RGE Anatomía Causas Diagnóstico Tratamiento
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Este documento trata sobre el reflujo gastroesofágico. Explica la anatomía, fisiología y epidemiología de esta afección. Describe los síntomas típicos y atípicos, así como las diferentes clasificaciones. Detalla los métodos de diagnóstico como endoscopia, pH-metría y manometría. Finalmente, resume los diferentes enfoques para el tratamiento de esta condición, incluyendo modificaciones en el estilo de vida, fármacos y terapias adyuvantes.
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RGE Anatomía Causas Diagnóstico Tratamiento
- 1. ReflujoReflujo gastroesofágicogastroesofágico Sandra Milena Acevedo Rueda MD Residente Medicina Interna Junio de 2013
- 7. 1. Longitud total de engrosamiento muscular esofágico distal. 2. Longitud de esófago intraabdominal 4. Presión tónica o presión de reposo del esfínter esofágico inferior 3. El ángulo de His Gastroenterol Clin North Am 2007 36:577 Zona de Alta PresiónZona de Alta Presión
- 8. HistologíaHistología • Epitelio plano estratificado. • Mucosa (tejido linfático difuso, glándulas mucosas). • Submucosa (vasos, nervios, plexo de Meissner, glándulas). • Muscular (interna, externa). 1/3 superior estriado, 2/3 inferiores liso. Plexo de Auerbach.
- 9. Estructura de la pared esofágica en la unión esofagogástrica. La túnica muscular está formada por una capa longitudinal y una capa circular. (a = muscular de la mucosa, b = lámina propia, c = epitelio, G1 = glándulas esofágicas, G2 = glándulas gástricas, Li= vasos linfáticos, N1 = plexo mientérico, N2 = plexo nervioso submucoso.)
- 12. DegluciónDeglución • Fase voluntaria • Fase involuntaria refleja • Fase esofágica Onda primaria ondas secundarias
- 13. Episodios de reflujo normal…Episodios de reflujo normal… Frecuentes durante y después de las comidas Duración <5 minutos Excepcionalmente >10 minutos Sin complicaciones Raros en las noches
- 14. Definición ERGE es una afección recurrente, relacionada con el reflujo retrógrado del contenido gástrico, con o sin contenido duodenal, hacia el esófago. Presenta un variado espectro de síntomas que pueden alterar la calidad de vida del paciente y puede presentarse con o sin daño tisular. (votación: 100% aceptación) Cohen et al. EUJ Gastroenterol Hepatol 2006 EnfermedadporReflujoEnfermedadporReflujo GastroesofágicoGastroesofágico
- 15. Definición • Montreal Working GroupMontreal Working Group Acidez es considerada molesta si síntomas leves ocurren dos o más días a la semana ó si hay síntomas moderados a severos más de un día a la semana Cohen et al. EUJ Gastroenterol Hepatol 2006
- 16. • Pirosis Sensación de quemazón retroesternal ascendente y para el diagnóstico de ERGE, debe estar presente 2 o más veces por semana, durante más de 3 meses en el último año, no necesariamente continuo. (votación: 71,4%) • Regurgitación Retorno sin esfuerzo del contenido gástrico al esófago y algunas veces a la boca. (votación: 100%) Cohen et al. EUJ Gastroenterol Hepatol 2006
- 17. EpidemiologíaEpidemiología • Acidez y regurgitación • 10-20% países del oeste – 5 casos por 1000 personas año • Menos del 5% en Asia • USA : 22% (ambos – 1 mes) – ≥2 veces/sem 6%
- 18. ERGE: ClasificaciónERGE: Clasificación Síntomas típicos Síntomas atípicos • Pirosis • Regurgitación • Disfagia • Odinofagia • Otros - Globus - Nausea - Hipersalivación - Singultus - Dolor epigástrico • Dolor torácico • Manifestaciones ORL • Manifestaciones respiratorias • Manifestaciones orales
- 19. Sindromes Esofágicos Sindromes sintomáticos Sindromes Extraesofágicos Sindromes con injuria esofágica Asociaciones establecidas Asociaciones propuestas 1) Sindrome de reflujo típico 2) Sindrome de dolor torácico por reflujo 1) Esofagitis por reflujo 2) Estenosis por reflujo 3) Esófago de Barrett 4) AdenoCa esofágico 1) Sd. tos por reflujo 2) Sd. laringitis por reflujo 3) Sd. asma por reflujo 4) Sd. erosión dental por reflujo 1) Faringitis 2) Sinusitis 3) Fibrosis pulmonar idiopática 4) Otitis media recurrente
- 20. Grado de esofagitis % Pacientes con pirosis moderada o severa 0 20 40 60 80 100 1 2 3 4 Carlsson et al 1996 Severidad de los síntomas y grado deSeveridad de los síntomas y grado de esofagitis no se correlacionanesofagitis no se correlacionan (meta-análisis, n=3478)(meta-análisis, n=3478)
- 21. Histopatología (A) Increased basal layer thickness (noncornified stratified squamous). (B) Papillary elongation (noncornified stratified squamous).
- 22. Diagnóstico • Endoscopia • Radiología • Ph Metría • Manometría • Radioisótopos • Otros
- 23. Endoscopia • Variabilidad interobservador • Biopsia • Ausencia de hallazgos no excluye el diagnóstico – Algunos aparecen en controles posteriores • Macroscópicamente normal pero histológicamente anormal
- 24. Clasificación de Los Angeles Grado AGrado A Armstrong D Bennett JR et al. The endoscopic assessment of esophagitis: A progress report on observer agreement. Gastroenterology. 1996; 111: 85-92.
- 25. Clasificación de Los Angeles Grado BGrado B Armstrong D Bennett JR et al. The endoscopic assessment of esophagitis: A progress report on observer agreement. Gastroenterology. 1996; 111: 85-92.
- 26. Clasificación de Los Angeles Grado CGrado C Armstrong D Bennett JR et al. The endoscopic assessment of esophagitis: A progress report on observer agreement. Gastroenterology. 1996; 111: 85-92.
- 27. Clasificación de Los Angeles Grado DGrado D Armstrong D Bennett JR et al. The endoscopic assessment of esophagitis: A progress report on observer agreement. Gastroenterology. 1996; 111: 85-92.
- 28. Trago de Bario
- 29. Manometría
- 30. pH-metría
- 32. Otros • Ecografía hepatobiliar • Electrocardiograma • Prueba de esfuerzo
- 33. Diagnóstico diferencial • Esofagitis infecciosa • Esofagitis medicamentosa • Esofagitis eosinofílica • Enfermedad ulcero-péptica • Dispepsia no-ulcerosa • Enfermedades tracto biliar • Enfermedad arterial coronaria • Trastornos motores esofágicos • Cáncer de esófago
- 34. Tratamiento
- 35. 14% de la población mayor de 65 años los toma regularmente. No requieren receta médica. Tienen alto perfil de seguridad, sin toxicidad aguda, y con pocos efectos adversos reportados, entre ellos: Neumonía adquirida en la comunidad Osteoporosis Hiperplasia de células G Deficiencia en absorción de B12 y hierro Pólipos fúndicos Efecto de “rebote” al suspenderlos Interacciones medicamentosas (Clopidrogel) World J Gastroenterol 2010, 16:2323 IBP’sIBP’s
- 36. Regímenes terapéuticosRegímenes terapéuticos Regardless of the potency of pharmacologic therapy, the patient should be counseled on lifestyle and dietary modifications. • Prescription H2 blockers should be prescribed in the ulcer dose; doubling the dose in a BID regimen has not been shown to be superior in the treatment of GERD.
- 38. Y los casos refractarios?Y los casos refractarios? • Síntomas o evidencia de esofagitis – IBP dos veces al día • 10-40% no responden • Sin esofagitis erosiva: Rta 40% • Con esofagitis erosiva: Rta 56%
- 39. Mecanismos de falla terapéuticaMecanismos de falla terapéutica • Dosis apropiada • “Compliance”
- 40. Mecanismos de falla terapéuticaMecanismos de falla terapéutica • Hipersensibilidad esofágica • Acidez funcional • Reflujo no-ácido (alcalino)
- 41. Mecanismos de falla terapéuticaMecanismos de falla terapéutica • Reflujo ácido residual • Reflujo de ácidos biliares
- 42. Mecanismos de falla terapéuticaMecanismos de falla terapéutica • Reflujo ácido residual • Reflujo de ácidos biliares
- 43. Mecanismos de falla terapéuticaMecanismos de falla terapéutica • Ruptura ácido normal • Diferencias en el metabolismo • Biodisponibilidad reducida
- 44. Mecanismos de falla terapéuticaMecanismos de falla terapéutica • Cicatrización retardada • Resistencia IBP • H. pylori • Factores psicológicos
- 45. Diagnóstico diferencialDiagnóstico diferencial • Acalasia • Ca esofágico distal • AINES • Cáusticos • Enfermedades infecciosas • Radiación • Farmacos • Esofagitis eosinofílica
- 46. RGE refractario (1)RGE refractario (1) Best Pract Res Clin Gastroenterol 2010; 24:923
- 47. RGE refractario (2)RGE refractario (2) Best Pract Res Clin Gastroenterol 2010; 24:923
- 48. • Modificaciones del estilo de vida – Comidas – Ejercicio – Sueño – Hora de dormir – Alcohol – Bebidas ácidas TratamientoenRGETratamientoenRGE
- 49. • Fármacos supresores secreción ácida – Bloqueadores H2 – IBP • Diferencias (magnitud significado incierto) TratamientoenRGETratamientoenRGE
- 50. • Terapia adyuvante – Procineticos: azitromicina, metoclopramida – Baclofeno – Lesogaberan – Tratamiento H. pylori TratamientoenRGETratamientoenRGE
- 51. • Terapia de mantenimiento • Terapia intermitente TratamientoenRGETratamientoenRGE
- 52. Gracias!Gracias!
Notas del editor
- Cuando se encuentra en reposo el esófago está colapsado ; forma un conducto muscular blando, aplanado en sus porciones superior y media, con un diámetro de 2,5 × 1,6 cm. La porción inferior del esófago es redondeda, con un diámetro de 2,5 × 2,4 cm.51 De vez en cuando existe una marca ocasionada por el diafragma, pero son más evidentes dos constricciones musculares funcionales: los esfínteres esofágicos superior e inferior. Estos pueden definirse mediante manometría, respectivamente, en el comienzo del esófago, a una distancia de 14 a 16 cm desde los incisivos , y en la desembocadura del esófago en el estómago, a una distancia de 40 a 45 cm desde los incisivos En el adulto varía entre 22 y 28 cm (24 ± 5 desviaciones estándar), de los cuales 3 a 6 cm se localizan en el abdomen.17,32,67 A diferencia de Lerche,32 Liebermann-Meffert y cols.35 encontraron que la longitud del esófago se relaciona con la estatura de la persona más que con su sexo Como estructura que sigue a la faringe (véase fig. 1-4), el esófago comienza en el cartílago cricoides a la altura de la sexta vértebra cervical . Penetra en el tórax a la altura de la muesca esternal y en la cavidad torá- cica se ubica en el límite anterior del mediastino posterior. Entre la abertura torácica superior y el diafragma se mantiene en contacto con la columna vertebral. Termina en la unión esofagogástrica, a la altura de la duodécima vértebra torácica.
- En el cuello, las arterias tiroideas superior e inferior emiten ramas descendentes pequeñas para el esófago cervical. En la concavidad del cayado aórtico surgen tres a cinco arterias traqueobronquiales que originan varias ramas esofágicas. De vez en cuando, de la pared anterior de la aorta torácica surgen una o dos arterias esofágicas. En la unión esofagogástrica la arteria gástrica izquierda (coronaria estomáquica) origina hasta 11 ramas ascendentes de gran tamaño que irrigan principalmente las caras anterior y derecha de la porción inferior del esófago35,37 (véase fig. 1-17). Los vasos originados en la arteria esplénica irrigan la pared esofágica posterior y parte de la curvatura mayor del estómago . Algunas ramas de gran tamaño se dirigen hacia arriba a través del hiato diafragmático y luego penetran en la pared esofágica
- Este autor clasificó las venas esofágicas en intrínsecas y extrínsecas, según se encontraran dentro o fuera de la pared esofágica. Las venas intraesofágicas incluyen el plexo subepitelial en la lá- mina propia de la mucosa cerca del epitelio. Este plexo recibe sangre de los capilares adyacentes y drena hacia el plexo submucoso, que incluye vasos que se unen y forman venas comunicantes pequeñas. Éstas se disponen principalmente a lo largo del eje longitudinal.64 Aharinejad y cols.1 estudiaron la microvasculatura del esófago humano minuciosamente. Describieron dos pequeñas venas que por lo general acompañan las arterias circunferenciales de la lámina submucosa como venas perforantes originadas a partir de las pequeñas venas comunicantes del plexo submucoso y atraviesan la pared muscular del esófago junto con las arterias perforantes. Éstas reciben venas tributarias provenientes de la capa muscular y forman entonces las venas extrínsecas extramurales en la superficie del esófago.1,7,64 En el sistema circulatorio venoso del esó- fago no se encontraron válvulas.1,7,64 Las venas extrínsecas drenan hacia los vasos locales de mayor tamaño correspondientes; éstos son las venas tiroideas superior e inferior, que desembocan en las venas braquiocefálica y yugular, las venas ácigos y hemiácigos (o ácigos menor) y las venas gástrica y esplénica
- No obstante, puede aceptarse que el sistema linfático del esófago incluye conductos y ganglios linfáticos, como los descritos en otras partes del intestino. ___ La inervación del esófago depende del componente visceral (esplácnico) del sistema nervioso autónomo . Éste incluye el sistema simpático y el sistema parasimpático, que ejercen influencias antagónicas sobre el esófago. Las distintas vías nerviosas se han descrito en detalle.8,20,66 Los troncos nerviosos y sus ramas principales están formados por haces nerviosos paralelos que contienen axones eferentes o aferentes. El tronco nervioso está rodeado por el epineuro, una vaina de tejido conectivo denso.
- El esófago normal está recubierto de epitelio escamoso estratificado, el cual se extiende hasta la unión gastroesofágica, que es una línea imaginaria donde hace contacto con el epitelio columnar gástrico en la interfaz que se denomina línea Z. O sea, que la línea Z es la unión escamo-columnar. La mucosa esofágica corresponde a un epitelio escamoso estratificado (no queratinizado) que recubre la lámina propia con numerosas papilas de tejido conjuntivo. (15-10) Stevens la mucosa (mismo tipo) pero con lamina propia y muscular de la mucosa. La zona basal del epitelio puede tener varias capas de células de grosor y consiste en células cubicas rectangulares con nucleos oscuros y un citoplasma que se tiñe de morado y no tiene glucógeno. Encima de la zona basal las células epiteliales son de mayor tamaño y ricas en glucógeno y se van aplanando conforme se acercan a la luz. La lamina propia esofágica esta compuesta por fibras de colágeno poco ordenadas y fibrtoblastos incluidos en una matriz acelular de glucosaminoglucanos, normalmente con linfocitos y eosinofilos diseminados. La muscular de la mucosa no existe en la parte superior del esófago, pero se organiza cerca del estómago. Tanto la mucosa como la submucosa del esófago no distendido crean pliegues longitudinales que dan a la luz un contorno irregular. Cuando el bolo alimentario desciende por el esófago, los pliegues desaparecen de forma transitoria y posteriormente reaparecen por la retracción de las fibras elásticas de la submucosa.
- Some degree of reflux is physiologic [1]. Physiologic reflux episodes typically occur postprandially, are short-lived, asymptomatic, and rarely occur during sleep. Pathologic reflux is associated with symptoms or mucosal injury, often including nocturnal episodes. In general terms, gastroesophageal reflux disease (GERD) is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with esophageal inflammation. Reflux esophagitis describes a subset of patients with symptoms of GERD who also have endoscopic or histopathologic evidence of esophageal inflammation.
- Due to the broad spectrum of conditions attributable to reflux, there is little agreement as to what constitutes typical reflux disease. A consensus statement (the Montreal Classification) defines GERD as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications [2]. According to the Montreal Working Group, heartburn is considered troublesome if mild symptoms occur two or more days a week, or moderate to severe symptoms occur more than one day a week
- There are limitations in the epidemiologic estimates of the prevalence of gastroesophageal reflux disease (GERD) as they are based upon the assumption that heartburn and/or regurgitation are the only indicators of the disease [3-5]. However, patients with objective evidence of GERD (such as esophagitis or Barrett's esophagus) do not always have heartburn and heartburn is not always indicative of GERD [6]. A systematic review identified 15 epidemiological studies of GERD that fulfilled strict quality criteria (at least weekly heartburn and/or acid regurgitation and studies also met criteria concerning sample size, response rate, and recall period) [4]. GERD prevalence was found to be 10 to 20 percent in the Western world and less than 5 percent in Asia. The incidence in the Western world was approximately 5 per 1000 person-years. In a subsequent population-based survey in the United States, 22 percent of respondents reported that they had heartburn or regurgitation within the last month while 16 percent reported regurgitation [5]. Heartburn or regurgitation was "clinically significant" (≥twice weekly) in 6 and 3 percent, respectively.
- Clinical manifestations — The most common symptoms of gastroesophageal reflux disease (GERD) are heartburn (pyrosis), regurgitation, and dysphagia. A variety of extraesophageal manifestations have been described including bronchospasm, laryngitis, and chronic cough. Complications from GERD can arise even in patients who lack typical symptoms. (See "Complications of gastroesophageal reflux in adults".) Heartburn is typically described as a burning sensation in the retrosternal area [2], most commonly experienced in the postprandial period. Regurgitation is defined as the perception of flow of refluxed gastric content into the mouth or hypopharynx [2]. Patients typically regurgitate acidic material mixed with small amounts of undigested food. Dysphagia is common in the setting of longstanding heartburn commonly attributable to reflux esophagitis but potentially indicative of a stricture [7]. Other symptoms of GERD include chest pain, water brash, globus sensation, odynophagia, and nausea. GERD-related chest pain may mimic angina pectoris, and is typically described as squeezing or burning, located substernally and radiating to the back, neck, jaw, or arms, lasting anywhere from minutes to hours, and resolving either spontaneously or with antacids. It usually occurs after meals, awakens patients from sleep, and may be exacerbated by emotional stress [1]. Patients with reflux-induced chest pain may also have typical reflux symptoms. However, heartburn is a poor predictor of whether patients with chest pain have evidence of GERD by objective testing [8]. Water brash or hypersalivation is a relatively unusual symptom in which patients can foam at the mouth, secreting as much as 10 mL of saliva per minute in response to reflux. Globus sensation is the almost constant perception of a lump in the throat (irrespective of swallowing), which has been related to GERD in some studies. However, the role of esophageal reflux in this disorder is uncertain. One study suggested that globus was associated with a hypertensive upper esophageal sphincter rather than with reflux [9]. (See "Globus sensation".) Odynophagia is an unusual symptom of GERD but, when present, usually indicates an esophageal ulcer. Nausea is infrequently reported with GERD, but a diagnosis of GERD should be considered in patients with otherwise unexplained nausea. In one report, nausea resolved after therapy for GERD in 10 patients who previously had intractable symptoms [10]. (See "Medical management of gastroesophageal reflux disease in adults" and "Surgical management of gastroesophageal reflux in adults".
- Histology — A review of the literature suggested that about two-thirds of patients who have symptoms of GERD, but have no visible endoscopic findings (ie, nonerosive reflux disease) have histologic evidence of esophageal injury that responds to acid suppression [11]. The most consistently observed histologic finding in this study was dilation of the intercellular spaces seen on transmission electron microscopy. This finding is also present in patients with reflux esophagitis. The mild histologic findings noted in GERD represent the reparative capacity of the esophageal epithelium after cell damage due to acid exposure [12]. Cellular injury stimulates cell proliferation, the morphologic equivalent of which is thickening of the basal cell layer and elongation of the papillae of the epithelium (picture 1) [13]. Other histologic features include the presence of neutrophils and eosinophils, dilated vascular channels in papillae of the lamina propria, and distended, pale squamous ("balloon") cells. However, none of these findings is specific for GERD
- DIAGNOSIS — The diagnosis of gastroesophageal reflux disease (GERD) can be based upon clinical symptoms alone. In patients presenting with any of the clinical manifestations described above, a presumptive diagnosis of GERD can be made. Response to antisecretory therapy is not a diagnostic criterion for GERD [15]. A meta-analysis of diagnostic test characteristics found that a response to proton pump inhibitors (PPIs) did not correlate well with objective measures of GERD such as ambulatory pH monitoring [16]. Pooled sensitivity was 78 percent while specificity was 54 percent. Thus, a response to PPIs does not correspond to a GERD diagnosis based on reflux testing. However, the observation that 40 to 90 percent of patients with symptoms suggestive of GERD [16] have a symptomatic response to PPIs raises the question of which diagnostic approach is more relevant in practice. Clearly, it is neither necessary nor practical to initiate a diagnostic evaluation in every patient with heartburn [2,17]. However, in a subset of patients, diagnostic testing is required to confirm the diagnosis of GERD and to rule out other diagnoses (see 'Overview' below).
- Upper gastrointestinal endoscopy — Upper endoscopy provides a mechanism for detecting, stratifying, and managing the esophageal manifestations of GERD. The indications for upper endoscopy in patients with GERD are controversial and are discussed in detail separately. (See "Medical management of gastroesophageal reflux disease in adults".) On upper endoscopy, biopsies should target any areas of suspected metaplasia, dysplasia, or, in the absence of visual abnormalities, normal mucosa (at least five samples to evaluate for eosinophilic esophagitis) [24]. Esophagitis on esophagoscopy — The interoperator variability of endoscopy in assessing the severity of peptic esophagitis spawned many endoscopic grading schemes; of the more than 80 proposed schemes, the two most dominant will be described Los Angeles classification — The Los Angeles classification is the most thoroughly evaluated classification for esophagitis and is widely used. The Los Angeles classification grades esophagitis severity by the extent of mucosal abnormality, with complications recorded separately. In this grading scheme, a mucosal break refers to an area of slough adjacent to more normal mucosa in the squamous epithelium with or without overlying exudate. Savary-Miller classification — Historically, the most widely referenced grading of esophagitis is the Savary-Miller classification [25]. Despite its widespread use, the Savary-Miller grading scheme has its limitations. Because it includes all complications, grade IV esophagitis is ambiguous. This has led to modifications which either offer subdivisions of grade IV or relegate metaplasia to grade V. With so many proposed modifications, grades IV and V no longer have any widely accepted meaning. The findings on endoscopy vary with the etiology of the inflammation: Infectious esophagitis is circumferential and tends to involve the proximal esophagus far more frequently than does reflux esophagitis. The ulcerations seen in peptic esophagitis are usually irregularly shaped or linear, multiple, and distal, whereas infectious ulcers are multiple and punctate. Pill-induced ulcerations are usually singular and deep, occurring at points of stasis (especially near the carina), with sparing of the distal esophagus. (See "Medication-induced esophagitis".) Eosinophilic esophagitis has been associated with a variety of morphological features in the esophagus. These include a ringed esophagus, strictures (particularly proximal strictures), attenuation of the subepithelial vascular pattern, linear furrowing that may extend the entire length of the esophagus, whitish papules (representing eosinophil microabscesses), and a small caliber esophagus. (See "Pathogenesis, clinical manifestations, and diagnosis of eosinophilic esophagitis", section on 'Endoscopy'.) Both infectious and pill esophagitis are usually accompanied by odynophagia, which is less common in peptic esophagitis. The absence of endoscopic features of GERD does not exclude the diagnosis. Some patients with initial negative endoscopies will develop mucosal lesions during follow-up examinations [26]. In addition, symptoms may be due to esophageal hypersensitivity. (See "Pathophysiology of reflux esophagitis".) It is also important to note that the accuracy of endoscopy for the diagnosis of GERD is subject to observer variability. (See "Wireless video capsule endoscopy".) Finally, even though the esophagus may appear endoscopically normal, it is not necessarily histologically normal (see 'Histology' above).
- Una o más rupturas de la mucosa confinadas a los pliegues mucosos, cada uno < 5 mm.
- Por lo menos una ruptura de la mucosa > 5 mm, confinada a los pliegues mucosos pero sin continuidad en los bordes de dos de los pliegues.
- Por lo menos una ruptura de la mucosa entre los límites de dos pliegues de la mucoosa, pero sin ser circuferencial.
- Ruptura circunferencial de la mucosa.
- Radiographic findings — Double contrast barium swallow examination is of limited use because of its low sensitivity in patients with mild GERD. Radiologic evaluation is most useful in the detection of peptic stricture. A number of changes may be seen on double contrast barium swallow: Double contrast barium swallow examinations can identify early stages of reflux esophagitis by a granular or nodular appearance of the mucosa of the distal third of the esophagus with numerous ill-defined, 1 to 3 mm lucencies [14]. Shallow ulcers and erosions are recognized on double contrast radiographs as tiny collections of barium in the distal esophagus near the gastroesophageal junction, sometimes surrounded by a radiolucent halo of edematous mucosa. The appearance of a smooth, tapered area of concentric narrowing in the distal esophagus, 1 to 4 cm in length and 0.2 to 2.0 cm in diameter is virtually pathognomonic of a benign peptic stricture (image 1). However, many peptic strictures have an asymmetric appearance with puckering of one wall of the stricture due to eccentric scarring.
- Esophageal manometry — Esophageal manometry should be considered in patients with symptoms of GERD and normal upper endoscopy, especially if there is any associated dysphagia, even though esophageal manometry is of minimal use in the diagnosis of GERD. However, manometry is useful in identifying alternative diagnoses such as achalasia, the symptoms of which sometimes closely mimic those of GERD [19]. The evaluation of peristaltic function to exclude major motor disorders is also important before antireflux surgery (see "Surgical management of gastroesophageal reflux in adults"), and it can also be used to ensure that ambulatory pH probes are placed correctly [19].
- Ambulatory esophageal pH monitoring — Ambulatory pH monitoring is useful for confirming gastroesophageal reflux disease in those with persistent symptoms (whether typical or atypical) who do not have evidence for mucosal damage on endoscopy, particularly if a trial of twice daily PPI has failed [27]. It can also be used to monitor the adequacy of treatment in those with continued symptoms [28]. Suggested clinical indications for ambulatory pH monitoring are listed in the Table (table 1) [28]. Ambulatory pH monitoring can be done with either a transnasally placed catheter or a wireless, capsule-shaped device that is affixed to the distal esophageal mucosa [29,30]. In each case, the pH sensor is coupled with compact, portable data recorders, and computerized data analysis. The catheter type pH electrode is positioned 5 cm above the manometrically defined upper limit of the lower esophageal sphincter. In the case of the wireless device, the pH capsule is attached 6 cm proximal to the endoscopically defined squamocolumnar junction. Tests are traditionally conducted for a 24-hour period with patients advised to consume an unrestricted diet. However, increasing monitoring to 48 hours in patients undergoing evaluation using a wireless device may increase the yield of the study for detecting reflux episodes and correlating those events with symptoms [31,32]. Because the validity of pH monitoring studies has only been established when conducted off of antisecretory drugs, studies should be done after withholding PPI therapy for seven days. However, in the case of the wireless device, studies can be conducted for two to four days, varying the dietary and/or therapeutic circumstances between days if desired [33]. The current consensus is to consider the percentage time with the intraesophageal pH below 4 as the most useful outcome measure in discriminating between physiologic and pathologic esophageal reflux [34]. Although symptom association is essential when evaluating atypical or sporadic symptoms, a direct one-to-one correlation between reflux events and symptoms rarely exists, leading to several proposed methods for quantifying the reflux-symptom relationship. However, none of the proposed symptom evaluation schemes has been prospectively validated against an independent parameter of diagnostic accuracy such as antireflux therapy with a symptomatic response [27,28]. Whether ambulatory esophageal pH monitoring should be performed with the patient on acid suppressive therapy is somewhat controversial. The unclear relevance of “normative” data for studies performed on PPI therapy makes it difficult to interpret the results [35]. Ambulatory pH monitoring is also used for the detection of pathologic reflux associated with supra-esophageal complications such as reflux laryngitis or cough. However, there has been no consensus on the pH criteria that should be used for defining pathologic reflux in this setting.
- Biliary tract ultrasonography should be considered in patients with nausea and/or epigastric pain. Double contrast barium swallow is used infrequently. When data from barium radiography and endoscopy were compared, the diagnostic accuracy of radiography was 25 percent with mild esophagitis, 82 percent with moderate esophagitis, and 99 percent with severe esophagitis [22]. The demonstration of reflux of barium during the study is of dubious significance since it can be provoked in 25 to 71 percent of symptomatic patients compared with 20 percent of normal controls [23]. Unexplained chest pain should be evaluated with at least an electrocardiogram and exercise stress test prior to a gastrointestinal evaluation.
- DIFFERENTIAL DIAGNOSIS — Gastroesophageal reflux disease (GERD) needs to be distinguished from infectious esophagitis, pill esophagitis, eosinophilic esophagitis, peptic ulcer disease, non-ulcer dyspepsia, biliary tract disease, coronary artery disease, and esophageal motor disorders. Symptoms alone do not reliably distinguish among these disorders [18]. Similarly, the severity and duration of symptoms correlate poorly with the severity of esophagitis. Dysphagia may be due to GERD, but slowly progressive dysphagia for solids with episodic esophageal obstruction is suggestive of a peptic stricture. Other, more common causes of dysphagia are reflux esophagitis, eosinophilic esophagitis, and impaired peristalsis. Another, fortunately rare, cause of dysphagia is esophageal cancer, either adenocarcinoma arising from Barrett's metaplasia or squamous cell carcinoma.
- Despite treatment with proton pump inhibitors (PPIs), some patients with gastroesophageal reflux disease (GERD) continue to have reflux symptoms or endoscopic evidence of esophagitis. Approximately 10 and 40 percent of patients with GERD fail to respond symptomatically, either partially or completely, to a standard dose PPI [1-4]. Failure of the PPI treatment to resolve GERD-related symptoms has become the most common presentation of GERD among clinical gastroenterologists. An approach to patients with refractory GERD will be discussed here. A review of the medical management of GERD is presented separately. DEFINITIONS — Most patients with GERD who do not respond to a PPI have either nonerosive reflux (NERD) or functional heartburn. In patients with NERD the pooled symptomatic response rate to PPI once daily at four weeks is 37 percent [5,6]. In contrast, in patients with erosive esophagitis, which accounts for 30 to 40 percent of the GERD population, the pooled symptomatic response rate is 56 percent [5]. The definition of refractory GERD is controversial. Because refractory GERD is a patient-driven phenomenon, PPI failure in patients who seek medical attention will exhibit different frequency and/or severity of GERD-related symptoms. As a result, any attempt to narrow the definition of refractory GERD might exclude many true sufferers [7]. Most investigators believe that only patients with GERD who exhibit partial or lack of response to PPI twice daily should be considered as PPI failures. However, we suggest that lack of satisfactory symptomatic response to PPI once a day is sufficient to consider patients as PPI failures.
- Proper dosing — PPIs should be taken 30 minutes before breakfast to maximize acid inhibition [8]. However, patients commonly take their PPI incorrectly, which may in part be because they have not received adequate instructions. One study found that only 46 percent of patients prescribed a PPI for GERD were taking it properly [9]. Of those not taking it properly, 39 percent took it at bedtime and 4 percent as needed. Although there is no direct evidence that proper dosing can improve symptoms in patients who are not taking a PPI 30 minutes before breakfast, most authorities emphasize the need to ensure proper dosing, especially in those with refractory GERD. Compliance — Several surveys have demonstrated that poor compliance with PPIs is common in patients with GERD. By the end of one and six months of PPI therapy, only about 55 and 30 percent of the GERD patients, respectively, still consume their PPI once daily as initially instructed [10]. In a large, population-based study, the main factors influencing compliance were the presence or absence of symptoms, the severity of symptoms, and a personal preference about when to take treatment [11]. The results emphasize that GERD is a symptom-driven disease in which patients adhere to treatment instructions as long as they experience symptoms. Other general factors that affect compliance such as knowledge about the treated disorder, desire for personal control, the prescribed drug (taste, consistency, etc), side effects, number of pills per day, concomitant therapies, age, personality, socioeconomic status, and healthcare coverage may also have a role in adherence to treatment instructions [12]. Compliance should be assessed in all GERD patients who report lack of response to PPI treatment, particularly prior to ordering any evaluative test. Unfortunately, not all patients disclose that they are poorly compliant during their clinic visit. Treating physicians should repeatedly emphasize the need to consume antireflux treatment on a daily basis. It is the role of the treating physician to ensure proper compliance with the prescribed PPI through patient education about the disease and the value of compliance with treatment [12].
- Functional heartburn and esophageal hypersensitivity — Studies evaluating patients who did not respond to PPI twice daily demonstrated that up to 58 percent of patients have functional heartburn [13,14]. Thus, functional heartburn is the most common cause for failure of PPI treatment. The underlying mechanisms responsible for symptoms in functional heartburn patients as defined by Rome III (burning retrosternal discomfort or pain, absence of evidence of GERD as the cause of symptoms, absence of histopathology-based esophageal motility disorders, with all three criteria fulfilled for the last three months and symptom onset at least six months prior to diagnosis) remain to be elucidated; most studies used the outdated Rome II criteria to diagnose functional heartburn. Many of these studies demonstrated increased esophageal sensitivity to chemical, mechanical, and electrical stimuli in this patient population [15-18]. However, one report suggested that not all functional heartburn patients (based on Rome II criteria) have increased esophageal sensitivity to intraluminal stimuli [16], and it is highly likely that functional heartburn represents a heterogeneous group of patients with different physiological mechanisms for their symptoms. Although a subset of patients with esophageal hypersensitivity may respond to acid suppressive therapy, this disorder is analogous to the visceral hyperalgesia described in a variety of other gastrointestinal disorders including noncardiac chest pain, functional dyspepsia, and irritable bowel syndrome. Weakly acidic or alkaline reflux (non-acid reflux) — Studies involving esophageal multichannel intraluminal impedance testing have revealed a potential role of weakly acidic or alkaline reflux in patients with persistent symptoms despite a PPI. The mechanism by which weakly acidic reflux causes GERD-related symptoms remains poorly understood. Two possible explanations have been proposed: esophageal distension by increased reflux volume and hypersensitivity to weakly acidic refluxate [19]. (See "Esophageal multichannel intraluminal impedance testing" and "Clinical manifestations, diagnosis, and treatment of non-acid reflux".) Thus far, there is no evidence that weakly acidic reflux is more commonly associated with increased volume of the refluxate than acidic reflux. Although this association has been proposed, esophageal impedance does not measure the volume of the refluxate and thus cannot define the relationship between the volume and the acidity. Thus, it is impossible to determine individual thresholds for the point at which weakly acidic reflux episodes consistently provoke symptoms.
- Residual acid reflux — Residual acid reflux has been documented in patients with persistent heartburn despite a PPI once or twice daily [13,14,20-22]. As an example, in one study, 31 and 4 percent of GERD subjects with refractory symptoms who underwent pH testing on PPI once daily or PPI twice daily, respectively, had an abnormal test [23]. On the other hand, several studies demonstrated that reflux characteristics in PPI failure patients are similar to those in PPI success patients [24]. These studies suggest that PPI failure is primarily an esophageal hypersensitivity phenomenon. Furthermore, it appears that proximal immigration of weakly acidic reflux and the presence of gas in the refluxate are pivotal for symptom generation [25]. Bile acid reflux — Although commonly considered as synonyms, bile reflux and non-acid reflux are different phenomena. Initial studies suggested that bile reflux probably accounts for 10 to 15 percent of non-acid reflux. However, a study using simultaneous Bilitec (a device to measure bile reflux) and impedance monitoring showed no correlation between esophageal bilirubin exposure and non-acid reflux parameters [26-28]. In other reports, the majority of bile reflux occurred concomitantly with acid reflux events, and thus acid rather than bile appears to be the dominant factor responsible for GERD symptoms [29]. On the other hand, experimental data support a role for persistent bile acids in the refluxate as a potential factor involved in refractory heartburn. Although PPI therapy reduces the occurrence of acid as well as bile reflux, complete acid suppression does not guarantee the elimination of bile reflux [30-32]. Perfusion of bile salts with nonacidic pH can still provoke heartburn [15], and exposure of rabbit esophageal mucosa to weakly acidic solutions containing bile acids (comparable situation to patients on PPI) increased mucosal permeability and induced dilated intercellular spaces, a proposed histopathological mechanism necessary for heartburn generation [33]. Studies in humans also suggested a possible role for bile reflux in both symptoms and erosive esophagitis in a subset of patients with difficult to manage symptomatic reflux. In a study that included 65 patients with persistent heartburn and regurgitation while on single-dose PPI therapy, a significant number of symptoms occurred in association with bile reflux as measured by Bilitec [34]. Furthermore, in a carefully selected group of patients with symptoms refractory to PPI therapy, baclofen 20 mg three times a day significantly reduced the bile reflux exposure as well as symptoms of heartburn. These studies suggest a role for measurement of bile reflux in patients with persistent reflux symptoms despite PPI therapy. However, the technique is not commonly available for the practicing physician and is presently limited to less than a handful of centers with interest in gastrointestinal motility
- Residual acid reflux — Residual acid reflux has been documented in patients with persistent heartburn despite a PPI once or twice daily [13,14,20-22]. As an example, in one study, 31 and 4 percent of GERD subjects with refractory symptoms who underwent pH testing on PPI once daily or PPI twice daily, respectively, had an abnormal test [23]. On the other hand, several studies demonstrated that reflux characteristics in PPI failure patients are similar to those in PPI success patients [24]. These studies suggest that PPI failure is primarily an esophageal hypersensitivity phenomenon. Furthermore, it appears that proximal immigration of weakly acidic reflux and the presence of gas in the refluxate are pivotal for symptom generation [25]. Bile acid reflux — Although commonly considered as synonyms, bile reflux and non-acid reflux are different phenomena. Initial studies suggested that bile reflux probably accounts for 10 to 15 percent of non-acid reflux. However, a study using simultaneous Bilitec (a device to measure bile reflux) and impedance monitoring showed no correlation between esophageal bilirubin exposure and non-acid reflux parameters [26-28]. In other reports, the majority of bile reflux occurred concomitantly with acid reflux events, and thus acid rather than bile appears to be the dominant factor responsible for GERD symptoms [29]. On the other hand, experimental data support a role for persistent bile acids in the refluxate as a potential factor involved in refractory heartburn. Although PPI therapy reduces the occurrence of acid as well as bile reflux, complete acid suppression does not guarantee the elimination of bile reflux [30-32]. Perfusion of bile salts with nonacidic pH can still provoke heartburn [15], and exposure of rabbit esophageal mucosa to weakly acidic solutions containing bile acids (comparable situation to patients on PPI) increased mucosal permeability and induced dilated intercellular spaces, a proposed histopathological mechanism necessary for heartburn generation [33]. Studies in humans also suggested a possible role for bile reflux in both symptoms and erosive esophagitis in a subset of patients with difficult to manage symptomatic reflux. In a study that included 65 patients with persistent heartburn and regurgitation while on single-dose PPI therapy, a significant number of symptoms occurred in association with bile reflux as measured by Bilitec [34]. Furthermore, in a carefully selected group of patients with symptoms refractory to PPI therapy, baclofen 20 mg three times a day significantly reduced the bile reflux exposure as well as symptoms of heartburn. These studies suggest a role for measurement of bile reflux in patients with persistent reflux symptoms despite PPI therapy. However, the technique is not commonly available for the practicing physician and is presently limited to less than a handful of centers with interest in gastrointestinal motility
- Nocturnal acid breakthrough — Up to 70 percent of patients takings PPIs twice daily have periods of gastric pH <4 for more than 60 minutes, particularly at night [35]. Nocturnal acid breakthrough (NAB) was initially proposed as a major cause of refractory GERD. In one study, for example, 24-hour pH studies during twice daily proton pump administration were compared in 76 patients with GERD and 31 healthy controls [35]. Abnormal esophageal acid exposure due to nocturnal acid breakthrough was significantly higher in patients with GERD and correlated with the severity of esophagitis (33 percent in patients with GERD and 50 percent in patients with GERD plus Barrett's esophagus versus 8 percent in controls). However, early reports about NAB did not attempt to demonstrate a correlation between this gastric phenomenon and nighttime GERD symptoms. Subsequent studies have shown that NAB events do not necessarily denote a temporal relationship with reflux-related symptoms [36]. Furthermore, in one report, 71 percent of patients with GERD who did not respond to treatment with PPI twice daily experienced NAB, but only 36 percent had correlation between symptoms and NAB events [37]. In addition, there is no relationship between NAB and nocturnal heartburn [38]. Thus, accumulating data do not support a significant role for NAB in precipitating failure of PPI treatment. Differences in metabolism — Proton pump inhibitors are metabolized through the hepatic cytochrome system (specifically the CYP2C isoenzyme). As a result, genetically determined variability in the processes underlying drug metabolism may influence their efficacy. Patients with rapid metabolism of PPIs may have a decreased effect on gastric acidity. On the other hand, CYP2C is absent in about 3 percent of Caucasian patients and in substantially higher numbers of Asians (greater than 10 percent), potentially leading to greater suppression of gastric acidity. (See "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders".) Reduced bioavailability — The bioavailability of the different proton pump inhibitors varies and may be influenced by environmental conditions and manufacturing [39]. However, for most patients, the differences in bioavailability among the proton pump inhibitors are not clinically significant during repeated dose administration since they do not translate into significant differences in the suppression of acid secretion [40]. As an example, the bioavailability of omeprazole is approximately 30 to 40 percent at doses of 20 to 40 mg. In contrast, the bioavailability of lansoprazole is much higher at approximately 80 percent for doses ranging from 15 to 60 mg. Despite these differences, the two drugs have equivalent efficacy for achieving acid suppression. This was illustrated in a controlled crossover study in which meal-stimulated acid secretion was decreased by 48 and 82 percent with 15 and 30 mg lansoprazole, respectively, and by 39 and 83 percent with 20 and 40 mg of omeprazole, respectively [41]. The general pharmacokinetic observations may not apply to individuals in whom the bioavailability of these drugs can vary significantly [42]. As a result, some patients may not achieve adequate acid suppression despite standard or relatively high-dose therapy.
- Drug resistance — Resistance to proton pump inhibitors is a rare condition that may be caused by mutations in the proton pump gene, a relationship that has only been described in a 1995 abstract [7,43]. It is unlikely that this condition has any significant role in refractory GERD. Delayed healing — Complete relief of heartburn with proton pump inhibitors occurs at a rate of approximately 11.5 percent per week [44]. Thus, endoscopic healing and symptom relief are achieved within eight weeks in the majority of patients. However, patients with severe esophagitis (eg, Los Angeles C or D esophagitis) may take longer to heal. Helicobacter pylori status — PPIs produce a modest increase in acid suppression in H. pylori-positive patients than H. pylori-negative patients, potentially leading to higher healing rates in patients with erosive esophagitis [45,46]. The suggested underlying mechanism is migration of H. pylori proximally in the stomach to the corpus or fundus during PPI treatment. These areas of the stomach contain parietal cells, which are responsible for acid production. However, the prevalence of H. pylori infection has been rapidly declining in the United States and other developed countries, resulting in a very low background prevalence that cannot explain the large percentage of PPI failure patients. (See "Helicobacter pylori and gastroesophageal reflux disease".) Psychological comorbidity — Patients with poor correlation of symptoms with acid reflux events display a high level of anxiety and hysteria as compared with patients who demonstrate a close correlation between symptoms and acid reflux events [47]. Anxiety and depression increase GERD-related symptoms reported in population-based studies [48]. Thus, it has been proposed that patients who did not respond to PPI therapy are more likely to have psychosocial comorbidity than those who were successfully treated with a PPI
- DIFFERENTIAL DIAGNOSIS — Other diseases that should be considered in patients with refractory GERD are achalasia, esophageal cancer, esophageal stricture, other causes of esophagitis, and gastric stasis: Patients with achalasia may develop heartburn as a result of fermentation of retained food in the esophagus. (See "Clinical manifestations and diagnosis of achalasia".) Patients with distal esophageal cancer may continue to have symptoms and have ulceration mimicking peptic esophagitis on endoscopy. (See "Diagnosis and staging of esophageal cancer", section on 'Diagnostic testing'.) Patients who have dysphagia associated with reflux may continue to be symptomatic despite adequate acid suppression if they have developed a stricture. Relief usually accompanies adequate dilation. Patients who are taking nonsteroidal antiinflammatory drugs (NSAIDs) can experience pyrosis and may be more susceptible to acid-related esophageal disease [50,51]. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".) Patients with rumination syndrome may be thought to have GERD. However, questioning regarding the symptoms of rumination syndrome should distinguish between the two disorders. (See "Etiology and diagnosis of delayed gastric emptying", section on 'Rumination syndrome'.) In addition to acid, a variety of caustic and infectious causes are associated with esophagitis. Examples include pill-induced esophagitis, caustic ingestion, Candida, herpes, and radiation. These causes should be excluded. (See appropriate topic reviews.) Patients who have impaired gastric emptying are predisposed to reflux. Symptoms may be improved after appropriate treatment. Eosinophilic esophagitis in adults is commonly associated with dysphagia while only about one-third of patients report classic heartburn symptoms [52-57]. Heartburn alone is uncommon. The relationship between eosinophilic esophagitis and reflux is complex and the prevalence of eosinophilic esophagitis in patients with heartburn refractory to PPIs has ranged between 0.9 percent and 8.8 percent. (See "Pathogenesis, clinical manifestations, and diagnosis of eosinophilic esophagitis".) Sensitization to foods appears to be common among patients with refractory GERD. In one study of 65 patients with refractory GERD, sensitization to foods was present in 18 patients (28 percent) based upon the results of skin testing [58]. Eosinophils were found in the esophageal mucosa of patients who were food sensitized more often than in patients who were not (38 versus 7 percent), but only one patient was diagnosed with eosinophilic esophagitis. Fifteen of the food sensitized patients followed a six-week restriction diet, with symptom improvement in 12 patients (80 percent). (See "Clinical manifestations of food allergy: An overview".) In one study, patients with GERD who also had irritable bowel syndrome (IBS) perceived their symptoms as more severe and tended not to achieve the same degree of symptom improvement during PPI treatment compared with patients with GERD without IBS [49].
- Management algorithm of gastroesophageal reflux disease (GERD) patient who failed PPI once daily (complete or partial*). PPI: proton pump inhibitor; SSRIs: selective serotonin reuptake inhibitors; TLESR: transient lower esophageal sphincter relaxation; H2RA: histamine 2 receptor antagonist. * Partial or incomplete relief of symptoms.
- Management algorithm of gastroesophageal reflux disease (GERD) patient who failed PPI once daily (complete or partial*). PPI: proton pump inhibitor; SSRIs: selective serotonin reuptake inhibitors; TLESR: transient lower esophageal sphincter relaxation; H2RA: histamine 2 receptor antagonist. * Partial or incomplete relief of symptoms.
- LIFESTYLE MODIFICATIONS — Minimal, but sensible, therapy for gastroesophageal reflux disease (GERD) patients is comprised of lifestyle modification, dietary modification, as needed antacid use, over-the-counter H2 receptor antagonists, and over-the-counter proton pump inhibitors. Lifestyle modifications are aimed at enhancing esophageal acid clearance, minimizing the incidence of reflux events, or both as with cessation of smoking and avoidance of late meals: Head of bed elevation, which can be achieved either by putting 6- to 8-inch blocks under the legs at the head of the bed or a Styrofoam wedge under the mattress. Head of bed elevation is important for individuals with nocturnal or laryngeal symptoms; its necessity in other situations is questionable. Dietary modification may be helpful, but prohibition of many enjoyable foods virtually ensures noncompliance. It is more practical to suggest avoidance of a core group of reflux-inducing foods (fatty foods, chocolate, peppermint, and excessive alcohol, which may reduce lower esophageal sphincter pressure) and then to suggest that the patient selectively avoid foods known to cause symptoms. As an example, a number of beverages have a very acidic pH and can exacerbate symptoms. These include colas, red wine, and orange juice (pH 2.5 to 3.9). Refraining from assuming a supine position after meals and avoidance of meals two to three hours before bedtime, both of which will minimize reflux. Avoidance of tight fitting garments, which reduces reflux by decreasing the stress on a weak sphincter. Obesity is a risk factor for GERD, erosive esophagitis, and esophageal adenocarcinoma [3]. However, improvement in symptoms following weight loss is not uniform [4-8]. Nevertheless, because of a possible benefit, and because of its other salutary effects, weight loss should be recommended. Promotion of salivation by either chewing gum or use of oral lozenges may also be helpful in mild heartburn. Salivation neutralizes refluxed acid, thereby increasing the rate of esophageal acid clearance. Restriction of alcohol use and elimination of smoking; smoking is deleterious in part because it diminishes salivation. Although these approaches have been used clinically, their effectiveness has not been extensively evaluated in clinical trials. A systematic review of the published literature concluded that there was only evidence supporting the effectiveness of weight loss and head of bed elevation [9]. Abdominal breathing exercises have been suggested as a way to improve GERD with the rationale of strengthening the anti-reflux barrier of the lower esophageal sphincter. This technique was examined in a randomized controlled trial with 19 patients with nonerosive GERD [10]. After four weeks, patients in the abdominal breathing group showed reduced esophageal acid exposure and improved quality of life scores compared with their baseline, whereas there were no changes among control patients. However, there were no significant differences in scores between the abdominal breathing group and the controls. At the end of four weeks, the control patients crossed over to abdominal breathing exercises. After nine months, those still performing the exercises (n = 11) had significant improvement in their quality of life scores and proton pump inhibitor usage compared with their baseline values, whereas those not performing the exercises showed no changes. Because the study was small and failed to show a difference between the patients assigned to abdominal breathing and the control patients, larger studies are required to confirm a benefit for this technique.
- ACID SUPPRESSIVE MEDICATIONS — Acid suppressive medication regimens include, in increasing order of potency, over-the-counter antacids and H2 blockers at non-prescription strength, prescription strength H2 blockers, and proton pump inhibitors, administered as needed, once, or twice daily. In patients with mild to moderate GERD, symptom severity and previous treatments can guide the selection of an initial acid suppressive regimen (table 1 and algorithm 1). The most common and effective treatment of peptic esophagitis or symptomatic gastroesophageal reflux disease (GERD) is to reduce gastric acid secretion with either an H2 blocker or a proton pump inhibitor (PPI) [11]. The medication dose is titrated to the severity of disease for each patient, with the goal being to raise the intragastric pH above 4 during the periods of the day that reflux is likely to occur [12]. The greater the degree of pathologic esophageal acid exposure, the greater the degree of acid suppression required. These therapies do not prevent reflux, but they reduce the acidity of the refluxate. (See "Pathophysiology of reflux esophagitis".) Many trials have established the efficacy of the various proton pump inhibitors and H2 antagonists in the treatment of esophagitis [13,14]. However, unless the medications are compared head to head, ascertaining the relative efficacy of these drugs is complicated by the fact that esophagitis exists along a continuum of severity, and comparability of study populations among trials cannot be assumed. One way of indexing esophagitis severity among trials is by the placebo healing rate. The placebo healing rate is very low with severe esophagitis and relatively high in mild esophagitis [15]. The H2 receptor antagonists offer a therapeutic gain of 10 to 24 percent relative to the placebo for healing esophagitis. However, the gain is nearly constant regardless of the placebo healing rate, indicating that these drugs are ineffective for severe esophagitis and do not exhibit a dose-response curve in the treatment of esophagitis. The different H2 receptor antagonist have equivalent efficacy if drug dose is adjusted for potency [16]. An increased dose or prolonged course of an H2 antagonist is unlikely to produce relief for patients who continue to have heartburn after six weeks of treatment with a standard dose of an H2 antagonist [17]. The proton pump inhibitors are more effective in healing esophagitis than the H2 receptor antagonists, with a therapeutic gain of 57 to 74 percent relative to placebo. In addition, proton pump inhibitors lead to more rapid healing and symptom relief than H2 receptor antagonists. In a meta-analysis, complete relief from heartburn occurred at a rate of 11.5 percent per week with a proton pump inhibitor compared to 6.4 percent per week with an H2 receptor antagonist [18]. Furthermore, proton pump inhibitors exhibit a dose-response curve for healing highgrade esophagitis as evidenced by higher healing rates with higher doses and/or more potent compounds. A systematic review demonstrated that for treatment of regurgitation among patients with GERD, proton pump inhibitor (PPI) treatment was superior to placebo or an H2 receptor antagonist. However, proton pump inhibitor treatment resulted in only a modest therapeutic gain in patients compared with placebo in those who reported the symptom at baseline (0 to 35 percent). This was similar to the therapeutic gain seen for proton pump inhibitor treatment over that with an H2 antagonist and/or cisapride (5 to 38 percent) Nonerosive gastroesophageal reflux disease — The majority of patients with typical symptoms of GERD do not have esophagitis; such patients have been referred to as having nonerosive reflux disease (NERD) [20]. Some of these patients have symptoms despite having normal levels of esophageal acid exposure as assessed by a 24-hour pH monitoring study. Such patients may have esophageal hypersensitivity to physiologic degrees of acid reflux. (See "Pathophysiology of reflux esophagitis", section on 'Esophageal hypersensitivity'.) Other NERD patients have abnormal acid exposure but have not developed overt mucosal injury. Still others have heartburn not attributable to acid reflux, sometimes referred to as "functional heartburn". The first two groups, but not the third group of patients, may respond to antisecretory therapy. At least three controlled trials and a meta-analysis suggest that proton pump inhibitors were associated with more effective symptom relief than placebo or H2 receptor antagonists in such patients [21-23]. Differences in proton pump inhibitors — A number of studies have compared the various proton pump inhibitors to one another. While some differences have been reported, the magnitude of differences has been small and of uncertain clinical significance.
- ADJUNCTIVE THERAPY Prokinetic agents — Prokinetic drugs (eg, bethanechol, metoclopramide, azithromycin) increase lower esophageal sphincter pressure, enhance gastric emptying, and improve peristalsis. They may also reduce hiatus hernia size and therefore impact the position of the gastric acid pocket, which serves as a reservoir for acid reflux [24]. However, it is unclear if treatment with prokinetics leads to a reduction in GERD symptoms. In addition, their use is limited by side effects [11]. Consequently, there is currently no role for the use of prokinetics as monotherapy or adjunctive therapy for the treatment of GERD Reflux inhibitors — Drugs that inhibit transient lower esophageal sphincter relaxation have also been considered for adjunctive treatment of GERD [25]. The gamma-aminobutyric type B receptors baclofen [26-29] and lesogaberan [30] have shown efficacy in decreasing reflux episodes in patients with GERD. Doses of baclofen used in these studies are higher than are typically used in the treatment of spasticity disorders. Baclofen, however, has not been used as a treatment option for GERD because of its adverse side effect profile (sedation, dizziness) at the doses that would be needed for effective treatment. In a double-blind, placebo-controlled, randomized phase IIA trial, treatment with lesogaberan, a novel gammaaminobutyric type B receptor agonist, resulted in significantly improved heartburn and regurgitation symptoms compared to placebo; however, the proportion of responders was small (16 versus 8 percent). Lesogaberan was well tolerated with adverse events of mostly mild to moderate intensity that were comparable to the placebo group (45 versus 37 percent) [31]. The role of lesogaberan as an add-on treatment in patients partially responding to PPIs has yet to be determined. TREATMENT OF HELICOBACTER PYLORI INFECTION — A possible role for H. pylori in the pathogenesis of gastroesophageal reflux disease (GERD) has been suggested in a number of studies. However, the link between GERD and H. pylori is complex and incompletely defined. The main linkage is in the effect that H. pylori has on gastric acid secretion. Hence, eradication of H. pylori is associated with mild worsening of GERD in patients with pan-gastritis (hyposecretors) and improvement in those with antral-predominant gastritis (hypersecretors). These effects must be balanced against the risks of continued infection. (See "Helicobacter pylori and gastroesophageal reflux disease".)
- MAINTENANCE THERAPY — Given the propensity of esophagitis to relapse, maintenance acid suppressive therapy is often necessary [32]. However, a trial off medications should be considered in all patients with gastroesophageal reflux disease (GERD) who have a good clinical response to acid suppression with the exception of those with severe esophagitis on upper endoscopy (Los Angeles classification Grade C and D) and Barrett’s esophagus [33]. Patients with severe esophagitis should remain on maintenance acid suppression as they are likely to have recurrent symptoms with discontinuation of acid suppression and are more likely to develop complications. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Los Angeles classification'.) The need for maintenance medical therapy is determined by the rapidity of recurrence. Recurrent symptoms in less than three months suggest disease best managed with continuous therapy, while recurrences occurring after more than three months can be managed by repeated courses of acute therapy as necessary [34]. Reducing the medication dose or attempting maintenance with a less potent agent than that used for healing often results in a high recurrence rate [34-36]. The following conclusions were made in systematic reviews [37,38]: Proton pump inhibitors (PPIs) at a standard dose (as suggested by the manufacturer's prescribing information) or a lower dose (usually one-half of the standard dose) were more effective than H2RAs in resolving GERD symptoms at four weeks and promoting healing esophagitis at eight weeks. PPIs at a standard dose were more effective than a lower dose in preventing relapse of symptoms. PPIs at a standard dose were more effective than PPIs at a lower dose in maintaining healing of esophagitis. Intermittent therapy — Intermittent (on-demand) therapy with an H2 receptor antagonist or proton pump inhibitor may be successful in some patients with mild to moderate heartburn without moderate-severe esophagitis. The optimal approach for prescribing intermittent therapy has not been established. One of the largest trials included 677 patients with mild to moderate heartburn and a normal endoscopy or only mild erosive changes were randomly assigned to omeprazole (10 or 20 mg/day) or ranitidine (150 mg twice daily) [39]. After two weeks, asymptomatic patients were given no further therapy unless symptoms returned upon which they were treated for two to four weeks with the drug that initially caused remission. At the end of one year, approximately 50 percent of patients in all three treatment groups had not required medication for at least six months