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Venelin Kounev, MDDivision of Gastroenterology and Hepatology

Medical College of Wisconsin

Disclosure Statement- nothing to disclose

Peptic ulcer disease is a term used broadly to include ulcerations and erosions in the stomach and duodenumUlcer (> 5mm)

Mucosal defect with appreciable depth orHistologic evidence of involvement of the submucosa

Erosions(<5mm)Breaks in the surface epithelium that do not have perceptible depth.

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Ulcers are believed to be caused by stress and dietary factors. Treatment focuses on hospitalization, bed rest, and prescription of special bland foods.

Later gastric acid is blamed for ulcer disease Antacids Later, gastric acid is blamed for ulcer disease. Antacids and medications that block acid production become the standard of therapy. Despite this treatment, there is a high recurrence of ulcers.

www.CDC.gov

1982 Australian physicians Robin Warren and Barry Marshall first identify the link between Helicobacter pylori (H. pylori) and concluding that the bacterium, not stress or diet, causes ulcers

991994 A NIH Consensus Development Conference concludes that there is a strong association between H. pylori and ulcer disease, and recommends that ulcer patients with H. pylori infection be treated with antibiotics.

1996The FDA approves the first antibiotic for treatment of ulcer disease.

www.CDC.gov

H. Pyloriinfection

NSAID use

H. pyloriNSAIDsOthers

Cocaine, methamphetamineBi h h t

unknownOthers

Gastric UlcersBisphosphanatesSmoking, alcoholStressViral infectionGastrinomaCrohn’s disease LymphomaIschemia

Duodenal Ulcers

Other unknown

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Gastric pit Columnar epithelium

Foveolar cells(mucus neck cells)

-mucin-gastric surfactantbicarbonate

Parietal cells

ECL cells

Chief cells

D cells

G cells

-bicarbonate

-gastric acid-intrinsic factor

-pepsinogen-gastric lipase

-somatostatin( - acid)

-gastrin(+acid)

-histamine

Gastric fundusand

Gastric body

Antrum

Epithelial regeneration

Gastric acid pH 1-2

Regulation of acid

D

Mucosal barrier

Apical G cells/Gastrin

D cell/Somatos

tatinacid acid

Hyperemia

Mucoid cap

Apical membrane resistance

Mucin

Gastric surfactant

Cell migration

Autonomic NS/Ach

Mucus layer•Flagella and adhesins

-Makes a defect in the mucus layer to

Gastric acid

ytravel close to the epithelial surface-Adheres to the surface epithelium

•pH sensitive receptors-Assisting migration to higher pH environment

•Urease-NH3 + CO2

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Bicarbonate layer

Gastricacid

PepsinSurface

epithelial cells

Mucuslayer

Neutral

H. pylori

• Increase acid production (inflammation)• G-cell stimulation• D cell inhibition• Stimulation of the

parasympathetic nervous environment

Mucus

XX

Inflammation

parasympathetic nervous system

• Disruption of the mucosal defense • Consumption of gastric

surfactant • Altered integrity of the

mucus layer• Destruction of epithelial

cells

NH3Cag AVac AHcpA

Patterns of Gastritis

Gastric pathology

Acid Output

Duodenal pathology

Peptic ulcer risk

Antrumpredominant

~20%

• Chronic inflammation

• Polymorphactivity Increased

• Gastric metaplasia

• H. pyloriinfection

Duodenal ulceractivity Increased infection

• Active chronicinflammation

ulcer

Pangastritis~80%

• Chronic inflammation

• Inhibition of acid

• Atrophy• Intestinal

metaplasia

Reduced Normal Gastric ulcerGastric CA

Dixon 1994

H. Pylori test Sensitivity Specificity

PPI/bismuth

Urea breath test(C13, C14)

88-95 95-100 +

Fecal Antigen(polyclonal)

86-94 70-93 +

Fecal Antigen 94-96 97 +

Non-invasi Fecal Antigen

(monoclonal)94-96 97 +

Serology (Ig G) 76-97 76-86 -Biopsy histology 70-87 90 +/-Biopsy urease test 67-98 89-95 +Biopsy culture 45-90 95 +

• Urea breath test -most reliable to document eradication.• Fecal antigen test-most cost effective.• Stop PPI, bismuth 2 weeks prior testing.

Br J Gen Pract. 2007 May 1; 57(538): 401Malfertheiner et al,Gut 2012;61:646-664Chei at al, Am J Gastro, 2007; 1808

veInvasive

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Patients exhibiting symptoms of dyspepsiaActive PUD or past history of PUDFamily history of gastric cancerMALT lymphomaMALT lymphomaPatients who need to initiate long term therapy with NSAIDsDon’t test if you don’t intend to treat

Treatment Regimen

Duration Eradication Rate

First line therapy

PPI, clarithromycin 500 mg, amoxicillin

1000 mg

10-14 days 70-85%

PPI, clarithromycin 500 mg, metronidazole

500 mg

10-14 days 70-85%

500 mg

First or second line therapy

PPI, Bismuth 525 mg, metronidazole 500 mg,

tetracycline 500 mg

10-14 days 75-90%

Alternative second or third line therapy

PPI, levofloxacin 250 mg, amoxicillin 1000mg

10 days 70-80%

PPI, amoxicillin 1000mgfollowed by

PPI, clarithromycin 500 mg, tinidazole 500 mg

BID

5 days

5 days

>90%

Am J Gastro 2007;102:1808Gut 2012;61:646

Guidelinespatients who had completed therapyACG-Patients with H. pylori associated PUD, MALT lymphoma, persistent dyspepsia, following resection of early gastric cancer.

Testing should be done at least 4 weeks after l i f hcompletion of therapy

Test of choiceNon-invasive testing

Urea breath testMonoclonal stool antigen

Biopsy based tests in MALT lymphoma or during follow up endoscopy for surveillance of gastric ulcers

No role for serology (60% seronegative in 18 months)

Am J Gastro 2007;102:1808Gut 2012;61:646

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Arachidonic acid

COX-1 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

Mechanism of Mechanism of NSAIDNSAID--associated associated mucosal mucosal damagedamage

•Direct cytotoxicity (topical route of injury)•COX -1 Inhibition (systemic route)

• Decreased

Bicarbonate layer

Gastricacid

NSAIDsPepsin

Surfaceepithelial cells

Mucuslayer

Neutral • Decreased prostaglandins

• Decreased bicarbonate• Decreased mucus • Decreased blood supply

•Cox -2 inhibition (systemic route)

• Impaired angiogenesis• Impaired regeneration

environment

Mucosalblood supply

Prostaglandin production Bicarbonate

production

Mucus production

NSAIDs

H+

H+

H+

XX XX

X

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6.4

7

9

13.5

Anticoagulant use

High dose NSAIDs

Multiple NSAIDs

Past Complicated Ulcer

Odds RatioHunt RH at al. Can J Gastro, 2010

2.2

2.9

3.1

3.6

5.6

6.1

0 2 4 6 8 10 12 14 16

Corticosteroid use

History of dyspepsia

Age>60

SSRI use

Age>70

Past uncomplicated ulcer

5.7

9.3

14

Ketoprofen

Piroxicam

Ketolorac

Relative Risk

2.7

4

4

5.2

5.3

0 2 4 6 8 10 12 14 16

Ibuprofen

Diclofenac (Voltaren)

Meloxicam (Mobic)

Naproxen

Indomethacin (Indocin)

p

Steroids

Low-dose ASA

Anticoagulants

SSRI

Aldosterone antagonist

n/a 5.55.04.54.03.53.0

RERI (95% CI)

Masclee, Gastro 10/2014

g

Antiplatelet agents

Nitrates

Calcium CB

Gastroprotective agents

nsNSAIDs Coxibs Low-dose aspirin

2.52.01.51.00.50.0

Avoid combination of:-ASA with steroids, coxibs, anticoagulant, antiplatelet-nsNSAIDs with steroids, aldosterone blockers, anticoagulant, antiplatelet, SSRI-coxibs with ASA, SSRI

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HIGH RISK (more than 2 risk factors)

History of complicated ulcer

COX-2 inhibitor +PPI or misoprostol

MODERATE RISK (1-2 risk factors)

Age >65High dose NSAIDs

Previous uncomplicated ulcer

Concurrent use of aspirin, clopidogrel,

steroids or anticoagulants

NSAID + PPI or misoprostol

LOW RISK No risk factors Lowest effective dose NSAID

Lanza et al., Am J of Gastro, 2009

Epigastric abdominal painGastric ulcer-shortly after eatingDuodenal ulcer-30 minutes to hours after eatingPUD related to NSAID use may be asymptomatic until the patient developed symptoms related to GIB until the patient developed symptoms related to GIB or iron deficiency anemia.

Nausea and vomitingPhysical exam is normal in patients with uncomplicated PUD

Epigastric tenderness is neither sensitive nor specific for ulcer

Age older than 50 years with new-onset dyspepsia without alarm symptomsAny age with alarm features

Family history of upper gastrointestinal cancerFamily history of upper gastrointestinal cancerGastrointestinal bleeding, acute or chronic, including unexplained iron deficiency Left supraclavicular lymphadenopathy (Virchow's node) Palpable abdominal mass Persistent vomiting Progressive dysphagia Unintended weight loss

ASGE Guidelines, GIE,2010;71;4:663

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Inhibition of acid secretion

Proton pump

Inhibition of proton pump

H+ Gastric gland

Parietalcell

Canalicularspace

Activation

Concentration

PPI(inactive) Blood

H+

Acid secretion Parietal cell

Gastric gland

Proton pump

Signal transductionto activate

proton pump

Histamine receptorHistamine (H2)-receptor antagonistHistamine

Inhibition of histamine receptor

SucralfateBinds electrostatically to positively charged proteins in damaged tissue, forming a protective barrierCan heal DU as efficacious as H2RBCautionCaution

Can bind several drugs when administered togetherIncreased aluminum levels in patients with chronic kidney disease

Misoprostolprostaglandin E1 analogenhances mucosal defense mechanisms but also inhibits gastric acid secretion

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Uncomplicated duodenal and gastric ulcersLong term PPI therapy not required after eradication of H. pylori or discontinuation of NSAIDs

Complicated duodenal ulcers or large gastric ulcers

Long term PPI required

Duodenal ulcers (medical therapy)No need for surveillance upper gastrointestinal endoscopy

Gastric ulcer (on therapy)Consider referring for surveillance endoscopy in 8 weeks if symptoms persist or biopsies were not obtained from the ulcer during the index endoscopy.

Little evidence that maintenance therapy with antisecretory agents is required if H. pylori had been eradicated or/and NSAIDs discontinued.However, antisecretory therapy is indicated for y pypatients with PUD who need to continue therapy with NSAID or have recurrence of idiopathic PUD.

Jaspersen D et al: Helicobacter pylori eradication reduces the rate of rebleeding in ulcer hemorrhage. Gastrointest Endosc 1995; 41:5-7Sung JJ et al: One-week antibiotics versus maintenance acid suppression therapy for Helicobacter pylori–associated peptic ulcer bleeding. Dig Dis Sci 1997; 42:2524-8

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Gastrointestinal Bleeding (GIB)Visceral perforationPenetration into adjacent abdominal organsObstructionObstruction

GI bleeding significant medical problemIncidence 36 to 160 cases per 100,000300,000 hospital admissions yearly (US)Among most common ICU admission5 – 20% mortality (depending on source)Up to 30,000 deaths per year in US$2.5 billion per year

Fallah et al. Acute gastrointestinal bleeding. Med Clin North Am 2008;84(5):1183–208

PUD 20-50%

Gastroduodenal erosions 8-15%

Esophagitis 5-15%

Esophageal varices 5-20%

AVM 5%

Mallory Weiss tear 5-15%

Tumor 4%

Dieulafoy lesion 1%

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8.4

10

16.6

Age <50

BUN/creatitine >30

Melena

Adjusted odds ratios

0.2

2.2

3.2

3.8

0 2 4 6 8 10 12 14 16 18

History of lower GIB

Male sex

Hematocrit <30

History of upper GIB

Witting et al ED predictors of upper gastrointestinal tract bleeding in patients without hematemesis AJEM(2006) 24, 280–285

Signs hematochezia,

Hematemesis 30%Melena 20%Both 50%Hematochezia 5%

hematemesis, 30

melena, 20

hematemesis + melena, 50

5

Melena50-100cc

HematocheziaHematochezia500-1000cc

Fecal Occult Blood Test (FOBT)From Upper GI: 10-20ccFrom Lower GI: 0.5cc

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Melenic stoolBlood turns black due to breakdown of Hgbby intestinal enzymes by intestinal enzymes and bacteria

Blood in GI tract >12 hours

Iron pills (ferrous sulfate)Bismuth (Pepto-Bismol)Black licoriceBlueberries

Assess severity of bleeding, volume status, and risk factorsTriage to ICU or wardgResuscitateEarly EndoscopyTriage again

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Hemodynamic instability - admit to ICUShockOrthostatic changesActive bleedingActive bleedingHct drop of > 6%>2 units of blood requirement

Elderly patients- consider ICU admission

Case examplePatient presents with large hematemesisAdmission Hct45%Plasma volume [solid bars]Red blood cell (RBC) volumes [stippled bars]

Patients with multiple comorbiditiesGoal hemoglobin > 10 g/dl

Young and healthy patientsYoung and healthy patientsGoal hemoglobin of > 7 g/dl

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Two groupsLiberal strategy-transfusion for goal Hgb >9Restrictive strategy-transfusion for goal Hgb >7

As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding.

Villanueva C et al. N Engl J Med 2013;368:11-21

Rockall Score Rockall, Gut 1996

Blatchford score Blatchford, Lancet 2006

Italian PNED score Marmo, AJG 2010

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Ia Spurting arterial vessel Ib Oozing hemorrhage IIa Non-bleeding visible vessel

12% 8 22%6 14%

IIb Adherent clot IIc Pigmented flat spot III clean base

12% 8-22%

8-10% 10-16% 32- 55%

6-14%

Endoscopicstigmata

Furtherbleeding

Surgery for bleeding

Mortality

Active 55% 35% 11%

Endoscopic stigmata Recurrent bleeding

Active arterial bleeding Approaches 100%

Activebleeding

55% 35% 11%

NBVV 43% 34% 11%

Adherent clot

22% 10% 7%

Pigmented flat spot

10% 6% 3%

Clean base ulcer

5% 0.5% 2%

Laine, AJG 2012

Non-bleeding visible vessel(NBVV)

Up to 50%

Adherent clot 8-35%

Ulcer oozing 10-27%

Pigmented flat spot <8%

Clean base ulcer <3%

GIE,75:6 2012

Active bleeding/NBVV

E d i

Adherent clot

May consider

Flat spotClean base

No Endoscopic therapy

IV PPI for 72 hrs

May consider endoscopic

therapy

IV PPI for 72 hrs

No endoscopic

therapy

Oral PPI

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Endotherapy

Medical Therapy

Most data favor endoscopic therapy

Rebleeding 8.2% 24.7% *

Mortality 9.8% 7%

Some data show lower rebleeding rate with high dose PPI

Kahi, Gastro 2005

Endoscopic therapy

Mechanical

Band Clips

Submucosalinjection

TamponadeVasospasmSclerosing

CoagulationThermal

Heather probe

Bipolarprobe

Coagrasper APC

$37-65$95-145 $230-335$530

$200 $155-250

GIE, 2009Combination therapy

Heater: A resistor electrode enveloped by a titanium capsule and covered by Teflon (reduce sticking ). The probe temperature rises to 250°C (482°F). (for coaptation coagulation)

ie heat energy

Bipolar: Alternating bands of electrodes (coated with gold to reduce adhesiveness) an electrical field that heats the mucosa and the vessel to max temperature of 100°C.

ie electric field energy

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Initial hemostasis

Definitive hemostasis

1.05 (0.84-1.07)

1.00(0.77-1.31)

RR95% CI

Forest plots comparison

RR95% CI

Favors clip +injection

Favors thermocoagulatuon/injection

Rebleeding

Need for surgery

Mortality

0.65 (0.21-2.02)

0.84(0.32-2.24)

0.96(0.34-2.76)

0.2 0.5 1.0 2.0 5.0

Snug, Gut, 2007

Endoscopy within 24 hours recommendedUGI bleeding Consensus Conference GroupUGI bleeding Consensus Conference Group

Ann Intern Med 2003

ACG guidelinesAJG 2012

Low risk patients safe dispositionHigh risk of patients

Decrease transfusions, emergent surgery, recurrent bleeding, hospital stay.

Decrease length of hospital stay

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Overall upper GIBNO benefit

Recurrent and continued bleedingBenefit: decrease rate of rebleeding and need for surgery

High risk group (tachycardia hypotension bloody emesis)High-risk group (tachycardia, hypotension, bloody emesis)Possible benefit: decreases mortality if EGD done within 12 hrs

IndicationsRecurrent/continued UGI bleedRisk for variceal bleedingRisk for aorto-enteric fistulaMultiple comorbidities

Laine, Am J Gastro 2012

Low-risk patientsNo improvement of recurrent bleeding, surgery or mortalityDecreased hospital stay and cost

High-risk patientsIncrease risk of oxygen desaturation and hemodynamic instability

Predictive Factor Rebreeding Rate

Post duodenal ulcerGastroduodenal artery

43.2-57.1

Lesser gastric curvature ulcerLeft gastric artery

22.9-35

Hemodynamic instability 19.2-47.1

Active Bleeding 12.1-48.9

Ulcer >2 cm 14.8-36.3

Lau, Gastro 2010

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Dopler ultrasonography probe Over-the-scope clipEndoscopic suturing devices

Tc 99m sulfur colloid scanBleeding rate of 0.05 to 0.1 ml/minCan obtain images for 10 min only due to rapid clearing

Labeled RBC scanIdentify slow bleeding rate 0.1-0.4 ml/minCan obtain delayed images in up to 24 hrsCan obtain delayed images in up to 24 hrsNot accurate localizationDoes not provide therapeutic options

Selective mesenteric angiographyBleeding rate 0.5-1 ml/minTherapeutic options-vasopressin or embolizationIndication- failed endoscopic therapy, unstable patient for surgery

CT angiography

Pepsin irreversibly inactivated at pH >6Clot lysis by pepsin at pH < 5Platelet aggregation improved pH >6Prevent stress ulcer bleeding pH >4g pThe evidence

Decreases rebleeding ratesDecreases blood transfusion requirementsDecreases length of hospitalizationBefore endoscopy: decrease active bleeding and need for endoscopic therapyNO change in mortality

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80 mg + 6 mg/hr

8

6

4

2

0

8

6

4

2

00 8 16 24 32 40 48

pH

Time

80 mg + 8 mg/hr

0

Van Rensburg, AJG 2003

5.9 % vs 10.3% for the PPI treated groupSignificant reduction in gfurther

bleeding (RR = 0.40)surgery (RR = 0.43) mortality (RR = 0.41)

Laine, Clin Gastroenterol Hepatol 2009 ; 7 Snug, Ann Intern Med. 2009;150(7

H. pylori infection and NSAIDs are responsible for more than 80% of peptic ulcers. Patients with peptic ulcers are commonly asymptomatic at diagnosis.y p gThe management of peptic ulcer disease includes acid suppression, testing for H. pylori infection, and assessing the use of NSAIDs

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