修回日期: 2018-11-02
接受日期: 2018-11-15
在线出版日期: 2019-03-08
炎症性肠病(inflammatory bowel disease, IBD)是一种主要累及消化道的慢性疾病, 除了肠道症状以外还有肠道外其他临床表现. IBD继发机会性感染、穿孔、狭窄、癌变等已有诸多报道. 随着IBD并发心血管事件报道越来越多, 且研究存有争议, 而临床医生也对其风险评估和重视不足. 本文查阅国内外近年来发表的相关文献, 就IBD心血管风险研究进展进行综述, 旨在让临床医生对其风险熟悉并结合临床制定好个体化管理.
核心提要: 炎症性肠病(inflammatory bowel disease, IBD)发病率和患病率在我国有上升趋势, 同时其合并症也多见. 机会性感染、穿孔、狭窄、手术风险、癌变等风险已存在诸多报道. 心脑血管风险在近年来报道逐渐增多, 了解和熟悉IBD继发心脑血管风险, 有助于临床对其风险的预估和患者个体化管理.
引文著录: 何琼. 炎症性肠病心脑血管及外周血管风险研究进展. 世界华人消化杂志 2019; 27(5): 341-346
Revised: November 2, 2018
Accepted: November 15, 2018
Published online: March 8, 2019
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that mainly affects the digestive tract. In addition to intestinal manifestations, it also has many extraintestinal manifestations. There have been a number of reports of IBD with secondary opportunistic infections, perforation, cancer, etc. IBD is reported with more and more cardiovascular events, but the conclusions are still controversial. At present, clinicians pay insufficient attention to the assessment of cardiocerebral and peripheral vascular risks in IBD. This article reviews the relevant literature on cardiovascular, cerebrovascular and peripheral vascular risks in IBD published in recent years, with an aim to help clinicians be familiar with these risks and develop individualized management regimens in clinical practice.
- Citation: He Q. Cardiocerebral and peripheral vascular risks in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2019; 27(5): 341-346
- URL: https://www.wjgnet.com/1009-3079/full/v27/i5/341.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v27.i5.341
炎症性肠病(inflammatory bowel disease, IBD)是一种主要累及消化道的慢性炎症性疾病, 主要包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(crohn's disease, CD)2种类型. UC好发年龄30-40岁, CD好发于20-40岁, 两者均无明显性别分布差异. 近年来的流行病学数据显示, IBD在世界范围内的发病率呈升高趋势, 其中发达国家高于发展中国家, 城市高于农村[1,2]. IBD是一种慢性疾病, 其并发症也多见, 既往研究对IBD并发机会性感染、穿孔、肠道狭窄、癌变、手术风险有诸多报道和描述. 随着近些年来IBD发病率在欧美和亚洲都有升高, 对IBD认识增多和诊疗水平的进步, 其继发心血管风险的报道逐渐增多, 我们就IBD心血管风险予以重点阐述.
近年来有研究发现, 促炎因子导致的炎症可引起动脉僵硬和内膜增厚. 动脉粥样硬化被认为是一种炎症性疾病, 其激活的内皮细胞产生的趋化信号驱使免疫细胞在动脉壁浸润[3]. 此外, 激活的巨噬细胞、T细胞、肥大细胞在斑块破裂的位置分泌促炎因子如IL-6、TNF、蛋白酶、凝血因子、氧自由基和活性分子等物质使其病变不稳定[4]. 这些分子抑制稳定的纤维帽的形成、促使血小板的激活、破裂、血栓形成和缺血的发生.
研究者把动脉僵硬度和颈动脉内膜厚度作为早期动脉粥样硬化的标志物, 结果发现IBD患者与主动脉僵硬度、左心室收缩和舒张功能不全有关, 他们发现IBD患者的平均动脉内膜中层厚度要比非IBD患者更厚, 血管扩张度更低, 但其潜在的机制并不十分清楚[5-8]. 众所周知, 临床上高脂血症与心血管疾病风险紧密相关, 增加心血管事件的发生率和死亡率. 进一步有研究发现高总胆固醇和高甘油三酯在IBD患者比对照组患者更为常见, 特别是CD, 且与IBD严重性呈正相关[9] .
随着基础研究和亚临床研究发现, 临床研究也进一步开展. 2008年由加拿大Bernstein等[10]人发起的一个群体研究发现相对于非IBD患者, IBD增加患缺血性心脏病风险高达26%, 其中CD患者风险比UC患者略高, 但没有性别差异. 另一项来自美国的临床研究发现, >40岁的女性IBD患者患心肌梗死(myocardial infarction, MI)的风险明显增加[11]. 同样, 一项来自美国单中心研究对纳入住院的IBD患者进行分析后发现, 住院IBD患者并发冠状动脉性心脏病(coronary heart disease, CHD)的风险是因其他原因住院非IBD患者的4倍, 在调节年龄、性别和其他CHD风险因素后分析后, 住院IBD患者CHD风险仍是对照组的2.6倍[12]. 一项纳入3个研究的系统回顾表明, 相对于普通人群, 不论是年轻IBD还是老年IBD患者, 其CHD风险都是增加的[13]. 然而一项横断面研究纳入住院IBD和对照组发现, IBD并不增加CHD风险, 反而是一种保护性因素[14]. 由于该研究存在明显的选择偏倚, 其结果仍需谨慎解释. 2011年一项来自英国社区数据库研究纳入了9829名CD患者, UC 15498名患者, 其研究结果发现IBD患者患急性MI的风险明显增加[15]. 由于该研究并未控制混杂因素而进行分析得出的结论, 其MI的风险可能更低.
另一项来自丹麦全国注册数据库超过4600000个体的研究分析了28833个IBD患者, 随访后发现IBD患者的CHD风险高达59%, 明显高于非IBD患者. 在排除混杂因素后分析发现, IBD明确诊断后随访的第1年内患者的CHD风险增加了2倍, 而在随后的随访1-13年期间, CHD的风险增加了20%, UC和CD风险无明显差异, 女性风险高于男性[16]. 随后的一项研究使用与上述研究同样的数据分析, 与其不同的是, 研究者将IBD分类为加重、持续活动、缓解期进行分析, 结果发现其增加CHD风险分别占49%、5%、1%, 可以认为IBD缓解期发生CHD的风险是很小的[17]. 然而, 该研究的测量偏倚和纳入人群的急性疾病(比如血容量过低、贫血)本身就增加短期心血管事件的发生率, 有助于增加上述的风险比. 而一项来自瑞典的研究发现住院UC患者明显增加CHD风险, CD风险也升高, 但不如UC明显[18].
一项来自台湾随访长达13年的队列研究显示, IBD急性冠脉综合征发生率高达占87%, 总体来说是非IBD患者的1.72倍, 其中20-39岁的IBD患者风险最高, 是非IBD患者的3.28倍[19]. 研究发现每年至少住院2次的IBD患者发生ACS风险是仅住院1次IBD患者20倍, 且与IBD严重程度密切相关. 而一项英国研究发现, IBD虽然并发缺血性心脏病的风险增高, 但许多患者在诊断IBD前就发生了心肌缺血, 而在IBD诊断后第1年缺血性心脏病发生率也发现明显升高, 其中UC并发缺血性心脏病风险最高[20]. 来自美国的McAuliffe等[21]人对30000多例IBD患者的数据分析后发现(其中60%患者随访超过1年), 中-重度IBD患者比轻度的更易发生MI. 而另一项来自美国的研究, 纳入超过500,000住院IBD患者发现, 相对于其他人群因急性MI住院, IBD发生急性MI住院的比例明显更少[22]. 同样地, Card等[23]和Emanuel等[24]人研究也发现IBD并未像既往报道的发生CHD的风险那么高. 最近一项纳入10个队列研究的Meta分析仍表明IBD CHD的风险是有增高, 但由于纳入研究异质性较大, 其结果仍需进一步研究验证[25].
总的来说大多数研究提示IBD有增加CHD的风险, 但由于上述研究性质以及混杂因素影响, 需要更严格设计、更多的随机对照研究来进一步证实. 对于在IBD前就诊断为高血压病、代谢综合征、糖尿病、高脂血症和动脉硬化的患者, 初次诊断IBD后, 是否继发心血管风险需要引起临床的高度重视, 而对于是否进行CHD的预防策略目前仍未有进一步研究.
众所周知, 高血压、糖尿病、高脂血症、心房颤动是卒中的高危因素, 明显增加卒中发生率. 而正如前述所说, 近十年来已发现炎症可以促进动脉粥样硬化的形成和发展, 一些研究者提出IBD是否是脑血管疾病(cerebrovascular disease, CVD)高危因素的假设, 由此一些研究者在此假设上进行了研究.
2008年Bernstein等[10]人的研究第一次对IBD的脑血管风险进行了评估, 他们发现CD的CVD风险是对照组的1.32倍, 而UC并未发现有CVD风险. 随后一项来自英国数据库的巢式病例对照研究表明, 该研究基于群体数据纳入8054个CD患者, 其中1748例患者发生缺血性脑卒中, 是对照组非CD患者的1.1倍[26]. 同时他们发现, 与对照组相比, 年轻的患者(<50岁, 18-49岁)比年龄稍大的患者(>50岁, 50-80岁)的脑卒中风险更高. 根据CD的流行病学特点, 为了排除年龄、性别对结果的影响, 他们根据年龄、性别进行分层分析, 最后认为年龄和性别对此结果无明显影响. 同样来自英国的另一项研究也表明, IBD与卒中明显相关, 主要是CD, 而UC并未发现关联[27]. 2012年, 一项来自瑞典的研究对分别纳入2万多名住院CD和UC患者的数据分析发现, CD和UC均增加脑卒中风险, 无论是缺血性脑卒中还是出血性脑卒中[28]. 由于该研究对纳入的CD和UC是缓解期还是活动期以及是否合并CVD疾病的高危因素疾病等并未明确说明, 因此该结果需要进一步验证. 而3项来自台湾的研究表明CD和UC均增加卒中的风险, 但由于这几项研究使用的数据有重叠, 其研究结果样本其代表性仍有不足[29-31]. Kristensen等[32]人的研究发现, 活动期的IBD不仅增加心房颤动风险, 也增加卒中的风险, 但该研究并未分层分析CD和UC其卒中风险差异. 进一步最新的两个系统回顾和Meta分析均表明IBD与卒中存在正相关关系, 其结果均提示IBD增加患者患卒中的风险[33,34].
IBD发生静脉栓塞(venous thromboembolism, VTE)在多年前就有报道, 但并未引起临床重视, 直到2008年美国胸科医师协会提出IBD是VTE的风险因素之一[35], 但在2012年版本又并未提及. 欧美国家曾发起问卷调查, 得出的结论是临床医师对其VTE的风险及管理仍是存在不确定性[36-38]. 随后陆续有研究开始对IBD的VTE风险进行大样本评估, 许多研究表明IBD发生VTE的风险是非IBD患者1-4倍, 有些研究甚至更高, 达8-9倍, 特别是活动期的IBD[39-41]. 这些研究显示, VTE常见的是深静脉血栓形成(deep vein thrombosis, DVT)和肺栓塞(pulmonary embolism, PE), 其他部位如脑静脉、门静脉、肠系膜静脉、视网膜静脉的VTE少见. 对于发生过静脉栓塞的IBD, 再发VTE的风险也升高[42-44]. 而对于术后IBD, 已有研究表明发生VTE风险是明显升高的[45,46]. 一项系统回顾和Meta分析研究, IBD患者患VTE是非IBD的2.2倍[39].
随着对VTE认识增多, 2010年ECCO共识[47]在对CD共识中指出: 一旦IBD患者诊断DVT和PE, 建议遵循国际指南进行抗凝治疗, 且如果没有明显禁忌, 建议至少抗凝治疗3 mo, 初始治疗可以使用低分子肝素、普通肝素和磺达肝癸钠, 随后用维生素K拮抗剂维持治疗. 同时建议对于严重的CD、长期卧床的和术后CD患者可以进行预防性抗凝治疗, 2017年最新共识意见仍继续上述推荐[48]. 对于UC, 2012年ECCO共识也提出, 预防性使用低分子肝素可以减少栓塞风险, [49]最新2017年ECCO共识仍继续建议对住院的或严重非住院UC患者预防性使用, 对已经诊断VTE的患者遵循国际指南进行抗凝治疗[50].
2014年加拿大胃肠病协会专门提出对IBD静脉血栓的风险评估、预防和治疗[51], 共识指出: 对于初发且病情活动、没有活动性出血或出血并不严重的住院IBD患者, 建议进行血栓预防性抗凝治疗; 同时对于中-重度的非住院患者, 既往有VTE病史的, 也建议预防性抗凝治疗. 2015年该协会对非住院UC患者的提出更具体和详尽的管理策略[52]. 次年, 多伦多共识对孕妇合并IBD进行更细化的阐述[53]. 由于孕妇本身生理的特殊性, 对于住院的孕妇合并IBD仍然推荐预防性抗凝治疗. 2016年亚太针对CD的共识意见对血栓的预防和治疗未针对性提出相关指导性意见.
2017年一项全国多中心研究显示我国IBD患者VTE发生率为41.45/10万, 54.17%为下肢深静脉血栓, 1.98%接受预防性抗凝治疗[54]. 既往的国内IBD诊治共识并未将心血管风险考虑在内, 随着对IBD认识的不断加深, 我国临床和基础研究更趋标准化和规范化, 最新炎症性肠病诊断与治疗共识意见(2018)已将IBD血栓的预防和治疗纳入规范, 考虑重度UC的血栓风险增加, 建议预防性使用低分子肝素[55]; 而对于CD, 目前暂未做出推荐.
总的来说, 即使当前对IBD的VTE风险认识明显提高, 各国也提出预防和治疗策略, 然而对于预防性和治疗性抗凝治疗的风险与获益目前尚未有大样本数据研究. 而且IBD治疗会使用激素、免疫抑制剂、生物制剂等药物, 这些药物使用会是机会性感染的风险增加, 从而增加VTE的风险.
近年来研究发现, 早期动脉粥样硬化在IBD患者中较为常见. 陆续一些研究发现, IBD跟外周动脉栓塞有关, 但由于样本量较小, 不足以说明IBD增加外周动脉栓塞的风险[10,11]. 最近有研究显示, IBD增加肠系膜动脉缺血的风险, 其风险达1-6倍[14,56,57]. 而对于外周动脉栓塞, 我国目前仍未有流行病学数据研究.
总体来说, 目前各国对IBD并发心血管风险有了进一步的认识和提高, 也提出来相应的预防和治疗管理策略. 但IBD病因复杂, 临床表现多样, 同时可继发其他疾病比如CHD、卒中或机会感染作为首要表现, 这些会导致我们对IBD并发心血管风险预防和治疗存在认识和重视程度不够, 且国内存在流行病学数据不足等情况, 对于今后的临床实践, 加深对其认识、 开展前瞻性、大样本的多中心临床研究, 同时进一步做好预防和获益分析, 以期更好地为IBD患者制定个体化防治策略.
学科分类: 胃肠病学和肝病学
手稿来源地: 广东省
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