Gastroesophageal and Supra-esophageal Reflux:

GERD & SERD

Arash BabaeiAssociate Professor of MedicineDirector of Esophageal Function LaboratoryNational Jewish HealthSeptember 20, 2019

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I have no conflicts of interest.

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Am J Gastroenterol 2013; 108:905–911; doi:10.1038/ajg.2013.69;

Extra-Esophageal Reflux Disease&

Prohibitive Economic Burden

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Extra-Esophageal Reflux Disease:Airway Symptoms

and Pulmonary Disease Upper Airway

• Chronic cough• Hoarseness• Clearing throat• Phlegm• Throat burning

Respiratory Disorder• Wheezing• Asthma• Recurrent pneumonia• Interstitial lung disease• COPD• …

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Cough and GERD: Patient PerspectiveThe Journey Through Competing Diagnoses

ENT

AllergyPulmonaryGI

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Reflux disease and laryngeal symptoms Is there a causative relationship?

REFLUX SYMPTOM

Direct injuryMicro-aspiration

Indirect responseNeural reflex

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Cough and Reflux

Gastroenterology. 2010 Sep;139(3):754-62. doi: 10.1053/j.gastro.2010.06.050.

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Acid Suppressive Therapy

Braz J Med Biol Res. 2016 Jul 4;49(7).

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Anti-reflux Surgery

Clin Gastroenterol Hepatol. 2017 May;15(5):675-681. doi: 10.1016/j.cgh.2016.10.031.

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Guideline

In adult patients with suspected chronic cough due to reflux-cough syndrome, but without heartburn or regurgitation, we recommend against using PPI therapy alone because it is unlikely to be effective in resolving the cough

Chest. 2016 Dec;150(6):1341-1360. doi: 10.1016/j.chest.2016.08.1458.

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Cough Hypersensitivity Syndrome

N Engl J Med. 2016 Oct 20;375(16):

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A Clinical Enigma

Epidemiology

Quality of Life

Diagnostic◦ Laryngoscopy◦ pH monitoring◦ Impedance◦ Pepsin

Medical Therapy

Surgical Therapy

Mechanism

Pathophysiology

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GERD

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Heartburn # Reflux

All “heartburn” is not reflux disease

Reflux disease patients may not even have

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Esophagogastric Junction Barrier The most important barrier against reflux is the constant lower esophageal sphincter (LES) tone

• LES prevents reflux of acidic gastric contents, which are under constant positive abdominal pressure

The lower esophageal sphincter and the crural diaphragm constitute the intrinsic and extrinsic sphincters, respectively. The two sphincters are anatomically superimposed and are anchored to each other by the phrenoesophageal ligament.

N Engl J Med. 1997 Mar 27;336(13):924-32

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Etiology of GERD:Transient LES Relaxation

N Engl J Med. 1997 Mar 27;336(13):924-32

Transient relaxation of the

lower esophageal sphincter appears to use the same neural pathway as swallow. The afferent signals for such relaxation may originate in the pharynx, the larynx, or the stomach. The efferent pathway is in the vagus nerve, and nitric oxide is the postganglionic neurotransmitter. Contraction of the crural diaphragm is controlled by the inspiratory center in the brain stem and the nucleus of the phrenic nerve. The crural diaphragm is innervated by the right and left phrenic nerves through nicotinic cholinergic receptors. Ach denotes acetylcholine, plus signs excitatory effects, and minus signs inhibitory effects.

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Pathophysiology Reflux of gastric juices is central to the development of mucosal injury in GERD Duodenal bile reflux may exacerbate the damage

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Diagnostic Approach

Structural evaluation1. Upper endoscopy (EGD)

2. Fluoroscopic barium swallow (Esophagram)

Functional evaluation1. Ambulatory reflux monitoring

2. Esophageal manometry

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EGD is 90% specific More than 50% of symptomatic patients have normal endoscopy Symptoms do not correlate with degree of mucosal damage

Upper Endoscopy

Erosive EsophagitisGrade A

Erosive EsophagitisGrade B

Erosive EsophagitisGrade C

Gastroenterology 2008; AGA Medical Position Statement.

Erosive EsophagitisGrade D

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Adenocarcinoma

Esophageal Ulceration

GERD Complications

Esophageal Stricture

Barrett’s Esophagus

Esophageal Hemorrhage

Esophageal Ulceration

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High-Resolution Manometry

Hiatal Hernia, Hypotensive LES and ineffective motility-10 mmHg

200 mmHg

20

Bolus Present

Bolus Absent

500

1000

Hiatal Hernia, Hypotensive LES and normal peristalsis

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Ambulatory Reflux Monitoring

Ambulatory reflux monitoring has slightly better sensitivity of (>70%)

Wireless and catheter-based modalities

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Ambulatory Reflux Monitoring

Impedance sensors Longer duration, more physiologic

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GERD Is Often Asymptomatic in Advanced Lung Disease

PERCENTAGE WITH GERD + SYMPTOMS

Pulmonary Fibrosis: 47%◦ Eur Respir J. 2006 Jan;27(1):136-42.

COPD: 58%◦ Eur Respir J. 2004 Jun;23(6):841-5.

Cystic Fibrosis: 43%◦ Gut. 2008 Aug;57(8):1049-55

Systemic Sclerosis: 70%◦ BMC Gastroenterol. 2015 Feb 15;15:24.

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Mechanisms of Abnormal Reflux in Advanced Lung Disease

Greater thoraco-abdominal pressure gradient (worsened with obesity)

Hypotensive LES (< ¼)

Increased coughing (stress reflux)

Delayed gastric emptying

Ineffective esophageal motility/aperistalsis

Reduced saliva for neutralizing acid

Anti-cholinergic medicationProp

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Difficulties in Identifying Reflux into the Airway

The inter-observer agreement on pharyngeal reflux events is poor

◦ Clin Gastroenterol Hepatol. 2013 Apr;11(4):366-72

Patients with Rx-refractory “LPR” symptoms don’t have LPR (or GER)

◦ Neurogastroenterol Motil. 2017 Jan;29(1). doi: 10.1111/nmo.12909.

Patients can feel “regurgitation” when refluxate extends up to, but not above, UES

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Role of the Gastroenterologist Assess for symptomatic GERD Assess for other underlying systemic disease –connective tissue disease? Objective assessment of asymptomatic GERD

• EGD/manometry/MII-pH or BRAVO/gastric emptying

Treat symptomatic GERD• Don’t forget lifestyle changes!

• ARS if symptoms PPI refractoryProp

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Unresolved Issues with GERD and Advanced Lung Disease

Value of treating asymptomatic reflux abnormalities Individual differences lung diseases Effect of long-term PPI on microbiome Lack of clear predictors for anti-reflux surgery success PPI vs anti-reflux surgery (vs PPI/UES) in terms of improving survival Identify biomarkers for progression, change in management

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Benefits of Anti-Reflux Surgery Not Seen in All Studies

No difference in lung inflammation with no reflux vs reflux/no ARS vs reflux/ARSSurgery. 2011 Oct;150(4):598-606

About 10% failure rate; some cases of mortality Concern with fundoplication in patients with poor motility: Will this lead to increased esophageal retention → supra-esophageal reflux ?Prop

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Esophageal DistentionPhysiologic Reflexes of Esophagus and

Upper Esophageal Sphincter

Esophageal Distention Peristalsis

Liquid Distention UES contraction Air Distention UES relaxation

Creamer and Schlegel, Journal of Applied Physiology 1957

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Heartburn ≠ GERD ≠ Aspiration≠ LPR ≠ Lung Disease

Reflux into esophagus provokes protective UES reflex responses• Impaired in GERD, but lung disease population not studied

Reflux also evokes protective laryngeal reflex responses• Again, these have not been studied in lung disease patients

Unknown what aspiration parameters, if any, result in lung disease Severe reflux/impaired motility a cause of or just marker for lung disease?

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Anatomy of the Esophagus0 - Lower

Sphincter

2- Upper

Sphincter

1- ~ 10“ of

esophagus

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150 mmHg

-10 mmHg

Slow Acid Infusion in HealthyS

low

Aci

dIn

fusi

on

10s

EUCR

Primary Peristalsis

Slo

w A

cid

Infu

sion

10sSecondary Peristalsis

Slo

w A

cid

Infu

sion

10sStriated Peristalsis

Persistent EUCR

Persistent EUCR

Babaei et al. Gastroenterology 2015

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150 mmHg

-10 mmHg

Slow Acid Infusion in SERD

30sSlo

w A

cid

Infu

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Persistent EUCR Non-PeristalticContractions

Slo

w A

cid

Infu

sion

10s

Primary Peristalsis

No response Repetitive Swallow

Babaei et al. Gastroenterology 2015

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0%

20%

40%

60%

80%

100%

Healthy GERD SERD

Upper Esophageal Sphincter

No Response Swallow UES Contraction

Freq

uenc

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Res

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Healthy GERD SERD

Esophagus

No Response Non-peristaltic Contraction Peristaltic Contraction

A B *# #

Babaei et al. Gastroenterology 2015

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Esophagopharyngeal Regurgitation During Acid Infusion

Esophageal pH

Pharyngeal pH

10 s

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Esophagopharyngeal Regurgitation During Acid Infusion

Esophageal pH

Pharyngeal pH

10 s

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Clinical Implication

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Babaei et al. DDW 2012

Upper Esophageal Sphincter Assist Device (UESAD)

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Effect of UESAD on UES pressure1- Cricoid Pressure 3- Therapeutic Pressure

2- UESAD Application

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0%

20%

40%

60%

80%

100%

Patients Infusions

Without UESAD With UESADE

soph

agop

hary

ngea

l Ref

lux

(EP

R)

9/13

1/39

16/39

1/13* #

Shaker and Babaei et al. Laryngoscope 2014

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Effect of UESAD on Nocturnal GERD Symptoms

Analysis of variance, P < 0.01 corrected* Compared to baseline, P < 0.05 corrected# Compared to sub-therapeutic, P < 0.05 corrected

* *** # *#* #

* #

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Therapeutic UESAD Magnitude of Response

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Summary Esophageal protective reflexes in a subgroup of GERD patients with regurgitation and respiratory manifestations (SERD) is impaired Impaired esophageal and UES reflexes demonstrably predisposed patients to esophagopharyngeal regurgitation (EPR) Application of a modest 20-30 mmHg of cricoid pressure using UES assist device reduced subjective and objective measures of EPR, and offered significant symptomatic improvement

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