Peptic Ulcer DiseaseHusam Barakat, M.D.

American Board in Gastroenterology

Assistant Professor of Medicine

Yarmouk University

Learning Objectives On completion of this lecture participants will be

able to:

• Recognize the typical clinical presentation and risk factors for peptic ulcer disease

• Understand pathophysiology of PUD focusing on H. pylori

• Describe an appropriate diagnostic plan based on individual risk factors

• Prescribe an appropriate therapeutic regimen

Disease Prevalence• Lifetime Prevalence = 10% of Americans develop PUD

• 10% of ER patients with abdominal pain diagnosed with PUD

• Prevalence decreasing over last 30yrs

• Male-to-female ratio of gastritis = 1:1

• Male-to-female ratio of PUD = 2:1

Definition• Peptic ulcer disease (PUD) = Mucosal defect in the

gastrointestinal tract (gastric or duodenal) exposed to acid and pepsin secretion

• Gastritis is the precursor to PUD and it is clinically difficult to differentiate the two

Differentiating gastric from peptic ulcer disease

• Duodenal ulcers - age 25-75 years.

• Gastric ulcer - age 55-65 years

• Pain awakening patient from sleep between 12-3 a.m. present in 2/3 duodenal ulcer patients and 1/3 gastric ulcer patients

Case Presentation

Mr. Jones is a 45 year old male who presents to your clinic with epigastric abdominal pain x 2 weeks.

What is your initial differential diagnosis at this pointgiven the limited information?

Initial Differential Diagnosis More Common:

• Gastroesophageal reflux disease

• Nonulcer dyspepsia/ Gastritis

• Ulcer disease

• Gastroenteritis

• Biliary colic or cholecystitis

• Pancreatitis

• Irritable bowel disease

Less Common:

• Mesenteric Ischemia

• Stomach/Pancreas/ Hepatobiliary cancers

• Atypical manifestion CAD/angina

• Posterior Wall AMI

• Aortic Aneurysm

• Inflammatory Bowel Dz

Mr. Jones HPI• Mr. Jones is a 45 year old male who presents to

your clinic with epigastric abdominal pain x 2 weeks. He describes it as a burning pain which is non-radiating and is worse after he eats. He has frequent belching with bloating sensation but denies nausea, vomiting, diarrhea, constipation, or weight loss. He has tried rolaids which do help a little.

• Which symptoms support the possible diagnosis of PUD?

Signs and Symptoms of PUD• Epigastric pain is most common symptom

• Pain described as gnawing or burning

• May radiate to the back (consider penetration)

• Occurs 1-3 hours after meals or at night

• Relieved by food, antacids (duodenal), or vomiting (gastric)

• Dyspepsia including belching/ bloating

• Hematemesis or melena with GI bleeding

Clinical Pearls

• NSAID-induced gastritis or ulcers are frequently “silent”

• Dyspeptic sx’s are non-specific – approx 20-25% of patients with sx’s will have peptic ulcer on further workup

Mr Jones History PMH: HTN stable, Osteoarthritis in knees, treated

for an ulcer 3 years ago

Meds: Hydrochlorothiazide, ibuprofen prn

Soc HX: Married, employed as bank manager, smokes 1ppd x 20years, drinks 2 beers per day, and 2-4 cups coffee per day

What risk factors can you identify for PUD?

Common Risk Factors for Gastric Mucosal Disruption

• H.pylori

• NSAIDs/ASA (even at low dose)

• Coffee/Caffeine

• Ethanol

• Tobacco

• Severe physiologic stress (Burns, CNS trauma, Surgery, Severe medical illness)

• Steroids

Pathophysiology PUD is a result of

acid/pepsin production imbalance with protective mechanisms such as mucous production

NSAIDs• Approximately 15% of patients on long-term

NSAID develop PUD

• NSAIDs/ASA - ↓prostaglandin (PG) by inhibiting the cyclooxygenase (COX) enzymes

• Three isoenzymes COX-1, COX-2, COX-3

• COX-1 → PG production in gastric mucosa

• COX-2 specific NSAIDs reduce GI side effects –cardiovascular side effects have limited use

Individual NSAID Risk High Risk

• Piroxicam/Feldene®

• Ketorolac/Toradol®

• Indomethacin/ Indocin®

Lower Risk

• COX-2 specific - Celebrex®

• Ibuprofen (< 1500mg/d)

• Relatively selective COX-2 nabumetone/Relafen®

etodolac/Lodine®

meloxicam/Mobic®

History of Ulcer Treatment• Early 20th Century – ulcers believed to be caused by

stress and dietary factors

• 1982 - Dr’s Warren and Marshall identify link between H. pylori and ulcers - medical community is slow to accept

• 1994 - NIH concludes a strong association between H. pylori and ulcer disease - recommends antibiotic treatment

History of Ulcer Treatment Cont’d

• 1995 - 75 percent of patients treated with antisecretory medications- only 5 percent receive antibiotic therapy

• 1996- FDA approves first antibiotic for treatment of ulcer disease

• 1997 - CDC launches national education campaign to inform health care providers about link between H. pylori and ulcers

http://www.cdc.gov/ulcer/history.htm

Discovery of Helicobacter pylori• “Two Australian physicians won the 2005 Nobel Prize

in Medicine or Physiology for showing - at least partly by accident -- that many ulcers are the result of a bacterial infection.”

“Robin Warren

and Barry

Marshall's work

on ulcers was

pioneering” Story from BBC NEWS:

http://news.bbc.co.uk/go/pr/fr/-

/2/hi/asia-pacific/4307826.stm

Published: 2005/10/04 10:39:09

GMT

© BBC MMVII

H. pylori• Curvelinear, gram (-) rod

with flagella

• H pylori is most common cause of PUD

• Transmission route fecal-oral

• Secretes urease→convert urea to ammonia

• Produces alkaline environment enabling survival in stomach.

H. pylori• Higher prevalence in Low SES

• In US more common in Hispanics/Blacks

• Estimated 60% of Americans older than 60 H pylori (+)

• Almost all duodenal and 2/3 gastric ulcer pt’s infected with HP

• Asymptomatic in approx 70% of those who are H pylori (+)

• Considered class 1 carcinogen → gastric cancer

Differentiating between H. pylori and NSAID-induced ulcer

Ulcers associated withH. pylori

• more often in duodenum

• often superficial• less severe GI bleeding

Ulcers associated withNSAIDs

• more often in stomach• often deep• more severe GI bleeding• sometimes

asymptomatic

Other Disease Conditions Associated with PUD

• Hypersecretory states: Gastrinoma (Zollinger-Ellison syndrome) or multiple endocrine neoplasia (MEN-I)

• Diseases assoc. with increased risk of PUD: cirrhosis, chronic pulmonary disease, renal failure

Mr. Jones Physical Exam • VS: BP 137/82, HR 85, afeb, RR 14

• HEENT: conjunctiva pink, OP MMM

• Heart: RRR no M/R/G

• ABD: Soft, NABS, mild-moderate epigastric TTP, no HSM or masses, no acute abd signs

• Skin: no pallor

• Rectal: stool brown, heme (-), no masses

What are typical PE findings in PUD?

Physical Exam Findings In uncomplicated PUD exam findings few and non-

specific:

• Epigastric tenderness - usually mild.

• Bowel sounds - normal.

• Rectal exam may show melena/guaiac+ stool from occult blood loss

• Signs of peritonitis with perforation

If Mr. Jones Hemoccult is Positive

What PE findings do you want to specifically document if Mr. Jones is Heme (+) indicating a possible active GI bleed?

• Look for signs of volume depletion: tachycardia, hypotension, orthostatics, skin turgor, MM appearance

• Look for signs of anemia: conjunctiva or skin pallor, new heart murmur

Lab Studies to Evaluate PUD• CBC - evaluate acute/chronic blood loss

• H. Pylori

- Serologic antibody test for HP – does not determine if active HP infection

- Fecal antigen test tests for active HP

- Urea breath test tests for active HP

Principles in Selecting H. pylori Test Based on the following:

• Probability of previously eradicated infection

• Probability of current active infection

• Need to document active infection

• Need for rapid result

• Patient preferences

• Cost (both of test and possible unnecessary treatment)

H. Pylori Serology Antibody Test

• Office based serology tests faster but less accurate than lab based ELISA tests

• Sensitivity and specificity of approx 90%

• Not useful for evaluating eradication - antibody levels can persist for a long time, need serial titers to evaluate

When is a Serology Test Useful?

Not useful in

• Populations with low disease prevalence

• Elderly populations to detect active disease

Useful in

• Patients who never received H. pylori treatment

• Symptomatic patients not using NSAIDs- if negative serology –unlikely PUD

H. Pylori Stool Antigen (HpSa) Test

• Useful in initial diagnosis + confirmation of eradication

• Sensitivity of 91% and a specificity of 92%*

• Test requires collection of stool sample- size of an acorn

• Performed in lab or newer POCT available

• Requires little preparation, however patients may not be compliant with collecting sample

*Gisbert JP, Pajares JM. Stool antigen test for the diagnosis of Helicobacter

pylori infection: a systematic review. Helicobacter 2004;9(4):347-68

Urea Breath Test• Useful for initial diagnosis + confirmation of eradication

• Sensitivity and specificity over 90%*

• Urease activity is present in the stomach in those infected with H pylori

• Ingest urea labeled with radioactive carbon

• Hydrolysis of urea → labeled carbon dioxide (CO2)

• Rapidly absorbed into bloodstream and within a few minutes, appears in breath

*Gatta L, Vakil N, Ricci C, et al. A rapid, low-dose, 13C-urea tablet for the detection of Helicobacter

pylori infection before and after treatment. Aliment Pharmacol Ther 2003;17(6):793-8

Breath Test Compared to HpSa• Requires more patient preparation

• More expensive

• Number of drugs can adversely affect accuracy

• Antibiotics and bismuth → stop for 4 weeks

• Proton pump inhibitors → stop for 7 days

• Patients need to fast for at least 6 hours.

• Breath test cannot be used in pregnant women

Imaging Studies• Chest x-ray if perforation is suspected to detect free

abdominal air

• Upper gastrointestinal series

– Performed by experienced radiologist is close to diagnostic accuracy of endoscopy

– Not as sensitive as endoscopy in diagnosis of small ulcers (<0.5 cm)

– Unable to obtain biopsy to rule out malignancy

Endoscopy Endoscopy indicated in following high risk

patients:

• >50 years old with new-onset dyspepsia• Dyspepsia with dysphasia and/or weight loss• Evidence of GI bleeding• Failed appropriate trial of empiric therapy• Using NSAIDs or other high risk meds• Signs of UGI tract obstruction (early satiety,

vomiting)• Ethnic background assoc. with increased risk UGI

malignancies

Excerpts from Guidelines prepared by The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy

Rapid Urease Test and Histopathology

Gastric mucosal biopsy obtained during endoscopy:

– Rapid urease tests (CLOtest, Hpfast, Pyloritek) bacterial urease converts urea substrate in kit to ammonia → changes pH producing color change.

– Histopathology often considered gold standard for diagnosis

Mr. Jones Prior Ulcer History On further questioning Mr. Jones states he had

similar abdominal pain three years ago and was told by his physician at that time that it was most likely due to an ulcer. He took “the purple pill” for a month and his symptoms resolved. He had no definitive diagnostic tests done at that time.

What would you do at this time?

Answer• H. pylori serology - many patients with history of

“ulcer” have not undergone eradication therapy

• Test for H. pylori antibody and treat if (+)

• Endoscopy if serology negative or if fails to improve with treatment

Moving on to Treatment Options……….

Over The Counter Remedies• Aluminum and magnesium hydroxide salt (Maalox®,

Mylanta®) Neutralizes gastric acidity.

• Aluminum side effect = constipation

• Magnesium side effect = diarrhea

• Magnesium and aluminum mixtures used to avoid side effects

Over the Counter Remedies cont’d

• Calcium Carbonate (Tums®, Rolaids®) – calcium salt neutralizes acid

• Bismuth subsalicylate (Peptobismol®) – binds to ulcer base forming a protective coat, has anti-inflammatory and bacteriocidal properties

H2-Blockers• Selectively block H2-receptors on parietal cells

reducing acid secretion

• Used primarily in ulcer disease not associated with H pylori

• Treatment duration is 6-8 wk.

Side Effects of Cimetidine/Tagamet®

• Elderly patients – confusion

• Young males - impotence +/- gynecomastia

• May alter levels of other drug - warfarin, TCA’s, triamterene, phenytoin, propranolol, metronidazole, antiarrythmics

• May alter renal function requiring lower doses

Proton Pump Inhibitors• Decreases gastric acid secretion by inhibiting the

parietal cell H+/K+ ATP pump

• Relieve pain and heal peptic ulcers more rapidly than H2 blockers

• Drugs in this class are equally effective

• Four weeks to treat active PUD

• Eight weeks to treat erosive esophagitis

Other Pharmacotherapy Agents• Sucralfate (Carafate®) Binds proteins in exudates

and forms a viscous adhesive that protects GI lining

• Misoprostol (Cytotec®) Prostaglandin analog-protects lining of GI tract by replacing depleted prostaglandin E1. Prevents peptic ulcers in patients taking NSAIDs

H. Pylori Triple Therapy Treatment• Triple therapy for 14 days is treatment of choice

• Two forms of triple therapy: PPI–based and bismuth-based

• PPI based = PPI + 2 antibiotics for 2 wk, cont PPI for additional 2 weeks.

• Bismuth-based = bismuth subsalicylate and 2 antibiotics, for 2 weeks with addition of H2- blocker to optimize ulcer healing.

H Pylori Treatment

Side Effect Rating Cure Rate

Three Drug Regimens

Clarithromycin + Metronidazole + PPI medium 80-90%

Amoxicillin + Clarithromycin + PPI medium-low 80-90%

Amoxicillin + Metronidazole + PPI medium 80-90%

Combination Products

Helidac + H2 blocker medium-high 80-85%

Prevpak low-medium 81-92%

http://www.drugdigest.org/DD/Comparison/NewComparison/0,10621,550540-21,00.html

H. Pylori Therapy cont’d• Successful eradication of H. pylori reduces PUD

recurrence rates from 90% to less than 10% per year.

• Patients no longer require ongoing chronic acid suppression.

• If symptoms return after treatment of PUD, then testing for recurrence should be pursued

PUD Complications• Hemorrhagic shock/peritonitis from a perforated

ulcer

• Symptomatic relief with PPI may mask symptoms of gastric malignancy

• Gastritis may present as bleeding, more likely in elderly

• Symptoms of anemia (fatigue, dyspnea)

Initial Treatment Plan in the Absence of High Risk Symptoms Based on current evidence, no single strategy has been

demonstrated to be more medically effective than any other.

• Empiric therapy with acid suppression

• Empiric H pylori testing and treating strategy

• Early endoscopy

Excerpts from Guidelines prepared by The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy

Final Recommendations• Alarm symptoms = endoscopy.

• No alarm symptoms = medical management favored approach

• Studies still in progress to evaluate if medical management versus vs endoscopy is both medically and cost effective in long-term

• Lack of response or the recurrence of symptoms warrants endoscopy

Medical Legal Pitfalls• Failure to consider non-GI cause of epigastric pain

(AMI/AAA)

• Failure to consider GI bleed in absence of abdominal pain (especially in elderly)

• Lack of follow-up care resulting in failure to diagnose gastric cancer

• Failure to recommend endoscopy early in high risk patients

• Failure to obtain a history regarding NSAID use

Alternate Scenarios of Mr. Jones Case

Mr Jones is a 63 yo male presenting with previously noted epigastric symptoms and PMH. On physical exam he is noted to have heme (+) stool.

What evaluation would you do next?

Alternate Scenarios to Mr. Jones Case Mr Jones is a 63 yo male presenting with previously

noted epigastric symptoms and PMH. On review of his prior ulcer history he was tested and had a positive H. pylori serology test. He was treated with triple therapy (PPI and 2 antibiotics) and symptoms resolved.

What would you do next? Would you recheck H. pylori serology? Repeat triple therapy?

Summary• H. pylori is the most common cause of PUD and is

a risk factor for gastric cancer• H Pylori eradication reduces risk of disease

recurrence• Test-and-Treat strategy is recommended for

patients with undifferentiated dyspepsia• Intial evaluation with endoscopy is recommended

for those with alarm symptoms or those failing treatment

• Optimum treatment regimens are 14d multidrug with antibiotics and acid suppressants

References• http://www.emedicine.com/med/topic1776.htm

• http://www.mcg.edu/som/pathology/GraduateEducation/Evidence%20Base%20Path/hpsa1.ppt

• http://www.acg.gi.org/physicians/guidelines/ManagementofHpylori.pdf

• http://www.cdc.gov/ncidod/dbmd/diseaseinfo/hpylori_t.htm

• http://courses.ahc.umn.edu/pharmacy/5880/LectureSlides/Peptic%20Ulcer%20Disease%20(PUD)_files/frame.htm

• http://www.cdc.gov/ulcer/history.htm

• http://www.drugdigest.org/DD/Comparison/NewComparison/0,10621,550540-21,00.html

References cont’d• Fendrick M, Forsch R etal. Peptic Ulcer Disease Guidleines for Clinical Care.

University of Michigan Health System May 2005

• American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.

• Krogfelt K, Lehours P, Mégraud F. Diagnosis of Helicobacter pylori Infection. Helicobacter 2005 10:s1 5

• Meurer L, Bower D. Management of Helicobacter pylori Infection. American Family Physician Vol 65, No. 7, 2002 pp 1327-1336

• Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy; The role of endoscopy in dyspepsia. Gastrointestinal Endoscopy Vol 54, No. 6, 2001 pp 815-817

• Vaira D, Gatta L, Ricci C, et al. Peptic ulcer and Helicobacter pylori: update on testing and treatment. Postgrad Med 2005;117(6):17-22, 46