Q J Med 2000; 93: 543-550
© 2000 Association of Physicians
Commentary Papers |
Are oesophageal disorders a common cause of chest pain despite normal coronary anatomy?
From the Cardiothoracic Centre and 1 Oesophageal Investigation Unit, Guy's and St Thomas' Hospital, London, UK
Introduction
On average 20%, but up to 39%, of patients undergoing coronary angiography for the investigation of chest pain are found to have normal coronary anatomy.1 These patients have a cardiac morbidity and mortality close to the normal population on short- or long-term follow-up,2 and the tendency is to reassure and discharge them from follow-up. However, 50% continue to have chest pain and 50% remain or become unemployed (Table 1
), therefore an effort should be made to make a positive diagnosis in order to start appropriate treatment. Abnormal oesophageal motility or reflux are found frequently in these patients (Tables 2 and 3), but how often these are causative remains uncertain.
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How good is the evidence for an oesophageal origin for chest pain?
Acid reflux
A number of studies have shown a high incidence of abnormal acid reflux.3–6 However, some studies used control ranges derived from normal asymptomatic subjects7,8 who may not be appropriate comparators. Furthermore, abnormal acid exposure times do not prove an oesophageal origin for chest pain unless the pain and reflux episodes are tightly temporarily associated and consistently related to each other. Temporal association is probably most reliably taken as a time window from 2 min before, up until the onset of pain.9 The strength of the relationship between reflux episodes and chest pain is measured by the symptom index, which is percentage of chest pain episodes associated with reflux. A symptom index>50% is an arbitrary pragmatic threshold that divides the bimodally distributed group of patients,10 suggesting a causative link in those with a symptom index of >50%. Therefore, although 38% of patients in the study of Cooke et al.11 had reflux, in only 16% was the symptom index >50%. Similarly, Lam et al.12 found that while 63% of their 44 patients had reflux, only 32% had a symptom index of >75%. Breumelhof et al.13 found that 20% of their patients had acid reflux, but only 5% reached a symptom index of 75%. Most of these studies demonstrate that less than half of the patients with significant reflux have a significant symptom index. Thus one must be cautious in interpreting studies that do not use the symptom index, or use an inappropriate cut-off or too wide a time window.
Furthermore, the response to specific therapies is variable. Proton-pump inhibitors have been shown to cause a dose-dependent improvement in pain in patients with normal coronary anatomy in some14,15 but not all studies.16 The effect may not be predicted by the results of oesophageal testing,17 leading to the suggestion that a therapeutic trial of omeprazole as a management strategy is reasonable even without performing oesophageal investigations.18 However, a positive omeprazole trial might be a result of a placebo effect and cannot be taken to prove causation.
Motility disorders
There is a wide range in the reported incidence of motility disorders (Table 2
). This is partly caused by disagreement over what constitutes a significant abnormality.
Achalasia is the only disorder associated with objective histopathological changes, but this usually causes dysphagia rather than chest pain. The remaining disorders of manometry have no histopathological basis. Therefore their significance lies only in their potential to cause chest pain, and this can only be determined by the strength of their association with chest pain episodes.
‘Diffuse oesophageal spasm’ and ‘non-specific motility disorder’ are poorly associated with chest pain episodes, and are now recognized to be normal, although they were previously thought to be a potential cause of pain. There is general agreement that ‘nutcracker oesophagus’ can be a cause of chest pain; but it is defined by a high amplitude of contraction for which the diagnostic threshold has varied from 120 mMHg to, more recently, 180 mMHg19–23 (Table 4). The current threshold is derived from a control population within one laboratory,21 but this may not be universally applicable. Individual laboratories can reasonably establish their own ranges of normality, since despite high inter-laboratory variability, the intra-laboratory variability is considerably lower.24 However, results also depend on the age, sex and state of health of the study population, and it is likely that healthy young subjects are an inappropriate group for comparison.25 Cooke et al.26 showed that age- and sex-matched patients with coronary artery disease had a similar incidence of motility disorders to those with chest pain despite normal coronary anatomy. These methodological limitations may be partly responsible for the poor association between chest pain and motility disorder. Thus as few as 10% of manometric abnormalities coincide with chest pain,27 and a similarly small proportion of episodes of chest pain are associated with manometric abnormalities.3,28 As with acid reflux, the literature is sometimes limited by excessive time windows and inappropriate symptom index levels. However, with manometric abnormalities, the control period is also extremely important. Some studies use healthy volunteers, others a short asymptomatic period, but the best method is to use the patient's own pain-free 24-h period as the control.3
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Furthermore, specific therapies directed at motility disorders give inconsistent results. Cattau et al.29 showed concordant improvement of both manometry and symptoms with treatment for nutcracker oesophagus. However, an improvement in motility with calcium antagonists30 or nitrates31 may not be associated with improvement in chest pain. In a double-blind cross-over study, Richter30 randomized 20 patients with non-cardiac chest pain and nutcracker oesophagus to treatment with nifedipine or placebo. There was a significant reduction in distal oesophageal contraction amplitude and lower oesophageal sphincter pressure with nifedipine compared with placebo, but this was not associated with improvement in chest pain.
Provocative tests
A positive Bernstein acid perfusion or edrophonium test occurs when the usual pain is exactly reproduced. A positive related test is one in which other symptoms occur with the Bernstein test or motility abnormalities with edrophonium. Most centres regard a positive test as significant and a positive related test as not. These strict definitions are not always used, which is one reason for the wide range in positive tests reported in the literature. Between 8% and 60% of patients with normal coronary angiograms have a positive Bernstein test and 16–30% have a positive edrophonium test (Table 5).
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Truly positive provocation tests correlate with 24-h ambulatory monitoring with varying sensitivity and specificity32–35 (Table 6
). Edrophonium is more useful in predicting acid-related events than motility events.35 Furthermore, a positive test only proves that the oesophagus can cause pain when provoked. It can be regarded as a reliable marker for spontaneous pain.
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Why is the association between chest pain and oesophageal abnormalities sometimes weak?
In some patients, there is a robust relationship between chest pain and an objective oesophageal abnormality. These often respond well to specific therapy,17 and a causative link seems certain or highly likely. However for others there is no such clear link.
One possibility is that the oesophagus is oversensitive to normal amounts of acid or mechanical contractions. Richter et al.36 demonstrated that patients with non-cardiac chest pain had lower pain thresholds in response to oesophageal distension with intra-oesophageal balloon when compared to age- and sex-matched controls. This increase in sensitivity to distension did not seem to correlate with contractile activity or increased wall tension. Other groups have described pain provocation by acid reflux despite a normal total time duration of acid exposure.37,38 Janssens39 has proposed that the oesophagus may be sensitized by previous acid exposure either to subsequent acid reflux39 or mechanical stimulation40 or both. The term ‘irritable oesophagus’ has been used for patients sensitive to normal levels of acid and mechanical stimulation.41,42
Studies with cerebral evoked potentials from oesophageal stimuli have shown that patients with non-cardiac chest pain have lower amplitudes of evoked potential when compared to controls.43,44 Smout et al. demonstrated this with oesophageal balloon distension,43 whilst Frobert et al. demonstrated the same phenomenon with electrical stimulation.44 However there was also an associated increase in thalamic activation. This has led to a theory of remembered pain, in which a non-noxious stimulus for example acid can induce thalamic memory of a previous pain. However, this theory assumes a previous episode of pain, which may be lacking in the patient. Scott et al.45 showed that patients with non-cardiac chest pain had a high incidence of symptoms of irritable bowel syndrome. They proposed that some of these patients might have an intestinal origin for the chest pain. However other investigators have suggested that sensitivity to visceral stimuli in such patients may also extend to the heart.46 They have reproduced chest pain with right atrial boluses of saline,47 and movement of catheters within the right atrium,48 although these are clearly non-physiological stimuli whose relevance to physiological events is uncertain.
Another possibility is that the oesophageal abnormality is coincidental to, or may be caused by, or interact with, a psychological abnormality. The incidence of psychiatric diagnoses in patients with normal coronary angiography varies from 30% to 80%, consistently higher than normal subjects or patients with coronary disease.49 Most have anxiety or panic disorders,49 although depression also occurs.50 Psychiatric diagnoses51,52 are also more common in patients with oesophageal manometric abnormalities than in those with normal manometry. Anxiety has been shown to cause motility disorders,53 possibly via hyperventilation,54 but in some patients it is possible that the oesophageal abnormality is coincidental. Thus Clouse et al.55 obtained improvement in symptoms with no change in manometry using trazodone in a double-blind placebo-controlled study of 29 patients with contraction abnormalities of the oesophagus. Cognitive behavioural therapy has also been effective in a number of randomized trials.56 However, other authors have not been able to confirm the association between psychiatric abnormalities and oesophageal motility disorders.57,58
Conclusions
Despite a high incidence of oesophageal abnormalities in patients with chest pain and normal coronary anatomy, a causative link is highly likely in only a small proportion. Psychiatric or psychological abnormalities also occur commonly, and it is possible that these are causative and the oesophageal abnormality coincidental. Psychologically-based therapies are effective whether or not oesophageal abnormalities are present. We suggest that oesophageal function testing should be reserved for patients not responding to reassurance or an initial trial of antacid therapy, or in those with features such as dysphagia which directly suggest an oesophageal origin.
Notes
Address correspondence to Dr E.B.Wu, Cardiothoracic Centre, 6th Floor, East Wing, St Thomas' Hospital, Lambeth Palace Road, London S1 7EH. 
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