Читать книгу The Esophagus - Группа авторов - Страница 39

The underlying mechanisms of esophageal hypersensitivity highlight a complex interplay between biochemical and psychological pathways that is not well understood. Recognizably, esophageal hypersensitivity is implicated with esophageal chest pain due to GERD and dysmotility and is the hallmark for patients with functional esophageal disorders. At the most basic level, esophageal hypersensitivity represents peripheral, central, and sensory somatization that impacts gastrointestinal disease [48–50]. There are two main types of hypersensitivity: (i) allodynia, in which a normally non‐painful stimulus is registered as a painful stimulus; and (ii) hyperalgesia, in which a painful stimulus is amplified [48]. As it relates to esophageal chest pain, hypersensitivity results from the increased sensitivity to mechanical, chemical, or central nervous stimulation, which manifests as clinically significant symptoms.

While each of these different types of sensory stimulation can cause hypersensitivity, the interactions between them result in a wide clinical spectrum. Studies focusing on mechanical stimulation have shown that patients with ECP experience lower sensory thresholds when undergoing balloon‐induced esophageal distension compared to healthy controls [51, 52]. Furthermore, Rao et al. showed that 83% (20/24) of patients reported reproduction of their chest pain with balloon distension [52]. Esophageal distension is not the only means by which mechanical stimulation causes pain; irregular contractile activity, including esophageal spasm and other motility disorders, may also trigger abnormal visceral processing of these mechanical stimuli. This was originally suggested by studies showing that prolonged contractions of the longitudinal smooth muscle layer can result in ECP, or more specifically that there appears to be a close temporal relationship between symptom hypersensitivity and contractile hypersensitivity during periods of esophageal acidification [53–55].

The causative relationship between esophageal pain and contractile activity has been somewhat redefined by recent, more advanced technology. A prospective double‐blind study comparing NCCP patients to controls undergoing high‐resolution esophageal manometry with esophageal acid infusion found that NCCP patients had neither an exaggerated shortening response to acid nor a temporal correlation between pain onset and esophageal shortening [56]. This suggests that potentially, pain signaling and smooth muscle contractility are being triggered simultaneously; therefore, the sustained esophageal contractions may be a marker for activation of these painful sensory pathways [56]. In fact, earlier studies support this coordinated role between the sensory modalities, where patients with functional heartburn have greater sensitivity to mechanical stimulation after chemical stimulation [57].

Based on these observations, chemical stimuli and the subsequent involvement of central sensitization likely play a greater role in the underlying mechanisms of esophageal hypersensitivity. This is an expanding area of research with a number of recently discovered chemical stimuli and other pathways overlapping with previously known inflammatory pathways. One of the most important observations regarding esophageal hypersensitivity was the observation of acid‐evoked responses from esophageal nerve fibers [58, 59]. Numerous ion channels and receptors are responsible for sensing acid in the esophagus. Central to hypersensitivity are the nociceptors, which detect noxious stimuli (impending and/or actual tissue‐damaging stimuli) mediated by spinal and vagal afferent pathways [58, 60, 61]. Overall, there are three core types of esophageal nociceptors, including acid‐sensing ion channels (ASIC), purinergic receptors (P2X), and transient receptor potential vallinoid receptors (TRPV) [49].

Figure 2.1 Diagnostic and treatment algorithm for esophageal chest pain.

Under normal conditions, the refluxed gastric acid is unable to activate these receptors; however, when acid is combined with other compounds such as pepsin or bile, it can lead to disruption of the epithelial barrier and expose these sensory nerve endings [62–64]. Evidence from animal studies showed that intraluminal acid infusion or capsaicin administration alone did not evoke action potentials from esophageal nodose C fibers; however, when exposed to an antigen challenge for mast cell activation, activation of these receptors occurred [65]. Conceptually, this is mediated by increased intestinal permeability from mast cell chymase release, which damages tight junctional proteins (e.g. ZO‐1 and occluding) through protease activating receptors and matrix metalloproteinases [66–69]. This data suggests that direct contact between the acid and nerve ending is required for the sensory response.

Esophageal mucosal damage as a prerequisite for nociception is further supported by evidence of neuro‐immunologic mechanisms mediated by inflammatory cytokines and mediators such as interleukin (IL)‐8, IL‐1β, IL‐33, and prostaglandin (PG) E₂ [48,70–73]. Other important esophageal receptors include the capsaicin‐responsive channel TRPV1 and purinergic P2X receptor [48]. The net effect of these inflammatory mediators is the potential aggregation at sites within the esophagus, causing submucosal inflammation and resulting in a decreased excitation threshold in the peripheral nociceptive nerves [48, 74, 75]. This corresponding activation of the peripheral nerves, potentially repeatedly, leads to the release of neurotransmitters including substance P, glutamate, and brain‐derived neurotrophic factors, all of which will ultimately increase the signal intensity of the spinal cord signal causing central sensitization [49]. Perhaps most important among the central sensitizing agents, glutamate activation of N‐methyl‐D‐aspartate (NMDA) receptors plays a significant role in visceral hypersensitivity and may be a leading mechanism of dysregulation in patients with functional GI disorders [76–78]. Acid contact leading to low‐grade inflammation and activation of the multiple acid‐sensitive channels subsequently causes peripheral sensitization and activation of dorsal horn neurons in the spinal cord, causing neurotransmitter release and central sensitization within the brain (Figure 2.2).

Another overlap with functional disorders is the phenomenon known as viserco‐somatic convergence, whereby esophageal pain can be referred to distinct somatic structures if there is any synapse at the same level of the spinal cord [79,80]. In a similar fashion, visceral pain syndromes from organs sharing part of the same spinal cord level innervation can lead to intensification of pain from the esophagus in what is known as viscero‐visceral hyperalgesia [80, 81]. These mechanisms highlight the complexity not only of pain signaling but also of the means by which esophageal chest pain closely overlaps with other somatic or functional disorders. There is data to support a strong influence of stress on the perception and signaling of esophageal hypersensitivity [48]. Fass et al. demonstrated that acute auditory stress resulted in a reduction in time to initial symptom perception, increased pain intensity score, and increased acid sensitivity store in GERD patients [82]. Additionally, psychological stressors can exacerbate symptoms of heartburn. This has been shown experimentally in patients with heartburn and acid reflux who are exposed to an acute psychological stressor while undergoing 24‐hour esophageal pH monitoring [83]. These patients showed a significant increase in cortisol and anxiety levels, in addition to a dissociation between the objectively measured reflux and reported symptom severity [83]. Similarly, Naliboff et al. found patients with stressful life events in the previous six months had a significant increase in heartburn symptoms during the following four months. However, most importantly, the stress ratings were not significantly associated with heartburn score; rather, anxiety showed the strongest relationship to impaired quality of life, depression, and heartburn medication use [84].

Figure 2.2 Mechanisms of esophageal injury and peripheral and central sensitization in esophageal hypersensitivity.

Neuro‐psychologic assessment of patients with NCCP compared to healthy controls also suggests subgroups of patients with NCCP and hypersensitivity. One subset of patients are those with normal esophageal evoked potential latencies but enhanced afferent transmission, with a consequent increased esophageal afferent pathway sensitivity [51]. Another group of patients are those with increased esophageal evoked potential latencies with reduced pain threshold, implying a heightened secondary cortical processing likely due to psychological factors such as hypervigilance [51]. Hypervigilance is becoming increasingly recognized as a factor contributing to patient symptoms. Guadagnoli et al. studied 117 patients with GERD undergoing four days of pH monitoring and completing questionnaires on reflux severity and esophageal hypervigilance and anxiety scale (EHAS) [85]. The EHAS scores and the number of days with positive acid exposure time (p = 0.378) or the number of days with positive symptom‐reflux association did not significantly differ (p = 0.125), suggesting that patients may be at risk for developing hypervigilance and anxiety over their symptoms even in the absence of acid exposure [85]. Although evidence suggests that stress impacts the perception of esophageal hypersensitivity, the mechanisms are not as well understood. The key mediator is likely related to the master hypothalamic stress control mediated by the release of corticotropin‐releasing hormone (CRH). In healthy subjects, the administration of CRH can lead to increased esophageal hypersensitivity to mechanical stimulation [86]. More specific to some of the previously discussed mechanisms, psychological stress may induce the systemic and peripheral release of CRH, resulting in increased mucosal permeability. This occurs due to the expression of CRH receptors by many of the cells within the lamina propria and the subsequent recruitment and activation of mast cells, eosinophils, and macrophages, which may worsen the underlying inflammation and increase the activation of the nociceptive receptors [87,88].

In summary, esophageal hypersensitivity represents a critical facet of esophageal chest pain. Most importantly, there are a number of mechanisms through which hypersensitivity can impact the perception of esophageal pain, including mechanical, chemical, and nociceptive pain receptors. At present, the full impact of inflammation and intestinal permeability on these signaling pathways is not well understood. Clearly, the role of stress in esophageal hypersensitivity strongly supports that psychological disorders play a significant role in esophageal hypersensitivity and overlap closely with other functional gastrointestinal disorders.