LA MALATTIA DA REFLUSSO GASTROESOFAGEO

1. LA MALATTIA DA REFLUSSO GASTROESOFAGEO

2. MALATTIA DA REFLUSSO GASTROESOFAGEO (MRGE) Ogni sintomo e/o alterazione anatomica micro-macroscopica dovuti al contatto con la mucosa dell’esofago (ma anche del cavo orale e delle vie aeree),di materiale gastro-duodenale refluito in eccesso

4. Severity 6% 12% Mild 18% Moderate 51% 37% 76% Severe Frequency 4% 10% Daily 16% Weekly 42% 24% 59% 21% Monthly 24% Occasionally Prevalence, severity and frequency of heartburn and acid regurgitation in 700 italian subjects Heartburn Regurgitation 77% 66% 23% 34% Valle et al, Dig Dis Sci, 1999

5. Prevalence of GORD by age and sex 900 Males 800 Females 700 600 Prevalence per 10,000 population 500 400 300 200 100 12-24 24-44 45-64 64-74 Age group El-Serag & Sonnenberg; Gut 1997; 41: 594-9.

6. Pathophysiology of reflux Modlin & Sachs; 1997

7. Anatomy of the Gastroesophageal junction

8. NormalVolunteers Non-inflammatoryGERD MildEsophagitis SevereEsophagitis Lower LES pressure associated with more severe GERD Kahrilas PJ, et al. Gastroenterology 1986;91:897.

9. MRGE fisiopatologia Rilassamenti transitori del LES Transient LES Relaxation = TLESR: (rilassamenti riflessi non collegati alla deglutizione che determinano una cavità comune fra stomaco ed esofago) • 100% dei reflussi nei controlli • 75% dei reflussi nei soggetti con MRGE

10. The physiologic record of a spontaneous transient relaxation of the lower esophageal sphincter Mittal et al,1997

11. Abnormal Esophageal clearance Up 48% of GERD patients have impaired esophageal clearance Inadequate peristalsis occurs in the lower esophagus Longer reflux contact time increases the risk of complications

12. Meccanismo di reflusso nei pazienti con ernia iatale

13. Model of relation among lower esophageal sphincter pressure, size of hernia, and the suscptibility to gastroesophageal reflux induced by provocative maneuvers as reflected by the reflux score Sloan et al, 1992

14. Abnormal oesophageal clearing Insufficient antireflux barrier TOO MUCH ACID IN THE WRONG PLACE Altered gastric emptying Diet, drugs smoking, etc

15. Clinical spectrum of GERD

17. Heartburn disturbs my sleep I can not eat and drink whatever I like My whole life is affected GI symptoms bother me! I´m worriedand concerned I can not bendover or exercise

18. Age distribution of patients with gastro-esophageal reflux disease (n=1440) Smout, Aliment Pharmacol Ther 1997.

19. (<3cm) (>3cm) Hiatal Hernia Distribution Cameron, Am J Gastroenterol 1999.

20. Abnormal 24-Hour Esophageal pH Monitoring in the Different GERD Groups n=40 n=40 n=71 Martinez, Gastroenterology 2001.

21. Dilated Intercellular Spaces Normal Intercellular Spaces

22. L’attacco acido-peptico indebolisce le giunzioni cellulari, portando ad un allargamento dell’interstizio cellulare e successiva aumentata penetrazione dell’acido

23. MILD MODERATE SEVERE Heartburn Severity in Patients With EE and Patients with NERD* Heartburn Grade 32 %ErosiveEsophagitis(n=316) 68 %NERD*(n=677) * Nonerosive reflux disease.Venables et al, Scand J Gastroenterol 1997; 32:965-973.

24. MRGE RIVISITATO Pirosi come risultato di reflusso acido capace di determinare Danno macroscopico nei pazienti con esofagite erosiva Esofagite microscopica nei pazienti con NERD

25. Sintomi tipici di reflusso gastroesofageo Pirosi Sensazione di bruciore retrosternale Rigurgito acido Liquido di sapore acido o amaro

26. Range of presentations of GORD Typical symptoms (Heartburn/regurgitation) Atypical symptoms Complications With oesophagitis Chest pain(visceral hyperalgesia) Oesophageal erosions and/or ulcers Without oesophagitis Stricture Hoarseness (‘reflux laryngitis’) Barrett’s oesophagus Asthma, chronic cough, wheezing Oesophageal adenocarcinoma Dental erosions Nathoo, Int J Clin Pract 2001; 55: 465–9.

27. MRGE : Qualità di vita

28. GERD and the risk of esophageal complications 30-40% of patients with acid-related diseases have an esophagitis Patients with acid-related diseases have a higher prevalence for esophageal complications • Esophageal ulceration 2 - 7 % • Barrett‘s esophagus 10 - 15 % • Esophageal stricture 4 - 20 % The risk of malignancy in patients with Barrett‘s esophagus may be up to 30 - 40 times that of the general population Richter; 1992 Spechler; 1992 De Vault & Castell; 1995

29. Long and Short Barrett's Esophagus and Intestinal Metaplasia of the Cardia IM 3 cm IM IM Long BE Short BE IM-Cardia CP1097000-11

30. Male Prevalence of Barrett's Esophagus at Different Ages Male + female Patients endoscopedwho had BE (%) Female 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 Age (years) Mean age of developing BE ~ 40Mean age at diagnosis of BE was 63 CP1097000-3

31. Incidence of Adenocarcinoma of Esophagus: U.S., Europe, Australia Cases/100,000/year 1950 1960 1970 1980 1990 2000 Median year of observation period CP1097000-15

33. Reflux Take a good history! Sensitivity 96% (PPV 87%) for GERD compared with endoscopy/ 24-hour pH monitoring ‘A burning feeling rising from your stomach or lower chest towards your neck’ Carlsson et al, 1998

34. The sensitivity of omeprazole and placebo during each day of study week Johnsson et al,1998

35. Diagnostic tests for gastro-oesophageal reflux disease Sensitivity Specificity 58% 84% LOS manometry (< 10 mm Hg) (6*) 68% 96% Endoscopy (> grade 1 oesophagitis) (2*) 77% 91% Mucosal biopsy (5*) 61% 95% Gastro-oesophageal scintiscanning (3*) 40% 85% Barium oesophagogram (3*) 79% 82% Acid-perfusion test (Bernstein) (7*) 84% 83% Standard acid-reflux test (8*) 88% 98% Prolonged oesophageal pH monitoring (5*) * Number of studies from which sensitivity and specificity were calculated

36. Indicazioni cliniche all’uso della pH-metria esofagea • Asma in paziente adulto, non allergico, con sospetto reflusso (un test positivo non prova casualità) • Laringite o tosse cronica con sospetto che possano essere dovuti a reflusso • Dolore toracico in paziente con valutazione cardiaca completa negativa • Sintomi tipici e atipici resistenti alla terapia antisecretiva maggiore con inibitori della pompa protonica (mentre il paziente assume il farmaco) • Valutazione pre-operatoria per chirurgia anti-reflusso in pazienti sintomatici con endoscopia negativa • Valutazione post-operatoria in pazienti con sintomi persistenti o poco modificati dall’intervento

37. Endoscopia

38. The LA Classification system for theendoscopic assessment of reflux esophagitis Grade A Grade B One (or more) mucosal break no longer than 5mm, that does not extend between the tops of two mucosal folds One (or more) mucosal break more than 5 mm long, that does not extend between the tops of two mucosal folds Grade C Grade D 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 One (or more) mucosal break which involves at least 75% ofthe esophageal circumference Lundell et al 1999

39. Barrett’s Esophagus CP1097000-27

40. Esofago di Barrett. Si osserva la presenza di metaplasia intestinale con cellule caliciformi (blu). A destra l’epitelio squamoso esofageo. Colorazione Alcian Blu-PAS

41. Scopi della terapia • Alleviare la sintomatologia dovuta al reflusso • Ottenere la guarigione delle lesioni anatomiche, quando presenti • Prevenire la ricomparsa delle lesioni e delle complicanze • Modificare la storia naturale della malattia

42. DIETARY FACTORS AND GERD Advice on diet Strength of scientific evidence? Pathophysiologically conclusive? Recommendable? Avoid fatty meals Equivocal Equivocal Not generally Avoid sweets Weak Yes Not generally Avoid spicy food Weak Equivocal Not generally and raw onions Avoid carbonated Moderate Yes Yes beverages Prefer decaffeinated Equivocal Equivocal Not generally beverages Avoid citrus products Weak Yes Not generally and juices Meining and Classen, 2000

45. Healing rates for various PPIs in GORD L = lansoprazole P = pantoprazole O = omeprazole R = rabeprazole 30 = 30 mg/day, 20 = 20 mg/day, 40 = 40 mg/day Petite et al. L30/O20 Castell et al. L30/O20 Mee et al. L30/O20 Mulder et al. L30/O40 Mossneret al. P40/O20 Corinaldesi et al. P40/O20 Hotz et al. P40/O20 Vicari et al. P40/O20 Thjodleifsson et al. R20/O20 Dekkers et al. R20/O20 0 20 40 60 80 100 Patients healed at 8 weeks (%) Thomson, Curr Gastroenterol Rep 2000; 2: 482–93.

46. Symptomatic relapse rates are similar in GERDpatients whether or not they have esophagitis 100 80 60 Patients in symptomatic remission (%) 40 25% 20 10% 0 4 6 3 5 0 1 2 Time since treatment cessation (months) Patients without esophagitis Patients with esophagitis Carlsson et al 1998

47. Omeprazole 20 mg odplus cisapride 10 mg tid ns Omeprazole 20 mg od ** **** Ranitidine 150 mg tidplus cisapride 10 mg tid ***** * **** Cisapride 10 mg tid *** Ranitidine 150 mg tid 100 80 40 20 60 0 Patients in remission at 12 months (%) Omeprazolo is superior to ranitidine and cisapridein maintaining patients with healed reflux oesophagitisin long-term endoscopic remission * p=0.02; ** p=0.03; *** p=0.05; **** p=0.003; ***** p<0.001; ns=not significant Vigneri et al., 1995