Gastroesophageal reflux disease (GERD) is a highly prevalent condition that affects nearly 20% of an urban population and can significantly impact both health care costs as well as a patient’s quality of life.1 In GERD, the reflux of stomach contents causes symptoms such as heartburn, regurgitation, pain in the chest, belching, and water brash, and can lead to more serious complications as well.

Treatment options for GERD include lifestyle modifications, pharmacological therapy, endoscopic therapy, and surgery.1 Proton-pump inhibitors (PPIs), which inhibit the secretion of gastric acid, are the mainstay pharmacological treatment option for patients with GERD. Unfortunately, it has been found that 20-42% of patients fail PPI therapy partially or completely, which leads to the continuation of heartburn symptoms, the manifestation of new symptoms, or the relapse of previously healed erosive esophagitis.

Refractory heartburn, or the persistence of heartburn despite treatment with a double dose of PPI therapy over at least an 8–12 week period, is believed to be caused by several different mechanisms (Table 1).1 Because the treatment of refractory heartburn is based on the underlying mechanism of the disease, proper diagnosis of the cause is a key step in treating a patient.

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Several diagnostic methods are available to assess patients with refractory heartburn.1 Once a patient meets the criteria for refractory heartburn, upper endoscopy should be used to rule out the possibility of anatomical abnormalities found in either the esophagus or the stomach. For patients with unrevealing endoscopic findings, reflux testing is the next appropriate step. For patients with no history of GERD and not taking PPI therapy, the 24-hour pH test should be used. On the other hand, the multichannel intraluminal impedance-pH test is appropriate for patients with a documented history of GERD or for those taking PPI therapy.

Once the underlying cause of a patient’s refractory heartburn is determined, appropriate therapy can be initiated.1 Figure 1 details the algorithm for the treatment of refractory heartburn based on the possible underlying mechanisms of the disease. Additionally, each mechanism is discussed in further detail in the remaining portion of this review.

Functional heartburn is an esophageal disorder that is caused by a change in esophageal pain perception.1 Patients with functional heartburn display similar symptoms seen in GERD and most often complain of a burning retrosternal discomfort. To properly diagnose a patient with functional heartburn, it is important for providers to rule out GERD, eosinophilic esophagitis, and esophageal motor disorders. Functional heartburn is typically treated with pain modulators, however, some evidence supports the use of psychotherapy, acupuncture, and hypnosis.

One of the most important mechanisms to consider for patients with persistent heartburn symptoms is poor adherence and/or compliance to PPI therapy.1 It is not only important for providers to assess whether a patient is compliant to their medication, but also to determine whether the medication is being administered properly. Approximately 70% of primary care physicians and 20% of gastroenterologists believe that PPIs should be taken at bedtime and do not consider administration in relation to food intake important. However, because PPIs only inhibit active proton pumps, it is imperative for providers to counsel patients to take their medication prior to a meal, as administration with or after a meal has shown to diminish its effect.

Another important mechanism to consider in patients with refractory heartburn is the presence of comorbidities in GERD patients.1 Common comorbidities include hypertension, dyslipidemia, arthritis, diabetes, depression, and obesity, which can exacerbate GERD symptoms or alter esophageal sensitivity. Additionally, research has shown that certain medications or drug classes used to treat these disorders can lead to alterations in therapeutic responses to PPIs. Some examples include statins, enalapril, sibutramine, fluoxetine, metformin, and nonsteroidal anti-inflammatory drugs.

Although generally uncommon, genetic variations in the metabolism of PPIs may be another factor to consider in patients with refractory heartburn.1 In the liver, cytochrome P450 2C19 (CYP2C19) metabolizes PPIs. It has been shown that patients with a CYP2C19*17 polymorphism rapidly metabolize PPIs, thus leading to a lower rate of erosive esophagitis healing. On the other hand, patients who are “slow” or “intermediate” metabolizers have an increased rate of erosive esophagitis healing. Individualizing the dosing regimen of a patient’s PPI therapy based on their CYP2C19 genotype has been suggested, however, this therapeutic strategy can be costly and is not currently readily available.

Another important mechanism of refractory heartburn is reflux hypersensitivity.1 Recently, the use of pH-impedance testing has become more widespread and has aided in identifying patients with weakly acidic reflux, neutral reflux, and weakly alkaline reflux. Studies have shown that the perception of reflux and presence of GERD symptoms is increased in patients due to the “proximal migration of weakly acidic reflux and the presence of mixed liquid-gas reflux.” Unfortunately, the management of patients with weakly acidic reflux as well as residual reflux (acidic or non-acidic) remains challenging as there are limited treatment options and studies in these patients are lacking.

Autoimmune skin disorders such as epidermolysis bullosa, pemphigus vulgaris, cicatricial pemphigoid, and lichen planus have been found to affect the esophagus and lead to refractory heartburn.1 This mechanism typically affects middle-aged women with heartburn and dysphagia who present with skin lesions not necessarily characteristic of the disease. Treatment includes referral to a dermatologist with experience in immunosuppression.

Although a relatively uncommon mechanism of refractory heartburn, eosinophilic esophagitis is something to consider in patients complaining of heartburn, chest pain, and dysphagia.1 This disorder is characterized by an increase in esophageal eosinophilia and is not responsive to acid suppression therapy.

Refractory heartburn is a prevalent condition with many different underlying mechanisms.1 Accurately diagnosing the cause of a patient’s refractory heartburn is imperative, as it will provide guidance to the appropriate therapeutic approach. Despite having various treatment options, refractory heartburn continues to be a challenging condition for both providers as well as for patients.

References

1. Domingues G, Moraes-Filho JP, Fass R. Refractory Heartburn: A Challenging Problem in Clinical Practice. Dig Dis Sci. 2018 Jan 20; DOI: https://doi.org/10.1007/s10620-018-4927-5.

Table 1 — Mechanisms of Refractory Heartburn1

• Reflux hypersensitivity
• Functional heartburn
• Poor compliance and/or adherence
• Misdiagnosis of GERD
• Existence of comorbidities 
• Differences in genotypes 
• Residual gastroesophageal reflux
• Eosinophilic esophagitis
• Autoimmune skin disorders


Figure 1 — Refractory Heartburn Treatment Algorithm1 (click on figure to open larger version)