IL REFLUSSO GASTROESOFAGEO E LA MALATTIA DA REFLUSSO GASTROESOFAGEO

1
IL REFLUSSO GASTROESOFAGEO E LA MALATTIA DA
REFLUSSO GASTROESOFAGEO

• Annamaria Staiano
• Dipartimento di Scienze Mediche Traslazionali
• Università Federico II Napoli, Italia

2
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
18-8-2016
3
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.

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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
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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
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WHEN GER CAUSES TROUBLESOME SYMPTOMS OR
COMPLICATIONS IT IS DEFINED AS GER DISEASE (GERD).
Am J Gastroenterol 2009
7
IN PEDIATRIC PATIENTS, ESOPHAGEAL COMPLICATIONS
OF GERD ARE REFLUX ESOPHAGITIS, HEMORRHAGE,
STRICTURE, BARRETTS ESOPHAGUS, AND, RARELY
ADENOCARCINOMA.
Am J Gastroenterol 2009
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COME DIAGNOSTICARE LA MRGE
2

• MANIFESTAZIONI GASTRO-INTESTINALI
• MANIFESTAZIONI RESPIRATORE

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COME DIAGNOSTICARE LA MRGE LE MANIFESTAZIONI
GASTRO- INTESTINALI E RESPIRATORE
Non cè evidenza nel prescrivere trial
farmacologici empirici in lattanti e bambini
piccoli con sintomi suggestivi di MRGE (Evidenza
B)
J Pediatr Gastroenterol Nutr 2009 49498-547
10

• 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
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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
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Trends of outpatient prescription drug
utilization in US children, 2002-2010. Chai G.
Pediatrics 201213023-31
Introduction Symptoms Prevalence Diagnosis
Treatment Colusion
12
12
8/18/2016
18-8-2016
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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 lt4.0 and the number of acidic reflux
  episodes gt5 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. 2013163692-698.e2
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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, 95CI, 1.15-2.46).
Trikha A. Pediatr Allergy Immunol. 201324582-8
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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

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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)
COME DIAGNOSTICARE LA MRGE LE MANIFESTAZIONI
GASTRO-INTESTINALI E RESPIRATORE
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MANIFESTAZIONI EXTRAINTESTINALI DI MRGE

• POLMONITI RICORRENTI
• PATOLOGIA LARINGEA
• SINUSITE
• OTITE MEDIA E OTALGIA
• EROSIONI DENTALI
• APNEA
• ASMA E TOSSE CRONICA

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PATOLOGIA LARINGEA
A
B
C
D
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.
19

• 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.

20
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. 20131924-9
21
Michele Ghezzi, Michela Silvestri, Edoardo Guida,
Angela Pistorio,Oliviero Sacco, Girolamo
Mattioli, Vincenzo Jasonni,Giovanni A.Rossi
Respiratory Medicine (2011) 105, 972e978
22
Effect of proton pump inhibition on acid, weakly
acid and weakly alkaline GER in children.
23
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. 2011159504-6
24
Lansoprazole for children with poorly controlled
asthma a RCT (2) Writing Committee for the
American Lung Association Asthma Clinical
Research Centers. JAMA.2012307373-81
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
18-8-2016
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PROTON-PUMP INHIBITOR THERAPY INDUCES
ACID-RELATED 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
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CASO CLINICO La dispepsia non ulcerosa

• Alberto giunge alla ns osservazione alletà 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.

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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

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CASO CLINICO La dispepsia non ulcerosa

• Il tempo intanto passa..Alberto continua a
  lamentare gli stessi sintomi, la mamma riferisce
  che riduce lassunzione 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 completamentead Aprile
  2010 bussa alla porta del nostro ambulatorio

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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 (25-50ct.)
• Cute pallida , mucose visibili ipoemiche.
  Idratazione sufficiente, refill lt 2 sec. P.A.
  100/60 mmHg. F.C. 138 battiti/min.

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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 (25-50ct.)
• Cute pallida , mucose visibili ipoemiche.
  Idratazione sufficiente, refill lt 2 sec. P.A.
  100/60 mmHg. F.C. 138 battiti/min.

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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

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CASO CLINICO La dispepsia non ulcerosa

• Considerata lassenza di ematemesi e melena ed il
  buon compenso emodinamico si decide di non
  trasfondere.
• A ricovero pratica.tra laltro
• Calprotectina fecale 29 micrg/g
• Occult test negativo
• Striscio periferico allesame 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.lt0.023)
• Test del sudore negativo, Steatocrito
  negativo

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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)

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CASO CLINICO La dispepsia non ulcerosa

• A questo punto.sono passati 3 giorni dal
  ricovero ..decidiamo di eseguire finalmente
  unEGDS
• 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.

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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

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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 dimissioneAlberto sta
  bene non lamenta sintomi e la sua Hb 9.6 mg/dl