World Gastroenterology Organisation Global Guidelines

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 of and 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 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