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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
2
PPI’s
� Available since mid 1980’s� Widely used: 113 million prescriptions/year
¡ $14 Billion in sales in USA
3
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
4
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
5
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
6
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
7
Documentation of GERD on Endoscopy
Erosive esophagitis
Peptic stricture
Barrett’s
Barrett’s
8
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
9
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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10
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
11
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
13
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
16
Incidence of esophageal adenocarcinoma
0
0.5
1
1.5
2
2.5
3
3.5
1975 1980 1985 1990 1995
Rat
e pe
r 100
,000
pat
ient
-yea
rs White males
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
18
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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
21
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
23
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
24
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)
25
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
26
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
27
Medical Therapy
� Regardless of etiology, treatment of peptic ulcers involves inhibition of gastric acid secretion
H2RA PPI
28
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
29
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
30
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
31
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)
32
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
35
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
36
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
37
Significance of H. pylori infection
- Helicobacter foundation
38
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
39
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*
43
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
44
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
45
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
46
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
47
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
48
WHO NEEDS TO STAY ON A PPI
� Barrett’s esophagus� Chronic NSAIDS ulcers with bleeding risk� Severe esophagitis� Documented history of bleeding GI ulcers
49
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
55
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