1. Gastroesophageal Reflux Disease and Barrett’s Esophagus Ryan D. Madanick, MD Assistant Professor of Medicine Director, UNC GI/Hepatology Fellowship Program Center for Esophageal Diseases and Swallowing UNC School of Medicine

2. GERD is a common and significant problem: US study Prevalence (%) 0 2020 40 6060 80 25–3435–4445–5455–6465–74 Age (years) Any episode of GERD symptoms At least weekly episodes of GERD symptoms females males Locke GR et al. Gastroenterology 1997;112:1448.

3. Hypertension, untreated Normal female Angina pectoris Duodenal ulcer, untreated Psychiatric patients 110 Normal male Heart failure (mild) Esophagitis, untreated PGWB Index score GERD has a greater impact on quality of life than other common diseases 60708090100 Dimenas E. Scand J Gastroenterol 1993;28 Suppl 199:18.

4. Clinical Presentation of GERD Typical/ Esophageal Heartburn Acid regurgitation Atypical/ Supraesophageal Chest pain Laryngitis Asthma Sinusitis Chronic cough Aspiration pneumonia Tooth decay

5. Describing heartburn as “a burning feeling rising from the stomach or lower chest up towards the neck” can help patients recognise this symptom. n=196 Patients do not always correctly identify the symptom of heartburn Clinician interview/endoscopy Functional dyspepsia diagnosed Predominant heartburn excluded Reflux questionnaire Identified a burning feeling rising from the stomach or lower chest up towards the neck as their main symptom 42% Carlsson R et al. Scand J Gastroenterol 1998;33:1023

6. Pathophysiology of GERD Impaired acid neutralization by saliva and HCO 3 Impaired esophageal motility Hiatal hernia LES (inappropriate relaxation) Delayed gastric emptying/ gastroparesis LES=lower esophageal sphincter

7. There is only weak evidence that lifestyle factors aggravate GERD symptoms Obesity: – severity of esophagitis correlates with weight only when BMI >30 kg/m 2 – contradictory studies into weight loss indicate no effect/improvement in GERD. Smoking: – lowers LES pressure and the acid-neutralising effect of saliva. Physical activity: – running might provoke GERD by increasing TLESRs. Meining A et al. Am J Gastroentero 2000;95:2692.

8. Medications may aggravate GERD symptoms Impairment of LES function: beta-adrenergic agonists theophylline anticholinergics tricyclic antidepressants progesterone alpha-adrenergic antagonists diazepam calcium channel blockers. Damage to the esophageal mucosa: acetylsalicylic acid and other NSAIDs tetracycline quinidine bisphosphates.

9. Cough response Stimulation of vagus nerve Gastric refluxate Esophageal–bronchial transmission via cough center Aspiration to lower respiratory tree Gastric refluxate Cough and GERD: 2 Possible Mechanisms

10. Phenotypic Classification of GERD GERD NERD* 60-70% Erosive Esophagitis 20-30% Barrett’s Esophagus 6-10% Fass et al. Alim Pharm Ther 2005 *NERD: Non-Erosive Reflux Disease

11. ARE YOU A NERD?

12. What are the Symptoms of Symptomatic GERD? Heartburn Regurgitation Chest pain Impaired QOL Others (burning mouth/tongue) Atypical (“supraesophageal”) symptoms These are the same symptoms as patients with erosive esophagitis and Barrett’s esophagus The severity of these symptoms CANNOT PREDICT the subtype of GERD into which a patient falls prior to endoscopic examination

14. Taken from Medscape.com

15. Endoscopic Images Normal Squamo- columnar junction LA Grade A Esophagitis LA Grade D Esophagitis

17. Esophageal stricture – endoscopic appearance

18. Metaplasia of the esophagus: Barrett’s esophagus Definition: a change in the esophageal epithelium of any length that can be recognised at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus and excludes intestinal metaplasia of the cardia. Squamous epitheliumColumnar epithelium

19. 20 0 5 1010 15 Number of episodes 0 1 2 3 Time (minutes) Barrett’s esophagus is associated with prolonged acid reflux Reflux episodes >5 minutesMean duration of reflux episode Barrett’s esophagus n=51 severe esophagitis n=30 moderate esophagitis n=45 controls n=24 Coenraad M et al. Am J Gastroenterol 1998;93:1068.

20. The prevalence of Barrett’s esophagus increases with the duration of reflux symptoms <11–55–10>10 Duration of symptoms (years) Prevalence of endoscopic Barrett's esophagus (%) 0 5 1010 15 2020 25 Lieberman DA et al. Am J Gastroenterol 1997;92:1293.

21. Does Barrett’s Esophagus Occur in the Absence of Heartburn? EGD done on 961 pts scheduled for colonoscopy; 556 never had heartburn Conclusions: – BE is relatively common in persons age >40 years with no prior endoscopy – LSBE is very uncommon in patients who have no history of heartburn HB (-) (n=556) Overall (n=961) Barrett’s 5.6%6.8% LSBE 0.36%1.2% Rex D et al. Gastro 2003

22. 0 500 1000 Size of study (patient-years) 0103030 Cancer risk per 1000 patient-years 20 Reported adenocarcinoma risk in Barrett’s esophagus is dependent on the study size 1500 Shaheen & Ransohoff 2002 True risk is estimated as 0.5% per patient-year

23. Dysplasia in Barrett’s Prevalence: LGD: 7.3%; HGD: 3% 1 Dysplasia MUST be confirmed HGD: must aggressively look for prevalent cancers Screening and surveillance intervals? Management options for HGD: – Esophagectomy – Ablation – Endoscopic mucosal resection 1 Sharma et al. Clin Gastro Hep 2006

24. A 35-year old woman presents to her primary care physician because of six months of heartburn. Her medical history is only notable for chronic migraines. She has no dysphagia, odynophagia, or weight loss. She experiences symptoms several times a week, usually during stressful days at her job as a high school teacher. What should be done at this point?

25. Initial Management of Heartburn A.Antacids and lifestyle changes B.H 2 -receptor antagonists C.Standard Proton pump inhibitor therapy D.High-dose Proton pump inhibitor therapy Continuous? On-Demand? E.Endoscopy and/or pH testing followed by therapy based on results

26. Proton Pump Inhibitor Test Empiric therapy with PPI for heartburn Functions as both diagnostic test and therapeutic trial Sensitivity 68-80% as defined by abnormal pH test or endoscopy May be falsely positive (does not actually make a true diagnosis or GERD) Kahrilas PJ. Am J Gastro 2003;98: S15-23

27. Indications for additional investigations Atypical history. Symptoms are frequent and long-standing or do not respond to therapy. Alarm symptoms are present: – severe dysphagia – weight loss – bleeding – hematemesis – mass in the upper abdomen – anemia

28. The PCP places her on H 2 -receptor antagonists and recommends lifestyle changes and intermittent antacids. She returns a month later with no change in her symptoms. She is placed on once daily PPI therapy and referred for an upper endoscopy 2 weeks later, which is normal. She is still symptomatic. What should be done now?

29. A.Increase proton pump inhibitor to twice a day B.Refer for endoscopic treatment (Stretta) C.Refer for surgical treatment D.Perform pH study E.Something else (like what?)

30. Why Do PPI’s Fail to Control Symptoms?

31. Reasons for PPI “Failure” Patient non-compliance Persistent esophageal acid exposure – Hypersecretory state – Large hiatal hernia – Nocturnal acid breakthrough Acid-sensitive esophagus Non-acid reflux Wrong diagnosis Functional heartburn (NOT GERD!!)

33. Wireless pH monitoring (Bravo®)

34. Placement of Bravo ® capsule

35. What Is Impedance (Z) ? Opposition to Current Flow  Measurement of resistance in an alternating current.  Inversely related to the electrical conductivity of an organ’s wall & contents

36. The Impedance Circuit A Voltage Is Applied Across Ring Set AC Generator

37. Why Does Impedance Change? No bolus = few ions = high impedance Bolus present = many ions = low impedance

38. Impedance Range Refluxate Esophageal Lining Food Saliva Air Low Conductivity = High Impedance High Conductivity = Low Impedance

39. ImpedanceImpedance Time Bolus Present Bolus entry Bolus exit Z-1 Z-2

40. Acid reflux Non-acid reflux MII-pH detected reflux 3 cm 5 cm 7 cm 9 cm 15 cm 17 cm Impedance 4 pH esophageal gastric 4

41. GERD DIAGNOSTIC ALGORITHM Possible GERD symptoms Trial of PPI Rx Success (Confirm Dx) Persistent symptoms Ambulatory monitoring on Rx (esophageal and gastric) (Combined MII/pH preferred) Acid GER with symptoms Non-acid GER with symptoms No GER

42. Treatment Goals for GERD Eliminate symptoms Heal esophagitis Manage or prevent complications Maintain remission

43. Changes to diet and lifestyle can impair quality of life without improving GERD symptoms Changes to diet and lifestyle are difficult for some patients and can significantly impair patient quality of life. Studies into the negative effects of diet and lifestyle on GERD are few in number and the findings are statistically weak. The criteria for evidence-based medicine are not met when diet and lifestyle changes are recommended. Dent 1992; Meining & Classen 2000

44. H 2 RAs block the histamine receptor, interfering with one of the stimulation pathways PPIs block acid at its source in the proton pump ACh=acetylcholine Mechanisms of Action of GERD Pharmacotherapy Antacids neutralize secreted HCl HCI Histamine ACh Gastrin K+K+ H+H+

45. Antireflux surgery – an alternative to pharmacological therapy The efficacy of antireflux surgery in controlling GERD is similar to that of chronic PPI therapy. The outcome of antireflux surgery is highly dependent on the skill and experience of the surgeon. Surgery does not always end the need for antisecretory therapy to control the symptoms of GERD. Lundell et al 2001; Spechler et al 2001

46. Nissen fundoplication and the Toupet procedure Nissen fundoplicationToupet procedure

47. Predictors of success of surgery

48. Medication use in follow-up of patients from VA cooperative GERD study Spechler et al, JAMA 2001; 285: 2331

49. No evidence that antireflux surgery protects against cancer development Ye et al, Gastroenterology 2001; 121: 1286