• Lower levels of IL-10
• Increased production of serotonin (5-HT) from gut cells
• Family history of functional gastrointestinal disorders
• History of abuse (physical, mental, emotional, sexual)
• History of psychological illness
• Acute stressors
The familial predisposition may be due to the influence of genetic, environmental, social, and psychological factors. This observation is substantiated by the health-seeking behavior of children of parents with FGID who reportedly have increased prevalence of IBS as compared to children with healthy parents . Similarly, there is clustering of IBS and other FGIDs among families. Furthermore, it was revealed that the concordance for FGID was twice as likely in monozygotic twins as compared to dizygotic twins . Children of adult patients with IBS make one-third more health care visits than the control children of parents without IBS . Thus, there seems to be some familial causes in the development of FGID, including functional heartburn.
In addition, increased prevalence of history of sexual, physical, and emotional abuse is reported in patients with FGIDs. One study demonstrated that 22% of subjects suffering from FGID reported some form of abuse, with the abused patients more likely to report IBS-like symptoms as compared to subjects with no history of abuse [26, 27]. Similarly, another study reported the frequency of rape or incest near 31% among patients with FGID as compared to 18% for those with organic disorders . History of abuse may be as high as 56% in female patients with FGID . Patients with FGIDs not only report an increased prevalence of abuse histories as compared to normal asymptomatic controls, but also experience more severe pain, greater psychological distress, greater impairment of functioning in their daily lives, and more frequent visits to the doctor . Several psychosocial factors are shown to play a pivotal role in exacerbating the symptoms of FH. Experiments have demonstrated acute symptom exacerbation following stress including auditory stress , sleep deprivation  and general life stress [7, 33]. Patients with functional gastrointestinal disorders show increased propensity to develop somatization, anxiety, and depression .
What Is the Pathophysiology of FH?
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 . This observation is attributed to the notion that fat modulates the duodenal perception during gastric distention. This effect is mediated by serotonergic  and peptidergic nerves which have cholecystokinin A receptors . Heartburn has also been associated with mechanical stimuli such as esophageal balloon distension . 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 .
Pathophysiology of FH
1. Chemical factors
• Cholecystokinin A
2. Mechanical factors
• Mechanical distension of the esophagus
• Pain receptors (TRPV1) activation
3. Neurogenic factors
• Activation of serotonergic and peptidergic nerves
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 .
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 . 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 . 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 . 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 .
How Is FH Diagnosed?
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 . 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 . Esophageal biopsies should be obtained to rule out eosinophilic esophagitis, irrespective of the endoscopic appearance of the mucosa . 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 . 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 .
How Is FH Treated?
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 . 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 . 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 . 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 .
Pharmacologic options for FH
Mechanism of action
Proton pump inhibitor
46% of the patients had a complete relief from reflux symptoms following 20 mg omeprazole after 4 weeks
Symptoms of gastrointestinal tract, headache, and respiratory infection
A 5-HT4 receptor partial agonist is shown to modulate the mechanoreceptor response to painful stimuli in the GI tract
Tegaserod increases the threshold for mechanical insult to the esophageal mucosa
Increased incidence of diarrhea
Regulation of multiple functions in GIT via their effect on melatonin receptors
Melatonin significantly alleviates the symptoms of heartburn
Abdominal distension and diarrhea
Increased efficacy of fluoxetine in providing 24-h heartburn-free days as compared to omeprazole or placebo
Headache, dry mouth, and decreased libido
transient receptor potential vanilloid 1 antagonist (TRPV1), which is a pain receptor, activated by noxious heat
AZD1386 modulates the pain sensed by heat pain receptors; however, there is no effect on the pain thresholds caused by electrical stimulation, which suggests the receptor-specific action of AZD1286
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 . 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 .