Are the Persistent Symptoms to Proton Pump Inhibitor Therapy Due to Refractory Gastroesophageal Reflux Disease or to Other Disorders?

Abstract

BACKGROUND: Gastroesophageal reflux disease (GERD) is a clinical condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Transient lower esophageal sphincter relaxation is the main pathophysiological mechanism of GERD. Symptoms and complications can be related to the reflux of gastric contents into the esophagus, oral cavity, larynx and/or the lung. Symptoms and other possible manifestations of GERD are heartburn, regurgitation, dysphagia, non-cardiac chest pain, chronic cough, chronic laryngitis, asthma and dental erosions. The proton pump inhibitor (PPI) is the first-choice drug and the most commonly medication used for the treatment of GERD. The most widespread definition of Refractory GERD is the clinical condition that presents symptoms with partial or absent response to twice-daily PPI therapy. Persistence of symptoms occurs in 25% to 42% of patients who use PPI once-daily and in 10% to 20% who use PPI twice-daily. OBJECTIVE: The objective is to describe a review of the current literature, highlighting the causes, diagnostic aspects and therapeutic approach of the cases with suspected reflux symptoms and unresponsive to PPI. CONCLUSION: Initially, the management of PPI refractoriness consists in correcting low adherence to PPI therapy, adjusting the PPI dosage and emphasizing the recommendations on lifestyle modification change, avoiding food and activities that trigger symptoms. PPI decreases the number of episodes of acid reflux; however, the number of “non-acid” reflux increases and the patient continues to have reflux despite PPI. In this way, it is possible to greatly reduce greatly the occurrence of symptoms, especially those dependent on the acidity of the refluxed material. Response to PPI therapy can be evaluated through clinical, endoscopic, and reflux monitoring parameters. In the persistence of the symptoms and/or complications, other causes of Refractory GERD should be suspected. Then, diagnostic investigation must be initiated, which is supported by clinical parameters and complementary exams such as upper digestive endoscopy, esophageal manometry and ambulatory reflux monitoring (esophageal pH monitoring or esophageal impedance-pH monitoring). Causes of refractoriness to PPI therapy may be due to the true Refractory GERD, or even to other non-reflux diseases, which can generate symptoms similar to GERD. There are several causes contributing to PPI refractoriness, such as inappropriate use of the drug (lack of patient adherence to PPI therapy, inadequate dosage of PPI), residual acid reflux due to inadequate acid suppression, nocturnal acid escape, “non-acid” reflux, rapid metabolism of PPI, slow gastric emptying, and misdiagnosis of GERD. This is a common cause of failure of the clinical treatment and, in this case, the problem is not the treatment but the diagnosis. Causes of misdiagnosis of GERD are functional heartburn, achalasia, megaesophagus, eosinophilic esophagitis, other types of esophagitis, and other causes. The diagnosis and treatment are specific to each of these causes of refractoriness to clinical therapy with PPI.

Salivary Pepsin as an Intrinsic Marker for Diagnosis of Sub-types of Gastroesophageal Reflux Disease and Gastroesophageal Reflux Disease-related Disorders

“…Previous studies have shown that there is no significant difference in the total episodes of reflux determined by 24-hour pH monitoring in unresponsive patients after PPI treatment, and the total episodes of weak-acid and non-acid reflux in refractory GERD patients were significantly more than that in the control group. 42,43 In addition, only 5.0% of reflux symptoms were related with acid reflux, while 16.7% were related to non-acid reflux, suggesting most unresponsive GERD patients after PPI treatment are caused by non-acid reflux. 42,43 Unresponsiveness after PPI treatment in patients with GERD is also associated with poor compliance, psychiatric comorbidities, and functional gastrointestinal disorders.…”

“…42,43 In addition, only 5.0% of reflux symptoms were related with acid reflux, while 16.7% were related to non-acid reflux, suggesting most unresponsive GERD patients after PPI treatment are caused by non-acid reflux. 42,43 Unresponsiveness after PPI treatment in patients with GERD is also associated with poor compliance, psychiatric comorbidities, and functional gastrointestinal disorders. 44,45 After taking PPI, gastric acid secretion is reduced, and the pH in the stomach rises to 4.0 or higher, inhibiting the activation of pepsinogen.…”

Introductory Chapter: Gastroesophageal Reflux Disease

“…Their dosages range from 20 to 40 mg daily. PPI will cure the esophagitis up to 90%; 80% will recur within 1 year if treatment is stopped [14][15][16][17].…”

Salivary microbiome with gastroesophageal reflux disease and treatment

“…Gastroesophageal reflux disease (GERD) is a condition that is believed to occur due to dysfunction of the lower esophageal sphincter, which is responsible for preventing back flow of stomach contents into the esophagus 6 . This regurgitation of gastric juices into the esophagus, oropharyngeal and oral cavity lowers their pH 7 . In the esophagus, this can contribute to chronic inflammation, histological changes in the mucosal cells lining the distal esophagus, and increased risk for esophageal cancer 8 , 9 .…”