Curr Gastroenterol Rep (2015) 17:25 DOI 10.1007/s11894-015-0451-3
INVITED COMMENTARY
PPI-Refractory GERD: an Intriguing, Probably Overestimated, Phenomenon Fabio Baldi 1,2
# Springer Science+Business Media New York 2015
Keywords Refractory GERD . Proton-pump inhibitors . GERD pathogenesis . GE reflux monitoring
The Concept of Refractoriness Proton-pump inhibitors (PPIs) are still a cornerstone of pharmacologic treatment for gastroesophageal reflux disease (GERD) because of their unquestionable efficacy in reducing the acid component of refluxate. However, their extensive use in the general population has revealed a subset of patients who are unsatisfied with these agents. These patients are considered unresponsive to PPIs, and this emerging phenomenon, defined as refractoriness to PPIs, may have a prevalence ranging from 10 to 40 % [1, 2]. Several drug-related variables, such as daily dosage and duration of therapy, clearly may be responsible for these numbers, and recently, it was proposed that the term PPI refractory be used only for patients unresponsive to a 12-week twice-daily course of PPI therapy [3•]. However, the greatest factor influencing PPI response likely is the type of patient to whom the drug is prescribed. It is now well established that the mechanisms underlying the symptoms in
* Fabio Baldi [email protected]; [email protected] 1
Center for the Study of Diseases of the Esophagus, University of Bologna, Bologna, Italy
2
GVM Care and Research, Cotignola, RA, Italy
patients with GERD are related not only to esophageal acid exposure, especially in those without mucosal erosions (i.e., with nonerosive reflux disease (NERD)) who have a possibly normal but still symptomatic acid reflux (i.e., hypersensitive esophagus (HE)). In all these patients, who represent a large proportion of the GERD population, another very important mechanism for symptom occurrence is enhanced esophageal sensitivity, which also may be associated with central sensitization. We can speculate that the two mechanisms—acid exposure and hypersensitivity—each might play a different role throughout the spectrum of GERD phenotypes. Acid exposure is a predominant factor in patients with erosive disease but is less important in those without mucosal lesions; on the contrary, hypersensitivity is the major mechanism in patients without lesions and with normal reflux (Fig. 1). Despite this heterogeneous pathogenesis, however, we treat our GERD patients with drugs—PPIs—characterized by a very selective mechanism of action, i.e., the inhibition of acid secretion. It thus is reasonable to expect that the efficacy of this therapy is related directly and proportionally to the role of acid exposure in the individual patient, and this is exactly what occurs in clinical practice. A recently published paper [4••] provides an elegant summary of PPI efficacy in patients with different manifestations of GERD. The authors analyzed randomized controlled trials and evaluated the placebo effect and therapeutic gain for each patient category. Their data clearly indicate that the greatest PPI success—75 % or more—occurred in patients with esophagitis or typical reflux symptoms, such as heartburn or reflux-induced chest pain. On the contrary, patients with regurgitation as their main symptom or with laryngeal manifestations such as hoarseness or chronic cough showed a poor response to PPIs, with
25
Curr Gastroenterol Rep (2015) 17:25
Page 2 of 3
Pathogenetic mechanisms in GERD phenotypes
ERD
NERD
HE
Hypersensitivity
Acid exposure
visceral
central
ERD = Erosive Reflux Disease NERD = Non Erosive Reflux Disease HE = Hypersensitive Esophagus
Fig. 1 Pathogenetic mechanisms in GERD phenotypes
a success rate of less than 50 %. In the latter case, we should not consider PPI refractoriness; rather, we should question whether acid reflux is the cause of the symptoms.
Diagnostic Approach The diagnostic approach to GERD classified as PPI refractory should follow an algorithm (Fig. 2) aimed at first establishing whether true refractoriness exists and, if so, determining its cause. In a patient with a diagnosis of GERD and a poor response to PPIs, the first question to answer is whether the symptoms the patient is reporting are the result of acid reflux. However, before we undertake an invasive investigation, we must
Diagnostic work-up in patients unresponsive to PPIs Clinical re-evaluation
Endoscopy (if indicated)
GERD probability
low
pH/pH-MII off tx
Fig. 2 Diagnostic work-up in patients unresponsive to PPIs
high
pH-MII on tx
reconsider the main symptoms of the patient. It is not unusual for GERD patients also to report dyspeptic symptoms, such as epigastric pain or postprandial fullness, and that they are unsatisfied with the therapy because these symptoms persist. Other patients have been treated for laryngeal or respiratory symptoms, even in the absence of typical reflux manifestations. In these cases, the lack of response to PPI administration too quickly is attributed to Brefractoriness^ without a reevaluation for extra-esophageal causes. Only patients with a well-established diagnosis of GERD, such as those with esophagitis or typical symptoms, or those with less typical manifestations but a high probability of having GERD should be managed as PPI-refractory patients. A diagnostic tool used very often in these patients is upper gastrointestinal (GI) endoscopy. The main objective of this examination is to rule out esophageal or gastric lesions; however, the sensitivity of endoscopy in PPI-refractory patients is very low. The few studies reporting endoscopic findings in this select patient group clearly indicate that the probability of detecting mucosal erosions is far less than 10 % [5]. Even histologic evaluation for eosinophilic esophagitis in these patients is disappointing, because its prevalence appears to be less than 5 % [6]. However, despite its poor sensitivity, upper GI endoscopy may be fundamental in reassuring both the patient and the doctor and may be reasonably indicated in three circumstances: (1) if it was not performed previously, (2) if mucosal biopsies are not available, and (3) if the patient previously had a diagnosis of severe esophagitis. Assessment of gastroesophageal reflux and its relationship to the symptoms is certainly the most appropriate investigation in GERD patients classified as PPI refractory. It may be performed in two different settings: in the absence of antisecretory therapy (off treatment) or during PPI administration (on treatment). The first approach may be followed using any of the methods now available—pH-metry, Bravo capsule (Given Imaging, Yoqne’am, Israel), and pH impedance—and requires interruption of drug administration for at least 10 days, whereas the second must be performed with the most recent technique: pH impedance. In deciding which method to use for assessing reflux, we must remember that each has a basically different aim. The off-treatment approach evaluates gastroesophageal reflux under a baseline condition and classifies the patient according to GERD phenotype. More specifically, this examination should establish whether the patient
Curr Gastroenterol Rep (2015) 17:25
has true NERD, i.e., pathologic acid exposure; HE, i.e., reflux falling within normal limits but causing the patient’s symptoms; or functional heartburn, i.e., normal reflux with no relationship to the patient’s symptoms. According to recent studies [7, 8•], functional heartburn, which excludes patients from the GERD category and consequently from the concept of refractoriness, may be found in about one third of cases. On the other hand, in measuring reflux while the patient is taking PPIs (on-treatment modality), the goal is to gain insight into the possible causes of treatment failure. This approach requires that the patient have symptoms during the study period, because we want to establish whether there is a correlation between the reflux episodes and the symptoms. This correlation is evaluated with symptom association probability (SAP), which expresses the probability that this temporal association is statistically significant. Reflux studies performed with pH multichannel intraluminal impedance (pH-MII) and SAP analysis in patients unresponsive to PPIs [7, 8•, 9, 10] have reported that SAP is positive for acid reflux in a minority of cases (less than 10 %), positive for weakly acidic or nonacid reflux in about one third, and negative in more than 50 %. These results indicate that the vast majority of these patients— certainly those with a negative SAP but even at least a portion of those with SAP positive for less acidic reflux—have been treated with a drug inadequate in relieving their symptoms. It seems reasonable to suggest off-treatment monitoring for patients with a low probability of having GERD, because in these cases we must confirm the initial diagnosis, and reflux monitoring with pH-MII during PPI administration for patients unresponsive to treatment but with a high probability of having GERD, because this way we have the chance to understand why the treatment failed. However, we must be aware that in most of these patients, the added value of reflux monitoring lies in excluding GERD and preventing unnecessary and even harmful measures. In conclusion, true PPI refractoriness—i.e., lack of response to an adequate dose of PPIs for an adequate period of administration in a patient whose symptoms are mainly the result of esophageal acid exposure—is an infrequent event. Although identifying it may be difficult, it may be crucial for patient management. Compliance with Ethics Guidelines
Page 3 of 3 25
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
2.
3.•
4.••
5.
6.
7.
8.•
9.
Conflict of Interest Fabio Baldi declares no conflict of interest. 10. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
Carlsson R, Dent J, Watts R, et al. Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. International GORD Study Group. Eur J Gastroenterol Hepatol. 1998;10: 119–24. Inadomi JM, McIntyre L, Bernard L, et al. Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs. Am J Gastroenterol. 2003;98:1940–4. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61:1340–54. In this review, that address very completely the management of GERD patients unresponsive to PPI therapy, the Authors provide a clear definition of PPI-refractory reflux symptoms. Kahrilas PJ, Boeckstaens G. Failure of reflux inhibitors in clinical trials: bad drugs or wrong patients? Gut. 2012;61:1501–9. This paper provides a summary of PPI efficacy in patients with different manifestations of GERD. The results are expressed in terms of therapeutic gain in comparison with placebo and clearly indicate that the greatest PPI success occurred in patients with esophagitis or typical reflux symptoms. Poh CH, Gasiorowska A, Navarro-Rodriguez T, Willis MR, Hargadon D, Noelck N, et al. Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment. Gastrointest Endosc. 2010;71:28–34. Garcia-Compean D, Gonzalez Gonzalez JA, Marrufo Garcia CA, et al. Prevalence of eosinophilic esophagitis in patients with refractory gastroesophageal reflux disease symptoms: a prospective study. Dig Liver Dis. 2011;43:204–8. Hemmink GJM, Bredenoord AJ, Weusten Bas LAM, Monkelbaan JF, Timmer R, Smout Andrèe JPM. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: ‘on’ or ‘off’ proton pump inhibitor? Am J Gastroenterol. 2008;103:2446–53. Zerbib F, Belhocine K, Simon M, et al. Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease. Gut. 2012;61:501–6. This paper reports clinical findings and reflux parameters in patients not-responding to PPIs . It is one of the few studies that show the prevalence of functional heartburn in this group of patients. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;55:1398–402. Zerbib F, Roman S, Ropert A, et al. Esophageal pHimpedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol. 2006;101:1956–63.
INVITED COMMENTARY
PPI-Refractory GERD: an Intriguing, Probably Overestimated, Phenomenon Fabio Baldi 1,2
# Springer Science+Business Media New York 2015
Keywords Refractory GERD . Proton-pump inhibitors . GERD pathogenesis . GE reflux monitoring
The Concept of Refractoriness Proton-pump inhibitors (PPIs) are still a cornerstone of pharmacologic treatment for gastroesophageal reflux disease (GERD) because of their unquestionable efficacy in reducing the acid component of refluxate. However, their extensive use in the general population has revealed a subset of patients who are unsatisfied with these agents. These patients are considered unresponsive to PPIs, and this emerging phenomenon, defined as refractoriness to PPIs, may have a prevalence ranging from 10 to 40 % [1, 2]. Several drug-related variables, such as daily dosage and duration of therapy, clearly may be responsible for these numbers, and recently, it was proposed that the term PPI refractory be used only for patients unresponsive to a 12-week twice-daily course of PPI therapy [3•]. However, the greatest factor influencing PPI response likely is the type of patient to whom the drug is prescribed. It is now well established that the mechanisms underlying the symptoms in
* Fabio Baldi [email protected]; [email protected] 1
Center for the Study of Diseases of the Esophagus, University of Bologna, Bologna, Italy
2
GVM Care and Research, Cotignola, RA, Italy
patients with GERD are related not only to esophageal acid exposure, especially in those without mucosal erosions (i.e., with nonerosive reflux disease (NERD)) who have a possibly normal but still symptomatic acid reflux (i.e., hypersensitive esophagus (HE)). In all these patients, who represent a large proportion of the GERD population, another very important mechanism for symptom occurrence is enhanced esophageal sensitivity, which also may be associated with central sensitization. We can speculate that the two mechanisms—acid exposure and hypersensitivity—each might play a different role throughout the spectrum of GERD phenotypes. Acid exposure is a predominant factor in patients with erosive disease but is less important in those without mucosal lesions; on the contrary, hypersensitivity is the major mechanism in patients without lesions and with normal reflux (Fig. 1). Despite this heterogeneous pathogenesis, however, we treat our GERD patients with drugs—PPIs—characterized by a very selective mechanism of action, i.e., the inhibition of acid secretion. It thus is reasonable to expect that the efficacy of this therapy is related directly and proportionally to the role of acid exposure in the individual patient, and this is exactly what occurs in clinical practice. A recently published paper [4••] provides an elegant summary of PPI efficacy in patients with different manifestations of GERD. The authors analyzed randomized controlled trials and evaluated the placebo effect and therapeutic gain for each patient category. Their data clearly indicate that the greatest PPI success—75 % or more—occurred in patients with esophagitis or typical reflux symptoms, such as heartburn or reflux-induced chest pain. On the contrary, patients with regurgitation as their main symptom or with laryngeal manifestations such as hoarseness or chronic cough showed a poor response to PPIs, with
25
Curr Gastroenterol Rep (2015) 17:25
Page 2 of 3
Pathogenetic mechanisms in GERD phenotypes
ERD
NERD
HE
Hypersensitivity
Acid exposure
visceral
central
ERD = Erosive Reflux Disease NERD = Non Erosive Reflux Disease HE = Hypersensitive Esophagus
Fig. 1 Pathogenetic mechanisms in GERD phenotypes
a success rate of less than 50 %. In the latter case, we should not consider PPI refractoriness; rather, we should question whether acid reflux is the cause of the symptoms.
Diagnostic Approach The diagnostic approach to GERD classified as PPI refractory should follow an algorithm (Fig. 2) aimed at first establishing whether true refractoriness exists and, if so, determining its cause. In a patient with a diagnosis of GERD and a poor response to PPIs, the first question to answer is whether the symptoms the patient is reporting are the result of acid reflux. However, before we undertake an invasive investigation, we must
Diagnostic work-up in patients unresponsive to PPIs Clinical re-evaluation
Endoscopy (if indicated)
GERD probability
low
pH/pH-MII off tx
Fig. 2 Diagnostic work-up in patients unresponsive to PPIs
high
pH-MII on tx
reconsider the main symptoms of the patient. It is not unusual for GERD patients also to report dyspeptic symptoms, such as epigastric pain or postprandial fullness, and that they are unsatisfied with the therapy because these symptoms persist. Other patients have been treated for laryngeal or respiratory symptoms, even in the absence of typical reflux manifestations. In these cases, the lack of response to PPI administration too quickly is attributed to Brefractoriness^ without a reevaluation for extra-esophageal causes. Only patients with a well-established diagnosis of GERD, such as those with esophagitis or typical symptoms, or those with less typical manifestations but a high probability of having GERD should be managed as PPI-refractory patients. A diagnostic tool used very often in these patients is upper gastrointestinal (GI) endoscopy. The main objective of this examination is to rule out esophageal or gastric lesions; however, the sensitivity of endoscopy in PPI-refractory patients is very low. The few studies reporting endoscopic findings in this select patient group clearly indicate that the probability of detecting mucosal erosions is far less than 10 % [5]. Even histologic evaluation for eosinophilic esophagitis in these patients is disappointing, because its prevalence appears to be less than 5 % [6]. However, despite its poor sensitivity, upper GI endoscopy may be fundamental in reassuring both the patient and the doctor and may be reasonably indicated in three circumstances: (1) if it was not performed previously, (2) if mucosal biopsies are not available, and (3) if the patient previously had a diagnosis of severe esophagitis. Assessment of gastroesophageal reflux and its relationship to the symptoms is certainly the most appropriate investigation in GERD patients classified as PPI refractory. It may be performed in two different settings: in the absence of antisecretory therapy (off treatment) or during PPI administration (on treatment). The first approach may be followed using any of the methods now available—pH-metry, Bravo capsule (Given Imaging, Yoqne’am, Israel), and pH impedance—and requires interruption of drug administration for at least 10 days, whereas the second must be performed with the most recent technique: pH impedance. In deciding which method to use for assessing reflux, we must remember that each has a basically different aim. The off-treatment approach evaluates gastroesophageal reflux under a baseline condition and classifies the patient according to GERD phenotype. More specifically, this examination should establish whether the patient
Curr Gastroenterol Rep (2015) 17:25
has true NERD, i.e., pathologic acid exposure; HE, i.e., reflux falling within normal limits but causing the patient’s symptoms; or functional heartburn, i.e., normal reflux with no relationship to the patient’s symptoms. According to recent studies [7, 8•], functional heartburn, which excludes patients from the GERD category and consequently from the concept of refractoriness, may be found in about one third of cases. On the other hand, in measuring reflux while the patient is taking PPIs (on-treatment modality), the goal is to gain insight into the possible causes of treatment failure. This approach requires that the patient have symptoms during the study period, because we want to establish whether there is a correlation between the reflux episodes and the symptoms. This correlation is evaluated with symptom association probability (SAP), which expresses the probability that this temporal association is statistically significant. Reflux studies performed with pH multichannel intraluminal impedance (pH-MII) and SAP analysis in patients unresponsive to PPIs [7, 8•, 9, 10] have reported that SAP is positive for acid reflux in a minority of cases (less than 10 %), positive for weakly acidic or nonacid reflux in about one third, and negative in more than 50 %. These results indicate that the vast majority of these patients— certainly those with a negative SAP but even at least a portion of those with SAP positive for less acidic reflux—have been treated with a drug inadequate in relieving their symptoms. It seems reasonable to suggest off-treatment monitoring for patients with a low probability of having GERD, because in these cases we must confirm the initial diagnosis, and reflux monitoring with pH-MII during PPI administration for patients unresponsive to treatment but with a high probability of having GERD, because this way we have the chance to understand why the treatment failed. However, we must be aware that in most of these patients, the added value of reflux monitoring lies in excluding GERD and preventing unnecessary and even harmful measures. In conclusion, true PPI refractoriness—i.e., lack of response to an adequate dose of PPIs for an adequate period of administration in a patient whose symptoms are mainly the result of esophageal acid exposure—is an infrequent event. Although identifying it may be difficult, it may be crucial for patient management. Compliance with Ethics Guidelines
Page 3 of 3 25
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
2.
3.•
4.••
5.
6.
7.
8.•
9.
Conflict of Interest Fabio Baldi declares no conflict of interest. 10. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
Carlsson R, Dent J, Watts R, et al. Gastro-oesophageal reflux disease in primary care: an international study of different treatment strategies with omeprazole. International GORD Study Group. Eur J Gastroenterol Hepatol. 1998;10: 119–24. Inadomi JM, McIntyre L, Bernard L, et al. Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs. Am J Gastroenterol. 2003;98:1940–4. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61:1340–54. In this review, that address very completely the management of GERD patients unresponsive to PPI therapy, the Authors provide a clear definition of PPI-refractory reflux symptoms. Kahrilas PJ, Boeckstaens G. Failure of reflux inhibitors in clinical trials: bad drugs or wrong patients? Gut. 2012;61:1501–9. This paper provides a summary of PPI efficacy in patients with different manifestations of GERD. The results are expressed in terms of therapeutic gain in comparison with placebo and clearly indicate that the greatest PPI success occurred in patients with esophagitis or typical reflux symptoms. Poh CH, Gasiorowska A, Navarro-Rodriguez T, Willis MR, Hargadon D, Noelck N, et al. Upper GI tract findings in patients with heartburn in whom proton pump inhibitor treatment failed versus those not receiving antireflux treatment. Gastrointest Endosc. 2010;71:28–34. Garcia-Compean D, Gonzalez Gonzalez JA, Marrufo Garcia CA, et al. Prevalence of eosinophilic esophagitis in patients with refractory gastroesophageal reflux disease symptoms: a prospective study. Dig Liver Dis. 2011;43:204–8. Hemmink GJM, Bredenoord AJ, Weusten Bas LAM, Monkelbaan JF, Timmer R, Smout Andrèe JPM. Esophageal pH-impedance monitoring in patients with therapy-resistant reflux symptoms: ‘on’ or ‘off’ proton pump inhibitor? Am J Gastroenterol. 2008;103:2446–53. Zerbib F, Belhocine K, Simon M, et al. Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease. Gut. 2012;61:501–6. This paper reports clinical findings and reflux parameters in patients not-responding to PPIs . It is one of the few studies that show the prevalence of functional heartburn in this group of patients. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut. 2006;55:1398–402. Zerbib F, Roman S, Ropert A, et al. Esophageal pHimpedance monitoring and symptom analysis in GERD: a study in patients off and on therapy. Am J Gastroenterol. 2006;101:1956–63.
