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- 2. Acid Related Disease Acid Related Disease Upper GI Bleeding Functional Dyspepsia Gastroduodenal ulcus GERD Stress Ulcer Wolfe MM. Gastroenterology 2000;118:S9-S31
- 3. DYSPEPSIA Talley et al. Am J Gastroenterol 2005;100:2324–2337) Dyspepsia is defined as chronic or recurrent pain or discomfort centered in the upper abdomen Discomfort is defined as a subjective negative feeling that is nonpainful, and can incorporate a variety of symptoms including early satiety or upper abdominal fullness Patients presenting with predominant or frequent (more than once a week) heartburn or acid regurgitation should be considered to have gastroesophageal reflux disease (GERD) until proven otherwise.
- 4. DIAGNOSTIC TESTING patients more than 55 yr old, or those with alarm features should undergo prompt endoscopy to rule out peptic ulcer disease, esophagogastric malignancy, and other rare upper gastrointestinal tract disease. In patients aged 55 yr or younger with no alarm features test and treat for H. pylori using a validated noninvasive test and a trial of acid suppression if eradication is successful but symptoms do not resolve an empiric trial of acid suppression with a proton pump inhibitor (PPI) for 4–8 wk. The test-and-treat option is preferable in populations with a moderate to high prevalence of H. pylori infection (≥10%), whereas the empirical PPI strategy is preferable in low prevalence situations. Talley et al. Am J Gastroenterol 2005;100:2324–2337
- 5. Management of Dyspepsia Uninvestigated Dyspepsia (uninvestigated) Age > 55 or alarm features Age < 55 No alarm features EGD HP prevalence < 10% HP prevalence > 10% PPI trial Test and treat for H pylori Consider EGD Test and treat For H pylori PPI Trial Consider EGD Fails Fails Fails Fails Talley et al. Am J Gastroenterol 2005;100:2324–2337) EGD: Esophagogastroduodenoscopy
- 6. EMPIRIC ANTISECRETORY THERAPY IN UNINVESTIGATED DYSPEPSIA In H. pylori-negative cases with uninvestigated dyspepsia and no alarm features, an empiric trial of acid suppression for 4–8 wk is recommended first-line therapy 1985 H2 receptor antagonist for 6–8 wk PPIs replace H2RA Now There are limited data that prokinetic therapy employed as an empiric strategy may be efficacious in uninvestigated dyspepsia Talley et al. Am J Gastroenterol 2005;100:2324–2337)
- 7. MANAGEMENT OF DOCUMENTED FUNCTIONAL DYSPEPSIA Once a diagnosis of functional dyspepsia is confirmed by a negative endoscopy, an empiric trial of therapy is commonly prescribed Many patients do not require medication for dyspepsia after they have had reassurance and education such as High-fat meals should be avoided; eating frequent and smaller meals throughout the day Antacids and sucralfate were not superior to placebo in functional dyspepsia based on a Cochrane review A Cochrane review of 8 trials of H2 receptor antagonists with 1,125 patients showed a relative risk reduction of 30% but the quality of the trials was generally poor PPIs in this review also produced a relative risk reduction of approximately 30% and the quality of the trials was better Talley et al. Am J Gastroenterol 2005;100:2324–2337)
- 8. SKEMA PENATALAKSANAAN PASIEN DI PELAYANAN KESEHATAN LINI PERTAMA DISPEPSIA ENDOSKOPI Terapi dihentikan Tidak ada sarana Umur < 45 tahun tanpa tanda- tanda bahaya Usia > 45 atau < usia 45 tahun dengan tanda-tanda bahaya DISPEPSIA (-) Terapi Eradiksi SEROLOGI (Tervalidasi secara lokal) DISPEPSIA (+) Terapi empiris selama 2 minggu - Antasid - H2 antagonis Penghambat Pompa Proton (PPI) -Obat-obat prokinetik Hasil (+) Hasil (-) RUJUK Internis, internis plus, Gastroenterologist atau dokter anak dengan fasilitas endoskopi UBT/HpSA Hasil (-) Hasil (+) Gagal
- 9. SKEMA PENATALAKSANAAN PASIEN DISPEPSIA OLEH GASTROENTEROLOGIS/INTERNIS DENGAN FASILITAS ENDOSKOPI DISPEPSIA Umur > 45 tahun Tanda bahaya/alarm Gagal terapi Riwayat ulkus peptikum + komplikasi Permintaan pasien Pengguna aspirin / NSAID Gastroeshopageal Reflux Disease (GERD) Tidak YA UBT/HpSA Hasi l (-) Hasi l (+) ENDOSKOPI Pemeriksaan Rapid Urease Test (CLO, MIO, Prontodry*) Histopatology Hasil (-) Hasil (+) Terapi Eradikasi Terapi Simtomatik Reevaluasi diagnostik Gagal Terapi Simtomatik
- 10. Peptic Ulcer A peptic ulcer is a deep and sharply demarcated break in the lining of the stomach or duodenum – when in the stomach it is described as a gastric ulcer and when in the duodenum a duodenal ulcer. The most common causal factor in this damage is infection of the stomach with the bacterium Helicobacter pylori. The other major cause of peptic ulcer disease, particularly gastric ulcer disease, is the use of nonsteroidal anti- inflammatory drugs
- 11. Treatment of H.pylori Infection First choice treatment ~ Triple Therapy • PPI (standard dose bid), clarithromycin (500 mg bid), amoxicillin (1000 mg bid) or metronidazole (400 or 500 mg bid), 14 day treatment is more effective than 7days (by 12% (95% confidence interval 7% to 17%). • A seven day treatment may be acceptable where local studies show that it is effective • Combination options • PPI-clarithromycin-amoxicillin or metronidazole treatment if less than 15–20% population resistance to clarithromycin • PPI-clarithromycin-metronidazole is preferable, if less than 40% population metronidazole resistance Malfertheiner P et al. Gut 2007;56:772-781
- 12. Second choice treatments ~ Quadruple treatments • Bismuth-containing quadruple treatments remain the best second choice treatment • PPI-amoxicillin or tetracycline and metronidazole are • recommended if bismuth is not available Treatment of H.pylori Infection Malfertheiner P et al. Gut 2007;56:772-781 Maastricht 3–2006
- 13. Test H.pylori • Non Invasive •13C urea breath test (UBT) •The diagnostic accuracy ~ 95% •Accurate, practical and readily available test •Result on 1 hour •False negative occur in patients taking antisecretory drug •Stool antigen tests •Appropriate when multiple specimen are tested as a batch •Need to store stool sample –20o C before testing •Sensitivity decrease to 69% after 2-3 days at room temperature Malfertheiner P et al. Gut 2007;56:772-781 Maastricht 3–2006
- 14. • Immunological test / serology test Widely used, inexpensive non-invasive test Diagnostic accuracy is low (80-84%) Recommend to assess H.pylori in patients with a bleeding ulcer and conditions associated with a low bacterial density Invansive • endoscopy with gastric biopsy for rapid urease test Test H.pylori Malfertheiner P et al. Gut 2007;56:772-781 Maastricht 3–2006
- 15. Baskin et al 1976 NSAIDs can cause gastroduodenal injury NSAID damage to the gastric mucosa Scanning electron micrographs of normal gastric mucosa (left) and mucosal surface (right) 16 minutes after administration of aspirin
- 16. Arachidonic acid COX-1 (constitutive) COX-2 (induced by inflammatory stimuli) Non-selective NSAIDs • Gastrointestinal cytoprotection • Platelet activity • Inflammation • Pain • Fever Prostaglandins Prostaglandins COX-2 selective NSAIDs Vane & Botting 1995 NSAIDs inhibit the COX enzyme, which exists in two forms
- 17. Gastric acid plays a central role in NSAID-associated gastroduodenal damage Aspirin and other NSAIDs PROTECTIVE FACTORS Mucus layer Ionic gradient Bicarbonate layer Prostaglandins Surface epithelial cells Mucosal blood supply H. pylori Pepsin Gastric acid AGGRESSIVE FACTORS Aspirin and other NSAIDs Prostaglandin production Bicarbonate production Mucus production Acidic environment Neutral environment
- 18. 0 1 2 3 4 5 2.0 4.0 5.5 7.0 Gastric luminal pH Total haemorrhagic mucosal area % Intraduodenal saline Intraduodenal indomethacin 40 mg/kg Elliott et al 1996 NSAID-associated gastroduodenal damage is pH-dependent
- 19. Cheatum et al 1999 0 10 20 30 40 50 Fenoprofen Diclofenac Naproxen Sulindac Ibuprofen Indomethacin Piroxicam Flurbiprofen Etodolac Ketoprofen Aspirin >1 NSAID Other NSAIDs High prevalence of peptic ulceration during NSAID treatment Patients with peptic ulcers %
- 20. “GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms and / or complications” Esophageal Syndromes Extra-esophageal Syndromes Symptomatic Syndromes Typical Reflux Syndrome Reflux Chest Pain Syndrome Syndromes with Esophageal Injury Reflux Esophagitis Reflux Stricture Barrett’s Esophagus Adenocarcinoma Established Associations Reflux Cough Reflux Laryngitis Reflux Asthma Reflux Dental Eros. Proposed Associations Pharyngitis Sinusitis Idiopathic Pulmonary Fibrosis Recurrent Otitis Media The Montréal definition of GERD Vakil N et al. Am J Gastroenterol 2006; in press
- 21. Katzka DA, DiMarino AJ. In: The esophagus, second edition, Castell DO (editor). Little, Brown & Company, Boston, USA. 1995:443–53. Defective esophageal clearance LES ‘dysfunction’ Hiatal hernia Delayed gastric emptying Increased intra-abdominal pressure Causes of increased exposure of the esophagus to gastric refluxate
- 22. GERD can be diagnosed based on symptoms alone Troublesome symptoms Heartburn Regurgitation Epigastric pain Extra-esophageal symptoms (chronic cough, hoarseness etc) Dysphagia – may indicate GERD *When cardiac causes have been excluded Retrosternal pain* (chest pain)
- 23. Symptom-based diagnosis Risk assessment Non-erosive reflux disease Reflux esophagitis ~35% Complicated reflux disease ~5% ~60% Endoscopy Alarm symptoms Empirical therapy 1DeVault KR, Castell DO. Am J Gastroenterol 2005;100:190–200; Rao G. J Fam Pract 2005;54 (12 Suppl):3–8. Adapted from Labenz J et al. World J Gastroenterol 2005;11:4291-99. Following a symptom-based diagnosis, almost all patients can be managed in primary care Treatment failure ~95% of patients in primary care1
- 24. Guidelines NSAID therapy 2006 No/low NSAID GI risk NSAID GI risk No CV risk (no aspirin) Traditional NSAID COX-2 selective inhibitors or Traditional NSAID + PPI or Consider non-NSAID therapy CV risk (aspirin) Traditional NSAID* + PPI if GI risk warrants gastroprotection or Consider non-NSAID therapy A “gastroprotective” agent must be added if any NSAID* is prescribed or Consider non-NSAID therapy Scheiman, JM, Fendrick AM. Arthritis Res Ther 2005, 7(suppl 4):S23-S29 *Ibuprofen should be used cautiously in individuals taking aspirin.
Editor's Notes
- NSAIDs can cause gastroduodenal injury NSAIDs provide a range of benefits, but they also carry significant gastroduodenal risks for the patient through injury of the gastroduodenal mucosa. When the mucosa is visualised by scanning electron microscopy only 16 minutes after administration of aspirin, there is evidence of significant localised foci and damaged cells, compared with the normal mucosa.20 Indeed, approximately 20% of patients taking NSAIDs on a daily basis have erosions or ulcers when investigated by endoscopy.20 Reference 20 Baskin WN, Ivey KJ, Krause WJ et al. Aspirin-induced ultrastructural changes in human gastric mucosa. Correlation with potential difference. Ann Intern Med 1976;85:299–303.
- 3. NSAIDs inhibit the COX enzyme, which exists in two forms NSAID-mediated inhibition of prostaglandin synthesis is the central mechanism behind both the therapeutic and toxic activity of these drugs. Prostaglandins are synthesised through the action of the COX enzyme on the cell membrane constituent, arachidonic acid.2 COX exists in two forms; the COX-1 isoform is constitutively expressed in most tissues and is believed to have a ‘housekeeping’ role, producing prostaglandins that regulate normal cell activity. The COX-2 isoform is virtually undetectable in most tissues under normal physiological conditions, but can be induced in the presence of inflammation, tissue damage or malignant transformation.2–4 Prostaglandins produced by COX-2 are thought to be mediators of pain, inflammation and fever,2–4 and the anti-inflammatory effects of NSAIDs appear to be largely attributable to inhibition of COX-2.2–4 The cardioprotective effects of NSAIDs stem from inhibiting the COX-1-mediated synthesis of thromboxanes by platelets. Aspirin has the most pronounced anti-thrombotic effect of all NSAIDs as it irreversibly inhibits COX-1 in platelets.5
- Gastric acid plays a central role in NSAID-associated gastroduodenal damage For the present, the majority of patients requiring NSAID therapy will continue to be treated with non-selective NSAIDs. All of these can cause damage to the gastroduodenal mucosa systemically after they are absorbed, by inhibiting the production of prostaglandins.45 This, in turn, reduces the synthesis and secretion of bicarbonate and mucus, and impairs mucosal blood flow. In addition, NSAIDs can cause direct topical physicochemical disruption of the mucosa. The net effect is that NSAIDs impair the mucosal barrier to gastric acid, which, together with pepsin, exacerbates the initial damage, potentially resulting in deeper erosions and peptic ulceration. Gastric acid can also enhance the direct absorption of some NSAIDs into the gastric mucosal cells, where they may interfere with cell metabolism, have a toxic effect on the mitochondria and cause cell disruption. Reference 45 Scarpignato C. Nonsteroidal anti-inflammatory drugs: how do they damage gastroduodenal mucosa? Dig Dis 1995;13 Suppl 1:9–39.
- All NSAIDs carry a risk of gastroduodenal side-effects NSAIDs act by inhibiting the enzyme cyclo-oxygenase (COX), which is responsible for the production of prostaglandins, key mediators in the inflammatory process. In addition to the role that they play in pain and inflammation, prostaglandins are necessary for the maintenance of the gastroduodenal mucosal barrier. Consequently, all NSAIDs inevitably have the potential, in the presence of gastric acid, to disrupt the gastroduodenal mucosal barrier and cause upper gastrointestinal symptoms. In a study in 1826 patients with osteoarthritis or rheumatoid arthritis taking NSAIDs for at least 6 months or unable to tolerate continuous NSAID use because of adverse gastrointestinal symptoms, the incidence of endoscopically confirmed peptic ulcers ranged from 14.8% with fenoprofen to 43.9% with aspirin.21 A meta-analysis of controlled trials found the lowest risk of gastrointestinal complications with ibuprofen; this was attributed to the low doses of this agent normally used in clinical practice.22 The highest risks were seen with tolmetin, ketoprofen and piroxicam. However, the authors suggested that the risks associated with ‘low-risk’ NSAIDs such as diclofenac might disappear with increasing doses. A prospective cohort study performed in the UK showed that the risk of gastrointestinal complications remained constant throughout NSAID treatment.23 Furthermore, the risk remained for at least 1 year after discontinuation of treatment. References 21 Cheatum DE, Arvanitakis C, Gumpel M, Stead H, Geis GS. An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs. Clin Ther 1999;21:992–1003. 22 Henry D, Lim LLY, Garcia Rodriguez LA et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996;312:1563–6. 23 MacDonald TM, Morant SV, Robinson GC et al. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997;315:1333–7.