Gastroesophageal Gastroesophageal Reflux Disease Reflux Disease

(GERD)(GERD)Dr. Kairu S. M. Dr. Kairu S. M.

Gastro-oesophageal reflux disease (GORD):Gastro-oesophageal reflux disease (GORD):Abnormal reflux of gastric juice (acid and bile) into Abnormal reflux of gastric juice (acid and bile) into

the oesophagus leading to symptomsthe oesophagus leading to symptoms

Pathological reflux ranges from simple to Pathological reflux ranges from simple to erosive to Barrett’serosive to Barrett’s

Non-erosive reflux disease (NERD):Non-erosive reflux disease (NERD):Reflux disease in which erosion does not Reflux disease in which erosion does not

occuroccur

Heartburn:Heartburn: Burning retrosternal pain radiating upward Burning retrosternal pain radiating upward due to exposure of the oesophagus to aciddue to exposure of the oesophagus to acid

Oesophagitis:Oesophagitis: Endoscopically demonstrated damage to the Endoscopically demonstrated damage to the

oesophageal mucosaoesophageal mucosa

GERD - DefinitionsGERD - DefinitionsGERD - DefinitionsGERD - Definitions

PrevalencePrevalence.. Increased prevalence last 10 years. Increased prevalence last 10 years.

Accompanied increase in Accompanied increase in adenocarcinoma lower esophagus. adenocarcinoma lower esophagus.

Obesity associated with increased Obesity associated with increased GERD. GERD.

Anti Reflux Anti Reflux Mechanism(ARM)Mechanism(ARM)

This has both:-This has both:- (1) Anatomical.(1) Anatomical. (2) Functional.(2) Functional.

Anatomical.Anatomical. The lower esophageal sphincter (LES) The lower esophageal sphincter (LES)

at the OG junction consists of tonically at the OG junction consists of tonically contracted smooth muscle at approx. 8-contracted smooth muscle at approx. 8-20 mmHg above the gastric pressure.20 mmHg above the gastric pressure.

The outside (extrinsic) compression at The outside (extrinsic) compression at the OG junction from the crural the OG junction from the crural diaphragm.diaphragm.

Sharp angle- entry of esophagus into Sharp angle- entry of esophagus into stomach (angle of His).stomach (angle of His).

TLESR TLESR (Transient Lower Esophageal Sphincter (Transient Lower Esophageal Sphincter

Relaxations)Relaxations) A normal phenomenon in A normal phenomenon in

healthy individuals. healthy individuals.

Dominant mechanism of Dominant mechanism of pathological reflux.pathological reflux.– Too frequent TLESRs.Too frequent TLESRs.– Too prolonged TLESRs.Too prolonged TLESRs.

Functional.Functional. Esophageal peristalsis that Esophageal peristalsis that

serves to clear luminal contents serves to clear luminal contents into the stomach.into the stomach.

Secretion and swallowing of Secretion and swallowing of saliva to neutralize the acid and saliva to neutralize the acid and enhance clearance.enhance clearance.

Prompt Gastric emptying.Prompt Gastric emptying.

Impaired mucosal defence

salivary HCO3

Hiatus hernia

Impaired LOS (smoking, fat, alcohol)

– transient LOS relaxations

– basal toneH+

PepsinBile 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 of GERD

Symptoms. Symptoms.

Heartburn and Regurgitation are the two Heartburn and Regurgitation are the two cardinal symptoms of GERD.cardinal symptoms of GERD.

Others:-Others:-

(1) Dysphagia-due to peptic stricture or (1) Dysphagia-due to peptic stricture or

peristaltic dysfunction.peristaltic dysfunction.

(2) Chest pain (NCCP).(2) Chest pain (NCCP).

(3) Water brash.(3) Water brash.

(4) Globus Sensation.(4) Globus Sensation.

(5) Odynophagia.(5) Odynophagia.

Extra Esophageal Extra Esophageal Manifestations.Manifestations.

1.1. Asthma.Asthma.

1)1) Microaspiration.Microaspiration.

2)2) Vagal reflex activation. Vagal reflex activation.

2.2. Laryngitis.Laryngitis. Complications of GERDComplications of GERD..a)a) Bleeding.Bleeding.

b)b) Stricture.Stricture.

c)c) Barrets esophagus Barrets esophagus adenocarcinomaadenocarcinoma

Role of Endoscopy in Role of Endoscopy in GERD.GERD.

Confirm diagnosis of GERD -Confirm diagnosis of GERD -erosions/ulcerations.erosions/ulcerations.

Diagnose endoscopy-negative reflux.Diagnose endoscopy-negative reflux. Exclude other causes of esophagitis/ Exclude other causes of esophagitis/

odynophagia e.g.Candida, Herpes odynophagia e.g.Candida, Herpes Simplex.Simplex.

Diagnose complications of chronic Diagnose complications of chronic GERD e.g Barrets esophagus, GERD e.g Barrets esophagus, stricture, adenocarcinoma.stricture, adenocarcinoma.

1.Savary-Miller 1.Savary-Miller classification.classification.

1.1. Solitary erythematous /erosions covering Solitary erythematous /erosions covering one mucosal fold.one mucosal fold.

2.2. Solitary erythematous /erosion covering Solitary erythematous /erosion covering more than one mucosal folds but not more than one mucosal folds but not circumferential.circumferential.

3.3. Circumferential erythematous / erosions.Circumferential erythematous / erosions.4.4. ComplicationsComplications Ulcers.Ulcers. Strictures.Strictures. Barrett’s esophagus.Barrett’s esophagus.

Grade I Grade I

Grade 1 Grade 1

Grade 2Grade 2

Grade 2Grade 2

Grade 2Grade 2

Grade 3Grade 3

Grade 4Grade 4

Grade 4 Grade 4

Grade 4Grade 4

Grade 4. Grade 4.

Modes of Treatment Modes of Treatment Proton Pump Inhibitors Proton Pump Inhibitors

– Longer acting PPI’s.Longer acting PPI’s.– Adverse events/effects of PPIs.Adverse events/effects of PPIs.

Potassium –competitive acid blockers Potassium –competitive acid blockers (PCABs)(PCABs)

Motility agents.Motility agents.– GABA agonists GABA agonists

Endoscopic therapy Endoscopic therapy – Full-thickness plication Full-thickness plication

The Step up Approach.The Step up Approach.

PPIPPI

LOW DOSE PBLOW DOSE PB..

H2RA +PROKINETIC.H2RA +PROKINETIC.

H2RA H2RA

OTC ANTACIDS + LIFESTYLE ADVICE.OTC ANTACIDS + LIFESTYLE ADVICE.

The Step Down ApproachThe Step Down Approach..

PPIPPI

LOW DOSE PB.LOW DOSE PB.

H2RA +PROKINETIC.H2RA +PROKINETIC.

H2RA+LIFESTYLE ADVICE.H2RA+LIFESTYLE ADVICE.

OTC OTC

ANTACIDS. ANTACIDS.

Long Term Therapy.Long Term Therapy. Many patients, GERD a chronic Many patients, GERD a chronic

relapsing problem because the relapsing problem because the underlying motor abnormalities persist.underlying motor abnormalities persist.

PPI’s.PPI’s. Majority of patients require PPI even in Majority of patients require PPI even in

low doses.low doses. Occasional patients may require high Occasional patients may require high

doses (double dose of PPI to control doses (double dose of PPI to control symptoms.)symptoms.)

Nocturnal acid breakthrough.Nocturnal acid breakthrough.

Surgery in GERD Surgery in GERD Nissan FundoplicationNissan Fundoplication

40-50% have required medical 40-50% have required medical treatment after surgery.treatment after surgery.

– High failure rate. High failure rate.

Mortality – operatorMortality – operator dependent. dependent.

Morbidity / complications: Morbidity / complications: ~ ~ 10% 10% dysphagia requiring repeated dysphagia requiring repeated esophageal dilatation. esophageal dilatation.

Potential Risks of Potential Risks of Chronic PPI TherapyChronic PPI Therapy

Hypergastrinemia, carcinoids Hypergastrinemia, carcinoids Gastritis, intestinal metaplasia, gastric Gastritis, intestinal metaplasia, gastric

cancercancer Achlorhydria and loss of gastric sterilityAchlorhydria and loss of gastric sterility

• Increased enteric infections, C, difficile.Increased enteric infections, C, difficile.• N-nitrosamine and carcinogen risk N-nitrosamine and carcinogen risk • Community =acquired pneumoniaCommunity =acquired pneumonia

Safety during pregnancy /lactation Safety during pregnancy /lactation Drug interactions. Drug interactions.

Potential Risks of Chronic PPI Therapy Potential Risks of Chronic PPI Therapy Hypergastrinemia, carcinoidsHypergastrinemia, 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)

Potential Potential Risks of Chronic PPI TherapyRisks of Chronic PPI Therapy

Achlorhydria, N-nitrosamine generationAchlorhydria, 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

Potential Risks of Chronic PPI Potential Risks of Chronic PPI Therapy Therapy

Achlorhydria, enteric infectionAchlorhydria, 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)

•PPPI 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

Potential Risks of Chronic PPI TherapyPotential Risks of Chronic PPI Therapy

Community –acquired pneumoniaCommunity –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 ?? (note how OR 4.08 dwindled to 1.73)

Laheji RJ et al. JAMA 2004: 292: 1955-60

Potential Risks of Chronic PPI Therapy Potential Risks of Chronic PPI Therapy

Safety during pregnancy/lactationSafety 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

PPI’s: Adverse PPI’s: Adverse Events/EffectsEvents/Effects

Clopidogrel Clopidogrel – Prospective studies of platelet Prospective studies of platelet

aggregation. aggregation. – Retrospepctive studies of clinical Retrospepctive studies of clinical

outcomes. outcomes. – Randomized, double-blind trail of PPI Randomized, double-blind trail of PPI

vs placebo among clopidogrel users.vs placebo among clopidogrel users.• No difference in cardiac events, mortality No difference in cardiac events, mortality • Significant reduction in GI events with PPISignificant reduction in GI events with PPI

GABA – GABA – ββ Agonist Agonist BaclofenBaclofen

Baclofen 40mg Baclofen 40mg – Reduced TLESR’s in patients with Reduced TLESR’s in patients with

GERD GERD – Reduced esophageal acid exposureReduced esophageal acid exposure

Limitations Limitations – CNS side-effects mainly drowsiness.CNS side-effects mainly drowsiness.– Short half-life.Short half-life.

Van Herwaarden et al. Aliment Phar,acol Ther 2002

New motility agent (GABA New motility agent (GABA ββ Agonist)Agonist)

Lesogaberan Lesogaberan Lesogaberan – a peripheral acting Lesogaberan – a peripheral acting

GABA GABA ββ agonist. agonist.

Study showed 35% ↓ in TLESR.Study showed 35% ↓ in TLESR.

A potential agent for treatment of A potential agent for treatment of GERD as co-therapy. GERD as co-therapy.

Summary Summary

PPI’s remain the standard treatment for PPI’s remain the standard treatment for GERD. GERD.

Well established to be very safe. Well established to be very safe.

Prevalence of GERD increasing with Prevalence of GERD increasing with increase in lower esophageal increase in lower esophageal adenocarcinoma.adenocarcinoma.

New motility drugs in development – New motility drugs in development – Lesogaberan.Lesogaberan.

THE ENDTHE END