Gastroesophageal Reflux

Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

Notre these est une contribution pour repenser les rapports entre sciences et ethiques, et avancer vers une democratie epistemique. Qu'il s'agisse de demontrer l'insoutenabilite d'une science contre l'Homme ou d'identifier les conditions d'une remontee de l'Homme dans les sciences, la visee nous semble la meme : il s'agit de reunir-sans-unifier ce qui, dans la science, est de l'ordre de l'epistemique, du technique et de l'ethique. Pour ce faire, il nous faut prealablement travailler en profondeur sur deux espaces - epistemologique et ethique -, et ceci sans d'abord les melanger ou les recouvrir l'un sur l'autre. Car si les sciences nous sont effectivement donnees dans leurs melanges (avec le technique, le politique, l'economique, le social ou le philosophique), rendant a la mode les themes de technoscience, de nouveau regime de production des savoirs ou encore de science post-normale, il ne s'agit pas pour nous d'un symptome de la fin de l'epistemologie mais de la necessite de son renouvellement. Celui-ci passera, et il s'agit la de notre these principale, par de nouveaux rapports avec l'ethique. Nous donnons a cette these le nom d'integrite epistemique et ethique des sciences. Afin de definir les conditions et la portee de celle-ci, nous proposons deux hypotheses, respectivement au sein de l'espace epistemologique et ethique : celle d'un pluralisme epistemique ordonne et celle d'une ethique generique. Nous defendons ces hypotheses a la lumiere d'un long travail d'instruction d'un objet des sciences et techniques contemporaines, le poisson genetiquement modifie. In fine, notre travail permet de re-interroger les postulats classiques de l'evaluation et de proposer de nouvelles pistes de recherches.

COMPARED TO OTHER GASTROINTESTINAL (GI) SYMPTOM COMPLEXES, the medical management of gastroesophageal reflux disease (GERD) appears fairly straightforward. Whereas there are few pharmacotherapeutic options for many other GI symptoms for which patients may seek medical advice, the majority of patients with troublesome GERD symptoms can be rendered asymptomatic with a once-daily dose of a proton pump inhibitor (PPI) within 4 to 8 weeks of starting therapy. Thus, many may consider GERD an easily treated problem that can be vanquished with the mere stroke of a pen. Yet as a gastroenterologist, I find my patients with GERD to be some of the most difficult to treat. The patients I see are the relatively small group who do not obtain relief with that PPI prescription. Unfortunately, there are currently few therapeutic options that are effective in alleviating GERD symptoms that persist despite PPI use. While I often recommend that patients take their PPI twice daily instead of once, or switch to another PPI, this decision is based on limited data from uncontrolled open-label trials with significant methodologic flaws.1,2 Stepping down PPI therapy from double-dose to standard doses is successful for most patients.3 There are no other proven therapies, and I am left with limited therapeutic options for patients with refractory GERD. These patients are the proverbial high-hanging fruit that are the most difficult to reach. However, these fruit can grow the largest, rewarding those who develop tools to snare them. It is important to gain a better understanding of GERD pathophysiology to devise better strategies for helping these patients to obtain relief. GERD has been traditionally thought of as the reflux of acidic gastric contents into the esophagus, resulting in symptoms and/or esophageal injury. The gold standard diagnostic criteria for GERD involves 24-hour esophageal pH monitoring, requiring an intra esophageal pH of less than 4 for more than 4% of the time over a 24-hour period. It is generally believed that if there is no gastric acid production, there can be no reflux symptoms. However, reflux symptoms often persist. Studies confirm that the majority of patients with GERD-like symptoms, despite high-intensity (double-dose or greater) PPI therapy, have a very low prevalence of reflux by the gold standard definition.4 So what are the mechanisms responsible for ongoing symptoms? Because PPIs have been so effective in relieving GERD symptoms, the basic mechanism that enables gastroesophageal reflux has been mostly ignored. I am referring here to the presence of both anatomic factors, such as the presence of a hiatus hernia, and physiologic factors, specifically the function of the lower esophageal sphincter (LES). It is possible that non-acid gastric contents that access the esophagus through a faulty LES may cause symptoms. Another possibility may be that GERD-like symptoms are independent of gastroesophageal reflux, and are merely interpreted as GERD. A new clinical tool may help both investigation and management. With multichannel impedance manometry (MIM), an impedance catheter is passed transnasally into the esophagus. It detects the presence of gas and fluid in the esophagus, and the direction of travel (i.e., towards the stomach with a swallow, towards the mouth with gastroesophageal reflux). With MIM and pH monitoring, reflux episodes can be counted and separated into acidic and non-acidic events. If further combined with a patient symptoms diary, a clinician can determine the relationship of GERD-like symptoms to reflux events. Using MIM, researchers have shown that patients with GERD who are treated with PPIs do not have fewer reflux events, but the refluxate composition changes from primarily acidic to primarily non-acidic.5 Baclofen, which decreases LES relaxation frequency, decreases reflux events and symptom burden.6 Unfortunately, due to its side-effect profile, baclofen will likely not be widely used for refractory GERD symptoms. However, there may be other medications that improve LES function and have similar effects. It is also possible that surgical interventions may be useful for patients with refractory GERD symptoms who have ongoing non-acidic reflux.7 Hopefully, the development of MIM will foster further research into the pathophysiology of refractory GERD, allowing pharmaceutical developers to better identify potential therapeutic targets, and giving clinicians the tools necessary to pluck the juiciest fruit right from the highest reaches of the trees. Meanwhile, pharmacists should strive to identify patients with symptoms refractory to PPI therapy, who may be candidates for a PPI reduction or discontinuation. ■

Nocturnal Gastroesophageal Reflux: Assessment and Clinical Implications

This is the second WGO guideline published to complement World Digestive Health Day themes. WGO guidelines are intended to highlight appropriate, context-sensitive and resource-sensitive management options for all geographical regions, regardless of whether they are considered to be “developing,” “semi-developed,” or “developed.” There is a concern that guidelines from developed countries, by emphasizing high-tech investigations and Barrett esophagus (BE) surveillance, for example, may divert research and clinical resources from more urgent problems in developing and semideveloped countries. However, one could argue that there are similar problems in developed countries and that an overemphasis on complications or “proposed GERD associations” (as in the Montreal Consensus1) is leading to inappropriate investigations and resource utilization even in developed regions. It is also important to emphasize to health care insurers and funding bodies that appropriate, effective therapy is both therapeutic and diagnostic and that conducting mandatory investigations [eg, esophagogastroduodenoscopy (EGD) to permit proton-pump inhibitor (PPI) therapy is not patient-centered and, more importantly, is likely not to be cost-effective. WGO Cascades are thus context-sensitive, and the context is not necessarily defined solely by resource availability. Neither the epidemiology of the condition, nor the availability of resources for the diagnosis and management of gastroesophageal reflux disease (GERD), is sufficiently uniform throughout the world to support the provision of a single, gold-standard approach. WGO Cascades: a hierarchical set of diagnostic, therapeutic, and management options for dealing with risk and disease, ranked by the resources available. GERD is now widely prevalent around the world (Table 1), with clear evidence of increasing prevalence in many developing countries. Prevalence estimates show considerable geographic variation, but it is only in East Asia that they are currently consistently lower than 10%.2 The high prevalence of GERD, and hence of troublesome symptoms, has significant societal consequences, impacting adversely on work productivity3 and many other quality-of-life aspects for individual patients.4,5TABLE 1: GERD Symptoms: Range of IncidencePractice recommendations should be sensitive to context, with the goal of optimizing care in relation to local resources and the availability of health care support systems. The expression of the disease is considered to be similar across regions, with heartburn and regurgitation as the main symptoms. For initial management, the patient may purchase over-the-counter (OTC) medication for heartburn relief or seek further advice from a pharmacist. When patients perceive that their symptoms are more troublesome, they may seek a doctor’s advice; depending on the patient’s circumstances and the structure of the local health care system, patients may seek advice at the primary care level or they may consult a gastroenterology specialist or surgeon, directly or by referral. The WGO Cascade approach aims to optimize the use of available health care resources for individual patients, based on their location and access to various health care providers. CLINICAL FEATURES Predisposing and Risk Factors GERD is a sensorimotor disorder associated with impairment of the normal antireflux mechanisms (eg, lower esophageal sphincter function, phrenicoesophageal ligament), with changes in normal physiology (eg, impaired esophageal peristalsis, increased intragastric pressure, increased abdominothoracic pressure gradient) or, very rarely, excess gastric acid secretion (Zollinger-Ellison syndrome). Eating and Lifestyle An increase in GERD symptoms occurs in individuals who gain weight.6 A high body mass index (BMI) is associated with an increased risk of GERD.7 High dietary fat intake is linked to a higher risk of GERD and erosive esophagitis (EE).8 Carbonated drinks are a risk factor for heartburn during sleep in patients with GERD.9 The role of coffee as a risk factor for GERD is unclear; coffee may increase heartburn in some GERD patients,10 but the mechanism is unknown and it may be due to caffeine, rather than coffee per se. Coffee is not a dominant risk factor. The role of alcohol consumption as a risk factor for GERD is unclear. Excessive, long-term use may be associated with progression to esophageal malignancy, but this may be independent of an effect of alcohol on GERD.11,12 The role of smoking as a risk factor for GERD is unclear, although like alcohol, it is associated with an increased risk of malignancy.13,14 Medication—Certain Medications May Affect GERD See the Patient history and physical examination section. The treatment of comorbidities (eg, with calcium channel blockers, anticholinergics, and nonsteroidal anti-inflammatory drugs (NSAIDs) may negatively affect GERD and its treatment.15 Some medications (eg, potassium supplements, tetracycline, bisphosphonates) may cause upper gastrointestinal (GI) tract injury and exacerbate reflux-like symptoms or reflux-induced injury. Pregnancy Heartburn during pregnancy usually does not differ from the classic presentation in the adult population, but it worsens as pregnancy advances. Regurgitation occurs with approximately the same frequency as heartburn, and GERD in the first trimester is associated with a number of altered physiological responses.16,17 Factors that increase the risk of heartburn18 are: heartburn before pregnancy, parity, and duration of pregnancy. Maternal age is inversely correlated with the occurrence of pregnancy-related heartburn.19 Symptomatology GERD has a wide spectrum of clinical symptom-based and injury-based presentations, which may manifest either separately or in combination. Symptom evaluation is key to the diagnosis of GERD, particularly in the evaluation of the effectiveness of therapy. Heartburn and regurgitation are the most common symptoms, but atypical symptoms of GERD may occur, with or without the common symptoms. Atypical symptoms may include epigastric pain20 or chest pain,1,21 which may mimic ischemic cardiac pain, as well as cough and other respiratory symptoms that may mimic asthma or other respiratory or laryngeal disorders. Dysphagia may also occur. A minority of GERD patients have multiple unexplained symptoms, which may be associated with psychological distress22 (Table 2).TABLE 2: GERD Symptoms23,24Natural History Most cases of GERD are mild and are not associated with a significant increase in morbidity or mortality in comparison with the general population. In most GERD patients, the severity of the condition remains stable or improves over a 5-year observation period during current routine clinical care.26 There is a relationship between GERD and obesity: a higher BMI or larger waist circumference and weight gain are associated with the presence of symptoms and complications of GERD, including BE.27 Complicated GERD is characterized by stricture, BE, and esophageal adenocarcinoma. The Montreal consensus includes EE as a complication of GERD (recognizing that the definition of “mucosal breaks” used in the Los Angeles classification includes esophageal ulceration in the range of reflux esophagitis).28 Nonerosive reflux disease (NERD) may progress to EE in approximately 10% of GERD patients,29 and EE may therefore be considered as a manifestation of more severe reflux disease. EE is associated with BE and is a major risk factor for BE. In comparison with patients who were free of GERD at follow-up, those with EE had a 5-fold increased risk of BE after 5 years, in a cohort of the general population in Sweden.30 Globally, BE is rare in patients with GERD. It is more common in western populations. It is not known when BE develops relative to the onset of GERD; however, it appears to be more prevalent in older individuals and is strongly associated with an increased risk of esophageal adenocarcinoma.31 There is a well-documented association between BMI and adenocarcinoma of the esophagus and gastric cardia, although the risk of malignancy in a given individual with GERD is very low.32 Alarm Features Most alarm features are not specific for GERD; many are associated with alternative diagnoses that are unrelated to GERD. In most countries, many of these features relate to gastric cancer, complicated ulcer disease, or other serious illnesses. Dysphagia.33 Odynophagia (painful swallowing). Recurrent bronchial symptoms, aspiration pneumonia. Dysphonia. Recurrent or persistent cough. GI tract bleeding. Frequent nausea and/or vomiting. Persistent pain. Iron-deficiency anemia. Progressive unintentional weight loss. Lymphadenopathy. Epigastric mass. New-onset atypical symptoms at age 45 to 55 years (a lower age threshold may be appropriate, depending on local recommendations). Family history of either esophageal or gastric adenocarcinoma.34 The WGO Global Guideline on common GI symptoms may also be consulted: http://www.worldgastroenterology.org/guidelines/global-guidelines/common-gi-symptoms and http://journals.lww.com/jcge/Fulltext/2014/08000/Coping_With_Common_Gastrointestinal_Symptoms_in.4.aspx. DIAGNOSIS Diagnostic Considerations The presence of heartburn and/or regurgitation symptoms 2 or more times a week is suggestive of GERD.35 Clinical, endoscopic, and pH-metric criteria provide a comprehensive characterization of the disease, although investigations are usually not required to establish a diagnosis of GERD—with the caveat that the pretest probability of GERD varies markedly between geographical regions. The initial evaluation should document the presence, severity, and frequency of heartburn, regurgitation (acid or otherwise), and alarm features; atypical esophageal, pulmonary, otorhinolaryngological, and oral symptoms should also be sought. It may be helpful to evaluate precipitating factors such as eating, diet (fat), activity (stooping), and recumbence; and relieving factors (bicarbonate, antacids, milk, OTC medications). At this point, it is important to rule out other GI diagnoses, particularly upper GI cancer and ulcer disease, especially in areas in which these are more prevalent. It is also important to consider other, non-GI diagnoses, especially ischemic heart disease. Diagnostic questionnaire tools for GERD (reflux disease questionnaires, RDQs) have been developed for epidemiological studies. However, RDQs did not perform particularly well in the Diamond study.36 In fact, diagnosis by a physician such as the family practitioner or GI specialist showed better sensitivity and specificity for the diagnosis of GERD than did the RDQ. Questionnaires are generally difficult to use in clinical practice. A careful history is the basis for symptomatic diagnosis, with EGD being reserved for identifying or excluding significant structural lesions in selected cases. A region-based assessment of the local “pretest probability” may provide some guidance with regard to the choices and sequence of diagnostic tests needed, given the relatively poor predictive value of most symptoms. PPI Treatment as an Aid to Diagnosis “PPI trial.” It is no longer recommended to administer an empirical short-term (1 to 2 week) course of high-dose PPI treatment to determine whether or not the patient’s symptoms are acid related,36 since this is neither sensitive nor specific. Nonetheless, this is commonly done in practice. A formal course of PPI therapy, of adequate duration (usually 8 weeks) is required to assess the treatment response in GERD patients. Weakly acidic reflux episodes may be a substantial proportion of all reflux episodes. If this is the case, such patients may not respond well to PPI therapy (20% to 40% of GERD patients may not respond to PPI treatment).20 In addition, genuinely alkaline reflux may comprise up to 5% of all reflux episodes. In a subset of PPI nonresponders, reflux-like symptoms may be due to functional heartburn, rather than GERD.20 Alternative diagnoses, including peptic ulcer disease, upper GI malignancy, functional dyspepsia, eosinophilic esophagitis, achalasia of the cardia, and cardiovascular disease should also be considered. In patients with cases that are refractory to PPI treatment, ambulatory 24-hour esophageal pH/impedance monitoring, with the patient off PPI therapy, may be considered to help characterize symptoms.37 If there has been complete failure to respond to PPI treatment, the PPI should be stopped at least 1 week before 24-hour pH monitoring is performed (rescue antacid may be allowed when necessary), to assess for acid reflux. If the refractory reflux symptoms have responded partially, 24-hour pH monitoring (with or without esophageal impedance monitoring) should be performed with PPI administration being continued, to assess for acid reflux that is persistent despite treatment. Occasionally, 24-hour pH monitoring with esophageal impedance monitoring may be required, with the patient both on and off PPI therapy.38 Helicobacter pylori Infection39 In many countries with a high prevalence of H. pylori infection, peptic ulcer and gastric cancer continue to be more common than GERD and cause much higher morbidity and mortality.40 In this setting, any approach to the diagnosis and management of upper gut symptoms must include an assessment of the risks of infection with H. pylori and an awareness of the overlap among, and difficulty of discriminating between, symptoms of GERD, peptic ulcer disease, and functional symptoms—with a decision regarding the relative merits of a test-and-treat approach in comparison with EGD to test for H. pylori and related diseases before empirical antireflux therapy. Although epidemiological studies show a negative association between the prevalence of H. pylori infection and the presence and severity of GERD, this is not proof of causation. H. pylori infection should be sought and eradication therapy given when indicated in accordance with international, national, or local guidelines.41 Although there may be an inverse correlation between H. pylori infection and GERD prevalence and severity, this may well reflect differing effects of a separate, distinct factor or factors on the 2 conditions, rather than a causal relationship between H. pylori and GERD. Physiological studies using pH monitoring have shown that abnormal esophageal acid exposure, which is the hallmark of esophageal reflux, is not influenced by the presence or absence of H. pylori infection. In most patients, H. pylori status has no effect on symptom severity, symptom recurrence, or treatment efficacy in GERD. H. pylori eradication does not exacerbate preexisting GERD or affect treatment efficacy.42 Indeed, in patients with H. pylori-positive uninvestigated dyspepsia, eradication therapy is associated with a lower prevalence of reflux-like symptoms (36%) than control therapy (49%).43 A subgroup of patients infected with more proinflammatory strains of H. pylori (virulence factors vacA and cagA) may be less likely to have severe esophagitis or BE. This may be because infection in these patients more often causes severe corpus gastritis with atrophy, resulting in reduced acid output. However, these patients are at much greater risk of developing gastric cancer. Eradication therapy in these patients has the potential to reduce the risk of gastric malignancy.41 PPIs and H. pylori PPIs are associated with a worsening of the histologic grade of gastritis in H. pylori-infected patients, accompanied by an increased prevalence of gastric mucosal atrophy and intestinal metaplasia44 that occurs earlier, as well as more frequently, than in H. pylori-infected patients who do not take PPIs. As gastric mucosal atrophy and intestinal metaplasia are known to be the major risk factors for the development of gastric adenocarcinoma, most expert guidelines recommend testing and treating for H. pylori before long-term PPI therapy, particularly in younger patients. Endoscopy EGD is usually performed for new-onset upper GI symptoms, almost irrespective of age, in regions where it is available and affordable and where both the frequency of ulcer disease and the concern about malignancy are high, as in most of Asia.45 The Cascades given below address the limited availability of endoscopy in less well-resourced areas by suggesting the use of empiric H. pylori eradication therapy as a first-line strategy. If EGD is performed in regions where the prevalence of GERD is low, the majority of GERD patients will have NERD; in these circumstances, the sensitivity of EGD for the diagnosis of GERD will be low and the main outcome will therefore be the exclusion of other upper GI diagnoses. Endoscopy is particularly recommended for patients with alarm features suggestive of GERD with complications or of other significant upper GI disease such as dysphagia, bleeding, odynophagia, or weight loss. Patients with dysphagia should undergo investigation for a potential complication or for an underlying motility disorder, achalasia, stricture, ring, eosinophilic esophagitis, or malignancy.25 In several Asian countries, the preference for EGD is driven by the risk of malignancy at an early age and by the availability of “affordable, direct-access” endoscopy—an “endoscopy first” approach. Additional investigations other than EGD are rarely needed; furthermore, they have variable accuracy and are often unavailable. Patient History and Physical Examination The goals of patient evaluation include the assessment of symptoms and risk factors for the diagnosis of GERD and the prediction of long-term sequelae. In this regard, it is important to consider the regional epidemiology of upper GI disease and the pretest probability of GERD relative to other conditions. In Asia, for instance, BE is uncommon and it is not therefore an important risk for esophageal adenocarcinoma, which is itself uncommon. The prevalence of peptic ulcer and gastric cancer are the greater drivers of endoscopy in Asia where, unlike in the west, esophageal adenocarcinoma is less common. Personal and Family History Features The following features may be helpful in making a diagnosis and assessing the severity of GERD: Predisposing factors and risk factors, including family history. Duration of symptoms. Daytime symptoms, including time of day and relationship to meals. Nocturnal symptoms, including impact on sleep and the effects of a recumbent position and large, late evening meals. Treatments and remedies tried, including symptomatic response to therapy; symptom improvement with acid-lowering medications including antacids supports a diagnosis of GERD. Periodic dysphagia or food bolus impaction may suggest reflux-related esophageal injury, stricture or malignancy, as well as eosinophilic esophagitis or esophageal dysmotility.46 Drug History The patient should be asked about any medications that may contribute to upper gut symptoms (not necessarily GERD): Aspirin/NSAIDs, iron, potassium, quinidine, tetracycline, bisphosphonates. Zidovudine, anticholinergic agents, α-adrenergic antagonists, barbiturates. β2-adrenergic agonists, calcium channel blockers, benzodiazepines, dopamine. Estrogens, narcotic analgesics, nitrates, progesterone, prostaglandins, theophylline. Tricyclic antidepressants, chemotherapy. Dietary History In some patients, bloating or constipation may be associated with an increased risk of GERD or gastroesophageal reflux symptoms (GERS).47 Several studies suggest that stopping smoking and some physical measures, as well as modification of meal size and timing, be but there is limited evidence for the of alcohol and dietary including caffeine, and In those who are weight may be associated with improvement in GERD or may increase the for Physical There are usually no physical of GERD. and BMI are to of rarely, be and to other problems such as cardiac disease, and cancer. Diagnostic for GERD A diagnosis of GERD be in the of heartburn and In pregnancy, GERD be on the basis of symptoms If the dominant or most troublesome symptoms are atypical for GERD, other diagnoses should be including H. diseases and disease. In regions with a high prevalence of H. pylori infection, an initial H. pylori test-and-treat or endoscopy should be considered. are pH or monitoring and esophageal be performed but are required to assess structural (eg, in patients with dysphagia symptoms. reflux symptoms or GERD complications be using (Table Diagnostic for Diagnosis ulcer disease. gut and functional heartburn on the basis of a clinical response to therapeutic acid pH monitoring, or impedance pH ring, of the body motility esophageal heart disease, disease. chest Cascades for the Diagnosis of GERD For perform esophageal in regions or for selected patients in regions with features suggest eosinophilic For consider this only there is a high prevalence of BE in the local population and there are For most EGD will not the management, in the absence of alarm features or access to antireflux There is no role for upper GI in the investigation of routine upper GI symptoms (Table Cascades for the Diagnosis of Although the severity and frequency of symptoms between GERD patients, reflux symptoms do not the criteria for a diagnosis of GERD and are with and as or severe symptoms with of and therapy to their of the management of GERD a both with to the and to the health care who or provide therapy. The of GERD management are and of esophageal acid either by local acid or by of gastric acid secretion using or, rarely, antireflux The primary goals of treatment are to symptoms, the patient’s of esophagitis, symptom recurrence, and or complications in the most heartburn less than per week will respond to with an antacid or a week or less medications are very to have any are and are to antacids in this of patients, of or that symptoms and of late at may be in those who are may also reduce the frequency of symptoms. Patients who have more symptoms should be for therapy. A diagnosis of troublesome symptoms 2 or more times per empirical therapy with an acid inhibitor or, may also be used PPIs or are or for symptom relief in patients a If OTC or patients will often to a or primary care The definition of treatment failure to a on the treatment being In treatment may because the patient does not have GERD; in it may be that the treatment is to address the severity of the GERD. In the case, there may be a response to treatment, and management will be by the availability and of more may to care initial management to reflux should on clinical with treatment of the symptoms being the It is to the effective of For patients with mild symptoms, and some patients with PPI therapy is a management in many cases. At the primary care PPIs or a of and therapy be at the for therapy, which may be more than therapy For better symptom patients should be about to use PPI treatment therapy may be defined as the PPI to before and in the of to before the meal of the day as Patients in PPI treatment with or without may from a of therapy to a PPI therapy may not work for a proportion of patients, either because the symptoms are not due to acid an alternative diagnosis should be because the of acid is to control the symptoms. to care should be considered for patients. OTC antacids show in patients with weight in the and is an important of the long-term management of GERD and should not be as a therapeutic as it may reduce the frequency and of symptoms and the grade of of late of precipitating factors, use of a sleep OTC or the most but usually symptom relief and be as Alarm features the Alarm features for patients in the of OTC treatment by the diagnosis, patients with alarm symptoms to and patients on the use of their OTC in some may include the availability of treatment choices varies between countries. for short-term or antacids gastric and these include acid with of for short-term to available than OTC Patients advice for reflux symptoms may from OTC PPI treatment. which have OTC availability in individual the of the OTC PPIs may be available in other Alarm features the Alarm features medication without investigation should be in the presence of the following Heartburn or regurgitation symptoms Duration with severe or after 2 of treatment with an OTC or when a or New-onset heartburn or regurgitation at age 45 to 55 age in several Asian regions. Dysphagia or or of GI and anemia. or of or weight loss. and/or suggestive of chest to or of In or below years of age for or below years for PPIs. The goals of are that the patient should and to an of with the most therapy. If and complete symptom relief is not patients should be recommended to a health care for diagnostic PPI who gastric acid should have an for long-term PPI the long-term for PPIs should be

Obesity Is Associated With Increased Transient Lower Esophageal Sphincter Relaxation

Reflux inhibitors, like the gamma-aminobutyric acid type B (GABA(B)) receptor agonist, baclofen, block transient lower esophageal sphincter relaxations (TLESRs) and are proposed as an add-on therapy in patients with proton pump inhibitor (PPI)-resistant gastroesophageal reflux. However, as other mechanisms of reflux become more important in the presence of a hiatal hernia (HH), the efficacy of reflux inhibitors to reduce acid and non-acid exposure may be hampered. Therefore, we compared the effect of baclofen in patients with no HH (-HH) and those with a large HH during PPI treatment. A total of 27 gastroesophageal reflux disease (GERD) patients on PPI were included; 16 had -HH and 11 had a large (> or =3 cm) HH (+HH). During PPI treatment, the effect of baclofen (3 x 20 mg) on acid and non-acid reflux was evaluated in a randomized, double-blind, placebo-controlled cross-over study. Reflux was measured during 24 h using combined esophageal impedance and pH-metry. The majority of reflux events consisted of both gaseous and liquid reflux with a significant increase in non-acid, mixed reflux episodes in +HH patients compared with those in -HH patients. Acid exposure time was in the normal range in both patient groups during both placebo and baclofen. In this study, baclofen significantly reduced the total number of reflux episodes with 36% in -HH patients and 43% in +HH patients, but did not change the number of acid reflux episodes or total acid exposure time. This study shows that baclofen is also effective in patients with GERD with +HH, further underscoring the potential of reflux inhibitors as treatment of GERD.

Issue Highlights

In 2009, an editorial by Putman focused on the dramatic increase in the use of proton pump inhibitors (PPIs) in infants [1]. Considering the increasing evidence that PPIs offer little benefit for most of the symptoms for which they are prescribed, Putman strongly highlighted the need for a serious effort to curtail their empiric use. The editorial was linked to a study by Orenstein et al, which detected no difference in efficacy between lansoprazole and placebo for symptoms attributed to gastroesophageal reflux disease (GERD) in infants [2]. A very recent review on the effects of PPIs on irritability and crying in infants confirmed the conclusion that these drugs do not offer relief from these symptoms for which they are commonly prescribed [3]. After all, it has recently been pointed out that volume rather than acid is often the key promoter of reflux-associated symptoms in infants. Distension-induced increase in gastric wall tension has been associated with high rates of transient lower esophageal sphincter relaxations and is considered one of the main mechanisms contributing to postprandial GER [4]. Despite all these evidences on PPIs uneffectiveness for many of the symptoms for which they are commonly prescribed, the rate of their prescriptions have exponentially increased over the last years. The latest combined NASPGHAN/ESPGHAN guidelines already in 2009 highlighted the need to distinguish physiologic GER events from GERD, limiting for the latter the use of PPIs [5]. However, a 2012 European survey carried out by our study group showed that only 1.8% of pediatricians reported a complete adherence to the guideline recommendations in their clinical practice. The most relevant violation of the guideline recommendations concerned the prescription of unnecessary acid suppressive medications [6] (Figure ​(Figure1).1). In order to inquire into the reasons why pediatricians did not follow the guideline recommendations, we performed another trial with the same pediatricians undergoing specific training on the guidelines being supervised in their clinical practice. As a result, trained pediatricians showed a significantly higher compliance with the international guidelines and infants with unexplained crying and distressed behaviour or with uncomplicated recurrent regurgitation and vomiting who were unproperly prescribed PPIs decreased dramatically [7]. Besides these data on PPI overuse, recent studies highlighted the occurrence of several adverse effects related to their assumption, such as a higher risk of bronchoalveolar lavage culture positivity and gastric bacterial overgrowth, food allergy, Clostridium difficile infection, gastric polyps and nodules [8-12]. Figure 1 Rates of pediatricians over-prescribing PPIs in the different European countries

PH studies: Clinical Indications

Infantile spasm (IS) is a specific rare type of seizure seen in an epilepsy syndrome of infancy; it is also known as West syndrome and is characterized by developmental regression and a specific pattern on electroencephalography (EEG) testing called hypsarrhythmia (chaotic brain waves). Gastroesophageal Reflux Disease (GERD) is considered a common clinical problem in every day paediatrics clinical practice. However, GERD diagnosis seems to be overestimated, mainly because such symptoms as crying, regurgitation, feeding refusal, back arching, wheezing, coughing and hoarseness are still considered suggestive for GERD, although they have already been demonstrated to be inaccurate (1), with consequent risk for disease overdiagnosis and inappropriate unnecessary Proton Pump Inhibitors (PPI) prescription. Herein, we report the cases of three patients with classical symptoms referable to IS who were initially misdiagnosed as having GERD. A newborn presented a history characterized by short episodes of crying associated with slight neck flexions and stiffening of the arms. Events tended to occur after feeding. Diagnosis of GERD was made, and PPI therapy started. However, as introducing treatment, no improvement was noted, on the contrary clinical manifestations exacerbated in the following 2 months: The child become even more irritable, jerks presented more frequently, occurring also while sleeping, neck flexions became more prominent as well as arms attacks. Flexion movements of legs were noticed as well. For this reason, the patient was admitted to our Gastroenterology Department. Infant's rate of growth was normal. Physical examination was totally unremarkable except for signs of psychomotor development regression: The child stopped to smile in response to face and to reach for objects. Medical history and physical examination were consistent with the diagnosis of IS. Neurological assessment was requested, and an EEG showed a hypsarrhythmic pattern, pathognomonic of IS. Brain magnetic resonance imaging (MRI) did not show any pathological finding confirming the diagnosis of cryptogenic IS. Adenocorticotrope hormone (ACTH) therapy was started with clinical improvement. A young baby was admitted for a 2-month history characterized by episodes of crying associated with flexion and extension movements of neck, arms and legs. Events occurred around sleeping and feedings. Clinical manifestations were initially classified as infant colics. However, after 3 weeks, the symptoms worsened (increasing in episodes frequency and duration, infant irritability) and were considered as suggestive for the diagnosis of GERD. PPI treatment was then started. Two months later, for persistence of symptoms, the child was admitted to our department. At admission, physical examination was negative, but the child presented extremely irritable and also in this case signs of psychomotor development regression were present: The infant could not show behaviour competences previously acquired like smiling on social contact, following objects with visual, sitting with supports. Medical history and physical examination were consistent with IS diagnosis. EEG showed a hypsarrhythmia pattern confirming diagnosis. Neurological examination and brain MRI scans were completely unremarkable. Cryptogenic IS was diagnosed. Therapy with steroids and ACTH was started with marked improvement on clinical symptoms. A 2-month-old boy who previously underwent surgical correction for intraventricular defect started to present frequent episodes of inconsolable crying, associated with neck extension, stiffening of the arms and trunk, sometimes followed by swallowing and vomiting. Symptoms were attributed to GERD, and therapy with PPI started. However, no improvement was noticed. In the following weeks, episodes became even more frequents with exacerbation of symptoms. His mother video recorded an attack (Video S1), which showed the presence of flexion spasms, presence of intractable GERD was suggested and the child eventually underwent fundoplicatio. No improvement was noticed: Persistence of symptoms and occurrence of spasms of the arms during acute episodes finally suggested diagnosis of West syndrome. IS was then confirmed by EEG while MRI was negative. Despite starting of appropriate therapy at 8 month of age, clinical signs of mental retardation were present. Although IS is a rare disorder, diagnosis is usually not hard: The age of patients is peculiar and a careful patient history with a complete neurological evaluation are usually sufficient conditions to suspect the disease. Traditionally, differential diagnosis of IS does not contemplate GERD (2). We have described the cases of three infants presenting with classical clinical findings attributable to IS who were initially diagnosed, and consequently treated, as having GERD. In all patients, irritability, spasms and crying were considered signs of gastrointestinal complaints rather than to psychomotor development regression. To our knowledge, this is the first report of IS misdiagnosed as GERD. We would like to underline that our patients presented classical signs of IS, and a more precise physical examination would have also revealed a psychomotor development regression. These findings were very consistent with IS that usually begins between age of 4 and 8 months and are characterized by brief symmetric contractions of neck, trunk and extremities. Spasms occur during sleep or arousal and have tendency to develop while patients are drowsy or immediately on awakening. These findings should always drive paediatricians to request for EEG, in which pattern most commonly associated with IS is hypsarrythmic. We have tried to examine the reasons underlying such an exceptional misinterpretation. Considering that both IS and GERD have not been changed their clinical presentation among past years, we believe that our report could be consider as the consequence of an extraordinary attention around GERD in the last decade. In confirmation of this statement, Barron et al. have recently demonstrated that PPI use in paediatric population increased steadily from 1999 to 2004 in the United States (3). We could speculate that a possible danger of such an attention towards GERD in children could be the erroneous attribution to GERD of symptoms clearly associated with other conditions like in patients we have described. Interestingly, it has already been shown that most of the symptoms classically related to GERD have revealed to be inconsistent with the clinical suspicion. In fact, only less of 10% of the symptoms conventionally associated with GER episodes (crying, regurgitation, feeding refusal, back arching, wheezing, coughing and hoarseness) are truly related to episodes of gastroesophageal reflux (GER) when detected with combined pH monitoring and impedance measurement (1). Similarly, Orenstein et al. (4) did not find any difference in efficacy between lansoprazole and placebo for symptoms attributed to GERD in infants. We have already suggested that these symptoms, if not associated with other major complaint as growth failure or psychomotor development regression, should be simply considered part of the physiological behaviours of infants, rather than pathological events (5). Unfortunately, most paediatricians dealing with irritable infants still seem to be more prone to start with anti-reflux therapy rather than to educate parents on how to cope with infant crying as a part of anticipatory guidance. In our experience, this unjustified and ineffective approach may confuse the family, leading at the end to food refusal in the baby, with an impact on growth (6). On the other hand, this particular attention to GERD in children may reduce attention towards other peculiar clinical conditions, like in cases we presented. We would like to underline that IS should be always considered in every infant presenting with symmetric spasms and psychomotor development regression. In conclusion, we have described for the first time three cases of children affected by IS initially misdiagnosed with GERD. We believe that it could be the result of a peculiar overestimation of clinical signs attributable to GERD, beard from a flourishing specific literature in the past years, leading to overdiagnosis of GERD in healthy infants and to lack diagnosis of other specific clinical conditions like in cases we have presented. In particular, IS long-term overall prognosis is poor, and mainly among those patients with long time from onset to treatment, cyptogenetic IS and age of onset <4 months, thereby prompt diagnosis is mandatory to start proper therapy. We would suggest to consider GERD only in those patients with high risk rate for developing GERD like children with cerebral palsy, in those with surgery complications after oesophageal atresia and/or in any child with very evocative GERD symptoms, such as hematemesis and or chronic vomiting with growth failure. Video S1 Epileptic attack in a patient affected by West syndrome. 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Free AccessCPAPAerophagia May Not Cause Gastroesophageal Reflux Meredith Snapp, M.D., Sunil Sharma, M.D., F.A.A.S.M. Meredith Snapp, M.D. Address correspondence to: Meredith Snapp, M.D., Thomas Jefferson University Hospital, Sleep Disorders Center, 211 South 9th Street, 5th Floor, Philadelphia PA 19107(215) 955-3156(215) 955-9783 E-mail Address: [email protected] or E-mail Address: [email protected] Thomas Jefferson University Hospital, Philadelphia, PA Search for more papers by this author , Sunil Sharma, M.D., F.A.A.S.M. Thomas Jefferson University Hospital, Philadelphia, PA Search for more papers by this author Published Online:June 15, 2013https://doi.org/10.5664/jcsm.2774Cited by:1SectionsPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONWith interest we read the findings of Shepherd et al.,1 “Symptoms of Aerophagia are Common in Patients on Continuous Positive Airway Pressure Therapy and are Related to the Presence of Nighttime Gastroesophageal Reflux.” Shepherd et al. examined the prevalence of continuous positive airway pressure (CPAP)-associated aerophagia utilizing patient questionnaires to identify symptoms of gastroesophageal reflux (GER) and aerophagia in CPAP users. One of the authors' conclusions is that the presence of aerophagia symptoms is the strongest predictor of GER symptoms and vice versa. Authors further conclude that aerophagia induced by CPAP may precipitate GER. However, we feel that the authors failed to discuss prior data suggesting evidence to the contrary. The study by Bredenoord et al.2 is especially important as it sheds more light on the connection between aerophagia and GER.In Bredenoord's study, esophageal impedance, pH, and pressure were monitored in patients with and without gastroesophageal reflux disease (GERD) before and after inflation of air into the gastric cavity, an experimental surrogate for physiologic aerophagia. Air infusion increased the incidence of gas reflux; however there was no increase in acid reflux episodes. These findings are supported by Sifrim et al., who also concluded that the liquid component of GER occurred as a primary event and not associated with gas.3 In light of this contradictory evidence, we should be cautious to assume that aerophagia precipitates GER, and in fact the opposite may be true.Furthermore, in data sub-analysis by Shepherd et al., patients with preexisting GER showed no more aerophagia after CPAP than non-GER patients. This finding is also at odds with Bredenoord et al.,2 who reported that in patients with GERD, the rate of belching is 60% higher than healthy subjects. GERD patients may be more prone to belching due to increased air swallows,2 baseline deficiency in lower esophageal sphincter (LES) tone, or increased rate of transient LES relaxation.4 The lack of aerophagia in GERD patients after CPAP raises the question, does CPAP actually improve baseline aerophagia in GERD patients?Given conflicting evidence in the literature regarding the relationship between GER, aerophagia, and CPAP, it may be premature to assume causality among these entities. The directionality of this link has consequences in the way we approach and treat CPAP users with symptoms of aerophagia.DISCLOSURE STATEMENTThis was not an industry supported study. The authors have indicated no financial conflicts of interest.CITATIONSnapp M; Sharma S. Aerophagia may not cause gastroesophageal reflux J Clin Sleep Med 2013;9(6):631.REFERENCES1 Shepherd K, Hillman D, Eastwood PSymptoms of aerophagia are common in patients on continuous positive airway pressure therapy and are related to the presence of nighttime gastroesophageal reflux. J Clin Sleep Med; 2013;9:13-7, 23319899. LinkGoogle Scholar2 Bredenoord A, Weusten B, Timmer R, Smout AAir swallowing, belching, and reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol; 2006;101:1721-6, 16817838. CrossrefGoogle Scholar3 Sifrim D, Silny J, Holloway RHet al.Patterns of gas and liquid reflux during transient lower oesophageal sphincter relaxation: A study using intraluminal electrical impedance. Gut; 1999;44:47-54, 9862825. CrossrefGoogle Scholar4 Kessing BF, Conchillo JM, Bredenoord AJ, Smout AJ, Masclee AAReview article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease. Aliment Pharmacol Ther; 2011;33:650-61, 21219371. CrossrefGoogle Scholar Previous article Next article FiguresReferencesRelatedDetailsCited byCPAP-induced Aerophagia May Precipitate Gastroesophageal RefluxShepherd K, Hillman D and Eastwood P Journal of Clinical Sleep Medicine, Vol. 09, No. 06, (633-634), Online publication date: 15-Jun-2013. Volume 09 • Issue 06 • June 15, 2013ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationMarch 1, 2013Accepted for publicationMarch 1, 2013Published onlineJune 15, 2013 Information© 2013 American Academy of Sleep MedicinePDF download

ABSTRACTObjectivesThe association between reflux events and esophageal motility abnormality is unclear. We aimed to determine the relevance between reflux events and esophageal motility in proton pump inhibitor (PPI)‐refractory gastroesophageal reflux disease (GERD).MethodsPatients with PPI‐refractory or PPI‐responsive GERD were enrolled. Ambulatory 24‐h esophageal pH–impedance–pressure monitoring was performed. Reflux symptoms, reflux events, and esophageal motility during acid reflux episodes were recorded and compared between the two groups.ResultsSixty patients with PPI‐refractory GERD and 18 with PPI‐responsive GERD were included, all of whom had pathological gastroesophageal reflux. There were no significant differences in the major acid reflux parameters (DeMeester score and proportion of patients with acid exposure time > 6%) between the two groups. However, the number of long acid reflux episodes and the time length of the longest reflux episodes were significantly higher in the PPI‐refractory GERD group than in the PPI‐responsive GERD group (both p < 0.05). Moreover, patients with PPI‐refractory GERD had higher rates of ineffective primary (62.0% vs. 36.0%, p < 0.001) and secondary peristalsis (83.5% vs. 57.0%, p = 0.001) during long acid exposure (LAE) than those with PPI‐responsive GERD. Patients with PPI‐refractory GERD having LAE had a significantly lower frequency of primary and secondary peristalsis per minute and required a longer time to initiate secondary peristalsis than those without during their longest acid reflux period in the upright position (all p < 0.001).ConclusionLonger acid reflux episodes in patients with PPI‐refractory GERD might result from frequent ineffective primary esophageal peristalsis and delayed initiation of effective secondary peristalsis.

Tu1105 Gastric Acid Output Suppression in Response to Proton Pump Inhibitor Therapy in Symptomatic Versus Asymptomatic GERD Patients: Results of a Prospective Study Measuring Control and Meal-Stimulated Gastric Acid Secretion

Studies of the relative frequency of transient lower esophageal sphincter relaxations (TLESRs) in patients with gastroesophageal reflux disease and asymptomatic controls have revealed conflicting data. We have therefore studied the frequency of TLESRs and the frequency and mechanisms of acid reflux episodes in patients with gastroesophageal reflux disease and age- and sex-matched asymptomatic controls using standardized criteria. Ten patients with symptomatic gastroesophageal reflux disease (four male, aged 50 [30-59] yr) and 10 asymptomatic matched volunteers (four male, aged 50 [32-59] yr) were studied. Esophageal, lower esophageal sphincter, and gastric manometric and esophageal pH readings were recorded for 1 h before and 1 h after a 200-kcal, 150 ml long-chain triglyceride meal. TLESR frequency increased after the meal in both volunteers (median 0 [range = 0-3] to 3 [0-8] per hour,p < 0.01) and patients (1 [0-6] to 2.5 [0-9] per hour, p = 0.08). There was no significant difference in the frequency of TLESRs between volunteers and patients. TLESRs were more likely to be associated with acid reflux in patients (65% vs 37%, p = 0.03), whereas volunteers were more likely to reflux gas or liquid without acid (30% vs 3.0%, p = 0.01). TLESRs are no more frequent in patients with gastroesophageal reflux disease than age- and sex-matched asymptomatic volunteers. However, when TLESRs occur in patients, they are twice as likely to be associated with acid reflux.