- 接诊量：- 平均响应：-

从事胸心外科临床及管理工作24年。省内率先独立开展胸腔镜微创肺叶切除；倡导并组织建立了成都医学院第一附属医院肺部肿瘤MDT 并任首任主席；组建我院肺结节诊疗团队，常规开展多孔、单操作孔及单孔全胸腔镜解剖学肺段切除、联合亚段切除、以及微创介入射频消融、微波消融、氩氦刀冷冻消融等多种个体化肺结节介入治疗手段；针对中晚期中央型肺癌独立开展常规开放及全腔镜支气管袖状肺页切除、双袖切除及上腔静脉成型、上腔静脉人工血管置换手术以及气管良恶性肿瘤切除重建等高难度胸科手术数百例；为近省内十家医院搭建胸心外科专业组并指导开展基层全院第一例胸腔镜肺癌根治手术，带领周边医院胸外科团队规范，高速发展。在国内外杂志发表学术论文近20篇；其中SCI 4篇，主持或参与省级科研项目两项。不接受心血管外科手术咨询。

false 戚龙副主任医师

三级甲等成都医学院第一附属医院

好评率：- 接诊量：- 平均响应：-

擅长心脑血管疾病、老年衰弱与老年痴呆、各种慢性疼痛、晚期癌症疼痛疾病的治疗与综合干预。

true 徐成飞主治医师

三级甲等成都医学院第一附属医院

好评率：- 接诊量：2 平均响应：-

乳腺结节，乳腺癌，乳腺疾病，甲状腺良恶性肿瘤，结直肠癌，胃癌，胃肠间质瘤，阑尾炎，肠梗阻肠，腹股沟疝，食管裂孔，造口旁疝，结肠造口，小肠造口护理

true 杨红胜副主任医师

三级甲等成都医学院第一附属医院

好评率：100% 接诊量：2 平均响应：17小时

擅长脊柱和关节退变疾患的诊治，在腰椎间盘突出，腰椎管狭窄症，腰椎滑脱，胸、腰椎骨折，脊柱后纵韧带及黄韧带骨化，股骨头坏死，髋膝骨关节炎有丰富的诊疗经验。对四肢骨与软组织肿瘤的诊治原则和保肢治疗有较深入研究。熟练掌握四肢关节周围骨折诊治及手术方案，在复杂膝、踝关节周围骨折，复杂肘关节骨折，骨盆骨折，复杂髋部及肱骨近端骨折等方面做了大量临床工作。

false 周鹏主任医师

三级甲等成都医学院第一附属医院

好评率：100% 接诊量：5 平均响应：-

冠心病，心肌缺血，动脉硬化，心慌，心累，支架，心律失常，心肌炎，起搏器，晕厥，高血压，心衰，心功能不全，神经官能症，更年期综合征

true 唐涛主治医师

三级甲等成都医学院第一附属医院

好评率：100% 接诊量：1086 平均响应：30分钟

唐涛，男，外科学硕士，成都医学院第一附属医院肝胆血管外科主治医师，毕业于重庆医科大学，2013年加入肝胆血管外科从事专科工作。擅长肝脏，胆囊，胰腺和脾脏等肝胆疾病，也从事主动脉夹层、腹主动脉瘤等大动脉疾病，颈动脉、锁骨下动脉、内脏动脉、下肢动脉等外周动脉疾病及下肢深静脉血栓、静脉曲张等静脉疾病的诊断与介入、手术治疗，尤其在下肢静脉曲张的微创治疗及静脉炎、深静脉血栓的规范化诊治等方面具有丰富的临床经验。发表SCI 1篇，国家核心期刊2篇，参与编译专著1部。

true 徐小平副主任医师

三级甲等成都医学院第一附属医院

好评率：100% 接诊量：1 平均响应：-

擅长老年骨质疏松骨折，股骨头坏死，膝关节骨关节炎，脊柱退变性疾病如颈椎病、腰椎间盘突出症、腰椎管狭窄、腰椎滑脱等的微创治疗

接诊医生：

2024-10-31 17:21:13

科普文章

什么是三手烟？

烟草危害已经成为世界上严重的公共卫生问题，中国是世界上最大的烟草消费国，有 3 亿多烟民和 7 亿多二手烟受害者，人们对烟草的认识仍然停留在主动吸烟和被动吸烟所带来的危害，很少有人关注过三手烟的问题，甚至也很少有人听说过三手烟。

那么，什么是三手烟？与二手烟有什么区别？

三手烟是指吸烟后吸附着在物体表面、灰尘颗粒甚至皮肤、毛发、衣物的烟草烟雾颗粒，以及这些颗粒被重新释放到空气中与空气污染物发生化学反应后生成的第二代污染物。

三手烟的主要化学成分包括尼古丁、可替宁、烟草特异亚硝胺、多环芳烃、3 - 乙烯基吡啶、甲酚、萘、甲醛、乙腈、苯，丙酮、甲苯等可吸入的挥发性有机化合物。

与二手烟相比，三手烟中 1- （ N - 甲基 - N - 亚硝胺基） - 1 - （3 - 吡啶基） - 4 - 丁醛［NNA］是三手烟中独有的成分，也是近年来被用作测定三手烟暴露情况的重要生物标志物和环境标志物。

三手烟广泛存在于吸烟的环境中，在环境中可以存在数月之久。不同于二手烟主要通过呼吸道被人体吸入，三手烟可以通过三种途径进入人体，呼吸道吸入，消化道吸收和皮肤渗透。

三手烟具有普遍性、持久性、隐蔽性、毒性强的特点，与成人相比，婴幼儿免疫系统及呼吸系统尚未成熟、呼吸频率高、接触家用物品的机会更多、在室内环境中的时间更长，婴幼儿吮吸手指行为较为普遍，唾液中蛋白质可能会增加口腔中毒物的摄取，所以婴幼儿群体相比成人更容易受到三手烟的危害。

经常有吸烟者说，我不在家里吸烟，不在家人面前吸烟，我吸烟都是在阳台或室外，对家人和孩子没有什么影响。殊不知，在吸烟者的身上、衣物上、头发上有会有浓重的烟味，都会携带着三手烟对家人和孩子带来危害。

三手烟有遗传毒性、参与机体的氧化应激、诱导炎症反应、影响物质代谢、促进肿瘤发生等，和一手烟、二手烟一样，同样会引发因烟草危害所带来的各种各样疾病，国外曾有学者做过动物实验，将幼鼠（ 4~7 周龄）暴露于三手烟环境中 3周，然后跟踪监测40周，发现暴露于三手烟组的小鼠肺腺癌的发病率、肿瘤大小均明显高于未暴露组小鼠，这项动物实验证实了在早期生命接触三手烟显著增加了小鼠的肺癌发病率。

吸烟危害健康已经是不争的医学事实，提高公众对三手烟的认识，了解三手烟作为一种潜在的健康风险，其对健康所带来的危害不容忽视。

在 2024 年世界无烟日到来之际，让我们一起行动起来，远离烟草，保护青少年免受烟草危害。

吸烟是一种慢性成瘾性疾病！

中国是全球第一大产烟国，2007年的产量达到21413.8亿支^[1]，卷烟生产量占世界的42% ^[2]。我国更是吸烟大国，成年男性吸烟率在60~70%之间^[3,4]，同时我国的烟草中尼古丁、焦油含量相对较高，因而可能造成的躯体损害也较大^[5]，根据统计，我国每年有2百万人死于吸烟相关疾病^[6]，从这个角度看，吸烟是一个公共卫生问题。

吸烟之所以流行广泛，原因涉及到生物、心理、社会等诸多原因，其中重要的原因是烟草里的尼古丁是成瘾性物质，从这个角度看，吸烟是一个成瘾性慢性成瘾性疾病。本讲座将从以下几个方面阐述吸烟是一个慢性成瘾性疾病。

一、成瘾的概念

根据Webster's New World医学字典，成瘾可以理解为一种慢性、复发性的状态，特征是冲动性觅药（compulsive drug seeking）与滥用成瘾性物质（又称药物、精神活性物质、物质等，例如海洛因、酒精、烟草等）的行为，并伴有长期的脑部适应性病例生理变化，导致耐受性增加、躯体依赖、强烈的渴求、复发。

我们可以从行为的角度，把成瘾理解为：

1. 成瘾者有行使某种行为的强烈欲望, 但其结果有害;

2. 如果控制不做, 则紧张、焦虑逐渐增加;

3. 一旦完成此行为, 则紧张、焦虑迅速、暂时得以解脱;

4. 过一段时间后, 如几小时、几天或几周又重新出现实施此行为的欲望;

5. 外部、内部环境刺激可条件反射性引起此欲望;

6. 成瘾者希望能控制此行为, 但屡屡失败。

成瘾（addiction)在专业文献中以及普通人群使用很广，并有歧义，在1964年，WHO建议将“依赖”来替代“成瘾”。ICD-10把依赖定义为：“一组生理、行为、认知现象，用药者将使用药物作为第一需要（priority），放弃了既往认为是重要的事情。依赖综合征的中心特征是期望（常常非常强烈，难以摆脱）使用成瘾性药物（可能医疗性或非医疗性的药物）、酒精或烟草^[7] 。”DSM-IV 的定义与之类似，认为“是一组认知、行为和生理症状群，表明个体尽管明白使用成瘾物质会带来明显的问题，但还在继续使用，自我用药的结果导致了耐受性增加、戒断症状和强制性觅药行为(compulsive drug seeking behavior)” ^[8]。从这两个定义可以看出，依赖的行为特征是失去控制，表现为强烈的渴求，将药物使用作为第一需要，为了使用药物可以不顾一切；躯体特征是耐受性增加和戒断症状。可以把失去控制理解为心理依赖（psychological dependence），将后者理解为躯体依赖（physical dependence）。

从心理学的角度看，任何能产生的快感的活动、物质，即能产生所谓的正性强化作用的东西，可能都具有成瘾性。根据以上描述与定义，成瘾行为大致可以分为以下两大类：

1. 对化学物质的成瘾，这些化学物质包括镇静催眠药、酒类、兴奋剂、阿片类，当然包括烟草。

2. 行为成瘾，如网络、电脑、购物、赌博等等。

一般来说，如果讲到成瘾，是指对化学物质的成瘾，即狭义的成瘾。

二、导致成瘾行为的相关因素

人们对药物滥用的原因从各方面进行了研究，结论不一。普遍认为，影响成瘾行为的相关因素有很多，不能用单一的模式来解释。社会、心理、生物学因素相互交织，在成瘾物质开始使用、持续使用、依赖的形成、复发、康复等方面都起着重要的作用。为了描述方便，将之分为以下几种^[9]。

（一）社会学因素

1．可获得性

不管药物的成瘾性多强，难以获得，则滥用的机会就少。从鸦片战争到解放初期，我国饱受鸦片之苦。新中国成立后，中央人民政府颁布严禁鸦片的通令，主要对走私、贩卖、种植、生产阿片类物质者进行严厉的打击，通过控制供给，阿片类滥用问题在中国大陆基本销声匿迹。改革开放以前，人们的生活水平较低，多仅能维持温饱问题，酒类供应紧张，故而人均饮酒量以及卷烟消耗量较低，改革开放以后，生活水平迅速提高，烟类、酒类供应丰富，各种广告铺天盖地，饮酒量以及卷烟生产量增加是必然的。

2．家庭

人类学习的早期形式之一是模仿，模仿学习的最早对象往往是家庭成员。儿童、青少年首先看到父母、兄长使用吸烟、喝酒、吸毒，并从他们那里得到这方面的知识。当然，良好的家庭环境可以防止个体产生药物成瘾。

3．同伴影响、社会压力

开始使用药物的年龄往往是发生在心理发育过程中的“易感期”──青少年，他们是一个亚文化体，有共同的世界观、认知系统，同时鉴别能力较差，价值观念受很易受其所在小团体的影响，加上好奇，寻求刺激，追求时髦，或欲与同伴打成一片或把使用成瘾物质作为成人的标志的趋使，虽然开始吸烟的味道并不好受，但均不惜一试。吸毒者多数也是在这种环境下吸上的。

4．文化背景、社会环境

不同的时代，不同的文化背景，对不同成瘾物质的滥用有着不同的看法和标准。例如，信奉伊斯兰教的民族对饮酒持强烈的厌恶态度，当然那些国家的饮酒问题就不会严重。中国人吸烟在世界上首屈一指，其中一个原因是中国人把吸烟作为社交手段之一，中国女性吸烟率很低，是因为社会对女性吸烟持厌恶的态度。国外妇女吸烟很普遍，据称妇女吸烟与妇女解放联系到了一起。

（二）心理因素

即使能随意得到药物，也只有一部分人会使用和成瘾。因此有人试图寻找成瘾者心理特征、成瘾前心理状态对药物滥用的影响，以揭示成瘾的心理学机制。

1．个性研究著名心理学家Eysenck的研究发现，吸烟者性格较为外向，我们的研究发现，吸烟者较为焦虑、较为敏感^[10]。

2．成瘾物质的心理强化作用根据行为学理论，精神活性物质有明显的正性、负性强化作用。多数精神活性物质都有增加正性情绪的作用，如“饭后一支烟，赛过活神仙”，“酒逢知己千杯少”，吸毒后的快感以及社会性强化作用都对使用精神活性物质起到了增强作用。同样成瘾物质有强烈的负性强化作用，如“一醉解千愁”，“无聊的烟”，“何以解忧，唯有杜康”，毒品更有对抗负性情绪的作用。重要的是，在成瘾后，由于戒断症状的出现，使成瘾物质使用者不能自拔，必须反复使用所成瘾的物质以解除戒断症状。这是失去自我控制的最强烈的负性强化作用^[9]。

（三）生物因素

研究表明，遗传因素在成瘾中起到重要的作用。即使是与社会心理因素关系密切的烟草成瘾与酒精成瘾也不例外。例如，酒依赖的遗传度大概在60%。

当然，成瘾的形成存在物质基础，对成瘾性物质的渴求这一心理现象同样有物质基础。目前认为，中脑腹侧被盖区（ventral tegmental area，VTA）、伏隔核（nucleus accumbens，NAc）、前额叶皮质（prefrontal cortex，PFC）和纹状体（striatum），的多巴胺（dopamine）能神经通路，以及从前额叶皮质、杏仁核（amygdala，AMG）和海马（hippocampus）向伏隔核的谷氨酸（glutamate）能神经投射，共同构成依赖的伏隔核相关的神经通路（NAc-related circuitry）。研究表明，此通路不仅是物种个体、种族保存相关行为，如，饮食、性等的神经解剖基础，而且是介导与成瘾药物使用相关的犒赏（reward）、动机（incentive motivation）和学习等的重要神经通路^[11]。

尽管不同种类的成瘾物质有不同的药理作用，但他们的最后共同通路是作用于伏隔核相关神经通路，增加中脑腹侧被盖区内多巴胺神经元的冲动，使伏隔核以及其他区域如前额叶皮质中多巴胺的释放增加。可卡因、苯丙胺类药物是通过抑制突触间隙多巴胺重吸收而间接激动多巴胺受体，而阿片类可能是通过激动μ、δ及解除GABA神经元对多巴胺的抑制作用，间接促进了多巴胺的释放。尼古丁通过作用与尼古丁受体，间接促进多巴胺的释放^[11]。

三、吸烟是成瘾行为的证据

（一）临床证据

如前所述，一旦成瘾，躯体表现为耐受性增加和戒断症状，行为表现则为失去控制。

临床证据表明，几乎每个吸烟者都有这样的经历，在首次吸烟并不好受，在开始吸烟的一段时间里，吸烟量并不大，随着烟龄的增加，烟量也逐渐增大，有人甚至每天超过60支，这60支烟对于一个非吸烟者是完全不能耐受的。吸烟成瘾后，不抽烟是痛苦的，表现为所谓的戒断症状，如注意力不集中﹑心律血压下降、唾液分泌增加、头痛、失眠、易激惹﹑食欲增加等[5]，所以吸烟主要的目的是防止戒断症状的出现。

一旦吸烟成瘾，吸烟者“失去了自由”，必须保证足够的香烟供给方能安定，烟瘾大着甚至身上带上两包烟，大烟瘾者对于禁烟的场所最为痛苦，如在上飞机之前，特别是长途飞行，非常紧张，怕在飞机上发烟瘾。下飞机的第一件事情不是取行李，不是上厕所，而是冲出去抽烟。

（二）实验证据

在成瘾行为的研究中，有很多比较能反应人类成瘾行为的实验动物模型，如自我给药模型（self-administration model），如图所示，自我给药模型是利用操作性条件反射原理，当试验动物在做出程序所设定的动作后，即可获得一定量的药物。由于该模型较好地模拟了人类的用药行为，故在成瘾研究中得到了广泛的应用。在评估成瘾物质奖赏和滥用潜力时具有很好的可靠性和可预测性。对人类有犒赏作用的药物，均能造成实验动物自我给药模型，最易造模的成瘾药物如兴奋剂（如苯丙胺类药物、可卡因）和阿片类药物（如海洛因、吗啡等），尼古丁同样可以是实验动物实施自我给药^[11]。

（三）神经生化证据

尼古丁能与中枢神经系统的尼古丁乙酰胆碱受体(nAchR)结合，使nAchR构象上发生变化，通道打开，阳离子通过，发生信号转导变化，引起伏核多巴胺释放. 这导致了吸烟后短暂的奖赏/满足感。对于烟草成瘾的戒断与渴求，临床上常常使用尼古丁戒烟糖替代，能起到缓解戒断症状与渴求的作用[12]。另外，nAchR半激动剂，Varenicline (Champix/Chantix,)能够激动受体，在治疗烟草依赖中也能起到较好的作用[13]。

四、小结

不管从社会、心理角度，还是从生物学角度，不管从临床角度，还是从动物实验角度，吸烟是一个成瘾性的问题。从公共卫生角度看，由于吸烟的人数很大，所导致的疾病负担远比吸毒更为严重。尽管烟草工业给政府创造的税利，但研究发现，由于吸烟所导致的总经济损失紧3 000亿人民币，约占当年国民生产总值的1.5% ^[14]。

当然，应对烟草危害的方法也应该从多方面，是一个系统工程，我们在期望新的戒烟方法的同时，社会控制也是一个重要的措施。

参考文献

1. 国家统计局. 中国统计年鉴，2008 （http://www.gov.cn/gzdt/2008-02/28/content_904170_2.htm，access on 2008.3.26）

2. Corrao MA, Guindon GE, Sharma N, Shokoohi DF. Tobacco Control Country Profiles. Atlanta, GA: American Cancer Society, 2000.

3. Yang G, Lixin F, Tan J et al. Smoking in China: Findings of the 1996 National Prevalence Survey. JAMA 1999, 282:1247–53.

4. Hao W, Young DS and Li LJ et al. Psychoactive substance use in China: Gender differences and related factors. Addiction. 1995, 90:1505-1517.

5. 朱尊权. 我国卷烟降焦与发展混合型卷烟是一项艰巨的系统工程, 烟草科技,1999, (3)3~5.

6. Yang G, Lixin F, Tan J et al. Smoking in China: Findings of the 1996 National Prevalence Survey. JAMA 1999; 282:1247–53.

7. WHO, The ICD-10 Classification of Mental and Behavioural Disorders, WHO, Geneva, 1992.

8. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Washington DC: American Psychiatric Association, 1994。

9. 郝伟(主编). 全国高等教育“十五”国家级规划教材, 精神病学(第五版) (5年制临床医学专业), 人民卫生出版社, 2004.

10. 郝伟杨德森. 107例戒烟就诊者的疗效相关因素分析,中国心理卫生杂志6:194-197,1992.

11. 郝伟. 犒赏与成瘾. 见: 鞠躬主编, 全国高等医药院校教材, 神经生物学(供研究生用) PP 543-557 人民卫生出版社, 2004.

12. West R., McNeill A, Raw M. Smoking cessation guidelines for health professionals: an update, Thorax 2000, 55:987–999.

13. Rollema H, Coe JW, Chambers LK et al. Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nAch receptors for smoking cessation. Trends in Pharmacological Science. 2007, 28: 316-325.

14. 李玲、陈秋霖、贾瑞雪等. 我国吸烟模式和烟草使用的疾病负担研究. 中国卫生经济, 2008, 27:26-30

本文是郝伟版权所有，未经授权请勿转载。

本文仅供健康科普使用，不能做为诊断、治疗的依据，请谨慎参阅

众所周知吸烟有害健康，想戒烟却往往半途而废，戒烟为何这么难？

香烟的外包装盒上，明明白白写着“吸烟有害健康”的字样，而对于相当于慢性自杀的吸烟危害，也是吸烟的人心知肚明的事情。但为什么明知道吸烟危害巨大，却依旧有那么多人都戒不了烟呢？

吸烟对于身体的危害

吸烟对人体的危害，最为人熟知的便是吸烟者易患肺病甚至肺癌，殊不知吸烟的对人体健康的损害远不止这一点。从大方向上来说，吸烟的人寿命比不吸烟的人平均要少十年，而二手烟导致的死亡人数也已超十万；具体来讲，吸烟不仅严重损害了人的肺部，还是脑血管病、癌症以及慢性呼吸系统疾病的重大危险因素；吸烟还会损伤人体的遗传物质，对人体内分泌系统输卵管功能、胎盘功能、以及免疫功能、胎儿心血管系统和组织器官发育等都会造成严重的不良影响。

为何戒烟如此困难

烟草中存在尼古丁，而尼古丁又会使人上瘾，甚至是产生依赖，所以很多人都认为戒烟之所以困难，就是因为尼古丁的存在。事实上，戒烟难，尼古丁只是其中的原因之一，吸烟表面上看只是人的一种习惯化行为，但其实早已被世界卫生组织确认为慢性成瘾性疾病，一般称之为“烟草依赖综合征”，属于物质滥用范畴。长期吸烟的人，无论是在生理上，还是在心理上，都有较大的成瘾性、习惯化的模式，再加上社会环境的影响以及戒烟动机不够强烈，因此成功戒烟的人少之又少，成功戒烟率也远低于想成功戒烟的人数。

想要成功戒烟应该如何做

想要成功戒烟，首先要做的就是强化自己戒烟的动机，明确自己戒烟的原因，不断强化戒烟所达目标的吸引力、获益性，才能让自己有足够的耐心和毅力坚持戒烟的过程；认识吸烟的危害，也是督促自己戒烟的一个重要方面。虽然吸烟的确对人体健康有很大的伤害性，但这种危害同时也是慢性的，再加上人们对吸烟危害的认知不够充分，所以戒烟的成功性很小。因此，想要戒烟的人，应该充分的了解吸烟所带来的诸多危害，并以此来强化自己戒烟的动机；戒烟，往往是一个人不能够完成的，尤其是有着许多年年龄且烟瘾较大的人，所以在决定戒烟的同时，应该找身边的家人、朋友对自己实施监督，并预先想好烟瘾发作时的应对措施，准备越充足，成功率也就越大。

需要注意的是，尤其对于年龄长、烟瘾大的人来说，在戒烟过程中很可能会出现戒断症状如失眠、流泪/流涕、出汗、震颤、呕吐或腹泻、腿抽筋等，因此，消除戒断带来的不适感所需要采用的办法也非常重要。具体可以在症状发生时多做些其他有兴趣的事情来分散注意力、适当利用运动、音乐等来放松自己的心情、充分了解戒断症状的实质，以减少出现症状时的恐惧心理等。如果感觉凭借日常的办法实在无法完成戒烟，也可以求助于医院戒烟科的医生。

烟草是新冠良药？又想骗我！

小史医生最近在林林总总的资讯中看到一则《8年前烟草制流感疫苗成功，这回又要用烟草研发新冠肺炎疫苗》的消息，而文章的网友评论也不时有支持和叫好的声音。

小史医生不由皱了下眉头：果然还是标题党吸引眼球啊！

那真的像所说的“用烟草能治愈新冠病毒呢”？断然不是啊！这篇资讯大致讲的是美国某烟草公司用基因编辑后的冠状病毒来感染生长迅速的烟草，看烟草是否能制造出抗体，以供制造针对病毒的疫苗。

举个例子——ZMapp

说到这里，不得不提到前些年流行的另一个病毒——埃博拉。这种以烟草提取成分进行治疗的综合疗法，曾被用于研发针对埃博拉病毒的疫苗ZMapp。美国马普（MAPP）生物制药公司研发出疫苗ZMapp，在没有进行人体临床试验的情况下，本着FDA（美国联邦食药监局）的“同情原则”，药物被用于治疗感染埃博拉的2名美国医护人员，结果这2名患者情况开始好转。

然而最后的结果大家也知道，并没有ZMapp通过安全性测试的消息，最后也没有大量投入生产该疫苗。疫苗从研发到测试再到生产需要经过非常科学和严谨的流程，仅因为2名感染者的病情好转并不能代表这个疫苗的安全。就算测试到最后该疫苗有一定效果，也可能意味着当其疫苗几近完美的时候，疫情可能已经过去了。而且，跟埃博拉病毒一样，一些疫苗不能保证对所有病毒链都百分之百有效。

本质还是“偷换概念”

那么回到这条资讯，文中的“烟草”又扮演什么角色呢？简单了说烟草其实就是一个载体，通过对将基因倒入烟草的叶片，使叶片产生预期的“植物抗体”蛋白，最后蛋白从植物中被提取出来并提炼成血清，用于疫苗的研发和测试。

但是说到这里，我们必须识破这个“偷换概念”的手法，“用烟草研制疫苗”≠“吸烟有益健康”。

对于“吸烟”和“健康”之间的矛盾无需多言，我再举个例子。前几日，中国天津大学的团队宣布研发出新型冠状病毒口服疫苗，以酿酒酵母为载体，以新型冠状病毒S蛋白为靶点产生抗体，通过口服途径免疫。

我们假设，也希望这个通过酿酒酵母研发的疫苗有效，但是这就意味着闭门酣歌能够免疫吗？我们买一罐酒酿回去，吃酒酿汤圆吃个够，能够免疫吗？

他们从烟草中提取并研发出疫苗，然后你吸烟吸个痛快，能免疫吗？

忽悠你的不是烟草，是烟草公司

如前文所述，疫苗的研发有较长的研发和测试周期，且是需要在专业机构的主导下进行临床试验和质量控制的。而这次所谓的“从烟草中研发新冠肺炎疫苗”，竟是由美国的烟草公司着手进行的。

不想当厨子的裁缝不是好司机，嗯！

随着对烟草管制的加强，和民众健康意识的提高，烟草业的业绩逐年下滑，因此不少国外的烟草公司在寻找其他的突破口，而医药则是他们比较看重的转型目标。老实说我们其实并不用排斥此类“烟草中研发疫苗”的研究，毕竟任何事物都不是绝对有害的，关键在于如何其利用。但是将烟草制成卷烟，致使每年有数百人因吸烟罹患肺癌、结核病、哮喘等疾病，我们拒绝！

至于这次烟草公司研发疫苗，不足以代表他们已经成功转型医药行业，倒更像是一次炒作和热点营销。

言归正传，请尽早戒烟

疫苗的开发滞后于疫情是这些年来新发突发传染病防控的一个窘境。我们期待疫苗能够最快速的开发出来，能马上用于遏制疫情蔓延和保护易感人群。

但我还是要提醒各位烟民：吸烟使人体免疫力下降，增加感染病毒的风险；吸烟产生的二手烟对周围的人也存在健康威胁。为了能够保护自己和身边人的健康，最重要的是远离烟草，尽早戒烟。此外，做好个人防护措施也是必要的，必须按照科学的方法佩戴口罩、勤洗手、少外出、不聚集。

有了科学防治，其实疫情并不可怕，可怕的是那些别有用心的谣言，骗你深陷疾病的“旋涡”。

罹患双癌，依然有办法治疗！“海外二诊”为客户快速链接全球权威专家资源！

病症：胃癌恶性黑色素瘤

患者：李女士

年龄：70岁

罹患癌症，毫无疑问对每个人都是重大打击。而如果一位患者不幸同时罹患两种癌症，我们可以想象得出他的心情会是怎样的沉重。

但时至今日，癌症早已不再是什么“不治之症”，很多良好的治疗方法，可帮助患者迈过重重困境，预后得到极大提升。

不仅如此，在医疗全球化的今天，中国患者也能通过“海外二诊”服务，快速触达到国际权威专家资源，为自己的治疗保驾护航！

今天的案例主人公李女士，正是一位“海外二诊”的受益者。我们来一起看看她的故事。*为保护隐私，文中患者个人信息均已经脱敏处理。

70岁的李女士在去年年底，因脚底疼痛去医院看病，结果发现脚后跟有一个1厘米的黑色肿物。医生判断是冻疮，于是开了点外用药，李女士也就没有再放在心上。

大概4个月后，真正的噩梦降临：李女士通过影像检查，被诊断为胃癌，而且有了淋巴结转移。她还出现了多次呕血，病情非常危急。很快,医生为她实施了全胃切除。令人意想不到的是，几天后通过检查，医生发现李女士后脚跟的肿物竟然也是癌症——恶性黑色素瘤。于是大概2个月后，医生又切除了她的足底肿瘤。

为了降低复发风险，李女士开始了3个周期的化疗联合免疫治疗（替吉奥联合纳武单抗）。

虽然该做的都已做完，但对于李女士来说，恐惧感还远未被消除。因为癌症最令人恐惧的，是其具有“复发转移”的能力。一旦癌症再次袭来，李女士不知道自己该如何应对。另外，两种癌症的治疗以及术后辅助药物治疗，也让李女士遭遇了一些副作用。比如腹泻、味觉障碍还有体重明显下降的问题。这些对于已经70岁的李女士来说，都很影响生活质量，所以迫切需要解决。

在本次的国际专家“海外二诊”服务中，李女士预约的是来自日本某知名综合性医院肿瘤中心的外科部长医生，他的专长领域既包括肿瘤外科，又包括各类癌症药物疗法、姑息治疗，是一位“内外兼修”的权威专家。在充分了解了李女士既往的病情和治疗经过后，医生很快通过远程会诊的方式，为患者详细解答了当前她的所有问题。

1、未来如果转移或复发了该怎么办？

医生：假如您未来不幸出现转移或复发，那么化疗是核心治疗手段。对于单发的孤立转移灶，可以选择手术、放疗来进行局部治疗。

具体化疗方案选择，我按使用的先后顺序列出了3类，当前面的方案失效后，可更换为后面的方案。

一类方案：化疗联合/不联合免疫方案

CAPOX (卡培他滨+奥沙利铂)±O药（即免疫药物纳武单抗）

SOX (替吉奥+奥沙利铂)±O药

FOLFOX (5-FU+奥沙利铂)±O药

二类方案：化疗联合/不联合抗血管药物方案

Taxane (紫杉醇/白蛋白结合型紫杉醇/多西紫杉醇)±雷莫芦单抗

三类方案：化疗方案

曲氟尿苷/盐酸替吡嘧啶

伊立替康

2、N K细胞疗法是否对我有帮助？副作用是否可控？ X医生：目前尚没有证据表明NK细胞疗法对癌症有效，因此不予推荐。

3、口服替吉奥会腹泻，是否需要调整方案？ II/III期胃癌患者术后采用辅助治疗方案，分别为：

替吉奥口服 1 年（口服 4 周，停药 2 周，共 8 个疗程或口服 2 周，停药 1 周，共 16个疗程）

CAPOX (卡培他滨+奥沙利铂) 共半年（每 3 周一次，共 8 个疗程）

SOX (替吉奥+奥沙利铂) 共半年（每 3 周一次，共 8 个疗程）

这三种方案中，替吉奥方案和CAPOX方案等效，但SOX要优于替吉奥。另外，胃癌术后直接使用纳武单抗免疫治疗无意义。

替吉奥确实会出现腹泻等代表性不良反应，患者可以考虑对症治疗，比如调节肠道的药物、止泻药等缓解副作用。如果副作用太严重，那么可以考虑减少药物剂量。

替吉奥的标准用药剂量为120mg，但用量低于80mg无法达到预期效果。如果当前患者用药为100mg，那么为了降低副作用，可以减少剂量到80mg；但如果目前剂量已经是80mg，则无法进一步降低剂量，此时考虑更换方案为CAPOX方案替代。如果不良反应严重到干扰日常生活，则患者可以选择停药，持续观察病情变化。

对于无淋巴结转移的II期B和II其C的患者，可选择使用1年帕博丽珠单抗免疫治疗。

4 、术后患者很瘦，味觉障碍，如何调理改善？通常，手术后患者体重会减轻20%左右。这是患者消化吸收能力低下、促食欲的胃肠激素减少引起的。大约6个月到1年时间，患者可以恢复正常。

味觉障碍可能是抗癌药的副作用引起的，也可能是饮食减少导致缺乏锌等微量元素引起的。建议患者采用少食多餐的方式饮食，每天分5-6次吃饭。在日本，我们有时也会给患者用一些营养补充剂。

另外，也可以考虑采用中草药的对症治疗，改善症状，比如十全大补汤、六君子汤。会诊结束后，李女士的心情得到了极大的平复。她对自己未来要走的路更清晰了，也对日本专家的细致指导和会诊的快速响应非常满意。

高龄+多基础病，该手术还是姑息治疗？日本专家为7旬胃癌患者一锤定音！

中国是消化道癌症发病数量较多的国家，根据国家癌症中心发布的《2022年中国恶性肿瘤疾病负担情况》数据，2022年我国胃癌新发病例约为35.87万例，死亡人数26.04万人。

总体来说，胃癌属于严重威胁我国国民生命健康的蕞常见癌症之一。胃癌如能在早、中期发现，还是有很大机会通过手术实现根治的，患者仍有一定机会得到临床治愈（术后5年不复发即为临床治愈）。

但在胃癌患者中，一部分人会因为【年龄较高】、伴有诸多【基础病】等问题，对手术存有疑虑，担心“下不来手术台”，甚至会放弃手术机会，选择吃药等姑息治疗。这样的选择真的正确吗？现如今的技术能否支持这类老年患者安全手术呢？接下来，我们一起看一个真实案例。

01七旬老人遭遇中期胃癌

一位七十多岁的“老胃病”项女士，因短时间体重骤降（8斤）前往就医。血液检测显示，她有一项指标异常升高。进一步检查发现，她的食道和胃连接的地方（贲门）以及胃的“外墙”（胃壁）都变得异常的厚，而且形状不均匀——这正是胃癌常见的表现。

医生随后通过胃镜检查和病例活检（取一小块组织观察上面的细胞），确诊了老人患有胃癌。由于还没有出现胃以外的远处其他器官的转移，也没有附近淋巴结转移，因此项女士的胃癌分期为中期。虽不是早期，但中期胃癌通常是可以手术的。为项女士提供诊疗的医生也表示，可以通过全胃切除手术实现根治。

但一来项女士已经七十多岁，二来她有20多年的糖尿病（手术伤口会更慢愈合、感染风险高、术后并发症风险高）、右肺还有一枚1.2厘米的肺结节。种种问题让老人和家人们都比较犹豫，担心扛不住治疗，最终“越治越糟”。在这样的背景下，项女士决定找一位足够权威的外科专家，来为自己进行全面评估，看看能不能兼顾好肿瘤根治以及手术的安全性。

不久后，项女士预约了来自日本癌研有明医院消化中心胃外科部长布部创也医生为自己提供指导。

02日本专家咨询内容分享

在充分了解了项女士的病情信息和全部资料后，布部创也医生给出了如下指导建议：首先，患者此前接受的是普通CT而非增强CT，胃镜也没有清晰展示食道上肿瘤具体侵犯的程度，因此很难得出精准的分期判断。

后面患者来癌研有明医院就医时，医疗团队会在治疗前为她做一套非常精细、全面的检查，此后就可以明确肿瘤情况了。届时如果发现患者的分期、肿瘤侵犯的范围确实和现在的结果相同，那么可以通过一个腹腔镜微创手术实现根治，损伤会非常小；如果届时发现肿瘤侵犯食道过多，则需要消化道联合食道外科共同进行胸腔镜手术治疗。

但无论是哪一种情况，患者都可以耐受手术，并且保留一部分胃。癌研有明医院是一家极为擅长肿瘤微创手术的知名癌症专科医院。在胃癌方面，2005年，医院开始导入腹腔镜，2019年又引入了达芬奇手术机器人，患者术后并发症更少了。如今，癌研有明医院98%的外科手术都采用微创。

受益于此，很多在别的医院需要胃全切的胃癌患者，到癌研有明后可以保留一部分胃，还能兼顾临床治愈。这对于术后患者的长期营养摄入和体重维持都很有帮助。布部创也医生所在科室的主要目标之一，正是在做到根治性切除的前提之下，将原本的胃全切术式变为次全胃切除术，尽可能为患者保留一些胃，让他们未来的生活质量得到提升。

那么项女士的糖尿病问题，会不会影响到手术呢？对此，布部创也医生认为完全不必担心，因为对于这类患者，癌研有明医院会进行详细的术前评估，并且有专业团队介入，从生活方式调整和专业治疗入手，帮助患者控制好血糖，让血糖水平达到符合手术的标准，从而降低术后愈合不良风险。

关于肺部的1.2厘米结节，布部医生认为可以暂不处理，无论它到底是良性还是恶性。因为这枚结节属于纯磨玻璃结节，即便是恶性，进展也非常缓慢，并不会快速出现转移扩散。而胃癌根治手术虽然会采用微创方式，但依然会给患者带来一定的负担，如果同时处理肺结节，会导致负担过重、患者难以承受。所以当前蕞好的处理办法，是先集中精力解决胃癌肿瘤，术后安排呼吸科专家为患者进行肺结节诊断，给出随访或手术或根治性放疗的建议。

03项女士术后，是否需要化疗来降低复发风险、争取更大治愈希望？

对此，布部创也医生表示，是否化疗现在还不能判断。因为术后患者能获得蕞精准的分期判断，有可能患者术前被认为是2期，但实际上术后成了1期（无需化疗）；有时也可能患者术前是1期，但术后成了2-3期。假如是2-3期，则患者术后需要坚持1年的辅助化疗，大概可以降低10%的复发风险。

有效减少不良反应，AD新药改良给药方案来了

当地时间10月29日礼来宣布了Ⅲb期临床试验（TRAILBLAZER-ALZ 6）的积极结果，对于早期症状性阿尔茨海默病成人患者，用改良滴定方案接受donanemab治疗的患者在24周主要终点时，伴水肿/积液的淀粉样蛋白相关影像学异常（ARIA-E）有所减少。

donanemab这个新药在今年7月获批于美国，又在之后获日本厚生劳动省、英国药品和医疗产品监管局批准，用于轻度阿尔茨海默病、轻度认知功能障碍的治疗。donanemab在国内2023年取得突破性治疗药物认定，并纳入优先审评审批程序，目前还在审评审批过程中。

CDE官网截图

但在FDA说明书中有黑框警告，大意是应用该药时应注意淀粉样蛋白相关影像学异常（ARIA），表现为ARIA-E和ARIA伴含铁血黄素沉积（ARIA-H），通常发生在治疗早期，且无症状，很少发生严重和危及生命的事件。本次试验的积极结果和这个黑框警告相关。一起来看详情。

FDA说明书截图

给药方式有哪些改变？会不会影响效果？

TRAILBLAZER-ALZ 6是一项多中心随机双盲Ⅲb期研究，主要研究donanemab的不同给药方案对早期症状性AD患者ARIA-E和淀粉样蛋白清除率的影响，这里的早期AD指的是轻度认知障碍（MCI）和轻度痴呆疾病阶段。

给药方式和既往不同，既往标准给药方案是在前三次输注时接受2瓶（700mg）donanemab，然后再接受4瓶（1400mg）；改良滴定方式是患者第一次输注1瓶（350mg），第二次输注2瓶（700mg），第三次输注3瓶（1050mg），此后每次输注4瓶（1400mg）。

研究的主要终点是第24周时患者出现ARIA-E占总参与者的比例，结果显示接受改良滴定方式的患者ARIA-E发生率为14%，而标准给药方案为24%，相对风险降低41%。载脂蛋白E（APOE）是已知的阿尔茨海默病遗传风险因素的携带者，在这些患者中，19%患者在改良滴定时患有ARIA-E，而标准给药方案中为57%，相对风险降低67%。

看到这里你或许也有疑问，虽然ARIA-E的发生风险降低了，但改良滴定方案会不会影响疗效？答案是不会。

与接受标准给药方案的患者相比，改良滴定患者淀粉样斑块和p-tau217减少。改良滴定的患者的淀粉样斑块水平较基线平均降低 67%，而标准给药组患者为69%。

参考来源

1.Modified Titration of Donanemab Demonstrated Reduction of ARIA-E in Early Symptomatic Alzheimer's Disease Patients in Phase Ⅲb study.

2.CED官网.

3.A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer's Disease (TRAILBLAZER-ALZ 6).

重磅！白血病一线新药获FDA加速批准

当地时间10月29日，阿西米尼（asciminib）获美国食品药品管理局（FDA）加速批准^[1] ，用于慢性期新诊断的费城染色体阳性慢性粒细胞白血病（Ph+CML）成年患者。CML是一种骨髓和血细胞癌症，通常由费城染色体的异常染色体引起。在一线治疗中，约1/3的患者会出现下列问题：由于不良反应或者治疗无效而停止酪氨酸激酶抑制剂（TKI）治疗。

为了解决这一问题，需要开发新的药物，asciminib就是解决这一困境的新药。早在2022年8月，加拿大药物和卫生技术局（CADTH）建议^[2] ：“若满足条件，可通过公共药物计划报销asciminib用于治疗费城染色体阳性慢性粒细胞白血病。”

asciminib为何得到FDA的青睐？

本次获批基于一项III期多中心随机研究，研究目的是比较每日80mg的asciminib与TKI治疗的疗效。TKI治疗是接受伊马替尼、尼洛替尼、达沙替尼或博舒替尼任意一种治疗。

共有405名患者被随机分配（1:1）进两组治疗。主要疗效结局指标是48周时的主要分子反应（MMR）率。这个指标是慢性髓性白血病的关键指标，这个比例越高，说明该治疗在基因水平上对疾病的控制效果越好，能够更有效地抑制疾病相关基因的表达，进而有望更好地控制疾病的进展、改善患者的症状和预后。

研究结果显示，48周时MMR率方面，asciminib组中为68%（95% CI: 61, 74)，TKI组为49%（95% CI: 42, 56），二者相差19%。细看具体的TKI，入组伊马替尼和其他TKI药物入组比例为1:1；asciminib组的MMR率为69%（95% CI: 59, 78），而伊马替尼组为40%（95% CI: 31, 50），相差近30%（95% CI: 17, 42）。

这个新药安全吗？每周需要打几次药？

根据FDA数据显示，在新诊断和既往接受过治疗的患者，应用新药最常见的不良反应（≥20%）是肌肉骨骼疼痛、皮疹、疲劳、上呼吸道感染、头痛、腹痛和腹泻。若只看新诊断的患者，最常见的实验室异常（≥40%）是淋巴细胞计数降低、白细胞计数降低、血小板计数降低、中性粒细胞计数降低等。

根据FDA已批准的asciminib说明书，用药期间还需要注意一下事项：

1.骨髓抑制：用药期间可能因出现骨髓抑制，发生血小板减少症、中性粒细胞减少症和贫血。用药应在治疗的前3个月，需要每两周进行一次全血细胞计数，此后每月进行一次检测，从而判断患者有无骨髓抑制症状。根据严重程度，咨询医生是否需要停药。

2.胰腺毒性：患者可能出现血清脂肪酶和淀粉酶无症状升高，每月需评估血清脂肪酶和淀粉酶水平，如果您有胰腺炎，则注意主动告知医生，需要进行频率更高的检测。

3.高血压风险：可能出现3级或4级高血压风险，应注意检测血压。

4.超敏反应：可能出现3级或4级超敏反应，包括皮疹、水肿和支气管痉挛。如果出现这些症状，需及时反馈医生，医生会根据超敏反应的体征和症状，开始适当的治疗。

5.心血管毒性：如果您有心血管病史，需要告知医生；对于3级或更高级别的心血管毒性，医生会考虑暂停用药、减少剂量或永久停药。

6.胚胎/胎儿毒性：若您在怀孕期间用药或在服用药物期间怀孕，可能对孩子有潜在风险。这个新药是口服药，需要根据不同的给药剂量（80mg或40mg）每天/或每两天用药。

近些年来，还有哪些白血病药物获批FDA？

根据FDA肿瘤学/血液系统恶性肿瘤批准通知，白血病相关新药整理如下表。

另外可以看出21年时asciminib已获批白血病治疗，但限定既往接受过两种或更多TKIs治疗，本次获批属于扩大适应证。

参考来源：

1.FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. 2.Asciminib(Scemblix):CADTHReimbursementRecommendation:Indication:ForthetreatmentofadultpatientswithPhiladelphiachromosome-positivechronicmyeloidleukemia(Ph+CML)inchronicphase(CP)previouslytreatedwith2ormoretyrosinekinaseinhibitors.Ottawa(ON):CanadianAgencyforDrugsandTechnologiesinHealth;2022Aug.PMID:38713779. 3.AStudyofOralAsciminibVersusOtherTKIsinAdultPatientsWithNewlyDiagnosedPh+CML-CP. 4.Product information：SCEMBLIX-asciminibtablet,filmcoated.UpdatedAugust7,2024. 5.Oncology(Cancer)/HematologicMalignanciesApprovalNotifications.

病例31-2023：一名79岁男性，身体不自主运动，一过性反应迟钝

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Carrie Chui (Neurology): A 79-year-old man was admitted to this hospital because of involuntary movements on the left side and transient unresponsiveness.

The patient had been in his usual state of health until 9 months before admission, when involuntary movements of the left shoulder and left side of the face developed. The movements were described by the patient as twitching, were not associated with a change in the level of consciousness, and resolved after 1 to 2 minutes. During the next 6 months, the patient had similar episodes approximately once per month, but the episodes increased in duration, lasting 5 to 6 minutes.

Three months before admission, the episodes of involuntary movements increased in frequency, and the patient was evaluated by his primary care physician. The physical examination was normal. Results of kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 129 mmol per liter (reference range, 135 to 145). There was a history of inappropriate antidiuretic hormone secretion, and the sodium level was similar to levels obtained during the past 4 years. Magnetic resonance imaging (MRI) of the head (Figure 1A), performed before and after the administration of intravenous contrast material, revealed a focus of enhancement in the right middle frontal gyrus that was thought to be a small vascular anomaly. Electroencephalography (EEG), performed with the patient in awake and drowsy states, revealed rare, brief, focal slowing in the left temporal lobe during drowsiness; no epileptiform abnormalities were present.

Figure 1

MRI of the Head and CT Angiogram of the Head and Neck.

Two months before admission, the patient was evaluated in the epilepsy clinic affiliated with this hospital. He reported that the episodes of involuntary movements had increased in both frequency and duration, occurring once or twice per day and lasting approximately 10 minutes. Episodes began with tingling and numbness in the left leg that prompted the patient to voluntarily stomp the left foot to relieve the uncomfortable sensation. Then, the patient had involuntary movements that he described as an uncontrollable invisible force moving the left leg and arm, with hyperextension of the arm backward and pronation of the wrist. There was associated numbness in the distal portions of the left third, fourth, and fifth fingers and involuntary movement of the left cheek. No prodromal symptoms occurred. The patient had awareness during the episodes, and after the episodes, he felt fatigued but had a normal level of consciousness, without confusion. The examination in the epilepsy clinic was normal. A diagnosis of seizure disorder was considered, and treatment with levetiracetam was started.

Three weeks before admission, the patient was again evaluated in the epilepsy clinic. He reported that the episodes of involuntary movements still occurred on a daily basis but had decreased in duration and involved only the left leg, without abnormal movements of the arm or face. Dizziness, headache, and weakness had developed and were attributed to the use of levetiracetam. The patient’s family had recorded a video of one of the episodes of involuntary movements. After reviewing the video, the patient’s neurologist thought that the episodes were less likely to be caused by seizures and more consistent with choreoathetoid movements. Cross-tapering of medications — with the simultaneous administration of levetiracetam in decreasing doses and clobazam in increasing doses — was initiated, and the patient was referred to the movement disorders clinic affiliated with this hospital.

On the morning of admission, an episode of involuntary movements of the left leg and left shoulder occurred and persisted for 1 hour. Several hours after the symptoms abated, the patient’s wife found the patient to be unresponsive; he was sitting in a chair. Emergency medical services were called, and when they arrived, the patient was responsive. The fingerstick blood glucose level was 180 mg per deciliter (10.0 mmol per liter) and the blood pressure 110/80 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the patient reported dysuria and increased urinary frequency. The patient’s daughter noted that he had been more anxious during the past 3 years and occasionally had trouble with memory. Other medical history included Barrett’s esophagus, benign prostatic hypertrophy, chronic hepatitis B virus infection, eczema, gastroesophageal reflux disease, hypertension, nonischemic cardiomyopathy, and osteoporosis. There was no history of head trauma or extended loss of consciousness. Medications included aspirin, atorvastatin, doxazosin, finasteride, omeprazole, metoprolol, sacubitril, and valsartan. There were no known drug allergies. The patient was a lifelong nonsmoker and drank alcohol rarely; he did not use illicit drugs. His mother had had gastric cancer, and his sister had had esophageal cancer; there was no family history of seizures.

On examination, the temporal temperature was 36.8°C, the blood pressure 152/97 mm Hg, the pulse 65 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 96% while the patient was breathing ambient air. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 21.7. The blood pressure decreased to 130/63 mm Hg with standing. The patient was alert and interactive. The lower jaw was held to the left, but the nasolabial folds and smile were symmetric with activation. There were nonrhythmic, nonstereotyped, writhing movements of the left arm. Tone was normal, and strength was assessed as 5 out of 5 in the arms and legs. Results of liver-function and kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 125 mmol per liter. The lactate level was 2.1 mmol per liter (19 mg per deciliter; reference range, 0.5 to 2.0 mmol per liter [5 to 18 mg per deciliter]). The urinalysis was normal. Intravenous fluids were administered. Imaging studies were obtained.

Dr. Rajiv Gupta: Computed tomographic (CT) angiography of the head and neck (Figure 1B) revealed extensively calcified plaque with severe stenosis of the distal right common carotid artery (CCA), extending into the proximal right internal carotid artery (ICA), as well as stenosis of the right and left paraclinoid ICAs and the left vertebral artery at its origin. There was no vascular abnormality on the CT angiogram that corresponded to the abnormality in the right middle frontal gyrus seen on the previous MRI.

Dr. Chui: The patient was admitted to the hospital. On the second hospital day, the sodium level had increased to 130 mmol per liter, and the lactate level was normal. Additional imaging studies were obtained.

Dr. Gupta: MRI of the head showed no evidence of acute infarction. The focus of enhancement in the right frontal lobe that had been noted previously was not seen on the current MRI.

Dr. Chui: Blood levels of thyrotropin, cobalamin, and glycated hemoglobin and results of coagulation tests were normal. Screening tests for Lyme disease, tuberculosis, and syphilis were negative, as were tests for antibodies to cardiolipin and β₂-glycoprotein. A test for antinuclear antibodies was positive, at a titer of 1:160 in a homogeneous pattern. During a physical therapy session, the patient had abnormal movements of the left leg, left arm, and left side of the face. The abnormal movements diminished when the patient used distraction techniques, such as thigh tapping, finger snapping, and walking while holding a glass of water.

The transient unresponsiveness that led to the patient’s admission was attributed to a combination of sedation from clobazam and hypovolemia. Treatment with clobazam was stopped, and hydration was encouraged. A diagnosis of functional neurologic disorder was considered; outpatient physical therapy with continued use of distraction techniques was recommended. The patient was discharged home on the third hospital day.

Episodes of involuntary movements continued to occur on a daily basis at home. Two weeks after discharge, when the patient was doing exercises while sitting in a chair and having a conversation with his wife, he suddenly stopped talking. She found him slumped in the chair with his eyes closed, no longer exercising. When she asked him questions, he repeatedly said “yes.” Emergency medical services were called, and when they arrived, the patient was alert, diaphoretic, and nonverbal. He had a facial droop on the left side and a right gaze preference. The fingerstick blood glucose level was 130 mg per deciliter (7.2 mmol per liter) and the blood pressure 120/60 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the temporal temperature was 36.6°C, the blood pressure 143/63 mm Hg, the pulse 66 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 98% while the patient was breathing ambient air. He was alert and interactive. There was a facial droop on the left side. There was no effort against gravity in the left arm. The patient was able to lift the left leg off the bed for 1 to 2 seconds. He had a right gaze deviation that could not be overcome and mild dysarthria. The remainder of the examination was normal. A diagnosis of stroke was considered, and emergency CT angiography was performed.

Dr. Gupta: CT angiography showed no evidence of acute territorial infarction and no changes in cerebrovascular disease.

Dr. Chui: On repeat physical examination performed after CT angiography, the gaze deviation and dysarthria had resolved, and strength was normal. Mild facial paralysis was present.

A diagnosis was made.

Differential Diagnosis

Dr. Albert Y. Hung: This 79-year-old man initially presented with involuntary movements of the left shoulder and face without associated loss of consciousness. Diagnosis of an unusual movement disorder, especially one that is present episodically, can be challenging. Videos brought in by the patient can be very useful.¹ Most movement disorders result from abnormal functioning of extrapyramidal circuits involving the basal ganglia, rather than a specific neuroanatomical lesion, and the first step toward diagnosis is to identify the type of abnormal movements.²

Four salient aspects of this patient’s involuntary movements can help in characterizing the movement disorder before generating a differential diagnosis. First, the movements were paroxysmal, lasting for short periods of time with resolution between episodes. Second, the movements were nonstereotyped, appearing randomly and variably. Third, the movements were restricted to the left side of his body throughout the course, localizing the disease process to the right cerebral hemisphere. Finally, the symptoms were progressive, increasing in both duration and frequency.

Movement Disorders

This patient had abnormal involuntary movements, symptoms indicative of a hyperkinetic movement disorder. Tremor, the most common hyperkinetic disorder, is unlikely because the patient did not have rhythmic movements. Dystonia is also unlikely, because he did not have sustained muscle contractions that were causing twisting or abnormal postures of the legs, arms, head, neck, or face. Although the patient initially described the movements as twitching, his later descriptions are not suggestive of myoclonus or tics, which manifest as sudden, rapid, recurrent movements.

This patient’s neurologist described the involuntary movements as “choreoathetoid” after reviewing a video of an episode. Chorea, athetosis, and ballism make up a spectrum of involuntary movements that often occur in combination. Chorea refers to involuntary movements that are “dancelike” — irregular, random, unintended, and flowing from one body part to another. When these movements are slow and writhing (with a lower amplitude) and involve the distal limbs, the term athetosis is used. The presence of both chorea and athetosis in the same patient is referred to as choreoathetosis. When the movements are fast and flinging (with a higher amplitude) and involve the proximal limbs, the term ballism is used. Although the description of this patient’s movements was not clearly suggestive of ballism, hemichorea and hemiballismus often occur together.

The term dyskinesia can refer to any abnormal movements and is often used to describe hyperkinetic disorders that are induced by specific drugs, such as tardive dyskinesia induced by dopamine antagonists or dyskinesia induced by levodopa in patients with Parkinson’s disease. Often, dyskinesia manifests as chorea or choreoathetoid movements, but chorea and dyskinesia are not synonymous. This patient appears to have involuntary dyskinesia with choreoathetosis as the primary phenomenology. Before constructing a differential diagnosis for dyskinesia in this patient, I will consider two conditions that mimic dyskinesia: seizures and functional movement disorder.

Seizures

Various movement disorders may be mistaken for seizures, although these movement disorders are not associated with EEG abnormalities during the episode. Patients with some forms of epilepsy may present with abnormal movements without other features that are typically associated with seizures, such as aura, change in responsiveness, incontinence, or a postictal state.^3,4 Seizures were initially suspected in this patient, and he was referred to the epilepsy clinic. Recurrent focal seizures were probably suspected because of the transient nature of the episodes. Initial MRI had shown a small abnormality in the right middle frontal gyrus, but this finding was not seen on follow-up imaging, which makes it unlikely to be related to the overall presentation. Baseline EEG had shown only brief left temporal slowing, without epileptiform abnormalities. The EEG was an interictal study, so the findings do not rule out seizures. However, the slowing was ipsilateral to the abnormal movements, so it is unlikely to be related to the episodes. In addition, the patient’s involuntary movements were nonstereotyped and nonrhythmic, which makes his presentation unlikely to be due to a seizure disorder.

Functional Movement Disorder

Because this patient’s movements diminished with the use of distraction techniques, a diagnosis of functional movement disorder was considered. Most cases of functional movement disorder begin abruptly after a trigger, such as a mild physical injury or illness; a psychological stressor can be present but is not required for diagnosis. Symptoms are typically most severe around the time of onset and may wax and wane over time. Although distractibility is a finding associated with functional disorders, abnormal movements that occur with nonfunctional syndromes can sometimes be suppressed by action or incorporated into voluntary movements in a manner that may appear distractible. Several clinical features in this patient make a diagnosis of functional disorder unlikely. Functional movement disorder is more common in women than in men, and the average age at onset is 40 years.⁵ In addition, tremor is the most common clinical phenotype seen in patients with functional movement disorder; chorea or choreoathetosis, which was seen in this patient, is very unusual in patients with functional movement disorder. Overall, functional movement disorder is unlikely to explain this patient’s presentation.

Dyskinesia

Primary paroxysmal dyskinesia refers to a group of heterogeneous syndromes characterized by recurrent involuntary movements that occur episodically and abruptly, without loss of consciousness.⁶ These disorders usually begin in childhood or young adulthood. Both the age of this patient and the described phenomenology make a diagnosis of primary paroxysmal dyskinesia unlikely.

The differential diagnosis in this case is therefore focused on causes of secondary dyskinesia, of which there are many.⁷ MRI ruled out the presence of a mass lesion suggestive of cancer. The patient had no history of acute illness suggestive of a viral or other infectious encephalitis, and there was no history of trauma or exposure to drugs or other toxins. Although his daughter mentioned trouble with memory, there was no compelling history suggestive of a neurodegenerative disease.

A common metabolic cause of secondary dyskinesia is diabetic striatopathy, a syndrome involving the acute-to-subacute onset of chorea and ballism in the context of hyperglycemia.⁸ This syndrome can occur as the initial manifestation of type 2 diabetes mellitus or as a complication of poorly controlled diabetes. Diabetic striatopathy is more likely to develop in women than in men, and the average age at onset is 70 years. Most patients present with hemichorea and hemiballismus, rather than bilateral symptoms. CT shows hyperdensity, and T1-weighted MRI shows hyperintensity, in the contralateral basal ganglia. However, this patient had no history of diabetes and had a normal blood glycated hemoglobin level, features that rule out a diagnosis of diabetic striatopathy.

Choreiform movements can also be a manifestation of autoimmune conditions.⁹ This patient’s initial presentation with unilateral shoulder and face movements would have suggested the possibility of faciobrachial dystonic seizures associated with anti–leucine-rich, glioma-inactivated 1 (anti-LGI1) encephalitis.¹⁰ This condition is often associated with hyponatremia, which was present in this patient. However, as the case evolved, leg involvement and sensory changes developed that would be atypical for anti-LGI1 encephalitis.

One key clue in this case is that the patient did not have an isolated movement disorder. In addition to motor symptoms, he had a variety of sensory symptoms involving both the left arm and the left leg. His first hospital admission was precipitated by an episode of unresponsiveness. The clinical event that led to his second presentation to the emergency department was distinctly different: an acute onset of speech difficulty accompanied by left hemiparesis and right gaze deviation that was worrisome for an acute right middle cerebral artery (MCA) syndrome. The symptoms resolved without intervention, which indicates that he may have had an acute transient ischemic attack (TIA). The most relevant imaging finding was severe cerebrovascular disease, including severe stenosis of the distal right CCA and proximal right ICA. Could this patient’s movement disorder be explained by a vascular lesion?

Limb-Shaking TIAs

Limb-shaking TIAs were first described by C. Miller Fisher in 1962.¹¹ In most case reports, these episodes are associated with high-grade stenosis of the ICA, which was seen in this patient.^12,13 The mechanism is thought to be cerebral hypoperfusion, and changes in posture or head position that decrease cerebral blood flow can precipitate these episodes. In this patient, the first episode of unresponsiveness that led to hospital admission occurred when he was sitting. He then had an acute episode involving right gaze preference that was provoked by exercise and was very suggestive of a TIA in the right MCA territory. These findings are highly suggestive of a diagnosis of limb-shaking TIAs, and I would refer this patient for emergency carotid endarterectomy.

Clinical Impression and Initial Management

Dr. Scott B. Silverman: When I evaluated this patient, his transient right gaze preference and left hemiparesis were consistent with a right MCA syndrome due to a TIA from symptomatic severe stenosis of the right ICA. The mechanism of this event was either artery-to-artery embolism or hypoperfusion. His previous, recurrent episodes of transient choreoathetosis on the left side that had occurred mainly while he was sitting, standing, or exercising were consistent with limb-shaking TIAs from hypoperfusion or low flow.

The pathogenesis of a low-flow state related to severe carotid stenosis resulting in limb-shaking TIAs is described in a small case series.¹⁴ In six out of eight patients, the transient, stereotyped, involuntary movements were eliminated with carotid artery revascularization. Positional cerebral ischemia in patients without orthostatic hypotension has been described.¹⁵

Treatment with atorvastatin was continued, the dose of aspirin was increased to 325 mg per day, and an intravenous heparin infusion was started. The strategy of permissive hypertension was used, with high blood pressure allowed to a maximum systolic blood pressure of 180 mm Hg. The patient was admitted to the stroke service, and carotid artery duplex ultrasonography was performed.

Dr. Gupta: Doppler ultrasonography of the carotid arteries (Figure 2) revealed markedly elevated Doppler flow velocities within the proximal right ICA. There was a parvus et tardus waveform in the distal right ICA, a finding indicative of low flow related to the more proximal high-grade stenosis. The Doppler waveform contours had poststenotic turbulence.

Figure 2

Doppler Ultrasound Image.

Dr. Silverman: The vascular surgery service was consulted, and the patient underwent right carotid endarterectomy.

Clinical Diagnosis

Limb-shaking transient ischemic attacks.

Dr. Albert Y. Hung’s Diagnosis

Limb-shaking transient ischemic attacks due to severe carotid stenosis, with secondary paroxysmal dyskinesia.

Pathological Discussion

Dr. Caroline F. Hilburn: The endarterectomy specimen included the carotid bifurcation and was notable for firm arterial walls, a finding consistent with calcification. On gross examination (Figure 3A), a large plaque was centered at the carotid bifurcation and protruded into the lumen, resulting in a maximal luminal stenosis of 80%. The plaque had an irregular and focally friable surface. On microscopic examination (Figure 3B), the plaque was characterized by extensive calcification. Some regions of the plaque had a smooth, healed fibrous cap, whereas other regions had an irregular surface suggestive of ulceration, which indicated potential sites of plaque rupture. Multiple smaller calcified plaques were present, affecting both branches of the artery.

Figure 3

Endarterectomy Specimen.

Pathological Diagnosis

Complex atherosclerotic plaque with portions of attached media.

Additional Management

Dr. Silverman: After the procedure, the patient had an uneventful recovery and was discharged home on the fifth hospital day. He was seen 1 month after discharge in the stroke prevention clinic. There had been no further episodes of involuntary movements or choreoathetosis and no stroke or TIA. The patient continues to take aspirin, atorvastatin, and antihypertensive medications.

Final Diagnosis

Limb-shaking transient ischemic attacks.

病例28-2024：一名75岁女性，患有水肿、关节炎和蛋白尿

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Christine M. Parsons (Medicine): A 75-year-old woman was evaluated at this hospital because of arthritis, abdominal pain, edema, malaise, and fever.

Three weeks before the current admission, the patient noticed waxing and waning “throbbing” pain in the right upper abdomen, which she rated at 9 (on a scale of 0 to 10, with 10 indicating the most severe pain) at its maximal intensity. The pain was associated with nausea and fever with a temperature of up to 39.0°C. Pain worsened after food consumption and was relieved with acetaminophen. During the 3 weeks before the current admission, edema developed in both legs; it had started at the ankles and gradually progressed upward to the hips. When the edema began to affect her ambulation, she presented to the emergency department of this hospital.

A review of systems that was obtained from the patient and her family was notable for intermittent fever, abdominal bloating, anorexia, and fatigue that had progressed during the previous 3 weeks. The patient reported new orthopnea and nonproductive cough. Approximately 4 weeks earlier, she had had diarrhea for several days. During the 6 weeks before the current admission, the patient had lost 9 kg unintentionally; she also had had pain in the wrists and hands, 3 days of burning and dryness of the eyes, and diffuse myalgias. She had not had night sweats, dry mouth, jaw claudication, vision changes, urinary symptoms, or oral, nasal, or genital ulcers.

The patient’s medical history was notable for multiple myeloma (for which treatment with thalidomide and melphalan had been initiated 2 years earlier and was stopped approximately 1 year before the current admission); hypothyroidism; chikungunya virus infection (diagnosed 7 years earlier); seropositive erosive rheumatoid arthritis affecting the hands, wrists, elbows, and shoulders (diagnosed 3 years earlier); vitiligo; and osteoarthritis of the right hip, for which she had undergone arthroplasty. Evidence of gastritis was reportedly seen on endoscopy that had been performed 6 months earlier. Medications included daily treatment with levothyroxine and acetaminophen and pipazethate hydrochloride as needed for cough. The patient consumed chamomile and horsetail herbal teas. She had no known allergies to medications, but she had been advised not to take nonsteroidal antiinflammatory drugs after her diagnosis of multiple myeloma.

Approximately 5 months before the current admission, the patient had emigrated from Central America. She lived with her daughter and grandchildren in an urban area of New England. She had previously worked in health care. She had no history of alcohol, tobacco, or other substance use. There was no family history of cancer or autoimmune, renal, gastrointestinal, pulmonary, or cardiac disease.

On examination, the temporal temperature was 37.1°C, the heart rate 106 beats per minute, the blood pressure 152/67 mm Hg, and the oxygen saturation 100% while the patient was breathing ambient air. She had a frail appearance and bitemporal cachexia. The weight was 41 kg and the body-mass index (the weight in kilograms divided by the square of the height in meters) 15.2. Her dentition was poor; most of the teeth were missing, caries were present in the remaining teeth, and the mucous membranes were dry. She had abdominal tenderness on the right side and mild abdominal distention, without organomegaly or guarding. Bilateral axillary lymphadenopathy was palpable. Infrequent inspiratory wheezing was noted.

The patient had swan-neck deformity, boutonnière deformity, ulnar deviation, and distal hyperextensibility of the thumbs (Fig. 1). Subcutaneous nodules were observed on the proximal interphalangeal joints of the second and third fingers of the right hand and on the proximal interphalangeal joint of the fourth finger of the left hand. Synovial thickening of the metacarpophalangeal joints of the second fingers was noted. There was mild swelling and tenderness of the wrists. She had pain with flexion of the shoulders and right hip, and there was subtle swelling of the shoulders and right knee. Pitting edema (3+) and vitiligo were noted on the legs. No sclerodactyly, digital pitting, telangiectasias, appreciable calcinosis, nodules, nail changes (including pitting), or tophi were present. The remainder of the examination was normal.

Figure 1

Photograph of the Hands.

The blood levels of glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin, globulin, lactate, lipase, magnesium, and phosphorus were normal, as were the prothrombin time and international normalized ratio; other laboratory test results are shown in Table 1. Urinalysis showed 3+ protein and 3+ blood, and microscopic examination of the sediment revealed 5 to 10 red cells per high-power field and granular casts. Urine and blood were obtained for culture. An electrocardiogram met (at a borderline level) the voltage criteria for left ventricular hypertrophy.

Table 1

Laboratory Data.

Dr. Rene Balza Romero: Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous administration of contrast material, revealed scattered subcentimeter pulmonary nodules (including clusters in the right middle lobe and patchy and ground-glass opacities in the left upper lobe), trace pleural effusion in the left lung, coronary and valvular calcifications, and trace pericardial effusion, ascites, and anasarca. The scans also showed slight enlargement of the axillary lymph nodes (up to 11 mm in the short axis) bilaterally and a chronic-appearing compression fracture involving the T12 vertebral body.

Dr. Parsons: Morphine and lactated Ringer’s solution were administered intravenously. On the second day in the emergency department (also referred to as hospital day 2), the blood levels of haptoglobin, folate, and vitamin B₁₂ were normal; other laboratory test results are shown in Table 1. A rapid antigen test for malaria was positive. Wright–Giemsa staining of thick and thin peripheral-blood smears was negative for parasites; the smears also showed Döhle bodies and basophilic stippling. Antigliadin antibodies and anti–tissue transglutaminase antibodies were not detected. Tests for hepatitis A IgG and hepatitis C antibodies were positive. Tests for hepatitis B core and surface antibodies were negative. A test for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was negative.

Findings on abdominal ultrasound imaging performed on the second day (Fig. 2A and 2B) were notable for a small volume of ascites and kidneys with echogenic parenchyma. Ultrasonography of the legs showed no deep venous thrombosis. An echocardiogram showed normal ventricular size and function, aortic sclerosis with mild aortic insufficiency, moderate tricuspid regurgitation, a right ventricular systolic pressure of 39 mm Hg, and a small circumferential pericardial effusion. Intravenous hydromorphone was administered, and the patient was admitted to the hospital.

Figure 2

Imaging Studies of the Abdomen and Hands.

On the third day (also referred to as hospital day 3), nucleic acid testing for cytomegalovirus, Epstein–Barr virus, and hepatitis C virus was negative, and a stool antigen test for Helicobacter pylori was negative. An interferon-γ release assay for Mycobacterium tuberculosis was also negative. Oral acetaminophen and ivermectin and intravenous hydromorphone and furosemide were administered.

Dr. Balza Romero: Radiographs of the hands (Fig. 2C through 2F) showed joint-space narrowing of both radiocarpal joints and proximal interphalangeal erosions involving both hands. Radiographs of the shoulders showed arthritis of the glenohumeral joint and alignment suggestive of a tear of the right rotator cuff. A radiograph of the pelvis showed diffuse joint-space narrowing of the left hip, without osteophytosis, and an intact right hip prosthesis.

Dr. Parsons: Diagnostic tests were performed, and management decisions were made.

Differential Diagnosis

Dr. Beth L. Jonas: This patient is a 75-year-old woman who recently emigrated from Central America. She presented to this hospital with a multisystem disease involving the respiratory, gastrointestinal, renal, and musculoskeletal systems. Her medical history is notable for seropositive erosive rheumatoid arthritis and multiple myeloma, which had been treated with melphalan and thalidomide. Relevant clinical features on presentation include unintended weight loss and cachexia, axillary lymphadenopathy, serositis, cytopenia in two cell lines, hypocomplementemia, and elevated serum free kappa and lambda light-chain levels (with a normal free light-chain ratio) with no monoclonal spike. The white-cell count was elevated, but she had no eosinophilia. CT images of the chest showed scattered subcentimeter pulmonary nodules. With respect to the patient’s anemia, no schistocytes were present, the haptoglobin level was normal, and the iron studies were unremarkable. These findings, in combination with the elevated ferritin level, indicate anemia of chronic inflammation. The renal findings are most salient in the context of the patient’s hypertension, anasarca, elevated cystatin C level, active urinary sediment with proteinuria in the nephrotic range, and small, echogenic kidneys on ultrasonography.

In constructing a differential diagnosis, I will consider medication use, cancer, infectious disease, and autoimmune disease. Medications can be eliminated as the cause of this patient’s illness, since she was taking only levothyroxine, acetaminophen, and the antitussive agent pipazethate.

Cancer

The patient has a history of multiple myeloma, which may manifest with a multisystem disease involving the kidneys, but serum protein electrophoresis showed no monoclonal protein. Given the presence of nephrotic syndrome in the context of multiple myeloma, systemic immunoglobulin light-chain amyloidosis would be highest on the differential diagnosis with respect to cancer; however, the patient’s normal light-chain ratio makes this diagnosis unlikely. The development of myeloid neoplasms, such as acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, is important to consider in the context of previous treatment with alkylating agents,¹ which this patient had received. However, the peripheral-blood smear showed no findings that would indicate a hematologic cancer, and such a diagnosis would not explain the patient’s acute kidney injury with nephrotic-range proteinuria.

Infectious Disease

Several features of this patient’s case warrant special consideration, including her history of immunosuppression due to rheumatoid arthritis and to previously treated myeloma, along with the fact that she had emigrated from Central America, where certain infections may be prevalent. Infection with hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV-1 and HIV-2, cytomegalovirus, Epstein–Barr virus, H. pylori, and M. tuberculosis can be ruled out on the basis of laboratory studies. A rapid antigen test for plasmodium species was reported to be positive, but this assay has a known cross-reactivity with rheumatoid factor.² Moreover, the thick and thin peripheral-blood smears were negative. Thus, malaria would be an unlikely diagnosis.

The patient has a history of infection with chikungunya virus, an arbovirus transmitted by a mosquito vector that has been responsible for large epidemics in the Americas since 2013.³ Acute symptoms include fever, rash, arthralgia, and myalgia. The development of a chronic arthritis that may meet the classification criteria for rheumatoid arthritis, as defined by the American College of Rheumatology and the European Alliance of Associations for Rheumatology, has been reported in up to 60% of patients infected with chikungunya virus.^4,5 In the context of this discussion, I considered whether chikungunya virus infection could be the cause of this patient’s symptoms, since this infection occurred before the diagnosis of rheumatoid arthritis. However, the degree of erosion and loss of joint space that was visible on radiographs would be most unusual for arthritis associated with chikungunya virus infection and would not explain the renal manifestations.

Strongyloidiasis is a helminth infection (caused by Strongyloides stercoralis) that is widespread in developing countries. Infection usually occurs through contact with soil, and most affected persons are asymptomatic. However, in immunosuppressed persons, strongyloides hyperinfection syndrome or a disseminated infection can develop as a consequence of accelerated autoinfection.⁶ The clinical presentation of strongyloides hyperinfection syndrome can include gastrointestinal symptoms (diarrhea, constipation, nausea, or vomiting), respiratory symptoms (cough, dyspnea, or wheezing), and rash due to migration of larvae through the subcutaneous tissues. Of note, only a minority of patients present with eosinophilia. Several case reports describe the development of nephrotic-range proteinuria, thrombotic microangiopathy, and IgA vasculitis in patients with strongyloides hyperinfection syndrome.^7-9 However, strongyloidiasis would not explain this patient’s cytopenias and hypocomplementemia.

Autoimmune Disease

The patient has a 3-year history of rheumatoid arthritis, although her clinical features of swan-neck deformity, boutonnière deformity, and joint instability suggest a longer duration of disease. We do not know whether she had received previous treatment with disease-modifying antirheumatic drugs or biologic agents, but the possible use of such treatments may be a consideration with respect to her progression of disease and overall degree of immunosuppression. The blood levels of rheumatoid factor and anti–cyclic citrullinated peptide antibodies were elevated, and radiographs of the hands showed erosive disease, although there was a relative paucity of metacarpophalangeal findings. A review of systems was negative for dry mouth, but her physical examination showed poor dentition and dry mouth — findings that make secondary Sjögren’s syndrome a consideration.

Renal disease can occur in patients with Sjögren’s syndrome. The two most typical presentations are tubulointerstitial nephritis and, less commonly, nephritic syndrome (membranoproliferative glomerulonephritis related to cryoglobulinemia). Tubulointerstitial nephritis may manifest with renal disease of varying severity, usually with a bland urinary sediment and often with abnormalities of tubular function such as distal renal tubular acidosis. Membranoproliferative glomerulonephritis caused by cryoglobulinemia is the most common glomerular disease associated with Sjögren’s syndrome. Although nephrotic-range proteinuria can occur with Sjögren’s syndrome, it is relatively uncommon.¹⁰ Renal disease is uncommon in patients with rheumatoid arthritis and is usually related to coexisting cardiovascular conditions. Medications used in the treatment of autoimmune disease — mainly nonsteroidal antiinflammatory drugs — may be associated with renal disease, but I would not expect the presence of an active urinary sediment, as was seen in this patient.

Amyloid A (AA) amyloidosis, a condition that is rare in the era of aggressive management of rheumatoid arthritis, has been described in patients with severe, long-standing seropositive erosive rheumatoid arthritis. Serum amyloid A (SAA) is a protein that is produced in the liver in response to chronic inflammation associated with interleukin-1, interleukin-6, and tumor necrosis factor α (TNF-α) in the context of chronic infections, autoimmune disease (classically rheumatoid arthritis), autoinflammatory disease, and cancers including renal cell carcinoma and non-Hodgkin’s lymphoma.¹¹ Signs and symptoms of AA amyloidosis are related to the deposition of the protein in organs, and patients often present with multisystem signs and symptoms. The kidney is the organ that is most often affected, but deposition can occur in the heart, gastrointestinal tract, nervous system, musculoskeletal system, and lungs. Proteinuria is the first clinical manifestation in almost 95% of patients with AA amyloidosis, and 50% of affected patients present with nephrotic syndrome.¹² The urinary sediment is generally bland, and complement levels in the blood are normal. AA amyloidosis remains on the differential diagnosis in this patient, but it would not completely explain her renal disease.

Hypocomplementemia

The key to this case is understanding the cause of this patient’s hypocomplementemia. Hypocomplementemia can be due to decreased complement production in the context of liver disease, congenital complement deficiency, or increased complement consumption resulting from activation of the innate immune system. This patient has no history of chronic liver disease and her laboratory test results indicated good hepatic synthetic function. Classical complement deficiency (including C4 deficiency) that begins early in life is associated with autoimmune disease, and early C3 deficiency is characterized by severe pyogenic infections. It would be unusual for a patient of this age to be deficient in both C3 and C4 without earlier clinical consequences. I therefore concluded that the hypocomplementemia in this case was related to complement consumption.

Rheumatic diseases that may be associated with prominent renal manifestations include antineutrophil cytoplasmic antibody–associated vasculitis, systemic sclerosis with renal crisis, cryoglobulinemic vasculitis, antiglomerular basement membrane disease, and systemic lupus erythematosus (SLE). Of those conditions, SLE would be the most likely to be manifested by an active urinary sediment and nephrotic-range proteinuria with consumption of both C3 and C4 in the context of fever, thrombocytopenia, and serositis. This patient’s fever, thrombocytopenia, and serositis also fit with this diagnosis.¹³

Because the patient has long-standing seropositive erosive rheumatoid arthritis, a diagnosis of AA amyloidosis is strongly suspected. Moreover, given the presence of thrombocytopenia, hypocomplementemia, and an active urinary sediment, I would recommend a kidney biopsy to evaluate for lupus nephritis and AA amyloidosis.

Dr. Beth L. Jonas’s Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus with amyloid A amyloidosis.

Pathological Discussion

Dr. Claire Trivin-Avillach: Testing for autoimmune antibodies was performed. A test for antinuclear antibodies was positive at a titer of 1:5120 with a homogeneous pattern, and a test for anti–double-stranded DNA antibodies was positive at a titer of 1:2560.

The diagnostic procedure in this case was a core-needle biopsy of the kidney. Examination of the specimen with light microscopy revealed 20 glomeruli, 45% of which were globally sclerosed, along with fibrosis involving approximately 60% of the interstitium and tubular atrophy. Diffusely enlarged glomeruli with thickened capillary walls and an expanded mesangium were weakly positive on periodic acid–Schiff staining; the glomeruli stained pale blue on Masson’s trichrome staining. Congo red staining revealed metachromatic salmon-colored deposition involving the glomeruli, the blood-vessel walls, and the interstitium, which was associated with apple-green birefringence when viewed under polarized light (Fig. 3A). In addition, mesangial and endocapillary hypercellularity was identified in approximately 30% of the nonsclerosed glomeruli and was associated with karyorrhexis (Fig. 3B). One cellular crescent was also detected. These features are characteristic of active proliferative glomerulonephritis.

Figure 3

Biopsy Specimen of the Kidney.

Immunofluorescence microscopy revealed prominent granular staining for IgG (4+), IgM (4+), C3 (3+), C1q (3+), IgA (1+), kappa (3+), and lambda (3+) along the glomerular basement membranes and within the mesangium, as well as focal granular deposits of IgG and C3 along the tubular basement membrane (Fig. 3C and 3D). Additional immunofluorescence studies showed strong positivity (4+) for SAA within the glomeruli, the blood-vessel walls, and the interstitium (Fig. 3E), whereas staining for beta₂-microglobulin, transthyretin, and apolipoprotein A1 was faint.

Electron microscopy revealed the presence of subendothelial and mesangial electron-dense deposits (with no substructure identified) adjacent to randomly arranged fibrils (measuring 8.2 to 10.6 nm in diameter) within the glomerular basement membranes and the mesangium (Fig. 3F). Glomerular endothelial cells appeared reactive and contained tubuloreticular inclusions, features that were suggestive of interferon-mediated activation.

The findings on Congo red staining were characteristic of amyloidosis with typical birefringent material. The strong positivity of SAA within the deposits as compared with the faint staining of other reactants identified the type of amyloid as SAA, which is consistent with the patient’s history of rheumatoid arthritis. The biopsy also showed an immune complex–mediated proliferative glomerulonephritis with a “full house” pattern (defined as positivity for the three immunoglobulin classes IgG, IgM, and IgA and the two complement components C3 and C1q, in reference to the “full house” hand in a poker game). Immune complex–mediated proliferative glomerulonephritis has been reported in patients with rheumatoid arthritis who were receiving anti–TNF-α therapy,¹⁴ which was not the case in this patient. The positive test for hepatitis C antibodies prompted consideration of hepatitis C–related membranoproliferative glomerulonephritis. However, taken together, the negative nucleic acid test for hepatitis C virus, the full house pattern on immunofluorescence, the tubular basement membrane deposits, and the positive test for anti–double-stranded DNA antibodies favor a diagnosis of lupus nephritis of at least class III (defined as focal proliferative glomerulonephritis), according to the criteria of the International Society of Nephrology and the Renal Pathology Society, superimposed on AA amyloidosis.

Pathological Diagnosis

Proliferative lupus nephritis of International Society of Nephrology and Renal Pathology Society class III, superimposed on amyloid A amyloidosis.

Discussion of Management

Dr. Pui W. Cheung: On the basis of the finding of echogenic kidneys on ultrasonography and the findings of extensive interstitial fibrosis and tubular atrophy on kidney biopsy, we know that this patient has advanced chronic kidney disease that is unlikely to be reversible. The patient is also noted to have a markedly lower glomerular filtration rate (GFR) than that predicted by the blood creatinine level owing to the presence of cachexia, and this is substantiated by the cystatin C–based GFR and a 24-hour creatinine clearance of 22 ml per minute per 1.73 m² of body-surface area. The typical induction therapy for stage III or IV lupus nephritis consists of high-dose glucocorticoids and either mycophenolate mofetil or cyclophosphamide. Other reasonable alternatives for initial therapy include mycophenolate mofetil in combination with either a calcineurin inhibitor or belimumab, or cyclophosphamide in combination with belimumab.¹⁵ Hydroxychloroquine is also recommended as part of the therapy, since it has shown benefits in improving the response to treatment and reducing disease flare.¹⁶ Mycophenolate mofetil and cyclophosphamide have similar efficacy with respect to clinical response, which includes a reduction in proteinuria and either an improvement in renal function or stabilization of renal function; the risks of infections and adverse events associated with these medications are also similar.^17,18

Given the severity of the lupus nephritis with overlying AA amyloidosis from active rheumatoid arthritis, the treatment options proposed were high-dose glucocorticoids and rituximab with either mycophenolate mofetil or cyclophosphamide.¹⁹ After discussions with multidisciplinary consultants from rheumatology, infectious diseases, and nephrology, lingering concerns were raised about infection and patient frailty; ultimately, the decision was made to initiate high-dose glucocorticoid therapy in combination with mycophenolate mofetil, rituximab, and hydroxychloroquine.

The patient’s mycophenolate mofetil dose regimen was inconsistent owing to gastrointestinal side effects, and the treatment was eventually withheld because of pancytopenia and fever. Unfortunately, her kidney function worsened, and renal replacement therapy was initiated within 3 weeks after the start of the induction therapy. The cause of her renal failure was thought to be disease progression, compounded by hemodynamically mediated tubular injury in the context of infection. While the administration of mycophenolate mofetil was stopped, treatment with rituximab was continued, with slow tapering of the glucocorticoid dose at the direction of the rheumatologist. She remained dependent on dialysis and was deemed to have end-stage kidney disease after 3 months of dialysis.

Dr. Lisa G. Criscione-Schreiber: The patient has SLE with nephritis, seropositive erosive rheumatoid arthritis, and systemic AA amyloidosis. AA amyloidosis is rare owing to the availability of effective therapies for rheumatoid arthritis and is managed through aggressive treatment of inflammation due to rheumatoid arthritis. Reports addressing the management of rheumatoid arthritis–induced AA amyloidosis generally cite stability of end-organ damage caused by AA amyloid as evidence of effective management of the condition (through treatment of the inflammation of rheumatoid arthritis). Methotrexate, the cornerstone of treatment for rheumatoid arthritis, is contraindicated in this case owing to the presence of kidney disease. The alkylating agent cyclophosphamide has been reported to be effective for the treatment of AA amyloidosis from rheumatoid arthritis²⁰ and has known efficacy in patients with lupus nephritis, both of which make it a viable treatment option. Rituximab has also been reported to be effective for managing rheumatoid arthritis–induced AA amyloidosis,²¹ is approved for the treatment of rheumatoid arthritis, and is used for manifestations of SLE, including thrombocytopenia and nephritis. Although anti–TNF-α agents, abatacept, and Janus kinase inhibitors are reported to be effective for the treatment of AA amyloidosis in patients with rheumatoid arthritis,²² recent publications have coalesced on the ability of anti–interleukin-6 therapy to block interleukin-6–induced hepatic production of SAA.^23-25

The overlap of seropositive erosive rheumatoid arthritis and SLE (sometimes termed “rhupus”) usually resembles rheumatoid arthritis more than SLE; manifestations include thrombocytosis, leukocytosis, an elevated erythrocyte sedimentation rate, an elevated blood level of C-reactive protein, and the presence of marginal erosions on radiographs.²⁶ In contrast, SLE without seropositive erosive rheumatoid arthritis characteristically manifests with thrombocytopenia, leukopenia, and an elevated erythrocyte sedimentation rate but usually not an elevated C-reactive protein level; in addition, nonerosive inflammatory arthritis with reversible deformities is commonly observed. This patient had a mixed laboratory profile, on the basis of the results of antinuclear antibody and anti–double-stranded DNA antibody tests. The challenge of treating an overlap syndrome of rheumatoid arthritis and SLE is choosing disease-modifying antirheumatic drugs that are effective and safe in both conditions. This patient’s most severe disease manifestation is lupus nephritis; therefore, the treatment regimen must target nephritis along with the AA amyloidosis and inflammatory arthritis.

As noted earlier, current induction therapy for lupus nephritis includes either mycophenolate mofetil or cyclophosphamide. Mycophenolate mofetil may provide inadequate treatment of the rheumatoid arthritis and amyloidosis, whereas cyclophosphamide would treat the lupus nephritis, has possible efficacy for treatment of the AA amyloidosis, and would treat the rheumatoid arthritis. Rituximab could be added to cyclophosphamide or mycophenolate mofetil to treat the rheumatoid arthritis and resultant AA amyloidosis and could also possibly help treat the lupus nephritis. The addition of anti–interleukin-6 therapy to mycophenolate mofetil or cyclophosphamide is an intriguing option that may effectively treat the rheumatoid arthritis and subsequent AA amyloidosis. The addition of belimumab to mycophenolate mofetil or cyclophosphamide has been reported to improve renal response in patients with lupus nephritis,²⁷ as has the addition of voclosporin to mycophenolate mofetil.²⁸ However, belimumab is ineffective for the treatment of rheumatoid arthritis, and voclosporin has not been studied in patients with rheumatoid arthritis or in those with a GFR of 45 milliliters per minute or less. The high-dose glucocorticoids that are used in induction therapy for lupus nephritis will effectively manage this patient’s inflammatory arthritis and probably also the subsequent AA amyloidosis. Finally, it is important that every patient with lupus nephritis receive hydroxychloroquine, which improves the treatment response to induction therapy.²⁹

Follow-up

Dr. Parsons: The patient’s hospital course was further complicated by suspected immune-mediated thrombocytopenia, for which she received intravenous immune globulin. Her pancytopenia and arthritis ultimately abated. Unfortunately, she did not have renal recovery and continues to receive hemodialysis. After a prolonged hospital course, she was discharged home.

Final Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.

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