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Vincenzo Savarino, Prof., MD

LE MANIFESTAZIONI EXTRASOFAGEE DELLA MRGE: REALI O IMMAGINARIE ?. Vincenzo Savarino, Prof., MD Head of the Department of Internal Medicine and Medical Specialties, University of Genoa, Italy

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Vincenzo Savarino, Prof., MD

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  1. LE MANIFESTAZIONI EXTRASOFAGEE DELLA MRGE: REALI O IMMAGINARIE ? Vincenzo Savarino, Prof., MD Head of the Department of Internal Medicine and Medical Specialties, University of Genoa, Italy Head of the Gastroenterology-Hepatology Unit, IRCCS Azienda Ospedaliera-Universitaria San Martino - IST, Genoa, Italy

  2. GERD - New Montreal Definition GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms and / or complications Esophageal Syndromes Extra-esophageal Syndromes Proposed Association Established Association Symptomatic Syndromes Syndromes with Esophageal Injury Sinusitis Pulmonary fibrosis Pharyngitis Recurrent otitis media Reflux cough Reflux laryngitis Reflux asthma Reflux dental erosions Reflux esophagitis Reflux stricture Barrett's esophagus Adenocarcinoma Typical reflux syndrome Reflux chest pain syndrome Vakil et al., Am J Gastroenterol 2006

  3. Abnormal 24-hour pH Monitoring in Patients With Suspected Reflux Laryngitis Vaezi et al, 2003

  4. Abnormal Acid Reflux Linked to Asthma 100 90 82 80 70 61 55 60 53 Patients with abnormal acid reflux (%) 40 33 20 0 Ducolone et al. (n=51) Nagel et al. (n=44) Giudicelli et al. (n=140) Sontag et al. (n=104) DeMeester et al. (n=77) Larrain et al. (n=105) Kiljander et al. (n=107) Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.

  5. Prevalence of reflux-associated chronic cough by esophageal pH monitoring Vaezi MF, APT 2006

  6. Dental erosions in GERD patients Ranjitkar S et al, J Gastroenterol Hepatol 2012

  7. Boxplots showing the total number and the chemical composition of reflux episodes in the two subgroups of SSC patients with and without pulmonary fibrosis and healthy volunteers. p<0.001 p<0.001 p<0.001 p<0.001 No. reflux episodes p<0.05 p<0.05 Savarino E et al, AJRCCM 2009

  8. Proximal migration of reflux episodes in scleroderma patients and in controls. p<0.001 p<0.001 No. reflux episodes 15 cm above LES Savarino E et al, Am J Resp Crit Care Med 2009

  9. Correlation between proximal migration of refluxes and total number of reflux events and pulmonary fibrosis score r2=0.637,p<0.001 r2=0.644,p<0.001 Savarino E et al, Am J Respir Crit Care Med 2009

  10. Number and types of gastro-esophageal reflux in IPF (n=40) and non-IPF patients (n=40) and in healthy controls (n = 50). Bars indicate median values. IPF= idiopathic pulmonary fibrosis Boxplots showing the number of total, acid and non-acidic reflux in patients with IPF and non-IPF and in controls N° REFLUX EVENTS Savarino E et al, DDW 2012

  11. Median number of reflux episodes reaching the proximal esophagus in IPF (n=40) and non-IPF patients (n=40) and in healthy controls (n = 50). Bars indicate median values. IPF= idiopathic pulmonary fibrosis N° PROXIMAL REFLUX EVENTS Savarino E et al, DDW 2012

  12. Correlationbetween the grade of pulmonaryfibrosis(HRCT score) and the number of totalrefluxepisodesatboth the distal (on the left) and proximal (on the right) esophagus r2=0.567,p<0.001 r2=0.632,p<0.001 Savarino E et al, DDW 2012

  13. Percentages of patients with presence of biliary acids and pepsin in IPF, non-IPF and controls SALIVA BAL • Biliaryacids • 61% IPF patients • 36% non-IPF patients • 0% controls • Pepsin: • 68% IPF patients • 39% non-IPF patients • 0% controls • Biliaryacids: • 62% IPF patients • 40% non-IPF patients • 0% controls • Pepsin: • 67% IPF patients • 40% non-IPF patients • 0% controls P < 0.01 Savarino E et al, DDW 2012

  14. PREVALENCE OF ATYPICAL SYMPTOMS • Prevalence of atypical symptoms concerning upper airways: • Sporadic manifestations between 7% and 15% • Frequent manifestations : 5 % Locke GR Gastroenterology 1997; 112:1448-56. • In more than 50% of patients with atypical symptoms, typical symptoms are lacking Koufmann JH. Laringoscope 1991

  15. GERD and respiratory symptoms PATHOPHYSIOLOGY • Microaspiration of gastric contents into the larynx or airways with consequent mucosal reaction • Vagal reflex stimulated by refluxate in the distal esophagus with the production of cough and/or bronchospasm

  16. DIAGNOSTIC STRATEGY (search for GERD in patients with extraesophageal symptoms) • Clinical features • Trial of aggressive acid suppression (PPI test) • Endoscopy • 24-h pH-metry [the choice of the diagnostic work-up should be based on test sensitivity, prevalence of the disease, cost-effectiveness, etc.]

  17. Suggested Regimens for Extra-esophageal Manifestations of GERD Katz et al, Am J Med 2000; 108(suppl 4a): 170S-177S.

  18. Cough scores dramatically decrease after the introduction of omeprazole 40 mg bid and the patient remains free of cough 1 yr after PPI withdrawal Ours T et al, Am J Gastroenterol 1999

  19. Usefulness of PPI test in GERD  Gold standard: pH-metry and/or endoscopy De Vault et al, 2000

  20. Endoscopy

  21. GERD and extraesophagealmanifestations It’s not simple to establish a cause-effect relationship between GERD and extraesophageal manifestations ! Regurgitation or pyrosis : 20%-75% Erosive Esophagitis : < 30% Irvin,1993; Ours,1999

  22. Ear, nose and throat (ENT) signs in normalvolunteers (n = 105) Hicks DM et al, 2002

  23. Therapeutic trial of anti-GORD therapy for asthma patients Adult asthma patients Monitor baseline asthma symptom, PEF, asthma medication use and spirometry 3-month trial with omeprazole 20 mg twice daily, lansoprazole 30 mg twice daily, or rabeprazole 20 mg twice daily Continue monitoring as above • Asthma improved • Begin maintenance anti-GORD therapy, which may include: • PPIs • H2RAs • Prokinetic agents • Surgery in selected patients Asthma not improved Perform 24-hour oesophageal pH test while on anti-GORD regimen pH+ Increase anti-GORD therapy or refer to gastroenterologist pH- Asthma is not GORD-related PEF = Peak Expiratory Flow Harding & Sontag, Am J Gastroenterol 2000; 95(Suppl): S23–32.

  24. 24-hour ambulatory pH-impedance

  25. Episode of acid gastroesophageal reflux

  26. Episode of weakly acidic GER

  27. Criteria for selection of patients with chronic cough in whom GERD should be investigated Galmiche JP et al, APT 2008

  28. Nonacid reflux episode associated with cough Rosen and Nurko, 2004

  29. Relevance of acid and/or weakly acidic reflux in chronic cough 22 Patients 10 SAP + Reflux-Cough 5 Acid Associated 3 Non acid Associated 2 Acid & Non acid Associated Weakly Acidic Reflux in Patients with Chronic Unexplained Cough During 24 Hour Pressure, pH and Impedance Monitoring; D. Sifrim et al; GUT; 2005; 54;449-454

  30. Identification of three subgroups with chronic cough Blondeau et al, APT 2007

  31. NEG Proposal of a diagnostic work-up in patients with suspected atypical GERD Quigley et al, 2008

  32. Therapeutic results in patients with atypical symptoms of GERD

  33. n Study design Therapy Asymtomatic patients (%) Irwin et al, ‘89 9 Uncontrolled Metoclopramide and/or H2RAs 100 Irwin et al, ‘90 28 Uncontrolled Metoclopramide and/or H2RAs 100 Fitzgerald et al, ‘89 20 Uncontrolled Antacids, Cimetidine, Metoclopramide 70 Waring et al, ‘95 25 Uncontrolled H2RAs, PPIs 80 Smyrnios et al, ‘95 20 Uncontrolled H2RAs  prokinetics 97 Vaezi et al, ‘97 11 Uncontrolled H2RAs or PPIs 100 Ours et al, ‘99 17 Double-blind, placebo-controlled PPI ( Ome 40 mg bid ) 35 Medical Treatment of Patients with Chronic Cough from Suspected GERD

  34. Results of Seven Randomized, Controlled Trials of PPIs in Subjects with GERD-related Asthma Shaheen N, DDW 2004

  35. Medical treatment trials for GERD-relatedasthma Richter et al, 2005

  36. Treatment difference (95% CI) in change in morning and evening PEF rate (L/min), classified according to GERD and nocturnal symptoms in asthmatic subjects receiving esomeprazole 40 mg twice daily or placebo Kiljander et al, AJRCCM 2006

  37. Questionnaire scores and lung function measures at 24 weeks of follow up Holbrook J et al, JAMA 2012

  38. Results of Uncontrolled Studies in the Treatment of Patients With Suspected Reflux Laryngitis Response (*PPIs were given generally twice daily, before breakfast and dinner) Vaezi et al, 2003

  39. Medical antireflux treatment of reflux laryngitis: placebo-controlled studies Richter et al, 2005

  40. Estimates of relative risk for improvement or resolution of laryngeal symptoms in patients treated with PPIs Gatta et al, APT 2007

  41. Summary of proton pump inhibitor efficacy for potential manifestations of GORD as assessed in randomised controlled trials. Kahrilas and Boeckxstaens, Gut 2012

  42. no. pts. Study design Treatment Asymptomatic (%) Pellegrini ‘79 5 Prospectic, uncontrolled Fundoplicatio 100 DeMeester ‘90 17 Prospectic, uncontrolled Fundoplicatio 100 Giudicelli ‘90 13 Prospectic, uncontrolled Fundoplicatio 85% Johnson ‘96 40 Prospectic, uncontrolled Fundoplicatio 76 Allen, Anvari ‘98 20 Prospectic, uncontrolled Fundoplicatio 51%(asintom) 31%(migliorati So ‘98 16 Prospectic, uncontrolled Fundoplicatio 56 Leeder ‘02 7 Prospectic, controlled Fundoplicatio 60 Surgicaltherapy of chroniccough due to GORD

  43. Preoperative and postoperative voice frequency (CFx) and amplitude (CFa) are compared in patients with documented irregularity in their preoperative electroglottography (n = 6). p < 0.0012 and p < 0.0415 Ayazi S et al, J Clin Gastroenterol 2012

  44. Shortcomings Shared by Studies on Extra-esophageal Reflux Disease • Moststudiesfeature small number of subjects • Case definitionisvariable (also 24-hour pH data are of limited utility) • In patients with abnormalpH data, a simpleassociationinstead of causationbetweenreflux and laryngeal-respiratorysymptomsmay be present • In a subgroup of patients with chroniccough acid and/or weaklyacidicgastroesophagealreflux can be present • Studyoutcomemeasures are notstandardized and mayvaryconsiderablyacrossstudies • Treatment amount and durationmay be inadequate

  45. Atypical GERD: key messages • GERD can manifest with atypical symptoms • Their prevalence ranges between 5% and 20% • There is no diagnostic method of adequate reliability • It is mandatory to distinguish simple association from causality between GERD and extra-esophageal disorders • It is recommended to treat these patients with higher-than-standard doses of PPIs and for longer-than-usual time periods • However, both medical and surgical therapies are frequently disappointing in controlled studies • Our future efforts should be addressed to identify the subgroup of patients who can respond to anti-reflux treatment

  46. The End

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