Research advances in functional heartburn based on Rome Ⅳ criteria

ZHANG Tai, ZHANG Bei-hua, MA Xiang-xue, WANG Feng-yun, WANG Ping, TANG Xu-dong

1. Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China

2. Graduate School of China Academy of Chinese Medical Sciences, Beijing 100091, China

3. China Academy of Chinese Medical Sciences, Beijing 100700, China

Keywords:Functional heartburn Impedance-pH monitoring High-resolution manometry

ABSTRACT Heartburn is among the most common gastrointestinal symptoms presenting to both generalist physicians and gastroenterologists. In the era of high utilization of proton pump inhibitors, a substantial proportion of patients presenting to the gastroenterologist with chronic symptoms of heartburn do not have a reflux-mediated disease. Subjects without objective evidence of reflux as a cause of their symptoms have functional heartburn (FH). FH has no evidence of abnormal esophageal acid exposure on ambulatory reflux monitoring, major esophageal motor disorders on high resolution manometry, or esophageal mucosal pathology, such as eosinophilic esophagitis on endoscopy with esophageal biopsies. The pathophysiology of FH is unknown but it is often associated with visceral hypersensitivity, and psychiatric disease. Importantly,anti-reflux surgery or other invasive anti-reflux modalities should be avoided. Although there are limited supporting data, modulation of pain perception, traditional Chinese medicine and psychological intervention may be potential therapeutic options in this population.

1. Introduction

Many patients with GERD-like symptoms who fail PPI therapy may in fact have a functional disorder, including functional heartburn, but without evidence of abnormal esophageal acid exposure on ambulatory reflux monitoring, and positive correlation between reflux events and symptoms[1]. FH is a kind of disease characterized by paroxysmal retrosternal burning or pain, which does not respond to acid suppression therapy, normal endoscopic and pathological examination, normal AET, and no correlation between reflux and symptoms. As a functional disease, acid suppression therapy is mostly ineffective. If the disease cannot be correctly identified, blindly increasing the intensity of acid suppression, or performing surgical treatment, it will cause unnecessary injury[2]. The pathogenesis of FH is unclear, and the drug efficacy is not good, leading to persistent symptoms and repeated visits, which seriously affects the quality of life of patients.In this paper, the pathophysiological mechanism and the progress of diagnosis and treatment of this disease were reviewed in order to provide a reference for clinical practice.

2. Epidemiology

Due to the heterogeneity of the definition of FH in different literatures, endoscopy and 24h pH monitoring for diagnosis of the disease[3], and low acceptance of examination by patients, the prevalence of the disease is difficult to estimate. Foreign literatures have reported that FH accounts for 10%-40% of patients with heartburn[4,5] and 21%-53% of patients with refractory heartburn[6,7].A single-center retrospective study in China showed that among 233 patients with heartburn, 78 patients with FH accounted for 34%[8].

3. Pathophysiological mechanism

The mechanism of FH is not clear at present, but it is similar to other functional gastrointestinal disorders (FGIDs), and it is believed that brain-intestinal axis sensitization is the key link. Balloon dilation studies have shown that the hypersensitivity of the esophagus and rectum is similar in FH patients, confirming that visceral sensitivity is generally increased, not limited to the esophagus[9]. Among them,peripheral sensitization is caused by esophageal lumen factors, such as afferent sensitization caused by mechanical stimulation. Central sensitization is mediated by psychological and cognitive factors to enhance the sensation of heartburn.

3.1 Peripheral sensitization

Compared with patients with nonerosive reflux disease(NERD), patients with FH have lower perceptive threshold for esophageal balloon dilation or electrical stimulation, so normal stimulation can sensitize peripheral afferent fibers and improve the sensitivity to esophageal pain[10]. However, compared with Reflux hypersensitivity (RH), although both of them belong to functional esophageal diseases, different from physiological acid or nonacid hypersensitivity of RH, sensitization caused by mechanical stimulation is more common in FH[11]. In addition, similar to the healthy control group, esophageal mucosal afferent nerve localization in FH patients is relatively deep[12], and there is no evidence of mucosal microscopic damage. Therefore, it is believed that low degree of micro-inflammation and cytokine-mediated neuroimmune effect may be the main mechanism of peripheral sensitization of FH[13].

3.2 Central sensitization

FH patients are often combined with affective disorders[14].Studies[15] have shown that FH shows a higher degree of anxiety and less social support compared with patients with a high association of reflux and symptoms. Severe and persistent stress has also been shown to exacerbate heartburn[16]. In addition, compared with healthy controls, cortical evoked potential responses induced by esophageal dilation and acid perfusion were stronger in FH,confirming the role of central sensitization mechanism[17]. The central sensitization link mediated by psychosocial disorder indicates that the treatment mode of FH is different from NERD and RH, and the underlying emotional disorder of FH patients should be fully paid attention to, otherwise it is difficult to improve the heartburn symptoms.

4. Diagnosis and differential diagnosis

A typical FH patient is a middle-aged and young female with a long history of heartburn (BBB 0 for 2 years) and poor efficacy of PPIs[18]. The severity of FH symptoms and the decrease of the Health Related Quality of Life Scale for Gastroesophageal Reflux Disease (GERD-HRQL) score were very similar to those of NERD and RH, so it was difficult to distinguish the three on the basis of medical history alone[19]. Endoscopic, pH impedance monitoring and high resolution esophageal pressure measurement were needed to provide objective basis for the diagnosis of FH.

4.1 Endoscopic examination

First of all, endoscopic examination is feasible for patients with intractable heartburn with PPIs, and combined with mucosal biopsy helps to eliminate Erosive esophagitis (EE), eosinophilic esophagitis,Barrett's esophagus and other diseases. White light endoscopy has a limited role in detecting small changes in esophageal mucosa,while enhanced imaging and confocal endoscopic microscopy can better monitor changes at the mucosal level in NERD to distinguish it from FH[2]. For example, intercellular widening can be used as a pathological feature of NERD mucosal injury, but is rare in FH patients[20].

4.2 Esophageal reflux monitoring

The diagnosis of FH depends on the assessment of acid exposure,but endoscopy is not sufficient for this purpose and reflux monitoring is required to exclude abnormal acid exposure and to identify the relationship between symptoms and reflux. Reflux assessment should be carried out on the basis of PPIS-free treatment[21].According to the Lyons consensus[22], AET＜4% for biological acid reflux and ＞6% for pathological acid reflux. Therefore, NERD should be considered when endoscopy is negative and AET＞ is 6%;Both Fh and Rh acid exposures were normal, so AET＜4%.

The correlation between symptoms and reflux can be evaluated by Symptom Index (SI) and Symptom Association Probability (SAP).Positive symptoms are defined as of SI＞50% or of SAP＞95%[23].Esophageal acid exposure is normal, and a positive association index is RH, while a negative index can be considered as FH after the exclusion of structural and movement disorders.

The pH impedance monitoring can clarify the nature of reflux and its correlation with symptoms. The related pH impedance studies[24]showed that NERD was mainly based on acid reflux, and the number of acid reflux in RH and FH was small, while the number of nonacid reflux was significant. It was speculated that non-acid reflux might be involved in the pathophysiology of RH and FH.

SI and SAP are mutually complementary, but limited to the influence of subjective symptom perception and variation rate of reflux events, their accuracy has been questioned[25]. The combined application of post-reflux wallow-induced peristaltic wave (PSPW)index and mean nocturnal baseline impedance (MNBI) increases the diagnostic value of pH impedance monitoring in the identification of endoscopic negative heart burn disease, especially when SI and SAP are not consistent or AET is at 4%-6%. PSPW reflects the ability of esophageal clearing, and the lower the value, the worse the ability[26].MNBI reflects the integrity of esophageal mucosa, while a lower MNBI indicates impaired mucosal integrity[27]. Studies[28] showed that the PSPW and MNBI values of NERD were significantly lower than those of RH, and NERD and RH were significantly lower than those of FH. Given the high variation rate and poor sensitivity of reflux monitoring during the day, MNBI and PSPW indices may be beneficial for the identification and treatment of refractory heartburn patients, but more evidence is needed to guide the significance of the two indices in clinical practice.

4.3 High resolution esophageal manometry

High resolution manometry (HRM) can be used to evaluate esophageal motion disorders. The diagnosis of FH requires the exclusion of esophageal motion disorders including cardia bradycardia, nutcracker esophagus and esophageal motility loss.

In addition, the relative position of the 1ower sphincter (LES) and the crural diaphragm (CD) could be accurately measured by HRM,so as to determine the separation and the degree of the LES and the diaphragmic foot. The distance between LES and CD is negatively correlated with the pressure of the esophagogastric junction (EGJ)and the ability of the anti-reflux barrier[29]. Based on this, the anatomical morphology of EGJ can be divided into 3 types, of which type 2 patients have more obvious reflux than type 1 patients,and type 3 patients have the most severe reflux, equivalent to hiatal hernia[29]. Zhang Yinghui et al.[30] found that NERD patients with type 2 and type 3 EGJ were more than Rh and FH. Thus, NERD antireflux barrier dysfunction is represented by an increased proportion of hiatal hernias, but is less common in FH and RH.

The esophagogastric Junction -contractile integral (EGJ-CI) is highly specific for differentiating endoscope-negative heartburn subtypes[31]. EGJ-CI combines the function of LES and CD, as well as respiratory changes and other factors, and is an important indicator for evaluating EGJ barrier function[31]. Studies[32] showed that EGJ-CI levels were negatively correlated with acid, weak acid and non-acid reflux events, and EGJ-CI levels in FH patients were significantly higher than those in NERD and RH patients, suggesting that EGJ-CI may have a certain significance in the differentiation of NERD, RH and FH.

The distal contractile integral (DCI) quantifies esophageal peristaltic function, and the poor esophageal motility (IEM) is defined as ≥50% contraction with DCI＜450 mmHg cm s in the Chicago typing[33]. IEM can cause abnormal clearance of acid in the esophagus and increase acid reflux time[34]. Compared with NERD and RH, IEM is rare in patients with FH, but the combination of IEM does not effectively rule out FH[35].

4.4 Esophageal mucosal impedance monitoring

Mucosal impedance (MI) can be measured directly by endoscopy,similar to MNBI, which is inversely proportional to DIS severity[36] and normalizes with effective treatment[37]. MI was lower in NERD patients near the scale-columnar junction and increased with distance from SCJ, while FH patients had higher MI throughout the esophagus[37,38]. Although MI monitoring technology has not been popularized in clinical practice and needs further standardization of detection interval, it is still a means to identify the characteristics of FH, RH, NERD and healthy population.

In summary, the differentiating points of NERD, FH, and RH are that NERD indicates abnormal acid exposure, evidence of microscopic mucosal damage, and sensitivity to acid reflux,regardless of whether symptoms are related to reflux. RH has reflux related symptoms, mostly sensitive to weak acid or nonacid reflux; FH is normal acid exposure, not related to reflux,sensitive to mechanical stimulation, no evidence of microscopic mucosal damage, and the overlap with psychosocial disorders such as depression, anxiety, somatization symptoms can be used as a characteristic suggestive of FH.

5. Treatment

At present, there is no high-quality clinical evidence to explore drug treatment options for FH. Empirically, FH patients are advised to improve their lifestyle and conduct acid suppression therapy.Neuromodulators, traditional Chinese medicine treatment and psychological intervention may be effective for FH patients. The disease has a chronic course and it is necessary to assure the patient of a favorable outcome.

5.1 Basic treatment

Evidence for the effect of lifestyle changes on FH is limited, but patients are generally advised to avoid overeating, eat more meals,minimize the intake of fats, spices, and carbonated beverages, and actively lose weight and raise the head of the bed. In addition, the identification of inducement is the key to improve the symptoms and quality of life of FH patients, which should be effectively identified and treated for co-existing psychological disorders such as anxiety,depression and low social support[39].

5.2 Antireflux therapy

FH is the potential cause of refractory heartburn in PPIs, and the patient's symptoms have nothing to do with reflux, so acid suppression and antireflux surgery have poor efficacy in FH patients[40]. However, in empiric treatment, acid suppression therapy is often the first choice of intervention. Ranitidine significantly reduced esophageal sensitivity to acid in patients with FH who received 150mg ranitidine or placebo twice daily for 7 days,suggesting that histomine-2 receptor antagonists may provide benefit to patients with FH by regulating pain perception threshold[41].However, it is undeniable that the placebo effect or the misdiagnosis of NERD and RH patients as FH may be responsible for the response to acid-suppression therapy in some patients[42-44].

Most patients have significantly worse subjective feelings after antireflux surgery, so FH patients do not benefit from antireflux surgery. For FH patients, antireflux surgery should be avoided[45].

5.3 Nerve modulators

Compared with acid suppression and surgical treatment, treatment for esophageal hypersensitivity and psychosocial comorbiditions may be more effective for FH. Especially for PPIS refractory GERD,overlap with FH and RH is a common cause of acid suppression and no response. For these patients, adjuvant neuromodulator therapy can be used for functional esophageal disease in addition to PPIs maintenance therapy.

For FH, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and other drugs can be considered to reduce esophageal hypersensitivity[46].FH patients treated with fluoxetine for more than 6 weeks were better at improving heartburn than those treated with omeprazole and placebo[47].

5.4 Other drug therapy

In addition to acid-suppressant therapy and neuromodulators,tegacerol has been shown to significantly improve the pain threshold of mechanical stimulation of the esophagusand reduce reflux and heartburn frequency in patients with FH[48]. In addition, taking melatonin before bedtime significantly improved GERD-HRQL scores in patients with FH compared with nortiline and placebo[49].

5.5 TCM(Traditional Chinese Medicine) treatment

Acupuncture and moxibustion, as a traditional treatment technique of Chinese medicine, is easy to operate, safe and effective.Combined with current treatment techniques, it has achieved satisfactory efficacy. Xu Dan et al.[50] found that, compared with western medicine alone, the total effective rate of esomeprazole enteric-coated tablets combined with acupuncture at body surface acupoints in the treatment of FH was 84.4%, higher than 59.4% in the control group, and could significantly improve the symptoms,anxiety and depression of patients, with statistical significance(P＜0.05). Another study showed that in patients with PPIs refractory heartburn, acupuncture significantly alleviated heartburn symptoms compared to double PPIs dose[51].

5.6 Psychological intervention

A controlled trial of 9 patients with FH, in which 6 patients received directed esophageal hypnosis 7 times a week, found that hypnotherapy significantly reduced visceral anxiety and symptom severity in patients[52]. Although the evidence for psychotherapy is limited, it can be considered when other interventions do not respond well.

6. Conclusion

FH is a disease characterized by negative endoscopic heartburn,which is classified as functional esophageal disease by Rome and is a common cause of refractory heartburn. Because FH often overlaps GERD with other FGIDs, a definite diagnosis is difficult.Endoscopy, reflux monitoring, and HRM can help identify FH and other disease subgroups that are characterized by heartburn, and guide and optimize treatment. The pathophysiological mechanism of FH is still unclear, which may be related to visceral hypersensitivity,nonspecific esophageal motility abnormalities, and psychosocial disorders. In terms of treatment, acid suppressant and antireflux surgery are not effective because of normal exposure to FH esophageal acid and no symptoms associated with reflux. Nerve modulator, psychological intervention and TCM treatment may be helpful to regulate brain-gut axis sensitization and improve heartburn symptoms. However, evidence on the efficacy of FH is still very limited and requires further study.

Author’s contribution:

Zhang Tai: put forward research ideas, write papers and revise them; Zhang Bei-hua, Ma Xiang-xue: Collect literature and sort out documents; Wang Feng-yun, Wang Ping, Tang Xu-dong: Suggestions for revision and guidance.

All authors declare no conflict of interest.