Noncardiac Chest Pain: Gastro esophageal Reflux Disease
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N o n c a rd i a c Chest Pain: G a s t ro e s o p h a g e a l Reflux Disease Amanke C. Oranu, MD, Michael F. Vaezi, MD, PhD, MSc (Epi)* KEYWORDS Noncardiac chest pain Gastroesophageal reflux disease Clinical presentation Diagnosis Noncardiac chest pain (NCCP) is not only a difficult disorder to define but is also complex in characterization and treatment.1–3 It represents a symptom of chest pain not of cardiac etiology characterized as burning or squeezing in nature with or without radiation. A cardiac cause must be ruled out in every patient in whom a work-up of potential NCCP is being considered. Approximately 20% to 30% of patients with chest pain have normal cardiac catheterization and may be classified as NCCP, representing more than 200,000 new cases annually in the United States.4 Patients with NCCP are a challenge to primary care and subspecialty services such as cardiology and gastroenterology. These patients are likely to have a high level of health care use and undergo many tests and empiric therapies, and they are usually poorly satisfied with the care provided.5 NCCP is often a heterogeneous disorder with many potential causes including gastroenterologic diagnoses (Box 1). Gastroesophageal reflux disease (GERD) represents 1 of the most common gastro- enterologic causes of NCCP.1–3 Nearly 25% to 60% of patients with NCCP have abnormal prolonged ambulatory pH findings.6 In this group of patients, the presence of baseline heartburn may be helpful but not definitive for the association of GERD with patients’ chest pain episodes. The current dilemma in this disorder is identifying when GERD may be responsible for the patient’s presentation and what to do if empiric therapy fails to resolve the patient’s symptoms. This article presents the current evidence for GERD as a cause of NCCP and highlights the best currently available tests for this group of patients. Division of Gastroenterology, Hepatology and Nutrition, Center for Swallowing and Esopha- geal Disorders, Vanderbilt University Medical Center, TVC 1660, Nashville, TN 37232-5280, USA * Corresponding author. E-mail address: Michael.vaezi@vanderbilt.edu Med Clin N Am 94 (2010) 233–242 doi:10.1016/j.mcna.2010.01.001 medical.theclinics.com 0025-7125/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
234 Oranu & Vaezi
Box 1
Potential gastroenterologic causes of NCCP
C Gastroesophageal reflux disease (GERD)
C Esophageal motility disorder
C Esophageal hypersensitivity
C Biliary colic
C Pancreatitis
C Hepatitis
C Pneumoperitoneum
C Peptic ulcer disease
C Splenomegaly
CLINICAL PRESENTATION
GERD-related NCCP may resemble angina. The pain may be described as squeezing
or burning in the substernal location with possible radiation to the neck, arms or back.
It may be worse postprandially and in the supine position and occasionally post exer-
cise or during emotional stress. Heavy exercise may induce the typical symptoms of
GERD, such as heartburn and regurgitation, and may cause NCCP. The pain may last
minutes or hours and may be intermittent for days. Symptoms usually resolve with
antacids, proton pump inhibitors (PPIs), or rest. The presence of typical GERD symp-
toms such as heartburn and regurgitation are independently associated with NCCP7
although they do not predict response to PPI therapy. In a population study by Eslick1
53% and 58% of patients with NCCP had concomitant heartburn and regurgitation.
Therefore, both conditions may coexist but the causal link may be more difficult to
establish. In a recent study8 the presence of classic reflux symptoms and response
to antacid therapy were important in establishing GERD-related NCCP.
PATHOPHYSIOLOGY
An esophageal origin for recurring NCCP was considered likely by William Osler in
1892 who first suggested that esophageal spasm might play a role in patients’ symp-
toms. However, later studies using ambulatory pH monitoring tests and pressure
monitoring suggested that reflux of gastric content, mainly acid, may be the most
common cause of patients’ symptoms of chest pain.1–3 Chemostimulation and
mechanostimulation are the 2 broad concepts put forward as the main pathogenesis
of reflux-induced symptoms.9,10 Esophageal pain may be a manifestation of nocicep-
tor activation by chemoreceptors responding to chemical or thermal stimulation or
mechanostimulation responding to esophageal wall stretch.11 Once activated, the
receptors transmit their signal through small unmyelinated C-fibers; the pain is usually
perceived as dull, burning, gradual, and poorly localized. In contrast, when the signals
are transmitted with myelinated fibers, the perception is of sharp, sudden, and well-
localized pain. The activated esophageal wall nociceptors transmit their signal periph-
erally and centrally. The latter is required for pain perception. It is suggested that,
because the esophagus and heart share a common innervation, esophageal nocicep-
tor activation may influence coronary circulation.12 In this study, the investigators
found a significant reduction in coronary blood flow with esophageal acid perfusion,Gastroesophageal Reflux Disease 235 which was also associated with typical angina pain. This finding was attributed to an esophagocardiac inhibitory reflex. Similar reduction in coronary blood flow was identified by Rosztoczy and colleagues13 in 45% of patients with NCCP. GERD may also cause a hypersensitivity response manifested as NCCP. Peripheral sensitization of esophageal sensory afferents may lead to heightened response to even normal physiologic acid reflux. Infusion of 0.1 N hydrochloric acid in normal subjects was found to reduce the perception threshold for pain.14,15 The reduction in the pain threshold is most likely caused by increased central excitability by activa- tion of the nociceptive C-fibers. Some also suggest autonomic dysfunction in patients with NCCP.16 In a study of NCCP and healthy volunteers, Tougas and colleagues16 showed that patients with acid sensitivity had a higher baseline heart rate and lower baseline vagal activity than acid-insensitive patients. Acid perfusion cardiac outflow increased in patients with acid sensitivity and not in those with insensitive esophagus. Distention of the esophagus may also play a role in spatial summation, as a result of input from multiple neuronal cells that are more in the upper striated muscle part of the esophagus. Esophageal distention with or without priming of esophageal mucosa by exposure to gastric content has some effect on the mechanostimulator pathway of GERD. The biomechanical and sensory characteristics of the upper, middle, and distal esophagus of 11 healthy volunteers were evaluated by Patel and Rao.17 This group reported a lower threshold of pain sensation in the proximal esophagus compared with the other esophageal segments and postulated that the proximal esophagus might have a larger number of mechanoreceptors than the distal esophagus with distention in the proximal esophagus contributing to the generation of symptoms during a reflux.17 The priming of the esophagus after exposure to gastric content was evaluated by Fass and colleagues18 and DeVault19 who unlike Mehta and colleagues20 and Peghini and colleagues21 found no accentuation of mechanical stimulation after acid exposure. Sarkar and colleagues22 demonstrated induction of hypersensitivity in the proximal esophagus after exposure of distal esophagus to hydrochloric acid suggesting that the latency of esophageal evoked potential is reduced thus leading to visceral hyper- sensitivity. Sustained contraction of the esophageal longitudinal muscle is also suggested as a potential causative factor in patients with NCCP.23 In this study, the investigators suggested that heartburn was associated with short duration of contrac- tion and chest pain was associated with longer contraction duration. In addition to reflux of acid, nonacid causes may be important in NCCP. Siddiqui and colleagues24 assessed the causative role of bile acids in esophageal symptoms with a modified Bernstein acid-infusion test and esophageal barostat balloon disten- sions, in healthy individuals and patients with nonerosive disease. 0.1 M hydrochloric acid; 2 mM and 5 mM chenodexycholic acid and ursodeoxycholic acid infusions were used at least 7 days apart. Significantly higher pain thresholds (with regard to volume and time) were found for ursodeoxycholic acid than for chenodeoxycholic acid, than for acid infusion, suggesting a possible role for bile acids in the generation of esophageal symptoms and pain.24 DIAGNOSTIC TESTING Given the lack of sensitivity of the current diagnostic testing in NCCP, no test can be considered as the gold standard. The most commonly used tests include barium swallow, upper endoscopy, ambulatory pH (with or without impedance monitoring), and PPI trial. Barium esophagram has a low sensitivity (20%–30%) in diagnosing GERD,25,26 and should be considered when there is an associated complication such as dysphagia in patients with GERD or NCCP. In addition, reflux of barium during
236 Oranu & Vaezi
an esophagram is of questionable significance and can seen in up to 20% of healthy
people.27 Upper endoscopy is valuable for diagnosing esophageal mucosal injury
related to GERD such as erosive esophagitis, ulceration, peptic stricture, and Barrett
esophagus. However, patients with NCCP have lower incidence of esophageal find-
ings at endoscopy. Thus, the clinical yield of this test is low in this group of patients.28
Ambulatory 24-hour pH monitoring is regarded as an important physiologic test in
diagnosing GERD. It has a sensitivity ranging from 79% to 96% and specificity from
85% to 100%.29–31 Normal pH findings on 24-hour esophageal pH monitoring are
present in up to 25% of patients with erosive esophagitis and 50% of patients with
nonerosive reflux disease.32–34 This is most commonly caused by diet and lifestyle
modification during the study period as a result of the nasopharyngeal location of
the traditional pH catheter. The introduction of a wireless ambulatory pH capsule
and longer duration (48 hours) of recording has somewhat improved the
sensitivity of pH testing.35 In patients with NCCP, pH monitoring is abnormal in 50%
to 60% of patients. Hewson and colleagues36 reported prevalence of abnormal pH
in 48% of 100 patients with NCCP; 60% had a positive symptom index (SI). The over-
zealous conclusion from this study was that pH monitoring and SI measurement is the
single best test in patients with NCCP. However, a subsequent study did not confirm
these conclusions37 reporting that SI positivity was not a common occurrence in
NCCP. Multichannel intraluminal impedance with a pH sensor allows the detection
of acidic and weakly acidic reflux.38 This recent technique dramatically improved
the detection of reflux, regardless of its pH. Well-controlled studies in NCCP patients
using impedance monitoring are needed to assess the role of weakly or nonacid reflux.
The PPI trial is currently the most attractive alternative to the modalities discussed
earlier because it combines knowledge of symptomatic response with a therapeutic
trial of acid suppression. The test uses a short course of high dose PPI to diagnose
GERD in those with NCCP. The main requirement of the PPI trial is to achieve a signif-
icant symptomatic improvement from as many patients as possible within a short time
period. Diagnostic accuracy of a PPI trial is summarized in Table 1.32,39–44 In most
studies the test was considered to be positive if symptom assessment scores
improved by 50% to 75% compared with baseline. Overall these trials suggest a sensi-
tivity ranging from 69% to 92% and a specificity ranging from 67% to 86% for a PPI
trial in NCCP. A recent meta-analysis45 of randomized controlled studies in NCCP
suggested that PPI therapy reduces symptoms in NCCP and may be useful as a diag-
nostic test in identifying abnormal esophageal acid reflux. The study reported a pooled
risk ratio for continued chest pain after PPI therapy of 0.54 (95% confidence interval
[CI] 0.41–0.71). The overall number to treat to achieve benefit was 3 (95% CI 2–4).
The pooled sensitivity, specificity, and diagnostic odds ratio for the PPI test versus
pH monitoring and esophagogastroduodenoscopy (EGD) were 80%, 73%, and 14%
(95% CI 5.5–34.9). However, the studies were heterogeneous and small in sample
size with evidence of publication bias. In a different meta-analysis,46 the investigators
used 6 of the published controlled trials and found that the use of a PPI trial as a diag-
nostic test for GERD in NCCP has an acceptable sensitivity and specificity and may be
used as an initial test. The investigators reported an overall sensitivity and specificity of
80% and 74%. The PPI trial showed significant higher discriminative power with
a summary diagnostic odds ratio of 19.4 (95% CI 8.5–43.8) compared with 0.61
(95% CI 0.2–1.9) in the placebo group. Thus, there seems to be adequate evidence
in support of a PPI trial as the initial test of choice in patients with NCCP to assess
if symptoms may be from GERD and this may be cost effective.32,47 The PPI test saved
US$575 per patient with NCCP and the test was associated with 79% and 81% reduc-
tion in the use of pH monitoring and EGD, respectively.Gastroesophageal Reflux Disease 237
Table 1
PPI trial studies in NCCP
Symptom
No. of Improvement Sensitivity Specificity
References Dosing Patients (%) (%) (%)
Young Omeprazole 30 75 90 80
et al39 80 mg/d
1 day
Squillace Omeprazole 17 50 69 75
et al40 80 mg/d
1 day
Xia Lansoprazole 68 50 92 67
et al41 30 mg/d
4 weeks
Pandak Omeprazole 37 50 90 67
et al42 40 mg twice a day
2 weeks
Fass Omeprazole 37 50 78 86
et al32 40 mg every morning and
20 mg every evening
7 days
Fass Lansoprazole 40 50 78 82
et al43 60 mg every morning and
30 mg every evening
7 days
Fass Rabaprazole 20 50 83 75
et al44 20 mg every morning and
20 mg every evening
7 days
Provocative tests such as the edrophonium test (Tensilon test) or the Bernstein test
are no longer recommended or commonly used in the evaluation of patients with
NCCP. Edrophonium, a short-acting acetylcholinesterase inhibitor, increases esoph-
ageal motility by increasing the amplitude and duration of esophageal contractions.1
This test initially showed clinical presentation of chest pain in 50% of patients;
however, a response to this test does not indicate a motility disorder as the cause
of the patients’ symptoms. The Bernstein test requires perfusion of 0.1 N hydrochloric
acid into the esophagus in an attempt to reproduce the patients’ symptoms of NCCP if
GERD related. It has low sensitivity and with the emergence of PPIs it has become less
valuable in NCCP.
MANAGEMENT
In patients with NCCP in whom a PPI trial is successful in improving symptoms,
tapering of the dose of PPI to once daily and subsequently to the minimal dose of
acid suppression is recommended. The role of lifestyle modification in GERD and
even in NCCP is questionable.48 The recent American Gastroenterological Association
guidelines for treating GERD question the role of lifestyle changes such as raising the
head of the bed, avoiding fat, chocolate, alcohol, caffeine, mints, or garlic.48 There is
no concrete evidence for their effectiveness. However, weight loss in those who may
be overweight or obese is recommended and may result in improvement of GERD and
subsequently NCCP. Similarly, given the lower efficacy of H2-receptor antagonists238 Oranu & Vaezi
(H2RAs) in suppressing acid, it is intuitive that they may not result in as great a benefit
in symptom relief as PPIs if GERD is the cause of patients’ presenting NCCP. H2RAs
have shown a limited response in this group of patients. In a small uncontrolled study
by Stahl and colleagues,49 13 patient with NCCP were treated with ranitidine 150 mg
orally four times a day. Seven of the 13 patients did not respond but increasing the
dose resulted in a clinical response in all patients. This study highlights the need for
aggressive acid suppression initially in this group of patients. In addition to
less aggressive acid suppression by H2RAs, tolerance usually develops with these
agents after 2–3 weeks of repeated use resulting in decline in efficacy. Therefore,
the initial use of PPIs in NCCP is the preferred initial approach.
The role of pH and/or impedance monitoring in those unresponsive to aggressive
acid suppression is to often document normality rather than abnormal results. One
important clinical question in the management of patients unresponsive to a PPI trial
is if pH monitoring should be performed on or off PPI therapy. The answer to this ques-
tion is currently controversial but the most recent study using impedance monitoring
on therapy and wireless pH monitoring off therapy suggests that a combined
approach may be necessary.50 Pritchett and colleagues50 studied 39 patients with
refractory extraesophageal symptoms with impedance/pH monitoring on twice daily
PPIs, and then the same patients were evaluated with wireless pH monitoring off
acid suppressive therapy. The study showed that on-therapy impedance testing
was normal in 64% of patients, whereas off PPI therapy resulted in normal pH findings
in only 28% of patients (Fig. 1). Thus, in most patients with persistent throat symp-
toms, on-therapy testing is more likely to exclude GERD as the cause than off-therapy
pH testing. If impedance/pH testing is negative in these patients, diagnosis other than
reflux should be considered.
An algorithm for the treatment of patients with NCCP is presented in Fig. 2. Given
the beneficial response and more aggressive acid suppression with PPIs and that
PPIs are also used as a diagnostic test to determine the cause of NCCP, an initial trial
of 1 to 2 months of PPI therapy is a reasonable approach (see Fig. 2). In patients who
respond to PPI therapy, tapering the dose to minimal acid suppression should be
attempted. If patients do not improve after 2 months of therapy with PPIs, diagnostic
testing such as pH monitoring or impedance pH monitoring may be useful in assessing
if the patient’s acid or nonacid reflux is controlled while on therapy. Impedance/pH
monitoring (if available) or pH monitoring should be used while patients are on therapy
to assess for continued reflux. If this test is normal then a search for causes other than
pH-Impedance on PPI
Normal (64%) Abnormal (36%)
40% 93%
Wireless pH off PPI
Normal pH (28%) Abnormal pH (72%)
Fig. 1. The likelihood of abnormal pH off therapy if abnormal impedance on therapy was
present. Efficacy of esophageal impedance/pH monitoring in patients with refractory
GERD, on and off therapy.Gastroesophageal Reflux Disease 239
NCCP
Bid PPI therapy
1-2 months
Response No response
Taper PPI Impedance/pH or pH monitoring
Lowest dose of acid suppression on Therapy
Normal Abnormal
Investigate other causes for NCCP Treat as GERD
Fig. 2. Treatment algorithm for GERD-related NCCP.
GERD should be initiated. pH testing off PPI therapy will only assess the presence of
acid reflux at baseline but does not suggest a causal link between GERD and NCCP.
Surgical fundoplication cannot be recommended if patients do not respond to PPI
therapy. In a selected population of patients (those responsive to PPI therapy) surgical
success is to be expected similar to typical GERD.51
SUMMARY
In patients with NCCP the most important clinical consideration is to rule out a cardiac
cause given its life-threatening nature. Because many patients with NCCP may not
present with the classic symptom of GERD, an empiric trial with PPI therapy can be
used as a diagnostic test and as therapy. Twice daily PPI therapy is recommended
for 1 to 2 months. Diagnostic testing such as EGD, pH, or impedance monitoring is
predominately used for those unresponsive to PPI therapy. Response to PPI therapy
can suggest a possible causal link between GERD and NCCP and lack of response
should prompt a search for other causes of NCCP.
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