title: Beyond heartburn: a systematic review of the extra-oesophageal spectrum of reflux-induced disease.
abstract: BACKGROUND
  Gastro-oesophageal reflux disease (GORD) is a chronic condition affecting up to one-quarter of the Western population. GORD is characterized by heartburn and acid regurgitation, but is reported to be associated with a spectrum of extra-oesophageal symptoms.
  
  
  OBJECTIVE
  The aim of this systematic review was to critically evaluate postulated extra-oesophageal symptoms of GORD.
  
  
  METHODS
  Extra-oesophageal symptoms were identified from population-based studies evaluating their association with GORD (either defined as heartburn and/or acid regurgitation, or diagnosed in general practice). The response of these symptoms to acid-suppressive therapy was investigated using randomized, double-blind, placebo-controlled studies. Pathogenic mechanisms were evaluated using clinical and preclinical studies.
  
  
  RESULTS
  An association between GORD and symptoms or a diagnosis of chest pain/angina, cough, sinusitis and gall-bladder disease was evident from three eligible population-based studies of GORD. Randomized placebo-controlled studies (n=20) showed that acid-suppressive therapy provides symptomatic relief of chest pain, asthma and, potentially, chronic cough and laryngitis. Mechanistic models, based on direct physical damage by refluxate or vagally mediated reflexes, support a causal role for GORD in chest pain and respiratory symptoms, but not in gall-bladder disease.
  
  
  CONCLUSIONS
  GORD is likely to play a causal role in chest pain and possibly asthma, chronic cough and laryngitis. Further investigation is desirable, particularly for other potential extra-oesophageal manifestations of GORD such as chronic obstructive pulmonary disease, sinusitis, bronchitis and otitis. Acid-suppressive therapy is likely to benefit patients with non-cardiac chest pain, but further placebo-controlled studies are needed for other symptoms comprising the extra-oesophageal spectrum of GORD.
authors: Cetre for Integrated Health Care Research, University of Durham--Stockton Campus, Wolfson Research Institute, Stockton-on-Tees TS176BH, UK. A.P.S.Hungin@durham.ac.uk
authors: A Pali S
authors: AP
authors: Hungin
authors: Anan S
authors: AS
authors: Raghunath
authors: Ingela
authors: I
authors: Wiklund
mesh_terms: D001249:Asthma / Q000209:etiology; D002637:Chest Pain / Q000209:etiology; D003371:Cough / Q000209:etiology; D004311:Double-Blind Method; D016021:Epidemiologic Studies; D005194:Family Practice; D005750:Gastric Juice; D005764:Gastroesophageal Reflux / Q000150:complications* / Q000188:drug therapy; D006356:Heartburn; D006801:Humans; D007827:Laryngitis / Q000209:etiology; D016032:Randomized Controlled Trials as Topic; D013222:State Medicine; D006113:United Kingdom