Caterina Mengoli (PV) Giusi Lorusso, Cecilia Susca (BA)

Università di Pavia

MALATTIE RESPIRATORIE E MALATTIA DA REFLUSSO

GASTROESOFAGEO

GERD: DEFINITION

Vakil et al, Am J Gastroenterol 2006

GERD is a condition which develops when the reflux of stomach contents causes

troublesome symptoms and/or complications

GERD: DEFINITION

Vakil et al, Am J Gastroenterol 2006

GERD: DEFINITION

Vakil et al, Am J Gastroenterol 2006

Typical reflux syndrome

HEARTBURN

REGURGITATION

Extraesophageal reflux syndromes

NON CARDIAC CHEST PAIN DYSPHAGIA

Atypical reflux syndrome

CHRONIC COUGH

LARYNGITIS

PHARYNGITIS

ASTHMA

Syndromes with esophageal injury

REFLUX ESOPHAGITIS

REFLUX STRICTURE

BARRETT’S ESOPHAGUS

ESOPHAGEAL ADENOCARCINOMA

GERD: EPIDEMIOLOGY

Loiano-Monghidoro Study

< twice/wk >twice/wk

Prevalence and frequence of typical GERD symptoms

Prev

alen

ce %

esophagitis Barrett’s esophagus

Prev

alen

ce %

Prevalence of oesophageal injury

12.1

1.2

Grade I

Grade II Grade III Grade IV

Zagari et al, Gut 2008

GERD: PATHOPHYSIOLOGY

Kahrilas, Clev Clin J Med 2003

GERD: DIAGNOSIS

Who What

Typical reflux symptoms without alarm signs Clinical history

Alarm signs Atypical reflux syndromes

Refractory GERD

Upper Endoscopy

Extra-esophageal syndromes Refractory GERD

24 hrs pH-impedance monitoring

Katz et al, Am J Gastroenterol 2013

GERD: DIAGNOSIS

Non erosive esophagitis

Barrett’s esophagus

Erosive esophagitis

Upper endoscopy

GERD: DIAGNOSIS

Esop

hage

al B

ody

(dis

tanc

e fr

om L

ES)

IMPE

DAN

CE

pH

Acid Reflux Weakly Acid Reflux

Reflux Reflux

Stomach

-5 cm from LES

Heartburn

24 hrs esophageal pH-impedance monitoring

GERD: DIAGNOSIS

24 hrs esophageal pH-impedance monitoring

Abnormal esophageal acid exposure

Reflux frequency

Reflux characteristics (acid/weakly acid/non acid; liquid/mixed)

Symptom association with reflux episodes

Symptom association probability (SAP) Symptom sensitivity index (SSI)

GERD: DIAGNOSIS OF EXTRAESOPHAGEAL SYNDROMES

GERD is a possibile co-factor in asthma, chronic cough,

laryngitis, pharyngitis

This association is rare if typical GERD symptoms are absent

Upper endoscopy is not useful in demonstrating the association

24 hrs esophageal pH-impedance monitoring

NEGATIVE

POSITIVE

direct the diagnosis toward non-GERD etiologies

evaluate temporal association between reflux and symptoms

Katz et al, Am J Gastroenterol 2013

GERD: THERAPY

Kahrilas, NEJM 2008

Dietary and lyfestyle recommandations Medical options

Protein pump inhibitors (PPI) 8 wk course of: omeprazole 20 mg/die pantoprazole 40 mg/die esomeprazole 40 mg/die lansoprazole 30 mg/die rabeprazole 20mg/die Histamine-receptors antagonists (H2RA) useful as a maintenance option Antiacids

Surgical options

Laparoscopic fundoplicatio Bariatric surgery

GERD AND LUNG

Strong epidemiological association between chronic lung

diseases and GERD

Evidence of benefit of GERD therapy on pulmonary function in

patients with chronic lung diseases

GERD AND LUNG

1 2 3 4

Foregut Anlage of the thyroid Anlage of the lungs Stomach

5 6 7

Anlage of the dorsal pancreas Midgut Hindgut

GERD AND LUNG

GERD AND LUNG

Emilsson et al, Gastroenterol Res Pract 2013

A proposed association between GERD and lung disease: possible ethiologies

GERD AND LUNG: MICROASPIRATION

Physiological and negligible during sleep in healthy subjects

Significant in consciousness alterations and pathological GERD

Gleeson et al, Chest 1997 Ravelli et al, Chest 2006

GERD AND LUNG: MICROASPIRATION

Chronic microaspiration

↑ TGF β

Lymphocytic bronchilitis obliterans

Pulmonary fibrosis

Perng et al, Chest 2007

The spectrum of lung disease due to Chronic Occult Aspiration

Cardasis et al, Ann Am Thorac Soc 2013

fibrosis granuloma giant cell

GERD AND LUNG: MICROASPIRATION

Proposed biomarkers

Emilsson et al, Gastroenterol Res Pract 2013

GERD AND LUNG: VAGAL REFLEX

Airway receptors

microaspiration

Esophageal receptors

Acidic pH High osmolality Pressure

GERD

Nucleus of the solitary tract

Vagal efferents

BRONCHOCONSTRICTION

Harding et al, Ann NY Acad Sci 2013

COUGH

Pulmonary autonomic system

TNFα, NGF and others

GERD AND LUNG: VAGAL REFLEX

Lang et al, Am J Physiol 2008 Wu et al, Chest 2000

GERD AND LUNG

Chronic lung diseases (COPD)

↑ abdominal pressure

↑ reflux episodes

Bronchoconstriction

↑ TLESR

Bronchodilator drugs

↓ LES tone

Chronic lung disease coud exacerbate GERD

Pulmonary hyperinflation

Diaphragm flattening

Harding et al, Ann NY Acad Sci 2013

GERD AND ASTHMA

Haveman et al, Gut 2008

Prevalence of reflux symptoms in patients with asthma

GERD AND ASTHMA

Haveman et al, Gut 2008

Prevalence of abnormal distal esophagus acid

exposure

Prevalence of esophagitis

GERD AND ASTHMA

Increased negative inspiratory intrathoracic pressure, bronchodilator therapy, chronic and acute airflow obstruction promote reflux

Microaspiration and vagally mediated bronchospasm are the proposed mechanisms by which reflux could trigger asthma

Esophageal acid exposure could enhance bronchial hyper-rensponsiveness rather than alter pulmonary function parameters

Temporal association between reflux and asthma has not been yet clarified.

Theodoropoulos et al, Allergy 1999

Harding et al, Ann NY Acad Sci 2013

Wu et al, Chest 2000

Haveman et al, Gut 2008

GERD AND ASTHMA

Morning peak expiratory flow and PPI

Chan et al, Arch Intern Med 2011

GERD AND ASTHMA

Author N patients

Treatment Asthma symptoms

Peak expiratory flow

Pulmonary function (FEV1)

Shimizu et al 30 Lansoprazole 30 mg for 8 wk Improved Improved Unchanged

Kiljander et al 107 Omeprazole 40 mg for 8 wk Improved Unchanged Improved

Kiljander et al 770 Esomeprazole 80 mg for 16 wk N/A Unchanged N/A

Stordal et al 38 Omeprazole 20 mg for 12 wk Unchanged N/A Unchanged

Boeree et al 36 Omeprazole 80 mg for 12 wk Unchanged Unchanged Unchanged

Littener et al 207 Lansoprazole 60 mg for 24 wk Unchanged Unchanged Unchanged

Jiang et al 30 Omeprazole 20 mg + domperidone 30 mg

Improved

Improved

Improved

Galmiche et al, Aliment Pharmacol Ther 2008

PPI therapy

Surgical therapy

Uncontrolled studies seem to show a benefit in relieving asthma symptoms Need for further evidence

GERD AND COPD

Prevalence of GERD symptoms

Prevalence of abnormal distal esophagus acid

exposure

30-53,6 57-62

Mokhlesi B, Chest 2001

Rogha M, J Gastrointest Liver Dis 2010

Casanova, Eur Respir J 2004

Kempainen, Chest 2007

GERD AND COPD

Typical GERD symptoms often absent The severity of GERD symptoms is higher in patients with more severe COPD

Hyperinflation is a factor risk for GERD

GERD is a factor risk for exacerbation Insufficient data on efficacy of PPI therapy

Kempainen, Chest 2007

Mokhlesi B, Chest 2001

Rascon-Aigiular, Chest 2006

Liang, Lung 2012

Sasaki, Ther Adv Respir Dis 2011

GERD AND IPF

In idiopatic pulmonary fibrosis a very high prevalence of asymptomatic GERD has been shown: abnormal distal reflux in 78% patients and proximal reflux in 33%

Pepsin documented in BALF of IPF patients with acute exacerbation

A history of laparoscopic fundoplication has found to be an indipendent predictor of longer survival

Gastro-esophageal reflux seem to be a contributor to the epithelial injury that leads to lung fibrosis and to the progression of the disease

Sweet, Ann Surg 2006

Lee, Eur Respir J 2012

Lee, Am J Respir Crit Care Med 2011

Allaix, J Gastrointest Surg 2013

GERD AND IPF

Lee, Am J Respir Crit Care Med 2011

GERD AND LUNG TRANSPLANT

Probable Potential

Acute rejection Aspergillus colonization of lower airways

CMV pneumonitis Aspiration

HLA mismatching CMV infection

Lymphocytic bronchitis/bronchiolitis Donor antigen-specific activity

Noncompliance with medications EBV reactivation

Primary graft disfunction Native lung disease

Gastroesophageal reflux

Older donor age

Pneumonia

Prolonged allograft ischemia

Recurrent infection other than CMV

GERD AND LUNG TRANSPLANT

Study No patients Abnormal distal reflux %

Increased nonacid reflux %

Hadjiliadis 2003 43 69.8

Cantu 2005 167 76

D’Ovidio 2006 50 at 3 mo 30 at 12 mo

26 50

Blondeau 2008 45 on PPI 18 off PPI

39 73

27 28

King 2009 61 65

Fisichella 2012 25 unilateral 30 bilateral 6 retransplant

24 63 100

GERD AND LUNG TRANSPLANT

upright recumbent total

Mea

n %

tim

e p

H <

4

P<0.05 P<0.05 P<0.05

ESOPHAGEAL ACID EXPOSURE IN LTx AND GERD

Di Stefano et al, SIGE 2011

GERD AND LUNG TRANSPLANT

upright recumbent total

Mea

n %

tim

e p

H <

4

P<0.05 P<0.05 P<0.05

ESOPHAGEAL ACID EXPOSURE IN LTx AND GERD

Di Stefano et al, SIGE 2011

GERD AND LUNG TRANSPLANT

Cantu et al, Ann Thorac Surg 2004

LUNG DISEASES AND GERD

No sufficient evidence for routine pulmonary function evaluation in GERD patients

No sufficient evidence for reflux screening and treatment (in absence of typical symptoms) in chronic lung diseases.

Further evidences are needed

Thank you for your attention