GASTRITIS AND GASTROPATHY
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 anatomical distribution or
proposed pathogenic mechanism.
Classification
of Gastritis
I.
Acute gastritis
|
II.
Chronic atrophic gastritis
|
A.
Acute H. pylori infection
|
A. Type A: Autoimmune, body-predominant
|
B. Other acute infectious gastritides
|
B. Type B: H. pylori–related, antral-predominant
|
1.
Bacterial (other than H. pylori)
|
C.
Indeterminant
|
2.
Helicobacter helmanni
|
III.
Uncommon Forms of Gastritis
|
3.
Phlegmonous
|
A.
Lymphocytic
|
4.
Mycobacterial
|
B.
Eosinophilic
|
5.
Syphilitic
|
C.
Crohn's disease
|
6.
Viral
|
D.
Sarcoidosis
|
7.
Parasitic
|
E.
Isolated granulomatous gastritis
|
8.
Fungal
|
|
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.
CLINICOPATHOLOGICAL
APPROACH TO GASTRITIS
Gastritis,
simply defined as the inflammation of the gastric mucosa, is a condition, not a
disease. With rare exceptions (e.g., lymphocytic gastritis and the extremely
rare phlegmonous gastritis), inflammation of the gastric mucosa per se does not
produce signs or symptoms; its complications do. Thus, clinicians rarely search
for gastritis. In dyspeptic patients with indications for endoscopy, biopsies
from the stomach are often obtained to determine the patient’s Helicobacter
pylori status. If an appropriate set of gastric mucosal specimens is collected
and properly examined, valuable information in addition to the often implicit
question “is there H.pylori?” may be obtained: the type, severity, and
distribution of gastritis and perhaps other causes of the gastric inflammation.
This chapter is a discussion of useful strategies gastroenterologists and
pathologists can use to optimize the diagnosis of gastric diseases.
Sydney System
The
discovery of H.pylori in 1982 coincided with a new trend in medicine: the birth
of the expert group, whose task is to sift through the best available evidence
(hence the term evidence-based medicine) and attempt to come to a consensus
with regard to treatment strategies (clinical guidelines) or classifications of
disease. Before the 1990 World Congress of Gastroenterology in Sydney,
Australia, such a group of European gastroenterologists and pathologists set
out to create a flexible matrix for the classification of gastritis. The
resulting Sydney System had both endoscopic and histological divisions. The
former was met with general indifference and faded into oblivion. The latter
unleashed passions that were distributed largely along geocultural lines:
enthusiasm in Europe, where the system was conceived; indignation in the
Americas and Asia, where investigators felt excluded both politically (none were
asked to participate in the expert group) and nosologically (the types of
gastritis commonly seen in Asia and South America received limited attention).
In spite of these operational shortcomings, the Sydney System described a
framework useful to generate diagnoses and flexible enough to incorporate new
ideas as they emerged. Four years after its introduction, the Sydney System was
reapprised by a group of pathologists including a wider geographic and disease
representation. This group established a terminology of gastritis and
identified, defined, and attempted to resolve some of the problems associated
with the original Sydney System. The Houston workshop resulted in what is known
as the Updated Sydney System, which is currently the most widely used and cited
method for the classification of gastritis.
To
create a report as suggested by the Sydney System, appropriate biopsy specimens
should be methodically evaluated and the findings synthesized. Whereas
gastroenterologists in some institutions have made a habit of obtaining mapped
specimens from each patient who undergoes gastroscopy, others continue to take
few and often topographically unidentified specimens. These diagnostic
guidelines can be best followed by those gastroenterologist-pathologist teams who
work together and communicate effectively.
Biopsy
Protocol
To
obtain adequately representative samples for the classification of gastritis,
the biopsy protocol is recommended. Biopsy specimens from the three
compartments (antrum, incisura angularis, and corpus) should be separately
identifiable when they are submitted to the laboratory. Proper orientation is
indispensable for optimal histological evaluation; it may be accomplished
either in the endoscopy suite when biopsy specimens are collected, or in the
histopathology laboratory at the time of embedding. This latter option is
generally preferable, unless endoscopy personnel are experienced and motivated
to perform the precise and tedious work required to orientate minuscule
fragments of fresh tissue properly.
To
translate histopathological observations into well-defined topographic
patterns, each feature is then graded using the standardized Visual Analogue
Scale. The final diagnosis issued should synthesize all individual evaluations,
for example, “H.pylori antrum-predominant gastritis” or “corpus-restricted
atrophic gastritis without H.pylori infection, suggestive of autoimmune
gastritis.”
The
Updated Sydney System is also suitable for evaluating and diagnosing the
special types of gastritis. A sample diagnosis might read “lymphocytic
gastritis, corpus predominant, with H.pylori infection.” In the case of
gastropathies, the Updated Sydney System is mainly useful for helping in the
orderly assessment of the histopathological features of the mucosa. This applies
even in the unlikely situation that the system’s recommended set of five biopsy
specimens is obtained from a patient with portal hypertension or watermelon
stomach. However, in most such cases, attempting to grade each specimen
individually is neither recommended nor necessary.
|
Chronic gastritis and Helicobacter
pylori organisms. A. H&E stain of gastric
mucosa showing surface foveolar cells, adherent mucus, and scattered
bacillary forms within the mucus. B. Steiner silver
stain of superficial gastric mucosa, showing abundant darkly staining
microorganisms layered over the apical portion of the surface epithelium.
Note that there is no tissue invasion.
|
TOOLS
TO DIAGNOSE AND CLASSIFY GASTRIC CONDITIONS
The
different types of gastritides and gastropathies are characterized by various
combinations of histological changes, many of which are expressions of immune,
inflammatory, and adaptive responses common to several conditions. However, the
presence, absence, and relative intensity of these responses provide important
etiologic clues and are crucial in the categorization of the process. These
histological changes can be viewed as the foundations for the terminology of
gastritis, and some familiarity with them is indispensable to understand both
the classification and the related manifestations of nonneoplastic gastric
conditions.
Epithelial Degeneration
Surface
epithelial degeneration is a nonspecific response to injury seen in all forms
of gastritis. It is most conspicuous in chemical gastritis and H.pylori
gastritis. In H.pylori gastritis, the intimate contact of bacteria with the
surface cell membrane makes epithelial degeneration particularly prominent.
Cell injury and necrosis can lead to erosions, which are seen endoscopically
either as flat superficial lesions or as elevated lesions whose chronic nature
is suggested by polypoid regenerative mucosa at the margins. The former are
often the result of acute damage caused by drugs, bile reflux, or ischemia,
whereas the latter are almost always associated with H.pylori gastritis.
Foveolar
Hyperplasia
Elongation
and increased tortuosity of gastric pits result from hyperplasia of the
foveolar cells, a presumed adaptive response to increased cellular exfoliation
from the surface epithelium. It can be viewed as a visual surrogate for
increased epithelial cell turnover. Hyperplasia is accompanied by
hyperchromatic nuclei and mitotic activity reaching an increased height of the
pit and by other signs of cellular immaturity, such as mucin depletion and a
high nucleocytoplasmic ratio. Marked foveolar hyperplasia is a prominent
feature of chemical injury, but lesser degrees are commonly seen in H.pylori
gastritis.
Hyperemia and
Edema of the Lamina Propria
Mucosal
hyperemia—often visible endoscopically—is considered to be an indicator of bile
reflux gastritis, and a significant correlation has been found with the
concentration of bilirubin in gastric juice. Histologically, marked edema of
the lamina propria with minimal inflammation is a characteristic finding in
bile gastritis.
Neutrophilic
Infiltration
The
presence of neutrophils characterizes the “activity” in chronic gastritis. The
cause is H.pylori in most cases, but other infectious and inflammatory
conditions (e.g., syphilis and Crohn’s disease) may be responsible for the
persistence of neutrophils, classically associated with “acute” inflammation.
Neutrophils are found in virtually every patient with H.pylori infection. The
intensity of neutrophil infiltration may help to distinguish among the acute
phase of infectious gastritis, Helicobacter gastritis with a particularly
active component, and acute hemorrhagic gastritis resulting from chemical
injuries (e.g., nonsteroidal antiinflammatory drugs [NSAIDs] or alcohol), in
which inflammation is a minor component. Neutrophils disappear rapidly after
successful eradication therapy; their persistence is a highly sensitive
indicator of therapeutic failure.
Eosinophilic
Infiltration
Rare,
scattered eosinophils may be present in the gastric lamina propria of healthy
persons, particularly in underprivileged populations. Prominent eosinophilic
infiltration of the gastric wall either may be part of the rare eosinophilic
gastroenteritis or may represent a process confined to the stomach. In either
case, the cause, suspected to have an allergic basis, is not known. Eosinophils
are a major component in the responses to anisakiasis and may be a constituent
of the granulomata that sometimes form around fragments of the helminths
remaining in the gastric wall. In adults with H.pylori gastritis, there are
usually small numbers of eosinophils. In contrast, children have been reported
to have a greater eosinophilic component in the H.pylori–infected gastric
mucosa. After eradication of the pathogen, eosinophils may increase for some
time and then decline in parallel with mononuclear cells.
Mononuclear
Cell Inflammation
Infiltration
of the lamina propria by lymphocytes, plasma cells, and small numbers of
eosinophils and mast cells is a major feature of H.pylori gastritis, except in
areas of severe atrophy and metaplasia, in which the infiltrate tends to be
sparse. When lymphocytes are seen infiltrating the surface or glandular
epithelium, the possibility of lymphocytic gastritis should be considered. In
autoimmune gastritis, there is a diffuse infiltrate of mucosal plasma cells and
lymphocytes. The latter are also present around and within oxyntic glands.
Lymphoid
Follicles
Lymphoid
follicles are rare in the stomach of healthy, H.pylori–free adults. When an
extensive biopsy protocol is used, lymphoid follicles or aggregates are found
in virtually all patients with H.pylori gastritis. In infected children and
young adults, these entities may produce a distinctive nodularity in the
gastric antrum, known endoscopically as follicular gastritis. H.pylori
infection is the major determinant of gastric acquired mucosa-associated
lymphoid tissue (MALT) and, therefore, a crucial factor in the origin of
primary gastric B-cell lymphomas (MALT lymphoma).
Atrophy
Gastric
atrophy is defined as the loss of appropriate glands in a given gastric
compartment; that is, glands that are expected to be present in the portion of
gastric mucosa under examination (e.g., oxyntic glands in the mucosa of the
corpus) have been replaced by tissues not normally found there. More recently,
the narrower definition of loss of specialized cells has been proposed.
Whenever the gastric mucosa is damaged, irrespective of the mechanism or cause,
it may either regenerate or return to normal (restitutio ad integrum), or it
may undergo adaptive reparative processes leading to the replacement of the
native mucosa with other structures. Destroyed native glands may be replaced by
fibroblasts and extracellular matrix, by glands of “pyloric” appearance (
pseudopyloric metaplasia), or by an intestinal-type epithelium ( intestinal
metaplasia). During chronic H.pylori infection, all these types of repair
occur, the respective proportion of each probably modulated by environmental,
genetic, and bacterial factors. Widespread atrophy also occurs in autoimmune
gastritis, as a consequence of the immune-mediated glandular destruction of the
oxyntic mucosa. Atrophic foci found in stomachs with evidence of chemical
gastropathy are probably the result of ulcer repair.
Intestinal
Metaplasia
Intestinal
metaplasia is the replacement of the mucous cells that line the normal gastric
mucosa with an epithelium similar to that of the small intestine. The different
types of intestinal metaplasia have been variously classified as follows:
complete versus incomplete; types 1, 2a, and 2b; and types I, II, and III,
based on their morphology and content in sulfomucins. In general, the greater
the extension of metaplasia in a stomach, the greater the proportion of the
incomplete types. Intestinal metaplasia is a virtually constant component of
atrophic gastritis, and is found more frequently in the stomach of patients
with H.pylori gastritis. Small antral foci of intestinal metaplasia are also
frequently found in bile reflux gastropathy, both in postoperative and in
intact stomachs.
Endocrine
Cell Hyperplasia
Endocrine
cell hyperplasia, a consequence of functional changes in chronic gastritis, is
most prominent in autoimmune atrophic gastritis. In this condition,
hypochlorhydria or achlorhydria lead to G-cell hyperplasia in the antral mucosa
with an accompanying rise in serum gastrin levels. This, in turn, induces the
histamine-producing enterochromaffin-like cells in the oxyntic glands to
undergo hyperplasia. The type, number, and distribution of endocrine cells can
now be established by using immunostaining techniques, which have replaced the
less reliable classical argentaffin and argyrophil histochemical stains.
Gastric endocrine cell proliferations are commonly classified according to the
criteria proposed by Solcia and colleagues, which distinguishes among
hyperplasia, adenomatoid hyperplasia, dysplasia, and neoplasia.
Mild
degrees of neuroendocrine proliferation may be seen, if they are searched for
by immunoenzymatic methods, in many routine gastric biopsies: they represent an
indirect and reversible effect of the widespread long-term use of proton pump
inhibitors. In this condition, hypertrophy occurs almost exclusively in
enterochromaffin-like cells, the most common type of endocrine cell in the
oxyntic mucosa, and is believed to depend on the trophic effect of the
concomitant hypergastrinemia.
Parietal Cell
Alterations
Protrusions
and pseudohypertrophy of oxyntic cells and glandular dilations are
characteristic yet reversible responses to the long-term administration of proton
pump inhibitors. These changes have also been described in patients with
gastric ulcer disease, although the pathogenetic connection remains unclear.
HELICOBACTER
PYLORI GASTRITIS
Chronic
gastritis, one of the most common chronic conditions of humankind, is now known
to be the result of specific and nonspecific responses mounted by the gastric
mucosa against H.pylori infection. H.pylori infection is associated with most
duodenal ulcer and gastric ulcers and with almost all primary gastric MALT
lymphomas. In certain regions of the world, many infected persons develop
metaplastic atrophic gastritis, a documented precursor of gastric carcinoma.
Furthermore, certain extragastric conditions, including systemic autoimmune
diseases, atherosclerosis, urticaria, and migraine, have been linked—albeit
tenuously—to H.pylori infection. Thus, the importance of H.pylori extends into
the realm of numerous major diseases that may have gastritis as their common
denominator.
Clinical
Manifestations
The
initial phases of H.pylori infection elicit an acute mucosal inflammatory
response whose clinical manifestations may include epigastric pain, nausea, and
vomiting. Such symptoms are uncommon and are usually short-lived. Because
patients rarely undergo endoscopic procedures in the early stages of H.pylori
infection, information regarding clinical aspects is limited. However,
well-documented case reports allowed a glimpse into the early aspects of the
infection and of iatrogenic H.pylori infection resulting from the use of inadequately
disinfected endoscopes. Most of these patients had multiple antral ulcers or
erosions, whereas others had a predominance of hemorrhagic lesions; both their
endoscopic and histopathological findings are virtually identical to those
reported in subjects from human ingestion studies and in patients with epidemic
gastritis and achlorhydria, a condition described before H.pylori was
discovered and later found to be a manifestation of acute H.pylori infection.
In
patients with uncomplicated chronic H.pylori gastritis, the prevalence of
dyspepsia is probably no greater than in uninfected persons, and among patients
with nonulcer dyspepsia, the prevalence of infected and noninfected persons is
similar. Furthermore, cure of H.pylori in patients with nonulcer dyspepsia has
not been shown conclusively to improve the dyspeptic symptoms, although the
reasons for this apparent lack of effect continue to be debated. Even with its
unclear relation to dyspepsia, H.pylori infection has been estimated to be
responsible for approximately 5% of gastrointestinal ailments in the community,
and patients with H.pylori gastritis are at increased risk of duodenal and
gastric ulcer, gastric cancer, and lymphoma.
Epidemiology
In
many developing countries, the prevalence of H.pylori in adults is close to
90%, with very high percentages of infected children, suggesting exposure to
the bacteria early in life. In established industrialized countries (Western
Europe, United States, Canada, and Australia), exposure occurs later, resulting
in minimal percentages of infected children (<1% in Swedish and Danish
schools in the year 2000) and low percentages of infected adults (~30% by age
50 years). Although the mechanisms of transmission remain poorly understood,
improved socioeconomic conditions result in a decreased prevalence of H.pylori,
as vividly illustrated by historical data from Finland, Sweden, and Japan.
Furthermore, innumerable people receive amoxicillin, which, used alone, may
cure approximately 10% of H.pylori infections, as well as other antibiotics for
the treatment of respiratory and other infections. Among H.pylori–infected
patients undergoing such therapies, a small but cumulatively significant
percentage is cured. Finally, it is likely that targeted anti– H.pylori treatment
in individual patients reduces transmission in the community and ultimately may
contribute to the decreased prevalence of the infection in the population.
Endoscopic
Appearance
Chronic
H.pylori gastritis has no distinct endoscopic pattern. Depending on the stage
or distribution of gastritis, hyperemia, erosions, ulcerations, hypertrophy,
and atrophy may coexist in various combinations in the same stomach, juxtaposed
to one another and to apparently normal areas. Yet, none of these features is
useful for predicting the presence or absence of chronic H.pylori. Therefore,
the diagnosis of H.pylori gastritis requires histopathological analysis.
Histopathology
H.pylori
organisms are found in greatest numbers in the gastric mucous gel and attached
to surface mucous cells. Bacteria are also present in the intercellular spaces
and, particularly in patients receiving long-term antisecretory therapy with
proton pump inhibitors, within the canaliculi of parietal cells. The difficulty
of visualizing bacteria in these latter locations before the development of
polyvalent staining techniques may explain the misconception that H.pylori is a
strict gastric surface dweller.
Antral,
oxyntic, and cardiac mucosae are equally susceptible to infection and are
colonized with similar frequencies. In patients with extensive antral
intestinal metaplasia, a type of epithelium to which H.pylori rarely adheres,
the infection is virtually confined to the nonmetaplastic areas of the corpus.
This is also the case in many patients who regularly use proton pump
inhibitors.
Infiltration
of the gastric epithelium by polymorphonuclear neutrophils is the most
distinctive feature of the gastric mucosa infected by H.pylori: neutrophils are
generally more abundant in the antrum and the cardia than in the corpus, where
they may be rare or even completely absent in spite of visible bacterial
colonization. This distribution of inflammation characterizes
antrum-predominant gastritis, the most common type of gastritis in Western
populations. Neutrophils are usually the only inflammatory cells that
infiltrate the gastric epithelium in H.pylori infection, but in the lamina
propria they are almost always mixed with lymphocytes, plasma cells, and
variable amounts of eosinophils. Inflammation tends to be most intense in the
superficial portions of the lamina propria, hence the term superficial
gastritis, still occasionally used as a synonym for nonatrophic gastritis.
Lymphoid
follicles are virtually always found in infected stomachs, and their presence
is a reliable indication of active or recently treated H.pylori gastritis.
Their greatest density is in the region of the incisura angularis, and the
lowest density is in the proximal greater curvature.
“Disease-Specific”
Virulence Factors
Since
the discovery of the H.pylori toxins VacA and CagA, which were linked to
certain types of damage to the gastric mucosa, there have been continuous
attempts to correlate them and other virulence factors with a specific
manifestation or complication of H.pylori gastritis. Although some of these
factors can affect the intensity of inflammation and, perhaps through this
mechanism, may ultimately influence the outcome of gastritis, the virulence of
H.pylori seems to be largely host dependent, and none of these factors are
disease specific. Thus, at present, there is no clinical application for tests
that purport to determine the potential pathogenicity of an individual
patient’s H.pylori strain. The best studied putative virulence factor is the
cytotoxin-associated gene product (Cag) A, the product of one of the genes in
the cag pathogenicity island. Subjects infected with H.pylori with a functional
cag pathogenicity island have elevated mucosal levels of interleukin-8, marked
neutrophilic infiltration into the gastric mucosa, and an increased risk of
developing a symptomatic outcome such as peptic ulcer or gastric cancer.
However, the relationship between the presence of the cag pathogenicity island
and outcome is not consistent in different geographic regions, especially in
East Asia, where more than 90% of isolates possess the cag pathogenicity
island. In Western countries, where H.pylori strains lacking the cag
pathogenicity island are found in a higher percentage than in Asian countries,
the increased likelihood of a symptomatic outcome can be seen. However, the
presence of a functional cag pathogenicity island has no value in predicting
current or future clinical presentation in individual patients.
Other
putative pathogenicity factors include the following: IceA (induced by contact
with epithelium), a bacterial restriction enzyme for which no biologic or
epidemiologic evidence as a virulence factor in H.pylori–related disease has
been confirmed; and VacA (vacuolating cytotoxin), which has been subtyped into
an s1 genotype (presumably associated with duodenal ulcer disease) and an s2
genotype with reportedly low ulcerogenic potential. A compilation of studies
involving approximately 1500 isolates from Europe, the United States, and Asia
has shown overwhelming that VacA genotyping is not useful to predict degree of
inflammation, symptoms, presentation, or response to therapy.
The
blood group antigen binding adhesin (BabA) is an outer membrane protein that
appears to be involved in the adherence of H.pylori to Lewis-b (Le b) blood
group antigens on gastric epithelial cells. A small study suggested that
infection with strains with the babA2 gene, cagA +, and vacA s1
(triple-positive strains) may be correlated with duodenal ulcer, but a larger
multinational study did not confirm the association.
Diagnosis
The
diagnosis of H.pylori gastritis rests on the identification of H.pylori in the
gastric mucosa. When the search for H.pylori relied exclusively on the
availability of gastric biopsy specimens (for histopathology, rapid urease
tests, or culture), only patients who required an endoscopic examination were
tested. The development of increasingly accurate noninvasive tests allows the
accurate diagnosis of H.pylori gastritis based on indirect methods, that is,
without necessarily visually identifying or culturing the organism.
Furthermore, the availability and popularization of new, simple, and
inexpensive tests have expanded the indications to a greater variety of
patients and settings, including self-referring patients in the general practitioners’
office.
Significant
progress has been made also in our knowledge of factors that may influence the
interpretation of the results and may interfere with the accuracy of each test.
The prevalence of a condition in the population studied influences both the
positive and negative predictive value of tests, even if a test’s sensitivity
and specificity are independent values inherent to the test itself. Therefore,
clinicians should be familiar not only with the performance parameters of the
tests they use, but also with their potential interpretative pitfalls as well
as with the prevalence of H.pylori in their patient population.
Invasive
Tests
Histopathological
examination of gastric biopsy specimens. Helicobacter spp. can be detected in
histological preparations of gastric biopsy specimens stained with a variety of
methods. Hematoxylin and eosin is a suboptimal choice of stains for the
specific task of detecting H.pylori. Reliable special stains include the
Warthin-Starry and the Steiner silver stains, the Giemsa, Diff-Quick, and
Gimenez stains, and a triple stain, which, by combining modified Steiner
staining, hematoxylin and eosin, and Alcian blue, allows the simultaneous
visualization of the features of gastritis, including intestinal metaplasia,
and the bacteria. Several modified versions of this stain have become
available. Anti– H.pylori antibodies for the immunohistochemical detection of
H.pylori in paraffin-embedded biopsy specimens have high sensitivity and
specificity; some laboratories use them for routine clinical diagnosis.
In
situ hybridization and polymerase chain reaction. In situ hybridization may be
used for the detection of H.pylori in paraffin-embedded sections, but high cost
and technical difficulties have relegated this procedure to the research
laboratory. Polymerase chain reaction for the detection of H.pylori infection
must also be considered a research tool because of its requirement for a
sophisticated molecular biology laboratory, the availability of appropriate
primers, and its high price.
Smear,
brush, and touch preparations. Smears of gastric mucus and exfoliated
epithelial cells, usually with Gram staining, may allow the detection of
bacteria within minutes of the endoscopic procedure. Rapid urease tests have
made cytologic assays obsolete.
Bacterial culture. H.pylori is
best cultured in a microaerophilic and humid atmosphere on culture media
requiring fresh horse or sheep blood and antibiotics to suppress contaminants.
Cultures for H.pylori are technically more complicated than those performed by
the usual clinical microbiology laboratory. Because many clinical facilities
are not equipped to perform the time-consuming procedures necessary to culture
H.pylori, several methods for transportation have been devised.
Rapid urease tests. These assays
exploit the high content of urease of H.pylori. A fragment of gastric mucosa is
placed into a broth or in agar containing various concentrations of urea. The
urease produced by H.pylori hydrolyzes the urea and releases ammonia, which raises
the pH of the broth or agar, and an appropriate indicator (e.g., phenol red)
changes color as the pH increases. In the first commercially produced rapid
urease test, the CLOtest, the original yellow gel capsule into which the
specimen is placed becomes red within minutes to hours, depending on the
quantity of bacteria present. Several rapid urease tests are now commercially
available. Both their specificity and sensitivity, compared with histopathological
examination, are extremely high, in most cases approaching 100%.
Noninvasive
Tests
Serology. The
development of new techniques has minimized the problems of cross-reactivity
that plagued first-generation serologic tests. Currently available tests are
highly reliable. The large numbers of studies aimed at the discovery of an
optimal diagnostic test for H.pylori infection have also provided valuable
information on the immune responses to this organism. For example, the
selection of H.pylori strains as sources of antigen is critical to the
specificity and sensitivity of a test, and it is imperative to evaluate
specific tests in the population to which it would be applied before selection
of a test for use in specific settings. This population specificity highlights
the importance of the many different geographic strains that infect different
world populations.
Simplified “in-office”
immunoenzymatic tests. Several in-office devices have been developed
for the rapid detection of IgG anti– H.pylori antibodies. Most of them consist
of disposable kits that provide a yes/no answer within a few minutes of placing
a drop of serum in a well that is preabsorbed with antigen and an
immunoenzymatic detection system. Although some of these tests are accurate,
results have been generally less than the minimum required sensitivity and
specificity of 90%. Antibodies (mostly of the IgG class) against H.pylori have
been detected in the saliva and the urine of infected patients. The specificity
and sensitivity of urine tests have been found to be satisfactory in several
studies, particularly in Japan.
Stool antigen assay. An enzymatic
immunoassay (HpSA) that detects H.pylori antigens in stools (thus providing
information on the presence of current infection) has become available for the
diagnosis of H.pylori infection and for monitoring the response to therapy. The
test is similar to an enzyme-linked immunosorbent assay, using polyclonal anti–
H.pylori antibody absorbed to microwells. A large European multicenter study
has yielded encouraging results.
Urea breath tests. The urea
breath tests are among the most important and innovative methods to detect
H.pylori infection. These tests rest on the ability of H.pylori to produce
large quantities of urease. The ingestion of a solution containing urea is
rapidly followed, in an infected patient, by the production of ammonia and
carbon dioxide. The latter rapidly appears in the subject’s breath. If the
ingested urea is labeled either with the radioactive isotope 14C or with the
nonradioactive isotope 13C, then the exhaled carbon dioxide will also be
labeled and, therefore, measurable by an appropriate detection method. When
14C-labeled urea is used, the general method consists of the ingestion of a
solution or a capsule containing quantities between 0.5 and 10 µCi of the
isotope-labeled urea. When 13C-labeled urea is used, test subjects are given a
solution of 125 g of 99.9% labeled urea followed by a meal aimed at increasing
its permanence in the stomach. After a period of time, the subject inflates a
balloon, which is immediately sealed and sent to a laboratory for the detection
of the isotope-labeled carbon dioxide. Both types of tests are now well
standardized and are approved by regulatory agencies in Europe and North
America. The urea breath tests are extremely sensitive and specific and, in
contrast to serologic tests, detect current active infection (not evidence of
past infection). Their widespread use has made them more affordable, and they
have become the test of choice for a variety of populations, including
children, pregnant women, and patients who cannot undergo an endoscopic
procedure.
Helicobacter
heilmannii Infection
More
than 35 species of Helicobacter have been described, but only few other than
H.pylori have been shown to cause gastritis in humans: H felis, H fennelliae, H
cinaedi, and H heilmannii. Among these, H heilmannii (formerly known as
Gastrospirillum hominis) is the most common, with an estimated prevalence of
approximately 1% of all human Helicobacter infections. In some rural areas in
Eastern Europe, this organism has been detected more commonly, leading to the
hypothesis of zoonotic transmission. The bacterial morphology is
characteristic: organisms measure 5 to 9 µm in length (twice as long as
H.pylori) and have five to seven spirals clearly visible with a silver stain.
Gastritis caused by H heilmannii is often milder and more patchily distributed
than H.pylori gastritis. The inflammation tends to be more circumscribed and to
affect mostly the antrum, although cases with severe corpus active inflammation
are seen. Concurrent erosions and ulcers have been reported to be less common
than in H.pylori gastritis. The diagnosis rests on the recognition of the
bacterial morphology, although the distinction between H heilmannii and H felis
is not possible by light microscopy.
Treatment of
Helicobacter pylori Infection
At
present, the only universally agreed on indications for treatment are
H.pylori–related duodenal and gastric ulcers and low-grade, primary B-cell MALT
lymphoma. H.pylori should be eradicated in patients with documented ulcer
disease, whether or not the ulcers are currently active, to reduce the
likelihood of relapse. Most clinical trials do not provide convincing data in
support of the benefits of eradication of infection in patients with nonulcer
dyspepsia, and there are no controlled studies showing that eradicating
H.pylori from a population will reduce the incidence of gastric cancer. For
various logistical and ethical reasons, it is unlikely that such trials will be
ever carried out to the satisfaction of those who demand unequivocal evidence.
The most pressing question then is whether we should hold back and wait for
more data or act now based on current information. Today, there is ample
epidemiologic and biologic evidence that whereas H.pylori gastritis may not be
the only cause of the development of atrophy and intestinal metaplasia, it
almost always provides the necessary background on which these lesions arise.
By treating H.pylori gastritis, we can prevent the development of atrophy and
metaplasia, and most likely we would also arrest the progress of these lesions
in infected persons who have already developed them. As a result, we should be
able to prevent millions of gastric cancers. The incidence of non–NSAID-induced
peptic ulcers would also be greatly reduced, and primary gastric lymphomas
would all but disappear. Thus, we ought to put aside the teleological questions
on the ultimate significance of our immemorial amphibiotic relationship with
H.pylori and its intriguing evolutionary and metaphysical implications and
proceed to cure infected patients.
In
vitro, H.pylori is susceptible to a wide range of antibiotics, but monotherapy
has been disappointing in vivo, probably because of inadequate antibiotic
delivery to the sites of colonization. Thus, several multidrug regimens have
been developed, the most successful of which are triple and quadruple
combinations that achieve H.pylori eradication rates of more than 90% in many
trials and more than 75% in clinical practice. The most commonly used 7- and
14-day drug regimens consisting of a proton pump inhibitor and two or three
antimicrobial agents. The major determinants of therapeutic failures are
inadequate patient compliance and drug resistance, particularly to
metronidazole and clarithromycin.
There
are no established guidelines for posttreatment testing. When eradication
therapy is given for gastric ulceration or MALT lymphoma, there is an
opportunity to retest for H.pylori at repeat endoscopy, which is performed to
evaluate healing or regression. For duodenal ulceration, a urea breath test, a
stool antigen test, or an endoscopy with gastric biopsy should be performed 4
to 6 weeks after treatment. When therapy is administered to treat asymptomatic
infections, posttreatment testing is generally not deemed necessary.
Evolution and
Associations of Helicobacter pylori Gastritis
H.pylori
gastritis is a life-long infection that can be viewed as a spectral disease. At
the one end of the spectrum, inflammation remains mostly confined to the antrum
and the cardia, the oxyntic mucosa is mildly affected, and atrophy is absent or
minimal. At the other end, severe inflammatory changes involve the entire
gastric mucosa and inflict progressive damage that results in loss of the
normal gastric glands and their replacement by fibrous tissue and metaplastic
epithelia. Although these are aspects of the same disease that can be placed on
a continuous scale, the epidemiologic distribution and the associations of the
two extremes are profoundly different. Gastritis confined to the antrum and
without significant atrophy does not impair acid secretion, is commonly present
in patients with duodenal ulcer, and has not been linked to increased cancer
risk. Conversely, generalized gastritis with atrophy reduces acid secretion and
is strongly associated with gastric adenocarcinoma. Thus, for the practical
purposes of classification and prognostic evaluation, it has been expedient to
divide gastritis into two phenotypes: nonatrophic antrum-predominant gastritis
and multifocal atrophic gastritis.
Antrum-Predominant Gastritis This is the
most common form of gastritis in the Western world. Its characteristics are as
follows: a moderately to severely inflamed antrum; a mildly inflamed or normal
corpus; minimal or absent atrophy or intestinal metaplasia, limited to the
antrum; and normal or increased acid secretion. Most patients with this type of
gastritis have neither symptoms nor complications. However, they have a risk of
duodenal ulcer, estimated at 20% over their lifetime.
Atrophic Gastritis Also called
multifocal atrophic gastritis, metaplastic atrophic gastritis, and atrophic
pangastritis, this disorder is characterized by marked diffuse mucosal
inflammation, often more severe in the oxyntic mucosa, by patches of atrophy
and intestinal metaplasia in both antrum and corpus, and by variously reduced
acid secretion. Atrophic gastritis is most prevalent in populations that are—or
were, until a few decades ago—living in suboptimal sanitary conditions,
including much of South and East Asia, Latin America, and parts of Central,
Eastern, and Southern Europe. Socioeconomic factors may be a surrogate for
other unknown agents that modulate the evolution of gastritis, because there
are notable epidemiologic exceptions to this association. Japan, a country with
high levels of sanitation and personal hygiene, has one of the world’s highest
prevalences of atrophic gastritis and a high incidence of gastric
adenocarcinoma. In contrast, Equatorial Africa, in spite of its precarious
socioeconomic texture, inadequate sanitary standards, and a prevalence of
H.pylori close to 90%, appears to have a low prevalence of atrophic gastritis
and a low incidence of gastric adenocarcinoma. Several explanations have been
proposed for this ‘African enigma,” ranging from diet, human and bacterial
genetics, to unreliable statistics. Atrophic gastritis is a risk factor for
gastric epithelial dysplasia, a precursor of the intestinal-type adenocarcinoma
of the stomach. It also predisposes patients to gastric ulcer.
Peptic Ulcers, Carcinoma,
and Lymphoma In addition to peptic ulcer disease and gastric carcinoma,
H.pylori infection is also epidemiologically related to primary gastric
MALT-lymphomas.
Extragastrointestinal
Manifestations of Helicobacter pylori infection H.pylori infection has been
proposed to be associated with an ever-growing number of extragastric
manifestations of H.pylori infection, even if their causal relationship with
H.pylori is far from conclusively demonstrated. Most of these associations are
founded on epidemiologic data; however, both H.pylori infection and of some of
the conditions allegedly associated with it (e.g., atherosclerosis) have a very
high prevalence in many populations. Thus, biologic rather than epidemiologic
data will be needed to prove causation. For one of these conditions, rosacea,
there are several randomized trials that essentially disprove the association
with H.pylori. Conversely, several clinical studies based on treatment results
lend some support to the possibility of a pathogenetic involvement of H.pylori
in iron deficiency anemia and autoimmune thrombocytopenic purpura. For most
other conditions, data are insufficient to reach informed conclusions; however,
the biologic plausibility in some of the proposed associations (e.g., with
migraine) is so low that one must wonder whether attempts to prove causality
are worth the effort.
INFECTIOUS
GASTRITIS (EXCLUDING HELICOBACTER)
Because
of the high acid content of the normal stomach, the gastric environment is
inhospitable to most infectious agents. However, in patients with atrophic
gastritis and decreased acid secretion, in patients with impaired immune
responses, or as part of systemic infections, numerous viruses, bacteria, and
parasites can infect the stomach. Although rare, some of these infectious
gastritides have characteristic clinical and pathological features.
Viruses
Enteric
rotaviruses and caliciviruses probably infect the stomach during the course of
gastroenteritis, but no pathological changes in the gastric mucosa have been
documented in volunteer studies with these agents. Only cytomegalovirus (CMV)
infection is known to have a distinct pathological appearance in the stomach.
CMV gastritis is seen almost exclusively in young children and
immunocompromised patients, and it is usually associated with concurrent CMV
infection of other sites of the digestive tract. Endoscopically, the gastric
mucosa may appear completely normal or may show erosions, shallow ulcers, or
hemorrhagic gastritis. Rarely, the condition may present as grossly nodular
mucosa that has been referred to as a pseudotumor. CMV inclusions may be
abundant and thus easily detected using the routine hematoxylin and eosin
stain, or they may be rare and impossible to demonstrate without using
immunohistochemistry or in situ hybridization techniques. A characteristic
manifestation of CMV infection in the stomach of young children is massive
foveolar hyperplasia accompanied by edema and mild inflammation of the lamina
propria. The resulting endoscopic appearance is that of a giant-fold
hypertrophic gastropathy indistinguishable from Ménétrier disease.
The
diagnosis of gastric CMV infection is made by demonstrating the characteristic
nuclear or cytoplasmic viral inclusions. The only effective therapeutic agent
is ganciclovir, a guanosine derivative that selectively inhibits CMV DNA
polymerase. In patients with acquired immunodeficiency syndrome (AIDS) and CMV
colitis, ganciclovir has a response rate of 70% to 90%.
Bacteria
Bacterial
overgrowth may occur in stomachs that have become achlorhydric as a result of
atrophy, complete antrectomy, or vagotomy or as a result of long-term use of
histamine H 2-receptor antagonists or proton pump inhibitors. Patients with
scleroderma and other severe motility impairments are also prone to bacterial
overgrowth. In contrast to H.pylori, however, these bacteria colonize rather
than infect the gastric mucosa, and they neither elicit inflammatory responses
nor cause symptoms.
An
extremely rare condition is acute suppurative gastritis, also known as
phlegmonous gastritis. This life-threatening condition is caused by pyogenic
bacteria (streptococci, staphylococci, Escherichia coli, Proteus, and
Haemophilus spp.) and is characterized by large areas of purulent necrosis
involving the full thickness of the gastric wall. When it is caused by
gas-forming organisms, the term emphysematous gastritis has been used. Few
cases have been reported, mostly in very young children, elderly persons,
patients with alcoholism, and immunocompromised patients. Potential iatrogenic
causes include polypectomy and mucosal injection with India ink. The diagnosis
is made endoscopically or at surgery. Antibiotic treatment may have to be
accompanied by surgical intervention.
Primary
gastric tuberculosis is rare, particularly in industrialized countries.
However, in patients with disseminated tuberculosis, necrotizing granulomata
may be found in the gastric mucosa. Another Mycobacterium that has gained
prominence with the spread of AIDS is Mycobacterium avium-intracellulare
complex, but the stomach is rarely involved; when it is, typical lesions
consist of accumulations of foamy histiocytes in the lamina propria, sometimes
with formation of ill-defined granulomata without necrosis.
In
the 1980s and early 1990s, increasing numbers of cases of gastric syphilis were
reported in patients infected with human immunodeficiency virus. When
associated with secondary syphilis, syphilitic gastritis is characterized by a
prominent mixed inflammatory infiltrate consisting predominantly of plasma
cells and with mucosal ulcerations. The infiltrate may be dense enough to cause
the swelling of gastric folds, which may also undergo erosion and ulceration,
sometimes mimicking the endoscopic appearance of lymphoma or infiltrating
carcinoma. Symptoms include severe dyspepsia, nausea, vomiting, and anorexia,
with rapid weight loss. The diagnosis is often delayed by a low index of
suspicion. Although spirochetes may be seen in sections stained with
appropriate silver stains (Dieterle, Steiner, or Warthin-Starry), the search
may be painstaking and is usually beyond the reach of the nonspecialist
pathologist. Standard treatment for secondary syphilis is rapidly effective.
Fungi
Candida
species, Histoplasma capsulatum, and Mucoraceae have been found in the stomach
of immunocompromised patients, particularly those with AIDS, with disseminated
infections, but none of these fungi have been reported as a primary cause of
gastritis.
Parasites
The
stomach is not a preferred site for human parasitic infections, but
Cryptosporidium spp. and Giardia intestinalis have been identified in the
gastric mucosa. Strongyloides stercoralis has been found in the stomach of a
few patients with widespread infections.
The
only nematodes that invade the human gastric wall are those of the family
collectively known as Anisakidae, or “sushi worms.” Anisakiasis is an important
cause of morbidity in countries such as Japan, where large quantities of raw
fish are consumed. The muscle of many species of edible fishes contain larvae
of Anisakidae. In a small proportion of persons who eat infected fish, larvae
penetrate the gastric wall and cause a sudden onset of epigastric pain. Because
the worms can be easily removed endoscopically by an experienced operator and
the disease is self-limited in any case, patients presenting with epigastric
pain in high-prevalence countries should be asked routinely about ingestion of
raw or undercooked fish within 12 hours before the onset of symptoms. This
practice would help to avoid unnecessary surgery.
AUTOIMMUNE
GASTRITIS
Autoimmune
gastritis is a corpus-restricted chronic atrophic gastritis associated with
circulating serum anti–parietal cell and anti–intrinsic factor antibodies and
intrinsic factor deficiency, with or without pernicious anemia.
Clinical
Manifestations
Most
clinical manifestations of autoimmune gastritis become apparent only many years
after the onset of the disease, when the parietal cell mass decreases beyond a
critical point and the stomach becomes unable to produce sufficient amounts of
acid, pepsinogens, pepsin, and intrinsic factor. Achlorhydria, the most direct
result of the destruction of acid-producing oxyntic cells, typically occurs in
the most advanced stages of the disease. Hypochlorhydria, however, may also
occur in patients with moderate to large numbers of surviving parietal cells,
suggesting that anti–proton pump antibodies or inhibitory lymphokines released
by subsets of inflammatory cells may participate in the inhibition of acid
secretion. Patients with corpus atrophy and achlorhydria have hypergastrinemia,
which tends to correlate with the severity of the mucosal damage. Injury to
chief cells leads to a reduction of pepsin activity in gastric juice and of
pepsinogens in blood. A low serum pepsinogen I level (<20 ng/mL) is a
sensitive and specific indication of corpus atrophy.
Many
patients with autoimmune gastritis develop either iron deficiency or pernicious
anemia. Hypochromic anemia is associated with corpus-restricted chronic
atrophic gastritis in approximately 15% of patients. Achlorhydria seems to be
the major contributor to the pathogenesis of iron deficiency anemia: gastric
acid is important in the absorption of nonheme iron, which in Western diets
supplies at least two thirds of nutritional iron needs. Pernicious anemia is
usually preceded by corpus-restricted chronic atrophic gastritis and reduced
acid secretion by approximately a decade, and it is generally associated with a
histological pattern of end-stage atrophic gastritis. Pernicious anemia is a rarely
diagnosed condition, with a reported prevalence of less than 1% even in elderly
persons in high-incidence countries. Its true prevalence could be higher, but
most patients are successfully treated by hematologists or general
practitioners for their anemia and cobalamin (vitamin B 12) deficiency, and
they are never referred to a gastroenterologist for the evaluation of atrophic
gastritis, pepsinogens levels, or anti–parietal cell antibodies. Cobalamin
deficiency affects the rapidly proliferating gastrointestinal epithelium, and
patients with severe deficiency may complain of a sore tongue, which may be
smooth and beefy red. Anorexia with moderate weight loss may also be evident,
possibly accompanied by diarrhea and other gastrointestinal symptoms. Neurological
manifestations include numbness and paresthesia in the extremities, weakness,
and ataxia. There may be sphincter disturbances.
Autoimmune
gastritis is a risk factor for hyperplastic and adenomatous polyps, carcinomas,
and endocrine tumors. Polyps are found in 20% to 40% of patients with
pernicious anemia, and they are mostly sessile, smaller than 2 cm in diameter,
and often multiple. Most polyps are hyperplastic, but up to 10% contain
dysplastic foci. Gastric cancers associated with pernicious anemia are of the
intestinal type and arise from intestinal metaplasia, a finding suggesting that
the link between autoimmune gastritis and carcinoma may be intestinal
metaplasia and its dysplastic transformation.
Pathogenesis
Autoimmune
gastritis is substantially more common in patients with other diseases thought
to be of immunologic origin (Graves disease, myxedema, thyroiditis, idiopathic
adrenocortical insufficiency, vitiligo, and hypoparathyroidism) than in the
healthy population. The high prevalence of specific familial histocompatibility
haplotypes such as human leukocyte antigen (HLA)-B8 and HLA-DR3 in patients
with corpus-restricted atrophic gastritis is another strong indicator of its
autoimmune origin. The precipitating factors, however, remain unknown. The
hypothesis that autoimmune gastritis could be initiated by H.pylori infection
has received considerable attention. A high prevalence of antibodies with high
specificity for gastric mucosa antigens has been reported in patients with
H.pylori–associated gastritis; preabsorption of the serum from these patients
with H.pylori removed most of these autoantibodies. Furthermore, 20% of these
patients had autoantibodies that reacted with the secretory canalicular
structures of parietal cells, which are among the major targets in autoimmune
gastritis. In other studies, H.pylori–positive patients with and without
previously demonstrated anticanalicular antibodies had a 30% to 50% prevalence
of anti–H +,K +-ATPase antibodies, in contrast to a less than 3% prevalence in
noninfected persons. It has also been demonstrated that H.pylori
lipopolysaccharides express Lewis x and y blood group antigens, which are also
expressed by either H +,K +-ATPase or gastric epithelial cells. Collectively,
this information lends support to the concept that a cross-mimicking mechanism
between H.pylori and gastric mucosa antigens participates in the pathogenesis
of autoimmune gastritis. This correlation, however, remains unproven, and much
stronger biologic, clinical, and epidemiologic evidence is needed before
H.pylori can be viewed as the cause of autoimmune gastritis.
Endoscopic
Appearance
Atrophy
causes a progressive thinning of the mucosa of the gastric corpus; this
explains why few folds are left and why fine submucosal vessels are easily
recognized on endoscopic examination, especially in advanced disease. The
antral mucosa is endoscopically normal in the majority of cases. Polyps become
common in the advanced stages of the disease; therefore, atrophic gastritis
must be ruled out in patients in whom multiple hyperplastic gastric polyps are
detected at endoscopy.
Histopathology
The
main histopathological features of autoimmune gastritis are diffuse
corpus-restricted chronic atrophic gastritis with mild to moderate intestinal
metaplasia and, in the absence of concurrent H.pylori infection, a normal
gastric antrum. This pattern is characteristic of the advanced stage of the
disease and is found in patients with pernicious anemia. Persons with parietal
cell antibodies and no pernicious anemia show a broad spectrum of atrophic
changes, from minimal oxyntic gland loss to severe and diffuse atrophy of the
oxyntic mucosa. In the early phases, one sees diffuse or multifocal, dense
mononuclear cell infiltration of the lamina propria and lymphocytic
infiltration of individual oxyntic glands. Later, marked atrophy of the oxyntic
glands with diffuse mononuclear cell infiltration of the lamina propria
develops. Pyloric metaplasia is extensive, whereas intestinal metaplasia tends
to be still limited to few foci. The end stage is characterized by a great
reduction in corpus mucosal thickness, foveolar hyperplasia, and replacement of
oxyntic glands by pyloric, pseudopyloric, or intestinal metaplasia. The
inflammatory infiltrate is minimal, although scattered lymphoid aggregates and
follicles may be found.
In
the majority of patients, the antral mucosa is either normal or shows only
focal areas of mild chronic inflammation with intestinal metaplasia, similar in
degree and extension to what is observed in the general asymptomatic
population. Hyperplasia of gastrin cells secondary to achlorhydria is often
seen. Enterochromaffin-like cell carcinoids may arise during the florid phase,
but they are found more commonly in association with an end-stage histopathological
pattern.
Diagnosis
Autoimmune
gastritis should be suspected in patients with megaloblastic anemia, with
evidence of clinically significant cobalamin deficiency with values lower than
150 pg/mL, or with multiple gastric polyps. The diagnosis must be confirmed by
the characteristic histopathological findings of corpus-restricted atrophic
gastritis and by the presence of serum anti–intrinsic factor or anti–parietal
cell antibodies.
Management
The
management of patients with autoimmune gastritis should address two aspects of
the condition: the gastric lesions and the manifestations related to the
cobalamin deficiency. Gastric mucosal atrophy is irreversible. Patients with
extensive intestinal metaplasia and those with multiple polyps may be at
increased risk of gastric cancer. Although there are no accepted guidelines, a
surveillance gastroscopy every 1 or 2 years may represent a sensible empiric
approach.
With
cobalamin replacement, most abnormalities resulting from cobalamin deficiency
undergo complete and lifelong correction, except for the neurological
manifestations. Their improvement depends on the extent that irreversible
changes in the nervous system may have occurred before treatment.
LYMPHOCYTIC
GASTRITIS
Lymphocytic
gastritis is characterized by the presence of large numbers of mature
lymphocytes infiltrating the surface and foveolar epithelium.
Clinical
Manifestations
In
his original report of this condition, Haot suggested that lymphocytic
gastritis corresponded to the endoscopic entity previously known as varioliform
gastritis. The histological features of lymphocytic gastritis may also be found
in endoscopically normal stomachs and in patients with celiac disease, and the
varioliform aspect (numerous thickened folds capped by small nodules that
contain a central erosion or ulceration) can be found in H.pylori–infected
stomachs.
Lymphocytic
gastritis is rare, found in 1% to 3% of persons who undergo endoscopy with
biopsy sampling. It is most commonly diagnosed in the sixth decade and appears
to affect men and women equally.
In
contrast to patients with chronic active gastritis, patients with the
varioliform type of lymphocytic gastritis are often symptomatic; rapid weight
loss and anorexia are reported in about half of affected patients, whereas epigastric
pain is less common. Hypoproteinemia, hypoalbuminemia, and peripheral edema
suggesting protein-losing gastroenteropathy have been documented in
approximately 20% of patients. Lymphocytic gastritis is a chronic disease, but
there have been few case reports of spontaneous resolution. When it is
associated with gluten enteropathy, the signs, symptoms, and clinical course
are those of celiac disease.
Pathogenesis
Both
the etiology and the pathogenesis of most lymphocytic gastritides are unknown.
Because virtually all intraepithelial lymphocytes are CD8 + suppressor T cells,
the same cells that form the intraepithelial infiltrate in celiac disease, an
allergic pathogenesis has been proposed. This hypothesis is supported by the
increasingly apparent association between a subtype of lymphocytic gastritis
and celiac disease. The relationship with H.pylori, initially enthusiastically
embraced, then vigorously rejected, is now viewed with an agnostic attitude by
most investigators.
Macroscopic
and Endoscopic Appearance
Approximately
80% of patients in whom a histopathological diagnosis of lymphocytic gastritis
is made have endoscopic lesions described as varioliform, aphthous, verrucous,
or chronic erosive gastritis. The appearance is that of a complex pattern of
enlarged folds, predominantly in the corpus, which are covered by thick mucus,
are crossed by large erosions, and may be crested with clusters of elevated
aphthoid nodules. Flat erosions may be found in the antrum. The remaining 20%
of patients (including those with celiac disease and collagenous gastritis)
have less dramatic lesions, with only scattered superficial erosions in the
corpus or antrum. Some patients have an endoscopically normal stomach. This
last group of patients with a normal-appearing stomach may have a
pathogenetically distinct condition, even though the histopathological features
are indistinguishable. Some authors have suspected a relationship between
lymphocytic gastritis and Ménétrier disease.
Histopathology
and Diagnosis
Because
the endoscopic appearance of varioliform gastritis may result from either
H.pylori infection or lymphocytic gastritis, the diagnosis can be suspected
clinically, but it can be confirmed only by histopathologists. In biopsy
specimens from these patients, a substantial increase in intraepithelial
lymphocytes, particularly in the corpus, is associated with a histopathological
spectrum ranging from marked chronic inflammatory cell infiltration of the
lamina propria, activity, and focal erosions to a minor increase in chronic
inflammatory cells with no activity. In most cases, the histological picture
can be readily distinguished from that of chronic H.pylori gastritis, in which
few intraepithelial lymphocytes are present (rarely more that 5 or 6 per 100
epithelial cells). The diagnostic threshold for lymphocytic gastritis is
generally accepted as more than 25 intraepithelial lymphocytes per 100
epithelial cells, but in most cases the counts are much greater, between 25 and
50 lymphocytes. If H.pylori infection is present, immunohistochemistry to
detect CD8 + T cells may be helpful: in pure lymphocytic gastritis, most
intraepithelial lymphocytes are CD8 +, whereas a heterogeneous infiltrate
characterizes H.pylori gastritis.
Therapy
When
concurrent H.pylori infection is present, eradication of the infection may
resolve the inflammation and is therefore recommended. Patients with gluten
enteropathy will benefit from the standard dietary limitations recommended to
restore the small intestinal integrity. For patients with “pure” lymphocytic
gastritis and severe gastric mucosal lesions, there are no consistently
effective therapies. The use of proton pump inhibitors has resulted in healing
of the ulcers and erosions in some patients. Therapy with glucocorticosteroids
or sodium cromoglycate, often successfully used for the treatment of
eosinophilic gastroenteritis, has obtained unclear results.
GRANULOMATOUS
GASTRITIS
Rather
than a clinical entity, granulomatous gastritis can be viewed as a
histopathological category to which stomachs bearing granulomata are
temporarily assigned while the condition responsible for their development is
identified. In most cases the morphologic appearance of granulomata does not
provide useful clues as to their cause, except when foreign materials,
acid-fast bacilli, or fungal forms are found. Thus, a specific diagnosis can be
made only by integrating histopathological data with clinical and laboratory
information.
Clinical
Manifestations and Pathogenesis
Because
granulomata can be found in the gastric mucosa of patients with infectious,
inflammatory, and neoplastic diseases, as well as in otherwise healthy persons,
neither clinical manifestations nor endoscopic appearances are useful to
predict the presence of gastric granulomata. Thus, the stomach may be
completely normal or may exhibit characteristics of the associated conditions.
Mycobacterium
tuberculosis and Histoplasma capsulatum Infection Tuberculosis is the most
common cause of granulomatous disease of the gastrointestinal tract, but the
stomach is rarely affected, even in the presence of severe ileocecal
involvement. Primary gastric tuberculosis has been reported mostly from
developing countries with a high prevalence of Mycobacterium tuberculosis
infection. In almost all such cases, gastric tuberculosis was diagnosed because
of the presence of a large, nonhealing gastric ulcer. A few cases of primary
infection of the stomach by the dimorphic fungus Histoplasma capsulatum have
been reported. As in patients with gastric tuberculosis, these patients
presented with signs and symptoms that led to the discovery of a large gastric
ulcer initially interpreted clinically as malignant.
Helicobacter
pylori Infection Unexplained granulomata have been found in patients with
H.pylori gastritis, but this finding is extremely rare, on the order of less
than 1 in 1000 infected patients. Although a role for H.pylori in the causation
of granulomata has been postulated, there is no evidence to support this
hypothesis.
Anisakiasis
Early lesions of anisakiasis range from interstitial edema with a loose,
eosinophilic inflammatory infiltrate to eosinophilic abscesses, in which
well-preserved larvae are often detected. In later lesions, the most common
finding is the presence of foreign body granulomata, sometimes associated with
fragments of helminthic cuticles.
Foreign Bodies A common
cause of gastric foreign body granulomata is suture material in patients who
have undergone a partial gastrectomy. In patients with gastric ulcer, food
particles may become engulfed in the ulcer crater and may cause a foreign body
reaction. When such granulomata are found in biopsy specimens obtained from
active ulcers, their origin is readily apparent; diagnostic difficulties may
arise when granulomata are found in specimens from healed ulcers and the
pathologist is unaware of the relevant clinical information.
Tumors
Rarely, adenocarcinomas (particularly mucin-secreting tumors) may induce the
formation of foreign body granulomata in the gastric mucosa or perigastric
lymph nodes. Granulomata have also been noted in the gastric mucosa of few
patients with gastric non-MALT lymphoma.
Other
Unusual Causes In rare instances, granulomatous gastritis may be part of an
immune-mediated vasculitis syndrome or Wegener granulomatosis. Sometimes, it
may assume a form akin to xanthogranulomatous cholecystitis.
Granulomatous
Gastritis in Sarcoidosis and Crohn’s Disease
Granulomata
detected in the gastric mucosa of a patient with established sarcoidosis or
Crohn’s disease can be assumed to be part of the systemic process, and no
further investigation is required. Because the finding of gastric mucosal
granulomata may precede the discovery of the disease in other organs, the
careful interpretation of gastric biopsy findings together with appropriate
suggestions for further tests may lead to the prompt diagnosis of a condition
that could otherwise remain obscure for a long time.
In
sarcoidosis, involvement of the gastrointestinal tract is found occasionally at
autopsy, but only rarely has it clinical importance. However, severe gastric
disease with outlet obstruction or bleeding has been reported. Endoscopic
findings may include nodularity, polypoid changes, erosions, ulcers, and
segmental, usually distal, rigidity resembling linitis plastica. These gross
changes reflect the presence of numerous mucosal granulomata and severe
fibrosis.
Studies
have challenged the perception that gastric involvement is rare in Crohn’s
disease, and they found a prevalence of gastric granulomata of approximately
10% to 15% and a prevalence of “focally enhanced” H.pylori–negative active
gastritis of between 30% and 70%. In these patients, focal gastritis was almost
twice as frequent in the corpus as in the antrum, and epithelioid granulomata
were twice as prevalent in the antrum.
Isolated
Granulomatous Gastritis
Isolated
granulomatous gastritis is a “holding category,” applied as a temporary
diagnostic label to cases of granulomatous gastric inflammation for which no
cause has yet been determined. Support for this approach derives from studies
showing that most gastric granulomata are an expression of either concurrent or
incipient Crohn’s disease or systemic sarcoidosis. Even after careful
evaluation, some gastric granulomata will remain unexplained. These lesions are
usually asymptomatic, there is no information on their natural history or
evolution, and, therefore, no treatment can be recommended.
CHEMICAL
(REACTIVE) GASTROPATHY
An
association between the presence of bile in the stomach and gastric mucosal
damage ( duodenogastric reflux) was first postulated by William Beaumont in
1859, and several subsequent clinical observations led to the development of
surgical techniques to prevent or minimize the regurgitation of duodenal
contents into the stomach. In 1983, Dewar, Dixon, and Johnston systematically
described the histopathological changes associated with bile reflux in the
stomachs of patients who had undergone gastrectomy as well as patients with
duodenal or gastric ulcer. The original term bile reflux was later replaced by
chemical gastritis, to include the recently discovered NSAID-induced changes in
the gastric mucosa. The terms reactive gastritis, type C gastritis, and
chemical gastropathy have also been used. Chemical gastropathy is now defined
as the constellation of endoscopic and histological changes caused by chemical
injury to the gastric mucosa. This is an implicit admission that this diagnosis
can be made only when converging clinical and histopathological evidence is
present. Radiation gastritis, which results from a physical agent rather than a
chemical one.
Clinical
Manifestations
Three
categories of patients may exhibit the endoscopic and histological changes of
chemical gastropathy: patients with alkaline reflux after partial gastrectomy,
patients with duodenogastric bile reflux as part of a poorly understood
dysmotility syndrome, and patients who take NSAIDs.
Postgastrectomy
alkaline reflux may present with a syndrome characterized by burning
midepigastric pain unresponsive to antacids and aggravated by eating and
recumbency. Bilious vomiting, anemia, and weight loss may occur. Endoscopic
confirmation of bile reflux and documentation of the characteristic
histopathological findings support the diagnosis, and corrective surgery (e.g.,
creation of a 40- to 50-cm Roux-en-Y gastrojejunostomy) is successful in about
half of all cases.
Duodenogastric
bile reflux secondary to gastroduodenal dysmotility or to cholecystectomy is a
controversial condition, rarely considered in the differential diagnosis of
dyspepsia in patients with an intact stomach. Thus, the frequency of endoscopic
or histological changes of chemical gastropathy in these patients is unknown.
Millions
of persons take daily doses of NSAIDs for indefinite periods, in many cases for
life, to control pain caused by osteoarthritis, rheumatoid arthritis, or other
chronic conditions. Unknown numbers of these NSAID users experience epigastric
pain; approximately 10% per year develop erosions or ulcers, and 1% to 2% per
year have a major gastric bleeding episode. Reactive gastropathy has been
documented histopathologically in 10% to 45% of long-term users of NSAIDs, but
no relationship could be established between the appearance of the mucosa and
dyspeptic symptoms.
Pathogenesis
Duodenogastric
reflux (with alkaline pancreaticoduodenal secretions as well as acids, bile
salts, and lysolecithin) disrupts the mucous barrier and directly damages the
gastric surface epithelium. This combined injury leads to accelerated
exfoliation of surface epithelial cells and a histamine-mediated vascular
response that manifests as edema and hyperemia. Persistent epithelial damage
may lead to the release of other proinflammatory agents, such as
platelet-derived growth factor, which among its many actions stimulates smooth
muscle and, later on, fibroblastic proliferation. Epithelial injury after
exposure to NSAIDs appears to be mediated by reduced prostaglandin synthesis.
Prostaglandins are important cytoprotective agents in the gastric mucosa and
exert their effects by maintaining mucosal blood flow, by increasing secretion
of mucus and bicarbonate ions, and by augmenting epithelial defense against
cytotoxic injury. Thus, NSAID-inflicted injury can be partially prevented by
simultaneous administration of prostaglandin analogs such as misoprostol and by
suppression of gastric acid production with proton pump inhibitors. Newer
selective cyclooxygenase 2 inhibitors (inhibitors, second-generation NSAIDs, or
selective NSAIDs) are reportedly better tolerated by the gastric mucosa.
Whether the initial encouraging results will hold true when these drugs become
widely used, remains to be evaluated.
Endoscopic
Appearance
In
patients who have undergone a Billroth II gastrectomy, the gastric mucosa at
the anastomotic site may have a polypoid appearance with congestion, edema, and
friability. Superficial erosions may be present in more proximal areas of the
gastric stump, but they are not specific, because they can be caused by a
variety of injuries. In patients with nonoperated stomachs and possible
duodenogastric bile reflux, the mucosa may exhibit congestion, edema, and
erosions. In long-term NSAID users, the mucosa may be normal or may show
congestion, erosions, or ulcers.
Histopathology
Although
some histological features are more frequently found in regular NSAID users,
the histopathological diagnosis of chemical gastropathy remains a challenging
problem. The histopathological changes that have been associated with reactive
gastropathy include evidence of epithelial regeneration, foveolar hyperplasia,
edema of the lamina propria, and expansion of the smooth muscle fibers into the
upper third of the mucosa, an area in which they are not normally found. Both
the specificity and the predictive value of these features are low because of
several potential confounding factors. Surreptitious use of NSAIDs, other
substances in the diet (e.g., alcohol, spices, salt) that may cause similar
mucosal changes, and clinically silent bile reflux can rarely be excluded;
furthermore, the difficulty of obtaining a perfect control population cannot be
overemphasized. H.pylori infection induces some of the features traditionally
considered characteristic of chemical gastropathy: mucosal hyperemia and edema,
superficial erosions, foveolar hyperplasia, and regenerative changes.
Therefore, the pathologist can suspect chemical gastropathy and communicate
this suspicion to the clinician, but a firm histopathological diagnosis can be
made only when supportive clinical data are available and H.pylori infection is
absent.
Partial
Gastrectomy and Carcinoma
The
polypoid appearance of the distal portions of the gastric stump in patients who
have undergone gastrectomy has been referred to as gastritis cystica polyposa.
Several studies, mostly conducted in Europe and Asia, have reported a high
prevalence of low-grade dysplasia in these polypoid areas, as well as an
increased incidence of gastric adenocarcinoma 2 to 3 decades after gastrectomy.
The implications of these findings, potentially important because of the
suggestion that patients who undergo partial gastrectomy may need endoscopic
surveillance, seem less urgent in the present era, when partial gastrectomy for
peptic ulcer disease has become an exceedingly rare operation.
HEMORRHAGIC
GASTROPATHY
Hemorrhagic
gastropathy (hemorrhagic gastritis) refers to a group of conditions
characterized by subepithelial hemorrhages and erosions. These mucosal lesions
do not cause major bleeding unless ulcers develop. Three major factors are
involved in the pathogenesis of hemorrhagic gastropathy: use of NSAIDs,
ingestion of large quantities of alcohol, and severe physical stress.
Aspirin
and other NSAIDs may induce mucosal edema, hyperemia, and multiple erosions and
ulcerations. Such lesions may occur suddenly, without warning symptoms such as
pain or discomfort, in first-time NSAID users and in patients who have taken
NSAIDs regularly for years. Except for generic risk factors such as older age,
female sex, and previous episodes, there is no known trait to identify NSAID
users prospectively who may be susceptible to severe gastric injury.
Similar
mucosal lesions, although usually less severe and only rarely evolving to
ulcerations, can be caused by ingestion of large quantities of alcohol. Because
alcohol and aspirin may act synergistically to break down mucosal defenses, one
wonders how many hemorrhagic gastropathies have been caused by attempts to
prevent hangovers by taking aspirin after an alcoholic binge.
The
most severe degrees of hemorrhagic gastropathy are those induced by stress.
Originally described in 1842 by Thomas Curling, stress-induced gastroduodenal
mucosal breakdowns (known as Curling ulcers) can be found in most patients
admitted to an intensive care unit; approximately 20% are a source of overt
bleeding, and 2% to 5% of these ulcers cause life-threatening hemorrhage.
Pathogenesis
The
pathogenesis of stress-induced hemorrhagic gastritis is not known, but lumenal
acid seems to be essential. Acid exerts its deleterious effects when the
mucosal defense mechanisms (e.g., the mucous-bicarbonate barrier and the
epithelial layer) lose their integrity. Vascular disturbances—in association
with stasis, vasoconstriction, and increased vascular permeability—may further
contribute to mucosal vulnerability. Aspirin and NSAIDs act by interfering with
prostaglandin synthesis, as noted earlier. Alcohol causes direct damage to the
gastric mucosa; at a concentration of 12.5% (that of table wine), it induces
hyperemia and petechiae, and concentrations greater than 40% (“hard liquors”)
cause necrosis of the surface epithelium and capillaries and subsequent
interstitial hemorrhage.
Clinical
Manifestations
Acute
hemorrhagic gastritis is characterized by a hyperemic edematous mucosa with
erosions and various degrees of active bleeding. The clinical history (e.g.,
shock, burns, recent alcohol binge, ingestion of aspirin), rather than the
widely overlapping nature of the lesions, will help the endoscopist to
determine the precipitating factors. Because the diagnosis is often clear from
the clinical context, gastric biopsies are rarely obtained from critically ill
patients who undergo endoscopy because of upper gastrointestinal hemorrhage.
Histopathology
Acute
hemorrhagic gastritis, irrespective of its cause, is characterized by dilation
and congestion of the capillaries, edema, and various degrees of interstitial
hemorrhage in the lamina propria. Epithelial erosions are generally small;
aggregates of fibrin and polymorphonuclear cells replace the eroded epithelium
and may project above the surface to form small, elevated clumps of necrotic
debris. In the absence of concurrent H.pylori infection, there is no
significant inflammation in the unaffected areas of the stomach. Therefore, a
diagnosis of erosive hemorrhagic gastritis can usually be made, and possible etiologic
agents may be listed (e.g., alcohol or NSAID ingestion). If H.pylori gastritis
is present, widespread active inflammation often obscures or worsens the
changes caused by other agents, and a separate diagnosis of the diverse causes
of the changes is usually impossible.
Management
The
suppression of acid with H 2-receptor antagonists or proton pump inhibitors
helps to reduce the severity of the mucosal damage and facilitates healing.
Sucralfate, although less commonly used, is also effective.
VASCULAR
GASTROPATHIES
Gastric
vascular gastropathies comprise a heterogeneous group of conditions
characterized by alterations in the gastric circulation and their effects on
the gastric mucosa. The best-defined conditions, from morphologic and
pathogenetic viewpoints, are the watermelon stomach, which is described, and
portal hypertensive gastropathy.
Portal
Hypertensive Gastropathy
Clinical
Manifestations and Pathogenesis Portal hypertensive gastropathy is a dilation
of the mucosal vessels, more prominent in the proximal stomach, that occurs in
a proportion of patients with cirrhosis of the liver; its prevalence parallels
the severity of portal hypertension. Bleeding from this lesion is relatively
uncommon and rarely severe; in general, patients with the most severe portal
hypertension have diffuse lesions and higher rates of gastric bleeding.
Endoscopic
Appearance The endoscopic appearance of portal hypertensive gastropathy is
nonspecific and does not correlate well with the degree of portal hypertension.
The endoscopic patterns have been variously described as snake skin, scarlatina
rash, cherry-red spots, and mosaic. The mosaic pattern was found by a consensus
conference to be the most reliable indicator of mild portal hypertensive
gastropathy with a low risk of hemorrhage. Red marks suggest a more severe
degree of hypertension and a greater risk of hemorrhage.
Histopathology
Dilation and tortuosity of small arteries and veins, with occasional thickening
of the walls, are among the pathological changes of portal hypertensive
gastropathy. The changes are more prominent in the corpus and are more apparent
in submucosal vessels than in mucosal capillaries. Because of the location of
these changes and the understandable reluctance of most gastroenterologists to
obtain large and deep biopsy samples from patients who may have an increased
risk of bleeding, the diagnosis of portal hypertensive gastropathy is not
commonly reached by evaluating mucosal biopsies. In patients with concurrent
H.pylori gastritis, it is difficult, if not impossible, to separate the
respective contribution of infection and congestion to the resulting complex of
changes observed in the mucosa.
Management
Because bleeding is relatively uncommon, most patients do no require specific
therapy. Sclerotherapy of esophageal varices does not seem to influence the
natural history of this condition. In severe cases, portal decompression
surgery, but not transjugular intrahepatic portosystemic shunting, is effective
in reducing the risk of hemorrhage.
HYPERTROPHIC
GASTROPATHIES
In
numerous inflammatory and noninflammatory conditions, the mucosal folds (
rugae) that confer a rugged appearance to the normal gastric corpus may become
extremely enlarged and may give the mucosa an appearance that has been compared
to that of the cerebral cortex (cerebriform). Based on this macroscopic
morphologic characteristic, shared in various degrees by all of them, certain
etiologically heterogeneous conditions have been categorized as hypertrophic
gastritis, hypertrophic gastropathy, or, more recently, giant-fold
gastropathies. To complicate our understanding of these diverse conditions
further, many authors have used indiscriminately the term Ménétrier disease,
after the condition described in 1888 by the French gastroenterologist who
initially called it polyadenomes en nappe (polyps in layers).
In
1973, Ming introduced the term hyperplastic gastropathies and proposed a
classification that recognizes three main histological types:
1.
Foveolar hyperplasia, with normal or atrophic oxyntic
glands and corresponding to Ménétrier’s description
2.
Hyperplasia of oxyntic glands, with a largely
unaffected mucous component and corresponding to Zollinger-Ellison syndrome
3.
A mixed type, in which both mucous and oxyntic glands
show variable degrees of hyperplasia; it incorporates various conditions that
may cause mixed glandular hyperplasia, including infections ( H.pylori
infection, CMV infection in children, syphilis, and histoplasmosis) and other
diseases of uncertain origin (lymphocytic gastritis, eosinophilic
gastroenteritis, sarcoidosis, and Cronkhite-Canada syndrome).
Ménétrier Disease
Ménétrier,
in his original description, included patients with multiple hyperplastic
polyps and patients with giant folds and focused his observations on the
increased gastric cancer risk of these patients. Today, the condition
associated with his eponym is defined as an idiopathic diffuse enlargement of
the gastric folds in the antrum. Histologically, glands show massive foveolar
cell hyperplasia with normal or slightly reduced numbers of parietal and chief
cells. Neither significant inflammatory infiltrates in the lamina propria nor
epithelial lesions (erosions, intestinal metaplasia, or cellular atypia) are
present. If chronic active inflammation or lymphocytic infiltration of the
epithelium is seen, the large-fold type of H.pylori gastritis or lymphocytic
gastritis should be considered. In children, giant folds are almost always
associated with CMV infection. This association has rarely been reported in adults.
The hyperplastic foveolar cells secrete large amounts of mucus and fluid
resulting in protein-losing enteropathy (found in almost all patients) and
hypoacidity (in part from dilution of the acid produced by oxyntic cells).
Pure
Ménétrier disease is a rare condition, with an estimated prevalence of no more
than 300 or 400 persons worldwide. Patients are more often men in their fifth
or sixth decade who present with dramatic weight loss, epigastric and abdominal
pain, nausea, and vomiting. Later in the course of the disease, usually
protracted for several years and even decades, virtually all patients develop
hypoalbuminemia as a consequence of the protein-losing enteropathy. The
pathogenesis is unknown, but an interesting hypothesis has been put forward. Transforming
growth factor-a (TGF-a), a critical mediator of gastric mucosal homeostasis
normally produced by the gastric mucosa, inhibits acid secretion, stimulates
mucosal repair, cell migration, and proliferation, and augments gastric mucin
levels Overproduction of TGF-a could
explain several of the disturbances occurring in Ménétrier disease. Support
for this hypothesis is further lent by the successful treatment of some
patients by a monoclonal antibody against the TGF-a receptor (the epidermal
growth factor receptor). Other forms of treatment, including antacids,
anticholinergic drugs, corticosteroids, H 2-receptor antagonists, and proton
pump inhibitors, have been proven consistently ineffective. Eradication of
H.pylori has been reported to have successfully cured patients with Ménétrier
disease. One of the possible pathological aspects of H.pylori gastritis is the
development of large, edematous folds, and this variant may have been
interpreted as a type of H.pylori–induced Ménétrier disease. Not surprisingly,
it regresses after the eradication of H.pylori infection.
GASTRIC CARDIA
Since
the 1970s, a rise in the incidence of adenocarcinoma of the cardia has occurred
in the very populations in which the incidence of gastric cancer has been
decreasing. Thus, there has been an emerging interest in exploring the
pathology of this relatively ill-defined area of the stomach. Virtually all
patients who have H.pylori gastritis in other regions of the stomach also have
bacteria and inflammation in the region immediately distal to the
gastroesophageal junction. Some patients, including those without H.pylori
infection and patients with and without gastroesophageal reflux disease, have a
localized inflammation of the cardia, commonly referred to as carditis. Intestinal
metaplasia is found in the cardia of approximately 20% of patients with a
variety of gastric disorders, even in the absence of H.pylori infection, and
apparently also in healthy persons. The relationship between intestinal
metaplasia in this location and adenocarcinoma of the junction remains unclear,
but it is important to differentiate the intestinal metaplasia of the cardia
from Barrett specialized epithelium. Cytokeratin and immunoreactive patterns
may help to distinguish between intestinal metaplasia in long-segment Barrett
esophagus and junctional metaplasia; conversely, the epithelium of
short-segment Barrett esophagus may be impossible to separate from metaplasia
originating in the cardia. Until the implications of such findings are clarified,
it is advisable to collect as much specific information as possible carefully
from each patient with changes at the gastroesophageal junction. Lesions of
uncertain prognostic value today could acquire clinical significance when new
knowledge is acquired.