The role of oesophageal physiological testing in the assessment of noncardiac chest pain

Abstract

Oesophageal physiology testing plays an important role in the diagnosis of noncardiac chest pain (NCCP) after cardiac, structural and mucosal abnormalities have been ruled out. Endoscopy can establish the presence of structural causes of chest pain such as cancer, oesophageal webs and diverticula. Even if macroscopically normal, eosinophilic oesophagitis is a common cause of chest pain and needs to be ruled out with an adequate biopsy regimen. In the remaining cases, diagnosis is focused on the identification of often subtle mechanisms that lead to NCCP. The most common oesophageal aetiologies for NCCP are gastro-oesophageal reflux disease (GORD), oesophageal dysmotility and functional chest pain. Ambulatory pH studies (with or without impedance or wireless measurements) can establish the presence of GORD, nonerosive reflux as well any association with symptoms of chest pain. High-resolution manometry, particularly with the inclusion of adjunctive testing, can rule out major motility disorders such as spasm, hypercontraction or achalasia. The EndoFLIP device can help define disorders with reduced distensibility, not easily appreciated with endoscopy or manometry. When all tests remain negative, a diagnosis of oesophageal hypersensitivity is normally made and therapy is shifted from targeting a disease to treating symptoms and patient affect.

Introduction

Noncardiac chest pain (NCCP) is defined as a recurrent pain that is hard to distinguish from cardiac angina even after thorough diagnostic work up has excluded coronary artery disease.^1,2 Symptoms primarily reported in association with NCCP include retrosternal or substernal squeezing and burning. Pain radiating to the arms, back and jaw are also sometimes reported, thus adding to the diagnostic difficulty. Chest pain occurrence and pain intensity seem to be higher in patients with NCCP and the use of sensory and affective vocabulary to describe this pain can be more pronounced as are psychological comorbidities.³ Patients with NCCP have an impaired quality of life and healthcare-seeking behaviour that is on par with cardiac angina.⁴

The prevalence of NCCP is high and ranges between 20% and 30% in specialist clinical settings and up to 60% in patients presenting with chest pain in general emergency rooms and general practitioner surgeries.^1,5,6 Patients tend to be younger and female, and prevalence decreases with age.⁷ The differential diagnosis of NCCP is broad, with 36–49% attributed to musculoskeletal aetiologies, up to 25% gastrointestinal, 5–11% psychiatric and 3% due to mediastinal and pulmonary causes; however an overlap can also occur.⁸

The most common gastrointestinal reasons for NCCP are gastro-oesophageal reflux disease (GORD), oesophageal dysmotility and functional chest pain as defined by the Rome IV criteria; however other causes of oesophageal pain also need to be considered, including oesophageal webs, infectious oesophagitis (e.g. herpes simplex) as well as eosinophilic oesophagitis (EoE). Table 1 summarizes the most common gastrointestinal causes of NCCP. This review will explore the role of oesophageal physiology testing with pH impedance and manometry for the diagnosis and better characterization of NCCP and propose a practical clinical algorithm for functional testing (Figure 1).

Table 1.

Summary of the most common gastrointestinal causes of noncardiac chest pain (NCCP) and their prevalence.^2,5,9

Disease	Mechanism	Prevalence
GORD	Nonerosive reflux disease	50–60%
Oesophageal dysmotility	Spastic motor disorders	15–18%
	Jackhammer oesophagus
	Distal oesophageal spasm
	Achalasia
Functional chest pain	Oesophageal hypersensitivity	32–35%
	Altered central processing of oesophageal stimuli
	Psychological comorbidity
Other causes	Oesophageal webs, diverticula	30%
	Eosinophilic oesophagitis
	Infectious oesophagitis

GORD, Gastro-oesophageal reflux disease.

Figure 1.

Diagnostic approach to noncardiac chest pain (NCCP). In patients presenting with chest pain, a cardiac cause needs to be ruled out first. A trial of antacid therapy can be recommended. In patients with acute symptoms or without improvement on antacid therapy, endoscopy should rule out structural diseases such as tumours, diverticula and oesophageal webs, as well as infectious or erosive oesophagitis. EoE should be ruled out via biopsy. Physiological testing with either catheter based or wireless 24 h pH impedance and manometry comes into play to assess the presence of GORD and to guide further treatment.

Gastro-oesophageal reflux disease (GORD)

GORD is one of the most common gastrointestinal disorders contributing to NCCP and should be considered as a primary differential diagnosis, especially if classical symptoms such as heartburn and regurgitation are present. Upper gastrointestinal endoscopy, high-resolution manometry (HRM) and ambulatory pH monitoring (both catheter based with or without impedance or wireless monitoring) are current ‘routine’ options for investigation, usually after a failed trial of proton pump inhibitor (PPI), the PPI test.¹⁰ Due to its low specificity, a barium swallow is not recommended for the diagnosis of GORD, although in NCCP it might help exclude other structural or functional disorders (e.g. achalasia, diverticulum, etc.; discussed below).^11,12 Other tools such as the acid perfusion test are primarily reserved for research purposes; although the sensitivity for the diagnosis of GORD as a cause of NCCP is reported as being up to 90%, its specificity is only 36% for acid-related NCCP.^13,14

In the absence of alarm symptoms (which warrant urgent endoscopy or radiology examinations) although not diagnostic of reflux disease, the PPI test is commonly the first, and simplest, diagnostic (and therapeutic) study; PPIs are prescribed up to twice daily at double the standard dose over 8 weeks. The PPI test has been shown to have a sensitivity and specificity of up to 89% and 53% respectively.^15,16 Controlled studies show that 52–95% of patients with proven GORD report improvement of chest pain symptoms compared with 10–50% of patients offered placebo.^15,17,18

Endoscopy is often the next test required. Its sensitivity in the diagnosis of GORD as a cause of NCCP is low, as only 30% of patients with GORD have suggestive macroscopic lesions, however erosive and infectious oesophagitis, strictures, diverticula and ulcers can be detected in up to 14%, all of which can be attributed to symptoms of NCCP.^19,20 EoE also needs to be considered as a primary cause of chest pain (discussed below). On the other hand, the probability of detecting pathology on endoscopy in NCCP is much lower than in patients with GORD without pain.^21,22

When endoscopy is normal, ambulatory pH monitoring (either catheter based or wireless) can help identify acid or nonacid reflux as a cause of symptoms in patients with NCCP.^23–25 Several studies show that between 20% and 60% of patients with NCCP report chest pain in relation to an acid-reflux event during ambulatory 24 h pH studies.^14,26–29 In a retrospective study, of patients with NCCP who underwent pH monitoring off acid-reducing therapy, 80.9% reported chest pain episodes, with patterns suggestive of GORD found in 62.2%. Of those, abnormal acid exposure was found in 53.1%; 26.5% of patients had a positive symptom association probability (a statistical function that expresses the likelihood that symptoms are related to reflux) and 25.5% had a positive symptom index (the percentage of symptoms that are related to reflux events).^27,30

The role of nonacid reflux is less clear, although it also seems to have a role in symptom generation.³¹ The advent of pH-impedance monitoring not only allows the association of reflux events with symptoms, but also provides insight into the degree and frequency of the proximal extent of the refluxate as well as the effectiveness of oesophageal clearance. In a recent study, 120 patients with NCCP underwent 24 h pH-impedance monitoring; 40% of those with NCCP had GORD as a possible cause of pain, and longer, more voluminous, acidic and proximal reflux episodes were more likely to be followed by symptoms of chest pain.³² In a study which investigated oesophageal baseline impedance as a surrogate marker of mucosal damage in healthy controls as well as NCCP with and without proven GORD, baseline impedance conductivity was shown to be decreased (and therefore suggestive of leaky, damaged mucosa) by approximately one third in those with pathological oesophageal acid exposure.³³ Furthermore, baseline impedance in the distal oesophagus in non-GORD-related NCCP was significantly higher than in GORD-related NCCP. In the proximal oesophagus, baseline impedance in non-GORD-related NCCP was lower than in the control group, but similar to GORD-related NCCP. This implies that mucosal integrity is impaired in the proximal oesophagus in patients with non-GORD-related NCCP and could represent a possible cause of NCCP.^34–38

Prolonged wireless pH monitoring can record up to 96 h and is more sensitive in documenting symptom association with reflux events than the standard 24 h, catheter-based pH study. There are many reasons for this. The absence of a nasal catheter is better tolerated, even in those who had previously failed catheter-based pH monitoring.³⁰ Furthermore, improved oral intake, increased physical activity and reduced social embarrassment can increase the likelihood of reproducing normal, reflux-provoking daily activities, and in turn, detecting reflux events as well as associating these with symptoms.^30,39–42 Compared with standard 24 h measurements, 48 h prolonged wireless pH monitoring can increase the diagnostic yield by up to 12% in identifying reflux in patients with NCCP.³⁰

Oesophageal dysmotility

Oesophageal manometry is key to assessing motility and oesophageal function in patients with NCCP.

Studies conducted with standard conventional manometry report normal studies in 35–70%, while the rate of identifying spasm, achalasia and nonspecific motility disorders varies between 10% and 40%.^43–45 The most common documented manometric abnormalities in most studies using conventional manometry are a hypotensive lower oesophageal sphincter (LOS) and spastic motor disorders; however, overall, these findings very rarely explain the cause of NCCP with confidence.⁴⁶ Using ambulatory 24 h oesophageal manometry in the evaluation of non-GORD-related NCCP seems to offer some, albeit limited, additional diagnostic information as it attempts to correlate symptoms and dysmotility over a prolonged period. In one study, oesophageal spasm related to NCCP was found in only 6.5% (4/59) of patients. When other abnormalities, such as simultaneous (rapid) or repetitive contractions, were also assessed, manometry had a sensitivity of 75% and a specificity of 98.2% for the diagnosis of oesophageal spasm.⁴⁷

The advent of HRM with colour representation of pressure phenomena has revolutionized the field and has added to the understanding and diagnosis of oesophageal dysmotility and bolus transport (Figure 2).^48–50 Furthermore, with the addition of novel parameters to help describe function more accurately, a new classification of motor disorders, coined the Chicago Classification, has helped define pathology most likely to impair bolus transport and trigger symptoms; namely gastro-oesophageal junction (GOJ) outflow obstruction including achalasia, spasm, hypercontractility and absent peristalsis, all of which are considered major motor disorders.⁴⁹

Figure 2.

Summary of the oesophageal motor disorders as described by the Chicago Classification.

A recent study utilizing HRM explored motility patterns in patients with either NCCP or typical GORD symptoms. Sixty percent of patients with NCCP showed impaired peristalsis, ineffective oesophageal motility, failed peristalsis or an abnormal number of large peristaltic breaks. In contrast, 24% of patients with GORD exhibited these patterns. On 24 h pH-impedance monitoring, symptoms of chest pain were often associated with gas in the acidic refluxate. This symptom, as well as poor motility leading to impaired clearance of the refluxate, have been identified as possible components in symptom generation in NCCP.⁵¹

Achalasia is a rare disease of unclear aetiology with a prevalence of 1:100,000. It can present with dysphagia, regurgitation of retained food content, weight loss as well as chest pain. The hallmark of all achalasia is a nonrelaxing LOS, with high sensitivity and specificity using parameters which are specific for HRM.⁵² Thereafter, HRM divides achalasia into three distinct subtypes based on the presence or absence of pressurization within the oesophagus or spasm (Figure 3).^49,53,54 In achalasia type I, a decompensated, dilated oesophagus is presumed to be the consequence of chronic obstruction. It is theorized that this is preceded by achalasia type II, which on manometry is defined by ‘panoesophageal pressurization’ as compression takes place within an oesophagus which has not yet dilated. In achalasia type III, peristalsis persists but is associated with rapid contractions in keeping with the spasm (Figure 3). Although all achalasia subtypes can be associated with pain as one of the pillars of presentation, type III in particular can lead to lumen obliterating contractions which can produce severe, sometimes excruciating pain and therefore can be the most difficult to treat.⁵⁵ Furthermore, in patients presenting with a type III achalasia pattern on manometry, special emphasis should be made to identify any history of opiate use, even if this is inadvertent and over the counter; opiates can induce hypercontractions and spasms within the oesophagus and LOS that can mimic any form of hypercontractility pattern, including achalasia type III.^56,57 Ratuapli and colleagues showed that in a cohort of 121 patients investigated for oesophageal symptoms, the incidence of type III achalasia and idiopathic GOJ outflow obstruction was higher in patients taking opiates, and in many, this can be reversible when opiates are terminated.^56–58

Figure 3.

High-resolution oesophageal manometry representation of a normal swallow and the three subtypes of achalasia. (a) A normal swallow begins with the relaxation of the upper oesophageal sphincter, deglutitive inhibition of the oesophagus and lower oesophageal sphincter (LOS), after which transport of the bolus through the oesophagus is driven by a sequential peristaltic wave and opening of the LOS. All achalasia subtypes are defined by a nonrelaxing LOS. (b) Achalasia type I shows no peristalsis and no oesophageal pressurization due to a dilated oesophagus. (c) Achalasia type II is defined by panoesophageal pressurization due to simultaneous contraction of all sensors within a nondilated oesophagus. (d) Achalasia type III requires the addition of premature contractions to suggest spasm in combination with the nonrelaxing LOS.⁴⁹

Hypercontractile disorders as defined by the Chicago Classification can be a cause of NCCP.⁴⁹ However, hypertensive peristaltic contractions can also sometimes be seen in asymptomatic individuals, so the relationship between symptoms and hypercontractility is not always straightforward, especially if symptoms are not reproduced during testing. Jackhammer oesophagus, a diagnosis which is defined by manometrically determined contractile vigour that is very high, is not seen in healthy individuals and commonly leads to symptoms, primarily chest pain or dysphagia. In a recent study using HRM in 34 patients with Jackhammer oesophagus, 43% reported primary symptoms of chest pain; however, the symptom of chest pain was not commonly related to dysmotility, suggesting another pathophysiological pathway of symptom generation.⁵⁹

The Chicago Classification bases the diagnosis of achalasia and other motility disorders on 5 ml water swallows. This does not reflect normal eating or drinking behaviour, and rarely triggers symptoms, which might underestimate the correlation between symptoms and dysmotility.⁴⁸ Adjunctive tests, such as the inclusion of swallows with different bolus viscosities, free drinking as well as a test meal have been shown to reproduce normal behaviour and trigger typical symptoms.^60,61 Ang and colleagues demonstrated that in patients undergoing oesophageal physiology studies, the use of a test meal increased the sensitivity of identifying a major motility disorder such as achalasia, GOJ outflow obstruction, oesophageal spasm or hypercontractility [321 (43%) patients diagnosed with a test meal versus 163 (22%) with single water swallows], as well as correlating symptoms of dysphagia and chest pain with the relevant dysmotility.^61–63 A recent international survey of clinical practice demonstrated that the inclusion of such adjunctive testing in HRM is becoming more commonly applied in routine clinical practice.⁶⁴

Eosinophilic oesophagitis

EOE is a chronic, immune-mediated disease of the oesophagus which should be suspected in all young adults presenting with solid food dysphagia, food bolus obstruction or chest pain; although chest pain can be the only presenting complaint.^65,66 EoE is frequently associated with atopic conditions such as asthma and food allergies. Endoscopic features include corrugated rings, linear furrows, and white exudates, but none are diagnostic and in more than 30% of cases the mucosa appears normal.⁶⁷ The diagnosis of EoE is made based on histological evidence of eosinophilic infiltration in the oesophageal mucosa in conjunction with symptoms; however, GORD and EoE can be coexisting conditions while symptoms of EoE can also mimic those of GORD. As such, initial treatment for both conditions is not uncommon with acid suppression such as a PPI.⁶⁸ Although 20% of patients with EoE show abnormalities on reflux testing, it is not clear what role pH monitoring can play in the diagnosis of EoE.^69,70 However, GORD can exacerbate symptoms of EoE, therefore excluding GORD with pH monitoring might help eliminate GORD as a cause or contributor of symptoms.⁷¹ The role of manometry in EoE is also unclear as the disease can produce almost any oesophageal motor disorder, ranging from obstruction to spasm. Furthermore, the manometric patterns are not always shown to correlate with symptoms.⁷² However, high-resolution oesophageal manometry has been shown to identify, sometimes subtle, changes in resistance to flow before therapy,^73,74 particularly if the oesophagus is challenged with solid bolus swallows.⁷⁵ Chronic eosinophilia can lead to fibrosis and tissue remodelling; however few tools can address the degree of oesophageal stiffness.⁷⁶ EndoFLIP (Crospon Medical Devices, Galway, Ireland) uses ‘impedance planimetry’ within an infinitely compliant bag that is sequentially inflated with saline to provide such measurements. Kwaitek and colleagues found that, in EoE, the cross-sectional area and distensibility within the GOJ and along the oesophageal body were significantly reduced compared with healthy controls.⁷⁷ Although interesting, this technology has not yet entered routine clinical practice.

Functional chest pain

It has been suggested that central processing of oesophageal stimuli plays a crucial role in symptom generation. Several physiological testing methods are available to clarify the presence of oesophageal hypersensitivity (acid perfusion test, balloon distension and electrical stimulation). Although these can confirm how such patients can exhibit lower thresholds for pain to various degrees of stimuli, they are uncomfortable, expensive and require particular expertise, and so are normally only available in research and tertiary care centres.^18,20,25,78 Furthermore, in 20–50% of patients, depression, anxiety and panic disorders are present, which can affect evaluation, diagnosis and treatment of NCCP with functional chest pain. When oesophageal hypersensitivity is present, pain modulators such as tricyclic antidepressants, trazodone and serotonin reuptake inhibitors can be used for treatment. Cognitive behavioural therapy can be used with success in refractory cases. Hypnotherapy has only been tested in small nonrandomized trials, but was successful in the treatment of NCCP.⁷⁹

When a cardiac cause has been excluded and gastroscopy, histology, radiology, manometry and reflux testing have confirmed that there is no structural disease or motility disorder and symptoms persist for 3 months with a frequency of at least once per week, a diagnosis of functional chest pain can be made according to the Rome IV criteria.^80,81

Summary

Oesophageal physiology testing plays an important role in the diagnosis of NCCP after cardiac, structural and mucosal abnormalities have been ruled out. Endoscopy can establish the presence of structural causes of chest pain, such as cancer, oesophageal webs and diverticula. Even if macroscopically normal, EoE is a common cause of chest pain and needs to be ruled out with an adequate biopsy regimen. In the remaining cases, diagnosis is focused on the identification of often subtle mechanisms that lead to NCCP. The most common oesophageal aetiologies for NCCP are GORD, oesophageal dysmotility and functional chest pain. Ambulatory pH studies (with or without impedance or wireless pH monitoring) can establish the presence of GORD, nonerosive reflux and their association with symptoms of chest pain. HRM, particularly with the inclusion of solid swallows and free drinking, can rule out major motility disorders such as spasm, hypercontraction or achalasia. EndoFLIP can help define disorders with reduced distensibility not easily appreciated with endoscopy or manometry. When all tests remain negative, a diagnosis of oesophageal hypersensitivity can be made and therapy shifted from targeting a disease to treating symptoms and patient affect.