IL REFLUSSO GASTROESOFAGEO E LA MALATTIA
DA REFLUSSO GASTROESOFAGEO
Annamaria Staiano
Dipartimento di Scienze Mediche Traslazionali
Università “Federico II” Napoli, Italia
Pediatric GERD and acid-related conditions (ARC):
trends in incidence of diagnosis and acid suppression therapy
• Between 2000 and 2005, annual incidence of GERD/ARC diagnosis
among infants (age ≤1 year) more than tripled (from 3.4 to 12.3%)
and increased by 30% to 50% in other age groups.
• Patients diagnosed by GI specialists (9.2%) were
more likely to be treated with PPIs compared to
patients diagnosed by primary care physician (PCP).
PPI-initiated patients doubled 1999
31.5%
2005
62.6%
when compared with H²RA-initiated patients
associated with 30% less discontinuation
90% less therapy switching in 1st month
higher comorbidity burden
pre-treatment total HCU
costs when diagnosed
2
Nelson SP. J Med Eco 2009;12:348-55
19-12-2015
Il reflusso gastroesofageo (RGE)
• Il reflusso gastroesofageo (RGE) è un
fenomeno fisiologico che si verifica in lattanti,
bambini e adulti.
• Il reflusso fisiologico si presenta solitamente
in circa il 70% dei lattanti di 4 mesi di età.
• Nella maggior parte dei lattanti il RGE non
causa alcun sintomo.
“PREVALENCE AND NATURAL HISTORY OF
GASTROESOPHAGEAL REFLUX:
PEDIATRIC PROSPECTIVE SURVEY” (1/2)
• A detailed questionnaire was completed by 59
primary care pediatricians .
• 2642 patients (0-12 months) were prospectively
enrolled during a 3-month period.
• Follow-up at 6, 12, 18 and 24 months of age
Campanozzi A. Pediatrics 2009
“PREVALENCE AND NATURAL HISTORY OF
GASTROESOPHAGEAL REFLUX:
PEDIATRIC PROSPECTIVE SURVEY” (2/2)
• 313 infants (12%; 147 girls) affected by infant regurgitation.
• Vomiting in 34/313 patients (10.9%).
•
•
•
•
•
Follow-up in 210/313: regurgitation disappeared
56 (27%) at 6 months
128 (61%) at 12 months
23 (11%) at 18 months
3 (1%) at 24 months
• Organic disease in 2/210 (0.1%)
Campanozzi A. Pediatrics 2009
WHEN GER CAUSES TROUBLESOME
SYMPTOMS OR COMPLICATIONS IT IS
DEFINED AS GER DISEASE (GERD).
Am J Gastroenterol 2009
IN PEDIATRIC PATIENTS, ESOPHAGEAL
COMPLICATIONS OF GERD ARE REFLUX
ESOPHAGITIS, HEMORRHAGE, STRICTURE,
BARRETT’S ESOPHAGUS, AND, RARELY
ADENOCARCINOMA.
Am J Gastroenterol 2009
2
COME DIAGNOSTICARE LA MRGE:
 MANIFESTAZIONI
GASTRO-INTESTINALI
 MANIFESTAZIONI RESPIRATORE
COME DIAGNOSTICARE LA MRGE: LE MANIFESTAZIONI GASTROINTESTINALI E RESPIRATORE
“Non c’è evidenza nel prescrivere trial farmacologici empirici
in lattanti e bambini piccoli con sintomi suggestivi di MRGE
(Evidenza B)
J Pediatr Gastroenterol Nutr 2009; 49:498-547
•162 infants with crying, regurgitation, refuse feed, coughing
•Treatment with lansoprazole or placebo for 4 weeks
•44/81 infants (54%) in each group were responders, identical for
lansoprazole and placebo
•Serious adverse events, expecially lower respiratory tract infections,
more frequently in the lansoprazole group compared with the placebo
group
Orenstein SR et al. J Pediatr 2009; 154: 514-20
“STOP THE PPI EXPRESS:
THEY DON'T KEEP BABIES
QUIET”
• Dramatic increase in the use of PPIs in infants (4-fold between 2000
and 2003), but with no evidence suggesting a change in the incidence
of GERD
• PPIs have become the modern effector in the old instruction to “take
two aspirins and call me in the morning” in clinical practice
• Given the increasing evidence that they offer little benefit for some of
the symptoms for which they are prescribed, a serious effort to curtail
their empiric use is warranted
Putnam PE. J Pediatr 2009; 154 (4); 514-520
Trends of outpatient prescription drug utilization in US children, 2002-2010.
Chai G. Pediatrics 2012;130:23-31
12
19-12-2015
12/19/2015
Introduction Symptoms Prevalence Diagnosis Treatment
Colusion
Efficacy and safety of once-daily esomeprazole for the treatment of
GERD in neonatal patients.
There were no significant differences between the esomeprazole and
placebo groups in the percentage change from baseline in the total number of
GERD-related signs and symptoms (-14.7% vs -14.1%, respectively).
Mean change from baseline in total number of reflux episodes was not
significantly different between esomeprazole and placebo (-7.43 vs -0.2,
respectively); however, the percentage of time pH was <4.0 and the number of
acidic reflux episodes >5 min in duration was significantly decreased with
esomeprazole vs placebo (-10.7 vs 2.2 and -5.5 vs 1.0, respectively; P ≤
.0017).
The number of patients with adverse events was similar between treatment
groups.
Signs and symptoms of GERD traditionally attributed to acidic reflux
in neonates were not significantly altered by esomeprazole treatment.
Esomeprazole was well tolerated and reduced esophageal acid exposure
and the number of acidic reflux events in neonates.
Davidson G. J Pediatr. 2013;163:692-698.e2
Development of food allergies in patients with GERD
treated with gastric acid suppressive medications.
Children with GERD who were treated with GAS were more likely to be diagnosed
with a food allergy (Hazard ratio (HR): 3.67, 95% CI 2.15-6.27),
as were children with GERD diagnosis but who were not treated
with GAS medications (HR: 2.15, 95% CI: 1.21-3.81).
A direct comparison of the two GERD cohorts showed that children with GERD
who were treated with GAS had a greater risk of food allergy than those with
GERD who were untreated (HR, 1.68, 95%CI, 1.15-2.46).
Trikha A. Pediatr Allergy Immunol. 2013;24:582-8
POTENZIALI RISCHI DEGLI
INIBITORI DI POMPA PROTONICA (IPP)
• Gli effetti collaterali attribuibili agli IPP tra cui cefalea, diarrea,
costipazione, nausea si verificano negli adulti fino al 14% dei casi
• Aumento del rischio di polmonite acquisita in comunità e gastroenterite
acuta nei bambini e negli adulti trattati con IPP
• Aumento del rischio di candidemia e di NEC nei neonati prematuri
trattati con terapia acido-soppressiva
• Nefrite interstiziale
• Possibile aumento del rischio di infezione da C. Difficile e di fratture
dell'anca negli adulti trattati cronicamente con IPP
COME DIAGNOSTICARE LA MRGE: LE MANIFESTAZIONI
GASTRO-INTESTINALI E RESPIRATORE
« Nei bambini più grandi e negli
adolescenti con bruciore e
dolore retrosternale, un trial
terapeutico con acido inibitori
può essere utile per
determinare se il reflusso è la
causa dei sintomi»
(Evidenza C)
MANIFESTAZIONI EXTRAINTESTINALI DI
MRGE
• POLMONITI RICORRENTI
• PATOLOGIA LARINGEA
• SINUSITE
• OTITE MEDIA E OTALGIA
• EROSIONI DENTALI
• APNEA
• ASMA E TOSSE CRONICA
PATOLOGIA LARINGEA
A
B
D
C
E
The data linking reflux to chronic hoarseness, chronic cough, sinusitis,
chronic otitis media, erythema, and cobblestone appearance of the
larynx come mainly from case reports and case series.
• In children, based on current data, PPIs should not be used empirically.
• The single relatively large high quality study on the utility of PPI for cough
associated with GORD found no beneficial effect in infants and those on
lansoprazole had significantly increased serious adverse events, in
particular lower respiratory infections.
• Data on milk modification for infants and cough with GORD is insufficient
to make specific recommendations.
• Until more evidence is available in the form of well-designed RCTs, other
causes of cough should be considered in children with cough and GORD,
prior to any consideration of empiric treatment with a prolonged course of
GORD medications/interventions.
Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD004823. DOI: 10.1002/14651858.CD004823.pub4.
Gastroesophageal reflux disease and childhood asthma.
Clinical studies show that GERD is highly prevalent in children with asthma, with
estimates as high as 80%, but nearly half of the children are asymptomatic.
However, there is no conclusive evidence per se that asymptomatic GERD
informs asthma control, and treatment of GERD in the few controlled trials
available for review does not substantively improve asthma outcomes.
In a recent large controlled clinical trial, treatment with a PPI was not
only ineffective, but adverse effects were common, including an
increased prevalence of symptomatic respiratory infections.
Current evidence does not support
the routine use of anti-GERD medication
in the treatment of poorly controlled asthma of childhood.
Blake K. Curr Opin Pulm Med. 2013;19:24-9
Michele Ghezzi, Michela Silvestri, Edoardo Guida, Angela Pistorio,Oliviero Sacco, Girolamo
Mattioli, Vincenzo Jasonni,Giovanni A.Rossi
Respiratory Medicine (2011) 105, 972e978
Effect of proton pump inhibition on acid, weakly acid
and weakly alkaline GER in children.
90
80
70
60
non-acid
weakly acid
acid
50
40
30
20
10
0
before therapy
on therapy
Turk H. World J Pediatr. 2013;9:36-41
Higher rate of bronchoalveolar lavage culture positivity in
children with nonacid reflux and respiratory disorders.
• ? children with chronic cough or wheezing and
with more full-column, nonacid reflux
have a higher likelihood of a positive BAL fluid culture
• 46 children with cough
patients who had a positive culture had
significantly more full-column, nonacid GER
than those who had a negative culture
PPI  ?  pos culture BAL
Rosen R. Pediatr. 2011;159:504-6
Lansoprazole for children with poorly controlled asthma: a RCT (2)
Writing Committee for the American Lung Association Asthma Clinical Research Centers.
JAMA.2012;307:373-81
…
115 children with pH metries: prevalence of GER was 43%
In the subgroup with a positive pH study,
no treatment effect for lansoprazole vs placebo
was observed for any asthma outcome.
Children treated with lansoprazole reported more respiratory infections
(relative risk, 1.3 [95% CI, 1.1-1.6]).
Children with poorly controlled asthma without symptoms of GER
who were using inhaled corticosteroids,
the addition of lansoprazole, compared with placebo,
improved neither symptoms nor lung function
but was associated with increased adverse events.
24
19-12-2015
“PROTON-PUMP INHIBITOR THERAPY INDUCES ACIDRELATED SYMPTOMS IN HEALTHY VOLUNTEERS
AFTER WITHDRAWAL OF THERAPY”
• RCT with 120 healthy adults volunteers
•Random
12 weeks of placebo
8 weeks of esomeprazole 40 mg/die followed by 4
weeks with placebo.
PPI therapy for
8 weeks induces acid-related symptoms in healthy volunteers
after withdrawal
Reimer C et al. Gastroenterology 2009; 137: 80-87
CASO CLINICO:
La dispepsia non ulcerosa
• Alberto giunge alla ns osservazione all’età di 5 anni e 4
mesi…..(Aprile 2010)
• Nessun problema clinico rilevante da segnalare fino a circa 1
anno prima quando manifesta tosse stizzosa
• Test allergometrici: positività per aeroallergeni
• Avvia profilassi con antileucotrieni.
• Dopo qualche mese…..(Maggio 2009) esordio di frequenti
eruttazioni, senso di sazietà precoce, vomito episodico
(2-3 episodi/mese) di colore scuro (!), sembra avere fastidio
allo “stomaco”.
CASO CLINICO:
La dispepsia non ulcerosa
• Dopo 4 mesi (Settembre 2009) la sintomatologia persiste …
pratica esami ematochimici
Hb 10,8 g/dl
MCV 70.6 fl
MCH: 22.3 Picogr
GR 4.630.000/micrL
Ferritina 3 ng/ml
Sideremia 21micrg/dl
Sierologia per malattia celiaca negativa
• Parametri auxologici: nella norma
• Per la lieve anemia ipocromica microcitica avvia una profilassi
marziale
CASO CLINICO:
La dispepsia non ulcerosa
• Il tempo intanto passa…..Alberto continua a lamentare
gli stessi sintomi, la mamma riferisce che riduce
l’assunzione di alimenti solidi anche se… continua a
mangiare grosse quantità di “junk food”
• Siamo a Gennaio 2010, considerata la comparsa di
saltuari episodi di rigurgiti e le modifiche del
comportamento alimentare, viene consigliato un trial
empirico con IPP (pantoprazolo per 28 gg)
• Alberto migliora ma non completamente……ad Aprile
2010 bussa alla porta del nostro ambulatorio
CASO CLINICO:
La dispepsia non ulcerosa
• Alberto si presenta estremamente pallido, appare
realmente sofferente, organizziamo un Day Hospital
urgente
E.O
• Peso: 20.200 Kg (50°-75° ct.)
Altezza: 141 cm (25°-50°ct.)
• Cute pallida , mucose visibili ipoemiche. Idratazione
sufficiente, refill < 2 sec. P.A. 100/60 mmHg. F.C. 138
battiti/min’.
CASO CLINICO:
La dispepsia non ulcerosa
• Alberto si presenta estremamente pallido, appare
realmente sofferente, organizziamo un Day Hospital
urgente
E.O
• Peso: 20.200 Kg (50°-75° ct.)
Altezza: 141 cm (25°-50°ct.)
• Cute pallida , mucose visibili ipoemiche. Idratazione
sufficiente, refill < 2 sec. P.A. 100/60 mmHg. F.C. 138
battiti/min’.
CASO CLINICO:
La dispepsia non ulcerosa
Dopo qualche ora arrivano i primi esami di laboratorio:
• RBC: 4.170 (x 106/µL); HB: 7.00 g/dl; HCT: 24.6 (%);
MCV: 59.00 fl; MCH: 16.8 picogr; PLT: 663 (x 103/µL);
WBC: 7.31 (x103/µL) (NEUT: 33.2 %; LINF: 51.5 %;
MON: 7.7 %; EOS: 3.4%; BAS: 0.3%)
• Ca: 8.7 mg/dl; Prot: 5.5 g/dl; Albumina: 3.5 g/dl;
• Quick, APTT e Fibrinogeno: nella norma
Si dispone il ricovero
CASO CLINICO:
La dispepsia non ulcerosa
• Considerata l’assenza di ematemesi e melena ed il buon compenso
emodinamico si decide di non trasfondere.
• A ricovero pratica….tra l’altro
Calprotectina fecale: 29 micrg/g
Occult test: negativo
Striscio periferico: all’esame dello striscio periferico si evidenziano
numerosi microciti ed ipocromia delle emazie, una discreta
anisopoichilocitosi
Sierologia per celiachia: negativa
QPE: lieve aumento delle alfa globuline, ipogammaglobulinemia
Ig tot: IgG 2.960 g/l, IgM 1.050 g/l, IgA 0.555 g/l, IgE tot: 99.80 KU/l
Carico di ferro: nella norma (T0: 7 micrg/dl, T 120 min: 311 micrg/dl)
Test di permeabilità intestinale: rapporto cellobiosio/mannitolo
0.005 (v.n.<0.023)
Test del sudore: negativo,
Steatocrito: negativo
CASO CLINICO:
La dispepsia non ulcerosa
Ricapitoliamo un attimo…..
• Alberto ha un anemia severa ipocromica microcitica:
Non presenta segni clinici (ematemesi e/o melena) e/o di
laboratorio (occult test e calprotectina fecale: negativi o
nella norma) di sanguinamento GI attivo
Non presenta malassorbimento (Test di permeabilità
intestinale, Carico di Fe: nella norma) o maldigestione
(Steatocrito e test del sudore: nella norma)
Non presenta alterazioni della coagulazione e/o problemi
midollari (striscio periferico nella norma)
CASO CLINICO:
La dispepsia non ulcerosa
A questo punto….sono passati 3 giorni dal ricovero …..decidiamo di
eseguire “finalmente” un’EGDS
Macroscopicamente: ESOFAGITE SEVERA (III grado sec. Hetzel-Dent)
Istologicamente: Mucosa esofagea: tessuto di granulazione attivo ed
essudato fibrino-leucocitario. Gastrite severa attiva (H.pylori. Neg) . Mucosa
duodenale con normale architettura e segni infiammatori.
CASO CLINICO:
La dispepsia non ulcerosa
•
Per escludere alterazioni anatomiche pratichiamo un Rx-digerente
con studio fino al cieco
• Esofago leggermente ectasico con ispessimento delle pliche mucose come
da esofagite. Cardias beante. Stomaco in sede, normale per forma e
volume, con ipertrofia del rilievo plicare, che si nota anche a livello del
duodeno da riferire a gastro-duodenite. Regolare morfologia, struttura e
svolgimento del digiuno ed ileo. Cieco in sede
CASO CLINCO:
La dispepsia non ulcerosa
La terapia di Alberto….
• IPP e.v.: 1 mg/kg/die per 4 gg, quindi esomeprazolo: 20 mg/die
per os per 12 settimane
• Ferro ev (fabbisogno di ferro calcolato= 338 mg) e quindi per
os per 2 mesi (30 mg/die)
Dopo un settimana dalla dimissione……Alberto sta bene
non lamenta sintomi e la sua Hb: 9.6 mg/dl