The GERD, The Bed, & The Ugly

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The GERD, The Bed, & the Ugly: Nighttime Gastroesophageal Reflux www.RxForSanity.com Patricia L. Raymond MD FACG Rx For Sanity

Evolving Concepts of Nighttime Reflux
Why is nighttime a special period of risk for reflux complications?
What symptoms are linked to nighttime reflux?
What areas should be explored to effectively diagnose nighttime reflux?
How should nighttime reflux be managed?
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What is GERD? “ GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications” Montr é al definition of GERD Vakil et al. Am J Gastroenterol 2006;101:1900–20

The Montréal definition of GERD “ GERD is a condition which develops when the reflux of stomach content causes troublesome symptoms and/or complications” Esophageal Syndromes Extra-esophageal Syndromes Symptomatic Syndromes
Typical Reflux Syndrome
Reflux Chest Pain Syndrome
Syndromes with Esophageal Injury
Reflux Esophagitis
Reflux Stricture
Barrett’s Esophagus
Adenocarcinoma
Established Associations
Reflux Cough
Reflux Laryngitis
Reflux Asthma
Reflux Dental Eros.
Proposed Associations
Pharyngitis
Sinusitis
Idiopathic Pulmonary Fibrosis
Recurrent Otitis Media
Vakil et al. Am J Gastroenterol 2006;101:1900–20

The prevalence of GERD is increasing Non-white men White men White women Non-white women Death rate per million Proportional rate per 10,000 hospitalisations 0.0 0.5 1. 0 1.5 2. 0 2.5 0 100 200 250 350 400 50 150 300 Reflux esophagitis (year) GERD (year) 1968– 1972 1973– 1977 1978– 1982 1983– 1987 1988– 1992 1970– 1974 1975– 1979 1980– 1984 1985– 1989 1990– 1992 El-Serag & Sonnenberg. Gut 1998;73:327–33

The prevalence of GERD is underestimated – many individuals do not consult a physician Consulted a physician Consulted a pharmacist Used antacids Heartburn sufferers (%) 0 20 4 0 60 8 0 100 n=568 Louis et al. Eur J Gastroenterol Hepatol 2002;14:279–84

GERD is common at all ages Prevalence (%) 0 2 0 40 6 0 80 25–34 35–44 45–54 55–64 65–74 Age (years) At least weekly episodes of GERD symptoms Females Males Locke et al. Gastroenterology 1997;112:1448–56

Frequency and severity of heartburn in antacid users who have not consulted a physician Daily Several times per week Mild Frequent antacid users (%) 0 20 4 0 60 8 0 100 n=155 Moderate Severe Heartburn frequency Heartburn severity Robinson et al. Arch Intern Med 1998;158:2373–6

Reflux esophagitis or GERD complications in antacid users who have not consulted a physician Wheezing Odynophagia Hoarseness Dysphagia Barrett’s esophagus (non-dysplastic) Reflux esophagitis 0 20 40 60 80 100 Frequent antacid users (%) n=155 Robinson et al. Arch Intern Med 1998;158:2373–6

Quality of life of patients with GERD is impaired compared with the general population Patients with GERD Mean HRQL score (SF-36) 0 20 40 60 80 100 Physical functioning Role physical Bodily pain General health Vitality Social functioning Role emotional Mental health German normative population Kulig et al. Aliment Pharmacol Ther 2003;18:767–76

Heartburn affects many aspects of everyday life in adults with GERD Individuals with activity affected (%) n>130,000 0 20 40 60 80 100 Liker et al. J Am Board Fam Pract 2005;18:393–400 Enjoying food Eating out Sleep Work Family activities Exercise Socialising Travel for pleasure Intimacy/sex Gardening Time with spouse Business Hobbies Playing with kids Team sports

Quality of life deteriorates as the severity of reflux symptoms increases Wiklund et al. Am J Gastroenterol 2006;101:18–28 Heartburn severity (GSRS score) General population of Malm ö , Sweden n=1476 PGWB, Psychological General Well Being GSRS, Gastrointestinal Symptom Rating Scale None Very severe Well-being (PGWB score) 0 20 40 100 140 1 2 3 4 5 6 7 60 80 120 Healthy individuals Clinically meaningful impairment of well being

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Economic impact related to symptom severity Moderate heartburn Severe heartburn No heartburn Mild heartburn Mean duration of absence from work per week (hours) 0 2 4 6 8 1 3 5 7 Reduction in productivity at work ( %) 0 10 20 25 35 5 15 30 Reduction in productivity during regular daily activities (%) 0 20 40 50 60 10 30 Wahlqvist et al. Value Health 2002;5:106–13

Reduction in work productivity due to GERD is comparable to that for other chronic diseases Productivity loss (hours/week) 5.7 6.1 5.7 4.8 4.1 3.3 1.0 0.7 1.3 0.6 0.6 1.1 0 2 4 6 8 10 GERD n=273 Back pain n=125 Headache n=129 Arthritis n=124 Allergies n=292 High blood pressure n=129 Present at work Absent from work Adapted from Dean et al. Gastroenterology 2003;124(Suppl 1):A505

Case Study: Excessive Daytime Sleepiness
66-y.o. man, recently retired, c/o daytime sleepiness
PMHx: Hypertension, hypercholesterolemia
Current meds: Hydrochlorothiazide, pravastatin
PE: 6 ' 0 '' , 96 kg; BP: 140/90 mm Hg;  daytime sleepiness
R/o: Sleep apnea, other sleep disorders
Prescribed lifestyle modifications: Reduce caffeine intake; increase daytime activity
Keep sleep log (including spouse report)
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Case Study: Return Visit at 3 Weeks
Adopted lifestyle modifications
Still very sleepy during the day
Sleep log
No snoring/choking episodes
Frequent nighttime cough (spouse aware, patient not)
Awakes unrefreshed, some morning hoarseness
Further questioning
Occasional epigastric discomfort, radiating toward throat/spine
Previous self-medication with antacids
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Supine Position/Sleep Diminish Protective Barriers Against GE Reflux www.RxForSanity.com  Esophageal acid clearance 1–3 1 Orr W, et al. Gastroenterology. 1984;86:814–819. 2 Orr W, et al. Am J Gastroenterol. 2000;95:37–42. 3 Orr W, et al. Am J Gastroenterol. 1994;89:509–512. 4 Kjell én G, Tibbling L. Scand J Gastroenterol . 1978;13:283–288.  Salivary flow and swallowing 1  Gravity-mediated drainage 4

Recumbent Reflux Events Can Be Prolonged www.RxForSanity.com * = Patient reported heartburn Courtesy of William C. Orr, PhD Esophageal pH Daytime (Upright) Reflux (GERD Patient) Nighttime (Recumbent) Reflux (GERD Patient) Elapsed Recumbent Time Elapsed Upright Time 8 6 4 2 0 1 hr 2 hr 2 hr Esophageal pH 8 6 4 2 0 1 hr * * *

Nighttime Heartburn: Prevalent in People With Heartburn www.RxForSanity.com Those Reporting Nighttime Heartburn 1 Shaker R, et al. Gastroenterology . 2001;120(Suppl 1):A-433. 2 Farup C, et al. Arch Intern Med . 2001;161:45–52. 74% 79% N=1,000 adults with heartburn at least once a week N=1,284 adults with GERD symptoms at least once a week AGA Survey 1 Farup et al. 2

Nighttime GERD Reduces Health Status Even More Than Daytime GERD www.RxForSanity.com N=1,552 SF-36=Medical Outcomes Study Short-Form 36 Health Survey * P <0.001 vs. control group for all scales except “Physical Functioning.” P <0.001 vs. daytime GERD for all scales. Adapted from Farup C, et al. Arch Intern Med . 2001;161:45–52. 30 50 70 90 Nighttime GERD* Daytime GERD Control Group Physical Functioning Role Limitations–Physical Bodily Pain General Health Vitality Social Functioning Role Limitations– Emotional Mental Health SF-36 Score (n=945) (n=339) (n=268) Worse Better

Recumbent Reflux Episodes Are More Frequent and Prolonged in Erosive GERD Patients www.RxForSanity.com * * * P <0.05 vs. nonerosive esophagitis patients Adapted from Orr WC, et al. Am J Gastroenterol . 1994;89:509–512. Recumbent Reflux Episodes Prolonged (>5 min) Recumbent Reflux Episodes 0 1 2 3 4 5 Nonerosive (n=21) Erosive (n=33) Number/Hr (mean) 0 0.1 0.2 0.3 0.4 0.5 Nonerosive (n=21) Erosive (n=33) Number/Hr (mean) Results of Ambulatory pH Monitoring

Nighttime Reflux Increases Risks of GERD Complications
Erosive esophagitis 1
Complicated erosive esophagitis 2
Ulceration
Strictures
Barrett’s esophagus
Adenocarcinoma 3
Sleep deprivation 4
www.RxForSanity.com 1 Orr WC, et al. Am J Gastroenterol . 1994;89:509–512. 2 Robertson D, et al. Gut . 1987;28:1484–1488. 3 Lagergren J, et al. N Engl J Med . 1999;340:825–831. 4 Gislason T, et al. Chest. 2002;121:158–163. Esophageal Disease Progression Atypical Complications Other Symptoms Respiratory disturbances 4

Common Symptoms Related to Daytime and Nighttime Reflux Events www.RxForSanity.com Symptoms reliably reported on by patients Symptoms masked by ‘sleep,’ resulting in less recall and reporting by patients * Symptom often experienced in daytime hours but results from nighttime reflux. 1 DeVault KR, et al. Am J Gastroenterol . 1999;94:1434–1442. 2 Gislason T, et al. Chest. 2002;121:158–163. Heartburn (variable) Sleep disturbance/daytime sleepiness* Coughing Wheezing 1 Nighttime Symptoms 1,2 Heartburn Regurgitation Wheezing Daytime Symptoms 1

At Night, GERD Patients May Not Present With Heartburn
Typical daytime presentation
Retrosternal burning sensation, radiating upward toward the neck 1
High specificity and sensitivity
Others present with pressure, epigastric pain, etc.
Extraesophageal manifestations may present without heartburn 2
Nighttime manifestations
During sleep, heartburn may not be felt
If present, patients may not recall or report
Daytime heartburn may be absent
Clinical pearl: Don’t rely on heartburn alone to diagnose nighttime GERD.
www.RxForSanity.com 1 New Considerations in the Evaluation and Management of Gastroesophageal Reflux Disease (GERD) . [Pamphlet]. Chicago: AMA; 2002. 2 Koufman JA. Laryngoscope . 1991;101:1–78.

Nighttime GERD Implicated in Sleep Disturbances www.RxForSanity.com Adapted from Gislason T, et al. Chest. 2002;121:158–163. * P <0.001; † P <0.01; ‡ P <0.05 Symptom Controls: No Nighttime Reflux (n=2,096) Nighttime Reflux (n=101) Nighttime symptoms (%) Snoring ( > 3 nights/wk) 5 16* Reported apnea ( > 1 night/wk) 1 5 † Nightmares ( > 1 night/wk) 4 17* Daytime symptoms (%) Daytime sleepiness ( > 3 days/wk) 14 30* Involuntary falling asleep ( > 1 day/wk) 4 8 ‡

Nighttime GERD and Associated Respiratory Disturbances www.RxForSanity.com Adapted from Gislason T, et al. Chest. 2002;121:158–163. * P <0.001; † P <0.05 Symptoms Controls: No Nighttime Reflux (n=2,096) (%) Nighttime Reflux (n=101) (%) Wheezing 24 47* Nighttime chest tightness 11 23* Nighttime breathlessness 4 13* Asthma 4 9 † Nighttime cough 31 59*

Assessing Regurgitation in Nighttime Reflux
Regurgitation
Possibly related to volume
May present as sour taste in mouth, but not always
May be nonacid
Nighttime presentation
May manifest as coughing
Micro-aspiration
Clinical pearl: At night, regurgitation may manifest as coughing and choking.
www.RxForSanity.com Koufman JA. Laryngoscope . 1991;101:1–78. Orr WC. Am J Gastroenterol . 2000;95:37–42.

Nighttime Reflux May Increase Risk of Micro-aspiration www.RxForSanity.com Tomonaga T, et al. Dig Dis Sci. 2002;47:9–14.
133 patients with airway disturbance and GERD
Proximal reflux episodes
Frequent in supine position
Correlated with nighttime cough
Distal probe Proximal probe

Case Study: Asthma Patient
28-y.o. man c/o chronic cough at night (2  /wk); wheezing daily
PMHx: Recent onset of mild asthma (1 yr)
Current meds: albuterol as needed
PE: wheezing
Pulmonary function tests
FEV 1 : 70% of predicted
FEV 1 /FVC = 0.65
PEF variability: >30%
Diagnosis: moderate, persistent asthma 1
Therapy changed: inhaled flunisolide; salmeterol (for nighttime symptoms); inhaled albuterol as needed
www.RxForSanity.com 1 National Institutes of Health. NAEPP. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. 1997. NIH Publication 97-4051.

Asthma Patient: Return Visit
3 months later: PFTs still abnormal, symptoms unchanged
High suspicion of nighttime GERD-related asthma 1
Adult onset
Wheezing worsened by supine position
Nighttime cough
Heartburn 2 times per week, at night
Diagnosis: Nighttime GERD
www.RxForSanity.com 1 New Considerations in the Education and Management of Gastroesophageal Reflux Disease. [Pamphlet]. Chicago: AMA; 2002.

Association of GERD and Asthma www.RxForSanity.com Adapted from Barish CF, et al. Arch Intern Med. 1985;145:1882–1888. Two Basic Mechanisms

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Some patients with GERD need additional investigations
Those with:
atypical history
reflux symptoms that are frequent and long-standing or do not respond to therapy
alarm symptoms:
severe dysphagia
weight loss
bleeding
haematemesis
mass in the upper abdomen
anaemia
Labenz & Malfertheiner. World J Gastroenterol 2005;11:4291–9

Radiology – limited value in the diagnosis of GERD
May be helpful for:
Detecting subtle strictures and large hiatal hernias in patients with dysphagia.
Identifying pathologies unrelated to GERD.

Investigate the degree and timing of reflux.
Correlate reflux events with symptoms.
Limitation: A quarter of patients (6/22) had different reflux patterns (from normal to pathological) when tested 6 weeks apart under identical conditions, due to diurnal variations.
Investigation of acidic reflux episodes by 24-hour pH-monitoring Franzén & Grahn. Scand J Gastroenterol 2002;37:6–8

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The most common findings during endoscopy for GERD 0 10 20 30 40 50 60 Patients (%) Non-erosive reflux disease 57 Reflux esophagitis 31 Barrett's esophagus 12 398 consecutive patients No alarm symptoms Sharma et al. Gastroenterology 2000;122(4 Suppl 1):A-584

The GERD symptom pattern is similar in patients with and without reflux esophagitis Belching Bloating Abdominal pain Nausea Regurgitation Heartburn (100%) Epigastric pain Scale=% of patients with symptom Without reflux esophagitis With reflux esophagitis Carlsson et al. Eur J Gastroenterol Hepatol 1998;10:119–24

Severity of heartburn is similar in patients with different grades of reflux esophagitis A B C D LA grade of reflux esophagitis Patients with heartburn (%) 0 10 20 30 40 60 50 No heartburn Mild heartburn Moderate heartburn Severe heartburn n=4283 Levine et al. Am J Gastroenterol 1999;94:2591

The LA Classification
Reflux esophagitis is defined by the presence of definite breaks in the esophageal mucosa, visible by endoscopy:
mucosal break – an area of slough or erythema that has discrete demarcation from the mucosa.
The extent of reflux esophagitis is described independently of other measures of severity in a clear, simple and highly reproducible way.
Complications, such as Barrett’s esophagus or esophageal stricture, are described separately.
Lundell et al. Gut 1999;45:172–80

The Los Angeles Classification system for the endoscopic assessment of reflux esophagitis One (or more) mucosal break, no longer than 5 mm, that does not extend between the tops of two mucosal folds Grade A One (or more) mucosal break, more than 5 mm long, that does not extend between the tops of two mucosal folds Grade B 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 Grade C One (or more) mucosal break that involves at least 75% of the esophageal circumference Grade D Lundell et al. Gut 1999;45:172–80

LA Grade C www.RxForSanity.com

LA Grade B is the most prevalent grade of esophagitis in western countries 34% 39% 20% 7% Grade A Grade B Grade C Grade D El-Serag & Johanson. Scand J Gastroenterol 2002;37:899–904

Direct visualisation of the esophageal mucosa by endoscopy
Optimal technique for determining the presence and severity of reflux esophagitis.
The only reliable technique for detecting endoscopically suspected esophageal metaplasia.
Allows biopsy to be performed to confirm histological changes characteristic to Barrett’s esophagus, dysplasia or carcinoma.
Dent et al. Gut 1999;44(Suppl 2):S1–16

Patients with persistent GERD are at risk of esophageal complications GERD Barrett ’s metaplasia Barrett ’s metaplasia with dysplasi a Adenocarcinoma

The incidence of esophageal adenocarcinoma is increasing 0 .0 0.6 1. 0 Incidence/100,000 person-years 1950 1960 1980 1970 1990 0 .2 0 .4 0 .8 1.2 1.4 Year Bytzer et al. Am J Gastroenterol 1999;94:86–91

Risks of Adenocarcinoma with Nocturnal Reflux
The risk of esophageal adenocarcinoma in subjects with weekly nighttime symptoms was
~11x
that of controls without weekly nighttime symptoms
www.RxForSanity.com Lagergren J et al. N Engl J Med . 1999;340:825-831. Freidin N et al. Gut . 1991;32:1275-1279.

Esophageal adenocarcinoma risk increases with frequency and severity of GERD symptoms 4 8 1 2 18 Odds ratio for esophageal adenocarcinoma 0 2 6 10 14 20 None 1/week 2–3/week > 3/week 16 None 1–2 2.5–4 4.5–6.5 Frequency of reflux symptoms Symptom severity score Lagergren et al. N Engl J Med 1999;340:825–31

Pathophysiology of Barrett’s esophagus
Adaptation to the longstanding exposure to excessive amounts of stomach acid and bile.
During healing, a metaplastic process occurs in which squamous epithelium is replaced by abnormal columnar epithelium.
Short segment Barrett’s esophagus

Screening for Barrett’s esophagus
Alarm symptoms (dysphagia, bleeding, weight loss) and chronic GERD should be referred for endoscopy.
A one-time endoscopy to exclude Barrett’s esophagus in 50-year-old patients with GERD has been proposed by some experts as a cost-effective alternative.

The prevalence of Barrett’s esophagus increases with the duration of reflux symptoms <1 1–5 5–10 >10 Duration of symptoms (years) Prevalence of endoscopic Barrett's esophagus (%) 0 5 1 0 15 2 0 25 Lieberman et al. Am J Gastroenterol 1997;92:1923–7

Barrett’s esophagus is associated with prolonged acid reflux 20 0 5 1 0 15 Number of episodes 0 1 2 3 Time ( minutes) Reflux episodes >5 minutes Mean duration of reflux episode Barrett’s esophagus, n=51 Severe reflux esophagitis, n=30 Moderate reflux esophagitis, n=45 Controls, n=24 Coenraad et al. Am J Gastroenterol 1998;93:1068–72

Who is at risk for Barrett’s?
5% to 13% of GERD patients verses <1% unselected patients with EGD
More common in white or Hispanic men and less frequent in black and Asian
Smoking, obesity are risk factors

Different GERD symptoms with Barrett’s?
Long history of gastroesophageal reflux disease (GERD)
Increased severity of nocturnal reflux symptoms.
But... 25 % of patients with Barrett’s esophagus have no reflux symptoms, most probably related to a diminished acid sensitivity.

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Premalignant metaplastic process
Normal squamous epithelium of the distal esophagus is replaced by columnar epithelium that is more resistant to acid and bile
Normal squamocolumnar junction between esophagus and stomach Barrett’s esophagus with displaced squamocolumnar junction Squamous epithelium Columnar epithelium

Pathology
Specialized intestinal metaplasia (SIM).
SIM is characterized by the presence of goblet cells.
Goblet cells Intestinal metaplasia

Short or long?

C&M staging for Barrett’s .

90-95% of patients who have Barrett's esophagus will not develop cancer.

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Goals of Therapy for Nighttime Reflux
Prevent, heal esophagitis (or eliminate recurrence)
Prevent complications
Eliminate symptoms
Improve sleep
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Therapeutic Modalities Used for GERD and Nighttime Heartburn
Lifestyle Modifications
OTC Medications
Prescription Medications
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The frequency of reflux symptoms is directly related to the time that the esophageal pH is <4 0 2 3 5 7 8 Intraesophageal acid exposure (% time pH <4) 6 – 9 9 – 12 12 – 15 15 – 18 18 – 21 21 – 24 0 – 3 3 – 6 Time of day (hours) A lmost continuous symptoms Daily symptoms Occasional symptoms H ealthy individuals n=190 1 4 6 Joelsson & Johnsson. Gut 1989;30:1523–5

The healing of reflux esophagitis is directly related to the duration of intragastric pH >4 0 20 40 60 80 100 Patients healed after 8 weeks (%) 2 4 6 8 10 12 14 16 18 20 22 Duration intragastric pH >4 ( hours ) Adapted from Bell et al. Digestion 1992;51(Suppl 1):59–67

Gastric pepsin activity declines if the pH is raised above 4 0 20 40 60 80 100 Maximum pepsin activity (%) Gastric juice pH 4 3 2 1 . Adapted from Berstad. Scand J Gastroenterol 1970;5:343–8

Increased exposure of the esophagus to acidic gastric content is a dominating cause of GERD “ In the majority of people with reflux disease, there is abnormally prolonged exposure of the distal esophagus to acid and pepsin.” “ The dominant mechanism of symptom production in reflux disease is by contact of the esophageal mucosa with acid and pepsin.” Dent et al. Gut 1999;44(Suppl 2):S1–16

PPIs and H 2 -receptor antagonists in relieving symptoms in patients with reflux esophagitis 0 20 40 60 Patients free from heartburn (%) 0 1–2 3–4 6–8 Weeks of treatment PPIs H 2 -receptor antagonists n=2198 p<0.0001 8 0 Chiba et al. Gastroenterology 1997;112:1798–810

PPIs and H 2 -receptor antagonists in healing of reflux esophagitis p<0.0005 0 20 40 60 80 Reflux esophagitis cases healed (%) 0 2 4 6 8 10 12 Time (weeks) PPIs H 2 -receptor antagonists Placebo 100 Chiba et al. Gastroenterology 1997;112:1798–810

H 2 -receptor antagonists inhibit signal transduction to the proton pump Proton pump Signal transduction to activate proton pump H + Acid secretion Parietal cell Histamine receptor Histamine (H 2 )-receptor antagonist Histamine Inhibition of histamine receptor Gastric gland Blood

PPIs control acid secretion by directly inhibiting the proton pump Inhibition of acid secretion Parietal cell Canalicular space Proton pump Inhibition of proton pump Activation Concentration PPI (inactive) H + Blood Gastric gland

Symptom response may be a useful indicator of healing of reflux esophagitis “ In more than 75% of patients with esophagitis who present with frequent episodes of symptoms, control of heartburn to less than two episodes per week with therapy is associated with healing of esophagitis.” Genval statement 62, accepted with some reservation Dent et al. Gut 1999;44(Suppl 2):S1–16

Progression and regression of GERD
Relapse or regression of endoscopic findings under routine care, without relation to symptoms, over 2 years.
* No erosions Labenz et al. Am J Gastroenterol 2006;101:2457 – 62 NERD n=1717 74.5% *50.4% *61.3% 24.9% 0.6% 1.6% Los Angeles A/B n=1512 Los Angeles C/D n=278 7.8% 37.1% 41.8%

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Areas to Explore to Uncover Nighttime Reflux
Assessment of nighttime-associated symptoms: heartburn, regurgitation, chronic cough/hoarseness, difficulty breathing, wheezing, or frequent throat clearing
Effect of position on symptom(s) (i.e., recumbent vs. upright)
Effect of symptom(s) on sleep (i.e., falling asleep, staying asleep, waking refreshed)
History and efficacy of patient ’ s symptom management
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The GERD, the Bed, and the Ugly
Why is nighttime a period of risk for reflux complications?
Protective mechanisms reduced/absent = prolonged esophageal exposure to refluxate
What symptoms are linked to nighttime reflux?
Nighttime asthma/cough, sleep disturbance, etc.
What areas should be explored to effectively diagnose nighttime reflux?
Effect on sleep, positional dependency
How should nighttime reflux be managed?
Acid suppression, possibly lifestyle modification
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The GERD, The Bed, & The Ugly

by Patricia Raymond on Jan 20, 2012

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