(ii) determining which patients should be referred for treatment of non‐GERD etiologies, and (iii) determining which patients may require further diagnostic testing and treatment focused on optimizing management of GERD [38]. These consensus guidelines recommend testing on medication to assess for the adequacy of acid control in patients with complicated GERD or to assess for the role of nonacid reflux in patients with a previously established diagnosis of GERD [38]. By performing the test while off PPI therapy, there is an increased opportunity for assessing baseline acid reflux, in particular in patients without a previous diagnosis of GERD. A limitation of these consensus guidelines in relation to the diagnosis of NCCP, however, is their focus solely on the diagnosis of GERD (including refractory, atypical, or extra‐esophageal symptoms). When investigating NCCP, failure of PPI trial lowers suspicion for reflux but increases that of esophageal hypersensitivity or motility disorder. Given that the overall goal of NCCP is symptom control, increased detection of symptom correlation with acid vs. nonacid reflux is critical in establishing a diagnosis of GERD or esophageal hypersensitivity. For this reason, we advocate for the performance of pH‐impedance while on PPI therapy in patients undergoing evaluation of NCCP.
Summary
Gastroesophageal reflux disease is the GI etiology in the majority of NCCP/ECP cases. We recommend that all patients with suspected ECP be evaluated for GERD, initially by empiric treatment with a two‐ to four‐week trial with PPIs (bid dosing if daily not responsive) and if not responsive by directed testing. The duration of trial treatment should be in view of the frequency of CP symptoms to ensure that the duration of intervention with PPI therapy appropriately captures the time windows for reported symptoms. If patients positively respond to the PPI, they should be continued on the PPI at the lowest dose necessary for symptom control. Patients who do not respond to PPI should undergo further investigation to evaluate any reflux with pH‐impedance monitoring. Our practice recommendation is to do on bid PPI (ensuring also good compliance with the timing of PPI ingestion – 30–60 min before breakfast and dinner). If pH‐impedance monitoring is negative, these patients should be evaluated for other causes of esophageal chest pain, as outlined in Figure 2.1.
Esophageal hypersensitivity
Pathophysiology
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