Lesson
N 7.
Clinical
discussion. Acute and chronic gastritis. Role of diseases of oral cavity in the
development of gastritis. Etiology, pathogenesis, clinical pattern. Stomatological manifestations. Diagnostics, treatment. Participation
of a doctor-dentist in the prophylaxis of gastritis.
Clinical
discussion. Peptic ulcer: etiology,
pathogenesis, classification, clinical pattern. Stomatological
manifestations. diagnostics, complications, treatment. Participoation
of a doctor-dentist in the prophylaxis of peptic ulcer.
Clinical
discussion. Stomach cancer. Ethiology, pathogenesis, clinical pattern, diagnostics, treatment. Participoation of a doctor-dentist in the prophylaxis of stomach
cancer.
Physiology of
Gastric secretion. Determination of the gastric acid-secretion function. Determination of
the gastric pepsin-secretion function.
The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching
into four or five gastric glands made up of highly specialized epithelial
cells. The makeup of gastric glands varies with their anatomic location. Glands
within the gastric cardia comprise <5% of the
gastric gland area and contain mucous and endocrine cells. The majority of
gastric glands (75%) are found within the oxyntic
mucosa and contain mucous neck, parietal, chief, endocrine, and enterochromaffin cells. Pyloric glands contain mucous and
endocrine cells (including gastrin cells) and are
found in the antrum.
The parietal cell, also known as the oxyntic cell, is usually found in the neck, or isthmus, or
the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and
intracellular canaliculi containing short microvilli along its apical surface. H+, K+-ATPase is expressed in the tubulovesicle
membrane; upon cell stimulation, this membrane, along with apical membranes,
transforms into a dense network of apical intracellular canaliculi
containing long microvilli. Acid secretion, a process
requiring high energy, occurs at the apical canalicular
surface. Numerous mitochondria (30 to 40% of total cell volume) generate the
energy required for secretion.
Gastroduodenal Mucosal Defense. The gastric epithelium is under a constant
assault by a series of endogenous noxious factors including HCl,
pepsinogen/pepsin, and bile salts. In addition, a
steady flow of exogenous substances such as medications, alcohol, and bacteria
encounter the gastric mucosa. A highly intricate biologic system is in place to
provide defense from mucosal injury and to repair any
injury that may occur.
The mucosal defense
system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial
elements. The first line of defense is a
mucus-bicarbonate layer, which serves as a physicochemical barrier to multiple
molecules including hydrogen ions. Mucus is secreted in a regulated fashion by gastroduodenal surface epithelial cells. It consists
primarily of water (95%) and a mixture of lipids and glycoproteins.
Mucin is the constituent glycoprotein that, in
combination with phospholipids (also secreted by gastric mucous cells), forms a
hydrophobic surface with fatty acids that extend into the lumen from the cell
membrane. The mucous gel functions as a nonstirred
water layer impeding diffusion of ions and molecules such as pepsin.
Bicarbonate, secreted by surface epithelial cells of the gastroduodenal
mucosa into the mucous gel, forms a pH gradient ranging from 1 to 2 at the
gastric luminal surface and reaching 6 to 7 along the epithelial cell surface.
Bicarbonate secretion is stimulated by calcium, prostaglandins, cholinergic
input, and luminal acidification.
Surface epithelial cells provide the
next line of defense through several factors,
including mucus production, epithelial cell ionic transporters that maintain
intracellular pH and bicarbonate production, and intracellular tight junctions.
If the preepithelial barrier were breached, gastric
epithelial cells bordering a site of injury can migrate to restore a damaged
region (restitution). This process occurs independent of cell division and
requires uninterrupted blood flow and an alkaline pH in the surrounding
environment. Several growth factors including epidermal growth factor (EGF),
transforming growth factor (TGF) a, and basic fibroblast growth factor (FGF)
modulate the process of restitution. Larger defects that are not effectively
repaired by restitution require cell proliferation. Epithelial cell
regeneration is regulated by prostaglandins and growth factors such as EGF and
TGF-a. In tandem with epithelial cell renewal, formation of new vessels
(angiogenesis) within the injured microvascular bed
occurs. Both FGF and vascular endothelial growth factor (VEGF) are important in
regulating angiogenesis in the gastric mucosa.
An elaborate microvascular
system within the gastric submucosal layer is the key
component of the subepithelial defense/repair
system. A rich submucosal circulatory bed provides
HCO3-, which neutralizes the acid generated by parietal cell secretion of HCl. Moreover, this microcirculatory bed provides an
adequate supply of micronutrients and oxygen while removing toxic metabolic
by-products.
Prostaglandins play a central role in gastric
epithelial defense/repair. The gastric mucosa
contains abundant levels of prostaglandins. These metabolites of arachidonic acid regulate the release of mucosal
bicarbonate and mucus, inhibit parietal cell secretion, and are important in
maintaining mucosal blood flow and epithelial cell restitution. Prostaglandins
are derived from esterified arachidonic
acid, which is formed from phospholipids (cell membrane) by the action of phospholipase A2. A key enzyme that controls the
rate-limiting step in prostaglandin synthesis is cyclooxygenase
(COX), which is present in two isoforms (COX-1,
COX-2), each having distinct characteristics regarding structure, tissue
distribution, and expression. COX-1 is expressed in a host of tissues including
the stomach, platelets, kidneys, and endothelial cells. This isoform is expressed in a constitutive manner and plays an
important role in maintaining the integrity of renal function, platelet
aggregation, and gastrointestinal mucosal integrity. In contrast, the
expression of COX-2 is inducible by inflammatory stimuli, and it is expressed
in macrophages, leukocytes, fibroblasts, and synovial
cells. The beneficial effects of nonsteroidal
anti-inflammatory drugs (NSAIDs) on tissue
inflammation are due to inhibition of COX-2; the toxicity of these drugs (e.g.,
gastrointestinal mucosal ulceration and renal dysfunction) is related to
inhibition of the COX-1 isoform. The highly
COX-2-selective NSAIDs have the potential to provide
the beneficial effect of decreasing tissue inflammation while minimizing
toxicity in the gastrointestinal tract.
Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Acid
secretion should be viewed as occurring under basal and stimulated conditions.
Basal acid production occurs in a circadian pattern, with highest levels
occurring during the night and lowest levels during the morning hours.
Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the
principal contributors to basal acid secretion. Stimulated gastric acid
secretion occurs primarily in three phases based on the site where the signal
originates (cephalic, gastric, and intestinal). Sight, smell, and taste of food
are the components of the cephalic phase, which stimulates gastric secretion
via the vagus nerve. The gastric phase is activated
once food enters the stomach. This component of secretion is driven by
nutrients (amino acids and amines) that directly stimulate the G cell to
release gastrin, which in turn activates the parietal
cell via direct and indirect mechanisms. Distention
of the stomach wall also leads to gastrin release and
acid production. The last phase of gastric acid secretion is initiated as food
enters the intestine and is mediated by luminal distention
and nutrient assimilation. A series of pathways that inhibit gastric acid
production are also set into motion during these phases. The gastrointestinal
hormone somatostatin is released from endocrine cells
found in the gastric mucosa (D cells) in response to HCl.
Somatostatin can inhibit acid production by both
direct (parietal cell) and indirect mechanisms [decreased histamine release
from enterochromaffin-like (ECL) cells and gastrin release from G cells]. Additional neural (central
and peripheral) and hormonal (secretin, cholecystokinin) factors play a role in counterbalancing
acid secretion. Under physiologic circumstances, these phases are occurring
simultaneously.
The acid-secreting parietal cell is
located in the oxyntic gland, adjacent to other
cellular elements (ECL cell, D cell) important in the gastric secretory process. This unique cell also secretes intrinsic
factor. The parietal cell expresses receptors for several stimulants of acid
secretion including histamine (H2), gastrin (cholecystokinin B/gastrin
receptor) and acetylcholine (muscarinic, M3). Each of
these are G protein-linked, seven transmembrane-spanning
receptors. Binding of histamine to the H2 receptor leads to activation of adenylate cyclase and an increase
in cyclic AMP. Activation of the gastrin and muscarinic receptors results in activation of the protein kinase C/phosphoinositide signaling pathway. Each of these signaling
pathways in turn regulates a series of downstream kinase
cascades, which control the acid-secreting pump, H+, K+-ATPase.
The discovery that different ligands and their
corresponding receptors lead to activation of different signaling
pathways explains the potentiation of acid secretion
that occurs when histamine and gastrin or
acetylcholine are combined. More importantly, this observation explains why
blocking one receptor type (H2) decreases acid secretion stimulated by agents
that activate a different pathway (gastrin,
acetylcholine). Parietal cells also express receptors for ligands
that inhibit acid production (prostaglandins, somatostatin,
and EGF).
The enzyme H+, K+-ATPase
is responsible for generating the large concentration of H+. It is a
membrane-bound protein that consists of two subunits, a and b. The active
catalytic site is found within the a subunit; the function of the b subunit is
unclear. This enzyme uses the chemical energy of ATP to transfer H+ ions from
parietal cell cytoplasm to the secretory canaliculi in exchange for K+. The H+,K+-ATPase is located within the secretory
canaliculus and in nonsecretory
cytoplasmic tubulovesicles.
The tubulovesicles are impermeable to K+, which leads
to an inactive pump in this location. The distribution of pumps between the nonsecretory vesicles and the secretory
canaliculus varies according to parietal cell. Under
resting conditions, only 5% of pumps are within the secretory
canaliculus, whereas upon parietal cell stimulation, tubulovesicles are immediately transferred to the secretory canalicular membrane,
where 60 to 70% of the pumps are activated. Proton pumps are recycled back to
the inactive state in cytoplasmic vesicles once parietal
cell activation ceases.
The chief cell, found primarily in the gastric fundus, synthesizes and secretes pepsinogen,
the inactive precursor of the proteolytic enzyme
pepsin. The acid environment within the stomach leads to cleavage of the
inactive precursor to pepsin and provides the low pH (<2.0) required for
pepsin activity. Pepsin activity is significantly diminished at a pH of 4 and
irreversibly inactivated and denatured at a pH of >7. Many of the secretagogues that stimulate
acid secretion also stimulate pepsinogen release. The
precise role of pepsin in the pathogenesis of PUD remains to be established.
Tongue in
chronic gastritis
SECRETORY STUDIES
There are many methods of secretory studies of stomach function by gastric
intubation: the acid output is measured in response to pentagastrin,
to broth, histamine, insuline.
The acid output is measured in
response to pentagastrin, a syntheric
pentapeptide which exerts the biological effects of gastrin. Preparation
consists of an overnight fast. H2-receptor antagonist drugs must be
stopped for at least 48 hours before the test and omeprasole
seven days before. The fasting contents of the stomach are aspirated and their
volume measured; then the secretions are collected continuously for one hour.
This is termed the ‘basal acid output’. Pentagastrin
is then injected subcutaneously and the gastric secretions are collected for a
further hour. The acid output in this hour is termed the ‘maximal acid output’.
|
USE OF THE PENTAGASTRINE TEST |
|
-
a large volume of fasting juice indicates obstruction of the gastric outlet -
a very high basal acid output suggests that the patient has the Zollinger-Ellison syndrome -
in patients with peptic ulcer it provides a preoperative base line -
achlorhydria can be demonstrated |
The insuline
test is used after gastric surgery to indicate the completeness of vagotomy.
Stomach contents:
Volume 2-3 l per 24 hours
Specific gravity – 1005
pH – 1,6 – 1,8
The fasting stomach contents:
Volume – 5-40 ml
Gastric juice total acidity <
20-30 mmol/l
Free hydrochloric acid < 15 mmol/l
Pepsin 0-21 mg %
Basal acid secretion
Total volume of 4 portions collecting
for 60 minutes, after aspiration of fasting contents 50 – 100 ml
Total acidity – 40 – 60 mmol/l
Free hydrochloric acid 20 – 40 mmol/l
Fixed hydrochloric acid 10 – 15 mmol/l
Debit-hour of the free hydrochloric
acid 1.5 – 5,5 mmol/hour
Debit-hour of the free hydrochloric
acid 1.5 – 5,5 mmol/hour
3. Bacteriological and immunological investigation in the diseases of
alimentary tract.
X-ray
examination is less informative in gastritis
DIAGNOSIS FOR H.PYLORI
Tests for H. pylori can be divided
into two groups: invasive tests, which require upper gastrointestinal endoscopy and are based on the analysis of gastric biopsy
specimens, and noninvasive tests (Table 2).
|
Table 2.
Tests for Detection of H. pylori |
||
|
Test |
Sensitivity/ Specificity,
% |
Comments |
|
INVASIVE
(ENDOSCOPY/BIOPSY REQUIRED) |
||
|
Rapid
urease |
80-95/95-100 |
Simple; false negative with recent use
of PPIs, antibiotics, or bismuth compounds |
|
Histology |
80-90/95 |
Requires pathology processing and
staining; provides histologic information |
|
Culture |
- |
Time-consuming, expensive, dependent on
experience; allows determination of antibiotic susceptibility |
|
NON-INVASIVE |
||
|
Serology |
80/90 |
Inexpensive, convenient; not useful for
early follow-up |
|
Urea
breath test |
90/90 |
Simple, rapid; useful for early
follow-up; false negative with recent therapy (see rapid urease
test) |
|
NOTE: PPI, proton pump inhibitor. |
||
. Endoscopic examination in chronic gastritis: the devise,
the principle of examination and the appearance of stomach mucosa in gastritis
(hyperemia, erosions)
Invasive tests are preferred for (1)
the initial management of dyspeptic patients, because the decision of whether
or not to eradicate H. pylori depends on ulcer disease status, and (2)
follow-up after treatment of patients with gastric ulceration to be certain
that the ulcer was not malignant. Follow-up endoscopy
should be performed at least 4 weeks after cessation of all anti-Helicobacter
drugs, since at earlier points the H. pylori load may be low and tests may be
falsely negative. The most convenient endoscopy-based
test is the biopsy urease test, in which two antral biopsy specimens are put into a gel containing urea
and an indicator. The presence of H. pylori urease
elicits a color change, which often takes place
within minutes but can require up to 24 h. Histologic
examination of biopsy specimens is accurate, provided that a special stain
(e.g., a modified Giemsa or silver stain) permitting
optimal visualization of H. pylori is used. Histologic
study yields additional information, including the degree and pattern of
inflammation, atrophy, metaplasia, and dysplasia, although these details are rarely of clinical
use. Microbiologic culture is most specific but may be insensitive due to
difficulty with H. pylori isolation. Once cultured, the identity of H. pylori
can be confirmed by its typical appearance on Gram's stain and its positive
reactions in oxidase, catalase,
and urease tests. Antibiotic sensitivities also can
be determined. Specimens containing H. heilmanii are
only weakly positive in the biopsy urease test. The
diagnosis is based on visualization of the characteristic long, tight spiral
bacteria in histologic sections.
The simplest tests for H. pylori
infection are serologic, involving the assessment of specific IgG levels in serum. The best of these tests are as
accurate as other diagnostic methods, but many commercial tests, especially
rapid office tests, perform poorly. In quantitative tests, a defined drop in
antibody titer between matched serum samples taken
before and 6 months after treatment (no sooner because of the slow decline in
antibody titer) accurately indicates that H. pylori
infection has been eradicated. The other major noninvasive
tests are the 13C and 14C urea breath tests. In these simple tests, the patient
drinks a labeled urea solution and then blows into a
tube. The urea is labeled with either the nonradioactive isotope 13C or a minute dose of the
radioactive isotope 14C (which exposes the patient to less radiation than a
standard chest x-ray). If H. pylori urease is
present, the urea is hydrolyzed and labeled carbon
dioxide is detected in breath samples. Unlike serologic tests, urea breath
tests can be used to assess the outcome of treatment 1 month after its
completion and thus may replace endoscopy for this
purpose in the follow-up of duodenal ulcer patients. As for endoscopic
tests, all anti-Helicobacter drugs should be avoided in this period or the test
may be falsely negative.
Chronic diarrhea
in a tropical environment is most often caused by infectious agents including
G. lamblia, Yersinia enterocolitica, C. difficile,
Cryptosporidium parvum, and Cyclospora
cayetanensis, among other organisms. Tropical sprue should not be entertained as a possible diagnosis
until the presence of cysts and trophozoites has been
excluded in three stool samples.
CLINICAL FEATURES History Abdominal pain is common
to many gastrointestinal disorders, including DU and GU, but has a poor
predictive value for the presence of either DU or GU. Up to 10% of patients
with NSAID-induced mucosal disease can present with a complication (bleeding,
perforation, and obstruction) without antecedent symptoms. Despite this poor
correlation, a careful history and physical examination are essential
components of the approach to a patient suspected of having peptic ulcers.
Epigastric pain described as a burning or gnawing discomfort can be present in
both DU and GU. The discomfort is also described as an ill-defined, aching
sensation or as hunger pain. The typical pain pattern in DU occurs 90 min to 3
h after a meal and is frequently relieved by antacids or food. Pain that awakes
the patient from sleep (between midnight and 3 A.M.) is the most discriminating
symptom, with two-thirds of DU patients describing this complaint.
Unfortunately, this symptom is also present in one-third of patients with NUD.
The pain pattern in GU patients may be different from that in DU patients,
where discomfort may actually be precipitated by food. Nausea and weight loss
occur more commonly in GU patients. In the
The mechanism for development of
abdominal pain in ulcer patients is unknown. Several possible explanations
include acid-induced activation of chemical receptors in the duodenum, enhanced
duodenal sensitivity to bile acids and pepsin, or altered gastroduodenal
motility.
Variation in the intensity or
distribution of the abdominal pain, as well as the onset of associated symptoms
such as nausea and/or vomiting, may be indicative of an ulcer complication.
Dyspepsia that becomes constant, is no longer relieved by food or antacids, or
radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset
of severe, generalized abdominal pain may indicate perforation. Pain worsening
with meals, nausea, and vomiting of undigested food suggest gastric outlet
obstruction. Tarry stools or coffee ground emesis indicate bleeding.
Criteria for diagnosis of the
gastritis.
A-gastritis.
B-gastritis.
C-gastritis.
The term gastritis should be reserved
for histologically documented inflammation of the
gastric mucosa. Gastritis is not the mucosal erythema
seen during endoscopy and is not interchangeable with
"dyspepsia." The etiologic factors leading to gastritis are broad and
heterogeneous. Gastritis has been classified based on time course (acute vs.
chronic), histologic features, and anatomic distribution
or proposed pathogenic mechanism .
The correlation between the histologic findings of gastritis, the clinical picture of
abdominal pain or dyspepsia, and endoscopic findings
noted on gross inspection of the gastric mucosa is poor. Therefore, there is no
typical clinical manifestation of gastritis.
Acute Gastritis. The most common causes
of acute gastritis are infectious. Acute infection with H. pylori induces
gastritis. However, H. pylori acute gastritis has not been extensively studied.
Reported as presenting with sudden onset of epigastric
pain, nausea, and vomiting, limited mucosal histologic
studies demonstrate a marked infiltrate of neutrophils
with edema and hyperemia.
If not treated, this picture will evolve into one of chronic gastritis. Hypochlorhydria lasting for up to 1 year may follow acute
H. pylori infection.
The highly acidic gastric environment
may be one reason why infectious processes of the stomach are rare. Bacterial
infection of the stomach or phlegmonous gastritis is
a rare potentially life-threatening disorder, characterized by marked and
diffuse acute inflammatory infiltrates of the entire gastric wall, at times
accompanied by necrosis. Elderly individuals, alcoholics, and AIDS patients may
be affected. Potential iatrogenic causes include polypectomy
and mucosal injection with India ink. Organisms associated with this entity
include streptococci, staphylococci, Escherichia coli, Proteus, and Haemophilus. Failure of supportive measures and antibiotics
may result in gastrectomy.
Chronic Gastritis. Chronic gastritis is
identified histologically by an inflammatory cell
infiltrate consisting primarily of lymphocytes and plasma cells, with very
scant neutrophil involvement. Distribution of the
inflammation may be patchy, initially involving superficial and glandular
portions of the gastric mucosa. This picture may progress to more severe
glandular destruction, with atrophy and metaplasia.
Chronic gastritis has been classified according to histologic
characteristics. These include superficial atrophic changes and gastric
atrophy.
The early phase of chronic gastritis
is superficial gastritis. The inflammatory changes are limited to the lamina propria of the surface mucosa, with edema
and cellular infiltrates separating intact gastric glands. Additional findings
may include decreased mucus in the mucous cells and decreased mitotic figures
in the glandular cells. The next stage is atrophic gastritis. The inflammatory
infiltrate extends deeper into the mucosa, with progressive distortion and destruction
of the glands. The final stage of chronic gastritis is gastric atrophy.
Glandular structures are lost; there is a paucity of inflammatory infiltrates. Endoscopically the mucosa may be substantially thin,
permitting clear visualization of the underlying blood vessels.
Gastric glands may undergo morphologic transformation
in chronic gastritis. Intestinal metaplasia denotes
the conversion of gastric glands to a small intestinal phenotype with
small-bowel mucosal glands containing goblet cells. The metaplastic
changes may vary in distribution from patchy to fairly extensive gastric
involvement. Intestinal metaplasia is an important
predisposing factor for gastric cancer.
Chronic gastritis is also classified according to the
predominant site of involvement. Type A refers to the body-predominant form
(autoimmune) and type B is the central-predominant form (H. pylori-related).
This classification is artificial in view of the difficulty in distinguishing
these two entities. The term AB gastritis has been used to refer to a mixed antral/body picture.
Type A Gastritis. The less common of
the two forms involves primarily the fundus and body,
with antral sparing. Traditionally, this form of
gastritis has been associated with pernicious anemia
in the presence of circulating antibodies against parietal cells and intrinsic
factor; thus it is also called autoimmune gastritis. H. pylori infection can
lead to a similar distribution of gastritis. The characteristics of an
autoimmune picture are not always present.
Antibodies to parietal cells have
been detected in >90% of patients with pernicious anemia
and in up to 50% of patients with type A gastritis. Anti-parietal cell
antibodies are cytotoxic for gastric mucous cells.
The parietal cell antibody is directed against H+,K+-ATPase.
T cells are also implicated in the injury pattern of this form of gastritis.
Parietal cell antibodies and atrophic
gastritis are observed in family members of patients with pernicious anemia. These antibodies are observed in up to 20% of
individuals over age 60 and in ~20% of patients with vitiligo
and Addison's disease. About half of patients with pernicious anemia have antibodies to thyroid antigens, and about 30%
of patients with thyroid disease have circulating anti-parietal cell
antibodies. Anti-intrinsic factor antibodies are more specific than parietal
cell antibodies for type A gastritis, being present in ~40% of patients with pernicious
anemia. Another parameter consistent with this form
of gastritis being autoimmune in origin is the higher incidence of specific
familial histocompatibility haplotypes
such as HLA-B8 and -DR3.
The parietal cell-containing gastric gland is
preferentially targeted in this form of gastritis, and achlorhydria
results. Parietal cells are the source of intrinsic factor, lack of which will
lead to vitamin B12 deficiency and its sequelae (megaloblastic anemia, neurologic dysfunction).
Gastric acid plays an important role
in feedback inhibition of gastrin release from G
cells. Achlorhydria, coupled with relative sparing of
the antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin levels
can be markedly elevated (>500 pg/mL) in patients
with pernicious anemia. ECL cell hyperplasia with
frank development of gastric carcinoid tumors may result from gastrin trophic effects. The role of gastrin
in carcinoid development is confirmed by the
observation that antrectomy leads to regression of
these lesions. Hypergastrinemia and achlorhydria may also be seen in non-pernicious anemia-associated type A gastritis.
Type B gastritis. Type B, or antral-predominant, gastritis is the more common form of
chronic gastritis. H. pylori infection is the cause of this entity. Although
described as "antral-predominant," this is
likely a misnomer in view of studies documenting the progression of the
inflammatory process towards the body and fundus of
infected individuals. The conversion to a pan-gastritis is time-dependent-estimated
to require 15 to 20 years. This form of gastritis increases with age, being
present in up to 100% of people over age 70. Histology improves after H. pylori
eradication. The number of H. pylori organisms decreases dramatically with
progression to gastric atrophy, and the degree of inflammation correlates with
the level of these organisms. Early on, with antral-predominant
findings, the quantity of H. pylori is highest and a dense chronic inflammatory
infiltrate of the lamina propria is noted accompanied
by epithelial cell infiltration with polymorphonuclear
leukocytes.
Multifocal atrophic gastritis, gastric atrophy with subsequent metaplasia,
has been observed in chronic H. pylori-induced gastritis. This may ultimately
lead to development of gastric adenocarcinoma. H.
pylori infection is now considered an independent risk factor for gastric
cancer. Worldwide epidemiologic studies have documented a higher incidence of
H. pylori infection in patients with adenocarcinoma
of the stomach as compared to control subjects. Seropositivity
for H. pylori is associated with a three- to sixfold
increased risk of gastric cancer. This risk may be as high as ninefold after adjusting for the inaccuracy of serologic
testing in the elderly. The mechanism by which H. pylori infection leads to
cancer is unknown. However, eradication of H. pylori as a general preventative
measure for gastric cancer is not recommended.
Infection with H. pylori is also associated with
development of a low grade B cell lymphoma, gastric MALT lymphoma. The chronic
T cell stimulation caused by the infection leads to production of cytokines
that promote the B cell tumor. Tumor
growth remains dependent upon the presence of H. pylori in that its eradication
is often associated with complete regression of the tumor.
The tumor may take more than a year to regress after
treating the infection. Such patients should be followed by EUS every 2 to 3
months. If the tumor is stable or decreasing in size,
no other therapy is necessary. If the tumor grows, it
may have become a high-grade B cell lymphoma. When the tumor
becomes a high-grade aggressive lymphoma histologically,
it loses responsiveness to H. pylori eradication.
H.pylori
History. Abdominal pain is common to many gastrointestinal disorders,
including DU and GU, but has a poor predictive value for the presence of either
DU or GU. Up to 10% of patients with NSAID-induced mucosal disease with a
complication (bleeding, perforation, and obstruction) without antecedent
symptoms. Despite this poor correlation, a careful history and physical
examination are essential components of the approach to a patient
suspected of having peptic ulcers
Epigastric pain described as a burning or gnawing discomfort can be present in
both DU and GU. The discomfort is also described as an ill-defined, aching
sensation or as hunger pain. The typical pain pattern in DU occurs 90 min to 3
h after a meal and is frequently relieved by antacids or food. Pain that awakes
the patient from sleep (between midnight and 3 A.M.) is the most discriminating
symptom, with two-thirds of DU patients describing this complaint.
Unfortunately, this symptom is also present in one-third of patients with NUD.
The pain pattern in GU patients may be different from that in DU patients,
where discomfort may actually be precipitated by food. Nausea and weight loss
occur more commonly in GU patients. In the
The mechanism for development of abdominal pain in
ulcer patients is unknown. Several possible explanations include acid-induced
activation of chemical receptors in the duodenum, enhanced duodenal sensitivity
to bile acids and pepsin, or altered gastroduodenal
motility.
Variation in the intensity or distribution of the
abdominal pain, as well as the onset of associated symptoms such as nausea
and/or vomiting, may be indicative of an ulcer complication. Dyspepsia that
becomes constant, is no longer relieved by food or antacids, or radiates to the
back may indicate a penetrating ulcer (pancreas). Sudden onset of severe,
generalized abdominal pain may indicate perforation. Pain worsening with meals,
nausea, and vomiting of undigested food suggest gastric outlet obstruction.
Tarry stools or coffee ground emesis indicate bleeding.
Physical Examination Epigastric
tenderness is the most frequent finding in patients with GU or DU. Pain may be
found to the right of the midline in 20% of patients. Unfortunately, the
predictive value of this finding is rather low. Physical examination is
critically important for discovering evidence of ulcer complication.
Tachycardia and orthostasis suggest dehydration
secondary to vomiting or active gastrointestinal blood loss. A severely tender,
boardlike abdomen suggests a perforation. Presence of
a succussion splash indicates retained fluid in the
stomach, suggesting gastric outlet obstruction.
Diagnostic Evaluation. In view of the
poor predictive value of abdominal pain for the presence of a gastroduodenal ulcer and the multiple disease processes
that can mimic this disease, the clinician is often confronted with having to
establish the presence of an ulcer. Documentation of an ulcer requires either a
radiographic (barium study) or an endoscopic
procedure.
Barium examination of the stomach and duodenum reveals an ulcer,
Barium studies of the proximal
gastrointestinal tract are still commonly used as a first test for documenting
an ulcer. The sensitivity of older single-contrast barium meals for detecting a
DU is as high as 80%, with a double-contrast study providing detection rates as
high as 90%. Sensitivity for detection is decreased in small ulcers (<
Endoscopy provides the most sensitive and specific approach for examining the
upper gastrointestinal tract. In addition to permitting direct visualization of
the mucosa, endoscopy facilitates photographic
documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU)
or H. pylori. Endoscopic examination is particularly
helpful in identifying lesions too small to detect by radiographic examination,
for evaluation of atypical radiographic abnormalities, or to determine if an
ulcer is a source of blood loss.
Treatment in
chronic gastritis is aimed at the sequelae and not
the underlying inflammation. Patients with pernicious anemia
will require parenteral vitamin B12 supplementation
on a long-term basis. Eradication of H. pylori is not routinely recommended
unless PUD or a low-grade MALT lymphoma is present.
Miscellaneous
Forms of Gastritis. Lymphocytic gastritis is
characterized histologically by intense infiltration
of the surface epithelium with lymphocytes. The infiltrative process is
primarily in the body of the stomach and consists of mature T cells and plasmacytes. The etiology of this
form of chronic gastritis is unknown. It has been described in patients with
celiac sprue, but whether there is a common factor
associating these two entities is unknown. No specific symptoms suggest lymphocytic gastritis. A subgroup of patients has thickened
folds noted on endoscopy. These folds are often
capped by small nodules that contain a central depression or erosion; this form
of the disease is called varioliform gastritis. H.
pylori probably plays no significant role in lymphocytic
gastritis. Therapy with glucocorticoids or sodium cromoglycate has obtained unclear results.
Marked eosinophilic
infiltration involving any layer of the stomach (mucosa, muscularis
propria, and serosa) is
characteristic of eosinophilic gastritis. Affected
individuals will often have circulating eosinophilia
with clinical manifestation of systemic allergy. Involvement may range from
isolated gastric disease to diffuse eosinophilic
gastroenteritis. Antral involvement predominates,
with prominent edematous folds being observed on endoscopy. These prominent antral
folds can lead to outlet obstruction. Patients can present with epigastric discomfort, nausea, and vomiting. Treatment with
glucocorticoids has been successful.
Several systemic disorders may be
associated with granulomatous gastritis. Gastric
involvement has been observed in Crohn's disease.
Involvement may range from granulomatous infiltrates
noted only on gastric biopsies to frank ulceration and stricture formation.
Gastric Crohn's disease usually occurs in the
presence of small-intestinal disease. Several rare infectious processes can
lead to granulomatous gastritis, including histoplasmosis, candidiasis,
syphilis, and tuberculosis. Other unusual causes of this form of gastritis
include sarcoidosis, idiopathic granulomatous
gastritis, and eosinophilic granulomas
involving the stomach. Establishing the specific etiologic agent in this form
of gastritis can be difficult, at times requiring repeat endoscopy
with biopsy and cytology. Occasionally, a surgically obtained full-thickness
biopsy of the stomach may be required to exclude malignancy.
Treatment of the ulcer diseases.
Before the
discovery of H. pylori, the therapy of PUD disease was centered
on the old dictum by Schwartz of "no acid, no ulcer." Although acid
secretion is still important in the pathogenesis of PUD, eradication of H.
pylori and therapy/prevention of NSAID-induced disease is the mainstay.
|
Table 1. Drugs Used in the Treatment of Peptic Ulcer
Disease |
|||
|
Drug Type/Mechanism |
Examples |
Dose |
|
|
Acid-suppressing drugs |
|
|
|
|
Antacids |
Mylanta, Maalox, Tums, Gaviscon |
100-140 meq/L 1 and 3 h after meals and hs |
|
|
H2 receptor antagonists |
Cimetidine Ranitidine Famotidine Nizatidine |
800 mg hs 300 mg hs 40 mg hs 300 mg hs |
|
|
Proton pump inhibitors |
Omeprazole Lansoprazole Rabeprazole Pantoprazole |
20 mg/d 30 mg/d 20 mg/d 40 mg/d |
|
|
Mucosal
protective agents |
|
|
|
|
Sucralfate |
Sucralfate |
|
|
|
Prostaglandin
analogue |
Misoprostol |
200 g qid |
|
|
Bismuth-containing
compounds |
Bismuth subsalicylate (BSS) |
anti-H.
Pylori regimens |
|
Acid Neutralizing/Inhibitory Drugs
Antacids Before we understood the important role of
histamine in stimulating parietal cell activity, neutralization of secreted
acid with antacids constituted the main form of therapy for peptic ulcers. They
are now rarely, if ever, used as the primary therapeutic agent but instead are
often used by patients for symptomatic relief of dyspepsia. The most commonly
used agents are mixtures of aluminum hydroxide and
magnesium hydroxide. Aluminum hydroxide can produce
constipation and phosphate depletion; magnesium hydroxide may cause loose
stools. Many of the commonly used antacids (e.g., Maalox, Mylanta) have a
combination of both aluminum and magnesium hydroxide
in order to avoid these side effects. The magnesium-containing preparation
should not be used in chronic renal failure patients because of possible hypermagnesemia, and aluminum may
cause chronic neurotoxicity in these patients.
Calcium carbonate
and sodium bicarbonate are potent antacids with varying levels of potential
problems. The long-term use of calcium carbonate (converts to calcium chloride
in the stomach) can lead to milk-alkali syndrome (hypercalcemia,
hyperphosphatemia with possible renal calcinosis and progression to renal insufficiency). Sodium
bicarbonate may induce systemic alkalosis.
H2 Receptor
antagonists Four of these agents are
presently available (cimetidine, ranitidine, famotidine, and nizatidine), and
their structures share homology with histamine. Although each has different
potency, all will significantly inhibit basal and stimulated acid secretion to
comparable levels when used at therapeutic doses. Moreover, similar
ulcer-healing rates are achieved with each drug when used at the correct
dosage. Presently, this class of drug is often used for treatment of active
ulcers (4 to 6 weeks) in combination with antibiotics directed at eradicating
H. pylori.
Cimetidine was the first H2 receptor antagonist used for the treatment of acid
peptic disorders. The initial recommended dosing profile for cimetidine was 300 mg four times per day. Subsequent
studies have documented the efficacy of using 800 mg at bedtime for treatment
of active ulcer, with healing rates approaching 80% at 4 weeks. Cimetidine may have weak antiandrogenic
side effects resulting in reversible gynecomastia and
impotence, primarily in patients receiving high doses for prolonged periods of
time (months to years, as in ZES). In view of cimetidine's
ability to inhibit cytochrome P450, careful
monitoring of drugs such as warfarin, phenytoin, and theophylline is
indicated with long-term usage. Other rare reversible adverse effects reported
with cimetidine include confusion and elevated levels
of serum aminotransferases, creatinine,
and serum prolactin. Ranitidine, famotidine,
and nizatidine are more potent H2 receptor
antagonists than cimetidine. Each can be used once a
day at bedtime. Comparable nighttime dosing regimens
are ranitidine, 300 mg, famotidine, 40 mg, and nizatidine, 300 mg.
Additional rare, reversible systemic
toxicities reported with H2 receptor antagonists include pancytopenia,
neutropenia, anemia, and
thrombocytopenia, with a prevalence rate varying from 0.01 to 0.2%. Cimetidine and rantidine (to a
lesser extent) can bind to hepatic cytochrome P450,
whereas the newer agents, famotidine and nizatidine, do not.
Proton pump (H+,K+-ATPase) inhibitors Omeprazole, lansoprazole, and the
newest additions, rabeprazole and pantoprazole,
are substituted benzimidazole derivatives that
covalently bind and irreversibly inhibit H+,K+-ATPase.
These are the most potent acid inhibitory agents available. Omeprazole
and lansoprazole are the proton pump inhibitors (PPIs) that have been used for the longest time. Both are
acid labile and are administered as enteric-coated granules in a
sustained-release capsule that dissolves within the small intestine at a pH of
6. These agents are lipophilic compounds; upon
entering the parietal cell, they are protonated and
trapped within the acid environment of the tubulovesicular
and canalicular system. These agents potently inhibit
all phases of gastric acid secretion. Onset of action is rapid, with a maximum
acid inhibitory effect between 2 and 6 h after administration and duration of
inhibition lasting up to 72 to 96 h. With repeated daily dosing, progressive acid
inhibitory effects are observed, with basal and secretagogue-stimulated
acid production being inhibited by >95% after 1 week of therapy. The
half-life of PPIs is approximately 18 h, thus it can
take between 2 and 5 days for gastric acid secretion to return to normal levels
once these drugs have been discontinued. Because the pumps need to be activated
for these agents to be effective, their efficacy is maximized if they are
administered before a meal (e.g., in the morning before breakfast). Standard
dosing for omeprazole and lansoprazole
is 20 mg and 30 mg once per day, respectively. Mild to moderate hypergastrinemia has been observed in patients taking these
drugs. Carcinoid tumors
developed in some animals given the drugs preclinically;
however, extensive experience has failed to demonstrate gastric carcinoid tumor development in
humans. Serum gastrin levels return to normal levels
within 1 to 2 weeks after drug cessation. As with any agent that leads to
significant hypochlorhydria, PPIs
may interfere with absorption of drugs such as ketoconazole,
ampicillin, iron, and digoxin.
Hepatic cytochrome P450 can be inhibited by these
agents, but the overall clinical significance of this observation is not
definitely established. Caution should be taken when using warfarin,
diazepam, and phenytoin concomitantly with PPIs.
Cytoprotective Agents: Sucralfate Sucralfate is a
complex sucrose salt in which the hydroxyl groups have been substituted by aluminum hydroxide and sulfate.
This compound is insoluble in water and becomes a viscous paste within the
stomach and duodenum, binding primarily to sites of active ulceration. Sucralfate may act by several mechanisms. In the gastric
environment, aluminum hydroxide dissociates, leaving
the polar sulfate anion, which can bind to positively
charged tissue proteins found within the ulcer bed, and providing a
physicochemical barrier impeding further tissue injury by acid and pepsin. Sucralfate may also induce a trophic
effect by binding growth factors such as EGF, enhance prostaglandin synthesis,
stimulate mucous and bicarbonate secretion, and enhance mucosal defense and repair. Toxicity from this drug is rare, with
constipation being the most common one reported (2 to 3%). It should be avoided
in patients with chronic renal insufficiency to prevent aluminum-induced
neurotoxicity. Hypophosphatemia
and gastric bezoar formation have also been rarely
reported. Standard dosing of sucralfate is
Bismuth-containing
preparations Sir William Osler
considered bismuth-containing compounds the drug of choice for treating PUD.
The resurgence in the use of these agents is due to their effect against H.
pylori. Colloidal bismuth subcitrate (CBS) and
bismuth subsalicylate (BSS, Pepto-Bismol) are the
most widely used preparations. The mechanism by which these agents induce ulcer
healing is unclear. Potential mechanisms include ulcer coating; prevention of
further pepsin/HCl-induced damage; binding of pepsin;
and stimulation of prostaglandins, bicarbonate, and mucous secretion. Adverse
effects with short-term usage are rare with bismuth compounds. Long-term usage
with high doses, especially with the avidly absorbed CBS, may lead to neurotoxicity. These compounds are commonly used as one of
the agents in an anti-H. pylori regimen.
Prostaglandin
analogues In view of their central role
in maintaining mucosal integrity and repair, stable prostaglandin analogues
were developed for the treatment of PUD. The prostaglandin E1 derivative misoprostal is the only agent of this class approved by the
U.S. Food and Drug Administration for clinical use in the prevention of
NSAID-induced gastroduodenal mucosal injury. The
mechanism by which this rapidly absorbed drug provides its therapeutic effect
is through enhancement of mucosal defense and repair.
Prostaglandin analogues enhance mucous bicarbonate secretion, stimulate mucosal
blood flow, and decrease mucosal cell turnover. The most common toxicity noted
with this drug is diarrhea (10 to 30% incidence).
Other major toxicities include uterine bleeding and contractions; misoprostal is contraindicated in women who may be
pregnant, and women of childbearing age must be made clearly aware of this
potential drug toxicity. The standard therapeutic dose is 200 ug four times per day.
Miscellaneous drugs. A number of
drugs aimed at treating acid peptic disorders have been developed over the
years. In view of their limited utilization in the