Atypical Manifestations of Gastroesophageal Reflux Disease

Michael F. Vaezi, MD, PhD, MSEpi


October 27, 2005

In This Article


Patients with atypical GERD are often more difficult to treat, and as a group, they have an unpredictable response to acid-suppressive therapy. The latter is most likely due to overdiagnosis of the condition. Response of these patients to therapy may represent the true prevalence of GERD in this population; GERD may be only 1 of several etiologies causing these patients' symptoms and signs. Other such etiologies may include coexistence of asthma, GERD, cough, postnasal drip, and other aggressive factors, such as alcohol and smoking. Thus, given the poor specificity of diagnostic testing, response to empiric therapy is currently the "gold standard" for diagnosing GERD in this group of patients. There are currently no accepted protocols for the most cost-effective treatment strategy for patients with atypical GERD. At best, histamine-2 receptor antagonists (H2RAs) usually produce only mild-to-moderate improvement in symptoms.[4,12] Although not approved by the US Food and Drug Administration for treatment of atypical GERD, recent studies recommend using the more effective proton-pump inhibitors (PPIs), often given twice daily.[16,17,18] Clinical response rates ranging from 60% to 98% have been reported with medical therapy.[4,12] This wide range in treatment response is most likely due to differences in subspecialty practices and differences in patient populations.

Previous studies using H2RAs have produced only mild-to-moderate improvements, at best.[5,19] As mentioned, recent studies have used the more effective acid-suppressive agents, the PPIs.[20,21,22,23] However, due to lack of consensus, most studies employed PPIs at varying doses and different durations of treatment. Because human studies suggest that nocturnal gastroesophageal reflux is more common in this group of patients,[24] the majority of studies used nocturnal dosing of PPIs, increased to twice-daily dosing in nonresponders. The PPIs are commonly given before meals in most studies. For example, Kamel and colleagues[19] and Wo and colleagues[21] used 40 mg of omeprazole at bedtime, and increased the dose to 40 mg twice daily in nonresponders after 2 months of treatment. However, each study reported a different rate of treatment response. (Kamel and colleagues found a 92% response rate, whereas Wo and colleagues reported a 67% response rate in their patients.) Our recent data confirm the response rate reported by the latter group, finding a 52% symptomatic response rate with twice-daily dosing of PPIs at 4 months.[25] On the basis of these studies, it is generally accepted that PPIs should be used at twice-daily dosing for empiric therapy of patients with ENT signs and symptoms.[2,4]

Meanwhile, recent placebo-controlled studies in this area[26,27,28,29,30] show that aggressive PPI therapy is equivalent to placebo in symptom relief for throat complaints. Such findings once again highlight the complexity of the association between GERD and extraesophageal symptoms and reflux. Because many individuals have GERD, the specific association between extraesophageal symptoms and GERD is often difficult to establish.

Surgical intervention is usually less effective in patients with atypical GERD than in patients with typical GERD symptoms of heartburn and regurgitation.[4,12] This again reflects the multifactorial nature of atypical GERD symptoms in many patients. Recent studies advise caution regarding the use of fundoplication in patients with atypical GERD who are unresponsive to PPI therapy.[31]

Studies show that response to surgical fundoplication is dependent on medical response to PPIs.[32,33,34] Recently, Swoger and colleagues[32] reported no benefit of fundoplication in patients with chronic laryngitis suspected to be GERD-related and who did not respond to twice-daily PPIs. Similarly, So and colleagues[33] studied 150 consecutive patients after fundoplication and found that only 56% had relief of atypical symptoms, whereas typical heartburn symptoms resolved in 93%. Furthermore, the only preoperative predictors of relief of atypical symptoms were prior clinical response to pharmacologic acid suppression and abnormal hypopharyngeal pH results. More specifically, a recent uncontrolled case series[34] evaluating the outcome of patients with laryngopharyngeal reflux reported 84% symptom improvement post fundoplication. However, this study again demonstrated a poor outcome in those patients previously unresponsive to PPI therapy.

A potential treatment algorithm for atypical GERD is shown in Figure 2. Initial empiric therapy with twice-daily PPIs for 2-3 months is generally recommended.

Treatment algorithm for atypical GERD.

For patients with laryngitis, longer treatment duration may be needed for resolution of all laryngeal inflammation. In patients with asthma, up to 3 months of treatment may be required to see improvement in bronchial symptoms.[4] However, many patients with atypical symptoms may report a partial response by 6-8 weeks of therapy. For those patients who have minimal or no improvement in their symptoms by 4 months of twice-daily PPI therapy, 24-hour pH/impedance monitoring on therapy may help identify that small subgroup that continues to have abnormal esophageal acid or nonacid exposure. However, in the majority of patients, lack of response is an indication that GERD is most likely not an etiologic factor in their atypical symptoms. In this subgroup of patients, other causes of symptoms should be investigated.


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