Peptic Ulcer Disease Cengiz Pata,MD Dept. Gastroenterology, Yeditepe University, Medical center

Case 30 year old male Epigatsric pain radiating to the back Questions? Possible diagnosis Deferential diagnosis Possible complications

Case Pain: What type of pain? How often? Awakes at night? Relation to food? Complications: Vomiting? (obstruction?) Stools? (melena?) Common deferential diagnosis: Pnacreatobiliary disease Dyspepsia Tumors

Case Next diagnostic step? Endoscopy Abdominal US UGI? DU Ulcer detected- next step? Test for H. pylori Exclude NSAID use Rare – assess gastrin, mainly in unusual cases

Benign gastric ulcer (B)

Peptic Ulcer A defect in the gastrointestinal mucosa extending through the muscularis mucosa. Two main forms: 1) Helicobacter associated 2) NSAID associated ( Steroids alone – no additional risk, Increased risk when combined with NSAIDS)

Peptic Ulceration : Additional Causes Acid hypersecretion: Gastrinoma ( ZE) Systemic mastocytosis Basophilia in myeloproliferative disorders Viral Herpes simplex CMV ( mainly in immune compromised)

Peptic Ulceration : Additional Causes Vascular Insufficiency ( including due to crack cocaine) Radiation induced Chemotherapy induced Stress ulceration

Electron micrograph of H. pylori

Prevalence of Helicobacter pylori in peptic ulcer

Seroprevalence of H. pylori with increasing age in developed and developing countries Developing countries Developed countries < < % 64-96% 6-39% 7-54% Age range (years) Prevalence (%) Adapted with permission from Heatley-Helicobacter pylori and Gastrointestinal Disease; Oxford, UK: Blackwell Scientific Publications

Risk factors for H. pylori infection Age Country of origin Socio-economic status ­ poor housing ­ bed sharing ­ overcrowding ­ large families

Modes of transmission of H. pylori infection Zoonosisunlikely Environmentunlikely Person-to-person ­ oral-oral likely ­ gastro-oral likely ­ faecal-oral likely

H. pylori infection and disease associations Chronic gastritis Duodenal ulcer Benign gastric ulcer Gastric carcinoma Gastric MALT and non-Hodgkin‘s lymphoma Ménétrier‘s disease

Pattern of gastritis Duodenal ulcer Gastric ulcer *H. pylori colonizes areas of gastric metaplasia, leading to chronic duodenitis and eventually duodenal ulcer. Antral gastritis * Corpusitis

NSAIDS In the USA 30 bil OTC 20 mil prescriptions 3-4% ulcerations 20,000 die of NSAID complications 80% have no preceding dyspepsia Important to identify at risk populations Previous gastritis Elderly

PD & Systemic Diseases COPD Renal Failure Cirrhosis Mastocytosis

Clinical Presentation Abdominal Pain: Epigastric dull “hunger pain” DU- 11/2 –3 hrs postprandial relived by food May awake at night GU – May occur with meals nausea weight loss more frequent in GU Sudden pain – perforation? Vomiting – obstruction?

Clinical Presentation Physical examination: Poor predictive value, not specific Pain may occur in RUQ ~ 20% Detect complications: Tachycardia, orthostasis- bleeding? Radiation to the back- perforation? Succussion splash – outlet obstruction?

Complications Bleeding ~ 15% ( More in >60 yrs –NSAID) 20% - no warning sign Perforation 6-7% Free Penetration: DU posterior to pancreas GU into Lt hepatic lobe Gastrocolic fistula

Complications Outlet obstruction 1-2% Inflammatory – reversible by Tx Scar tissue – balloon dilatation, Surgery Presentation : Gradual onset Sudden

Clinical manifestations of ulcer disease

Differential Diagnosis Non ulcer dyspepsia Tumors of the UGIT Biliary disease Reflux disease Vascular diseases Pancreatitis Coronary heart disease

Diagnosis Radiology: Single contrast 80% sensitivity Double 90% (worse for ulcers<0.5 cm, scar tissue) Endoscopy: examination of choice good for small ulcers biopsy samples for HP and malignancy therapeutic Assay for HP infection

Diagnostic methods for H. pylori Diagnostic method Histology Main indication Diagnosis Sensitivity (%) 90 Specificity (%) 90 Culture H. pylori antibiotic sensitivities Rapid urease test Endoscopy room diagnosis 90 SerologyScreening and diagnosis 90 Urea breath test To confirm eradication 95100

The principle of the urease test NH 2 C O + 2H 2 O + H + 2NH HCO 3 - Urease UreaCLOtest pH change

The principle of the 13 C- or 14 C-urea breath test Reproduced with permission from Mr Phil Johnson, Bureau of Stable Isotope Analysis, Brentford, UK.

Therapy Treat H. pylori Healing by inhibition of acid secretion: H2 receptor antagonists (H2RA) Proton Pump inhibitors ( PPI) Anti Acid Cytoprotection Sucralfate Anti Acid Bismuth-Based Prostaglandin Analogs

Therapy of DU H2RA – Cure in 80% at 4 wks ~95% at 8 wks Split and once daily equally effective PPI- Cure in 60-93% at 2 wks % at 4 wks Omeprazole Vs ranitidine 14% advantage at 2 wks 9% advantage 4 wks

Therapy of GU Suppress acid by H2RA or PPI Advantage of PPI less apparent Sucralfate comparable to H2RA Prepyloric ulcers may resemble more DU in terms of response to acid suppression

Risk stratification of Ulcer Pts Low risk: Intermittent symptoms Nonsmoker Discontinued NSAID Uncomplicated Easy healing

Risk stratification of Ulcer Pts High risk: Frequent recurrence Refractory to Tx Smoking Continued NSAID Giant Ulcer ( DU >2 cm GU > 3 cm) Anticoagulation Deformity & scarring Elderly Acid hypersecretion

General Scheme HP positive – Eradicate If Non complicated – No further Tx If high risk: Follow by acid suppression for 4-6 wks Withdraw – NSAID Smoking Excess Alcohol In GU – Biopsy? Cost and effect- Most CAs detected in first round of endoscopy

Refractory Ulcers Consider refractory after 8-12 wks of Tx Ensure that refractory symptoms = refractory ulcer ( endoscopy) If no ulcer - investigate pain Consider “silent” refractory ulcer in high risk pts ( ~25% of refractory ulcers)

Refractory Ulcers - causes Persistent HP infection Persistent NSAID use Poor pt compliance Giant ulcers ( healing at 3 mm/wk) Smoking Under laying pathology ( ZE, bands, crohn’s,infections I.e. TB syphilis, Ly, scarcoidosis ) Impaired response to PPI ( 5% of population)

Refractory Ulcers - Approach Seek causes: DU- HP, NSAIDS, r/o ZE ( gastrin levels) GU- main concern CA Repeat multiple Bx Evidence for malignancy: CT, EUS No explanation - surgery

Surgery - DU Refractory bleeding (~5% of transfused Pts) Perforation (2-3%) Outlet obstruction Vagotomy + antrectomy Rec.  (1%) Comp  Vagotomy + pyloroplasty intermediate (10%) Highly selective vagotomy Rec.  Comp 

Zollinger Ellison Syndrome Severe peptic ulcer diathesis + gastric acid hypersecretion due to  -cell endocrine tumor 0.1-1% of PUD patients Sporadic, or associated with MEN type I (25%)

Zollinger Ellison Syndrome >80% Localized to gastrinoma triangle: cystic & common bile ducts, duodenum, junction head and body of pancreas. 60 % malignant, up to 50% with metastasis Clinical: PUD >90% (recurrent, multiple, refractory, complicated)

Zollinger Ellison Syndrome Esophageal complaints ~60% Diarrhea ~50% (fluid overload, pancreatic enzyme dysfunction, epithelial dysfunction) Combination should raise clinical suspicion

Clinical features of Zollinger- Ellison syndrome

MEN I Autosomal Dominant: Parathyroid (~90%), Pancreas (40-80%) Pituitary (30-60%) Contributory effect of hyperparathyroidism, hypercalcemia  hypergastrinemia  acid secretion Higher incidence of carcinoids Smaller and multiple duodenal gastrinomas

Diagnosis of Gastrinoma Combination of clinical signs Fasting gastrin levels (> 150 pg/ml) Avoid confounding factors (hypochlorhydria, PPIs, outlet obstruction, renal failure) Assess acid secretion (if low- excludes) Provocative tests (calcium, secretin)

Treatment Localization (EUS, Oct scan, MRI, CT) Exclusion of metastasis If positive – symptomatic cure If negative attempt surgical resection ( less likely in MEN I ~ 6%)

Case year old lady, RA Dizziness and weakness for the last week. Mild abdominal pain Questions?

Case-2 Stools? Melena Drugs? NSAIDS Next action? Gastroscopy

Gastric Ulcer with Stigma

Treatment H2RA Oral PPI Oral PPI + H2RA IV PPI

H2 RA Very safe drugs Tolerance after 48 hrs IV treatment Less effective than PPIs in suppressing acid secretion (block only histamin)

Treatment Heavy consumption of NSAID Should H. pylori be tested for? Treated? YES

Drugs for treatment of acid disorders and H. pylori infection H2 Receptor antagonists PPI Anti H. pylori regimens

Overall Control of Acid Secretion

The parietal cell

The proton pump

Biologic mechanism of action of substituted benzimidazoles (proton pump inhibitors)

Kinetics of PPI Effect

Summary of PPI effects Inhibit ~70% of acid secretion Need to coordinate pump activation & PPI availability (t/2~60-90 min) Pump re-synthesis (half life ~ 50 hours  25% synthesis between single day doses) Cysteins accessible to reducing activity of glutathione Spontaneous pump recycle every min (Potential to block)

Optimization of acid control

Guidelines for use of antibiotic therapy in patients with Helicobacter pylori infection

Treatment regimens for eradication of Helicobacter pylori

Therapeutic options clarithromycin 2 x mg metronidazole 2 x mg amoxycillin 2 x 1000mg PPI X 2 eradication rate 90% eradication rate >80% _ < _ <

Choice between treatments

Treatment failures