修回日期: 2011-03-21
接受日期: 2011-04-11
在线出版日期: 2011-04-18
Hent于1950年发现糖皮质激素(glucocorticoids, GCs), 明确了GCs在风湿性疾病治疗上的确切效果, 并因此获得诺贝尔奖. 此后数十年GCs被广泛应用于临床, 但也带来一些胃肠道不良反应. 不过, GCs究竟是否为消化性溃疡(peptic ulcer disease, PUD)及上消化道出血的危险因素一直有争议, 其相关胃黏膜损伤的发生机制也不明了. 本文就国内外关于GCs对胃肠道的作用及相关机制的研究进展作一综述.
引文著录: 马娟, 王启仪, 沙卫红. 糖皮质激素与胃黏膜损伤. 世界华人消化杂志 2011; 19(11): 1145-1149
Revised: March 21, 2011
Accepted: April 11, 2011
Published online: April 18, 2011
Hench found glucocorticoids (GCs), defined their roles in controlling rheumatic diseases, and thereby won the 1950 Nobel Prize in physiology and medicine. In the next few decades GCs were widely used in clinical practice; however, they were associated with some side effects, such as gastric mucosal lesions. Currently, it is still controversial whether GC use is a risk factor for peptic ulcer disease and upper gastroduodenal bleeding. This review aims to elucidate the potential role of GCs in inducing gastric mucosal lesions and to highlight possible mechanisms involved.
- Citation: Ma J, Wang QY, Sha WH. Glucocorticoids and gastric mucosal lesions. Shijie Huaren Xiaohua Zazhi 2011; 19(11): 1145-1149
- URL: https://www.wjgnet.com/1009-3079/full/v19/i11/1145.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i11.1145
1950年, Hent发现糖皮质激素(glucocorticoids, GCs), 明确了在风湿性疾病治疗中的确切效果, 并因此获得诺贝尔奖, 此后数十年GCs被广泛应用于临床. 众所周知, GCs是肾上腺皮质分泌的主要激素, 生理情况下肾上腺皮质每日分泌GCs约10 mg, 起着调节机体物质代谢、调控器官发育功能并参与应激反应, 维持内环境稳定等重要作用; 超生理剂量的外源性GCs作为一种固醇类消炎药, 有着抗炎、抑制免疫、抗休克、抗毒素等主要药理作用. 但随着GCs的普遍应用临床上出现各种并发症, 如骨质疏松、高血压、白内障、消化性溃疡(peptic ulcer disease, PUD)等. 其中究竟GCs是否有胃肠道毒性的观点尚未确定, 究竟GCs是否增加胃肠道溃疡及出血的危险性一直有争议, GCs对胃肠道的具体作用机制也未阐明. 数十年来人们一直在探索中.
1.1.1 外源性GCs有致溃疡作用: 多个临床研究认为GCs有致溃疡作用, 增加了PUD及严重并发症的发生风险. 一项71例临床对照试验结果显示GCs治疗的患者PUD和上消化道出血的发生率较对照组显著增加, 发生风险升高2.3和1.5倍[1]. 一项回顾性研究报道, PUD或上消化系出血的患者GCs使用率显著多于非消化性溃疡及出血者[2]. 一项队列研究报道, 口服GCs的PUD穿孔患者首次入院后30 d死亡率较未口服GCs者显著升高, 死亡风险为2.1[3]. 急性颈髓损伤患者早期接受大剂量MP冲击治疗后, 87%的MP使用者出现了不良反应, 甚至1人死于PUD穿孔导致的脓毒症[4].
不过也有多项临床研究没有证实GCs的致溃疡作用. Conn等[5]研究报道GCs使用者PUD的发生率与非GCs服用者或安慰剂无明显差异. 也有研究发现类风湿关节炎[6]、特发性肺纤维化[7]患者PUD发生风险与GCs无明显相关性. 尽管有16.4%的系统性红斑狼疮患者出现胃黏膜损伤, 但单独使用GCs的系统性红斑狼疮患者则无1例出现胃黏膜损伤[8]. 同样, 从美国医疗保险制度数据库检索得到的数据也显示单独GCs不会增加胃肠道事件的风险[2]. 但由于存在众多的混杂因素, 这些研究的阴性结果并不能否定GCs致溃疡作用的存在.
尽管GCs与PUD关系不确定, 但事实上临床工作中PUD患者在GCs使用者中增多了, 尤其是那些长期使用GCs的患者, 甚至儿童极少发生的溃疡在GCs治疗后也有所升高[9], 故大多数临床医师尤其胃肠病学医师仍然认同GCs有胃肠毒性, 会导致PUD的发生, 并建议GCs治疗同时使用抑酸剂等预防性药物[10].
1.1.2 危险因素: 尽管多个因素可能与GCs相关PUD发生风险相关, 但GCs剂量和维持时间长短、联合非固醇类消炎药(nonsteroidal anti-inflammatory drugs, NSAIDs)是GCs导致PUD及并发症的确切危险因素. (1)剂量与维持时间: 大剂量长期应用GCs增加了胃黏膜损伤的发生风险. Messer等[1]报道PUD发生与GCs剂量直接相关, 而GCs应用途径(口服或胃肠外途径)及PUD病史似乎与GCs相关PUD的发生无明显关联. Olsen等[11]报道7 486例因PUD出血首次住院的患者中, 无论GCs维持时间长短, 大剂量GCs使用者的30 d死亡率高于低剂量GCs使用者. Pincus等[12]报道大剂量强的松(20-40 mg/d)有胃肠毒性, 而小剂量强的松(5 mg/d)的胃肠不良反应则与安慰剂无差别. Bijlsma等[13]进一步强调了长期维持GCs的PUD发生风险, 即使是应用小剂量强的松(<5 mg/d), 持续时间至1.5年和5年以上, PUD的发生风险则分别增加至1.8倍和2.1倍; (2)联合用药: 联用NSAIDs大大增加了GCs相关胃黏膜损伤的风险. Börsch等[2]报道PUD患者中联合使用GCs和NSAIDs者明显多于对照组(OR = 4.4). Luo等[14]报道20%的自身免疫性疾病患者接受GCs治疗发生PUD, 其中62%的患者联合使用GCs和NSAIDs(OR = 4.71). Luo等[8]进一步研究发现NSAIDs/阿司匹林增加甲基强的松龙冲击治疗的系统性红斑狼疮患者胃黏膜损伤的发生风险. Olsen等[11]报道单用GCs者发生PUD出血后30 d死亡率为14%, 而GCs联合应用其他致溃疡药物使用者30 d死亡率为18.9%. 我们以往的研究[15,16]也报道联合应用泼尼松和NSAIDs使胃黏膜损伤的风险增加; (3)幽门螺杆菌(Helicobacter pylori, H.pylori)感染: H.pylori能否增加GCs胃黏膜损伤的风险未能得到证实. 目前证据[8,14]反而显示H.pylori感染不是GCs使用者胃黏膜损伤的危险因素. Luo等[14]报道接受GCs治疗的自身免疫性疾病患者中, 33%的PUD可能与H.pylori低繁殖有关, 进一步又报道H.pylori感染不会增加接受甲基强的松龙治疗的系统性红斑狼疮患者胃黏膜损伤的发生风险[8]; (4)其他: 性别是GCs胃黏膜损伤的可能危险因素. 一项12年的追踪调查显示强的松组男性患者PUD发生率亦大于安慰剂组, 提示性别起着一定作用[17]. 某些疾病如慢性阻塞性肺病可能使胃黏膜易于受GCs损伤[18]. 年龄(>60岁)和合并病(>2种)使GCs使用者PUD穿孔30 d死亡风险显著升高[3].
1.1.3 发病机制: 尽管各报道不同, 但大家普遍接受了GCs有致溃疡作用的观点并不断探究相关机制. 总体来说, GCs可促进胃酸和胃蛋白酶的分泌, 减少胃黏液分泌, 促使各种细胞因子和炎症介质表达异常, 使胃黏膜失去保护和修复能力, 故能诱发或加剧溃疡病, 甚至引起出血、穿孔的危险. 现分述如下: (1)胃酸分泌增加: Cooke等[19]发现较长时间的GCs刺激会使狗的胃酸分泌增加, 切除肾上腺后显著减少了动物的胃酸分泌, 若术后数小时内补充GCs可使降低的胃酸回升[20]. GCs可致胃腺G细胞增生, 数目增加, 胃泌素水平升高, 最终胃酸分泌增加[21]; (2)胃黏膜血流量增加: Dolcini等[22]研究发现GCs增加胃酸分泌的同时, 显微镜下显示胃黏膜血流量增加, 两者可能有因果关系. 不过Jacobson等[23]却发现两者无必然联系; (3)胃黏液分泌异常: Okazaki等[24]用不同浓度的地塞米松(dexamethasone, DXM)培养人胃黏膜细胞后, 发现胃黏液素的生物合成减少, MUC1表达水平下降. Elitok等[25]发现DXM在导致大鼠胃黏膜损伤的同时引起胃黏液分泌增加, 血清和胃黏膜中上皮生长因子表达水平下降; (4)胃黏膜上皮细胞再生受抑; Carpani de Kaski等[26]用强的松龙及NSAIDs建立鼠胃溃疡模型, 证实GCs可致溃疡, 而且溃疡形成后3 d, BrdU标记的胃黏膜增殖细胞数及增殖细胞核抗原显著下降, 胃黏膜损伤的上皮细胞再生受抑; (5)细胞因子及炎症介质的表达异常: Montuschi等[27]报道GCs抑制IL-1合成释放, 削弱了IL-1对胃黏膜的保护作用. Lü等[28]的动物实验研究显示泼尼松龙皮下注射SD大鼠后, 大鼠胃黏膜损伤指数显著高于正常对照组, 胃黏膜HSP70和c-Fos表达水平高于对照组, 提示GCs胃黏膜损伤与胃黏膜HSP70和c-Fos表达升高有关. Luo等[29]发现DXM抑制胃溃疡边缘前列腺素E2(prostaglandin E2, PEG2)、及血管内皮生长因子(vascular endothelial growth factor, VEGF)表达, 从而延缓溃疡愈合. Takeuchi等[18]报道泼尼松龙降低动脉氧分压, 提高过氧化脂质、PGE2、低氧诱导因子-1α和VEGF的水平, 从而易于发生胃黏膜损伤. Takahashi等[30]发现肝细胞生长因子可以抑制DXM相关胃黏膜损伤. Filep等[31]的动物实验研究结果显示DXM所致大鼠胃黏膜损伤有剂量和时间依赖性, 伴有胃腺体血小板活性因子(platelet activating factor, PAF)含量的增加. 如使用PAF抑制剂抑制PAF, 则可明显减少胃黏膜损伤, 提示PAF可能是GCs胃黏膜损害的内源性调节因子.
1.2.1 内源性GCs的胃黏膜保护作用: 由于人体肾上腺皮质生理情况下就分泌GCs, 对机体有着重要的生理性作用, 各种应激情况下, GCs大量释放, 同时会有急性胃黏膜损害发生. 因此, 内源性GCs对胃肠道是否也存在致溃疡作用引起人们疑问. 近来部分动物实验研究结果显示GCs有抑制应激性溃疡的作用. Filaretova课题组一系列研究揭示了内源性GCs的胃黏膜保护作用: (1)Filaretova课题组报道肾上腺素切除术或是GCs受体拮抗剂加重了NSAIDs所致胃黏膜损伤, 而GCs替代疗法则可抑制这种损伤, 提示内源性GCs对NSAIDs相关胃黏膜损伤有保护作用[32,33]; (2)Filaretova等还报道内源性GCs能抑制各种应激性胃黏膜损伤[34-38]. 大鼠在给予冷刺激前12 h内事先接受DXM 1 mg/kg, 可以减少胃黏膜损伤面积, 而超过12 h接受DXM者, 胃溃疡损伤会加重[35]; 大鼠在持续严重的缺血再灌注前给予缺血预处理后, GCs水平会升高, 从而削弱缺血再灌注导致的胃黏膜损伤[36]; 类似的, 大鼠在严重应激前给予轻度预刺激, 可使GCs释放, 从而减轻严重应激造成的胃溃疡[38]. Takeuchi等[39]也支持了上述观点, 报道双侧肾上腺切除术使NSAIDs胃黏膜损伤恶化. Filaretova[40]综述了下丘脑-垂体-肾上腺系统调节的激素与胃肠道的相互作用及胃黏膜保护作用, 并提出大胆假设: 大剂量GCs致溃疡作用主要由于肾上腺功能受抑, 导致内源性GCs释放受阻, 从而损伤胃黏膜.
1.2.2 相关机制: Filaretova课题组揭示GCs预处理可以维持胃血流量和粘胶含量、抑制增强的胃动力、降低微血管通透性, 防止胃黏膜损伤或促进损伤愈合[41-43], 下丘脑-垂体-肾上腺系统抑制是NSAIDs致溃疡作用恶化的原因[44]. Szabo等[45]认为前列腺素、硫氢化物和甲氰米胍在肾上腺切除术的大鼠中失去了胃黏膜保护作用, 但GCs替代治疗则恢复了这种胃黏膜保护作用, 提示GCs可能调节前列腺素表达而抑制胃黏膜损伤. Perretti等[46]报道内源性GCs调节IL-1β的表达, 抑制了阿司匹林所致的胃黏膜损伤. Takeuchi等[39]也发现内源性GCs不足使NSAIDs胃黏膜损伤恶化, 与胃动力增强有关. 这些研究提示我们: 致溃疡剂量的NSAIDs及其他应激因素能诱使内源性GCs释放, 后者反过来有助于保护胃黏膜免受损伤或损伤减轻. 即是说内源性GCs增强了胃黏膜对NSAIDs或应激的抵抗力, 降低了易感性.
GCs对胃肠黏膜有着双重作用, 我们要认真对待、全面认识. 一句话可以概括: 少量GCs像一杯葡萄酒, 对许多人有益; 大量GCs像一瓶葡萄酒, 对所有人都是有害的. 现已知道, GCs既有胃肠毒性又有黏膜保护作用, 究竟发挥那种作用, 要看所处具体环境. 生理剂量GCs能增加胃液、胰液和其他消化酶的分泌, 促进胆汁合成和分泌, 增进食欲和消化功能; 还能改善黏膜的状态, 保护黏膜不受应激侵害. 相反大量长时间应用GCs则使胃肠黏膜容易受损, 发生溃疡及出血穿孔并发症的机率增加. 至于作用机制是复杂的, 近来又有学者从受体角度研究GCs对胃肠黏膜的影响. 可以假设: 受体缺陷者对GCs抵抗, 胃黏膜损害小; 受体对GCs敏感者, 易出现不良反应. 将来可能从药物代谢、生物信号转导及基因水平去进一步研究, 相信科研工作者就GCs胃肠作用及机制会给我们一个全面肯定的答案.
糖皮质激素(GCs)是由肾上腺皮质分泌的一类含固醇类激素, 主要为皮质醇, 因其良好的抑制免疫应答、抗炎、抗毒、抗休克等药理作用而广泛应用于自身免疫性疾病. 然而随着GCs在临床的广泛应用, 药物相关性胃黏膜损伤逐渐增多, 轻者胃黏膜充血水肿、出血点, 重者发生溃疡(PUD), 乃至出现出血、穿孔等严重并发症.
吕宾, 教授, 浙江中医学院附属医院消化科
外源性GCs确切的胃肠道损伤风险、危险因素的确定及其分子生物学机制仍然是目前研究热点. 大样本多中心随机对照研究是需要的. 内源性GCs对应激性胃黏膜损伤的保护作用也逐渐受到重视, 相关机制也值得进一步探讨.
Messer等报道PUD发生与GCs剂量直接相关, 而GCs应用途径(口服或胃肠外途径)及PUD病史似乎与GCs相关PUD的发生无明显关联.
本文对于进一步了解和研究糖皮质激素对胃黏膜的双重作用及机制等具有参考价值, 但可读性一般.
编辑: 曹丽鸥 电编:何基才
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