
表1:14岁男童嗜酸性食管炎的症状
吊杆朗斯代尔*
美国俄亥俄克利夫兰克利夫兰诊所基金会名誉会员*通讯作者:德里克·朗斯代尔,美国俄亥俄州克利夫兰诊所基金会名誉退休研究员,E-mail: derricklonsdale@hotmail.com
嗜酸性食管炎是一种炎症病症,导致吞咽困难,食物障碍和胸痛。诊断需要通过食管活检每次高功率场中最少15个嗜酸性粒细胞。过去二十年来,它已成为胃肠道发病率越来越重要的原因。一个14岁的男孩在8岁时被诊断为嗜酸性食管炎。直到内窥镜检查都有很多年,他的病史已经被认为是心理族。唯一的其他正实验室研究是嗜酸性粒细胞症。尽管常规治疗,但没有一种改善整体症状,食管炎持续存在,并且他未能增加体重和身材。体格检查揭示了许多自主功能障碍和红细胞转铁糖蛋白酶试验表明硫胺素稳态异常。静脉注射水溶性维生素的静脉注射(THCL)开始治疗。因为转铁糖酶试验变得更差,所以用硫胺素四氢呋喃二硫化物(TTFD)代替,随后改善了转酮酶和对症反应。 There was a family history of alcoholism and the patient was addicted to sugar, suggesting a genetic risk to explain the abnormal thiamine homeostasis. Beriberi causes dysautonomia in its early stages. Inflammation is now known to be suppressed reflexly through the vagus nerve, itself dependent on acetylcholine. Abnormal motility of the esophagus has been reported in eosinophilic esophagitis. Failure of THCL to improve transketolase activity suggested a genetic failure in a thiamine transporter and its consequent correction with TTFD that does not require the thiamine transport system.
嗜酸性;食管炎;炎症;硫胺素稳态
嗜酸性食管炎(EoE)是迄今为止最常见的嗜酸性胃肠道疾病。它是一种定义明确的慢性特应性疾病,由辅助性T细胞2型(Th2)炎症引起,通常由食物过敏原触发。它通常对治疗反应很差,并且没有普遍接受的长期治疗[1]。它代表了食物过敏的最新形式,通过避免不良食物来控制它已越来越多地成为实现和维持缓解的治疗替代方案[2]。在一个拥有70多万居民的小镇上,一项研究表明,10年内,EOE迅速增加[3]。据报道,EoE具有介体复合物亚单位12(MED12)突变[4]。在793例EoE患者中,72%为男性[5]。173例食管食物团塞患者中,27%为EoE[6]。食管的脊髓和迷走神经传入似乎都有助于疼痛感觉[7],其生理学对其运动性很重要[8]。食管的神经功能依赖于乙酰胆碱,食管运动障碍已在EoE中得到证实[9]。
一个14岁的男孩在8岁时被诊断为嗜酸性食管炎。他的病史始于婴儿期,复发性耳部感染和哮喘。他的许多症状(表1),最初被认为是心身的,混淆了诊断,直到内镜检查。除了嗜酸性粒细胞增多和食管病理持续性外,许多实验室研究一直是阴性的。常规治疗对症状没有影响。他的体重和身材都没有增加。体格检查发现腹部轻触有严重的痛觉过敏。心脏听诊提示二尖瓣脱垂。髌骨深肌腱反射无反应,即使在詹德拉纪操作。轻拍大腿内侧和腿部导致一个非常缓慢的外观短暂的白色皮肤描记。 Laboratory studies are shown in (Table 2). He was treated first with a course of intravenous infusions of watersoluble vitamins that included thiamine hydrochloride (THCl) (Table 3). Because of increasing abnormality of erythrocyte transketolase, thiamine tetrahydrofurfuryl disulfide (TTFD) was substituted for THCL with consequent improvement in transketolase and symptomology. Body weight at the beginning of treatment was 105 pounds, placing him in the 25th百分位。经过一年的治疗,他的体重增加到122磅,使他进入了50人的行列th百分位数。在同一时期,他的身高从64.5英寸上升到68.5英寸,从50英寸上升到68.5英寸th75年th百分位。
这个男孩在写这篇文章的时候18岁。腹痛是可变的,并与可见的腹部肌肉收缩有关。头痛、恶心、关节疼痛和疲劳似乎与食物摄入有关。夜间腹痛,需要排尿。
硫胺缺乏(TD)可导致能量代谢受损和大脑易损性[10]。直到最近,有关硫胺摄取、激活和活性辅因子与靶酶结合的遗传缺陷才被描述。SLC19A3硫胺素转运体的遗传变异可能对酒精依赖综合征[12]的遗传易感有一定的贡献,可能在该患者的家族史中具有重要意义。TD引起脑线粒体[13]氧化应激。在一名萎缩性脚气患者中,硫胺转运体[14]的SLC家族中有37个突变。大鼠TD降低了含有功能性内皮[15]的主动脉中乙酰胆碱介导的舒张和苯肾上腺素介导的血管收缩。TD诱导hif1介导的基因表达与缺氧胁迫[16]中观察到的类似。在小鼠中删除该因子可导致痛觉过敏加剧,提示其在疼痛调节[17]中的二重性,并可能与患者表达的痛觉过敏/异位痛觉有关。危重患者的败血症可能与TD有关,实验性TD导致小鼠[18]氧化应激和炎症反应改变。人体组织中总硫胺素含量低于其他动物。 The high sensitivity of humans to thiamine deficiency may be linked to this [19].
表1:14岁男童嗜酸性食管炎的症状
表2:一名男孩的嗜酸性食管炎化验结果
表3:静脉滴注水溶性维生素给一个患有嗜酸性食管炎的男孩
梅奥诊所指出,测定硫胺素缺乏的最好方法是测定血液中硫胺素的含量。就像镁一样,这可能会误导人,因为重要的是它的细胞内含量。在加入硫胺素焦磷酸(TPPE)之前和之后,测定硫胺素依赖酶的功能和红细胞转酮醇酶活性明显表明硫胺素缺乏。在给予硫胺[20]后,TKA在正常范围内随着TPPE的减少而增加。
彼得斯是第一个认识到硫胺素和葡萄糖之间的关系的人。硫胺素缺乏鸽子的神经系统的病理与Beriberi和Peters在TD鸽子细胞与硫胺素的呼吸相比之下相似。没有发生差异,直到在葡萄糖中加入到制剂中,当它变得很明显,二氧化碳的生产在硫胺素足够的细胞中立即开始,而它不在Td细胞中。Peters称为该试剂素效应[21],从而强调摄取过量的简单碳水化合物,称为高卡路里育营养不良,自动增加对维生素的需要[22]。硫胺素焦磷酸盐是过氧化物组中的2-羟基乙基COA裂解酶(HACL1)的辅助壳,使α氧化依赖于硫胺素用于脂肪代谢,[23-25]。
起源于迷走神经的动作电位调节T细胞,T细胞反过来产生乙酰胆碱,这是控制先天免疫反应所必需的。胆碱能神经元需要丙酮酸脱氢酶衍生的乙酰辅酶a来合成对食管[7]功能至关重要的乙酰胆碱[27]。推测TD导致该患者乙酰胆碱缺乏和迷走神经炎症抑制失败,并影响食管运动。
自主神经异常不会产生独特的症状。这是一组症状,综合起来,表明存在一种自主神经异常状态。家族性自主神经异常(FD)于1949年被描述,但Riley和Moore后来继续注意到其他自主神经异常综合征[28,29]。鉴于大脑对葡萄糖的严重依赖,它能够通过神经内分泌轴来控制葡萄糖的代谢。因此,我们对疾病的理解应该扩展到在病理生理过程[30]的概念中考虑神经输入。该病人表现出许多临床现象,表明自主神经功能障碍。1979年[31]时,检查发现二尖瓣脱垂(MVP)的收缩期中期发出明确的声响,并伴有自主神经异常。94例患者被鉴定为MVP,其中59例红细胞[32]中红细胞镁浓度低。硫胺和镁作为硫胺依赖酶的辅助因子共同作用。吸入二氧化碳会引起一种情绪,类似于自发性恐慌发作[33],这是该患者病史中记录的症状之一。 Since hypoxia results in sympathetic overdrive in animal studies [34] and TD causes oxidative imbalance described as pseudo-hypoxia, it is hypothesized that panic attacks are fragmented fight-or-flight reflexes, initiated by TD in this patient. His history of ADD/OCD, that had caused some diagnostic confusion before the diagnosis of EoE showed some clinical improvement as a result of his vitamin treatment. Oxidative stress has been reported in ADD/ADHD) [35]. In his early history, this patient had recurrent otitis media, a frequent disorder attributed to oxidative stress [36]. He also had experienced recurrent asthma, a disease that occurred in the history of a child with intermittent cerebellar ataxia due to thiamin dependency [37]. Of 1,180 patients with EoE, 160 (14%) were suspected of having aeroallergen-associated triggers by history and 32 (20%) had biopsy confirmation of this. Most of them were boys (84%). All had a history or examination consistent with allergic rhinitis and 75% had a history of asthma [38]. Several pathogenic mechanisms related to the nervous system have been reported in non allergic rhinitis, including dysautonomia [39]. Riley noted that failure of general body growth in Familial Dysautonomia appears to be a regular feature despite normal growth hormone [29]. Perhaps the delay in growth would not have been noticed in this patient if he had not had a phenomenal growth acceleration of 4 inches in height and a weight increase of 17 pounds in one year of treatment. The higher percentiles for both showed that this was an unusual acceleration of growth. It is unknown whether the mechanism for growth failure in FD is directly related to the genetic cause of the disease or because of the resulting dysautonomia. Since the dysautonomia in this patient appears to have been acquired in relationship to thiamine metabolism, it suggests that growth failure was related to the dysautonomia.
如果TD是该患者的主要生化损伤,其临床效应始于婴儿期,则需要解释红细胞转酮醇酶对盐酸硫胺的不良反应。其机制尚不清楚,但临床和实验室对硫胺四氢糠酰二硫化(TTFD)的反应表明,基因决定的硫胺转运体问题。TTFD是硫胺的一种开环形式,在细胞膜上非酶性还原。噻唑环闭合,一种完整形式的硫胺被引入细胞[40]。TD的早期症状是由自主神经异常引起的,常被诊断为心身疾病,在这个阶段很容易逆转。据推测,如果这些症状没有被识别出来,生化损害由于TD的纠正失败而继续,[41]可能会出现不可预测的并发症。遗传风险的作用正在扩大:例如,硫胺素焦磷酸缺乏或依赖可导致丙酮脱氢酶[41]、支链氨基酸[42]的脱氢酶或硫胺素焦磷酸激酶[43]的缺陷,尽管临床效果不同。所有这些由基因决定的病症都可以用药理学剂量的硫胺素治疗。因此,酚类疾病的典型表达远不如发现生化病变重要。由于这种类型的遗传缺陷,可能有许多人需要更多的硫胺,通常不是由饮食提供。 Thiamine precursor drugs can achieve these high blood levels and result in increased concentrations in the central nervous system [44,45]. An experiment in DBA/J2 mice suggested also that TTFD had a cholinergic effect [46]. An S-alkyl derivative of thiamine (benfotiamine) has had a beneficial effect on peripheral nerve function and inflammatory markers in type I diabetes [47] and significantly decreased pro-inflammatory mediators in liposaccharide-stimulated murine BV-2 microglia [48]. It has been shown, however, that this derivative is practically insoluble in water, organic solvents or oil, making it unsuitable for intravenous use. When solubilized in hydroxypropyl-beta-cyclodextrxin and given to mice, thiamine levels rapidly increased in blood and liver but there was no significant increase observed in the brain. These investigators proposed that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases, entering the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. This derivative should therefore be differentiated from true lipid-soluble thiamine disulfide derivatives and used appropriately [49]. It has been shown that TTFD inhibits the arachidonic acid cascade-line activation that would make it potentially more suitable for brain inflammation [50]. Thiamine pyrophosphate prevented cisplatin-associated oxidative stress, whereas thiamine did not prevent this [51]. TTFD rapidly increased thiamine activity in whole blood, erythrocytes, CSF and urine in normal and thiamine-deficient subjects. Such repletion was equal to that produced by parenteral, water-soluble thiamine hydrochloride or thiamine pyrophosphate [52], suggesting that this derivative might be useful in the correction of TD in the peroxisome where thiamine pyrophosphate is the cofactor required [23]. It is very unlikely that thiamine deficiency or abnormal homeostasis is the ultimate biochemical lesion in causing EoE. For example vitamin D deficiency has been associated with increased risk for severe asthma, challenge proven food allergy, severe atopic dermatitis and EoE [53]. It is hypothesized therefore that the biochemical lesion, whether it be genetically determined, nutritional in origin, or a combination of the two, represents the etiology for EoE that might be applicable to the etiology of other diseases.
有证据表明,单例EoE患者的根本病因是硫胺代谢异常。有假说认为,由于柠檬酸循环功能低下导致的乙酰胆碱缺乏干扰了食道的运动,无法抑制食物过敏原引起的炎症反应。由于迷走神经供应肠,这可能解释嗜酸性肠炎和食管炎的发病率。通过测定红细胞转酮醇酶(TKA)的活性以及添加硫胺素焦磷酸盐(TPPE)对该酶的影响,可以区分TD相关EoE的发生率。
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Aritcle类型:病例报告
引用:嗜酸性食管炎是糖敏感疾病吗?J胃失调2 (1):doi http://dx.doi.org/10.16966/2381-8689.114
版权:©2016 Lonsdale D.这是一篇开放获取的文章,在知识共享署名许可的条款下发布,该条款允许在任何媒体上无限制地使用、发布和复制,前提是注明原作者和来源。
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