GERD: Navigating a Diagnostic Dilemma

Gastroesophageal reflux disease (GERD), already one of the most common gastrointestinal conditions, is increasing in prevalence, yet it remains a difficult disease to diagnose.

In North America, estimates range from 18% to 28%, with more than 4.7 million medical visits for GERD or reflux esophagitis taking place annually in the United States.

Fundamentally, GERD is “a condition in which the reflux of gastric contents into the esophagus results in symptoms and/or complications.” It is “objectively defined by the presence of characteristic mucosal injury seen at endoscopy and/or abnormal esophageal acid exposure demonstrated on a reflux monitoring study.”

The typical GERD symptoms are heartburn or regurgitation. But there is a wide range of symptoms that could be attributable to GERD alone, may signify the presence of GERD and another condition, or could be the result of a separate disease altogether.

Gastrointestinal “alarm” symptoms include difficult or painful swallowing, unintentional weight loss, gastrointestinal bleeding, anemia, and persistent vomiting.

Additionally, there are atypical, extra-esophageal symptoms, such as persistent cough, sore throat, pharyngitis, laryngitis, chest pain, pulmonary fibrosis, and asthma, as well as dental erosion and periodontal disease.

“These symptoms may be coexistent or associated with GERD, but they’re challenging to investigate and manage clinically because there can also be differences between association and causation,” Amit Patel, MD, professor of medicine, Duke University, Durham, North Carolina, told Medscape Medical News. “Just because these symptoms occur in the setting of GERD doesn’t necessarily mean that GERD has caused these symptoms.”

This complexity can make figuring out the proper diagnosis difficult and may make referral to specialists and a multidisciplinary treatment strategy necessary.

Often, the best approach is thoughtful, multidisciplinary team investigation with diagnostic evaluation not only in gastroenterology but also potentially with our colleagues in pulmonology, allergy, otolaryngology, and/or speech pathology, Patel said.

Not a Single Entity

The pathophysiology of GERD includes impairment of the anti-reflux barrier, which consists of the lower esophageal sphincter (LES) and crural diaphragm, coupled with impaired esophageal clearance and alterations in esophageal mucosal integrity. Reflux esophagitis arises when refluxed gastric juice triggers the release of cytokines and chemokines that attract inflammatory cells, contributing to symptoms.

Other contributors to symptoms include decreased salivary production, delayed gastric emptying, and esophageal hypersensitivity.

For these reasons, GERD is not a single entity but rather a condition with “multiple phenotypic presentations and different diagnostic considerations.”

There are two different pathways through which reflux might contribute to extra-esophageal symptoms, Patel explained.

“One is the reflux pathway: Gastric content rising through the esophagus can worsen inflammation through microaspiration,” he said. On the other hand, in the reflex pathway, “reflux contributes to increased inflammation in the larynx or airways through vagally mediated or neurologic airway reactions.”

Common Comorbidities

GERD is frequently comorbid with asthma, said Amy Eapen, MD, MS, senior staff allergist, Henry Ford Health System, and clinical assistant professor, Michigan State University College of Human Medicine, Wayne State University School of Medicine, Detroit. About 20% of patients with asthma can have GERD, she noted.

Laryngopharyngeal reflux (LPR) is also a common comorbidity.

“When patients present to us, we screen for GERD when assessing for asthma,” Eapen said. “Treatment of GERD can improve symptoms of asthma and laryngitis/pharyngitis.”

GERD can “mimic asthma, and asthma can mimic GERD,” she said. Patients can present with wheezing and upper airway sounds that might represent reflux or asthma flares. “Our job is to decide if these are two conditions that coexist or if one or other condition is responsible for the symptoms.”

In determining the cause, Eapen and colleagues collaborate with gastroenterologists, pulmonologists, otolaryngologists, and respiratory therapists.

“We know that if you have one atopic condition, such as asthma, allergic rhinitis, atopic dermatitis, or food allergies, you may have other comorbid atopic conditions,” Eapen said. “Gastric reflux itself can cause damage to the upper airway and respiratory tract by the mechanism of reflux: Microaspirations of gastric content can affect the lower respiratory tract, damaging the epithelium. By damaging that tissue, it can cause inflammation and lead to cytokine release and the effects we see in asthma.”

But asthma, in turn, is an obstructive airway disease that can cause hyperinflation of the lungs, and “hyperinflated lungs lead to increased intrathoracic pressure and an increased pressure gradient from the chest to the abdomen. This can lead to herniation of the LES, with worsening regurgitation of stomach contents,” she explained.

Moreover, asthma medications (beta-adrenergic agonists, theophylline, and high doses of oral corticosteroids) may exacerbate GERD by reducing LES pressure, leading to the reflux of gastric content into the esophagus. The regurgitation of gastric content into the laryngopharynx can cause both mechanical and pH-sensitive stimulation, resulting in the sensitization of the peripheral nerves that mediate cough, regardless of whether the content is acidic or nonacidic.

One study suggests that even in the absence of respiratory symptoms, patients with GERD have a significantly higher rate of airway resistance than those without.

Eapen said that the relationship is thought to be bidirectional. With severe asthma, GERD is more likely; in turn, severe uncontrolled reflux increases the risk for asthma.

Two longitudinal analyses, encompassing an 11-year period, confirmed this bidirectionality. The first study compared patients with GERD to matched controls without GERD. The GERD group demonstrated a 1.46-fold higher hazard ratio for asthma compared with the control group. The second study compared patients with asthma to control participants without asthma. The asthma group showed a 1.36-fold higher hazard ratio for GERD compared with the control group.

Another study investigated the evidence for shared genetic architecture between asthma, allergic rhinitis, and eczema with GERD by using structural equation models and polygenic risk score analyses applied to three Swedish twin cohorts. A genetic correlation between GERD and asthma, but not the other conditions, was found, as well as bidirectional and phenotypic associations. A “common genetic architecture unique to asthma and GERD” may explain the comorbidity, the researchers concluded.

Other Overlapping Conditions

Chronic cough and postnasal drip (PND) are two other extra-esophageal GERD symptoms that may overlap with each other or other conditions. GERD is one of the three main causes of chronic cough, along with asthma and PND. In up to 75% of GERD-related cough cases, reflux is otherwise clinically silent.

Attempting to identify the cause of PND-induced cough also is complicated by GERD, which is associated with a high prevalence of upper respiratory symptoms and therefore can either coexist or mimic PND.

Additionally, GERD and asthma are associated with vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO), which is defined as “wheezing due to adduction of the true and false vocal cords during inspiration.”

VCD/ILO may be triggered by anxiety and dysfunctional breathing, but activation of laryngeal reflexes may occur if the process is augmented by GERD, LPR, low forced expiratory volume in 1 second value, sinusitis, psychiatric conditions, or intense exercise.

It is hypothesized that the vagal nerve mediates afferent signals to the brainstem and efferent responses to laryngeal muscles, which aligns with the concept of the reflex pathway in GERD, Eapen said.

Symptoms particularly suggestive of each condition are listed in Table, but there is a good deal of overlap between presenting symptoms of these conditions.

Table. Suggestive Symptoms by Condition

The Diagnostic Journey

In patients with the classic GERD symptoms of heartburn and/or regurgitation with no alarm symptoms, the American College of Gastroenterology (ACG) recommends starting with an 8-week trial of empiric proton pump inhibitors (PPIs) once daily before a meal and then attempting to discontinue the PPIs in patients who respond to this regimen.

Diagnostic endoscopy is warranted if symptoms don’t respond or return 2-4 weeks after PPI discontinuation.

If alarm features (ie, trouble swallowing, unintentional weight loss, gastrointestinal bleeding, anemia, or persistent vomiting) are present, the most appropriate step is often upper endoscopy to examine the esophagus, Patel said. “This helps us evaluate not only for evidence or complications of GERD, such as erosive esophagitis or Barrett’s esophagus, but also alternate, non-GERD etiologies.”

The ACG recommends evaluation for non-GERD causes in patients with possible extra-esophageal symptoms. In those with extra-esophageal symptoms but not typical symptoms, the guidelines call for reflux testing for evaluation before PPIs.

Ambulatory reflux monitoring can be helpful to objectively quantify reflux, Patel noted.

There are two broad types of ambulatory reflux monitoring. The 24-hour pH test (often with impedance) utilizes a transnasal catheter with sensors to detect reflux, while the wireless esophageal pH probe placed at endoscopy provides more longitudinal information (up to 4 days) about the reflux burden that the patient is experiencing.

Both tests allow patients to press buttons to log when they experience symptoms to help assess symptom-reflux association, Patel said.

For patients with extra-esophageal and typical GERD symptoms, the ACG suggests considering a trial of twice-daily PPI therapy for 8-12 weeks before additional testing.

Other diagnostic procedures include laryngoscopy to look for nonspecific signs of laryngeal irritation and inflammation (edema and erythema, particularly in the posterior region). To determine if the patient has VCD/ILO, direct visualization of the condition on laryngoscopy is necessary. If VCD/ILO is suspected, a dynamic CT of the larynx can be performed once the patient has been stabilized. Allergy testing can be helpful in homing in on the cause of PND and asthma.

Many patients also require a diagnostic workup for asthma, which includes spirometry to demonstrate the potential presence of obstruction and assess reversibility. The asthma control test, a patient-based tool, can help identify patients with uncontrolled asthma and monitor their response to treatment over time.

In patients with chest pain, cardiovascular conditions should be ruled out, after which objective testing for GERD is recommended.

Treating GERD and Its Comorbidities

Lifestyle modifications are “first line and key” for GERD treatment, Eapen said.

According to the ACG guidelines, such modifications include weight loss in patients who are overweight/obese, avoidance of large meals within 2-3 hours of bedtime and dietary triggers (eg, fried foods, caffeine, or alcohol), and elevation of the head of the bed by 6-8 inches.

For patients who require maintenance medication, the ACG recommends the lowest daily PPI dose that effectively controls symptoms and maintains healing of reflux esophagitis.

Other agents include antacids, histamine-2 receptor antagonists (H2RAs), prokinetic agents, alginate, and sucralfate. However, antacids have limited long-term effectiveness. The ACG recommends against prokinetic agents unless there is objective evidence of gastroparesis and against sucralfate unless the patient is pregnant. H2RAs may be a beneficial add-on to PPIs on an as-needed basis for patients with nocturnal symptoms.

Extra-esophageal symptoms don’t necessarily respond as well or as consistently to PPIs, Patel noted.

Potassium-competitive acid blockers (P-CABs), now available in the United States, are a promising therapeutic option for patients with GERD, according to Patel, who served as the lead author of a recent clinical practice update on P-CABs from the American Gastroenterological Association.

P-CABs “may be associated with more potent acid suppression than PPI formulations,” he said. For GERD, P-CABs can be effective “for patients with more severe erosive esophagitis or those who fail twice-daily PPI therapy.”

In light of their rapid onset of acid inhibition, P-CABs “may also have utility for the on-demand therapy of reflux-associated heartburn symptoms,” Patel added.

Asthma, allergies, and any other comorbidities should be treated appropriately, whether GERD is present or absent, especially if a trial of PPI therapy doesn’t bring relief.

For PND, avoidance of allergens identified on allergy testing is the first-line approach, followed by nasal steroid treatment and antihistamines, treatment of concomitant infections, and correction of associated sinonasal anatomical abnormalities.

If first-generation antihistamines or decongestants don’t bring partial or complete resolution of chronic cough, patients should undergo sinus imaging.

Additional allergy skin testing can ascertain whether there’s an environmental cause for persistent upper airway symptoms. Other diagnostic testing may yield further clues that will inform additional treatments.

Patients may use complementary/alternative therapies to self-treat GERD and some of its comorbidities. Among the strategies that studies have found to be helpful are traditional Chinese medicine, including acupuncture and Chinese herbs; transcutaneous electrical acustimulation; behavioral therapy, including cognitive behavioral therapy (CBT); diaphragmatic breathing therapy; and mindfulness-based therapy.

Some evidence suggests that breathing exercises, CBT, and mindfulness-based approaches are useful in asthma treatment as well.

For VCD/ILO, speech therapy, diaphragmatic breathing and other breathing techniques, and psychological counseling can be helpful.

Patel reported being a consultant for Medpace, Renexxion, and Sanofi. Eapen reported no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).