Epidemiologia

Most previous studies reported that the prevalence of RE increases with age

First, our results showed that men are more likely to develop RE (men: 9.8%, women: 2.4%)

Fourth, most previous studies have shown positive correlations between RE and drinking as well as
between RE and smoking.

In the present study, we found no significant association between EE and an increasing BMI in children.

In adult patients, several cross-sectional studies have proven that there is a positive relationship
between obesity and the prevalence of GERD

howed that a higher prevalence of GERD was closely associated with the BMI level in adults but not in
patients aged < 20 years.

central body fatness, measured by the waist circumference (WC), is also a risk factor for symptoms of
GERD in children

eating heaving foods; eating at night; consuming greasy food, salty, and spicy food; and drinking soda
(from 18.665.1%) (22). Such dietary habits (i.e., foods with high fat and salt content) are known to cause
a decrease in the lower esophageal sphincter (LOS) pressure and an increase in the frequency of transient
LOS relaxations, thereby increasing the risk of reflux disease (23). Furthermore, GERD symptoms and
unfavorable dietary habits were significantly correlated to sleep disturbance, which impacts patients
quality of life (24). The EE-related NCCP group had a significantly greater number of sleep-related reflux
events compared to the non-ERD-related NCCP.

Sleep-related reflux has been associated with prolonged acid mucosal contact time, which increases the
risk of esophagitis

Furthermore, multiple medications more frequently taken by the elderly for co-morbid illnesses,
such as hypertension, cardiovascular disease, and pulmonary disease and depression are well known
to decrease LES pressure
Our findings proved that there were strong positive correlations with EE-related NCCP and an older age; a
family history; unfavorable dietary habits; chest pain related to food; chest pain related to sleep;
epigastric pain; and nausea, vomiting, and/or regurgitation in children.

In summary, we suggest that pediatric patients with chest pain should be adequately evaluated by
pediatric gastroenterologists for GERD.

Salivary production slightly decreases with age and is associated with a significantly decreased
salivary bicarbonate response to acid perfusion of the esophagus

Many diseases that can negatively affect esophageal motility appear with greater frequency with
advancing age, such as Parkinsons disease, cerebrovascular disease, cardiovascular disease,
pulmonary disease and diabetes mellitus.

Direct esophageal injury occurs more frequently in the elderly, because of medications given for co-
morbid illnesses such as cardiovascular diseases, cerebrovascular disease, arthritis and osteoporosis
that can directly injure the esophageal mucosa. These medications include nonsteroidal anti-
inflammatory drugs (NSAIDs), potassium tablets, iron supplements and bisphosphonates.

It is now clear that the antireflux barrier at the GEJ consists of an intrinsic and extrinsic sphincteric
component. The intrinsic sphincter is called the LES, which is a combination of a thickening of the
circular smooth musculature of the esophagus and oblique sling fibers of the proximal stomach [6].
The extrinsic sphincter is formed by striated muscular fibers of the diaphragm, which encircle the
esophagus at the level of the LES. At the level of LES, the distal esophagus is attached to the
diaphragm by the phrenoesophageal ligament.

The swallow-associated LES relaxation is mediated through the central nervous system (dorsomotor
nucleus of the vagus nerve).

Pharyngeal intubation increases the rate of TLESRs.

Afferent fibers, which signal gastric distension, are known to project to the NTS [71] and to the
dorsal motor nucleus of the vagus (DMV), either directly or via interneurons [72]. The DMV contains
the cell bodies of vagal efferent neurons that project to the LES.

Gastric mechanoreceptors have been postulated to serve as the afferent pathway for a number of
vagal reflexes, including reflex relaxation of the gastric corpus. Such a neural pathway could
therefore potentially mediate TLESRs. In the opossum, LES relaxation can also be induced by intrinsic
gastric nerves independently of extrinsic nerves [73]. Whether such a pathway mediates TLESRs is
not known, but it cannot be involved in the associated inhibition of the crural diaphragm during
TLESRs. The complete abolition of TLESRs by cervical vagal cooling [66] also argues against a
dominant role for a local intramural pathway in mediating TLESRs.

the severity of esophagitis appears to correlate directly with the size of the hiatal hernia and
indirectly with the magnitude of the LES pressure.

Patients with erosive esophagitis usually have low LES pressure.

Hiatal hernia is associated with an increased prevalence of reflux during swallow-induced LES
relaxation presumably because of pooling of acid in the herniated gastric pouch.

The initial pathologic event in reflux disease is most likely frequent TLESRs and acid reflux episodes.
Acid in the esophagus causes esophagitis, which leads to low LES pressure and esophageal
hypotension [105]. Furthermore, esophagitis induces esophageal shortening through acid-induced
contraction of the longitudinal muscles [111]. Subsequently, fibrosis develops, which results in a
hiatal hernia. The hiatal hernia, in turn, enlarges the esophageal hiatus, thus impairing the sphincter
function of the crural diaphragm. The appearance of a hiatal hernia and a weak diaphragmatic
sphincter introduces additional mechanisms of reflux, thus exacerbating the esophagitis.

There is good experimental evidence to indicate that acid injury to the esophagus can impair
esophageal contraction. However, healing of esophagitis in patients with low contraction amplitudes
does not restore the contraction amplitude back to normal. Patients with scleroderma and mixed
connective disorders have a similar defect in peristalsis due to the replacement of esophageal
muscles with fibrous connective tissue

Pre epithelial
Epitelial

*barrier that protects against the permeation of luminal ions and aqueous molecules from the
lumen to the serosa

*lipid bilayer * protein bridges of the AJC that partially seal off the lumen from the aqueous
intercellular space of neighboring cells.

(1) the epithelial Na+ channel (ENaC); (2) buffering capacity; and (3) intracellular pH (pHi) regulation

Buffersareintracellular(proteins,phosphates,andbicarbonates)aswellasextracellular(matrixprot
eins, bicarbonates).

Postepithelial:

Blood flow: nutrients, oxygen, CO2, acidbase balance Reparative mechanisms: cell restitution, cell
replication

Tissue acidbase balance is preserved under physiologic conditions by the delivery of HCO3 to
buffer acidic by-products of cell metabolism, and under pathologic conditions by the delivery of
HCO3 to neutralize back-diffusing luminal H+ (see Figure 22.1). The blood supply also removes CO2
from the tissue to the lungs after H+ is neutralized by HCO3 and carbonic acid degraded by the
action of tissue carbonic anhydrases. Further, the blood supply can rapidly adapt to changing
conditions such as an increase in acid load; this by an increase in blood flow

demonstratedagradedincreaseofesophagealexposuretoboth acid and

duodenogastroesophageal reflux across the GERD
spectrum[112].Thuspathologicalacidandbilesaltexposure
wasobservedin89%ofpatientswithBarrettesophaguscomparedto79%
ofpatientswithesophagitisand50%ofpatients withNERD.

The major histologic components of reflux esophagitis include squamous epithelial injury and
inflammation. Squamous epithelial injury includes basal hyperplasia, cell ballooning, intercellular
edema (acantholysis), squamous cell necrosis, erosion, and ulceration.

These abnormalities are likely a consequence and not the cause of inflammation due to the release
of inflammatory mediators such as prostaglandin E2, PAF, and IL-6. These products impair
contractility of esophageal circular smooth muscle by inhibiting acetylcholine release or relaxing
smooth muscle.

It has been suggested that undifferentiated multipotent stem cells in the basal layer of the
esophagus can differentiate into columnar epithelium if exposed to components of the DGER
The mechanism by which bile acids cause mucosal damage is controversial. The most favored
hypothesis suggests that bile acids gain entrance across the mucosa because of their lipophilic state,
causing intramucosal damage primarily by disorganizing membrane structure or interfering with
cellular function

Surgical treatment has been shown to be quite effective in decreasing DGER, at least in the short
term. Stein et al. compared the effect of Nissen fundoplication 312 months after the operation to
omeprazole 20 mg bid and rtfound that duodenal reflux exposure was normalized in 15 of 16 GERD

The likely mechanism whereby PPIs decrease DGER is a marked decrease in the volume of gastric
secretions [114, 115], which means there is less gastric content available to reflux into the
esophagus. These data have important implications, suggesting that PPIs are an effective treatment
not only for acid, but also for bile reflux.

Baclofen, a GABAB agonist currently used by neurologists to treat spasticity, has been evaluated in
16 patients with persistent heartburn or regurgitation and ongoing pathological DGER in spite of

PPI therapy

Vaezi et al. have shown that in 32 patients with partial gastrectomy and upper gastrointestinal
symptoms, 92% of heartburn and 89% of regurgitation episodes were associated with mixed acid
and DGER reflux, suggesting that PPIs should be the first choice in these patients as well

Esophagitis is defined as visible breaks of the esophageal mucosa [4]. Esophagitis is present in 15
62% of children with GER symptoms. Incidence of erosive esophagitis in 017-year-old children with
GER symptoms was 12.4%, and increased with age [29]. Erosive esophagitis is rare in infants and
premature babies. This finding is in sharp contrast with the extremely high incidence (24.8%) of
antireflux medication prescribed in extremely low birth weight infants at the moment of discharge
[30]. Hiatal hernia is more frequent in children with erosive esophagitis than in those without (7.7%
vs 2.5%) [29]. Esophagitis typically presents with pain, but it can also be asymptomatic. Children with
severe neurologic impairment may have a limited ability to localize the source of their distress and
constitute the most difficult group to diagnose and treat appropriately.

. In children with EoE, the mucosa may appear pale, granular, and furrowed, and occasionally rings
may be seen during endoscopy [4, 31]. In reflux esophagitis, the distal and lower eosinophilic
infiltrate is mostly limited to fewer than 5/high power field (HPF). In primary eosinophilic
esophagitis, there are more than 20 eosinophils/ HPF. Recently, failure of PPI treatment as a
condition to diagnose EoE has increased the attention on GER as a coexistent or even predisposing
factor for the development of EoE [31]. It has been suggested that excessive use of PPIs may be
associated with the development of EoE

Esomeprazole for the treatment of erosive

esophagitis
LES muscle strips show that products of inflammation induce excessive production of hydrogen
peroxide, which in turn accelerates the production of platelet activating factor, prostaglandin E2
(PGE2), and F2-isoprostane to cause a decrease in the LES muscle tone.

When prolonged, intercellular acidification leads to cell edema and necrosis.

Bilitec: n 1993 a fiberoptic sensor was developed (Bilitec 2000), which uses the optical properties of
bilirubin, the most common bile pigment [84]. Bilirubin has a characteristic spectrophotometric
absorption band at 450 nm. The working principle of this instrument is that absorption near this
wavelength implies the presence of bilirubin and, therefore, represents DGER

Fat does delay gastric emptying, which may increase the risk of reflux.

Alcohol is a smooth muscle relaxant and reduces LES pressure

The vagal afferent mechanoreceptors in the gastric

cardiaprojecttothenucleustractussolitariiinthebrainstem
andsubsequentlytothedorsalmotornucleiofthevagus.Dorsal
motornucleusneuronsprojecttoinhibitoryneuronslocalized
withinthemyentericplexusofthedistalesophagusinducing
tLESR.GammaaminobutyricacidreceptortypeB(GABAB)
agonistinhibitsthevagalpathwayfortLESRsbothcentrallyand peripherally