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JAMA:意外!是炎症而非胃酸导致了胃食管反流病?

2016-05-18 MedSci MedSci原创

一篇发表于JAMA的小型单中心研究称,造成胃食管反流病(GERD)的原因可能是由于免疫反应的损伤而非胃酸反流导致的化学性损伤。该研究的第一作者、德克萨斯州的退伍军人医疗中心的Kerry Dunbar博士和其同事称:“在研究初期,PPI成功治愈了患有严重胃食管反流病的12名患者,而PPI的停用与T淋巴细胞主导的食管炎症、基底细胞和乳头状增生无表面细胞丢失有关。”他们补充,“如果能成功复制这个模型,那

导语:胃食管反流病,免疫反应损伤机制or胃酸反流机制?

来自动物实验的启发

自1935年来举办的专业会议都认为,影响了大约20%美国人的胃食管反流病的病因是由于胃酸对食管粘膜的刺激。最近一项动物试验发现,GERD可能不是由于胃酸的化学损伤,而是由于一种免疫反应的损伤。这一发现促使研究者将这一假说应用到人类身上。

这项小型单中心研究近期发表于JAMA,研究称造成胃食管反流病(GERD)的原因可能是由于免疫反应的损伤而非胃酸反流导致的化学性损伤。

该研究的第一作者、德克萨斯州的退伍军人医疗中心的Kerry Dunbar博士和其同事称:“在研究初期,PPI成功治愈了患有严重胃食管反流病的12名患者,而PPI的停用与T淋巴细胞主导的食管炎症、基底细胞和乳头状增生无表面细胞丢失有关。”

他们补充,“如果能成功复制这个模型,那可能提示反流性食管炎的病因可能是由于细胞因子介导的损伤而非胃酸导致的化学性损伤”。

该研究纳入了退伍军人医疗中心的患有严重胃食管反流病的12例患者(11例为男性,平均年龄57.6岁),他们都成功的被PPI治愈。在基线水平时,所有研究对象均停用PPI制剂并接受评估,并在停药1周及2周后再次接受评估。评估包括24小时食管pH监测及阻抗监测(反映粘膜完整性的指数)和食管镜(包括高分辨率激光共聚焦纤维内镜)。研究者取患者食管未被损伤的区域进行活检,发现其免疫活性低于受损伤的区域。

在基线水平,几乎所有研究对象(11/12)都没有明显的食管炎的证据,但在停用PPI2周后,所有研究对象均发展为食管炎,其中5例为严重食管炎。

在2周的研究期间,所有研究对象都出现了GERD的异常特征:基底细胞和乳头增生(P<0.01),乳头延长(P<0.01),食管鳞状上皮的细胞间隙增宽(P<0.001),粘膜阻抗减少(P=0.001),食管远端酸暴露增加。从基线至2周时,酸暴露增加了16.2%(95%可信区间,26.5%-4.4%;P=0.005)。

淋巴细胞浸润与粒细胞浸润的不同

活检结果显示停用1周及2周PPI后上皮内淋巴细胞浸润显著增加,并且表现为T淋巴细胞优势型(1周时,P =0.005;2周时,P =0.002)以及中性粒细胞和嗜酸性粒细胞减少或缺失。

“表面没有糜烂的区域出现了食管基底细胞和乳头增生。如果传统的观念,即急性GERD是由于胃酸回流引起表皮细胞的化学损伤是正确的,那么基底细胞和乳头增生本应该仅出现在表面糜烂区,浸润的炎性细胞则应是粒细胞为主,”作者写道。他们还需要进一步的研究来证实这些结果。

芝加哥西北大学费因伯格医学院的博士Peter Kahrilas认为,“这项研究的结果显示:最早的病理变化发生在上皮细胞,而不是在粘膜表面,在表面的细胞死亡之前,机体修复开始启动,从而导致了这些变化。”

“尽管这个刺激的病理生理变化无疑是胃和十二指肠分泌物回流到食道引起的,但是证据表明,回流的影响引发了炎症细胞因子的启动,而不像以往认识到的是酸、胃蛋白酶和胆汁直接对食管上皮细胞化学作用。”他写道。

研究的局限性和前景

他指出,在这项研究中的患者患有严重的GERD和食管裂孔疝,可能代表了所有GERD患者的1%-5%,因此这一结果可能并不适用于所有的GERD患者。然而,这一结果让人们将注意力从胃酸的“烧灼”作用转向免疫反应,这可能有助于解释最近被发现的胃食管反流病的亚型。

他还指出,研究结果还可能对治疗有一定的影响。虽然PPI仍然会是继续治疗的中坚力量,但炎症级联反应的发现可能成为新治疗的靶点,该治疗可能对于患有更严重或难治性胃食管反流病的患者有效。

“基于这些发现,也许难治性GERD应该根据临床表现和疾病进展分步治疗,”他说,“这个疾病有着多种多样的病人,治疗难题只能一块一块解决。Dunbar等人可能解决了非常重要的一块。”

原始出处:

Dunbar KB, Agoston AT, Odze RD,et al.Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes.JAMA. 2016;315(19):2104-2112.

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    2016-05-20 zhouqu_8
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    2016-05-20 feifers
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    2016-05-19 milkshark

    顶级杂志

    0

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    2016-05-19 milkshark

    好文章啊

    0

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