Ivano-Frankivsk national medical university

Peptic ulcer disease

Vyshyvanyuk Vira Yuriivna
Chair of internal medicine #1 with course of clinical immunology and allergology

Definition
Peptic ulcer disease is chronic poliethiologic disease of the stomach or duodenum, the main sign of which is an chronic excoriated segment (ulcer defect) on gastro-intestinal mucosa
About 10% of the population in different countries are suffered this disease

Prevalence and Incidence of Peptic Ulcer

DU most common in Europe, GU in Japan Incidence of DU declining, GU stable

Probably most common chronic disease of humans. Human populations throughout the world affected. Incidence increases with age and occurs earlier and at increased rates in the developing world and lower socioeconomic groups. Up to 90% of some populations affected.

Ethiology

Predisposing factors:
1. Modifying factors - Alimentary factors (sharp, spice diet,
nonregulatory diet)

- Smoking, alcohol, coffee abuse

(chronic ischemia of mucosa)

- Stress, psychogenic overexertion

(hypersecretion)

- Professional factors (bussines trip)

- Scull and brain trauma - Other GI diseases (gastritis, duodenitis)

Predisposing factors:
2. Nonmodifying factors a) age and sex b) hereditary predisposition - High quantity of parietal cells - 0 (I) blood group - Fucoglycoprotein deficiency - Intensified response of parietal cells for food stimulation and gastrin - Factors of local immunity

Pathogenesis: protective factors

Unique acid environment requires functional gastric surface mucus barrier, bicarbonate buffering and epithelial integrity

Pathogenesis: protective factors

1. Gastroduodenal zones resistance Mucous stratum Bicarbonate secretion Active regeneration of epithelium Optimal blood flowing in GD wall 2. Local protective action of prostaglandins (PG E2)

3. Antiulcerative food (food fibers, milk; mode of a meal)

Pathogenesis: aggressive factors

1. Acid-peptic factor (hyperproduction of HCl and pepsin) - Hyperplasia of the major and parietal (parietal) cells - Vagotony - Increase sensitivity of the gastric glands to the nervous and humoral regulation 2. Gastroduodenal dismotility 3. Contact difusion H+ ions 4. Proulcerative nutritional factors (hot, spice food, irregular diet) 5. Autoimmune factors 6. Helicobacter pylori infection

Pathogenesis
The traditional theory regarding pathogenesis of peptic ulcer focus on pepsin action and acid hypersecretion. According to this theory, hydrochloric acid and pepsin is the main reason of damage gastrointestinal mucosa, in situation, when local defense factors are decreased. These findings are not universal and it is now known that hypersecretion is not the primary exclusive mechanism ulcerogenesis.

Pathogenesis
Infectious theory now is very important. According to this theory, the main cause of ulcerogenesis is Helicobacter pylori, which produce enzyme urease, mucinase, phospholipase, which may erode the mucous barrier, leading to epithelial damage. Mucolitic enzymes (eg bacterial proteases, lipase) appear to be involved in degradation of the mucous layer, making the epithelium more susceptible to acid damage.

Warren J. R. (1983) Unidentified curved bacilli on gastric epithelium in active chronic gastritis Lancet (i): 1273

Marshall B. J. & Warren J. R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration Lancet (i): 1311-1314

The Nobel Prize in Physiology or Medicine 2005

"for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"

Barry J. Marshall
Australia
b. 1951

J. Robin Warren
Australia
b. 1937

 I preferred to believe my eyes, not the medical textbooks of the medical fraternity
R. Warren (2002)

Helicobacter pylori
Gramnegative microaerophilic curved S-like or spiral shaped bacterium 2,5-3,5 m in length with 2-6 flagella. The optimum pH for it 6,5-7,5

H. pylori produces: - urease - mucinase - phospholipase - superoxide dismutase - hemolysin - vacuolating cytotoxin - proteins adhesins

Helicobacter pylori
Adapted to live in association with surface epithelium beneath mucus barrier Causes cell damage and inflammatory cell infiltration

H. pylori is a causal factor in most

cases of peptic ulcer disease
Gastric ulcer
25%

Duodenal ulcer
5% 1% 2%

3% 2%

92%

70%

H. pylori NSAID Cancer (Zollinger Ellison) Other

Marshall 1994

Helicobacter pylori
Source H. pylori - the patient or bacillicarriers Natural environment habitat of H. pylori are fossa gastric epithelium, intercellular connections, gastric mucus

Transmission - oral-oral or fecal-oral (including at fibrogastroduodenoscopy, pH-metry, probing for poor sterilization processing equipment)

In 1983, Warren (a biologist) and Marshall (a clinician) described Helicobacter pylori (HP). At first, they named the bacterium Campylobacter pyloridis. Later, it was named Campylobacter pylori. Since then, a large number of reports have been produced on HP and its pathogenetic potential.

Pathogenesis: the role of neuroendocrine factors

1. Dysfunction of the parasympathetic NA 2. Dysfunction of the sympathetic NA 3. Dysfunction of the hypothalamuspituitary-endocrine gland 4. Gastrointestinal endocrine dysfunction

Pathogenesis

In normal acid/pepsin attack is balanced by mucosal defences Increased attack by hyperacidity

Weakened mucosal defence the major factor (H. pylori related)

Pathomorphology
Sites:
Duodenum (DU) Stomach (GU) Oesophagus Gastro-enterostomy stoma Related to ectopic gastric mucosa (e.g. in Meckels diverticulum)
ulcer

ulcer

ulcer

stomach

Peptic ulcer

Classification
I. By association with H. pylori - H. Pylori-assosiated - Nonassosiated

II. By the number of ulcers: - Single ulcer - Multiple

III. The size of the defect - Small - large - gigantic IV. Localization of ulcers - gastric ulcer - duodenal - combined gastric and duodenal - ulcer of gastrojejunoanastomosis

Complications of peptic ulcer

Haemorrhage by erosion of vessel in base Perforation leading to peritonitis Penetration of surrounding organ

(liver/pancreas) Obstruction (by scarring) pyloric stenosis (Cancer rare event in true peptic ulcer)

Complains of patient
- Attack of epigastric pain, which arise after food from 30-60 min (ulcer stomach) or 1,5-2 hours and fasting or in the night (ulcer duodenum) and relieved by vomiting, alkali food and medicines. Pain may be near the xiphoid process or in the epigastrium to the left of the midle line and may radiation to the back near the angle of the left scapula

Clinical findings

Heartburn
on height of the pain and is afferent relief

Nausea Vomiting

Constipation

Clinical findings On examination:

Usually low weight, tongue is furred Tenderness and cutaneous hyperalgesia in the epigastrium Mendel symptoms positive (tenderness in one point on middle line due to percussion) Muscular rigidity of the upper rectus muscle due to free perforation

Diagnosis
Complaints, anamnesis

Gastroscopy Roentgenoscopy (a barium meal test) Endoscopic biopsy and histologic evaluation pH-metry of stomach Tests for Helicobacter infection

FIBEROPTIC ENDOSCOPY
FIBEROPTIC ENDOSCOPY is a powerful method for the diagnosis and management of peptic ulcer disease Signs of the peptic ulcer disease are * ulcer defect on mucosa * hyperemia and edema of mucous membrane around ulcer defect
Contraindications to fibrogastroduodenoscopy: - Acute myocardial infarction - insult - severe arrhythmias - frequent attacks of angina and asthma - CHF B-III - mental disorders

Double-contrast barium X-ray

Direct symptom of ulcer disease:
* niche - symptom or permanent filling defect in the stomach wall * * * * * pyloric spasm Forefinger symptom of de Kerven gastric folds convergence Local changes of gastric moving Duodenal deformation

Nondirect symptoms of ulcer:

Views demonstrate projection of crater away from the lumen

Intragastral -metry

Hyperacidity

Diagnosis of H. pylori
Endoscopy-based Invasive tests Rapid urease test Direct microscopy Histology Culture DNA probes/PCR

Diagnosis of H. pylori

Non-invasive tests
13/14C-urea

breath test (UBT)

Serology (lgG, lgA) PCR in saliva and faeces

In this test, a mucosal biopsy is inoculated into a well that contains urea and a pH-sensitive dye (phenol red). If urease is present in the biopsy, urea in the medium is converted to NH4+, which will raise the pH. In response to an elevation in pH, the pH sensitive dye causes the well to change color. This figure is an example of a rapid urease test, the CLOtest. In this test, presence of H.pylori in a mucosal biopsy will be evidenced by a color change from yellow to red.

Diagnosis of Helicobacter pylori (H. pylori) by the urea b r e a t h t e s t i s b a s e d o n u r e a s e m e t a b o l i s m o f i n g e s t e d u r e a . E i t h e r 1 3 C - o r 1 4 C - l a b e l e d u r e a i s i n g e s t e d . T h e former is a nonradioactive carbon isotope. If H. pylori is present, urea is metabolized to ammonia and carbon-labeled carbon dioxide. The labelled carbon dioxide is then excreted in breath as labeled carbon dioxide, which is then collected and q u a n t i f i e d .

Breathtest

Infra-red spectroscope IRIS (Germany)

Bags with exhaled air

Treatment
Non-pharmacological therapy
1. Elimination of harmful factors (ulcerogenic drugs, smoking, alcohol) 2. Rational diet - mechanically, thermally, chemically bland food 3. Curative treatment - bed rest lax 7-10 days + light phisical activity

Drug therapy

1. Antisecretory tools

2. Antacids 3. Gastrocytoprotection 4. Reparants 5. Means, normalizes motility 6. Centrally acting drugs 7. Eradication of Helicobacter pylori infection

Decrease of acid secretion

Drug Category: Antacids - Aluminum-containing and magnesium-containing antacids can be helpful in relieving symptoms of gastritis by neutralizing gastric acids. These agents are inexpensive and safe.

Drug Name

Aluminum and magnesium hydroxide (Almagel, Maalox, Mylanta) -- Neutralizes gastric acidity, resulting in increase in stomach and duodenal bulb pH. Aluminum ions inhibit smooth muscle contraction, thus inhibiting gastric emptying. Magnesium and aluminum antacid mixtures are used to avoid bowel function changes. 2-4 tsp PO qid prn

Adult Dose

h.s. or HS - At bedtime (hour of sleep) b.i.d. or BID - Twice daily q.i.d. or QID - Four times a day q.d. or QD - Every day p.r.n. or PRN - As needed

Drug Category: H2-receptor antagonists - Inhibit the action of histamine on the parietal cell, which inhibits acid secretion. The 4 drugs in this class are all equally effective and are available over the counter in half prescription strength for heartburn treatment. Although the IV administration of H2 blockers may be used to treat acute complications (eg, GI bleeding), the benefits are yet to be proven.

Drug Name

Ranitidine (Zantac) -- Competitively inhibits histamine at the H2 receptors of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.

Adult Dose

150 mg PO bid or 300 mg PO qhs; not to exceed 300 mg/d 50 mg/dose IM/IV q6-8h
Famotidine (Pepcid) -- Competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations. 40 mg PO qhs 20 mg/dose IV q12h; not to exceed 40 mg/d Nizatidine (Axid) -- Competitively inhibits histamine at H2 receptors of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations. 300 mg PO hs or 150 mg PO bid

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Drug Category: Proton pump inhibitors -- Bind to the proton pump of parietal cell, inhibiting secretion of hydrogen ions
into gastric lumen. Proton pump inhibitors relieve pain and heal peptic ulcers more rapidly than H2 antagonists do. Drugs in this class are equally effective. They all decrease serum concentrations of drugs that require gastric acidity for absorption, such as ketoconazole or itraconazole. Omeprazole (Prilosec) -- Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers. Physicians may prescribe for up to 8 wk to treat all grades of erosive esophagitis. 20 mg PO qd for 4-8 wk Lansoprazole (Prevacid) -- Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers. Physicians may prescribe for up to 8 wk to treat all grades of erosive esophagitis. 30 mg PO qd for 4-8 wk Rabeprazole (Aciphex) -- Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. For short-term (4-8 wk) treatment and symptomatic relief of gastritis. Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers. Physicians may prescribe for up to 8 wk to treat all grades of erosive esophagitis. 20 mg tab PO qd 4-8 wk Pantoprazole (Protonix) -- Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. For short-term (4-8 wk) treatment and symptomatic relief of gastritis. Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers. Physicians may prescribe for up to 8 wk to treat all grades of erosive esophagitis. 40 mg PO qd Esomeprazole (Nexium) -- S-isomer of omeprazole. Decreases gastric acid secretion by inhibiting the parietal cell H+/K+ ATP pump. Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers. Physicians may prescribe for up to 8 wk to treat all grades of erosive esophagitis. 20-40 mg PO qd

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Drug Category: Antidiarrheals

The approved antidiarrheal for this infection is bismuth subsalicylate. It has both antisecretory and antimicrobial activity.

Drug Name

Bismuth subsalicylate (Bismatrol, Pepto-Bismol) Has cytoprotective effect on GI mucosa, probably due to stimulation of prostaglandin production and modulation of immune response. In addition, has been demonstrated that some deposits (probably bismuth salts) appear on both surfaces of the cell wall of HP after <1 h. Such deposits induce distortion and vacuolization of the bacterial cell and loss of adherence of HP from antral epithelium. 120 mg PO qid; not to exceed 4.2 g/d

Adult Dose

Drug Category: Gastrointestinal agents - Are effective in the treatment of peptic ulcers and in preventing relapse. Their mechanism of action is not clear. Multiple doses are required, and they are not as effective as the other options.
Sucralfate (Carafate) -- Binds with positively charged proteins in exudates and forms a viscous adhesive substance that protects the GI lining against pepsin, peptic acid, and bile salts. Used for short-term management of ulcers. 1 g PO qid

Drug Name

Adult Dose

Drug Category: Prostaglandins - Can prevent peptic ulcers in patients taking NSAIDs and may be used with NSAIDs in patients at a high risk of complications.
Drug Name Misoprostol (Cytotec) -- A prostaglandin analog that protects the lining of the GI tract by replacing depleted prostaglandin E1 in prostaglandin inhibiting therapies. 200 mcg PO qid with food; if not tolerated, decrease to 100 mcg qid or 200 mcg bid with food

Adult Dose

The Maastricht European Consensus Guidelines Indications strongly recommended for H. pylori eradication therapy:
peptic ulcer disease (active or inactive)

bleeding peptic ulcer low-grade gastric MALT lymphoma gastritis with severe abnormalities following early resection for gastric cancer

H. pylori eradication regimens supported

by the Maastricht Consensus Report
PPI standard dose amoxicillin 1000 mg clarithromycin 500 mg PPI metronidazole clarithromycin PPI amoxicillin metronidazole standard dose 400 mg 250 mg twice daily for 1 week

twice daily for 1 week

standard dose 1000 mg 400 mg

twice daily for 1 week

3 times daily for 1 week

Resistance of H. pylori to metronidazole is common, but shows geographic variation

Primary resistance % 100
84

80 60
41.2

7 7

40
27 26 27.5 24 17 6.4 10.8

20 0

Mgraud 1994

Drug Category: Antibiotics Use agents known to be effective against HP.

Drug Name

Metronidazole (Flagyl) Reduced to its active form intracellularly only by anaerobic organisms, then disrupts helical structure of DNA and inhibits bacterial nucleic acid synthesis. 250-500 mg PO qid Tetracycline (Sumycin) Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). 500 mg PO qid Clarithromycin (Biaxin) Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. 500 mg PO q12h Amoxicillin (Amoxil, Trimox) Inhibits final stage of bacterial cell wall synthesis due to binding to specific PBPs on inner part of bacterial wall, leading to bacterial lysis. 1 g PO bid

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Prevention
Primary prevention of NSAID-induced ulcers includes the following: - Avoid unnecessary use of NSAIDs. - Use acetaminophen or nonacetylated salicylates when possible. - Use the lowest effective dose of an NSAID and switch to less toxic NSAIDs, such as the newer NSAIDs or cyclooxygenase-2 (COX-2) inhibitors, in high-risk patients without cardiovascular disease. Consider prophylactic or preventive therapy for the following patients: - Patients with NSAID-induced ulcers who require chronic, daily NSAID therapy

- Patients older than 60 years

- Patients with a history of PUD or a complication such as gastrointestinal bleeding - Patients taking concomitant steroids or anticoagulants or patients with significant comorbid medical illnesses Prophylactic regimens that have been shown to dramatically reduce (prevent) the risk of

NSAID-induced gastric and duodenal ulcers include the use of a prostaglandin analogue or
a PPI. - Misoprostol 100-200 mcg PO 4 times per day - Omeprazole 20-40 mg PO every day - Lansoprazole 15-30 mg PO every day

Thank you for attention!