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PEPTIC ULCER AND NON ULCER DYSPEPSIA DR BANU NISA ABDUL HAMID MASTER IN FAMILY MEDICINE 1ST YEAR POSTGRADUATE , UKM Objective • most likely causes of dyspepsia • risk factors of recurrent peptic ulcer disease • role of Helicobacter pylori in the pathogenesis of peptic ulcer • disease and its relationship to ulcer relapses • manage patients presented with dyspepsia • role of available drugs for the treatment of dyspepsia • recognise the indications for long-term maintenance therapy • manage patients with PUD and concomitant high CVD risk needing antiplatelet therapy DYSPEPSIA • Defination: - having one or more symptoms of epigastric pain, burning, post-prandial fullness, or early satiation. 5 MAJOR CAUSE a) Gastro-esophageal reflux (GERD) b) Medications c) Functional dyspepsia (FD) – non ulcer dyspepsia d) Peptic ulcer disease (PUD) e) Malignancy Some medications that commonly cause dyspepsia • • • • • • • NSAIDS Cox-2 inhibitors Bisphosphonates Erythromycin Tetracyclines Iron Potassium supplements • • • • • Acarbose Digitalis Theophylline Orlistat Aspirin FUNCTIONAL DYSPEPSIA FUNCTIONAL DYSPEPSIA • Rome III working group defined FD presence of symptoms thought to originate in gastro-duodenal region, in the absence of any organic, systemic ,or metabolic disease that is likely to explain them.[Tack et al. 2006]. FUNCTIONAL DYSPEPSIA • Non ulcer dyspepsia FD FD (subgroups) • Irritable bowel syndrome • Post prandial distress syndrome (PDS) • Epigastric pain syndrome (EPS) Rome III diagnostic criteria for functional dyspepsia At least 3 months of one or more of the following: • bothersome postprandial fullness • early satiation • epigastric pain • epigastric burning AND • no evidence of structural disease (including upper endoscopy) that is likely to explain the symptoms. Pathophysiological mechanism • Delayed gastric emptying • Impaired gastric accommodation to a meal • hypersensitivity to gastric distention • H. pylori infection • altered duodenal response to lipids or acid • abnormal duodenojejunal motility • central nervous system dysfunction [Tack et al. 2004]. Pathophysiologic mechanisms in functional dyspepsia. H+, acid exposure. CNS modulation stress,illness Visceral hypersensitivity (fat, ,wall distension) Vagal neuropathy Inflammation gastric contents [bacteria (H. pylori), viruses, etc.] Acid hypersensitivity Decrease fundic accommodation Abnormal distribution of Igastric contents Gastric dysarrhytmias Delayed gastric emaptying/ Antral hypomotility Overdistended antrum Duodenal hypersensitivity Small bowel dysmotility Diagnostic criteria: PDS 1. Bothersome postprandial fullness, occurring after ordinary sized meals, at least several times per week AND/OR 2. Early satiation that prevents finishing a regular meal Supportive criteria 1. Upper abdominal bloating, postprandial nausea or excessive belching can be present 2. Epigastric Pain Syndrome may coexist Diagnostic criteria: EPS 1. Pain or burning localized to the epigastrium of at least moderate severity at least once per week AND 2. The pain is intermittent AND 3. Not generalized or localized to other abdominal or chest regions AND 4. Not relieved by defecation or passage of flatus AND 5. Not fulfilling criteria for gallbladder and sphincter of Oddi Diagnostic criteria: EPS Supportive criteria 1. Upper abdominal bloating, postprandial nausea or excessive belching can be present 2. The pain is commonly induced or relieved by ingestion of a meal but may occur while fasting 3. Postprandial distress syndrome may coexist Management of functional dyspepsia. PPI FD H.pylori eradiacation Promotility agents Nonresponders Alternative therapies Tricyclics SSRI Promotility agents PEPTIC ULCER DISEASE PEPTIC ULCER • Defination: mucosal lesions that penetrate the muscularis mucosae layer and form a cavity surrounded by acute and chronic inflammation. Two types: Gastric ulcer Duodenal ulcer • Located in the stomach often along the lesser curvature • Located in the duodenal bulb. In Malaysia • Few reports on the pattern of peptic ulcer in Malaysia. • Male are more prone than female • In both sexes, GU –older age grp compare to DU • Of the 3 main Malaysian ethnic grp, Chinese of both sexes had the highest frequency of peptic ulcer. • Chinese female had the highest frequency of DU. (Source: Profile of PUD in Malaysia,M V Kudva) Prevalence of PUD reached a peak early in 20th century but decreased during more recent decades. Widespread use of ASA & NSAIDS esp in older patients and those with comorbidities. The decreasing prevalance both from the reduction of patient with recurrent ulcer treated for H.pylori AND from the decreasing prevalence of H.pylori infection in the population. Risk factor • Major risk factor: Helicobacter pylori infection NSAIDS ASA Etiology and risk factors for peptic ulcer disease Odds Ratio Nonsteroidal anti-inflammatory drugs 3.7 Helicobacter pylori 3.3 Chronic obstructive pulmonary disease Chronic renal insufficiency 2.34 2.29 Current tobacco use 1.99 3 or more doctor visits in a year 1.49 Coronary heart disease 1.46 Former alcohol use 1.29 obesity 1.18 Clinical Manifestation • Night time awakening /episodic epigastric pain relieved following food intake (most specific clinical sign) • Epigastric pain describe as episodic , dull, burning (dyspepsia) pain. • 46% of patients had reflux symp (heartburn, acid regurgitation) ~ GERD Clinical manifestation DU GU • Awakening at night between 12 to 3am • Pain improves with food intake • Weight loss precipitated by fear of food intake Clinical manifestation • Most common symp of PUD (> 80 yo) : 1) Epigastric pain (74%) 2) Nausea (23%) 3) Vomiting ( 20%) • - Less common features: Indigestion Belching Vomiting Associated with gastric/pyloric stenosis - LOA - Intolerance to fatty foods - Positive FHX Definitive diagnosis • direct visualization of the ulcer via radiography (upper GI barium swallow, double contrast) or upper GI endoscopy (EGD). • Referral to EGD should be considered in all patients: 50 years of age or older, with persistent symptoms, anorexia, weight loss, vomiting, and in the presence of signs of GI bleeding. Differential diagnosis of peptic ulcer disease CONDITION TEST(s) FINDINGS Gastritis Upper gastrointestinal endoscopy Gastric inflammation Gastroesophageal reflux disease Symptoms Dyspepsia worse with eating and upon lying down Gastroparesis History History of diabetes Cholelithiasis Examination Abdominal ultrasound Right upper quadrant tenderness Gallstones Pancreatitis Amylase/lipase Elevated Gastric cancer Upper gastrointestinal endoscopy Abdominal CT scan Biopsy Abdominal aortic aneurysm Abdominal ultrasound Abdominal CT scan Size of aorta Hepatitis Liver function tests Elevated Condition Test(s) Findings Myocardial ischemia Cardiac enzymes Electrocardiogram Elevated CPKMB Elevated troponin ST segment changes Deep symmetric T wave inversion Mesenteric ischemia Symptoms Abdominal CT Pain after meals Mesenteric edema; bowel dilatation; bowel wall thickening; intramural gas; mesenteric stranding Common Complication GI bleeding Perforation Gastric outlet obstruction GI Bleeding • 80 % stop spontaneously- only supportive Rx required • Asymptomatic/hematemesis,coffee ground emesis,malena, tachycardia,shock. • Urgent OGDS –detect cause of bleeding, start on appropriate therapy. • Shock presentaggressive resuscitation & blood transfusion needed. • Surgery remains a definate indication and best Rx – OGDS/interventional radiology fails. Perforation • Lifetime prevelance of • S/S of septic shock perforation in PUD pts tacycardia,hypotension, ~5%. lethargy,anuria,cyanosis • Cause: NSAIDS, H.pylori • Simple surgical • Bleeding, sudden onset closures, intensive of sudden severe, sharp medical treatment, H abdominal pain/ pylori eradication, epigastric pain NSAID withdrawal have been reported to result • Abd : generalized in very low recurrence tenderness, guarding, rates. rigidity, rebound tenderness Gastric outlet obstruction • more commonly due to malignancy than PUD. • nausea, vomiting, bloating, indigestion, epigastric pain, and weight loss. • endoscopy has the advantage of being diagnostic and can rule out possible malignancy. • Malignant obstruction is reported in 66% of patients. • Outcomes may be improved with effective ulcer therapy with acid reduction and eradication of H pylori. • Surgery is associated with significant morbidity and mortality and should be reserved for endoscopic treatment failures. • Surgical palliation for malignant disease has poor results and high rates of morbidity and mortality. HELICOBACTER PYLORI HELICOBACTER PYLORI (HP) • Gram negetive spiral bacteria • Transmitted: fecal-oral ,oral-oral, mother to child routes, iatrogenic. • Highly prevalent in developing country & lower socioeconomic . • HP +ve subjects have 10-20% lifetime risk of developing PUD. PIC of halicobacter Common Treatment Regimn Regimen Comment Trile therapy PPI; amoxicillin 1 g BID; clarithromycin 500mg BID for 10 -14 days First line treatment Sequential therapy PPI and amoxicillin 1 g BID for 5 days followed by PPI, clarithromycin 500mg BID, tinidazole 500mg BID for 5 days May be first line where macrolide resistance is common Quadruple therapy PPI; bismuth 525mg QID; metronidazole 500mg QID; and tetracycline 500mg QID for 14 days Treatment for failure • Overall ,triple therapy for 14 days has been shown to be more effective at eradication of H pylori than dual therapy. • A recent meta-analysis did not find a difference in H pylori eradication rate between quadruple (PPI +bismuth +metronidazole + tetracycline for 10–14 days) and triple therapy (PPI+clarithromycin +azithromicin for 7–14 days). • H. pylori has been found more frequently in dyspeptic patients than in controls and has been shown to affect acid secretion and, to a lesser extent, gastric motility . • “Test and treat strategy”(< 50YO, no alarming symp) • In areas of low H. pylori prevalence (< 20%), the empirical use of PPIs alone is considered to be an equal option for symptom relief . • NICE guidelines recommend initiation of a 4 week trial of full dose PPI therapy in patients with uninvestigated dyspepsia. Test available for H.pylori: • Blood antibody test (enzyme-linked immunosorbent assay [ELISA]). This test detects exposure to H pylori but cannot be used to confirm successful treatment. • Urea breath test. This test is adequate for screening and for confirming cure following treatment. The use of PPIs within 2 weeks of testing can interfere with the results. • Stool antigen test. This test is adequate for screening and for confirming cure following treatment. • Stomach biopsy. Gold standard. It is adequate for screening and for confirming cure. Results depend on the number of biopsies and the experience of the pathologist. RELATIONSHIP WITH ULCER RELAPSES • Studies showed that the rate of Helicobacter pylori "reappearance" and of duodenal ulcer relapse up to 6 years after eradication of H. pylori. (Archimandritis A, Balatsos V. 'Bacteriology and epidemiology of Helicobacter pylori infection. J Clin Gastroenterol. 1999;28(4):345.) • Recent studies have suggested that the eradication of H. pylori affects the natural history of duodenal ulcer disease such that the rate of relapse decreases markedly. (Asaka M, Ohtaki T, Kato M. Causal role of Helicobacter pylori in peptic ulcer relapse. Gastroenterol. 1994 Jul;29 Suppl 7:134-8.) • Chronic PUD was almost exclusively due to H. pylori infection with up to 90% of duodenal ulcers and 70% of gastric ulcers attributed to this bacterium. • However, NSAIDs and aspirin are now responsible for most ulcer disease in developed countries. (d2- advances in public health, effective H.pylori eradication therapy). EGD (Esophagogastroduodenoscopy) Alarm symptoms that require prompt EGD in dyspeptic patients. • • • • • • • Anemia Evidence of acute/chronic bleeding Previous history of peptic ulcer Odynophagia Dysphagia Recurrent or persistent vomiting Unintentional weight loss • Prompt endoscopy is recommended in patients with alarm symptoms or patients over a threshold age (35-55 years). • Men , younger age ↑prevalence at diagnosis of upper GI malignancy • Once failed a 48 week trial of PPI therapy (in an area of low prevalence of H. pylori)/ failed to respond to eradication of H. pylori (in an H. pylori endemic region) upper endoscopy is indicated. • Performing upper endoscopy during a symptomatic period especially while the patient is off acid-suppressant therapy is important to making a diagnosis of functional dyspepsia by excluding other potential causes of symptoms. • Upper GI barium radiography: inferior to upper endoscopy and is generally not recommended as part of the work up for dyspepsia. Management of dyspepsia Dyspepsia Age>50 or alarm symptoms Age<50 and no alarm symptoms EGD Dyspepsia without GERD or offending medication High or intermediate Prevalence of H. pylori (>20%) Use of NSAIDs or other probable offending medication Typical GERD symptoms Trial off medication or change to an alternate medication Full dose PPI trial Continued symptoms despite adequate PPI trial Yes Test and treat for H. pylori (Stool antigen or breath test off PPI for >2 weeks) Symptom resolution No Negetive Treat as GERD Empiric trial of PPI 4–6 weeks Test and treat for H. pylori (Stool antigen or breath test off PPI for >2 weeks) Empiric trial of PPI 4–6 weeks No respond No response EGD Abnormal EGD Treatment based on endoscopic findings Normal EGD 1. Biopsy for H. pylori (unless negative H. pylori stool antigen or breath test OFF PPI for greater than 2 weeks) 1. Reassurance 4. Evaluate and treat for IBS 2. Consider alternate causes of abdominal pain 3. Consider trial of low dose trycydic antidepressant or antispasmotic Note: diagnostic algorithm may differ based on regional cancer risk, gender, and age of patient at presentation. Refractory Functional Dyspepsia • Patients who do not respond to empiric PPI therapy, have normal upper endoscopy, and who either are negative for H. pylori or have cleared infection following treatment yet continue to have dyspepsia represent a challenging group. • First, the diagnosis should be re-evaluated, considering other disorders that may be mistaken for dyspepsia. • In the absence of an alternate disease, reassurance and education of the patient with functional dyspepsia becomes important. • Although not validated in the functional dyspepsia population, a positive physicianpatient interaction including reassurance can reduce health care seeking behavior. • Patients are often also educated to eat smaller, more frequent meals to avoid gastric distention and to avoid food that aggravates symptoms. TREATMENT • Treatment of PUD consists of healing the ulcer and prevention of complications. All plans should include appropriate management of PUD risk factors. • discontinue smoking; offered stress management programs and counseled to avoid NSAIDs, aspirin, and alcohol abuse. • Management of patients with PUD requires detection and eradication of H pylori infection and the administration of antisecretory therapy, preferably PPIs, for a minimum of 4 weeks. • If patients recover after the first course of treatment, they should be observed. • If symptoms persist, antisecretory therapy with PPIs / histamine receptor (H2) blockers should be continued for an additional 4 to 8 weeks, and repeat EGD should be considered. • re-evaluated for H pylori infection NSAIDS • Economic modeling suggests that Cox-1 NSAIDs + H2 blockers or Cox-1 NSAIDs + PPIs are the most cost-effective strategies for avoiding endoscopic ulcers in patients requiring long-term NSAID therapy. • PPIs are more effective than H2-blockers at standard dosages in reducing the risk of gastric and duodenal ulcer, and are superior to misoprostol in preventing duodenal but not gastric lesions. ASPIRIN • Aspirin is commonly recommended to reduce the risk of cardiovascular events. • Several factors have been identified to increase the risk of patients to develop aspirin-associated GI bleeding. These include a history of previous GI ulcer, ulcer complications, dyspepsia, H pylori infection, and simultaneous use of aspirin with NSAIDs or clopidogrel. • The use of enteric-coated or buffered aspirin does not significantly decrease the risk of ulcer complications due to its systemic effect. • PPI + aspirin significantly reduces the risk recurrent ulcer bleeding. MEDICATION CLASS Medication Typical dose Precautions Histamine -2 Receptor blocker Cimetidine (Tagamet) 400 mg BID High incidence of side effects and potential for drug interactions due to inhibition of CYP450 150mg BD Ranitidine (Zantac) 20 mg BD Famotidine (Pepcid) Proton pump inhibitors Omeprazole 20-40 mg daily Altered metabolism of medications through CYP450 Lansoprazole 15-30 mg daily Pantoprazole 40mg BD Prostaglandin s Misoprostol 200 mg QID Dose-dependent diarrhea and abdominal pain Avoid in fertile women and during pregnancy Other medications Sucralfate 1 g QID Contains aluminum, should be avoided in patients with renal failure Can prevent absorption of other medications INTERACTIONS H2 RECP ANTAGO • Cimetidine (Tagamet) will inhibit drug metabolizing enzymes and increase plasma concentrations for: • • • • • • Benzodiazepines Theophylline Oral hypoglycemics Tricyclic antidepressants Propranolol Tegretol Coumadin Caffeine Dilantin Flagyl PROTON PUMP INHIBITORS • Omeprazole (Prilosec) • Lansoprazole (Prevacid) • In a cost-simulation model, PPI therapy was calculated as the most cost effective strategy in dyspeptic patients at 30 years of age and in areas of low H. pylori prevalence. • For 60-year-old patients, H. pylori test and treat was the most cost-effective strategy . • Significantly better response rate for omeprazole (31%) than for ranitidine (21%), cisapride (13%) and placebo (14%). MISOPROSTIL • Prostaglandin analog that replaces prostaglandins lost in stomach as result of NSAID therapy • Only indicated for NSAID induced ulceration • Side effects : diarrhea and abdominal pain SULCRALFATE - CARAFATE • Viscous gel • Adheres to ulcerated tissue and protects it from acid / pepsin • Minor side effect is constipation • No major side effects • May impede absorption of some drugs NON-DRUG THERAPY • Diet plays only a minor role in ulcer management. • No conclusive evidence that caffeine containing beverages promote ulcer formation or interfere with recovery. • Thought that alcohol can be harmful to lining of stomach • Beneficial to eat 5-6 small meals a day instead of 3 large ones to decrease fluctuations in gastric pH. When to refer • Patient ≤ 55 yo presenting with dyspepsia without red flags, routine endoscopy is unnecessary ( chances of devp GIT cancer is 1 in a million). • Older than 55yo with new onset persistant dyspepsia despite lifestyle & drug modification & 4/52 Rx. • Younger than 55 & symp unresponsive to full dose PPI ,HP eradication,& lifestyle modification where concern exists about diagnosis. Case Scenario Case scenario: • • • • • • • • A 60 year old man k/o :Diabetes Mellitus and Hypertension for 10 years c/o: epigastric discomfort for 1 month duration. The pain worsened at night and would awaken him from sleep. He denied of other GIT symptoms such as malena, lost of weight or anorexia. He also suffered Left hemiparesis from Ischaemic Stroke since 3 months ago. His current treatment is metformin 1gm bd, perindopril 4mg od, aspirin 150mg od and Simvastatin 20mg ON. Currently, his vital signs are stable and examination including abdomen was unremarkable. Proceed with management • This history is typical of dyspepsia. • Non-pharmacology : stop aspirin Explain that dyspepsia is a common condition that usually responds well to treatment Offer lifestyle advice, including smoking cessation, weight loss, reduced alcohol and caffeine intake, and regular exercise. • Pharmacological: Aspirin + PPI Caspirin + PPI Ticlid