Chemical, mechanical, and neurogenic factors have all been implicated in the pathophysiology of FH (Table 11.2). Some have also suggested a role for central and peripheral neural factors. One such study demonstrated that infusion of fat into the duodenum remarkably shortened the latency to onset of heartburn and intensified the perception of heartburn in subjects with GERD [35]. This observation is attributed to the notion that fat modulates the duodenal perception during gastric distention. This effect is mediated by serotonergic [36] and peptidergic nerves which have cholecystokinin A receptors [37]. Heartburn has also been associated with mechanical stimuli such as esophageal balloon distension [38]. A study compared the cortical cerebral responses induced by esophageal balloon distension and acid perfusion (using 0.1 N HCl) between FH patients and healthy controls, using Functional magnetic resonance imaging (FMRI). The findings suggest that the chemical stimulation of the esophageal mucosa is relayed to the cerebral cortex and the response is modulated accordingly. This study also found a comparatively longer latency period in cerebral response to chemical stimulation as compared to mechanical distention, which might be explained by the time required for the stimulation of the peripheral nerve endings [39].

Patients with FH, by definition, do not have reflux. A study investigated the role of reflux-promoting factors in the pathophysiology of FH and compared the results between nonerosive reflux disease (NERD), FH, and controls. The factors taken into account were the presence of hiatal hernia, mean lower esophageal sphincter tone, and number of upright diurnal acid refluxes lasting more than 5 min. The study showed minimal difference in the prevalence of hiatal hernia between the FH and control group, while an increased prevalence was observed in patients with NERD. Similarly, LES pressure and upright acid reflux episode duration varied significantly between these groups, with values in FH being closer to controls, while in the NERD group, the results were comparable to GERD [40].

Regardless of the inciting stimulus, the underlying pathophysiology is attributed to the conventional notion of penetrating noxious stimuli through the damaged mucosa owing to inflammatory process or increased intercellular spaces having the detrimental effect on the integrity of the esophageal barrier. This concept is substantiated by demonstration of the strong stimuli piercing through the dilated intercellular spaces to activate nociceptive receptors, such as the TRPV1 receptor or the transient receptor potential acid-sensing ion channel (ASIC), which then trigger strong vagal and spinal responses from the central nervous system [41]. TRPV1 (vanilloid receptor 1) receptor is activated when exposed to heat or any pungent stimuli. It is also activated by endogenous hydrogen ions released in tissues during inflammation [42]. The expression of TRPV1 is significantly higher in patients with painful inflammatory bowel disease (IBD). This increased expression is linked to an increased release of substance P and calcitonin gene-related peptide, which induces neurogenic inflammation resulting in pain [43]. Another study evaluating the role of TRPV1 in esophagitis found that the fraction of TRPV1-expressing nerve fibers in these cases is increased, suggesting its contribution to the visceral hypersensitivity often seen in patients with GERD and chest pain [44].

FH poses a challenging clinical situation due to lack of any specific symptomatic picture. It is, by definition, a diagnosis of exclusion, where initial trial of PPI therapy fails to ameliorate patients’ symptoms [2]. The essential tests necessary before diagnosing FH include endoscopy, ambulatory reflux monitoring, and esophageal motility testing. Upper gastrointestinal endoscopy must be performed, preferably after discontinuation of the PPIs for 2 weeks. Endoscopic evidence of esophagitis (erosions and gross inflammatory changes) favors the diagnosis of reflux and essentially rules out FH [5]. Esophageal biopsies should be obtained to rule out eosinophilic esophagitis, irrespective of the endoscopic appearance of the mucosa [45]. This will help in ruling out other potential causes of heartburn. In order to rule out GERD, testing with prolonged ambulatory pH monitoring must be undertaken [3]. Ambulatory reflux monitoring with impedance monitoring combined with pH may give a better overall diagnostic yield and may aid in describing the temporal relationship between the symptoms and reflux episodes. Finally, studies have reported association of achalasia or other esophageal motility abnormalities with heartburn. Hence manometric studies must be a part of the diagnostic workup [4].

Treatment of patients with FH includes both pharmacological and non-pharmacologic approaches. Non-pharmacologic options include cognitive-behavioral therapy (CBT) , relaxation training, combined psychotherapies, dynamic psychotherapy, and hypnotherapy. CBT is shown to be effective in patients with functional bowel disorders (FBD). A study compared the clinical efficacy and safety of cognitive-behavioral therapy (CBT) against education (EDU) and desipramine (DES) against placebo (PLA) in female patients with moderate to severe FBD (irritable bowel syndrome, functional abdominal pain, painful constipation, and unspecified FBD). CBT showed statistically significant benefit when compared with EDU (composite score, P < 0.0001). The most notable factor that gauged the composite measure of treatment benefit was patient satisfaction with the treatment. Similarly, noticeable results were found when relaxation techniques were employed in patients with FBD [46]. Combined psychotherapies are also effective in alleviating the symptoms in FGIDs. A study compared standardized multicomponent behavioral therapy plus standard medical treatment (SMBT) to standard medical treatment alone (SMT) in the treatment of IBS. The combination therapy proved to be more potent than SMT alone resulting in better symptom reduction and overall patient satisfaction [47]. Hypnotherapy was also found to be effective in several trials, but a methodologically strong research trial with generalizable results to assess the unbiased efficacy of this method in the treatment of FGIDs is not yet available.

Acid suppression with PPIs is among the most commonly employed pharmacologic therapies in FH (Table 11.3). PPI therapy not only excludes reflux disease as the cause but may also be beneficial in those with FH. One study in patients with heartburn who were not stratified based on Rome criteria showed significant symptomatic improvement following 20 and 10 mg omeprazole therapy once daily in a group of patients with heartburn. The subjects were noted to have experienced moderate to severe reflux symptoms a week prior to the inclusion in this study. Moreover, 20 mg dose proved to be more effective as compared to 10 mg, establishing a distinctive dose-response effect [2]. However, considering the pathophysiology of FH, the therapeutic benefit of acid-suppressive therapy in this group is perplexing and likely due to response by those with NERD and not FH, especially as it is being defined based on Rome IV. Similarly, a randomized controlled study demonstrated the benefit of a single dose of ranitidine in FH, but the response was likely due to those experiencing “reflux hypersensitivity ” as characterized by the Rome IV definition [48].

Tegaserod , a 5-HT4 receptor partial agonist, modulates the mechanoreceptor response to painful stimuli in the GI tract. A study investigated the role of tegaserod in the management of reflux symptoms in FGID. The findings revealed that the patients taking tegaserod had a higher threshold for mechanical insult to the esophageal mucosa. However, tegaserod reportedly had no effect on the chemical stimulation of the mucosa [9]. Another study compared the efficacy of melatonin to nortriptyline and placebo in the symptomatic management of FH. Since depression and other psychological factors are known to play a role in the pathophysiology of FGID, it was not surprising that nortriptyline was more effective in alleviating symptoms as compared to placebo. Melatonin also showed efficacy and in fact had better results as compared to nortriptyline. In this study, patients receiving melatonin reported increased incidence of adverse effects like abdominal distension and diarrhea as compared to placebo or nortriptyline, while daytime somnolence, dry mouth, and constipation were recorded more frequently in the other two groups [10].