This document provides an overview of gastroesophageal reflux disease (GERD). It begins with phenotypic classifications of GERD and discusses the Montreal definition. It then covers the pathogenesis of GERD including antireflux mechanisms, gastric factors, esophageal clearance mechanisms, and esophageal epithelial resistance. The document discusses the clinical presentation of GERD and diagnostic tests including endoscopic examination, pH monitoring, and testing. It concludes with an overview of treatment approaches including pharmacologic therapy, antireflux surgery, and endoscopic antireflux procedures.

1. GERD
PRESENTER: DR.ABHINAV KUMAR

2. OUTLINE
• Phenotypic Classification of GERD
• GERD: Montreal Definition
• Pathogenesis of GERD
• Clinical Presentation
• Endoscopic examination
• Diagnostic tests
• TREATMENT
Pharmacologic Therapy
Antireflux Surgery
Endoscopic Antireflux Procedures

3. Phenotypic Classification of GERD
GERD
NERD*
60-70%
Erosive
Esophagitis
20-30%
Barrett’s
Esophagus
6-10%
Fass et al. Alim Pharm Ther 2005
*NERD: Non-Erosive
Reflux Disease

5. GERD: Montreal Definition
• A condition which develops when the reflux of stomach
contents causes troublesome symptoms and/or complications
• > 2 heartburn episodes/week
• Adversely affect an individual’s well being
From Vakil N et al. Am J Gastroenterol 2006;101:1900-20.

6. • Prevalence of at least twice weekly heartburn and/or acid
regurgitation
• 10-20% in Western world
• < 5% in Asia
Dent J et al. Gut 2005;54:710-7.

7. The Montreal Classification: Symptom Definitions
• Heartburn & regurgitation are the characteristic symptoms of
typical reflux syndrome
Heartburn
• Burning sensation in retrosternal area
Regurgitation
• Perception of flow of refluxed gastric contents into mouth or
hypopharynx
From Vakil N et al. Am J Gastroenterol 2006;101:1900-20.

8. Physiologic vs Pathologic
• Physiologic GERD
– Postprandial
– Short lived
– Asymptomatic
– No nocturnal
symptoms
• Pathologic GERD
– Symptoms
– Mucosal injury
– Nocturnal
symptoms

9. Pathogenesis of GERD
• Antireflux mechanisms
• Gastric Factors
• Esophageal Clearance Mechanisms
• Esophageal Epithelial Resistance

10. Antireflux Mechanisms:
• Positive pressure gradient between the abdomen and the thorax
Reflux
• Absence of effective antireflux mechanisms  gastroesophageal
reflux.

11. Anatomic Features

12. Lower Esophageal Sphincter (LES)
Types of LES dysfunction:
1) Intrinsic weakness of the
LES muscle:
• Responsible for > 25% of
reflux episodes in patients
with severe GERD.
2) Inadequate LES response to
increased abdominal
pressure.
3) Transient LES relaxation
(TLESR):
• LES relaxes for 3-10 sec
swallowed bolus to enter the
stomach.
• TLESR is not preceded by
swallowing & lasts for up to
45 seconds.
• Responsible for 70% of reflux
episodes

13. Vagal Pathways Involved in TLESR: Importance of
GABA Receptors
From Falk GW. Gastroenterology 2010;139:377-86

14. Relationship Between BMI & TLESr
Wu JC et al. Gastroenterology 2007;132:883-9.

15. Gastric Factors
1) Irritant potency of the refluxed material
• Esophageal injury occurs when the refluxed material is
caustic to the esophageal mucosa.
• Caustic agents  acid, pepsin, bile & pancreatic enzymes.

16. Gastric Factors
2) Delayed gastric emptying
Gastric distention that can stimulate gastric acid secretion &
trigger TLESR.
Causes:
1- Pyloric channel or duodenal ulcers.
2- Mechanical obstruction e.g. by tumour.
3- Neuromuscular abnormalities e.g. DM, collagen
diseases, hypothyroidism, …

17. Esophageal Clearance Mechanisms
• Impaired esophageal clearance can occur in:
• Sleep: due to
1) Elimination of the effect of gravity.
2) Salivation & swallowing cease during sleep “no peristalsis due
to absent swallowing”.
• Scleroderma: due to impaired peristalsis.
• Cigarette smoking: due to decreased salivation.
• Hiatus hernia.

18. Esophageal Epithelial Resistance:
Pre-epithelial defenses:
1) Mucous layer:
Acts as a lubricant & a protective barrier against noxious & irritant
luminal contents.
2) Unstirred water layer:
Lies under the mucous layer & its rich in bicarbonate.
It provides a protective alkaline microenvironment.

19. Impaired
mucosal
defence
salivary HCO3
Hiatus hernia
Impaired LES
(smoking, fat, alcohol)
– transient LOS
relaxations
– basal tone
H+
Pepsin
Bile and
pancreatic
enzymes
oesophageal
clearance of acid
(lying flat, alcohol,
coffee)
acid output
(smoking, coffee)
intragastric pressure
(obesity, lying flat)
bile reflux gastric emptying (fat)
PATHOPHYSIOLOGY OF GERDPATHOPHYSIOLOGY

20. Clinical Presentation
Heartburn (Pyrosis):
• Substernal burning sensation
radiating to the chest
sometimes to the throat or the
back.
• The pain is usually relieved by
ingestion of antacids. within 5
minutes
• Foods decrease the LES
pressure as chocolate, onions,
peppermint, coffee, tea
• High content of fat & sugar.
• Ingestion of foods that
irritate the esophageal
mucosa directly as spicy
foods, citrus products and
tomato products.
• Practices that increase the
intra-abdominal pressure
e.g. bend over, lift a heavy
object,strain to defecate or
run.

21. - Clinical Presentation
Regurgitation:
• Reflux of sour or bitter
material into the mouth
usually at night, when lying
down or bending over.
Dysphagia:
• Usually indicates narrowing
or stricture of the
esophagus.
• It may occur due to
inflammation & edema.

22. Clinical Presentation
Odynophagia:
• Presence of esophageal
ulceration
Night-time GER
• Sleep apnoea
• Insomnia
• Daytime sleepiness
Water brash:
• Filling of the mouth
suddenly with saliva.
• Its due to reflex salivary
secretion stimulated by acid
in the esophagus.

23. Clinical Presentation
Chest pain:
• Resembles anginal pain.
• Acid induced irritation of
the nerve endings.
• GER-induced esophageal
spasm.
Pulmonary symptoms:
• chronic cough, hoarseness
of voice, wheezing,
hemoptysis, asthma &
recurrent aspiration
pneumonia.
• Manifestations may be due
to aspiration or vagus
mediated neural reflexes.

24. Cough
response
Stimulation of
vagus nerve
Gastric refluxate
Esophageal–bronchial
transmission via
cough center
Aspiration to lower
respiratory tree
Gastric refluxate
Cough and GERD: 2 Possible Mechanisms
Irwin RS, French CL, Curley FJ, Zawacki JK, Bennett FM. Chronic cough due to
gastroesophageal reflux. Clinical, diagnostic, and pathogenic aspects. Chest 1993;104:1511–
17 Suppl:S9–14.

25. Montreal GERD Consensus Conference:
Atypical Symptoms
• Extraesophageal symptoms rarely occur in the absence of
typical GERD symptoms
• Extraesophageal symptoms typically multifactorial
• Data substantiating beneficial effect of treatment weak

26. • All diagnostic tests to establish GERD as the cause of extra-
esophageal symptoms have serious limitations
• Diagnosis of reflux laryngitis should not be based on ENT
examination
• Abnormalities in > 80% healthy controls
• Poor concordance among observers
Montreal GERD Consensus Conference:
Atypical Symptoms

27. Aging & GERD
• No change in symptom frequency
• Decreased symptom intensity
• Increase in complications
LA C & D esophagitis
Barrett’s esophagus

28. Obesity (BMI >30 kg/m2) & GERD Symptoms
From Hampel H et al. Ann Intern Med 2005;143:199-211.

29. Rates of Symptomatic & Asymptomatic Reflux
Episodes With High Proximal Extent
From Zerbib F et al. Gut 2008;57:156-60.

30. GERD As A Cytokine Mediated Mechanism:
Animal Model
• Sequence of reflux damage
• Lymphocytic infiltration starts in sub-mucosa
• Progresses to epithelial surface
• Basal cell hyperplasia precedes erosions
• Exposure of squamous cells to acidified bileIL8 & IL1β secretion
• Bottom line: refluxate stimulates esophageal cytokine production
 inflammatory cells  inflammatory response

31. Diagnostic tests
Indications:
1) Patients with atypical signs or symptoms.
2) Patients with typical signs & symptoms that don’t respond
well to acid suppression.

32. Endoscopic examination:
• EGD  Presence and severity of esophagitis , Barrett’s esophagus
• More sensitive than radiology
• Endoscopic evidence of esophagitis  50-70% of patients with
typical history of GERD so a normal EGD (NERD) doesn’t exclude
GERD.

33. The LA Classification system
– Grade A reflux esophagitis
Stomach
Grade A: One (or more) mucosal break, no longer than 5 mm,
that does not extend between the tops of two
mucosal folds.

34. The LA Classification system
– Grade B reflux esophagitis
Stomach
Grade B: One (or more) mucosal break, more than 5 mm long, that
does not extend between the tops of two mucosal folds.

35. The LA Classification system
– Grade C reflux esophagitis
Stomach
Grade C: One (or more) mucosal break that is continuous between
the tops of two or more mucosal folds, but which involves
less than 75% of the circumference.

36. The LA Classification system
– Grade D reflux esophagitis
Stomach
Grade D: One (or more) mucosal break that involves at least
75% of the esophageal circumference.

37. Savary-Miller Classification of esophagitis
• Grade I: Single or multiple
erosions are found on a
single fold; erosions may be
erythematous or exudative.
• Grade II: Multiple erosions
affect multiple folds.

38. Savary-Miller Classification of esophagitis
• Grade III: Multiple
circumferential
erosions.
• Grade IV: Ulcer,
stricture, and
esophageal shortening.

39. Savary-Miller Classification of esophagitis
• Grade V: Barrett’s epithelium

40. Barium swallow
a) Signs of esophagitis
including:
• 1- Thickening of the
esophageal folds.
• 2- Erosions.
• 3- Ulcerations.
• 4- Strictures.
• Disadvantages:
• Less sensitive than
endoscopy for
demonstrating esophagitis.
• Biopsy specimens can't be
taken.

41. Ambulatory monitoring of esophageal pH
• Document the pattern, frequency & duration of acid reflux & to seek
correlation between reflux episodes & symptoms.
• Normally, esophageal pH remains below 4 for less than 4.5% of the
24-hour monitoring period.
• Acid reflux episode: a drop in esophageal pH below 4 & the total
Reflux episodes exceed 5% of the total monitoring time.

44. Acid perfusion (Bernstein) test:
• It has been used to support acid reflux as the cause of
symptoms.
• The esophagus is perfused with 0.1 N HCl. Reproduction of
chest pain with acid perfusion implicates GERD as a cause of
chest pain.

45. Morphology of GERD
basal zone hyperplasia, Elongation of lamina propria papillae
Eosinophils and neutrophils

46. TREATMENT
A) Medical Treatment:
a) Lifestyle Modifications.
b) Pharmacologic Therapy:
1) H2 blockers
2) Proton Pump Inhibitors.
3) Antacids.
4) Prokinetic Drugs.
5) Sucralfate.
B) Antireflux Surgery.
C) Endoscopic Antireflux Procedures.

47. Pharmacologic Therapy
1) H2 Blockers:
• These drugs block the effect of histamine on H2 receptors which is
present normally in gastric mucosa, vascular smooth muscle & the
heart.
• Reduce the basal, food stimulated & nocturnal secretion of gastric
HCl.
• Usually effective in controlling symptoms of mild to moderate GER &
heal esophagitis (grade I,II) within 12 weeks in about ½ to 2/3 of
patients.

48. Proton Pump Inhibitors (PPIs)
• Drugs inhibit parietal cell proton pump (H+ K+ - ATPase).
• Proton pump is responsible for extrusion of H+ into the gastric lumen
in exchange of K+ which is the final step in gastric acid production.
• PPIs are effective in control of symptoms & signs of GERD, heal
erosive esophagitis & diminish formation of esophageal strictures.
• PPIs improves dysphagia & decrease the need for esophageal
dilatation in patients who have esophageal strictures.

49. Proton Pump Inhibitors (PPIs)
From Maton PN et al. Drug Safety 2001;24:625-35

50. Proton Pump Inhibitors (PPIs)
• In equivalent doses different PPI preparations do not show
statistically significant difference in healing effect
• Double dose therapy associated with modest improvement in
healing of erosive esophagitis
From Moayyedi P et al. Cochrane Database of Systematic Reviews 2007;2

51. Potential Risks of Chronic PPI Therapy
Hypergastrinemia, carcinoids
RATS
•Elevated gastrin
•ECL cell hyperplasia
•ECL cell carcinoid tumors
HUMANS
•Elevated gastrin
•ECL cell hyperplasia
•NO CARCINOID TUMORS
Species specific problem (rat)
Up to 8 year continuous use in patients (as of 2000)

52. Potential Risks of Chronic PPI Therapy
Achlorhydria, N-nitrosamine generation
The RISK The REALITY
• Achlorhydria
permits growth of
bacteria that can
convert nitrates to
nitrites to N-
nitrosamine
(carcinogen)
• Increased UGI
bacteria has been
detected in PPI takers.
•N-nitrosamine
formation is also
catalyzed by acid.
Data on PPI use and increased gastric N-nitrosamine
remain uncertain and the cancer risk is speculative

53. Potential Risks of Chronic PPI Therapy
Achlorhydria, enteric infection
The RISK The REALITY
• Achlorhydria
disables the gastric
barrier to ingested
pathogens
•Case-control study: Small increase in
enteric infections with PPIs for 2 months.
–Relative risk 1.6 (Cl 1.0-2.4)
•PPI use is independent risk of C. difficile
diarrhea in antibiotic users.
–PPI use OR 2.1 (Cl 1.2-3.5)
–≥3 AB OR 2.1 (Cl 1.3-3.4)
–Medical ward OR 4.1 (Cl 2.3-7.3)
Only occasional cases of enteric infections in patients taking PPI’s
have been reported.
Garcia Rodriguez LA et al. Epidemiol 1997:8:571-4, Dial S et al CMAJ 2004: 171: 33-8

54. Potential Risks of Chronic PPI Therapy
Community –acquired pneumonia
The RISK
The REALITY
 Gastric colonization followed by
reflux and aspiration of gastric
contents results in pneumonia
 Case-control Dutch primary case
database 1/1/95-12/31/2002.
–364,683 Individuals
–5551 1st Pneumonias
–PPI user risk 0.60/100 pt yrs
Nested case control analysis to reduce
confounding effects of indication
–Non-PPI user risk 0.60/100 pt yrs
Adjusted OR all 1.27 (Cl 1.06-1.54)
–Adjusted OR PPI 1.73 (Cl 1.33-2.25)
Association does not prove causation
PPI takers are also more likely to smoke, drink, be obese, have GERD, and ??
Laheji RJ et al. JAMA 2004: 292: 1955-60

55. Potential Risks of Chronic PPI Therapy
Safety during pregnancy/lactation
The RISK The REALITY
Omeprazole crosses placenta,
category C; Other PPI’s category
B
A. controlled human studies no
risk.
B. animal studies or, adverse fetal.
C. no adequate studies or, adverse
fetal effects in animals at some
dose.
D. evidence of fetal risk: benefit >
risk
X. Evidence of fetal risk: benefit <
risk
1992-2001 prospective
controlled evaluation of PPI
gestational exposures
–Omeprazole: 247 births
3.6% major anomalies.
–Lansoprazole: 50 births,
3.9% MA
–Pantoprazole: 48 births,
2.1% MA
–Controls: 787 births,
3.8%MA
European Network of Teratology Information Services…the PPI’s do not
represent a major teratogenic risk in humans
Diav-Citrin O et al, Aliment Pharmacol Ther 2005: 21: 269-75

56. Short Term (1-12 Week) Treatment of GERD
Symptoms Or Endoscopy Negative GERD
From Van Pinxteren B et al. Cochrane Database of Systematic Reviews 2006:3:CD002095.

57. Healing of Erosive Esophagitis: Systematic Review
From Khan M et al. Cochrane Database Sys Rev 2007;2CD003244.

58. Definition of Failure of PPI Therapy: AGA
Position Paper
• Inadequate response of heartburn to twice daily PPI therapy
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.

59. Possible Causes for Failure of PPI
Therapy
Ongoing reflux/acid exposure
• Noncompliance
• Incorrect dose timing
• Pathologic acid secretion
• Rapid PPI metabolism
• Hypersecretory state
• Large hiatal hernia
Nonacid reflux
From Dellon E et al. Gastroenterology 2010;139;7-13.

60. Possible Causes for Failure of PPI Therapy
• Visceral hypersensitivity
• Non-reflux esophageal causes
• Dysmotility
• Eosinophilic esophagitis
• Pill induced esophagitis
• Infectious esophagitis
From Dellon E et al. Gastroenterology 2010;139;7-13.

61. Antacids
• Antacids may be aluminum, magnesium, or calcium based
• Antacids neutralize the acid in the stomach so that there is no acid to
reflux.
• Antacids emptied from the empty stomach quickly so they should be
given an hour after meal to prolong their duration of action.
• Effective in controlling mild symptoms of GERD.

62. Prokinetic Drugs:
These agents act by:
a) Increasing LES pressure.
b) Enhancing gastric & esophageal emptying.
Examples:
1) Metoclopramide HCl.
2) Domperidone.
3) Mosapride citrate.

63. Metoclopramide HCl:
• Dopamine antagonist, centrally
acting antiemetic.
• Effective in treatment of mild
disease.
• It crosses BBB
Side effects:
• Agitation,
• restlessness,
• somnolence,
• anxiety,
• insomnia, extrapyramidal
manifestations & galactorrhoea.
Domperidone:
• Dopamine antagonist & produce
effects similar to
metoclopramide.
• Unlike metoclopramide it doesn’t
cross BBB so there is no central
side effects.
Mosapride citrate:
• 5-HT4 receptor agonist & partial
5-HT3 antagonist.
• Unlike cisapride  Doesn’t
• block K+ channels  no cardiac
toxicity
• D2 receptors no
extrapyramidal manifestations.

64. Sucralfate:
- An aluminum sucrose polysulfate.
- Effective in treatment of mild reflux esophagitis.
- It is efficacy is comparable to that of H2 blockers.

65. H2RAs block the
histamine receptor,
interfering with one
of
the stimulation
pathways
PPIs block acid at
its source in the
proton pump
ACh=acetylcholine
Mechanisms of Action
of GERD Pharmacotherapy
Antacids
neutralize
secreted HCl
HCI
HistamineACh
Gastrin
K+H+

66. Nissen fundoplication
Antireflux Surgery
• There are a number of different antireflux operations (e.g.
Nissen, Belesy, Toupet fundoplication).
• The most popular is Nissen fundoplication (open or
laparoscopic).

67. Principle of antireflux surgery:
The surgeon
1) Creates an intra-abdominal segment of esophagus.
2) Reduces the hiatal hernia.
3) Approximates the diaphragmatic crurae.
4) Wraps a portion of gastric fundus around the distal esophagus.

68. - There is relief of symptoms & signs in > 85% of patients.
- Antireflux surgery was associated with a significant decrease in
long term survival so it should be restricted to:
1) Patients who no longer need to take antisecretory
medications.
2) The procedure will prevent esophageal cancer

69. RCT of Laparoscopic Antireflux Surgery Vs.
Esomeprazole for GERD
From Galmiche J. et al. JAMA 2011;305:1969-1977.

70. AGA GERD Practice Guidelines: Surgery
• Patients with esophagitis who are well maintained on medical
therapy have nothing to gain from surgery
Incur added risk
Should be advised against surgery
• Patients likely to benefit from surgery:
PPI intolerance
Persistent symptoms especially regurgitation
From Kahrilas PJ et al. Gastroenterology 2008;135:1383-91.

71. Complications of Laparoscopic Antireflux
Surgery
• Death: 0.1-0.2%
• Life threatening complications: 1.2-3.4%
• Redo surgery: 1.5-7%
• Dysphagia requiring dilation: 3.5- 12%
From Kahrilas PJ et al. Gastroenterology 2008;135:1392-1413.

72. Endoscopic antireflux procedures (FDA approved)

73. GI Motility online (May 2006) | doi:10.1038/gimo55
Figure 2 The Stretta radiofrequency delivery system.

74. Stretta procedure
• Decrease in symptom
score
• Decreased PPI
• No effect on LESP
• No effect on acid
exposure
• Some serious thermal
injury complications

75. GI Motility online (May 2006) | doi:10.1038/gimo55
Figure 3 The Plicator system.

76. Endoscopic suturing
• Decreased heartburn symptoms
• PPI eliminated in 74% of patients at 6 months
• Decreased esophageal acid exposure; however, only 30%
completely normalized
• Long term follow-up needed

77. GI Motility online (May 2006) | doi:10.1038/gimo55
Figure 5 Enteryx implantation.

78. Enteryx injection

79. Enteryx injection
• Decreased in heartburn symptoms
• Decreased 24 hour acid exposure
• Decreased need for PPI
• No improvement in severity of esophagitis at EGD
• Long term safety issues not known

80. I’m worried
& concerned
GI symptoms
bother me!
My whole life is
affected
Heartburn
disturbs my
sleep
I cannot eat &
drink whatever
I like
I cannot bend
over or exercise
Illustrator: Eric Werner