Expert Review of Gastroenterology & Hepatology
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Refractory gastroesophageal reflux disease: advances and treatment Fehmi Ates, David O Francis & Michael F Vaezi To cite this article: Fehmi Ates, David O Francis & Michael F Vaezi (2014) Refractory gastroesophageal reflux disease: advances and treatment, Expert Review of Gastroenterology & Hepatology, 8:6, 657-667, DOI: 10.1586/17474124.2014.910454 To link to this article: http://dx.doi.org/10.1586/17474124.2014.910454
Published online: 19 Apr 2014.
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Date: 08 October 2017, At: 01:19
Review
Refractory gastroesophageal reflux disease: advances and treatment Downloaded by [Southern Cross University] at 01:19 08 October 2017
Expert Rev. Gastroenterol. Hepatol. 8(6), 657–667 (2014)
Fehmi Ates1, David O Francis2 and Michael F Vaezi*1 1 Division of Gastroenterology, Hepatology, and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, C2104-MCN, Nashville, TN, USA 2 Voice Center, Vanderbilt University Medical Center, Nashville, TN, USA *Author for correspondence: Tel.: +1 615 322 3739 Fax: +1 615 322 8525 [email protected]
‘Refractory gastroesophageal reflux disease’ is one of the most common misnomers in the area of gastroesophageal reflux disease. The term implies reflux as the underlying etiology despite unresponsiveness to aggressive proton pump inhibitor therapy. The term should be replaced with ‘refractory symptoms.’ We must acknowledge that in many patients symptoms of reflux often overlap with non-GERD causes such as gastroparesis, dyspepsia, hypersensitive esophagus and functional disorders. Lack of response to aggressive acid suppressive therapy often leads to diagnostic testing. In majority of patients these tests are normal. The role of non-acid reflux in this group is uncertain and patients should not undergo surgical fundoplication based on this parameter. In patients unresponsive to acid suppressive therapy GERD is most commonly not causal and a search for non-GERD causes must ensue. KEYWORDS: achalasia • acid suppressive therapy • functional upper gut symptoms • gastroparesis • refractory symptoms
Gastroesophageal reflux disease (GERD) is a chronic condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications [1]. Besides classical symptoms such as heartburn and regurgitation, other symptoms such as chest pain, cough, asthma and hoarseness also occur. GERD is very common affecting 20% of the US adult population weekly and 7% daily [2]. It results in significant morbidity and considerable impairment of quality of life, such as permanent discomfort to the patient with repeated visits to the doctor as well as high costs of examinations and treatment [3]. The introduction of proton pump inhibitors (PPIs) has had a significant positive impact in treating GERD. A substantial improvement in mucosal healing as well as symptom resolution is expected with this new class of drugs which is superior to that achieved by histamin-2 receptor antagonists (H2RA). Despite the high efficacy of PPIs, treatment of GERD fails in a proportion of patients. ‘PPI failure’ has become a common clinical predicament. This PPI-refractory patient group constitutes a significant proportion of patients treated by general practitioners, internists and gastroenterologists. In this review, we will discuss newly accumulated information about the
informahealthcare.com
10.1586/17474124.2014.910454
management of this difficult group of patients, with an emphasis on diagnosis and treatment of other possible comorbid conditions. Definition of ‘refractory GERD’
The term ‘refractory GERD’ has traditionally been employed to define a heterogeneous group of patients with varying symptom presentation (frequency and severity), PPI dosing regimen (once or twice daily) and response to therapy (from partial to absent). There is no established consensus regarding the definition of ‘refractory GERD’ [4]. The US FDA does not particularly approve the use of PPIs in dosages greater than once daily even though higher doses are prescribed regularly in clinical practice. Thus, some investigators consider failure to achieve satisfactory symptomatic response (e.g., less than 50% improvement) to once-daily PPI as refractory disease. Other investigators consider inadequate response to twice-daily PPI treatment as refractory disease [5]. Because ‘refractory GERD’ is a patient-driven phenomenon, PPI-failure patients who seek medical attention will exhibit different frequency and/or severity of symptoms with varying causal etiology [6]. It is important to recognize that the term ‘refractory GERD’ is a misnomer since it implies underlying GERD,
Ó 2014 Informa UK Ltd
ISSN 1747-4124
657
Review
Ates, Francis & Vaezi
Box 1. Potential causes of refractory symptoms. Not gastroesophageal reflux disease • Delayed gastric emptying (common) • Motility disorder – achalasia (common) • Functional (common) • Aerophagia (less common) • Rumination (less common) • Eosinophilic esophagitis (if dysphagia is present)
Weakly acidic/nonacidic (less likely) • If regurgitation is as and mechanical failure (hiatal hernia)
is present
Downloaded by [Southern Cross University] at 01:19 08 October 2017
Insufficient acid suppression • Dosing (common) • Compliance (common) • Zollinger-ellison (rare) • Proton pump inhibitor resistance (less common)
Functional/hypersensitivity
which is not true in many patients. Thus, the term should be replaced by ‘refractory symptoms’ presumed GERD initially. This term is more apt without suggesting reflux disease as the only potential link. One suggested reasonable definition may be ‘symptoms (heartburn and/or regurgitation) that are not responding (persistent symptoms at least three-times per week) to a stable double dose of a PPI during a treatment period of at least 12 weeks’ [7]. Thus, in the forthcoming discussion we will use the term ‘refractory symptoms’ which we believe better describes this group of patients. Approach to refractory symptoms Symptom evaluation
In clinical practice, diagnosis and subsequent treatment of patients depend on subjective reporting of a constellation of symptoms attributed to GERD, which in most may not be GERD related. This may explain refractoriness to acid suppressive therapy. Thus, a careful and detailed investigation of patient complaint is key to identifying potential reasons why patients do not respond to PPI therapy [8]. Substernal burning is an important symptom attributed to GERD. In clinical trials on GERD symptoms, questionnaires are often employed to diagnose GERD. However, many are neither sensitive nor specific to reflux. The GerdQ questionnaire is a revision of the Reflux Disease Questionnaire that, in addition to having positive predictor questions about heartburn and regurgitation, includes negative predictors about epigastric pain and nausea [9]. It achieves a sensitivity of 65% and a specificity of 71% for the diagnosis of GERD, similar to that achieved by the clinical judgment of gastroenterologists [10]. Reanalysis of data from two large randomized trials involving acid suppression therapy found that PPI was most effective in individuals with symptoms limited to ‘substernal burning’ [11]. Heartburn is characterized by a painful retrosternal burning sensation of a fairly 658
short duration (several minutes). It is also important to recognize that regurgitation, an important presentation in patients with GERD, may not respond to acid suppressive therapy since it is due to volume reflux and mechanical defects of the reflux barriers. In clinical trials, the efficacy of PPIs in alleviating regurgitation is considerably lower than for heartburn [12]. As a result, a patient with both heartburn and acid regurgitation may have sufficient relief of heartburn ‘on’ PPIs but persisting regurgitation [13]. Thus, when faced with patients with refractory symptoms, it is essential to identify which symptoms respond and which do not respond to PPI therapy. A more detailed questioning of patients often help clarify the cause for a patient’s persistent symptoms (BOX 1). PPI therapy alone may not be enough in those patients in whom regurgitation continues despite PPI therapy and objective testing suggests the presence of hiatal hernia and moderate-to-severe reflux at baseline by pH monitoring. Atypical symptoms such as cough, chest pain or sleep disturbance, for example, may also respond poorly to PPI therapy since in this group of patients GERD is often overdiagnosed [14]. The presence of functional gastrointestinal disorders should be carefully assessed because they negatively impact treatment of reflux symptoms [15,16]. Patients with severe dyspeptic symptoms should be evaluated for gastroparesis. It is not uncommon that patients are initially diagnosed with GERD based on a constellation of symptoms such as heartburn and regurgitation as well as bloating and early satiety, which point to GERD as secondary to gastroparesis or functional dyspepsia. In patients with refractory symptoms one must proactively inquire about the presence of dyspeptic symptoms. The prevalence of dyspeptic symptoms is high in patients with functional heartburn [17]. Zerbib et al. have recently reported that functional dyspepsia and irritable bowel syndrome (IBS) are also strongly associated with PPI failure in patients with documented abnormal reflux [18]. Some patients may have dyspeptic symptoms that could be misinterpreted as reflux symptoms, and in this group response to PPI is erratic at best. How IBS impacts the treatment efficacy of GERD is not exactly known, but it is hypothesized that reflux and IBS symptoms share the same underlying mechanisms (e.g., increased visceral perception) since both conditions coexist very frequently [19,20]. The presence of psychological disorders such as hysteria, anxiety and psychological distress should also be evaluated in patients with refractory symptoms. A systematic review of nine clinical trials reported that high levels of anxiety at baseline were associated with persistent reflux-like symptoms [21]. In short, not all that sounds like reflux may be reflux and a high level of suspicion for overlapping conditions is needed to more efficiently identify true causes for patients’ underlying symptoms. Additional important and common factors associated with PPI failure in patients initially diagnosed with GERD are poor compliance to medication use, obesity and overeating (FIGURE 1) [14]. Compliance to once-daily PPI in GERD is reported to be lower in patients with refractory symptoms (46–55%) as compared with patients with adequate relief (84%) [14]. A recent Expert Rev. Gastroenterol. Hepatol. 8(6), (2014)
Downloaded by [Southern Cross University] at 01:19 08 October 2017
Refractory GERD advances & treatment
Review
systematic review showed that compliance Compliance to medication is better in patients with Inadequate Dosing acid severe symptoms and Barrett’s esophaZE suppression gus [22]. The reason for higher compliPPI resistance ance in this group is the recognition that NAB PPIs help symptoms in those with true objective GERD and when patients discontinue their therapy symptoms recur. In Refractory addition to compliance, dosing time symptoms 60–70% Rumination should also be scrutinized since taking Aerophagia PPIs 15–30 min before a meal results in a Motility disorder NOT Regurgitation better gastric pH control [23]. A recent Non-acid (achalasia) reflux Bile reflux study showed that optimal PPI dosing related DGE Non-acid (before meals) occurred in only 46% of EoE 100 patients who were referred for persisFunctional tent GERD symptoms despite treatFigure 1. Refractory symptoms may be caused by continued acid or nonacid reflux ment [24]. A survey of 491 physicians due to lack of compliance with acid suppressive therapy or incompetent lower found that nearly 70% of primary care esophageal barrier, respectively. However, in most cases it is due to nonreflux causes. physicians and 20% of gastroenterologists EoE: Eosinophilic esophagitis; NAB: Nocturnal acid breakthrough; PPI: Proton pump in the US advised patients to take the PPI inhibitor; ZE: Zollinger-ellison. dose at bed time or did not believe that the relationship to meals was important [25]. Therefore, any patient with refractory symptoms should endoscopy. This may be due to either prior PPI use or nonbe instructed regarding optimal dosing of PPIs. Once compliance GERD-related patient symptoms. Stein et al. studied the test and appropriate dosing are ensured, a single trial of a different characteristics of endoscopy for diagnosing GERD and PPI can be considered. Recent evidence from a multicenter ran- observed poor sensitivity (37%), specificity (70%) and positive domized trial showed this strategy to be helpful in some predictive value (55%) when compared to pH monitoring [29]. patients [26]. A randomized controlled trial in patients with persis- Nonetheless, endoscopy remains an important tool for identifytent GERD symptoms despite a single daily dose of PPI showed ing mucosal disease, but most importantly for ruling out more that increasing the PPI dose to twice daily or switching to ominous pathology or causes other than GERD in those with another PPI both resulted in symptomatic improvement in continued symptoms despite PPI therapy. Once dosing and timing of PPI therapy is optimized, those roughly 20% of patients, without a clear advantage for either with typical esophageal symptoms should undergo upper strategy [27]. However, it is important to recognize that switching endoscopy principally to exclude non-reflux esophageal disorPPIs will not ensure symptom control in the majority of patients ders such as eosinophilic esophagitis (EoE), which can present presenting with refractory symptoms. with esophageal symptoms refractory to PPI and to look for the rare patient with erosive esophagitis, a finding that provides Upper gastrointestinal endoscopy Direct visualization using esophagogastroduodenoscopy (EGD) evidence of ongoing acid reflux. A recent Markov model found is critical for identification of gross esophageal disease (i.e., stric- that obtaining esophageal biopsies to diagnose EoE in refractures, ulcerations, Barrett’s esophagus) and a standard compo- tory GERD patients is cost-effective only when the prevalence nent of refractory GERD evaluation. The main objective of of EoE is 8% or greater [30]. Recent studies have suggested its EGD in patients who are refractory to PPI therapy is to identify prevalence to be from 4 to 8% [31,32]. However, we cannot recpersistent reflux or, most commonly, causes other than GERD ommend esophageal biopsy in all patients with refractory sympresponsible for patients’ continued symptoms. The Los Angeles toms and suggest targeting it to younger males and those with classification has become the most widely employed means of concomitant dysphagia and/or esophageal mucosa suspicious for grading esophageal inflammation due to GERD [28]. It grades EoE. If esophageal biopsies are taken, it should be both from the esophagitis from A through D employing erosion not edema or distal and proximal esophagus so that reflux is not confused with erythema as the objective measure for esophageal mucosal injury. EoE. Distal esophageal eosinophilia can occur in GERD alone. Endoscopy is usually of limited value in most since the majorTherefore, the grade of esophageal injury is determined by the ity of patients will have normal endoscopic findings. As an examnumber, length and location of mucosal breaks. While EGD represents a critical part of any refractory reflux ple, it is reported that only 6.7% of patients with refractory evaluation, it remains primarily a screening tool. Only the heartburn on once-daily PPI therapy have erosive esophagitis [33]. most severe cases of GERD are associated with endoscopic evi- In patients with esophagitis while on PPI therapy, other causes of dence of esophagitis. A large majority of patients with refrac- esophageal inflammation must be entertained. Pill-induced tory reflux have normal-appearing esophageal mucosa on esophagitis and skin diseases with esophageal involvement are informahealthcare.com
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Review
Ates, Francis & Vaezi
other causes of PPI refractoriness and they are usually easily differentiated from peptic ulcerations located at the lower third of the esophagus [34]. The presence of mucosal breaks despite PPI therapy may reflect poorly controlled acid reflux, which could be in some rare cases related to the Zollinger–Ellison syndrome and commonly due to poor compliance or continued volume reflux due to defective antireflux barriers, especially in those with Barrett’s esophagus.
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Ambulatory monitoring for reflux
If endoscopy is negative, as is frequently the case, the next step is to perform reflux monitoring to quantify the degree of reflux, if any, and to establish if reflux is the underlying etiology of patients’ continued symptoms. Reflux monitoring enables further characterization of the refractory patient, as the study may reveal: PPI failure with ongoing acid reflux, which will require escalation of therapy to control acid reflux; adequate acid control but ongoing symptomatic nonacid reflux, which may respond to specific therapy; or no reflux. Among refractory GERD patients with a negative reflux monitoring study, those with heartburn may be classified as having ‘functional heartburn,’ while those with extraesophageal symptoms (asthma, cough, laryngitis) will need additional or repeat workup for non-GERD (pulmonary, allergic, ENT) etiologies. Two key issues to consider are whether reflux monitoring should be performed after stopping PPI therapy or while on medication and what technique to use (catheter-based pH, wireless pH or impedance pH). Currently, there are limited data and no clear consensus regarding the optimal testing methodology for refractory GERD. The approach to testing may be chosen based on the patient’s clinical presentation and pretest likelihood of GERD as well as on the available technology and expertise. Reflux monitoring both off as well as on PPI offers important and clinically useful information. Reflux monitoring off PPI (7 days after cessation of PPI) can be performed with any of the available techniques (catheter-based, wireless or impedance pH). If reflux monitoring off medication is negative (normal distal esophageal acid exposure), GERD is unlikely to be the cause for patients’ continued symptoms. In a patient with a negative test off therapy, PPI use should be discontinued and the diagnostic effort should be steered toward non-GERD etiologies. On the other hand, a positive test after PPI cessation offers objective evidence of GERD but it does not provide insight into the reason for the failure to respond to treatment. Moderate-to-severe degree of reflux at baseline on ambulatory monitoring may be a helpful finding. A recent uncontrolled study in patients with continued symptoms despite PPI therapy suggested that the presence of a moderate-sized hiatal hernia, regurgitation or moderate-tosevere acid reflux at baseline is a predictor of GERD as the etiology of continued symptoms [35]. Reflux monitoring on PPI may be performed with impedancepH monitoring to enable measurement of nonacid reflux. The yield of pH monitoring alone in a patient on PPI therapy is very low because in acid-suppressed patients reflux constituents become predominantly nonacidic [36]. In fact, pH monitoring in 660
patients on twice-daily PPI therapy is likely to be normal in 90– 96% of patients with refractory symptoms [37]. Although rare, an abnormal pH test in a patient taking PPIs (i.e., ongoing acid reflux despite treatment) is evidence of therapeutic failure or noncompliance. A negative pH test in treated patients makes ongoing acid reflux as the cause of their symptoms very unlikely, but it cannot account for the possibility of nonacid reflux, which can be measured using impedance-pH monitoring. A study that used the symptom index (SI) to evaluate 144 patients refractory to twice-daily PPI therapy found that ongoing symptoms were related to nonacid reflux in 37% and acid reflux in 11% [38]. In the remaining 52% of patients, there was no relationship between reflux (either acid or nonacid) and symptoms. A positive SI was more common in patients with typical symptoms (heartburn, regurgitation and chest pain) compared with those with an atypical presentation (55 vs 25%). A different study using the symptom association probability (SAP) in patients who were symptomatic despite PPI therapy found a relationship between reflux and symptoms in 37% of 60 patients; the SAP was positive due to nonacid reflux in 17%, acid reflux in 5% and acid plus nonacid reflux in 15% [39]. A systematic review which quantified acid and nonacid (both weakly acidic and weakly alkaline) reflux in studies of GERD patients on PPI therapy found that weakly acidic reflux underlies the majority of reflux episodes in these patients and is the main cause of persistent symptoms despite PPI therapy [40]. However, there are no controlled outcome studies on the clinical relevance of nonacid or weakly acidic reflux in patients with persistent symptoms while on PPI therapy. Finally, a negative impedance-pH test on medication strongly supports that the patient’s complaints are not due to reflux of any type. Needless to say, the full context of the patient (including clinical presentation, presence of hiatus hernia, endoscopy findings and/or degree of response to therapy) always needs to be considered [41]. Studies comparing the yield of ‘off versus on’ therapy reflux monitoring in refractory GERD patients are limited. Hemmink et al. concluded that testing should be performed off PPI [42]. In contrast, Pritchett et al. found that reflux monitoring on PPI may be the preferred strategy [43]. At present, no single approach can be recommended due to the heterogeneous group of patients. A recent technical review on this topic suggested that, in the absence of high-quality studies to guide this decision, the method of testing may be chosen based on the patient’s clinical presentation [44]. In patients with a low probability of GERD (e.g., atypical presentations without concomitant typical GERD symptoms), pH monitoring off medication may be preferred as it will enable ruling out GERD. Patients with a higher probability of GERD (typical symptoms, at least partial response to PPI) can be tested using impedance-pH testing on medication in search of ongoing reflux (either acid or nonacid) despite PPI. Obviously, more studies are needed to bring clarity to this issue. Finally, it is important to emphasize the importance of stopping PPI therapy in patients with refractory symptoms in whom all testing is negative. In a recent study, after a negative evaluation for refractory GERD that included normal endoscopy and impedance-pH Expert Rev. Gastroenterol. Hepatol. 8(6), (2014)
Refractory GERD advances & treatment
Review
Symptoms suspected GERD related
Warning symptoms/signs (dysphagia/weight loss/anemia/chest pain)
(-)
(+)
Once daily PPI therapy (two months)
Esophagogastroduodenoscopy
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Response Taper to minimum dose Intermittent or on-demand therapy Life-style modification (weight loss) EGD for chronic symptoms (rule out Barrett’s)
No or partial response
Response
Increase to twice daily PPI Ensure proper PPI dosing and time
No or partial response
EGD pH monitoring (off therapy)
Moderate/large hiatal hernia (>4 cm) Moderate/severe reflux (% time pH 10%)
Normal or mild reflux (% time pH
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Refractory gastroesophageal reflux disease: advances and treatment Fehmi Ates, David O Francis & Michael F Vaezi To cite this article: Fehmi Ates, David O Francis & Michael F Vaezi (2014) Refractory gastroesophageal reflux disease: advances and treatment, Expert Review of Gastroenterology & Hepatology, 8:6, 657-667, DOI: 10.1586/17474124.2014.910454 To link to this article: http://dx.doi.org/10.1586/17474124.2014.910454
Published online: 19 Apr 2014.
Submit your article to this journal
Article views: 228
View related articles
View Crossmark data
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierh20 Download by: [Southern Cross University]
Date: 08 October 2017, At: 01:19
Review
Refractory gastroesophageal reflux disease: advances and treatment Downloaded by [Southern Cross University] at 01:19 08 October 2017
Expert Rev. Gastroenterol. Hepatol. 8(6), 657–667 (2014)
Fehmi Ates1, David O Francis2 and Michael F Vaezi*1 1 Division of Gastroenterology, Hepatology, and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, C2104-MCN, Nashville, TN, USA 2 Voice Center, Vanderbilt University Medical Center, Nashville, TN, USA *Author for correspondence: Tel.: +1 615 322 3739 Fax: +1 615 322 8525 [email protected]
‘Refractory gastroesophageal reflux disease’ is one of the most common misnomers in the area of gastroesophageal reflux disease. The term implies reflux as the underlying etiology despite unresponsiveness to aggressive proton pump inhibitor therapy. The term should be replaced with ‘refractory symptoms.’ We must acknowledge that in many patients symptoms of reflux often overlap with non-GERD causes such as gastroparesis, dyspepsia, hypersensitive esophagus and functional disorders. Lack of response to aggressive acid suppressive therapy often leads to diagnostic testing. In majority of patients these tests are normal. The role of non-acid reflux in this group is uncertain and patients should not undergo surgical fundoplication based on this parameter. In patients unresponsive to acid suppressive therapy GERD is most commonly not causal and a search for non-GERD causes must ensue. KEYWORDS: achalasia • acid suppressive therapy • functional upper gut symptoms • gastroparesis • refractory symptoms
Gastroesophageal reflux disease (GERD) is a chronic condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications [1]. Besides classical symptoms such as heartburn and regurgitation, other symptoms such as chest pain, cough, asthma and hoarseness also occur. GERD is very common affecting 20% of the US adult population weekly and 7% daily [2]. It results in significant morbidity and considerable impairment of quality of life, such as permanent discomfort to the patient with repeated visits to the doctor as well as high costs of examinations and treatment [3]. The introduction of proton pump inhibitors (PPIs) has had a significant positive impact in treating GERD. A substantial improvement in mucosal healing as well as symptom resolution is expected with this new class of drugs which is superior to that achieved by histamin-2 receptor antagonists (H2RA). Despite the high efficacy of PPIs, treatment of GERD fails in a proportion of patients. ‘PPI failure’ has become a common clinical predicament. This PPI-refractory patient group constitutes a significant proportion of patients treated by general practitioners, internists and gastroenterologists. In this review, we will discuss newly accumulated information about the
informahealthcare.com
10.1586/17474124.2014.910454
management of this difficult group of patients, with an emphasis on diagnosis and treatment of other possible comorbid conditions. Definition of ‘refractory GERD’
The term ‘refractory GERD’ has traditionally been employed to define a heterogeneous group of patients with varying symptom presentation (frequency and severity), PPI dosing regimen (once or twice daily) and response to therapy (from partial to absent). There is no established consensus regarding the definition of ‘refractory GERD’ [4]. The US FDA does not particularly approve the use of PPIs in dosages greater than once daily even though higher doses are prescribed regularly in clinical practice. Thus, some investigators consider failure to achieve satisfactory symptomatic response (e.g., less than 50% improvement) to once-daily PPI as refractory disease. Other investigators consider inadequate response to twice-daily PPI treatment as refractory disease [5]. Because ‘refractory GERD’ is a patient-driven phenomenon, PPI-failure patients who seek medical attention will exhibit different frequency and/or severity of symptoms with varying causal etiology [6]. It is important to recognize that the term ‘refractory GERD’ is a misnomer since it implies underlying GERD,
Ó 2014 Informa UK Ltd
ISSN 1747-4124
657
Review
Ates, Francis & Vaezi
Box 1. Potential causes of refractory symptoms. Not gastroesophageal reflux disease • Delayed gastric emptying (common) • Motility disorder – achalasia (common) • Functional (common) • Aerophagia (less common) • Rumination (less common) • Eosinophilic esophagitis (if dysphagia is present)
Weakly acidic/nonacidic (less likely) • If regurgitation is as and mechanical failure (hiatal hernia)
is present
Downloaded by [Southern Cross University] at 01:19 08 October 2017
Insufficient acid suppression • Dosing (common) • Compliance (common) • Zollinger-ellison (rare) • Proton pump inhibitor resistance (less common)
Functional/hypersensitivity
which is not true in many patients. Thus, the term should be replaced by ‘refractory symptoms’ presumed GERD initially. This term is more apt without suggesting reflux disease as the only potential link. One suggested reasonable definition may be ‘symptoms (heartburn and/or regurgitation) that are not responding (persistent symptoms at least three-times per week) to a stable double dose of a PPI during a treatment period of at least 12 weeks’ [7]. Thus, in the forthcoming discussion we will use the term ‘refractory symptoms’ which we believe better describes this group of patients. Approach to refractory symptoms Symptom evaluation
In clinical practice, diagnosis and subsequent treatment of patients depend on subjective reporting of a constellation of symptoms attributed to GERD, which in most may not be GERD related. This may explain refractoriness to acid suppressive therapy. Thus, a careful and detailed investigation of patient complaint is key to identifying potential reasons why patients do not respond to PPI therapy [8]. Substernal burning is an important symptom attributed to GERD. In clinical trials on GERD symptoms, questionnaires are often employed to diagnose GERD. However, many are neither sensitive nor specific to reflux. The GerdQ questionnaire is a revision of the Reflux Disease Questionnaire that, in addition to having positive predictor questions about heartburn and regurgitation, includes negative predictors about epigastric pain and nausea [9]. It achieves a sensitivity of 65% and a specificity of 71% for the diagnosis of GERD, similar to that achieved by the clinical judgment of gastroenterologists [10]. Reanalysis of data from two large randomized trials involving acid suppression therapy found that PPI was most effective in individuals with symptoms limited to ‘substernal burning’ [11]. Heartburn is characterized by a painful retrosternal burning sensation of a fairly 658
short duration (several minutes). It is also important to recognize that regurgitation, an important presentation in patients with GERD, may not respond to acid suppressive therapy since it is due to volume reflux and mechanical defects of the reflux barriers. In clinical trials, the efficacy of PPIs in alleviating regurgitation is considerably lower than for heartburn [12]. As a result, a patient with both heartburn and acid regurgitation may have sufficient relief of heartburn ‘on’ PPIs but persisting regurgitation [13]. Thus, when faced with patients with refractory symptoms, it is essential to identify which symptoms respond and which do not respond to PPI therapy. A more detailed questioning of patients often help clarify the cause for a patient’s persistent symptoms (BOX 1). PPI therapy alone may not be enough in those patients in whom regurgitation continues despite PPI therapy and objective testing suggests the presence of hiatal hernia and moderate-to-severe reflux at baseline by pH monitoring. Atypical symptoms such as cough, chest pain or sleep disturbance, for example, may also respond poorly to PPI therapy since in this group of patients GERD is often overdiagnosed [14]. The presence of functional gastrointestinal disorders should be carefully assessed because they negatively impact treatment of reflux symptoms [15,16]. Patients with severe dyspeptic symptoms should be evaluated for gastroparesis. It is not uncommon that patients are initially diagnosed with GERD based on a constellation of symptoms such as heartburn and regurgitation as well as bloating and early satiety, which point to GERD as secondary to gastroparesis or functional dyspepsia. In patients with refractory symptoms one must proactively inquire about the presence of dyspeptic symptoms. The prevalence of dyspeptic symptoms is high in patients with functional heartburn [17]. Zerbib et al. have recently reported that functional dyspepsia and irritable bowel syndrome (IBS) are also strongly associated with PPI failure in patients with documented abnormal reflux [18]. Some patients may have dyspeptic symptoms that could be misinterpreted as reflux symptoms, and in this group response to PPI is erratic at best. How IBS impacts the treatment efficacy of GERD is not exactly known, but it is hypothesized that reflux and IBS symptoms share the same underlying mechanisms (e.g., increased visceral perception) since both conditions coexist very frequently [19,20]. The presence of psychological disorders such as hysteria, anxiety and psychological distress should also be evaluated in patients with refractory symptoms. A systematic review of nine clinical trials reported that high levels of anxiety at baseline were associated with persistent reflux-like symptoms [21]. In short, not all that sounds like reflux may be reflux and a high level of suspicion for overlapping conditions is needed to more efficiently identify true causes for patients’ underlying symptoms. Additional important and common factors associated with PPI failure in patients initially diagnosed with GERD are poor compliance to medication use, obesity and overeating (FIGURE 1) [14]. Compliance to once-daily PPI in GERD is reported to be lower in patients with refractory symptoms (46–55%) as compared with patients with adequate relief (84%) [14]. A recent Expert Rev. Gastroenterol. Hepatol. 8(6), (2014)
Downloaded by [Southern Cross University] at 01:19 08 October 2017
Refractory GERD advances & treatment
Review
systematic review showed that compliance Compliance to medication is better in patients with Inadequate Dosing acid severe symptoms and Barrett’s esophaZE suppression gus [22]. The reason for higher compliPPI resistance ance in this group is the recognition that NAB PPIs help symptoms in those with true objective GERD and when patients discontinue their therapy symptoms recur. In Refractory addition to compliance, dosing time symptoms 60–70% Rumination should also be scrutinized since taking Aerophagia PPIs 15–30 min before a meal results in a Motility disorder NOT Regurgitation better gastric pH control [23]. A recent Non-acid (achalasia) reflux Bile reflux study showed that optimal PPI dosing related DGE Non-acid (before meals) occurred in only 46% of EoE 100 patients who were referred for persisFunctional tent GERD symptoms despite treatFigure 1. Refractory symptoms may be caused by continued acid or nonacid reflux ment [24]. A survey of 491 physicians due to lack of compliance with acid suppressive therapy or incompetent lower found that nearly 70% of primary care esophageal barrier, respectively. However, in most cases it is due to nonreflux causes. physicians and 20% of gastroenterologists EoE: Eosinophilic esophagitis; NAB: Nocturnal acid breakthrough; PPI: Proton pump in the US advised patients to take the PPI inhibitor; ZE: Zollinger-ellison. dose at bed time or did not believe that the relationship to meals was important [25]. Therefore, any patient with refractory symptoms should endoscopy. This may be due to either prior PPI use or nonbe instructed regarding optimal dosing of PPIs. Once compliance GERD-related patient symptoms. Stein et al. studied the test and appropriate dosing are ensured, a single trial of a different characteristics of endoscopy for diagnosing GERD and PPI can be considered. Recent evidence from a multicenter ran- observed poor sensitivity (37%), specificity (70%) and positive domized trial showed this strategy to be helpful in some predictive value (55%) when compared to pH monitoring [29]. patients [26]. A randomized controlled trial in patients with persis- Nonetheless, endoscopy remains an important tool for identifytent GERD symptoms despite a single daily dose of PPI showed ing mucosal disease, but most importantly for ruling out more that increasing the PPI dose to twice daily or switching to ominous pathology or causes other than GERD in those with another PPI both resulted in symptomatic improvement in continued symptoms despite PPI therapy. Once dosing and timing of PPI therapy is optimized, those roughly 20% of patients, without a clear advantage for either with typical esophageal symptoms should undergo upper strategy [27]. However, it is important to recognize that switching endoscopy principally to exclude non-reflux esophageal disorPPIs will not ensure symptom control in the majority of patients ders such as eosinophilic esophagitis (EoE), which can present presenting with refractory symptoms. with esophageal symptoms refractory to PPI and to look for the rare patient with erosive esophagitis, a finding that provides Upper gastrointestinal endoscopy Direct visualization using esophagogastroduodenoscopy (EGD) evidence of ongoing acid reflux. A recent Markov model found is critical for identification of gross esophageal disease (i.e., stric- that obtaining esophageal biopsies to diagnose EoE in refractures, ulcerations, Barrett’s esophagus) and a standard compo- tory GERD patients is cost-effective only when the prevalence nent of refractory GERD evaluation. The main objective of of EoE is 8% or greater [30]. Recent studies have suggested its EGD in patients who are refractory to PPI therapy is to identify prevalence to be from 4 to 8% [31,32]. However, we cannot recpersistent reflux or, most commonly, causes other than GERD ommend esophageal biopsy in all patients with refractory sympresponsible for patients’ continued symptoms. The Los Angeles toms and suggest targeting it to younger males and those with classification has become the most widely employed means of concomitant dysphagia and/or esophageal mucosa suspicious for grading esophageal inflammation due to GERD [28]. It grades EoE. If esophageal biopsies are taken, it should be both from the esophagitis from A through D employing erosion not edema or distal and proximal esophagus so that reflux is not confused with erythema as the objective measure for esophageal mucosal injury. EoE. Distal esophageal eosinophilia can occur in GERD alone. Endoscopy is usually of limited value in most since the majorTherefore, the grade of esophageal injury is determined by the ity of patients will have normal endoscopic findings. As an examnumber, length and location of mucosal breaks. While EGD represents a critical part of any refractory reflux ple, it is reported that only 6.7% of patients with refractory evaluation, it remains primarily a screening tool. Only the heartburn on once-daily PPI therapy have erosive esophagitis [33]. most severe cases of GERD are associated with endoscopic evi- In patients with esophagitis while on PPI therapy, other causes of dence of esophagitis. A large majority of patients with refrac- esophageal inflammation must be entertained. Pill-induced tory reflux have normal-appearing esophageal mucosa on esophagitis and skin diseases with esophageal involvement are informahealthcare.com
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other causes of PPI refractoriness and they are usually easily differentiated from peptic ulcerations located at the lower third of the esophagus [34]. The presence of mucosal breaks despite PPI therapy may reflect poorly controlled acid reflux, which could be in some rare cases related to the Zollinger–Ellison syndrome and commonly due to poor compliance or continued volume reflux due to defective antireflux barriers, especially in those with Barrett’s esophagus.
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Ambulatory monitoring for reflux
If endoscopy is negative, as is frequently the case, the next step is to perform reflux monitoring to quantify the degree of reflux, if any, and to establish if reflux is the underlying etiology of patients’ continued symptoms. Reflux monitoring enables further characterization of the refractory patient, as the study may reveal: PPI failure with ongoing acid reflux, which will require escalation of therapy to control acid reflux; adequate acid control but ongoing symptomatic nonacid reflux, which may respond to specific therapy; or no reflux. Among refractory GERD patients with a negative reflux monitoring study, those with heartburn may be classified as having ‘functional heartburn,’ while those with extraesophageal symptoms (asthma, cough, laryngitis) will need additional or repeat workup for non-GERD (pulmonary, allergic, ENT) etiologies. Two key issues to consider are whether reflux monitoring should be performed after stopping PPI therapy or while on medication and what technique to use (catheter-based pH, wireless pH or impedance pH). Currently, there are limited data and no clear consensus regarding the optimal testing methodology for refractory GERD. The approach to testing may be chosen based on the patient’s clinical presentation and pretest likelihood of GERD as well as on the available technology and expertise. Reflux monitoring both off as well as on PPI offers important and clinically useful information. Reflux monitoring off PPI (7 days after cessation of PPI) can be performed with any of the available techniques (catheter-based, wireless or impedance pH). If reflux monitoring off medication is negative (normal distal esophageal acid exposure), GERD is unlikely to be the cause for patients’ continued symptoms. In a patient with a negative test off therapy, PPI use should be discontinued and the diagnostic effort should be steered toward non-GERD etiologies. On the other hand, a positive test after PPI cessation offers objective evidence of GERD but it does not provide insight into the reason for the failure to respond to treatment. Moderate-to-severe degree of reflux at baseline on ambulatory monitoring may be a helpful finding. A recent uncontrolled study in patients with continued symptoms despite PPI therapy suggested that the presence of a moderate-sized hiatal hernia, regurgitation or moderate-tosevere acid reflux at baseline is a predictor of GERD as the etiology of continued symptoms [35]. Reflux monitoring on PPI may be performed with impedancepH monitoring to enable measurement of nonacid reflux. The yield of pH monitoring alone in a patient on PPI therapy is very low because in acid-suppressed patients reflux constituents become predominantly nonacidic [36]. In fact, pH monitoring in 660
patients on twice-daily PPI therapy is likely to be normal in 90– 96% of patients with refractory symptoms [37]. Although rare, an abnormal pH test in a patient taking PPIs (i.e., ongoing acid reflux despite treatment) is evidence of therapeutic failure or noncompliance. A negative pH test in treated patients makes ongoing acid reflux as the cause of their symptoms very unlikely, but it cannot account for the possibility of nonacid reflux, which can be measured using impedance-pH monitoring. A study that used the symptom index (SI) to evaluate 144 patients refractory to twice-daily PPI therapy found that ongoing symptoms were related to nonacid reflux in 37% and acid reflux in 11% [38]. In the remaining 52% of patients, there was no relationship between reflux (either acid or nonacid) and symptoms. A positive SI was more common in patients with typical symptoms (heartburn, regurgitation and chest pain) compared with those with an atypical presentation (55 vs 25%). A different study using the symptom association probability (SAP) in patients who were symptomatic despite PPI therapy found a relationship between reflux and symptoms in 37% of 60 patients; the SAP was positive due to nonacid reflux in 17%, acid reflux in 5% and acid plus nonacid reflux in 15% [39]. A systematic review which quantified acid and nonacid (both weakly acidic and weakly alkaline) reflux in studies of GERD patients on PPI therapy found that weakly acidic reflux underlies the majority of reflux episodes in these patients and is the main cause of persistent symptoms despite PPI therapy [40]. However, there are no controlled outcome studies on the clinical relevance of nonacid or weakly acidic reflux in patients with persistent symptoms while on PPI therapy. Finally, a negative impedance-pH test on medication strongly supports that the patient’s complaints are not due to reflux of any type. Needless to say, the full context of the patient (including clinical presentation, presence of hiatus hernia, endoscopy findings and/or degree of response to therapy) always needs to be considered [41]. Studies comparing the yield of ‘off versus on’ therapy reflux monitoring in refractory GERD patients are limited. Hemmink et al. concluded that testing should be performed off PPI [42]. In contrast, Pritchett et al. found that reflux monitoring on PPI may be the preferred strategy [43]. At present, no single approach can be recommended due to the heterogeneous group of patients. A recent technical review on this topic suggested that, in the absence of high-quality studies to guide this decision, the method of testing may be chosen based on the patient’s clinical presentation [44]. In patients with a low probability of GERD (e.g., atypical presentations without concomitant typical GERD symptoms), pH monitoring off medication may be preferred as it will enable ruling out GERD. Patients with a higher probability of GERD (typical symptoms, at least partial response to PPI) can be tested using impedance-pH testing on medication in search of ongoing reflux (either acid or nonacid) despite PPI. Obviously, more studies are needed to bring clarity to this issue. Finally, it is important to emphasize the importance of stopping PPI therapy in patients with refractory symptoms in whom all testing is negative. In a recent study, after a negative evaluation for refractory GERD that included normal endoscopy and impedance-pH Expert Rev. Gastroenterol. Hepatol. 8(6), (2014)
Refractory GERD advances & treatment
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Symptoms suspected GERD related
Warning symptoms/signs (dysphagia/weight loss/anemia/chest pain)
(-)
(+)
Once daily PPI therapy (two months)
Esophagogastroduodenoscopy
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Response Taper to minimum dose Intermittent or on-demand therapy Life-style modification (weight loss) EGD for chronic symptoms (rule out Barrett’s)
No or partial response
Response
Increase to twice daily PPI Ensure proper PPI dosing and time
No or partial response
EGD pH monitoring (off therapy)
Moderate/large hiatal hernia (>4 cm) Moderate/severe reflux (% time pH 10%)
Normal or mild reflux (% time pH
