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.
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.
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