Refractory Gastroesophageal Reflux

Refractory Gastroesophageal Reflux

Despite treatment with proton pump inhibitors (PPIs), some patients with gastroesophageal reflux disease (GERD) continue to have reflux symptoms or endoscopic evidence of esophagitis. Approximately 10 and 40 percent of patients with GERD fail to respond symptomatically, either partially or completely, to a standard dose PPI [1-4]. Failure of the PPI treatment to resolve GERD-related symptoms has become the most common presentation of GERD among clinical gastroenterologists.

Most patients with GERD who do not respond to a PPI have either nonerosive reflux (NERD) or functional heartburn. In patients with NERD the pooled symptomatic response rate to PPI once daily at four weeks is 37 percent [5,6]. In contrast, in patients with erosive esophagitis, which accounts for 30 to 40 percent of the GERD population, the pooled symptomatic response rate is 56 percent [5].

The definition of refractory GERD is controversial. Because refractory GERD is a patient-driven phenomenon, PPI failure in patients who seek medical attention will exhibit different frequency and/or severity of GERD-related symptoms. As a result, any attempt to narrow the definition of refractory GERD might exclude many true sufferers [7].

Most investigators believe that only patients with GERD who exhibit partial or lack of response to PPI twice daily should be considered as PPI failures. However, we suggest that lack of satisfactory symptomatic response to PPI once a day is sufficient to consider patients as PPI failures.


Proper dosing — PPIs should be taken 30 minutes before breakfast to maximize acid inhibition [8]. However, patients commonly take their PPI incorrectly, which may in part be because they have not received adequate instructions. One study found that only 46 percent of patients prescribed a PPI for GERD were taking it properly [9]. Of those not taking it properly, 39 percent took it at bedtime and 4 percent as needed. Although there is no direct evidence that proper dosing can improve symptoms in patients who are not taking a PPI 30 minutes before breakfast, most authorities emphasize the need to ensure proper dosing, especially in those with refractory GERD.

Compliance — Several surveys have demonstrated that poor compliance with PPIs is common in patients with GERD. By the end of one and six months of PPI therapy, only about 55 and 30 percent of the GERD patients, respectively, still consume their PPI once daily as initially instructed [10]. In a large, population-based study, the main factors influencing compliance were the presence or absence of symptoms, the severity of symptoms, and a personal preference about when to take treatment [11]. The results emphasize that GERD is a symptom-driven disease in which patients adhere to treatment instructions as long as they experience symptoms. Other general factors that affect compliance such as knowledge about the treated disorder, desire for personal control, the prescribed drug (taste, consistency, etc), side effects, number of pills per day, concomitant therapies, age, personality, socioeconomic status, and healthcare coverage may also have a role in adherence to treatment instructions [12].

Compliance should be assessed in all GERD patients who report lack of response to PPI treatment, particularly prior to ordering any evaluative test. Unfortunately, not all patients disclose that they are poorly compliant during their clinic visit. Treating physicians should repeatedly emphasize the need to consume antireflux treatment on a daily basis. It is the role of the treating physician to ensure proper compliance with the prescribed PPI through patient education about the disease and the value of compliance with treatment [12].

Functional heartburn and esophageal hypersensitivity — Studies evaluating patients who did not respond to PPI twice daily demonstrated that up to 58 percent of patients have functional heartburn [13,14]. Thus, functional heartburn is the most common cause for failure of PPI treatment.

The underlying mechanisms responsible for symptoms in functional heartburn patients as defined by Rome III (burning retrosternal discomfort or pain, absence of evidence of GERD as the cause of symptoms, absence of histopathology-based esophageal motility disorders, with all three criteria fulfilled for the last three months and symptom onset at least six months prior to diagnosis) remain to be elucidated; most studies used the outdated Rome II criteria to diagnose functional heartburn. Many of these studies demonstrated increased esophageal sensitivity to chemical, mechanical, and electrical stimuli in this patient population [15-18]. However, one report suggested that not all functional heartburn patients (based on Rome II criteria) have increased esophageal sensitivity to intraluminal stimuli [16], and it is highly likely that functional heartburn represents a heterogeneous group of patients with different physiological mechanisms for their symptoms.

Although a subset of patients with esophageal hypersensitivity may respond to acid suppressive therapy, this disorder is analogous to the visceral hyperalgesia described in a variety of other gastrointestinal disorders including noncardiac chest pain, functional dyspepsia, and irritable bowel syndrome. (See “Chest pain of esophageal origin”.)

Weakly acidic or alkaline reflux (non-acid reflux) — Studies involving esophageal multichannel intraluminal impedance testing have revealed a potential role of weakly acidic or alkaline reflux in patients with persistent symptoms despite a PPI. The mechanism by which weakly acidic reflux causes GERD-related symptoms remains poorly understood. Two possible explanations have been proposed: esophageal distension by increased reflux volume and hypersensitivity to weakly acidic refluxate [19]. (See “Esophageal multichannel intraluminal impedance testing” and “Clinical manifestations, diagnosis, and treatment of non-acid reflux”.)

Thus far, there is no evidence that weakly acidic reflux is more commonly associated with increased volume of the refluxate than acidic reflux. Although this association has been proposed, esophageal impedance does not measure the volume of the refluxate and thus cannot define the relationship between the volume and the acidity. Thus, it is impossible to determine individual thresholds for the point at which weakly acidic reflux episodes consistently provoke symptoms. (See “Clinical manifestations, diagnosis, and treatment of non-acid reflux”.)

Residual acid reflux — Residual acid reflux has been documented in patients with persistent heartburn despite a PPI once or twice daily [13,14,20-22]. As an example, in one study, 31 and 4 percent of GERD subjects with refractory symptoms who underwent pH testing on PPI once daily or PPI twice daily, respectively, had an abnormal test [23]. On the other hand, several studies demonstrated that reflux characteristics in PPI failure patients are similar to those in PPI success patients [24]. These studies suggest that PPI failure is primarily an esophageal hypersensitivity phenomenon. Furthermore, it appears that proximal immigration of weakly acidic reflux and the presence of gas in the refluxate are pivotal for symptom generation [25].

Bile acid reflux — Although commonly considered as synonyms, bile reflux and non-acid reflux are different phenomena. Initial studies suggested that bile reflux probably accounts for 10 to 15 percent of non-acid reflux. However, a study using simultaneous Bilitec (a device to measure bile reflux) and impedance monitoring showed no correlation between esophageal bilirubin exposure and non-acid reflux parameters [26-28]. In other reports, the majority of bile reflux occurred concomitantly with acid reflux events, and thus acid rather than bile appears to be the dominant factor responsible for GERD symptoms [29].

On the other hand, experimental data support a role for persistent bile acids in the refluxate as a potential factor involved in refractory heartburn. Although PPI therapy reduces the occurrence of acid as well as bile reflux, complete acid suppression does not guarantee the elimination of bile reflux [30-32]. Perfusion of bile salts with non-acidic pH can still provoke heartburn [15], and exposure of rabbit esophageal mucosa to weakly acidic solutions containing bile acids (comparable situation to patients on PPI) increased mucosal permeability and induced dilated intercellular spaces, a proposed histopathological mechanism necessary for heartburn generation [33].

Studies in humans also suggested a possible role for bile reflux in both symptoms and erosive esophagitis in a subset of patients with difficult to manage symptomatic reflux. In a study that included 65 patients with persistent heartburn and regurgitation while on single-dose PPI therapy, a significant number of symptoms occurred in association with bile reflux as measured by Bilitec [34]. Furthermore, in a carefully selected group of patients with symptoms refractory to PPI therapy, baclofen 20 mg three times a day significantly reduced the bile reflux exposure as well as symptoms of heartburn.

These studies suggest a role for measurement of bile reflux in patients with persistent reflux symptoms despite PPI therapy. However, the technique is not commonly available for the practicing physician and is presently limited to less than a handful of centers with interest in gastrointestinal motility. (See “Pathophysiology of reflux esophagitis” and “Clinical manifestations, diagnosis, and treatment of non-acid reflux”.)

Nocturnal acid breakthrough — Up to 70 percent of patients takings PPIs twice daily have periods of gastric pH <4 for more than 60 minutes, particularly at night [35]. Nocturnal acid breakthrough (NAB) was initially proposed as a major cause of refractory GERD. In one study, for example, 24-hour pH studies during twice daily proton pump administration were compared in 76 patients with GERD and 31 healthy controls [35]. Abnormal esophageal acid exposure due to nocturnal acid breakthrough was significantly higher in patients with GERD and correlated with the severity of esophagitis (33 percent in patients with GERD and 50 percent in patients with GERD plus Barrett's esophagus versus 8 percent in controls). However, early reports about NAB did not attempt to demonstrate a correlation between this gastric phenomenon and nighttime GERD symptoms. Subsequent studies have shown that NAB events do not necessarily denote a temporal relationship with reflux-related symptoms [36]. Furthermore, in one report, 71 percent of patients with GERD who did not respond to treatment with PPI twice daily experienced NAB, but only 36 percent had correlation between symptoms and NAB events [37]. In addition, there is no relationship between NAB and nocturnal heartburn [38]. Thus, accumulating data do not support a significant role for NAB in precipitating failure of PPI treatment. Differences in metabolism — Proton pump inhibitors are metabolized through the hepatic cytochrome system (specifically the CYP2C isoenzyme). As a result, genetically determined variability in the processes underlying drug metabolism may influence their efficacy. Patients with rapid metabolism of PPIs may have a decreased effect on gastric acidity. On the other hand, CYP2C is absent in about 3 percent of Caucasian patients and in substantially higher numbers of Asians (greater than 10 percent), potentially leading to greater suppression of gastric acidity. (See “Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders”.)

Reduced bioavailability — The bioavailability of the different proton pump inhibitors varies and may be influenced by environmental conditions and manufacturing [39]. However, for most patients, the differences in bioavailability among the proton pump inhibitors are not clinically significant during repeated dose administration since they do not translate into significant differences in the suppression of acid secretion [40].

As an example, the bioavailability of omeprazole is approximately 30 to 40 percent at doses of 20 to 40 mg. In contrast, the bioavailability of lansoprazole is much higher at approximately 80 percent for doses ranging from 15 to 60 mg. Despite these differences, the two drugs have equivalent efficacy for achieving acid suppression. This was illustrated in a controlled crossover study in which meal-stimulated acid secretion was decreased by 48 and 82 percent with 15 and 30 mg lansoprazole, respectively, and by 39 and 83 percent with 20 and 40 mg of omeprazole, respectively [41].

The general pharmacokinetic observations may not apply to individuals in whom the bioavailability of these drugs can vary significantly [42]. As a result, some patients may not achieve adequate acid suppression despite standard or relatively high-dose therapy.

Drug resistance — Resistance to proton pump inhibitors is a rare condition that may be caused by mutations in the proton pump gene, a relationship that has only been described in a 1995 abstract [7,43]. It is unlikely that this condition has any significant role in refractory GERD.

Delayed healing — Complete relief of heartburn with proton pump inhibitors occurs at a rate of approximately 11.5 percent per week [44]. Thus, endoscopic healing and symptom relief are achieved within eight weeks in the majority of patients. However, patients with severe esophagitis (eg, Los Angeles C or D esophagitis) may take longer to heal.

Helicobacter pylori status — PPIs produce a modest increase in acid suppression in H. pylori-positive patients than H. pylori-negative patients, potentially leading to higher healing rates in patients with erosive esophagitis [45,46]. The suggested underlying mechanism is migration of H. pylori proximally in the stomach to the corpus or fundus during PPI treatment. These areas of the stomach contain parietal cells, which are responsible for acid production. However, the prevalence of H. pylori infection has been rapidly declining in the United States and other developed countries, resulting in a very low background prevalence that cannot explain the large percentage of PPI failure patients. (See “Helicobacter pylori and gastroesophageal reflux disease”.)

Psychological comorbidity — Patients with poor correlation of symptoms with acid reflux events display a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid reflux events [47]. Anxiety and depression increase GERD-related symptoms reported in population-based studies [48]. Thus, it has been proposed that patients who did not respond to PPI therapy are more likely to have psychosocial comorbidity than those who were successfully treated with a PPI [49].

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