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H O M A Y O N I R A N I N E Z H A DS E P T E M B E R 2 0 2 0

The Role of Proton Pump Inhibitors in the Management of

Upper GI Disorders1

GOALS

� Introduction� GERD� Barrett esophagus� Eosinophilic esophagitis� Dyspepsia � H.pylori� Acute GI bleeding� Safety concerns

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PPI’s

� Available since mid 1980’s� Widely used: 113 million prescriptions/year

¡ $14 Billion in sales in USA

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GERD Definitions

� GERD: Reflux of stomach contents into the esophagus causing troublesome symptoms and complications

� Severe GERD: having > 2 episodes per week� Reflux (erosive) esophagitis: endoscopic evidence of

inflammation

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GERD: Clinical Spectrum

PhysiologicReflux

SymptomaticGERD Esophagitis

ComplicatedReflux

Typical Atypical UlcerationStrictureBleedingBarrett’s

Adenocarcinoma

HeartburnRegurgitation

Worse: after mealslying down

bending forwardsDysphagia

Chest painAsthma

HoarsenessCough

LaryngitisBronchitis

Tooth decay

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GERD: Pathophysiology

� Decreased resistance to reflux- inappropriate LES relaxation- diaphragmatic or hiatus hernia- weak or hypotensive LES

� Decreased esophageal clearance- ineffective esophageal peristalsis

� Enhanced reflux/caustic potential- gastric & downstream factors- medications

Normal physiology

Hiatus hernia

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Investigation

� Empiric treatment as test (PPI test)¡ Typical GERD - sensitivity 80%, specificity 57%¡ Atypical chest pain - sensitivity 78%, specificity 54%

� Endoscopy¡ Evaluates for mucosal inflammation, complications¡ Yield for reflux evidence in treatment naïve patients is only 50-

60%� Ambulatory pH testing/impedance pH testing

¡ Quantifies acid exposure, correlates symptoms to reflux events¡ Impedance - detects nonacid reflux

� Manometry¡ Excludes achalasia, scleroderma; assesses peristalsis

preoperatively¡ Excludes concurrent motility disorders

� Barium swallow - anatomic considerations, hiatal hernia size

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Documentation of GERD on Endoscopy

Erosive esophagitis

Peptic stricture

Barrett’s

Barrett’s

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GERD: Alarm Symptoms

� Dysphagia, odynophagia� Weight loss� Age > 45 or symptoms >5 years� GI bleeding� Immunocompromised host� Family history of GI cancer� Atypical manifestations

Alarm symptoms are indications for endoscopy

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Principles of GERD Therapy

Reduce reflux events Improve LES tone

Enhance gastric emptying

Decrease postprandial tendency

Improve esophageal clearance Enhance esophageal motility

Promote gravitational benefits

Improve salivation

Eliminate hernia

Decrease caustic quality of refluxate Neutralize pH

Inhibit pepsin activity

surgery

baclofen & analogues

surgery

Acid

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Lifestyle changes in treatment of GERD

Consumption of small meals

No food or drink within 3 to 6 hours of bedtime

Head-of -bed elevation of 4 to 6 inches

Reduced consumption of coffee, alcohol, chocolate, fat

Reduction or elimination of cigarettes

Weight loss by obese patients

Avoidance of tight-fitting garments

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Lifestyle changes in treatment of GERD12

GERD: Principles of Pharmacological Treatment

� Acid and pepsin damage esophageal mucosa� Acid suppression:

¡ controls symptoms¡ heals esophagitis¡ does not correct pathophysiology

� Proton pump inhibitors¡ Most potent agents for acid suppression¡ Heal complicated esophagitis

� H2 receptor antagonists¡ Minimum of BID dosing, higher doses may be needed¡ Works best between meals, bedtime dose for nocturnal symptoms¡ Tachyphylaxis is a problem

� Recurrence is common when treatment withdrawn

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GERD: Surgery

� Indications:� Inadequate response of documented

reflux to medical therapy� Need for lifelong medical therapy� Reflux induced aspiration pneumonia� Inadequate response of extra-

esophageal manifestations to medical therapy

� Success rate ~85%� Complications ~10%

Nissen fundoplication

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Barrett’s Esophagus 15

GERD: Development of Barrett’s Esophagus and Cancer

Healthyesophagus

Squamous epithelialinjury

Dysplasia

Adenocarcinoma

Gastroesophageal refluxRole established

Gastroesophageal refluxRole not established

Specialized intestinalmetaplasiaBarrett’s Esophagus

Reversible

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Incidence of esophageal adenocarcinoma

0

0.5

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1.5

2

2.5

3

3.5

1975 1980 1985 1990 1995

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Black males

-Devasa, Cancer 1998-Sharma, Gastro 2004-Wang, AJG 2008

Risk factors (Barrett’s):Age >50, male, whiteLongstanding refluxObeseSmoker, Alcohol use

Risk of adenoca:White: 3.6/100,000Barrett’s: 0.4-0.5%/yrDysplasia (high grade): 30%/5yr

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Barrett’s esophagus

ScreeningIn patients with multiple risk factors for esophageal adenocarcinoma:

Age 50 years or older, male gender, white raceChronic GERD, hiatal herniaElevated BMI, intra-abdominal distribution of body fat

General population with GERD do not need to be screened for BE

SurveillanceNo dysplasia: 3-5 yearsLow grade dysplasia: 6-12 monthsHigh grade dysplasia: 3 months (if not eradicated)

Wang & Sampliner AJG 2008Spechler, Sharma, et al, Gastroenterology 2011

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Use of PPI’s in Barrett’s

� PPIs may decrease progression to neoplastic Barrett’s esophagus

� ACG guidelines recommends that patients with Barrett’s esophagus receive once-daily PPI but this “deserve consideration” when without reflux symptoms

� AGA guidelines recommend that risks and potential benefits of long-term PPI be discussed carefully with Barrett’s patients given the 0.25% annual risk of non-dysplastic Barrett’s esophagus to adenocarcinoma, and absolute benefit will be small.

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Eosinophilic Esophagitis

� Eosinophilic infiltration of the esophageal mucosa, resulting in mucosal edema, luminal narrowing

� Seen predominantly in young males� Symptoms: dysphagia, food impaction, chest

pain, heartburn, failure to thrive� Endoscopy: ringed esophagus, linear furrows,

whitish exudates, erythema, edema� Barium: narrowed caliber of esophagus,

strictures� Biopsy: >15 eos/HPF

Gothenberg, Gastro 2009

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Medical treatment for Active EoE22

NSAIDs

� PUD develops in 25% of chronic NSAID users

� Mechanism of injury¡ Direct contact injury¡ Prostaglandin inhibition

through the cyclooxygenase pathway

Conn HO, J Intern Med 1994Shorr RI, Arch Intern Med 1993

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Risk Factors for NSAID ulcers

ESTABLISHED RISK FACTORSAdvanced age History of an ulcer Concomitant use of glucocorticoidHigh dose NSAIDS Multiple NSAIDSConcomitant use of anticoagulation Serious or multisystem diseasesConcomitant infection with H Pylori

POSSIBLE RISK FACTORSTobacco smoking Alcohol consumption

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Zagari, R. M. et al. BMJ 2008;337:a1400

Approach to dyspepsiaCauses

Upper GI tractGERDPeptic ulcerCancerFunctional dyspepsia

Other originsGallstones, cholecystitisPancreatitis, cancerHepatobiliary disordersCoronary artery diseaseDrugs (NSAIDs, ASA,

steroids, antibiotics, calcium blockers, bisphosphonate)

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Alarm features in dyspepsia

Alarm symptoms or signs

High risk factors for cancer

Gastrointestinal bleeding Family historyIron deficiency anemia Previous gastric ulcerProgressive unintentional weight loss; early satiety

Previous gastric surgery

Progressive dysphagia Known Barrett’s esophagusOdynophagia Known intestinal

metaplasia or atrophic gastritis

Persistent vomitingEpigastric mass

Zagari, BMJ 2008

Other indications for endoscopyFailure to respond to an empiric PPI trialNew onset dyspepsia in patients older than 45-55 years

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Alarm Situations

gastric ulcer duodenal ulcer cancer

14-22% with uninvestigated dyspepsia

Bytzer, Lancet 1994

In absence of alarm sx0.1% gastric cancer0.3% Barrett’s

Breslin Gut 20001 per million

Gillen AJG 1999

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Medical Therapy

� Regardless of etiology, treatment of peptic ulcers involves inhibition of gastric acid secretion

H2RA PPI

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Duration of Therapy

� Duodenal ulcers heal within 8 weeks of continuous acid suppression

� Gastric ulcers heal more slowly, and can take 12 weeks or more for complete healing

� Successful H pylori eradication accelerates ulcer healing

� Non-healing gastric ulcers must be biopsied to exclude cancer. Therefore, follow-up endoscopy to document healing is indicated at 8-12 weeks

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NSAID ulcers: Principles of management

1. Discontinue NSAID, reduce dose, or change formulation2. Look for H pylori, eradicate3. Identify patients at high risk

a. PPIs: Best option in the following-Patients with cardiovascular disease-Low dose aspirin for cardiovascular prophylaxis-History of peptic ulcer disease

b. Misoprostol: use full doses-Beneficial if small bowel protection is also needed-When NSAIDs are used in setting of anticoagulation

c. COX-2-Coagulation disorders, anticoagulation, high dose NSAIDs

4. High risk or refractory patients:a. May need to consider PPI and COX-2

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Zollinger-Ellison Syndrome

� Consists of chronic peptic ulcer disease, secretory diarrhea, acid induced esophageal injury

� Incidence <1% in patients with peptic ulcers� Can occur as part of MEN I� Fasting serum gastrin >1000 pg/mL when not taking

a PPI is diagnostic, if gastric pH is <3.0� Secretin stimulation results in paradoxical rise in

serum gastrin of >200 pg/mL in patients with gastrinoma

� Imaging studies help identify curable gastrinomas

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Refractory Ulcers

� Peptic ulcers are considered refractory if not healed after 8-12 weeks of continuous acid suppression

� Prime suspects:¡ H pylori infection: poor compliance with eradication

resistant strain of H pylori, undiagnosed H pylori¡ NSAID use¡ Cancer (nonhealing gastric ulcers)¡ Hypersecretory states (Zollinger Ellison syndrome)

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Stress Ulcers

� Gastric mucosal injury during extreme physiologic stress� Gastrointestinal bleeding is an important manifestation� Risk Factors:

¡ Mechanical ventilation¡ Coagulopathy¡ Renal failure¡ Head injury, CNS diseases¡ Burns¡ Sepsis

� Management: ¡ Supportive¡ Prophylaxis: H2RA, sucralfate, PPI

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The stomach34

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Helicobacter pylori

� First discoved by Warren and Marshall in 1983� Gram-negative bacterium found on the luminal surface

of stomach� Usually contracted in the first few years of life� Prevalence increases with older age and with lower

socioeconomic status during childhood and thus varies markedly around the world

� The higher prevalence in older age groups is thought to reflect a cohort effect related to poorer living conditions of children in previous decades

� 50% of the world’s human population has H. pylori infection

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Helicobacter pylori

- urease activity- 6 unipolar spiral shaped flagella- Urea (gastric juice) à NH3 and CO2

- Transmission è fecal-oral or oral-oral - Natural habitat è gastric mucosa of antrum- H.pylori à loss of D cells (no somatostatin) à

G cells release gastrin uninhibited- If found in duodenum à this is associated

with metaplastic gastric epithelium

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Significance of H. pylori infection

- Helicobacter foundation

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Benefits of treating H. pylori

Disease or condition Benefit Strength of evidencePeptic ulcer Healing

Prevents recurrencePrevents rebleeding

Meta-analysisCost effectiveness analysis

MALT lymphoma Durable remission Non-randomized observation and prospective studies

Uninvestigated dyspepsia

Management of dyspepsia symptoms

Meta-analysisCost effectiveness analysis

Risk of gastric cancerFirst degree relativeAfter cancer resection

Prevent development or recurrence of non-cardia gastric cancer

Randomized controlled trialsSystematic reviewsInternational guidelines

Fuccio et al, BMJ 2008

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H pylori EradicationTriple therapy

7, 10 or 14 daysPPI

+Clarithromycin 500 mg bid

+Metronidazole 500 mg bid OR Amoxicillin 1000 mg bid

- Fuccio, BMJ 2008

Medical Therapy for Acute GI Bleeds

� Principles

¡ Stability of a blood clot is poor in an acidic environment

÷ Goal: raise intragastric pH > 6 for majority of 24-hour period÷ Promote clot stability÷ Facilitate hemostasis

¡ Since major GI bleeding is due to arterial erosion, reduction of arterial blood flow by agents such as octreotide could achieve hemostasis and prevent further bleeding

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Omeprazole and bleeding Peptic ulcers

� Double blind, placebo-controlled trial of omeprazole 40 mg PO bid vs. placebo

� 220 patients with peptic ulcers and: ¡ Active bleeding, non-bleeding visible vessels or clots

� Outcomes measure of further bleeding, surgery or death

� No endoscopic therapy performed

Khuroo. N Engl J Med 1997;336:1054

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Omeprazole and bleeding Peptic ulcers

Khuroo. N Engl J Med 1997;336:1054

NNT to prevent one death was 25 NNT to prevent one surgery was 7

Trial criticized because it included young patients with little comorbidities and majority of patients had adherent clots at time of endoscopy*

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Omeprazole – Rebleeding rate

Placebo Omeprazole PO BID

Spurting 90% 75%

Oozing 20% 15%

Visible vessel 50% 10%

Adherent clot 20% 0%

Khuroo. N Engl J Med 1997;336:1054

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GI Bleeding study

� 240 patients � High risk ulcers with active bleeding or non-bleeding

visible vessels� Injection + heater probe thermocoagulation

(adherent clots were removed)� Randomization of patients:

¡ Omeprazole 80mg à then 8 mg/hr IV x 72 hours ¡ Placebo

� Monitor for hemostasis

Lau. N Engl J Med 2000;343:310

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Omeprazole and Endoscopy therapy

Lau. N Engl J Med 2000;343:310

Conclusion:

Rebleeding rates, length of hospital stay and blood transfusion requirements were significantly lower in the omeprazole group

However, there was a trend towards fewer operations and deaths in the omeprazolegroup, but these differences were not statistically significant

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Omeprazole and randomized Endoscopic Therapy

� Non Bleeding visible vessel of visible clot� Omeprazole 80mg à then 8 mg/hr IV� Endoscopic therapy vs. Sham therapy

Sung. Ann Intern Med 2003; 139:237-43

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Omeprazole Infusion and randomized Endoscopic therapy

ShamN=24

EndoscopyN = 24

Rebleeding in Hospital

07 0

Rebleeding in 30 days

09 01

Deaths 04 02

Sung. Ann Intern Med 2003; 139:237-43

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WHO NEEDS TO STAY ON A PPI

� Barrett’s esophagus� Chronic NSAIDS ulcers with bleeding risk� Severe esophagitis� Documented history of bleeding GI ulcers

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DE-ESCALATION OF PPI

� ALTERNATIVES¡ DGL licorice¡ Acupuncture¡ MATY’S ACID REFLUX RELIEF¡ Plant slippery elm - powder mix with water and slurry fiber

source¡ Carafate¡ Anxiety component¡ Breathing exercises

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DGL LICORICE51

MATY’S ACID REFLUX RELIEF52

MATY’S ACID REFLUX RELIEF53

SLIPPERY ELM BARK54

Proton Pump Inhibitors

Uses Adverse effectsGastroesophageal reflux disease Headache, diarrhea, abdominal painPeptic ulcer disease Impaired absorption of medications

(e.g. ketoconazole)Empiric PPI test May decrease activation of

clopidrogrelAcute nonvariceal GI bleeding May impact calcium homeostasis, and

lead to bone demineralizationGastroprotective (e.g. with NSAIDs) May impair absorption of vitamins,

ironEmpiric management of dyspepsia, heartburn, atypical chest pain

May increase GI infections, including C difficile colitis, infectious colitis, SIBO

Hypersecretory states (ZES) May increase community acquired pneumonia

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