Gastro Esophageal Reflux Disease

Gastro-Esophageal Reflux Disease 胃食道逆流症 義大醫院 胃腸肝膽科 一般醫學科 張吉仰 Gastro-Esophageal Reflux Disease • Epidemiology • Pathogenesis • Clinical manifestation • Diagnosis • Treatment Terminology • Gastroesophageal reflux (GER): a normal physiologic process • Gastroesophageal reflux disease (GERD): refluxed gastric contents esophagus symptoms or mucosal damage (esophagitis) BMJ 2001; 323:736-739 BMJ 2001; 323:736-9 Epidemiology (I) • The prevalence of GERD differs depending on the analysis (symptoms or diagnostic tools) • The overall prevalence of GERD in the west is 20-40% • Incidence: 86/100,000 population per year (symptomatic), 4.5/100,000 population per year (endoscopic), in Scoland Scand J Gastroenterol 1989;24:7-13 Digestion 1992;51(suppl 1):24-9 Epidemiology (II) Incidence increasing dramatically after 40 y/o Male : female 2–3: 1 Gut 1969;10:831-837 Scand J Gastroenterol 1989;24:7-13 Epidemiology (III) • The prevalence of GERD higher in the West than in Asia • Recently, the prevalence of GERD in Asia is either increasing or being recognized more frequently J Gastroenterol Hepatol 2000;15:230-238 Possible factors contributing increasing prevalence of GERD in Asia • Increasing diagnosis improved diagnostic tools • Body mass index & obesity • Life style change dietary fat carbonated soft drinks • H. pylori eradication? J Gastroenterol and Hepatol 2000;15:230-238 Prevalence of GERD in Taiwan • Wang et al. 1978 9% of 165 patients, by endoscopy had mucosal injury • Chen et al. 1979 2% of 1000 patients, by endoscopy had erosive esophagitis • Chang et al. 1997 17% of 2044 patients recored one GERD symptom, 5% had reflux esophagitis • Yeh et al. 1997 15% of 464 patients, by endoscopy had erosive esophagitis, 2% had Barrett’s esophagitis J Gastroenterol Hepatol 2000;15:230-238 Reflux esophagitis in endoscopic study at NTUH (1992-2001.11) 20% 15% 10% 5% 0% · Ë ° À 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 í | ù E ¦ ° ª ¶ H. pylori and GERD (I) • H. pylori eradication for duodenal ulcer development of GERD • Barrett’s high-grade dysplasia & adenocarcinoma more prevalent in not infected with H. pylori • No increase of GERD after H. pylori eradication Gut 1995;36: 831 Am J Gastroenterol 2000;95:387-394 Gastroenterology 1998;114:306A H. pylori and GERD (II) • Possible mechanisms for protection from GERD Corpus gastritis acid production Ammonia production neutralizing acid Am J Gastroentrol 1998;93:1800-1802 Mechanism of GER • Three mechanism 1. Transient lower esophageal sphincter relaxation (TLESR) 2. Transient increase intra-abdominal pressure 3. Spontaneous free reflux associated with lower resting pressure of LES N Eng J Med 1982;307:1547-1552 N Eng J Med 1997;336:924-932 Pathogenesis of GERD • Esophageal defense Antireflux Barriers Luminal Acid Clearance Tissue Resistance • Potency of refluxate Gastric secretion Pyloric competence Yamada T et al: Textbook of gastroenterology 3rd ed 1999; 1235-1244 BMJ 2001; 323:736-739 Antireflux Barriers N Eng J Med 1997;336:924-932 Antireflux Barriers Hiatal Hernia N Eng J Med 1997;336:924-932 Luminal Acid Clearance • • • • Gravity Esophageal peristalsis Saliva Esophageal gland secretion Yamada T et al: Textbook of gastroenterology 3rd ed 1999;1235-1244 Luminal Acid Clearance (Oral aspiration of saliva) N Eng J Med 1984;310:284-288 Tissue Resistance • Preepithelial defense mucus layer surface bicarbonate concentration • Epithelial defense tight junction buffers pH regulatory processes • Postepithelial defense blood flow Am J Gastroenterol 1997;92:S3-S7 Potency of Refluxate • • • • • HCL Pepsin Bile salts Pancreatic enzymes (trypsin, lipase) Associated with pH level Yamada T et al: Textbook of gastroenterology 3rd ed 1999;1235-1244 Risk Factors • Dietary factors eating habits fatty diet carbonated drinks • Obesity (BMI) • Life style alcohol, smoking physical activity sleeping position Am J Gastroenterol 2000;95: 2692-2697 The Symptoms of GERD BMJ 2001; 323: 736-739 The Pathophysiology of Atypical Symptoms • Direct Gastropharyngeal reflux with or without microaspiration • Indirect The stimulation by refluxate of an esophageal receptor-esophagopulmonary/ laryngeal reflex Gastroenterol Clin North Am 1999;28(4):861-873 Prevalence of GERD in Asthmatic patients • Symptomatology : 72% - 77% • Endoscopic finding: 30-50% • pH studies: 78%-90% Chest 1996;109:316-322 Gastroenterology 1990;99:613-620 Chest 1999;115:654-659 Pathophysiology (GERD causing Asthma) • Esophageal Acid-Induced Bronchoconstriction Vagally mediated esophageal bronchial reflex Heightened bronchial activity Microaspiration • Evidence of Airway Inflammation Substance P and tachykinin release • Increase in minute ventilation & respiratory rate Am J Gastroenterol 2000;95(8):S23-S32 Pathophysiology (Asthma causing GERD) • Mechanical Cause Airway obstruction ↑ negative pleural pressure  ↑ pressure gradient across diaphragm Air trapping  diaphragm flattening • Asthma Medication Theophylline ↑ gastric secretion, ↓ LES pressure Systemic beta2-receptor agonists ↓ LES pressure Inhaled β2 -receptor agonists not effect LES pressure in normal Mayo Clin Proc 2000;75:1055-1063 GERD-associated non-Cardiac Chest Pain • Of patients with typical cardiac chest pain and normal coronary arteries, 4050% have GERD documented by ambulatory esophageal PH monitoring. • Nitrates and calcium channel blocker--↑ reflux-induced chest pain Postgraduate Medicine 1999;105:53-66 Gastroenterol Clin North Am 1999; 28(4):861-873 GERD-associated non-Cardiac Chest Pain • Retrosternal chest pain– lasting several hours, occurring postprandially, and associated with dysphagia or odynophagia. • Cardiac disease must be excluded firstly Postgraduate Medicine 1999;105:53-66 GERD and Barrett’s esophagus • Definition The presence of intestinal metaplasia in the esophagus • Prevalence 2% to 12% of patients by endoscopy Mayo Clin Proc 2001; 76:331-334 Med Clin North Am 2000;84:1137-1161 Barrett’s esophagus Mayo Clin Proc 2001;76:217-225 Barrett’s esophagus and Esophageal adenocarcinoma • The prevalence of adenocarcinoma in Barette’s esophagus : 10% • A 30- to 125-fold increase risk over the general population Mayo Clin Proc 1998;73: 457-461 Gastroenterol Clin North Am 1999; 28(4):861-873 Diagnosis of GERD • • • • • Endoscopy 24 Hour pH Monitor Therapeutic Trial Radiological Testing Provocative Testing Gastroenterol Clin North Am 1999;28:893-904 SAVARY - MILLER Classification Grade 1 • Grade 2 Grade 3 Grade 4 Los Angeles Classification Grade A One (or more) mucosal break, no longer than 5 mm, that does not extend between the tops of two mucosal folds Grade B One (or more) mucosal break, more than 5 mm long, that does not extend between the tops of two mucosal folds Grade C One (or more) mucosal break, that is continuous between the tops of two or more mucosal folds, but which involves less than 75% of the circumference Grade D One (or more) mucosal break, that involves at least 75% of the esophageal circumference Gut. 1999;45(2):172-180 24-hour Ambulatory pH Monitor Indication • Evaluation of persistent symptoms on medical therapy or after fundoplicating • Detection of reflux in patients with atypical manifestation of GERD • Preoperative evaluation of GERD in patients with negative endoscopy • Assessment of treatment Med Clin North Am 2000;84:1137-1161 24-hour pH monitor DeMeester score Total score 121.4 Normal < 14.72 (95th percentile) Therapeutic Trial Omeprazole test • Advantage : ease of availability, noninvasiveness and reasonable cost • Method: 40mg in the morning and 20 mg in the evening for 7 days Mayo Clin Proc 2001;76:97-101 Treatment of GERD • • • • Lifestyle modification Medical therapy Surgical therapy Endoscopic therapy Lifestyle Modification (I) Advice on Diet Strength of Pathophysiologically Scientific Conclusive Evidence Equivocal Equivocal Recommedable Fatty meals Not generally Sweets Spicy food and raw onions Carbonated beverages Prefer decaffeinated beverages Weak Weak Moderate Equivocal Yes Equivocal Yes Equivocal Not generally Not generally Yes Not generally Citrus products and juice Weak Yes Not generally Am J Gastroenterol 2000;95: 2692-97 Lifestyle Modification(II) Advice on Eating Habits Voluminous meals Strength of Scientific Evidence Weak Pathophysiologically Conclusive Yes Recommendable Yes Advice on Obesity Lose weight Strength of Scientific Evidence Equivocal Pathophysiologically Conclusive Equivocal Recommendable Yes (a risk factor for cancer of the distal esophagus) Lifestyle Modification (III) Advice on Strength of Alcohol Scientific Consumption Evidence Avoid alcoholic beverages Weak Pathophysiologically Conclusive Mechanisms not fully understood ; different effect of various beverages Recommendable Not generally Advice on Smoking Quit smoking Strength of Scientific Evidence Weak Pathophysiologically Conclusive Yes Recommendable Yes (a risk factor for cancer of the distal esophagus) Lifestyle Modification (IV) Advice on Strength of Pathophysiologically Physical Activity Scientific Conclusive Evidence Excessive physical activity Weak Yes Recommendable Yes (in symptomatic persons) Advice on Sleeping Position Sleep with an elevated head position Prefer the left side Strength of Pathophysiologically Scientific Conclusive Evidence Equivocal Equivocal Recommendable Not generally Unequivocal Yes Yes, if possible Medical Therapy (I) Conventional Drugs Al(OH)3, Mg(OH)2, MgCO3, CaCO3 (Plus) Alginic acid Simethicone Mechanism Comment Antacid and Alginic acid Buffer HCL Increase LESP Viscous mechanical barrier (1) (2) (3) More effective than placebo Effective symptom relief and mucosal healing about 20% Less effective than acidsuppressants H2-Receptor Antagonist Cimetidine Famotidine Ranitidine Nizatidine Decrease HCL secretion by inhibiting H2 receptors (1) (2) (3) More effective than antacid and alginic acid Effective symptom relief and mucosal healing about 50% Less effective than PPI Medical Therapy (II) Conventional Drugs Prokinetics Cisapride Metoclopramide Increase LESP Increase gastric emptying Increase esophageal acid clearance (1) (2) (3) Comparable to H2-receptor antagonist in symptom relief Do not heal esophagitis High incidence of side effects Mechanism Comment Mucosal Protectants Sucralfate Increase tissue resistance Buffer HCL Bind pepsin and bile salts (1) (2) Therapeutic efficacy not uniformly been observed May be useful in maintenance therapy, but in in acute therapy Medical Therapy (III) Conventional Drugs 1st generation Omeprazole Lansoprazole Pantoprazole Rabeprazole Mechanism Comment Proton Pump Inhibitors Decrease HCL secretion by irreversible inhibiting intra-cytoplasmic H+ K+ ATPase (1) (2) (3) Should be taken before meals The most effective agents Effective symptom relief and mucosal healing range about 62%~96% No clinical advantage in choosing 1st generation PPI New generation PPI could achieve more rapid and profound effects than older agents (4) New generation Esomeprazole (5) The same as above S-isomer of omeprazole Medical Therapy (IV) Conventional Drugs Others Baclofen GABAB agonist in reducing TLESR Mechanism CCK-A antagonist (Devazepide) NO synthase inhibitor (LNAME) Atropine and Morphine Compound D (Pro-PPI) Imidazopyridine Inhibit vagal efferent fiber neurotransmitters NO in reducing TLESR Anti-cholinergic Pro-drug of PPI Acid-pump antagonist (APA) by binding extracytoplasmic H+ -K+ ATPase Gastroenterol Clic North Am. 1999;28 (4): 831-845 Eur J Gastroenterol Hepatol 2001; 13 Supp 1: S29-47 Textbook of Gastroenterology, Yamada 1999 3 rd. Edition : P1252-55 Intragastric pH and Mucosal Healing ' Digestion 1992; 51 Supp 1: 59 Relative Medical Efficacy Digestion 1992; 51 Supp 1: 59 Relative Efficacy of Medical Antireflux Therapy Efficacy Highest Therapy PPI twice daily with H2RA at bedtime PPI twice daily PPI at A.M., H2RA at bedtime PPI and promotility agents PPI once daily High-dose H2RA H2RA and promotility agents H2RA or promotility agents OTC H2RA Gastroenterol Clin North Am 1999;28(4):831-845 Lowest Esomeprazole versus Omeprazole Optical Isomers A B D C S-isomer A B D C R-isomer Plasma concentrations of esomeprazole and omeprazole Mean plasma concentration (nmol/L) 4000 Day 5 3500 Esomeprozole 40 mg once daily 3000 Esomeprazole 20 mg once daily 2500 2000 1500 1000 500 Omeprazole, 20 mg once daily n=36 0 0 1 2 3 4 5 6 Time after dose (hours) 7 8 Aliment Pharmacol Ther 2000;14: 861-867 Time with intragastric pH > 4 per 24 hours with esomeprazole and omeprazole Hours/day 24 16.8 Esomeprazole, 40 mg once daily 12.7 18 *** ** 10.5 Esomeprazole, 20 mg once daily Omeprazole, 20 mg once daily n=36 ** p0.01 *** p0.001 12 6 0 Repeat dosing, day 5 Aliment Pharmacol Ther 2000;14: 861-867 Esomeprazole versus 1st generation PPI 70 60 50 40 30 20 10 0 Versus omeprazole 20 mg Versus Versus Versus Versus omeprazole pantoprazole lansoprazole rabeprazole 40 mg 40 mg 30 mg 20 mg Esomeprazole 20 mg/d Esomeprazole 40 mg/d Comparator P < 0.01 P < 0.001 Aliment Pharmacol Ther 2000;14:861-867 Am J Gastroenterol 2000;95 (9):2432-2433 Gastroenterology 2000;118 (Suppl 2):A20-22 Maintenance Therapy Indications for Maintenance Therapy 1. Severe esophagitis, especially presenting with complications (such as strictures, bleeding, peptic ulcers) 2. Barrett’s esophagus (although there is no evidence that continuous treatment prevents evolution of cancer) 3. Symptoms (typical or atypical) relapsing as soon as treatment is stopped Percentage of continuing remission in GERD with symptomatic relief by omeprazole 20 mg/d BMJ 2001;323: 736-739 Indications for Anti-reflux Therapy Need for continuous drug treatment •Young patient •Financial burden •Non-compliance with drug therapy •Patient preference for surgery •24-hour esophageal pH monitoring •Esophageal manometry •Endoscopy Positive for GERD Reflux surgery Negative for GERD Pursue another diagnosis Gastroenterol Clin North Am 1999;28(4):993 Increasing doses of medication Long Term Outcome of Medical and Surgical Therapy for GERD Outcome Symptom score Medical Treatment Group 83.1 96.7 1.89 31.0 92 % 64 % 65 % Surgical Treatment Group 78.7 82.6 1.80 17.1 62 % 32 % 41 % P Value with medication without medication Endoscopic grade of esophagitis 24-hr esophageal pH < 4 0.07 0.003 0.76 0.50 < 0.001 0.002 0.02 Regular medical control Any reflux medication PPI H2RA Prokinetics Further antireflux surgery Treatment for peptic stricture 15 % 10 % 8% 8% 16 % 14% 0.39 0.38 0.46 JAMA 2001;285(18):2331-2338 Nissan Fundoplication • Laparoscopic surgery v.s. conventional open surgery • 360° plication of the gastric fundus around the lower esophagus • Suitable for patients with good esophageal motility Toupet Fundoplication •240° to 270° partial wrap of the gastric fundus •Commonly used in patients with impaired esophageal clearance and function •Less effective than Nissan fundoplication in preventing acid reflux Hill Repair •Creating an angulation in the lower esophagus by fixing the LES to the abdomen •Technical demanding and timeconsuming • A successful technique in preventing reflux Collis Gastroplasty • •Performed in patients with esophageal shortening • An effective anti-reflux barrier • Occasionally complicated by the presence of acid-secreting mucosa proximal to the fundoplication Endoscopic Therapy (I) Stretta Device (Radiofrequency Ablation) Step 1. The catheter is placed through the mouth and into the valve between the stomach and the esophagus. Step 2. The physician deliveres safe, controlled levels of radiofrequency (RF) energy to LES muscles and the gastric cardia to create thermal lesions. Step 3. When the lesion heals, the barrier function of the LES improves. Endoscopic Therapy (II) EndoCinch Device (Endoscopic Gastroplasty) The gastroenterologist uses the EndoCinchTM system to place sutures - much like a tiny sewing machine - near the valve between the stomach and the esophagus. These sutures are then tied together to create pleats and tighten the valve. Clinical studies have demonstrated that the procedure can significantly reduce heartburn symptoms and regurgitation, and allow patients to reduce or eliminate their dependence on acid controlling medication. Endoscopic Therapy (III) Endoscopic Nissen Plication The procedure involves the invagination and fixation of the gastroesophageal junction, thus creating a functional nipple valve at the lower esophagus comparable to the effect of a Nissen fundoplication Endoscopic Therapy (V) Endoscopic Implantation Injection of ethinylvinyl-alcohol (EVA) into the muscle of gastric cardia to obtain a circular diffusion of the material with increase in LES pressure and symptoms relief Thank you