Is the tide finally receding? Extraesophageal symptoms and GERD

I cannot think of many areas in medicine where there are more divergent opinions than in extraesophageal manifestations (EEMs) of gastroesophageal reflux disease (GERD). There are fervent believers and deniers, with frequent swings of the pendulum depending on the latest proposed mechanism and the tests used to support them. Furthermore, the long list of purported EEMs of GERD are commonly lumped together when in fact there is evidence-based support for some but many others are linked by association alone. Given the commonality of heartburn and/or measured abnormal esophageal acid exposure in the general population, association of an EEM to these variables alone is not necessarily meaningful.

Another challenge in deciphering the cause of EEMs is the complex and varied pathophysiology proposed. In this regard, there are two camps: injury that occurs through direct exposure of supraesophageal structures to gastric refluxate and increased activation of common neural pathways between the esophagus and aeropulmonary structures. Although the former camp can infer injury of these supraesophageal strictures to noxious gastric content, little exists in the way of separating injurious from unrelated exposure by measuring volume, substrate concentration and sustained duration of exposure needed to invoke symptoms. For the latter, one can experimentally create and measure, to some degree, neurologic response to stimulation such as esophageal balloon distention or pulmonary function. Alternatively, assessing these reflexes under patient conditions with physiologic rather than experimental stimulation is difficult, to say the least.

The testing used to corroborate or refute the existence of EEMs is also insufficient to yield the information we need to better understand this field. These are often modalities, such as pH/impedance monitoring, that measure exposure of a structure generally to gastric content or more specified tests such as the measurement of pepsin in the lung where data are limited to case series. Similarly, assessing pathophysiology by demonstrating a favorable response to treatment is also lacking in EEMs. The response of EEMs to high-dose, acid-suppressing therapy and fundoplication is moderate at best in most series, even when patients are stringently limited to those with a high suspicion of GERD as the cause. This may result from the limitations outlined above and by the theory that reflux may be a co-contributor to EEMs. For example, esophageal distention by a bolus of refluxate, whether acid or non-acid, may activate neurons that innervate bronchial constriction and sensitize pharyngeal or respiratory epithelial afferent pathways. The challenge of dissecting out the existence and specific contributions of reflux in these multi-step pathways is daunting. Finally, specificity is lacking for the laryngopharyngeal signs seen by our colleagues in otorhinolaryngology. Indeed, multiple studies have demonstrated the limited accuracy of these findings.

Yet, patients are regularly referred to us with symptoms, such as cough, or because of abnormal findings seen on laryngoscopy and we are asked to evaluate and/or treat their GERD as the putative cause of their symptoms and findings. There are a few principles one might keep in mind.


Patients are regularly referred to us with symptoms or because of abnormal findings seen on laryngoscopy and we are asked to evaluate and/or treat their GERD as the putative cause of their symptoms and findings.


First, it is unlikely that one test will demonstrate a clear cause and effect relationship of GERD with the EEM. The diagnosis typically rests with multiple tests, often including a response to aggressive reflux therapy, that prove the presence of GERD and disprove other causes for the EEM. Because many of these patients will be referred as “proton pump inhibitor” failures, it is imperative that all other non-GERD causes be evaluated and treated before we consider fundoplication. This may seem obvious, but oftentimes I see that basic treatments related to allergy or speech have not been performed. In my practice, I have had to become facile with the many types of nasal sprays and lavages and simple voice treatments that may be effective for EEMs. The second principle is evaluating each EEM as an individual symptom. There are far more data evaluating chronic cough and asthma than more tenuous symptoms such as sinusitis, bruxism, or otitis. As a result, I am much more likely to pursue an evaluation for EEMs where there are clearer data implicating a relationship to GERD.

One also must consider the impact of the symptom. Throat clearing may be bothersome but is not something for which I would consider fundoplication. Alternatively, life-threatening diseases such as rejection of a transplanted lung, uncontrollable asthma, or worsening pulmonary fibrosis can often require drastic measures to control objectively demonstrated, persistent reflux when all other potential etiologies have been treated and the disease continues to progress. One must also put into context the symptom and the patient. Chronic cough may threaten the livelihood of persons whose profession involves public speaking or singing. In these patients, a lower threshold of success with some type of mechanical repair may be more acceptable than in patients in whom the symptom is primarily bothersome.

Just as the causes of EEMs of GERD may be multifactorial, so must be the treatment in many of these patients. This represents the third principle. As gastroenterologists, we need to decide how many of these treatments to implement as opposed to leaving some to specialists. With the benefit of being at an academic medical center, it has been easy for me to assemble a medical team to care for patients with EEMs that includes specialists in pulmonary medicine, otolaryngology, allergy, speech therapy and surgery. You will also be surprised at how much extra knowledge, often with simple therapies, you learn from your colleagues and learn to apply yourself.

Patients have to be re-educated on the role or lack thereof of GERD as the cause of their symptoms. This is particularly true when discussing aggressive and riskier therapies. Some day we will be better at understanding, diagnosing and treating EEMs. Until then, this medical landscape remains rocky with some deep chasms if we perform fundoplication in the wrong patient. A multidisciplinary evaluation, avoiding the overinterpretation of tests and a careful approach to therapy will help level the path for effective treatment.

Dr. Katzka is on the advisory board for Shire and Celgene. Dr. Katzka is on the Clinical Gastroenterology and Hepatology editorial board.

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