LA MALATTIA DA
REFLUSSO
GASTROESOFAGEO
MALATTIA DA REFLUSSO
GASTROESOFAGEO (MRGE)
Ogni sintomo e/o alterazione anatomica micro-macroscopica
dovuti al contatto con la mucosa dell’esofago
(ma anche del cavo orale e delle vie aeree),
di materiale gastro-duodenale refluito in eccesso
Prevalence, severity and frequency of heartburn
and acid regurgitation in 700 italian subjects
Heartburn
Regurgitation
77%
66%
23%
34%
Severity
12%
51%
37%
6%
18%
Mild
Moderate
Severe
76%
Frequency
10%
42%
24%
Weekly
Monthly
24%
4%
16%
Daily
59%
21%
Occasionally
Valle et al, Dig Dis Sci, 1999
Prevalence per 10,000 population
Prevalence of GORD by age and sex
900
Males
Females
800
700
600
500
400
300
200
100
12-24
24-44
45-64
64-74
Age group
El-Serag & Sonnenberg; Gut 1997; 41: 594-9.
Pathophysiology of reflux
Modlin & Sachs; 1997
Anatomy of the Gastroesophageal junction
Lower LES pressure associated with
more severe GERD
LES Pressure cv
(mmHg)
100
80
60
40
20
0
Normal
Volunteers
Non-inflammatory
Mild
GERD
Esophagitis
Kahrilas PJ, et al. Gastroenterology 1986;91:897.
Severe
Esophagitis
MRGE fisiopatologia
Rilassamenti transitori del LES
Transient LES Relaxation = TLESR:
(rilassamenti riflessi non collegati alla
deglutizione che determinano una cavità comune
fra stomaco ed esofago)
• 100% dei reflussi nei controlli
• 75% dei reflussi nei soggetti con MRGE
The physiologic record of
a spontaneous transient
relaxation of the lower
esophageal sphincter
Mittal et al,1997
Abnormal Esophageal clearance
Up 48% of GERD patients have impaired esophageal
clearance
Inadequate peristalsis occurs in the lower esophagus
Longer reflux contact time increases the risk of
complications
Meccanismo di reflusso nei pazienti con ernia iatale
Model of relation among lower esophageal sphincter pressure, size of
hernia, and the suscptibility to gastroesophageal reflux induced by
provocative maneuvers as reflected by the reflux score
Sloan et al, 1992
Abnormal
oesophageal
clearing
Insufficient
antireflux
barrier
TOO MUCH
ACID IN THE
WRONG PLACE
Altered
gastric
emptying
Diet, drugs
smoking, etc
Clinical spectrum of GERD
35%
NON EROSIVE REFLUX
DISEASE = NERD
COMPLICATED GERD
60%
5%
ESOPHAGITIS
GI symptoms
bother me!
I´m worried
and concerned
Heartburn
disturbs my
sleep
My whole life is
affected
I can not bend
over or exercise
I can not eat
and
drink whatever
I like
Age distribution of patients with gastroesophageal reflux disease (n=1440)
Smout, Aliment Pharmacol Ther 1997.
Hiatal Hernia Distribution
96%
100%
% of patients
80%
71%
72%
EE
SSBE
LSBE
(<3cm)
(>3cm)
60%
40%
29%
20%
0%
NERD
Cameron, Am J Gastroenterol 1999.
Abnormal 24-Hour Esophageal pH Monitoring
in the Different GERD Groups
100%
90%
75%
% patients
80%
60%
50%
n=40
40%
20%
n=40
n=71
0%
NERD
Martinez, Gastroenterology 2001.
Erosive
Esophagitis
Barrett's
Esophagus
Dilated Intercellular Spaces
Normal Intercellular Spaces
L’attacco acido-peptico indebolisce le giunzioni cellulari,
portando ad un allargamento dell’interstizio cellulare e
successiva aumentata penetrazione dell’acido
Heartburn Severity in Patients With EE and
Patients with NERD*
Heartburn Grade
MILD
MODERATE
32 %
Erosive
Esophagitis
(n=316)
SEVERE
68 %
NERD*
(n=677)
* Nonerosive reflux disease.
Venables et al, Scand J Gastroenterol 1997; 32:965-973.
MRGE RIVISITATO
Pirosi come risultato di reflusso acido capace di determinare
Esofagite microscopica
Danno macroscopico nei
nei pazienti con NERD
pazienti con esofagite erosiva
Sintomi tipici di reflusso
gastroesofageo
Pirosi
Sensazione di bruciore retrosternale
Rigurgito acido
Liquido di sapore acido o amaro
Range of presentations of GORD
Typical symptoms
(Heartburn/regurgitation)
With
oesophagitis
Atypical symptoms
Chest pain
(visceral
hyperalgesia)
Without
oesophagitis
Complications
Oesophageal
erosions
and/or ulcers
Stricture
Hoarseness
(‘reflux
laryngitis’)
Asthma,
chronic cough,
wheezing
Dental erosions
Barrett’s
oesophagus
Oesophageal
adenocarcinoma
Nathoo, Int J Clin Pract 2001; 55: 465–9.
MRGE : Qualità di vita
GERD and the risk of esophageal complications
30-40% of patients with acid-related diseases have an
esophagitis
Richter; 1992
Patients with acid-related diseases have a higher
prevalence for esophageal complications
• Esophageal ulceration 2 - 7 %
• Barrett‘s esophagus 10 - 15 %
• Esophageal stricture 4 - 20 %
Spechler; 1992
The risk of malignancy in patients with Barrett‘s
esophagus may be up to 30 - 40 times that of
the general population
De Vault & Castell; 1995
Long and Short Barrett's Esophagus and
Intestinal Metaplasia of the Cardia
IM
3 cm
IM
IM
Long BE
Short BE
IM-Cardia
CP1097000-11
Prevalence of Barrett's Esophagus at Different Ages
Patients endoscoped
who had BE (%)
1,4
Male
1,2
1,0
Male + female
0,8
0,6
Female
0,4
0,2
0,0
0
0-9
1
2
3
4
5
6
7
8
10-19
20-29
30-39
40-49
50-59
60-69
70-79
80-89
Age (years)
Mean age of developing BE ~ 40
Mean age at diagnosis of BE was 63
CP1097000-3
Incidence of Adenocarcinoma of Esophagus:
U.S., Europe, Australia
2,5
2
Cases/ 1,5
100,000/
1
year
0,5
0
1950
1960
1970
1980
1990
2000
Median year of observation period
CP1097000-15
Reflux
Take a good history!
‘A burning feeling
rising from your
stomach or lower
chest towards
your neck’
Sensitivity 96%
(PPV 87%)
for GERD compared
with endoscopy/
24-hour pH
monitoring
Carlsson et al, 1998
The sensitivity of omeprazole and placebo during
each day of study week
100
90
Sensitivity (%)
80
70
60
50
40
30
20
10
0
Day 1
Day 2
Day 3
Day 4
Omeprazole 20 mg bid
Day 5
Placebo
Day 6
Day 7
Johnsson et al,1998
Diagnostic tests for gastro-oesophageal
reflux disease
Sensitivity
LOS manometry
(< 10 mm Hg) (6*)
58%
Endoscopy (> grade 1
oesophagitis) (2*)
Standard acid-reflux
test (8*)
Prolonged oesophageal
pH monitoring (5*)
96%
77%
Gastro-oesophageal
scintiscanning (3*)
Acid-perfusion test
(Bernstein) (7*)
84%
68%
Mucosal
biopsy (5*)
Barium
oesophagogram (3*)
Specificity
61%
91%
95%
40%
85%
79%
84%
88%
* Number of studies from which sensitivity and specificity were calculated
82%
83%
98%
Indicazioni cliniche
all’uso della pH-metria esofagea
• Asma in paziente adulto, non allergico, con sospetto reflusso (un
test positivo non prova casualità)
• Laringite o tosse cronica con sospetto che possano essere dovuti a
reflusso
• Dolore toracico in paziente con valutazione cardiaca completa
negativa
• Sintomi tipici e atipici resistenti alla terapia antisecretiva maggiore
con inibitori della pompa protonica (mentre il paziente assume il
farmaco)
• Valutazione pre-operatoria per chirurgia anti-reflusso in pazienti
sintomatici con endoscopia negativa
• Valutazione post-operatoria in pazienti con sintomi persistenti o
poco modificati dall’intervento
Endoscopia
The LA Classification system for the
endoscopic assessment of reflux esophagitis
Grade A
One (or more)
mucosal break no
longer than 5mm,
that does not
extend between the
tops of two mucosal
folds
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
Grade B
One (or more)
mucosal break more
than 5 mm long, that
does not extend
between the tops of
two mucosal folds
Grade D
One (or more)
mucosal break
which involves at
least 75% of
the esophageal
circumference
Lundell et al 1999
Barrett’s Esophagus
CP1097000-27
Esofago di Barrett. Si osserva la presenza di metaplasia intestinale con cellule
caliciformi (blu). A destra l’epitelio squamoso esofageo. Colorazione Alcian Blu-PAS
Scopi della terapia
• Alleviare la sintomatologia dovuta al reflusso
• Ottenere la guarigione delle lesioni anatomiche, quando
presenti
• Prevenire la ricomparsa delle lesioni e delle complicanze
• Modificare la storia naturale della malattia
DIETARY FACTORS AND GERD
Advice
on diet
Strength of scientific Pathophysiologically Recommendable?
evidence?
conclusive?
Avoid fatty meals
Equivocal
Equivocal
Not generally
Avoid sweets
Weak
Yes
Not generally
Avoid spicy food
and raw onions
Weak
Equivocal
Not generally
Avoid carbonated
beverages
Moderate
Yes
Yes
Prefer decaffeinated
beverages
Equivocal
Equivocal
Not generally
Avoid citrus products
and juices
Weak
Yes
Not generally
Meining and Classen, 2000
Healing rates for various
PPIs in GORD
L = lansoprazole
P = pantoprazole
O = omeprazole
R = rabeprazole
30 = 30 mg/day, 20 = 20 mg/day, 40 = 40 mg/day
Petite et al. L30/O20
Castell et al. L30/O20
Mee et al. L30/O20
Mulder et al. L30/O40
Mossneret al. P40/O20
Corinaldesi et al. P40/O20
Hotz et al. P40/O20
Vicari et al. P40/O20
Thjodleifsson et al. R20/O20
Dekkers et al. R20/O20
0
20
40
60
80
100
Patients healed at 8 weeks (%)
Thomson, Curr Gastroenterol Rep 2000; 2: 482–93.
Patients in symptomatic remission (%)
Symptomatic relapse rates are similar in GERD
patients whether or not they have esophagitis
100
80
60
40
25%
20
10%
0
0
1
2
3
4
5
6
Time since treatment cessation (months)
Patients without esophagitis
Patients with esophagitis
Carlsson et al 1998
Omeprazolo is superior to ranitidine and cisapride
in maintaining patients with healed reflux oesophagitis
in long-term endoscopic remission
ns
Omeprazole 20 mg od
plus cisapride 10 mg tid
**
Omeprazole 20 mg od
*
****
*****
****
Ranitidine 150 mg tid
plus cisapride 10 mg tid
***
Cisapride 10 mg tid
Ranitidine 150 mg tid
0
20
40
60
80
100
Patients in remission at 12 months (%)
* p=0.02; ** p=0.03; *** p=0.05; **** p=0.003; ***** p<0.001; ns=not significant
Vigneri et al., 1995