2454 PART 10 Disorders of the Gastrointestinal System

evaluation of a patient suspected of having ZES is to obtain a fasting

gastrin level. A list of clinical scenarios that should arouse suspicion

regarding this diagnosis is shown in Table 324-8. Fasting gastrin levels

obtained using a dependable assay are usually <150 pg/mL. A normal

fasting gastrin, on two separate occasions, especially if the patient is

on a PPI, virtually excludes this diagnosis. Virtually all gastrinoma

patients will have a gastrin level >150–200 pg/mL. Measurement of

fasting gastrin should be repeated to confirm the clinical suspicion.

Some of the commercial biochemical assays used for measuring serum

gastrin may be inaccurate. Variable specificity of the antibodies used

have led to both false-positive and false-negative fasting gastrin levels,

placing in jeopardy the ability to make an accurate diagnosis of ZES.

Multiple processes can lead to an elevated fasting gastrin level, the

most frequent of which are gastric hypochlorhydria and achlorhydria,

with or without pernicious anemia. Gastric acid induces feedback

inhibition of gastrin release. A decrease in acid production will subsequently lead to failure of the feedback inhibitory pathway, resulting in

net hypergastrinemia. Gastrin levels will thus be high in patients using

antisecretory agents for the treatment of acid peptic disorders and

dyspepsia. H. pylori infection can also cause hypergastrinemia. Additional causes of elevated gastrin include retained gastric antrum; G-cell

hyperplasia; gastric outlet obstruction; renal insufficiency; massive

small-bowel obstruction; and conditions such as rheumatoid arthritis,

vitiligo, diabetes mellitus, and pheochromocytoma. Although a fasting

gastrin >10 times normal is highly suggestive of ZES, two-thirds of

patients will have fasting gastrin levels that overlap with levels found

in the more common disorders outlined above, especially if a PPI is

being taken by the patient. The effect of the PPI on gastrin levels and

acid secretion will linger several days after stopping the PPI; therefore,

it should be stopped for a minimum of 7 days before testing. During

this period, the patient should be placed on a histamine H2

 antagonist,

such as famotidine, twice to three times per day. Although this type of

agent has a short-term effect on gastrin and acid secretion, it needs to

be stopped 24 h before repeating fasting gastrin levels or performing

some of the tests highlighted below. The patient may take antacids for

the final day, stopping them ~12 h before testing is performed. Heightened awareness of complications related to gastric acid hypersecretion

during the period of PPI cessation is critical.

The next step at times needed for establishing a biochemical

diagnosis of gastrinoma is to assess acid secretion. Nothing further

needs to be done if decreased acid output in the absence of a PPI is

observed. A pH can be measured on gastric fluid obtained either during endoscopy or through nasogastric aspiration; a pH <3 is suggestive

of a gastrinoma, but a pH >3 is not helpful in excluding the diagnosis.

In those situations where the pH is >3, formal gastric acid analysis

should be performed if available. Normal BAO in nongastric surgery

patients is typically <5 meq/h. A BAO >15 meq/h in the presence of

hypergastrinemia is considered pathognomonic of ZES, but up to 12%

of patients with common PUD may have elevated BAO to a lesser

degree that can overlap with levels seen in ZES patients. In an effort

to improve the sensitivity and specificity of gastric secretory studies, a

BAO/MAO ratio was established using pentagastrin infusion as a way

to maximally stimulate acid production, with a BAO/MAO ratio >0.6

being highly suggestive of ZES. Pentagastrin is no longer available in

the United States, making measurement of MAO virtually impossible.

An endoscopic method for measuring gastric acid output has been

developed but requires further validation.

Gastrin provocative tests have been developed in an effort to differentiate between the causes of hypergastrinemia and are especially

helpful in patients with indeterminate acid secretory studies. The tests

are the secretin stimulation test and the calcium infusion study; the

latter is rarely, if ever, utilized in our current environment due to the

cumbersome nature of the test and its lower sensitivity and specificity

than secretin stimulation. The most sensitive and specific gastrin provocative test for the diagnosis of gastrinoma is the secretin study. An

increase in gastrin of ≥120 pg within 15 min of secretin injection has a

sensitivity and specificity of >90% for ZES. PPI-induced hypochlorhydria or achlorhydria may lead to a false-positive secretin test; thus, this

agent must be stopped for 1 week before testing.

In light of the limited availability of the biochemical studies outlined

above, more studies make a diagnosis of gastrinoma based on the presence of elevated gastrin and low gastric pH in the right clinical setting

coupled with tumor localization tests outlined below and positive

histology by biopsy (difficult to obtain). Revised guidelines for the best

approach to establishing a diagnosis of gastrinoma taking into consideration the above outlined limitations are being considered, but none

have replaced the established guidelines outlined earlier in this section.

Tumor Localization Once the biochemical diagnosis of gastrinoma has been confirmed (if possible), the tumor must be located.

Multiple imaging studies have been used in an effort to enhance

tumor localization (Table 324-9). The broad range of sensitivity is

due to the variable success rates achieved by the different investigative groups. Endoscopic ultrasound (EUS) permits imaging of the

pancreas with a high degree of resolution (<5 mm). This modality is

particularly helpful in excluding small neoplasms within the pancreas

and in assessing the presence of surrounding lymph nodes and vascular involvement, but it is not very sensitive (43%) for finding duodenal

lesions. This latter observation has led some to not include EUS in

the routine preoperative evaluation of a patient suspected of having

a gastrinoma. Several types of endocrine tumors express cell-surface receptors for somatostatin, in particular the subtype 2 (SSTR2).

This permits the localization, staging, and prediction of therapeutic

response to somatostatin analogues (see below) by gastrinomas.

The original functional scinitigraphic tool developed measuring the

uptake of the stable somatostatin analogue 111In-pentetreotide (OctreoScan) has demonstrated sensitivity and specificity rates of >80%.

More recently, positron emission tomography (PET)–computed

tomography (CT) with 68Ga-DOTATATE has been developed and is

superior than OctreoScan for assessing tumor presence in patients

with well-differentiated NETs such as gastrinomas, with sensitivity

and specificity of >90%, making it the functional imaging study of

choice when available. 18F-Fluordeoxyglucose (18F-FDG) PET imaging

TABLE 324-8 When to Obtain a Fasting Serum Gastrin Level

Multiple ulcers

Ulcers in unusual locations; associated with severe esophagitis; resistant

to therapy with frequent recurrences; in the absence of nonsteroidal antiinflammatory drug ingestion or H. pylori infection

Ulcer patients awaiting surgery

Extensive family history for peptic ulcer disease

Postoperative ulcer recurrence

Basal hyperchlorhydria

Unexplained diarrhea or steatorrhea

Hypercalcemia

Family history of pancreatic islet, pituitary, or parathyroid tumor

Prominent gastric or duodenal folds

TABLE 324-9 Sensitivity of Imaging Studies in Zollinger-Ellison

Syndrome

SENSITIVITY, %

STUDY

PRIMARY

GASTRINOMA

METASTATIC

GASTRINOMA

Ultrasound 21–28 14

CT scan 55–70 >85

Selective angiography 35–68 33–86

Portal venous sampling 70–90 N/A

SASI 55–78 41

MRI 55–70 >85

OctreoScan 67–86 80–100

EUS 80–100 N/A

Abbreviations: CT, computed tomography; EUS, endoscopic ultrasonography;

MRI, magnetic resonance imaging; N/A, not applicable; OctreoScan, imaging with

111In-pentetreotide; SASI, selective arterial secretin injection.

2455Peptic Ulcer Disease and Related Disorders CHAPTER 324

has been found to be useful in pancreatic NETs, including gastrinomas,

particularly as a prognostic marker.

Up to 50% of patients have metastatic disease at diagnosis. Success

in controlling gastric acid hypersecretion has shifted the emphasis of

therapy toward providing a surgical cure. Detecting the primary tumor

and excluding metastatic disease are critical in view of this paradigm

shift. Once a biochemical diagnosis has been confirmed, the patient

should first undergo an abdominal CT scan, magnetic resonance imaging (MRI), or OctreoScan/PET-CT with 68Ga-DOTATATE (depending

on availability) to exclude metastatic disease. Once metastatic disease

has been excluded, an experienced endocrine surgeon may opt for

exploratory laparotomy with intraoperative ultrasound or transillumination. In other centers, careful examination of the peripancreatic area

with EUS, accompanied by endoscopic exploration of the duodenum

for primary tumors, will be performed before surgery. Selective arterial

secretin injection may be a useful adjuvant for localizing tumors in a

subset of patients. The extent of the diagnostic and surgical approach

must be carefully balanced with the patient’s overall physiologic condition and the natural history of a slow-growing gastrinoma.

TREATMENT

Zollinger-Ellison Syndrome

Treatment of functional endocrine tumors is directed at ameliorating the signs and symptoms related to hormone overproduction,

curative resection of the neoplasm, and attempts to control tumor

growth in metastatic disease.

PPIs are the treatment of choice and have decreased the need

for total gastrectomy. Initial PPI doses tend to be higher than those

used for treatment of GERD or PUD. The initial dose of omeprazole, lansoprazole, rabeprazole, or esomeprazole should be in the

range of 60 mg in divided doses in a 24-h period. When gastric acid

analysis was more widely available, dosing was adjusted to achieve

a BAO <10 meq/h (at the drug trough) in surgery-naive patients

and to <5 meq/h in individuals who have previously undergone an

acid-reducing operation. Close monitoring of clinical symptoms

when starting PPIs and increasing the dose accordingly are paramount. Although the somatostatin analogue has inhibitory effects

on gastrin release from receptor-bearing tumors and inhibits gastric

acid secretion to some extent, PPIs have the advantage of reducing

parietal cell activity to a greater degree. Despite this, octreotide or

lanreotide may be considered as adjunctive therapy to the PPI in

patients with tumors that express somatostatin receptors and have

peptic symptoms that are difficult to control with high-dose PPI.

The ultimate goal of surgery would be to provide a definitive

cure. Improved understanding of tumor distribution has led to

immediate cure rates as high as 33% with 10-year disease-free intervals as high as 95% in sporadic gastrinoma patients undergoing

surgery. A positive outcome is highly dependent on the experience

of the surgical team treating these rare tumors. Surgical therapy of

gastrinoma patients with MEN 1 remains controversial because of

the difficulty in rendering these patients disease-free with surgery.

In contrast to the encouraging postoperative results observed in

patients with sporadic disease, <5% of MEN 1 patients are diseasefree 5 years after an operation. Moreover, in contrast to patients

with sporadic ZES, the clinical course of MEN 1 patients tends to be

benign and rarely leads to disease-related mortality, recommending

that early surgery be deferred. Some groups suggest surgery only if

a clearly identifiable, nonmetastatic lesion is documented by structural studies. Others advocate a more aggressive approach, where

all patients free of hepatic metastasis are explored and all detected

tumors in the duodenum are resected; this is followed by enucleation of lesions in the pancreatic head, with a distal pancreatectomy

to follow. The outcome of the two approaches has not been clearly

defined. Laparoscopic surgical interventions may provide attractive

approaches in the future but currently seem to be of some limited

benefit in patients with gastrinoma because a significant percentage

of the tumors may be extrapancreatic and difficult to localize with a

laparoscopic approach. Finally, patients selected for surgery should

be individuals whose health status would lead them to tolerate a

more aggressive operation and obtain the long-term benefits from

such aggressive surgery, which are often witnessed after 10 years.

Therapy of metastatic endocrine tumors in general remains suboptimal; gastrinomas are no exception. In light of the observation

that in many instances tumor growth is indolent and that many

individuals with metastatic disease remain relatively stable for

significant periods of time, many advocate not instituting systemic

tumor-targeted therapy until evidence of tumor progression or

refractory symptoms not controlled with PPIs are noted. Medical

approaches, including biologic therapy (IFN-α, long-acting somatostatin analogues, and peptide receptor radionuclides), systemic

chemotherapy (streptozotocin, 5-fluorouracil, and doxorubicin),

and hepatic artery embolization, may lead to significant toxicity

without a substantial improvement in overall survival. Use of

temozolomide with capecitabine has demonstrated radiographic

regression and progression-free survival in patients with welldifferentiated NETs in the range of 70% and 18 months, respectively. Systemic therapy with radiolabeled somatostatin analogues

(peptide receptor radiotherapy [PRRT]) has been used in the

therapy of metastatic NETs and appears to be very promising in

terms of radiographic regression, symptoms, and progression-free

survival, but additional studies are warranted. Several promising

therapies are being explored, including radiofrequency ablation or

cryoablation of liver lesions and use of agents that block the VEGF

receptor pathway (sunitinib), the mammalian target of rapamycin,

and immune checkpoint inhibitors (Chap. 87).

Surgical approaches, including debulking surgery and liver

transplantation for hepatic metastasis, have also produced limited

benefit.

The overall 5- and 10-year survival rates for gastrinoma patients

are 62–75% and 47–53%, respectively. Individuals with the entire

tumor resected or those with a negative laparotomy have 5- and

10-year survival rates >90%. Patients with incompletely resected

tumors have 5- and 10-year survival rates of 43 and 25%, respectively. Patients with hepatic metastasis have <20% survival at

5 years. Favorable prognostic indicators include primary duodenal

wall tumors, isolated lymph node tumor, the presence of MEN 1,

and undetectable tumor upon surgical exploration. Poor outcome is

seen in patients with shorter disease duration; female sex; older age

at diagnosis; higher gastrin levels (>10,000 pg/mL); poor histologic

differentiation; high proliferative index; large pancreatic primary

tumors (>3 cm); metastatic disease to lymph nodes, liver, and bone;

and Cushing’s syndrome. Rapid growth of hepatic metastases is also

predictive of poor outcome.

■ STRESS-RELATED MUCOSAL INJURY

Patients suffering from shock, sepsis, massive burns, severe trauma, or

head injury can develop acute erosive gastric mucosal changes or frank

ulceration with bleeding. Classified as stress-induced gastritis or ulcers,

injury is most commonly observed in the acid-producing (fundus and

body) portions of the stomach. The most common presentation is GI

bleeding, which is usually minimal but can occasionally be life-threatening. Respiratory failure requiring mechanical ventilation and underlying coagulopathy are risk factors for bleeding, which tends to occur

48–72 h after the acute injury or insult.

Histologically, stress injury does not contain inflammation or H.

pylori; thus, “gastritis” is a misnomer. Although elevated gastric acid

secretion may be noted in patients with stress ulceration after head

trauma (Cushing’s ulcer) and severe burns (Curling’s ulcer), mucosal

ischemia, breakdown of the normal protective barriers of the stomach,

systemic release of cytokines, poor GI motility, and oxidative stress

also play an important role in the pathogenesis. Acid must contribute

to injury in view of the significant drop in bleeding noted when acid

inhibitors are used as prophylaxis for stress gastritis.

Improvement in the general management of intensive care unit

patients has led to a significant decrease in the incidence of GI bleeding

2456 PART 10 Disorders of the Gastrointestinal System

due to stress ulceration. The estimated decrease in bleeding is from

20–30% to <5%. This improvement has led to some debate regarding

the need for prophylactic therapy. The high mortality associated with

stress-induced clinically important GI bleeding (>40%) and the limited

benefit of medical (endoscopic, angiographic) and surgical therapy in a

patient with hemodynamically compromising bleeding associated with

stress ulcer/gastritis support the use of preventive measures in high-risk

patients (mechanically ventilated, coagulopathy, multiorgan failure, or

severe burns). Meta-analysis comparing H2

 blockers with PPIs for the

prevention of stress-associated clinically important and overt GI bleeding demonstrates superiority of the latter without increasing the risk

of nosocomial infections, increasing mortality, or prolonging intensive

care unit length of stay. Therefore, PPIs are the treatment of choice for

stress prophylaxis. Oral PPI is the best option if the patient can tolerate

enteral administration. Pantoprazole is available as an intravenous formulation for individuals in whom enteral administration is not possible. If bleeding occurs despite these measures, endoscopy, intraarterial

vasopressin, and embolization are options. If all else fails, then surgery

should be considered. Although vagotomy and antrectomy may be

used, the better approach would be a total gastrectomy, which has an

exceedingly high mortality rate in this setting. Concerns with the effect

of PPIs on the immune system coupled with the high cost of this agent

have led to several comparative studies of PPIs and H2

 receptor antagonists for stress prophylaxis in patients requiring mechanical ventilation.

Although the PEPTIC trial demonstrated comparative efficacy between

the two agents regarding mortality, technical aspects of the study led to

some limitation in the final interpretation of the results.

■ 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 (Table 324-10).

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. It is reported as

presenting with sudden onset of epigastric pain, nausea, and vomiting,

and 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.

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 species. Failure of supportive measures and antibiotics may result in gastrectomy.

Other types of infectious gastritis may occur in immunocompromised individuals such as AIDS patients. Examples include herpetic

(herpes simplex) or CMV gastritis. The histologic finding of intranuclear inclusions would be observed in the latter.

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 association of atrophic gastritis with the development of gastric

cancer has led to the development of endoscopic and serologic markers

of severity. Some of these include gross inspection and classification

of mucosal abnormalities during standard endoscopy, magnification

endoscopy, endoscopy with narrow band imaging and/or autofluorescence imaging, and measurement of several serum biomarkers including pepsinogen I and II levels, gastrin-17, and anti–H. pylori serologies.

The clinical utility of these tools is currently being explored.

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. 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, and 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 (Chap. 80).

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 antral-predominant form (H. pylori–related).

This classification is artificial in view of the difficulty in distinguishing

between 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 (Chap. 95) in the

presence of circulating antibodies against parietal cells and IF; 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. The parietal cell antibody is directed against H+,K+-ATPase.

T cells are also implicated in the injury pattern of this form of gastritis.

A subset of patients infected with H. pylori develop antibodies against

TABLE 324-10 Classification of Gastritis

I. Acute gastritis

A. Acute Helicobacter pylori infection

B. Other acute infectious gastritides

1. Bacterial (other than H. pylori)

2. Helicobacter heilmannii

3. Phlegmonous

4. Mycobacterial

5. Syphilitic

6. Viral

7. Parasitic

8. Fungal

II. Chronic atrophic gastritis

A. Type A: Autoimmune, body-predominant

B. Type B: H. pylori–related, antral-predominant

C. Indeterminate

III. Uncommon forms of gastritis

A. Lymphocytic

B. Eosinophilic

C. Crohn’s disease

D. Sarcoidosis

E. Isolated granulomatous gastritis

F. Russell body gastritis

2457Peptic Ulcer Disease and Related Disorders CHAPTER 324

H+,K+-ATPase, potentially leading to the atrophic gastritis pattern

seen in some patients infected with this organism. The mechanism

is thought to involve molecular mimicry between H. pylori LPS and

H+,K+-ATPase.

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 aged >60 and in ~20% of patients

with vitiligo and Addison’s disease. About one-half of patients with

pernicious anemia have antibodies to thyroid antigens, and ~30%

of patients with thyroid disease have circulating anti–parietal cell

antibodies. Anti-IF 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 HLA-DR3.

Low pepsinogen levels have also been observed; thus, this marker has

been used as an additional diagnostic tool in autoimmune gastritis.

The parietal cell–containing gastric gland is preferentially targeted

in this form of gastritis, and achlorhydria results. Parietal cells are the

source of IF, the 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. Hypergastrinemia and achlorhydria may also be seen in nonpernicious 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 toward the body and fundus of infected individuals. The conversion to a pangastritis is time dependent and estimated

to require 15–20 years. This form of gastritis increases with age, being

present in up to 100% of persons aged >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 (Fig. 324-16).

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

(Fig. 324-8; Chap. 80). 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, but it appears to be related to the chronic inflammation

induced by the organism. Eradication of H. pylori as a general preventative measure for gastric cancer is being evaluated but is not yet

recommended.

Infection with H. pylori is also associated with development of a lowgrade B-cell lymphoma, gastric MALT lymphoma (Chap. 108). The

chronic T-cell stimulation caused by the infection leads to production

of cytokines that promote the B-cell tumor. The tumor should be initially staged with a CT scan of the abdomen and EUS. Tumor growth

remains dependent on the presence of H. pylori, and 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 2–3 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.

TREATMENT

Chronic Gastritis

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 often recommended even if PUD

or a low-grade MALT lymphoma is not present. Expert opinion

suggests that patients with atrophic gastritis complicated by intestinal metaplasia without dysplasia should undergo surveillance

endoscopy every 3 years.

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.

FIGURE 324-16 Chronic gastritis and H. pylori organisms. Steiner silver stain of

superficial gastric mucosa showing abundant darkly stained microorganisms

layered over the apical portion of the surface epithelium. Note that there is no tissue

invasion.