levels are elevated and acid secretion is high. Inhibitory control of gastric acid production is impaired in

this form of gastritis. As a result, duodenal and prepyloric ulcers are common. The third form of

inflammatory response, occurring in 1% of infected individuals, is least common but most serious. This

form is characterized by corpus-predominant gastritis, hypochlorhydria, and gastric atrophy. This form

of inflammatory response is considered a precursor state for gastric cancer. Individuals with the third

pattern of inflammation demonstrate hypergastrinemia, low acid secretion, and diminished secretion of

pepsinogen.

Environmental Factors

NSAIDs have emerged as a significant risk factor for the development of acute ulceration. Although

acute mucosal injury caused by NSAIDs is more common in the stomach than in the duodenum, NSAIDinduced ulcer complications occur with equal frequency in these two sites. NSAIDs produce a variety of

lesions, ranging from hemorrhage, to superficial mucosal erosions, to deeper ulcerations. In the

duodenum, it appears likely that invasive NSAID-associated ulcers result from underlying peptic ulcer

diathesis compounded by the direct injurious effects of these drugs.

The ulcerogenic actions of NSAIDs have been attributed to their systemic suppression of prostaglandin

production. Numerous experimental models have demonstrated the ability of NSAIDs to injure the

gastroduodenal mucosa. Ulcers resembling those caused by NSAIDs can be produced experimentally by

antibodies to prostaglandins. Conversely, NSAID-associated gastric ulcers can be prevented by the

coadministration of prostaglandin analogues. Ulcers associated with NSAIDs usually heal rapidly when

the drug is withdrawn, corresponding to the reversal of antiprostaglandin effects. All available NSAIDs

appear to pose the hazard of gastroduodenal ulceration. Clinically important ulceration (of both the

stomach and duodenum) is estimated by the U.S. Food and Drug Administration to occur at a rate of 2%

to 4% per patient-year. The risks inherent with NSAID use appear to be increased by a history of H.

pylori infection, by cigarette smoking, and by alcohol use. The incidence of NSAID-caused ulcer

complications is highest in older patients, as is the attendant mortality rate. Peptic ulcer disease is rare

in individuals who are H. pylori negative and who are not receiving NSAID medications.

A role of NSAIDs in upper gastrointestinal (GI) hemorrhage is widely recognized. The risk of bleeding

is particularly acute for peptic ulceration. In three reports, spanning two decades, NSAIDs were linked

to 50% to 75% of bleeding peptic ulcers, one-third of deaths due to hemorrhage, and 30% of

hospitalizations.10,11 Use of NSAIDs increases the risk of bleeding from peptic ulcer threefold for those

under 65 years of age, but by eightfold for individuals over 75 years of age. The odds ratio for bleeding

is 13 for patients with a prior history of bleeding ulcer.

Because of the risk of gastrointestinal side effects, a selective class of cyclooxygenase-2 (COX-2)

inhibitors was developed for long-term pain relief and anti-inflammatory therapy. Selective COX-2

inhibitors have reduced potential to injure the gastrointestinal mucosa relative to standard NSAIDs.11

Concurrent use of aspirin with COX-2 inhibitors significantly undermines the safety advantages of the

COX-2 agents, as does smoking.12

DIAGNOSIS

The cardinal feature of duodenal ulceration is epigastric pain. The pain is usually confined to the upper

abdomen and is described as burning, stabbing, or gnawing. Unless perforation or penetration into the

head of the pancreas has occurred, referral of pain is not common. Many patients report pain on arising

in the morning. Ingestion of food or antacids usually provides prompt relief. In uncomplicated cases,

abnormal physical findings are minimal. The differential diagnosis is broad and includes a variety of

diseases originating in the upper gastrointestinal tract. The most common disorders to be distinguished

include nonulcerative dyspepsia, gastric neoplasia, cholelithiasis and related diseases of the biliary

system, and both inflammatory and neoplastic disorders of the pancreas. In dyspeptic patients, the

principal diagnoses that must be differentiated definitively are peptic ulceration and gastric cancer.

The evaluation of patients with suspected peptic ulceration usually involves endoscopy, the standard

against which other diagnostic modalities are measured. Endoscopy is employed because it permits

biopsy of the esophagus, stomach, and duodenum. Endoscopy must be recommended with discretion

because of associated morbidity (approximately 1 per 5,000 cases) and higher costs.

Duodenal ulcer is characterized by lesions that are erosive to the bowel wall. When viewed

endoscopically, the ulcers have a typical appearance. The edges are usually sharply demarcated and the

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underlying submucosa is exposed. The ulcer base is often clean and smooth, although acute ulcers and

those with recent hemorrhage can demonstrate eschar or adherent exudate. Surrounding mucosal

inflammation is common. The most frequent site for peptic ulceration is the first portion of the

duodenum, with the second portion less commonly involved. Ulceration of the third or fourth portions

of the duodenum is unusual, and occurrence in these sites should arouse suspicion of an underlying

gastrinoma. Ulceration in the pyloric channel or the prepyloric area is similar in endoscopic appearance

to duodenal ulceration, and ulcers in these areas demonstrate other clinical features similar to duodenal

ulcers. Endoscopic demonstration of a duodenal ulcer should prompt mucosal biopsy of the gastric

antrum to demonstrate the presence of H. pylori and guide subsequent therapy.

The hallmarks of the histologic appearance of duodenal ulcers are chronicity and invasiveness.

Chronic injury is suggested by surrounding fibrosis; collagen is deposited in the submucosa during each

round of ulcer relapse and healing. The adjacent mucosa often demonstrates evidence of chronic injury

with infiltration of acute and chronic inflammatory cells. Gastric metaplasia, in which the duodenum

exhibits histologic features of gastric mucosa, is common in the surrounding nonulcerated mucosa. The

ulcer can extend for a variable distance through the wall of the duodenum, including the full thickness

of the bowel in cases of perforation.

DRUG TREATMENT OF ULCER DISEASE

4 In the absence of active treatment, H. pylori infection is lifelong. Spontaneous healing of infected

mucosa is very rare, occurring in less than 0.5% per patient-year. Current treatment of peptic ulceration

involves a combination of an antisecretory drug, usually a proton pump inhibitor, with antibiotics.13

This therapy is rational for most patients who are H. pylori positive and results in a high rate of

sustained ulcer healing.

A large number of drug regimens have been described, but the most widely used treatment protocols

combine a proton pump inhibitor, usually omeprazole, with two antibiotics, usually clarithromycin and

metronidazole or amoxicillin. A combination of antibiotics is more effective than one antibiotic alone in

almost all series. This triple therapy is administered for 7 or 14 days. Triple-drug therapy is cost

effective and associated with a low rate of side effects, low rates of antibiotic resistance, and acceptable

levels of patient compliance. H. pylori eradication rates of greater than 90% have been reported.

After elimination of H. pylori, ulcer recurrence rates reflect the rate of reinfection. In developed

countries, reinfection rates of less than 10% at 5 years have been reported. Eradication of H. pylori

improves quality of life, as measured by symptoms, drug prescriptions, physician visits, and days of

missed employment. To date, antibiotic resistance has been low, approximately 18% for clarithromycin,

14% for levofloxacin, and 35% for metronidazole. Resistance to amoxicillin has been close to zero.14

HISTAMINE-RECEPTOR ANTAGONISTS

Histamine, released into the interstitial fluid by cells in the fundic mucosa, diffuses to the mucosal

parietal cell. Histamine stimulates acid production by occupying a membrane-bound receptor and

activating parietal cell adenylate cyclase. Histamine is released in response to a number of physiologic

stimuli; blockade of histamine receptors inhibits most forms of stimulated acid secretion in humans.

Parietal cell histamine receptors are classified as H2

receptors because they are activated by agonists

such as 4-methylhistamine and are selectively blocked by agents such as cimetidine. Some H2

-receptor

antagonists also possess nongastric actions by binding to androgen receptors, by interacting with the

hepatic microsomal oxidase system, and by crossing the blood–brain barrier. All clinically useful gastric

histamine receptor antagonists are of the H2

type.

H2

-receptor antagonists bind competitively to parietal cell H2

receptors to produce a reversible

inhibition of acid secretion. An enormous worldwide experience has accumulated with the use of H2

-

receptor antagonists. The agents are effective and safe when used in the treatment of peptic ulcer. The

various compounds have similar efficacy in terms of ulcer healing when used in doses that produce

similar reductions in acid output. It is clear that H2

-receptor blockers do not affect the underlying ulcer

diathesis; if H2

-receptor antagonists are stopped, recurrent ulceration occurs in more than half of

patients within 1 year. The current understanding of the role of H. pylori in ulcer pathogenesis has

changed the role of H2

-receptor antagonists from primary therapy to that of a substitute for proton

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pump inhibitors in conjunction with antibiotic treatment.

PROTON PUMP BLOCKERS

Acid secretion by the gastric parietal cells is due to the active transport of hydrogen ions from the

parietal cell cytoplasm into the secretory canaliculus in exchange for potassium. Because this so-called

proton pump is tissue specific, being present only in gastric mucosa, its blockade would be expected to

have minimal effects on nongastric functions. Omeprazole is representative of a family of compounds

that selectively block the parietal cell proton pump.

Omeprazole is a weak base, with a pKa of approximately 4. The drug is nonionized and lipid soluble

at neutral pH, but it becomes ionized and activated at a pH of less than 3. In its activated state,

omeprazole binds to the membrane-bound H+-K+-adenosine triphosphatase (ATPase) of the parietal

cell. Because the compound is a weak base, omeprazole accumulates selectively within the acidic

environment of the parietal cell secretory canaliculus; 4 hours after administration, the drug is

detectable in appreciable quantities only in the gastric mucosa. If enough drug is administered to occupy

all parietal cell–binding sites, anacidity can be produced. Omeprazole, in doses from 20 to 30 mg,

causes nearly complete inhibition of stimulated gastric acid secretion within 6 hours. At 24 hours after

drug administration, a 60% to 70% reduction in acid secretion persists.

Repeated daily dosing with omeprazole results in increasing inhibitory action on gastric secretion and

thus in decreased intragastric degradation of the drug. Acid suppression stabilizes after approximately 3

days. Because of tissue accumulation, the secretory actions of omeprazole do not correlate with plasma

levels. Several studies have demonstrated a significant inhibition of peak acid output, marked relief of

epigastric pain, and decreased use of supplemental antacids during omeprazole therapy. Direct

comparisons with H2

-receptor antagonists have generally favored omeprazole in terms of pain relief and

rate of ulcer healing.

OPERATIVE TREATMENT OF ULCER DISEASE

Surgical Goals

Operative intervention is reserved for the treatment of complicated ulcer disease. Three complications

are most common and constitute the indications for peptic ulcer surgery – hemorrhage, perforation, and

obstruction. The first goal in the surgical treatment of the complications of ulcer disease is treatment of

coexisting anatomic complications, such as pyloric stenosis or perforation. The second major goal should

be patient safety and freedom from undesirable chronic side effects. To achieve these goals, the gastric

surgeon can direct therapy through endoscopic or operative means, the appropriate choice depending on

the clinical circumstances.

Operative Procedures

A number of operative procedures have been used to treat peptic ulcer, but with decreasing frequency

in the past decade. There is currently no indication for surgical treatment of uncomplicated ulcer

disease. Operative treatment of gastric outlet obstruction has decreased by approximately 50%. Most

surgical patients are now treated emergently for the complications of bleeding or perforation.

Three procedures – truncal vagotomy and drainage, truncal vagotomy and antrectomy, and proximal

gastric vagotomy – were widely used in the past in the operative treatment of peptic ulcer disease. With

increasing frequency, surgical therapy of peptic ulcer is directed exclusively at correction of the

immediate problem (e.g., closure of duodenal perforation) without gastric denervation. The underlying

ulcer diathesis is then addressed after surgery by antibiotic therapy directed at H. pylori. This approach

is applicable to most patients with peptic ulcer undergoing emergent operation and implies a very

limited role for vagotomy in the future.

Division of both vagal trunks at the esophageal hiatus – truncal vagotomy – denervates the acidproducing fundic mucosa as well as the remainder of the vagally supplied viscera (Fig. 45-1). Because

denervation impedes normal pyloric coordination and can result in impairment of gastric emptying,

truncal vagotomy must be combined with a procedure to eliminate pyloric sphincteric function. Usually,

gastric drainage is ensured by performance of a pyloroplasty (Fig. 45-2).

When truncal vagotomy is combined with resection of the gastric antrum there is a further reduction

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in acid secretion, presumably by removing antral sources of gastrin. The limits of antral resection are

usually defined by external landmarks, rather than the histologic transition from fundic to antral

mucosae. The stomach is divided proximally along a line from a point above the incisura angularis to a

point along the greater curvature midway from the pylorus to the gastroesophageal junction.

Restoration of gastrointestinal continuity by a gastroduodenostomy is termed a Billroth I reconstruction.

A Billroth II procedure uses a gastrojejunostomy (Fig. 45-3).

Figure 45-1. Truncal vagotomy and proximal gastric vagotomy. A: With truncal vagotomy, both nerve trunks are divided at the

level of the diaphragmatic hiatus. B: Proximal gastric vagotomy involves division of the vagal fibers that supply the gastric fundus.

Branches to the antropyloric region of the stomach are not transected, and the hepatic and celiac divisions of the vagus nerves

remain intact.

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Figure 45-2. Pyloroplasty formation. A: A Heineke–Mikulicz pyloroplasty involves a longitudinal incision of the pyloric sphincter

followed by a transverse closure. B: The Finney pyloroplasty is performed as a gastroduodenostomy with division of the pylorus.

C: The Jaboulay pyloroplasty differs from the Finney procedure in that the pylorus is not transected.

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Figure 45-3. Antrectomy involves resection of the distal stomach (pink area in inset). Restoration of gastrointestinal continuity may

be accomplished as a Billroth I gastroduodenostomy (A) or Billroth II gastrojejunostomy (B) reconstruction.

Physiologic Consequences of Operation

Division of efferent vagal fibers directly affects acid secretion by reducing cholinergic stimulation of

parietal cells. In addition, vagotomy also diminishes parietal cell responsiveness to gastrin and

histamine. Basal acid secretion is reduced by approximately 80% in the immediate postoperative period.

Acid secretion increases slightly within months of surgery but remains unchanged thereafter. The

maximal acid output in response to exogenously administered stimulants such as pentagastrin is reduced

by approximately 70% in the early period after surgery. After 1 year, pentagastrin-stimulated maximal

acid output rebounds to 50% of prevagotomy values but remains at this level on subsequent testing.

Acid secretion due to endogenous stimulation by a liquid meal is reduced by 60% to 70% relative to

normal subjects.

The inclusion of antrectomy with truncal vagotomy causes further reductions in acid secretion.

Pentagastrin-stimulated maximal acid output is reduced by 85% relative to values recorded before

surgery. Little rebound in acid secretion occurs with the passage of time.

Operations that involve vagotomy alter gastric emptying. Proximal gastric denervation abolishes

vagally mediated receptive relaxation. Thus, for any given volume ingested, the intragastric pressure

rise is greater and the gastroduodenal pressure gradient is higher than that in normal subjects. As a

result, emptying of liquids, which depends critically on the gastroduodenal pressure gradient, is

accelerated after proximal gastric vagotomy. Because nerve fibers to the antrum and pylorus are

preserved, the function of the distal stomach to mix and triturate solid food is preserved, and emptying

of solids is nearly normal in patients who have undergone proximal gastric vagotomy. Truncal

vagotomy affects the motor activities of both the proximal and distal stomach. Solid and liquid

emptying rates are usually increased when truncal vagotomy is accompanied by pyloroplasty.

Dumping, a postprandial symptom complex of abdominal discomfort, weakness, and vasomotor

symptoms of sweating and dizziness, occurs in 10% to 15% of patients with truncal vagotomy and

antrectomy in the early postoperative period and is chronically disabling in 1% to 2%. After truncal

vagotomy and pyloroplasty, dumping is present initially in 10% and remains severe in approximately

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