GERD, Current trends, Diagnosis, Treatment, Guidelines, Proton pump inhibitors, pantoprazole

2. Prevalence of GERD
18-46%
7.4%
22%21%
16%18%
Russia South
America
North
Europe
South
Europe
South
Asia
Southeast
Asia
Gut. 2018 Mar;67(3):430-440.

3. Gastroesophageal Reflux
• Gastroesophageal reflux
– Normal physiologic phenomenon experienced intermittently by most people,
particularly after a meal
• Gastroesophageal reflux disease (GERD)
– Amount of gastric juice that refluxes into the esophagus exceeds the normal
limit, causing symptoms with or without associated esophageal mucosal
injury

4. GERD-Definition
Am J Gastroenterol 2013;108:308-328
“Symptoms or complications resulting from the reflux of gastric
contents into the esophagus or beyond, into the oral cavity (including
larynx) or lung”

5. Pathophysiology of GERD
Abnormal
esophageal
sphincter
Increase
abdominal
pressure

6. Pathophysiology of GERD
Abnormal lower esophageal
sphincter
Functional
(frequent transient LES relaxation)
Mechanical
(hypotensive LES)
Foods
(Coffee, alcohol)
Medications
(Calcium channel blockers)
Increase abdominal pressure
Obesity
Pregnancy
Increased gastric volume

7. Clinical Manifestations
• Heartburn
• Regurgitation
• Hypersalivation
• Nausea/Vomiting
• Bloating/Belching
• Cough/Wheezing
• Dysphagia/Odynophagia
• Weight loss
• Digestive hemorrhage
Typical Atypical Alarming
J Clin Gastroenterol. 2017 Jul;51(6):467-478.

8. Phenotypic Presentations of GERD
GI Motility online (2006) doi:10.1038/gimo42

9. GERD Phenotype-Association
1. Nonerosive Reflux Disease vs. Erosive Esophagitis
 NERD may progress to EE in approximately 10% of GERD patients
 EE is a manifestation of more severe reflux disease
2. Erosive Esophagitis vs. Barrett’s esophagus
 EE is a major risk factor for BE
 EE patients have 5-fold increased risk of BE if GERD is not controlled in 5
years compared to patients who are free of GERD in 5 years
1. Curr Treat Options Gastroenterol. 2007;10:294–304.
2. Am J Gastroenterol. 2011;106:1946–1952.

10. Nonerosive reflux disease (NERD)
Troublesome reflux-related symptoms without esophageal mucosal
erosions/breaks at conventional endoscopy
No Erosion
Parameter Characteristic of NERD as
compared to EE
Gender  More female
Age  Younger
Weight  Leaner
Symptom duration  Shorter
Motility abnormalities  Slightly increased
Distal esophageal acid exposure (total,
supine, and erect)
 Mildly increased
Duodenogastroesophageal reflux  Slightly increased
GI Motility online (2006) doi:10.1038/gimo42

11. Erosive Esophagitis
Erosive esophagitis (EE)
Esophageal mucosal erosive changes/recurrent, reflux, regurgitant, peptic and
marginal esophagitis

12. Barrett’s esophagus (BE)
• Premalignant condition
– Squamous epithelium of the distal esophagus is replaced by an abnormal columnar
epithelium known as specialized intestinal metaplasia
• Risk Factors
– Male Sex, Age (older than 50 years of age)
– Prolonged GERD symptoms (O5 years)
– Family history of BE and/or adenocarcinoma of the esophagus
– Nocturnal reflux symptoms, hiatal hernia
– Increased body mass index (BMI R25 kg/ m2), Intra-abdominal distribution of fat
Barrett’s esophagus (BE)
Gastrointest Endosc. 2015;81(6):1305-10.

13. Diagnosis of GERD

14. Diagnostic test Indication Recommendation
Empirical PPI
therapy (“PPI trial”)
Classic symptoms, no alarm
features, extraesophageal GERD
A negative trial does not rule out GERD
Urea breath test or
Helicobacter pylori
stool antigen test
For uninvestigated dyspepsia & high
(>20%) H. pylori prevalent area
Subject to local cost-benefit
Considerations, should be based on
noninvasive test (UBT, monoclonal stool
antigen test)
Endoscopy
For alarm symptoms screening of
high-risk patients, chest pain,
Differentiates EE from NERD,
Diagnoses other causes or upper
gut symptoms
Consider early for elderly, those at risk
for BE, noncardiac chest pain patients
unresponsive to PPI, prompt endoscopy
is recommended in areas with high
incidence of upper GI cancer
pH or impedance pH
monitoring
For atypical symptoms, For PPI-
refractory GERD, Preoperatively, for
nonerosive disease
Correlate symptoms with reflux,
document abnormal acid exposure or
reflux frequency
J Clin Gastroenterol. 2017 Jul;51(6):467-478.

15. Management of GERD

16. Management of GERD
Gut Liver. 2018 Jan 15;12(1):7-16.

17. Proton Pump Inhibitors - GERD

18. Mechanisms acid secretion
18
Histamine (H2) Gastrin Acetylcholine (M3)
Activates the acid-secreting pump
Proton pump
Final common step

19. 19

20. 2013 ACG-Recommendations
Am J Gastroenterol 2013;108:308-328

21. Management of GERD-Non Medical
1. Weight loss
 Patients with overweight or have had recent weight gain
 Conditional recommendation, MLOE
2. Head of bed elevation and avoidance of meals 2 – 3 h before
bedtime for nocturnal GERD patients
 Conditional recommendation, LLOE
3. Routine global elimination of food that can trigger reflux not
recommended
 Eg. Chocolate, caffeine, alcohol, acidic and / or spicy foods
 Conditional recommendation, LLOE
Am J Gastroenterol 2013;108:308-328
HLOE: High Level of Evidence, MLOE: moderate level of evidence, LLOE: Low Level of Evidence

22. Management of GERD-PPIs
4. 8-week course of PPIs
 Therapy of choice for symptom relief and healing of erosive esophagitis
 Strong recommendation, HLOE
5. PPIs should be initiated at OD dosing, before first meal of the day
 Strong recommendation, MLOE
6. Traditional delayed release PPIs should be administered 30 – 60
min before meal for maximal pH control
 Strong recommendation, MLOE
Am J Gastroenterol 2013;108:308-328

23. Management of GERD-PPIs
7. For patients with partial response to once daily therapy, adjust dose
timing and/or BID dosing should be considered in patients with
 Night-time symptoms, variable schedules, and / or sleep disturbance
 Strong recommendation, LLOE
8. Maintenance PPI therapy should be administered for GERD patients
 Who continue to have symptoms after PPI is discontinued
 Patients with complications including EE & BE
 Strong recommendation, MLOE
9. Non-responders to PPI should be referred for evaluation
 Conditional recommendation, LLOE
Am J Gastroenterol 2013;108:308-328

24. Management of GERD-Other agents
10. H2 -receptor antagonist (H2 RA)
 can be used as a maintenance option in patients without EE if patients
experience heartburn relief
 Conditional recommendation, MLOE
11. Therapy for GERD other than acid suppression
 Prokinetic therapy, baclofen
 Should not be used in GERD patients without diagnostic evaluation
 Conditional recommendation, MLOE
12. There is no role for sucralfate in the non-pregnant GERD patient
 Conditional recommendation, MLOE
Am J Gastroenterol 2013;108:308-328

25. World Gastroenterology Organization Global Guidelines
GERD Global Perspective on Gastroesophageal Reflux Disease
J Clin Gastroenterol. 2017 Jul;51(6):467-478

26. Management of GERD: Level of Resources - Medium
Therapy
Non-medical
1. Lifestyle modifications (diet, weight loss)
2. Locally available symptomatic remedies if they are safe, effective, and less costly
than prescription medications
Medical acid-suppression therapy
1. Alginate-antacid (AA)
2. Histamine 2 receptor antagonists (H2RA)
3. Proton pump inhibitors (PPI) OD  BID
Recommendation:
1. Stop after 8wk to assess response; Resume, as needed, at lowest effective dose
(Intermittent/on demand)
2. Continue for, frequent symptoms, stricture, BE (to control Symptoms)
3. Consider H. pylori “test-and-treat” for continuous PPI therapy
J Clin Gastroenterol. 2017 Jul;51(6):467-478.

27. Management of GERD-PPIs: Level of resources – Medium &
High
Therapy
1. PPI OD  8-12 wk, then reassess
2. PPI BID  8-12 wk for persistent symptoms
3. Switch PPIs to a modified-release PPI (effect lasting >14h/d, MR-PPI) if available
(OD or BID)
1. MR-PPI OD for 8 to 12 wk, then reassess
2. MR-PPI BID for 8 to 12wk for persistent symptoms
3. More frequent PPI therapy if incomplete response symptomatically & on pH
monitoring
Added Recommendation:
1. Laparoscopic antireflux surgery for structural disease (hiatus hernia) or volume
reflux causing regurgitation, aspiration, stricture, or persistent nocturnal symptoms
despite PPI BID
J Clin Gastroenterol. 2017 Jul;51(6):467-478.MR: Modified-release (Delayed, Sustain release)

28. Recommendation on Helicobacter pylori Infection
• In high prevalent countries consider H. Pylori assessment in
management & treatment of upper GI symptoms before empirical
antireflux therapy, to discriminate between symptoms of GERD,
peptic ulcer disease, and functional symptoms
• H. pylori status has no effect on symptom severity, recurrence, or
treatment efficacy in GERD
• Indeed, in patients with H. pylori-positive uninvestigated dyspepsia,
eradication therapy is associated with a lower prevalence of reflux-
like symptoms (36%) than control therapy (49%)
J Clin Gastroenterol. 2017 Jul;51(6):467-478.

29. Management of GERD-Pregnancy
J Clin Gastroenterol. 2017 Jul;51(6):467-478.

30. 2013 ACG vs. 2017 WGO Guidelines
Particular ACG WGO
Weight loss Recommended Recommended
PPI use 8 weeks 8-12 weeks
PPI partial response Increase dose Increase dose
Delayed release PPI For EE & BE Recommended Recommended
PPI refractoriness Consider evaluation
Secondary care
(Gastroenterologist, Surgeon)
Use of other therapy
Moderately
recommended
Recommended for short to
medium term
PPI Continuous therapy & H.
Pylori test
Not recommended
Test & Treat recommended in
high prevalent country

31. Proton pump inhibitors in GERD

32. Proton Pump Inhibitors-Pharmacokinetic
Parameters Ome Esome Lanso Pantoprazole
Bioavailability (%) 30-40 64 80 77
Factors affecting
absorption
Food Food
Antacids,
food
none
Elimination t1/2 0.7 0.9 1.2 1.2
Half-life of recovery
of acid secretion
< 30 h - <15h 46 h
Linear PK no no yes yes
Interaction with CYP
450
Inhibits
CYP2C19
Inhibits
CYP2C19
Inhibits
CYP2C19
none

33. Efficacy of Different PPIs

34. Acid suppression by different Proton pump inhibitors

35. Gastric & Duodenal Ulcer Healing Rate
Complete ulcer healing significantly higher in Pantoprazole users than
Omeprazole & Ranitidine
58
77
87
0
50
100
Ranitidine Omeprazole Pantoprazole
Cumulative ulcer healing rate
(% patients) at 4 weeks
Drugs 1996 Mar;51(3):460-82
Patients randomly administered Pantoprazole 40mg OD, Ranitidine 150 mg BID &
Omeprazole 20mg OD
52
76
65
89
71
95
50
60
70
80
90
100
2 weeks 4 weeks
Ranitidine
Omeprazole
Pantoprazole
Cumulative ulcer healing rate (% patients)

36. Pantoprazole produces significantly more symptom- and heartburn-
free days/nights as compared to Ranitidine
Aliment Pharmacol Ther 2004; 20: 567-75
58
83
73
92
50
100
Sympton - free days Heartburn free days
Ranitidine Pantoprazole
349 GERD patients
Intervention: Pantoprazole 10,20 or
40 mg OD or Ranitidine 150 mg BD
Duration: 1 year
PPI vs. H2RA in Erosive Esophagitis

37. Pantoprazole offers superior action in GERD with 22% & 15% faster
symptomatic relief in wk 2 & wk 4
47
65
69
80
40
45
50
55
60
65
70
75
80
85
Week 2 Week 4
%ofpatientwithrelief
Rantidine Pantoprazole
Digestion . 2001; 63 (3): 163 – 70
277 GERD patients
Intervention: Pantoprazole 20 OD or
Ranitidine 150mg BD
Assessment: Primary criterion was
relief from heartburn, acid eructation
& pain in swallowing
Comparison of pantoprazole 20 mg to ranitidine 150 mg b.i.d.
in the treatment of mild gastroesophageal reflux disease

38. Pantoprazole versus omeprazole in the treatment of reflux
esophagitis
76%
95%
71%
93%
0%
20%
40%
60%
80%
100%
4 weeks 8 weeks
HealingRates
60 Patients: Pantoprazole 40/day & 60 Patients: Omeprazole 20
mg/day
Pantoprazole
Omeprazole
Acta Med Croatica. 1999;53(2):79-82.
Healing rate superior in Pantoprazole compared to omeprazole

39. Comparison of pantoprazole versus omeprazole in the
treatment of acute duodenal ulceration—a multicentre study
96%
88%
89%
90%
91%
92%
93%
94%
95%
96%
97%
4 weeks
Ratesofcompleteulcer
healing
185 Patients: Pantoprazole 40 mg/day; 91 patients:
Omeprazole 20 mg/day
Pantoprazole
Omeprazole
Pantoprazole was shown to be a highly‐effective and well‐tolerated treatment for
acute duodenal ulcer Aliment Pharmacol Ther. 1995 Aug;9(4):411-6.

40. Patients of GERD on Pantoprazole had a significantly lower risk of
relapse and fewer symptom episodes
46
48
50
52
54
56
58
60
62
Esomeprazole Pantoprazole
61
51
% patients experiencing a symptomatic relapse
529 patients of GERD treated with 20mg Pantoprazole or 20 mg Esomeprazole over 4 weeks
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Esomeprazole Pantoprazole
0.74
0.56
No. of symptom episodes
Pantoprazole 40 mg is superior regarding the prevention of
symptomatic relapse than esoeprazole
Digestion. 2006;74(3-4):145-54

41. 0
2
4
6
8
10
12
14
Esomeprazole Pantoprazole
13
10
Median time to sustained symptom relief
(in days)
Median time to sustained symptom relief was 3
days shorter with Pantoprazole
529 patients of GERD treated with 20mg Pantoprazole or 20 mg Esomeprazole over 4 weeks
Superior & Faster Sustained Symptom Relief
Digestion. 2006;74(3-4):145-54

42. Summary
1. Weight loss is recommended for GERD management
2. PPIs are mainstay in the GERD management
3. In GERD persistent symptoms, dose modifications is advised
4. Modified release PPIs are recommended for long term management
5. PPI refractory patients needs re-evaluation/referred to specialist
6. In EE & BE continuous PPI therapy is required
7. 2017 WGO recommends H. pylori test to discriminate between GERD, functional
symptoms, GI ulcer
8. Consideration to H. Pylori test is advised in continuous PPI users by 2017 WGO
9. Amongst several PPIs discussed, Pantoprazole appeared superior in efficacy