COMMENTARY

Atypical Manifestations of Gastroesophageal Reflux Disease

Michael F. Vaezi, MD, PhD, MSEpi

Disclosures

October 27, 2005

In This Article

Introduction

Gastroesophageal reflux disease (GERD) may manifest typically with heartburn and regurgitation or atypically as laryngitis, asthma, cough, or noncardiac chest pain. The diagnosis of these atypical manifestations may be difficult for primary care physicians because most patients do not have heartburn or regurgitation. Diagnostic tests have low specificity and it is difficult to establish a cause-and-effect association between GERD and atypical symptoms. Response to aggressive acid suppression is often the most commonly employed initial tool to indicate GERD etiology in a patient with atypical symptoms.

Symptoms Associated With GERD

GERD commonly presents as heartburn and regurgitation, experienced daily by 7% and monthly by up to 40% of the US population.[1] In addition to heartburn and regurgitation, GERD may present with other less typical symptoms. Most common "atypical" manifestations may include ear, nose, and throat (ENT); pulmonary (chronic cough or asthma); or cardiac (noncardiac chest pain) symptoms (Figure 1).[2,3,4,5] Patients with atypical manifestations may not have concomitant complaints of heartburn. Classic reflux symptoms are absent in 40% to 60% of asthmatics, in 57% to 94% of patients with ENT complaints,[4,5] and in 43% to 75% of patients with chronic cough in whom reflux is suspected as the etiology. Due to the latter, many patients may not be appropriately diagnosed initially. Thus, GERD should be included in the differential diagnosis of patients presenting with atypical symptoms,[3,4] especially when alternative diagnoses are excluded.

Figure 1.

Atypical GERD.

Key: ENT = ear, nose, throat; CA = cancer

Two mechanisms have been proposed to explain atypical symptoms of GERD: microaspiration of gastric contents and vagally mediated events.[3,4] A disturbance in any of the normal protective mechanisms may allow direct contact of noxious gastroduodenal contents with the larynx or the airway, resulting in laryngitis, chronic cough, or asthma. As to indirect mechanisms, embryologic studies show that the esophagus and bronchial tree share a common embryologic origin and neural innervation via the vagus nerve. Acidification of the distal esophagus can stimulate acid-sensitive receptors, resulting in noncardiac chest pain, cough, or bronchoconstriction and asthma.

Many pulmonary conditions are associated with GERD (Figure 1); the strongest association appears to be with asthma.[6,7] Of the 15 million persons in the United States with asthma, 50% to 80% may also have GERD. Most patients with asthma complain of coexisting heartburn,[7] and up to 75% of patients have excess esophageal acid exposure by pH monitoring.[7] Although many patients with refractory asthma may improve on acid-suppressive therapy, the cause-and-effect relationship between asthma and GERD is difficult to establish; this is because either condition may induce the other. Asthma attacks can cause esophageal reflux of gastric contents by creating a negative intrathoracic pressure, overcoming the lower esophageal sphincter barrier.[7] Alternatively, gastroesophageal reflux -- either by direct aspiration or indirectly by stimulating the distal esophageal sensory vagal nerve -- may induce bronchospasm and asthma. Additionally, it is recognized that asthma medications may promote GERD. Theophylline, beta 2-agonists, and even prednisone may increase esophageal exposure to acid reflux by affecting protective mechanisms against GERD.[8]

The patient's medical history is the most important clue in diagnosing GERD as the potential etiologic factor in asthmatics. Indeed, certain "clues" can be helpful in identifying GERD-related asthma. Patients who should be suspected of having GERD include those with nocturnal cough and worsening asthma symptoms after eating big meals, drinking alcohol, or being in the supine position; those with asthma presenting initially in adulthood; and those who have poor control of asthma symptoms with their usual asthma medications. Additionally, symptoms of heartburn and regurgitation before the onset of asthma may suggest reflux as the causal factor.

Chronic cough (cough duration greater than 3 weeks) accounts for up to 38% of referrals to pulmonary physicians and is one of the most common clinical presentations in primary care practice. GERD, along with postnasal drip and asthma, is 1 of the 3 most common causes of chronic cough in all age groups.[9,10] More than 1 etiologic factor may be the cause of chronic cough in many patients. Similar to asthma, a cause-and-effect association is often difficult to establish because chronic cough can induce GERD[9,10] as well as be caused by it.

GERD-related cough occurs predominantly during the day and in the upright position. It is often nonproductive and long-standing in nature. Cough may be the sole manifestation of GERD in more than 50% of patients,[9] with many denying symptoms of heartburn or regurgitation. GERD should be suspected in patients with cough whose symptoms have been chronic, not smokers, not on any cough-inducing medications (such as ACE inhibitors), with normal chest x-ray, and in those in whom there is no evidence of asthma or postnasal drip.

There is increasing evidence that GERD may be associated with chronic laryngeal signs and symptoms.[4,5] This is often referred to as "reflux laryngitis," "ENT reflux," or recently as "laryngopharyngeal reflux." Laryngeal symptoms often associated with GERD may include hoarseness, throat clearing, cough, sore or burning throat, dysphagia, and globus. Hoarseness is caused by GERD in an estimated 10% of all cases. Chronic laryngitis and difficult-to-treat sore throat are associated with acid reflux in as many as 60% of patients.[4] GERD is the third leading cause of chronic cough (after sinus problems and asthma), accounting for 20% of cases.[9,10] Globus sensation (a feeling of choking or a lump in the throat more prominent between meals and generally disappearing at night) may be caused by GERD in 25% to 50% of cases. The most common mechanism for laryngeal irritation due to GERD is via direct contact with the gastroduodenal contents.[4] Recent studies show that pepsin and conjugated bile acids in acidic pH ranges result in laryngeal tissue inflammation, whereas nonacid exposure of any gastroduodenal agents does not cause injury.[11]

Clinically, patients are initially evaluated by primary care physicians and subsequently referred to ENT physicians for laryngoscopy. Laryngoscopic evaluation is usually the initial test in patients suspected of having GERD. Normal laryngeal tissue is often smooth and glistening in nature; however, GERD may be responsible for causing laryngeal pathology such as ulcerations, vocal cord nodules, granuloma, or even leukoplakia and cancer. Many laryngeal signs have been attributed to GERD, including erythema and edema of the posterior larynx, vocal cord polyps, and granuloma and subglottic stenosis. However, most signs are not specific for GERD and may also occur as a result of other laryngeal irritants, such as smoking, alcohol, postnasal drip, viral illness, voice overuse, or environmental allergens. This may explain why many patients with laryngeal signs do not respond to GERD therapy. Recent studies suggest that laryngeal abnormalities involving the vocal cords and medial arytenoid walls may be more specific for GERD, suggesting that the subjective laryngeal signs of erythema and edema currently in common use should be abandoned in an effort to increase confidence in GERD diagnosis.[4]

Approximately 20% to 30% of patients with chest pain exhibit normal or insignificant cardiac catheterization findings and are classified as having "noncardiac" chest pain.[12,13] GERD may be the most common cause of noncardiac chest pain. However, spastic esophageal motility disorders such as nutcracker esophagus or diffuse esophageal spasm may also be important etiologies for patients' symptoms once GERD is excluded. Recent data suggest that GERD may account for symptoms in 25% to 55% of patients with noncardiac chest pain.[12] Direct contact of the esophageal mucosa with gastroduodenal agents such as acid and pepsin is the most likely cause of these symptoms.[12,13]

Initially, it may be difficult to distinguish GERD-related chest pain from angina. GERD-related chest pain can be squeezing or burning in nature, substernal in location, and may radiate to the back, neck, jaws, or arms. The pain may be worse after meals and wake the patient from sleep. Exercise may induce GERD, resulting in chest pain, which can be indistinguishable from chest pain due to coronary disease. Symptoms may last for minutes or hours and are often relieved by antacids or acid-suppressive agents. Similar to GERD-related asthma patients, many individuals may also report a history of heartburn and regurgitation; however, up to 20% of patients may have silent reflux.[12] Given the serious dilemma of distinguishing GERD-related chest pain from coronary disease, the clinician should always rule out the latter before considering the former.

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