Acid-Peptic Disorders, Gastritis, and Helicobacter pylori

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[edit] Acid-Peptic Disorders, Gastritis, and Helicobacter pylori

Robert C. Lowe

M. Michael Wolfe

The incidence of peptic ulcer disease (PUD) has been decreasing steadily since the 1950s, but PUD continues to affect 200,000 to 400,000 people each year, with estimated annual costs of $3 billion to $4 billion. The discovery of Helicobacter pylori in the early 1980s and its association with PUD have dramatically altered the approach to management of this condition. Despite the importance of H. pylori infection, however, gastric acid continues to play a critical role in the pathogenesis of ulcers, and “no acid, no ulcer” remains a valid principle.

[edit] EPIDEMIOLOGY

PUD affects 1.8% of the U.S. population and, despite previous studies suggesting male predominance, appears to affect males and females equally. A study of male physicians reported a 10% lifetime risk of developing a duodenal ulcer (DU). The most common risk factors for ulcer development are use of nonsteroidal antiinflammatory drugs (NSAIDs), infection with H. pylori, and cigarette smoking. The common belief that alcohol, stress, and spicy food are important in ulcerogenesis has not been borne out in clinical studies. A family history of DU is reported in 20% to 50% of DU patients in published series, compared with 10% of patients without ulcer disease. These epidemiologic studies, however, antedate the discovery of H. pylori, and fecal-oral transmission of H. pylori or a genetic predisposition to H. pylori infection may be responsible for this apparent familial clustering. Previous studies showing an association of DU with blood type O may also reflect a predisposition to H. pylori infection in persons with this blood type. Some patients, however, may have a genetic predisposition to gastric acid hypersecretion that contributes to DU pathogenesis. The incidence of PUD is also increased in patients with underlying illnesses (e.g., cirrhosis, chronic obstructive pulmonary disease, renal failure) and after renal transplantation.

[edit] ANATOMY AND PHYSIOLOGY

The proximal stomach (i.e., cardia, fundus, body) is compliant and, besides secreting acid and pepsin, functions as a reservoir for the mixing of food and gastric secretions. The distal stomach (antrum and pylorus) is more muscular, provides the force to mix food and gastric juice, and propels chyme into the small intestine for further digestion and subsequent absorption. The stomach possesses an extensive blood supply that forms two vascular arcades along the greater curvature (left and right gastroepiploic arteries) and lesser curvature (left and right gastric arteries). Lymphatic drainage parallels this vascular supply. The vagus nerve provides parasympathetic input to the stomach that modulates both motor function and acid secretion.

Functionally the stomach can be divided into two areas: the oxyntic gland and pyloric gland regions. Oxyntic glands are located in the gastric fundus and body and are composed of several cell types, including parietal cells (which secrete hydrochloric acid [HCl] and intrinsic factor), chief cells (which secrete pepsinogen), mast and enterochromaffin-like (ECL) cells (which generate histamine), D cells (which produce somatostatin), and mucus-secreting cells. The pyloric glands are located in the antrum and contain mucus-secreting cells, D cells, and G cells, which synthesize and secrete gastrin. Parietal cells generate hydrogen ions (H⁺), which are secreted into the lumen by a cellular H⁺/K⁺ (potassium ion) adenosinetriphosphatase (ATPase) that constitutes the final common pathway of H⁺ secretion.

The generation of H⁺ is mediated by three pathways: neurocrine, paracrine, and endocrine (Fig. 102-1). The principal neurocrine transmitter is acetylcholine, which is released by vagal postganglionic neurons and causes parietal cells to increase gastric acid secretion both directly and indirectly by stimulating histamine release from ECL cells. Histamine (H₂) is the primary paracrine transmitter that binds to H₂-specific receptors on parietal cells; adenylate cyclase is then activated, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and subsequent generation of H⁺. Histamine receptors can be selectively and competitively blocked by H₂ receptor antagonists (H₂RAs, H₂ blockers), agents that constituted the mainstay of ulcer therapy during the 1980s and early 1990s. The secretion of gastrin from antral G cells constitutes the endocrine pathway and stimulates gastric acid secretion predominantly by stimulating histamine secretion from ECL cells. Gastrin represents the principal pathway by which acid secretion is stimulated during the gastric phase of a meal. Antral distention provides the initial stimulus for gastrin release through a β-adrenergic pathway in humans. The effect of antral distention is transient, however, and the maintenance of gastrin release is mediated by two principal components of the ingested meal: protein content and pH. Gastrin is secreted when the luminal pH increases above 3.5, whereas gastrin release is abolished at a pH of less than 1.5.

Figure 102-1 Gastric acid secretion by parietal cell, as influenced by neurocrine (acetylcholine [A] from vagal efferent neurons), paracrine (histamine [H] release from gastric enterochromaffin-like [ECL] cells), and endocrine (circulating gastrin [G]) factors. Dashed arrows indicate potential sites of pharmacologic inhibition of acid secretion, either through receptor antagonism or inhibition of H⁺/K⁺ ATPase, the common pathway for gastric acid secretion. H₂RA, Histamine receptor antagonists;L365,260, synthetic gastric receptor antagonist;PGE, prostaglandin E.

These neurocrine, paracrine, and endocrine pathways are not independent; interactions among them are coordinated to promote or inhibit the secretion of gastric acid. Histamine appears to represent the dominant route because gastrin and (to some extent) acetylcholine stimulate H⁺ secretion principally by promoting histamine release from ECL cells. Thus ECL cells are often referred to as controller cells in the process of gastric acid secretion.

Acid secretion in response to a meal can be divided into three phases: cephalic, gastric, and intestinal. The cephalic phase is mediated by the vagus nerve in response to the sight, smell, or thought of food and accounts for 30% to 35% of the total acid output in response to a meal. Basal and nocturnal acid secretion is also mediated by the vagus nerve; thus both the cephalic phase of a meal and the basal circadian rhythm of acid secretion can be abolished by vagotomy. The gastric phase of acid secretion accounts for 50% to 60% of total meal-stimulated acid release, and more than 90% of this phase is mediated by gastrin release from antral G cells. The intestinal phase of acid secretion plays only a minor role, accounting for less than 5% of the acid response to a meal, and appears to result from the effects of absorbed amino acids.

A negative feedback loop governs the means by which both gastrin release and acid secretion return to basal levels. This process represents a vital autoregulatory mechanism for preventing postprandial acid hypersecretion. After ingestion of a meal, gastrin release stimulates the secretion of gastric acid. The intraluminal pH begins to decrease as the buffering capacity of the meal is overwhelmed by continued acid secretion. The increasing acidity appears to stimulate the release of somatostatin from antral D cells. Somatostatin in turn acts through a paracrine mechanism to inhibit the further release of gastrin from G cells, and acid secretion is subsequently diminished. D cells may also directly inhibit acid secretion from parietal cells or may suppress histamine release from ECL cells.

[edit] PATHOPHYSIOLOGY

Historically, acid and pepsin have been considered the sole determinants of ulcer pathogenesis. Although patients with gastric ulcers tend to have normal or reduced levels of acid secretion, DU patients on average are hypersecretors of acid. When compared with age-matched controls, DU patients secrete approximately 70% more acid during the day (meal stimulated) and about 150% more acid at night (basal secretion). As noted, gastric acid secretion during the day is regulated primarily by postprandial gastrin release and subsequent inhibition of the hormone's secretion after acidification of the gastric lumen. Individuals infected with H. pylori have diminished antral D cells, which decreases the magnitude of the somatostatin response during acidification of the gastric lumen. Thus, in patients with infection limited to the antrum, the negative feedback inhibition of gastrin release is attenuated, resulting in higher postprandial gastrin levels and hypersecretion of acid.

Despite the enhanced daytime rate of acid secretion in DU patients, the presence of food in the stomach has a buffering effect that helps protect the mucosa from acid-induced injury. At night, however, acid bathes the bare mucosa, and in DU patients the increase in nocturnal acid secretion magnifies this effect. Also, duodenal bicarbonate secretion is impaired in patients with DU, as well as in those infected with H. pylori, making the mucosal exposure to acid even greater. These observations, as discussed later, form the rationale for single nocturnal dosing of H₂RAs in the treatment of DU, which is at least as effective as multiple dosing regimens. Vagotomy also provides an effective means of healing DUs because nocturnal acid secretion is mediated primarily by vagal activity and appears to be predominantly H. pylori independent.

Factors other than acid and pepsin are involved in the pathogenesis of PUD, since only 30% of patients with DUs and very few patients with gastric ulcers are acid hypersecretors. Another important element is the balance between aggressive factors that act to injure the gastroduodenal mucosa and defensive factors that normally protect against noxious agents; when this balance is disrupted for any reason, an ulcer may develop (Fig. 102-2). The aggressive factors include acid (dominant role), pepsin, and bile salts. The mucosal defensive factors include (1) mucus secretion, which traps H⁺ and permits bicarbonate secreted by surface epithelial cells to titrate acid effectively; (2) mucosal blood flow, which delivers oxygen, nutrients, and bicarbonate and removes metabolites (“alkaline tide”); (3) intercellular tight junctions that prevent transepithelial penetration of H⁺; and (4) cell restitution and epithelial renewal, which enable the mucosa to repair itself after injury. These defensive properties appear to be mediated largely by endogenous prostaglandins. When prostaglandin synthesis is diminished by the use of NSAIDs, the ability of the gastroduodenal mucosa to resist injury is decreased. Thus even normal rates of acid secretion may be sufficient to injure the mucosa and produce gastroduodenal ulcers.

Figure 102-2 Pathogenesis of peptic ulcer modeled as an imbalance between aggressive and defensive factors within gastroduodenal mucosa. Ulcers form when aggressive factors (e.g., acid, pepsin) overwhelm defensive mechanisms normally present within mucosa. In most instances, acid and pepsin secretion is not increased; rather, mucosal resistance is diminished by factors such as ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) or infection with Helicobacter pylori.

[edit] ETIOLOGY

H. pylori infection, NSAID use, and hypersecretory states (e.g., Zollinger-Ellison syndrome) appear to account for the vast majority of gastric and duodenal ulcers.

[edit] Helicobacter pylori

Chronic antral infection with H. pylori results in increased postprandial acid secretion through increased and prolonged gastrin release. This abnormality occurs as a result of amarked decrease in the number of D cells in the antrum, which decreases somatostatin activity and consequently diminishes inhibitory signaling to antral G cells and possibly ECL and parietal cells. DU patients infected with H. pylori have an increased acid secretory response to gastrin compared with volunteers who are H. pylori negative and who do not have ulcers. Thus H. pylori–infected DU patients not only secrete more gastrin but also are more responsive to the hormone. These abnormalities are largely reversible after successful eradication of the organism.

H. pylori and pH are closely related etiologic factors in PUD (Fig. 102-3). Unknown genetic factors lead to gastric acid hypersecretion, which can produce gastric metaplasia of the duodenum. Because of a predilection for infection of gastric-type mucosa, secondary colonization of the duodenum with H. pylori may occur, which may in turn incite an immune response, leading to duodenitis and DU. Despite the clear epidemiologic association between H. pylori and PUD, however, the percentage of ulcers associated with H. pylori may not be 90% to 95% but as low as 32% in nonreferral-based populations. Thus peptic ulceration is not caused solely by H. pylori, but rather involves several factors, most notably the erosive properties of acid and pepsin.

Figure 102-3 Pathways depicting postulated pathogenesis of Helicobacter pylori–associated duodenal ulcer. Gastric metaplasia in duodenum provides environment that enhances colonization by H. pylori, with subsequent duodenal inflammation and possible progression to peptic ulcer.

[edit] Nonsteroidal Antiinflammatory Drugs

Approximately 15% to 20% of chronic NSAID users develop gastroduodenal ulcers. Although NSAIDs damage the gastric mucosa more frequently than the duodenal mucosa, the mechanisms of injury are the same: the disruption of mucosal defenses by both topical and systemic effects. The topical effects of NSAIDs, seen primarily in the stomach, result from a direct toxic insult by these agents or their metabolites on the gastric mucosal surface. The systemic effects are mediated through inhibition of cyclooxygenase in the gastric epithelium and consequently a decrease in the production of mucosal prostaglandins. The diminished prostaglandin levels alter gastric mucus secretion, mucosal blood flow, ion transport, and other defensive properties of the gastroduodenal mucosa, allowing acid and pepsin to induce mucosal damage, which results in formation of peptic ulcers. Even enteric-coated or intravenous NSAID formulations can induce gastroduodenal ulcers because of their systemic effects.

Risk factors for PUD and its complications include age over 65 years, prior history of PUD, use of high doses of NSAIDs, and concurrent steroid use. Patients with these risk factors or those who would poorly tolerate any complications of PUD may benefit from ulcer prophylaxis. Both proton pump inhibitors (PPIs) and misoprostol (a prostaglandin E₁ analog) provide effective ulcer prophylaxis in users of NSAIDs. Misoprostol is clearly superior to H₂RAs in the prevention of gastric ulcers, whereas both are equally effective in preventing DUs. Famotidine in high doses (40 mg twice daily) may also offer some protection against gastric ulcers, although not as effectively as misoprostol or PPIs. PPIs may be as effective as misoprostol in the prevention of gastroduodenal ulcers caused by NSAIDs. In addition to the use of prophylactic agents, new NSAIDs have been developed that may lack the ulcerogenic properties of earlier preparations. Agents such as meloxicam, celecoxib, and rofecoxib preferentially or selectively inhibit inducible cyclooxygenase II (COX-II), which is responsible for inflammation, while having a minimal effect on constitutively expressed cyclooxygenase I (COX-I), the enzyme that plays a key role in preserving mucosal integrity.

[edit] Hypersecretory States

Hypersecretory states such as Zollinger-Ellison syndrome (ZES), antral G-cell hyperplasia, and systemic mastocytosis are also associated with PUD. A reported 0.1% of all DUs are caused by ZES. Classically, hypersecretory states are associated with multiple DUs, ulcers in unusual locations (beyond the first portion of the duodenum), or ulcers that fail to respond to standard therapy. More often, however, they behave as ulcers associated with H. pylori, often with additional symptoms, such as pyrosis, diarrhea, or cutaneous flushing.

A significant number of patients with PUD are H. pylori negative, and the appropriate evaluation of such patients is presently unclear. A number of these patients are taking NSAIDs (57% to 75% in studies), whereas others have an underlying hypersecretory state or another illness associated with gastroduodenal ulceration (e.g., Crohn's disease). The remaining patients with truly “idiopathic” ulcers may have a disturbance of gastric motility; delayed gastric emptying may predispose to gastric ulceration by increasing the contact time between acid and the mucosa, and rapid gastric emptying may have similar consequences for the duodenal mucosa. Most authorities recommend that patients with PUD who are H. pylori negative and who deny NSAID use should be evaluated with a fasting serum gastrin level (to identify a hypergastrinemic syndrome) and a biopsy of the ulcer to look for granulomatous infiltration or evidence of neoplasia (adenocarcinoma or lymphoma).

[edit] CLINICAL PRESENTATION

The most common symptom of PUD is nonradiating epigastric pain. The pain of DU is classically described as occurring 2 to 3 hours after a meal, improving with food or antacids, and awakening patients at night several hours after retiring (2 to 4am). Gastric ulcer pain is said to worsen with food, although the response to a meal cannot reliably distinguish gastric ulcers from DUs. Other symptoms of PUD include nausea and vomiting, which may occur in up to 60% of patients, especially those with prepyloric or pyloric channel ulcers. Unfortunately, the classic symptom complex occurs only in a minority of patients with PUD, and it is difficult even to determine the percentage of patients who experience pain, since a significant number of patients with PUD lack any symptoms. In one study, 10% of patients presenting with a complication of ulcer disease (perforation or hemorrhage) reported no prior symptoms. In studies of patients with hemorrhage from NSAID-induced gastroduodenal ulcers, as many as 50% to 60% had no antecedent symptoms. Another confounding factor is that the relief of pain has not proved to be a reliable indicator of a successful response to therapy, since some patients will have continued pain despite ulcer healing, whereas others will report relief of their symptoms in the presence of a persistent ulcer.

The physical examination in patients with uncomplicated PUD is largely unrevealing, with most patients having little more than epigastric tenderness. When complications supervene, however, the range of clinical presentations includes an acute abdomen after perforation, hematemesis and melena after hemorrhage, and early satiety, nausea, and vomiting from gastric outlet obstruction.

[edit] DIAGNOSIS

Although some authors report accurately predicting endoscopic findings in 66% of patients with PUD, establishing the diagnosis solely on the basis of history and examination is usually difficult and uncertain. Given the nonspecific symptoms and signs of PUD, the differential diagnosis is broad and includes gastroesophageal reflux disease (GERD), gastric cancer, gastroduodenitis, cholecystitis, biliary tract disease, pancreatic cancer, pancreatitis (acute or chronic), intestinal ischemia, pain associated with ischemic heart disease, and nonulcer dyspepsia. The diagnosis of PUD is most often made by esophagogastroduodenoscopy (EGD) or upper gastrointestinal (UGI) series. The two modalities tend to correlate well, although reported sensitivities and specificities may not be applicable to all centers because they depend largely on examiners' expertise in radiology and gastroenterology. In the best hands, using double-contrast fluoroscopic technique, EGD and UGI series correlate 80% to 90% of the time in diagnosing duodenal ulcers. The UGI series is not as effective in detecting small ulcers (less than 0.5 cm) and does not allow for biopsy. Therefore, if available, endoscopic evaluation is clearly preferred for patients with suspected PUD.

Laboratory tests are generally of little help in evaluating patients with uncomplicated PUD. A fasting serum gastrin level for the presence of ZES may be useful in DU patients with a reasonable index of suspicion. Measurement of gastric acid secretion is generally helpful only in patients with elevated serum gastrin levels. In these patients a gastric pH measurement at endoscopy is useful in distinguishing atrophic gastritis or other causes of decreased acid secretion from ZES. A pH greater than 2.5 in the absence of antisecretory medication (not taking H₂RAs for 24 hours or PPIs for 5 days) virtually excludes the diagnosis of ZES.

Laboratory tests do play an important role in the diagnosis of H. pylori infection, most often through serologic determination of immunoglobulin G (IgG) antibodies in peripheral blood, which is greater than 90% sensitive and 90% specific for H. pylori infection.¹³C-urea and¹⁴C-urea breath tests also can establish H. pylori infection and are the most sensitive methods (invasive or noninvasive) for determining successful eradication of the organism. The patient ingests urea labeled with carbon-13 or carbon-14. If H. pylori is present on the gastric mucosa, bacterial urease metabolizes the urea into ammonia and labeled carbon dioxide, which is absorbed into the bloodstream and excreted through the lungs. Breath samples are collected at intervals after urea ingestion and are analyzed using either mass spectrometry (¹³C) or a scintillation counter (¹⁴C). Urea breath testing is 95% sensitive and 98% specific for the diagnosis of H. pylori infection. The high diagnostic accuracy and noninvasive nature make the test a superior means of documenting H. pylori and confirming eradication of the organism at 4 to 6 weeks after cessation of treatment.

For patients undergoing upper endoscopy, several tests for H. pylori can be performed on biopsy specimens of the gastric mucosa. Culture of H. pylori is difficult and at present is rarely used to diagnose infection in clinical practice. Direct histologic examination of biopsy specimens is a sensitive and specific means of diagnosing H. pylori infection and remains the gold standard. The rapid urease test provides a faster and less expensive way of establishing H. pylori infection from a biopsy specimen. These tests use a gel matrix impregnated with both urea and a pH-sensitive color indicator. Gastric biopsies are placed into the gel, and in the presence of H. pylori–associated urease, ammonia is generated from urea, and the gel turns red as the pH becomes increasingly alkaline. Rapid urease testing is 92% sensitive when read at 3 hours and 98% sensitive at 24 hours, with 100% specificity.

[edit] TREATMENT

The treatment of PUD has changed dramatically since the discovery that ulcer recurrence rates decrease dramatically after eradication of H. pylori infection, compared with annual recurrence rates of 50% to 80% when antisecretory therapy alone is used (Table 102-1). Determining whether a patient with PUD is infected with H. pylori is critical to appropriatemanagement. If a patient is not infected with H. pylori, an alternative etiology must be sought, such as NSAID use, hypersecretory states, or less common causes.

Table 102-1 Healing Rates with Pharmacologic Treatments of Peptic Ulcer

[edit] Nonpharmacologic Therapy

Historically, bed rest and dietary modification were the mainstays of treatment for PUD. Bland diets rich in milk were advocated with recommendations to eat smaller, more frequent meals to decrease gastric distention and subsequent acid secretion. These treatments were never evaluated in controlled clinical trials, and it was later discovered that milk itself was a potent stimulus of gastric acid secretion. Dietary modification is thus no longer advised, besides counseling patients to avoid any specific foods that precipitate dyspepsia. General measures recommended in the treatment of ulcer disease include cessation of smoking and alcohol and, if possible, discontinuation of NSAID use.

[edit] Pharmacologic Therapy

[edit] Antacids.

Antacids are effective in relieving the symptoms of PUD, and a double-blind study demonstrated that antacids are superior to placebo in healing DUs (although no difference in symptom relief was noted in that trial). Later studies evaluated the dose and dose intervals of antacids and found that as little as a single antacid tablet before meals or at bedtime was effective in healing ulcers with minimal side effects. The toxicity of antacids is generally low, with the predominant side effects of diarrhea with magnesium hydroxide–containing preparations and constipation with aluminum hydroxide–based formulations.

[edit] H₂ Receptor Antagonists.

The discovery of the role of selective histamine receptors in regulating gastric acid secretion generated a search for a receptor antagonist, culminating in the introduction of cimetidine in the mid-1970s. As with antacids, cimetidine (0.8 to 1.2 gm/day) promotes healing of duodenal ulcers in 70% to 80% of patients after 4 to 6 weeks, compared with placebo healing rates of 20% to 45%. Later formulations (ranitidine, famotidine, nizatidine) retained the basic structure of cimetidine, with minor modifications affecting potency, bioavailability, and side effect profile. Overall, H₂RAs are among the safest classes of drugs available. They may cause mild central nervous system (CNS) effects, including drowsiness, agitation, and headache, because of their ability to cross the blood-brain barrier and cross-react with CNS histamine receptors. Cimetidine and ranitidine both interact with the hepatic cytochrome P-450 system (ranitidine having fivefold to tenfold less avidity than cimetidine) and may affect the metabolism of various drugs. However, only patients receiving warfarin sodium, theophylline, or phenytoin are at small risk of developing a clinically significant alteration in drug levels; since monitoring of drug levels and coagulation parameters is routine in these patients, an adverse outcome rarely results from this interaction. Other reported side effects of H₂ blockers include gynecomastia (cimetidine only) and rarely thrombocytopenia. In general, a 50% dose reduction is recommended in patients with a glomerular filtration rate of 30 ml/minute or less. All the H₂RAs are equally effective in healing duodenal ulcers, with 90% to 95% healing rates achieved after 8 weeks of therapy. Twice-daily dosing regimens have been replaced by a single evening-dose regimen (with an equivalent total daily dose), since ulcer healing is proportional to the effectiveness of nocturnal acid secretion. Although both modes of therapy are equally effective, patient compliance improves with the single-dose regimen, which is thus preferred for treatment of PUD with H₂RAs.

[edit] Sucralfate.

Sucralfate (an aluminum salt of sucrose octasulfate) has been used for the past two decades in the treatment of PUD and possesses healing rates similar to antacids and H₂RAs. Although sucralfate has no effect on gastric acid secretion, it is thought to protect the gastroduodenal mucosa through adhesion to the ulcer base, adsorption of bile acids, inactivation of pepsin, and stimulation of bicarbonate and mucus secretion. In addition to its use as primary therapy for PUD (1 gm orally four times daily), sucralfate is also effective in preventing DU relapse (1 gm twice daily). Sucralfate is generally well tolerated and has an excellent safety profile because only 3% to 5% of a single dose is absorbed into the circulation. In patients with renal disease, however, sucralfate must be used cautiously, since even this small systemic dose may lead infrequently to aluminum toxicity.

[edit] Prostaglandin Analogs.

The prostaglandin analogs misoprostol, arbaprostil, and enprostil have been used in the treatment of PUD; only misoprostol is available in the United States. These agents protect the gastroduodenal mucosa by stimulating the secretion of bicarbonate and mucus and by enhancing mucosal blood flow and mucosal cell restitution. When given at higher doses, these drugs also exhibit an antisecretory effect. These agents are effective in healing peptic ulcers and in preventing ulcer recurrence, but only when given in antisecretory doses. Thus the relative contributions of mucosal protection and inhibition of gastric acid secretion are difficult to distinguish clinically. Because prostaglandin analogs require frequent dosing (for misoprostol, 200 μg two to four times daily) and are associated with significantly more side effects than H₂RAs, they are generally not used in the treatment of PUD. Currently, these agents are primarily used to prevent NSAID-induced gastroduodenal ulceration. Diarrhea is the most frequently reported side effect of these agents, occurring in up to 20% to 30% of patients. The diarrhea is dose dependent and is related to the drug's ability to increase cAMP levels in intestinal mucosal cells, thereby inducing a secretory diarrhea. Prostaglandin analogs also possess abortifacient properties and should not be used during pregnancy or in women of childbearing age.

[edit] Proton Pump Inhibitors.

The PPIs, which include omeprazole, lansoprazole, rabeprazole, and pantoprazole, are the most powerful inhibitors of gastric acid secretion available. These agents are substituted benzimidazoles that irreversibly inhibit the activity of H⁺/K⁺ ATPase. Administered as prodrugs with a pK_a of approximately 4.0 (5.0 for rabeprazole), they become concentrated in the secretory canaliculus of the activated parietal cell, where the local pH is less than 1.0. In this acidic environment these agents are protonated to form sulfonamides, which then irreversibly bind H⁺/K⁺ ATPase. PPIs are most effective when the parietal cell is stimulated to secrete acid in response to a meal; thus these drugs should only be taken before a meal and should not be used in conjunction with H₂RAs or other antisecretory agents, including prostaglandins. PPIs are extremely potent inhibitors of acid secretion and are also the agents of choice for treatment of ZES.

The safety profile of PPIs is similar to that of H₂ blockers. Although high doses of PPIs precipitated ECL cell hyperplasia and subsequent gastric carcinoid tumors in rats, these drugs have been used for more than 15 years in Europe and 10 years in the United States with no increased tumor incidence. This interspecies difference may be related to a lower mucosal ECL density and a less pronounced increase in circulating gastrin in humans vs. rodents in response to antisecretory medications. PPIs heal peptic ulcers more rapidly than H₂RAs; lansoprazole (30 mg daily) healed 74% of duodenal ulcers after 2 weeks vs. 51% with ranitidine, although at 4 weeks, healing rates were comparable, 95% and 89%, respectively. PPIs are best administered when parietal cells are stimulated (i.e., with meals, optimally before breakfast). Although these agents are less effective in patients not receiving enteral nutrition, evidence suggests that they can be given in suspension through a nasogastric tube in critically ill patients and still induce a significant but inconsistent decrease in acid secretion.

[edit] Summary.

All peptic ulcers eventually heal, as evidenced by placebo responses. Antisecretory therapy accelerates healing and allows more rapid relief of symptoms. Antacids, sucralfate, H₂RAs, prostaglandin analogs, and PPIs have similar healing rates when given for at least 4 weeks, although PPIs appear to heal ulcers more rapidly than the others. Moreover, because they are often used in H. pylori eradication regimens and because they heal gastroduodenal ulcers in patients continuing NSAIDs, PPIs have become the mainstay of therapy for healing peptic ulcers.

[edit] Maintenance Therapy

The practice of continuing antisecretory therapy after ulcer healing evolved from observations regarding the natural history of PUD. In both preendoscopy and postendoscopy studies, up to 82% of DU patients had persistent symptoms after the initial diagnosis, with some lasting up to 30 years. Only 26% of patients with an untreated DU were free of symptoms 1 year after diagnosis. After a median follow-up of 38 weeks, only 12% of patients who underwent H. pylori eradication relapsed, compared with 95% of patients who received H₂RAs alone. Other studies report similar relapse rates after H. pylori therapy, so the maxim “once an ulcer, always an ulcer” no longer holds true.

The role of maintenance antisecretory therapy has changed in recent years. Before embarking on long-term therapy, the most important risk factors for ulcer recurrence, H. pylori infection and NSAID use, must be eliminated. Several studies have demonstrated the cost-effectiveness of H. pylori eradication compared with maintenance antisecretory therapy, which may cost more than $1200 per year. The American College of Gastroenterology currently recommends that only high-risk ulcer patients receive maintenance antisecretory therapy. This group includes patients with a history of ulcer complications, those with frequent recurrences, those who are H. pylori negative, and those who fail to clear H. pylori infection despite appropriate therapy. Some experts, however, state that even patients with a complication of PUD do not require maintenance therapy provided H. pylori infection is cured. Thus, although maintenance therapy plays a role in select situations, the most important principles in treating PUD are to identify and treat H. pylori infection and to discontinue or minimize the use of NSAIDs.

[edit] Helicobacter Pylori Infection

Optimal treatment of H. pylori infection continues to be an area of active research, with a plethora of therapeutic regimens currently available and many others being studied in clinical trials. The two important issues are (1) the determination of which patients should be treated for H. pylori infection and (2) the choice of one effective therapeutic regimen from the many available to the practicing physician (Box 102-1). Recurrence rates of DU in H. pylori–infected patients decrease significantly after eradication of infection, both in patients with active ulcers and those with a past history of DU disease who are H. pylori positive. Patients with gastric ulcer and H. pylori infection should also be treated, even if NSAID use is the etiologic factor in the ulcer's pathogenesis. The diagnosis of a gastric mucosa-associated lymphoid tissue (MALT) lymphoma in an H. pylori–infected patient is also an indication for treatment, since eradication of infection may induce regression of the malignant lesion. See Chapter 105 for the relationship between H. pylori and MALT and gastric carcinoma.

Although H. pylori has been associated with an increased incidence of gastric adenocarcinoma, mass screening and eradication of infection as a chemopreventive strategy is not currently recommended. Eradication of infection in patients with a strong family history of gastric cancer, however, can be considered a reasonable strategy. Similarly, patients with type B antral gastritis and H. pylori infection may benefit from treatment, but this issue is still unresolved; optimally, patients should be treated in the context of a clinical trial. The treatment of H. pylori infection in patients with nonulcer dyspepsia is controversial (see later discussion).

Once the decision to treat H. pylori infection is made, a regimen should be chosen that meets two important criteria: (1) it must be effective against the organism, and (2) it must be simple and inexpensive enough to ensure patient compliance. The first effective therapies against H. pylori combined bismuth subsalicylate with two antimicrobial agents, tetracycline and metronidazole. In clinical trials, eradication rates of 77% to 89% were obtained. Although inexpensive, however, this therapy has a complex dosing regimen that decreases compliance outside clinical studies. In addition, the rising rate of metronidazole resistance among strains of H. pylori further decreases the efficacy of this regimen, and the need for concurrent antisecretory therapy during treatment of active PUD further increases its cost and complexity.

Dual therapies consisting of a PPI and an oral antibiotic have the advantages of easy use and high compliance. Unfortunately, the combination of amoxicillin and omeprazole has an eradication rate of only 30% to 50% and clarithromycin with omeprazole only 70% to 74%. These low rates of clearance of H. pylori make these regimens suboptimal for the treatment of H. pylori–associated PUD.

At present, three-drug regimens consisting of clarithromycin, a PPI, and either metronidazole or amoxicillin are the most frequently used therapies for H. pylori in the United States. The three agents are given twice daily, which improves compliance, and eradication rates are high (Fig. 102-4). Duration of treatment has an important effect on eradication rates. Although European studies reported clearance rates of 90% to 95% using 7-day regimens, U.S. clinical trials have shown rates less than 90% for 7-day regimens; eradication in 14-day regimens has been as high as 92%, however, even though compliance decreases as duration of therapy increases.^[1] The Food and Drug Administration (FDA) has approved the following twice-daily oral regimen for treatment of H. pylori: clarithromycin, 500 mg; amoxicillin, 1 gm; and lansoprazole, 30 mg. In practice, any PPI may be used (e.g., omeprazole, 20 mg), and metronidazole (500 mg) may replace amoxicillin, with eradication rates possibly lower in areas where metronidazole-resistant H. pylori is prevalent.

Figure 102-4 Effect of duration of therapy on compliance and rate of eradication of Helicobacter pylori. Oral twice-daily regimen consisted of omeprazole (20 mg), clarithromycin (500 mg), and amoxicillin (1 gm) for 7, 10, or 14 days.

[edit] COMPLICATIONS OF PEPTIC ULCER DISEASE

Despite a decreasing incidence of PUD, the incidence of the major complications of ulcer disease—hemorrhage (see Chapter 109 ), ulcer perforation, and gastric outlet obstruction—has not diminished, and the rate of hospitalization for complications of gastric ulcer disease is increasing.

[edit] Ulcer Perforation

Perforation of a gastric or duodenal ulcer occurs most often in the fifth or sixth decade of life, with an approximate incidence of 7 to 10 cases/100,000 persons/year. The risk factors for ulcer perforation are similar to those for PUD in general:H. pylori infection, NSAID use, and smoking. The use of NSAIDs in particular is associated with a high risk of complications from PUD (hemorrhage and perforation), and although the use of steroids alone is not considered a risk factor for peptic ulcer, the combined use of systemic steroids and NSAIDs carries a significant risk of ulcer complications. The most common presenting symptom of gastric or duodenal ulcer perforation is severe abdominal pain. The pain is sudden in onset and most severe in the epigastrium, but with time the pain may become more diffuse and radiate to the lower quadrants or be referred to the shoulders due to diaphragmatic irritation. Nausea and vomiting may occur, and 10% to 15% of patients present with concomitant gastrointestinal (GI) hemorrhage. A history of prior PUD can be elicited in 60% to 75% of patients.

On examination, patients may have a low-grade fever but are often afebrile. Tachycardia and tachypnea are common, and the abdomen is usually diffusely tender, with signs of peritonitis (guarding, rebound tenderness, or rigidity). Laboratory examination often reveals a mild leukocytosis. Serum amylase is generally normal but may be elevated above 200 Somogyi units in up to 15% of patients. Plain films of the chest and abdomen reveal free air under the diaphragm or on decubitus films in 70% of cases; patients should remain upright or in the decubitus position for 10 to 15 minutes before obtaining these films so that intraperitoneal air can percolate to the highest point. Contrast radiographs are usually unnecessary, but when the diagnosis is unclear, an upper GI series using water-soluble contrast may be helpful.

The treatment of a perforated peptic ulcer is surgical in approximately 95% of patients, and consultation with an experienced surgeon is essential, even if medical management is contemplated. Medical therapy may be considered in patients who meet these criteria: longstanding perforation (more than 24 hours), evidence of a contained perforation on contrast upper GI study, absence of peritoneal signs, and presence of a comorbid illness that significantly increases the risk of operative repair. These criteria apply only to perforated DUs; gastric ulcer perforation should always be managed surgically. Medical management consists of nasogastric suction, intravenous (IV) hydration, and the continuous IV infusion of an H₂RA or pantoprazole.

[edit] Gastric Outlet Obstruction

Gastric outlet obstruction is a common complication of PUD, with an incidence ranging from 6% to 21.5%. Effective antisecretory therapy for PUD has decreased the incidence of ulcer-induced obstruction. Case series before 1975 reported PUD as the most common cause of gastric outlet obstruction, whereas more recent studies demonstrate that gastric carcinoma has surpassed PUD as the leading cause of this syndrome. Patients with gastric outlet obstruction generally have a long history of peptic ulcer pain. The obstruction is marked by the onset of nausea and vomiting in about 90% of patients. Additional symptoms include early satiety, bloating, and a sense of fullness in the epigastrium. Patients report progressive weight loss if the obstruction develops slowly, but an acute presentation with dehydration and electrolyte disturbances can occur. Physical examination is remarkable for signs of weight loss and a succussion splash over the epigastrium while the abdomen is shaken from side to side. This sign is present in 25% to 49% of patients with outlet obstruction from any cause. The diagnosis can be confirmed with barium contrast radiography, which reveals a greatly dilated stomach and delayed emptying of contrast from the stomach. Endoscopy is recommended to visualize the gastric outlet and biopsy the obstructed region to look for malignancy.

Initial treatment of gastric outlet obstruction consists of nasogastric suction, IV hydration, antisecretory therapy, and depending on the patient's nutritional status, hyperalimentation. Once a diagnosis of an ulcer-induced benign obstruction is established, a treatment plan is made in consultation with both a gastroenterologist and a GI surgeon. Medical therapy alone may often relieve edema-related obstruction in the short term, although recurrence is common. More definitive therapy can be performed using endoscopic dilation of the stenotic region or a surgical drainage procedure.

[edit] GASTRITIS

Gastritis refers to inflammation of the gastric mucosa; it is a nonspecific lesion observed in a number of unrelated disorders. H. pylori is responsible for most episodes of gastritis. Acute inflammation with H. pylori causes gastric mucosal inflammation that is often asymptomatic but may be associated with mild epigastric discomfort. Persistent infection results in a chronic inflammatory state known as type B gastritis. Usually confined to the antrum, this inflammatory process may extend proximally with time to involve the body and fundus of the stomach as well. H. pylori gastritis may also progress to atrophic gastritis, which is associated with transformation into gastric adenocarcinoma in a minority of patients. The natural history of H. pylori also includes the development of lymphoproliferative diseases, such as T-cell-derived lymphoma and the rare low-grade, B-cell-derived MALT lymphoma (Fig. 102-5).

Figure 102-5 Schematic depiction of natural history of Helicobacter pylori infection. (Modified from Blaser MJ, Parsonett J:J Clin Invest 94:4, 1994.).

Other infectious agents may also cause acute gastritis, and most infections occur in immunocompromised hosts. Among patients with human immunodeficiency (HIV) disease, gastritis caused by herpes simplex virus (HSV) or cytomegalovirus (CMV) infection has been recognized, as has gastritis caused by mycobacterial infections and syphilis. In immunocompetent hosts, bacterial gastritis is uncommon but is often life threatening and associated with systemic sepsis; predominant organisms in these cases include Streptococcus, Staphylococcus, and enteric gram-negative rods. In all such patients, treatment consists of appropriate IV antimicrobial therapy, with gastric resection reserved for the most severe cases of bacterial gastritis.

Noninfectious gastritis accounts for most cases of chronic gastritis not attributable to H. pylori. The classic type A gastritis is characterized by involvement of the fundus and body, in contrast to the antral predominance of the type B lesion. Type A gastritis is considered autoimmune in origin because it is often associated with circulating antibodies to parietal cells or intrinsic factor and, in many cases, with frank pernicious anemia. This form of gastritis usually progresses to mucosal atrophy, resulting in decreased acid secretion and subsequent hypergastrinemia. Atrophic changes predispose to gastric carcinoma, whereas persistent high gastrin levels are associated with the development of carcinoid tumors.

Other types of chronic gastritis include the eosinophilic and lymphocytic gastritidies, as well as granulomatous gastritis from fungal, mycobacterial, or treponemal infection and rarely from gastric Crohn's disease or sarcoidosis.

[edit] NONULCER DYSPEPSIA

The term dyspepsia refers to a constellation of symptoms, including upper abdominal pain or discomfort, often accompanied by bloating, abdominal distention, nausea, or early satiety. Despite this vague definition, dyspepsia is a common problem, with a 14% to 26% prevalence. Up to 5% of office visits in general medical practice are for dyspeptic symptoms. The differential diagnosis of dyspepsia is similarto that of PUD, as detailed earlier. In addition, numerous medications cause dyspepsia, including NSAIDs, antibiotics (most often macrolides and metronidazole), estrogens, narcotics, and digitalis preparations. Certain systemic illnesses may also present with dyspepsia, including hyperthyroidism, hyperparathyroidism, and rheumatologic disorders.

In 40% to 60% of patients with dyspepsia, no organic cause is discovered, a condition known as functional (nonulcer)dyspepsia. The pathogenesis of this disorder is not well understood and may involve heightened visceral sensitivity to painful stimuli, abnormal gastric and duodenal motility, and psychologic factors. The role of H. pylori infection in nonulcer dyspepsia is controversial, but studies show no clear-cut relationship between H. pylori status and presence of dyspeptic symptoms (Fig. 102-6).^[2][3]

Figure 102-6 Results of two randomized, controlled trials for treatment of Helicobacter pylori (HP) infection in patients with nonulcer dyspepsia. (Data from Blum AL, Tallet NJ, O'Marain C, et al:N Engl J Med 339:1875, 1998; and McColl K, Murray L, El-Omar E, et al:N Engl J Med 339: 1869, 1998.)

The diagnostic evaluation of dyspepsia begins with a thorough history and physical examination, with particular attention to alarm symptoms and signs that necessitate prompt endoscopic examination. These include age over 45 years, weight loss, dysphagia, significant vomiting, a palpable epigastric mass, or guaiac-positive stools. The presence of any of these or the finding of iron deficiency anemia on laboratory examination is associated with a greater prevalence of structural disease (malignancy, PUD) and warrants early endoscopy.

Several strategies have been proposed for the evaluation of dyspepsia in patients younger than 45 without alarm symptoms. The American Gastroenterological Association^[4] proposes that dyspeptic patients first undergo serologic testing for H. pylori infection. Patients with documented infection are treated empirically; if symptoms fail to resolve within 4 to 8 weeks, endoscopy should be performed. In patients who are H. pylori negative, an empiric trial of an H₂RA or PPI or a prokinetic agent for 4 to 8 weeks is recommended, with endoscopy reserved for patients who fail to improve or who relapse after cessation of therapy. This strategy attempts to treat PUD (the cause of dyspepsia in 15% to 20% of patients) without invasive testing. However, the widespread use of antibiotics in dyspeptic patients infected with H. pylori, although often advocated, will likely hasten the development of antibiotic-resistant strains of H. pylori. In addition, H. pylori may be responsible for a smaller proportion of peptic ulcers than originally postulated, further decreasing the effectiveness of empiric treatment. Finally, as noted, the eradication of H. pylori improves dyspeptic symptoms in a minority of individuals, if at all (see Fig. 102-6). Thus alternative approaches have been recommended (Fig. 102-7).

Figure 102-7 Algorithm for evaluation and treatment of dyspepsia. H₂RA, Histamine receptor antagonist (H₂ blocker);EGD, esophagogastroduodenoscopy;UGI, upper gastrointestinal series.

Pharmacologic treatment of nonulcer dyspepsia is not well established, and clinical studies have been hampered by differing definitions of symptoms, small patient numbers, and high placebo response rates. Antisecretory agents (H₂RAs, PPIs) may improve dyspeptic symptoms in patients with 7 gt]]] refluxlike symptoms but not necessarily in those with other symptom complexes. Prokinetic agents, if available, may confer a benefit in dyspeptic patients, with response rates of 65% to 90% vs. 13% to 42% for placebo. Tricyclic antidepressants, effective in several pain syndromes, have not been adequately studied in dyspepsia. In Europe the opioid agonist fedotozine has been shown to be superior to placebo in treating dyspepsia, presumably by decreasing visceral sensitivity to painful stimuli; this agent is not currently available in the United States.

Since drug therapy is not reliably effective in treating nonulcer dyspepsia, the focus of treatment is a supportive physician-patient relationship. After ruling out structural disease and symptoms caused by medications or exogenous agents, the physician should explain to the patient that nonulcer dyspepsia is not psychosomatic but a real disorder likely related to abnormal pain sensitivity of the GI tract. Patients should be reassured that their illness is not life threatening, and the physician and patient should work together to develop a plan for symptomatic relief without multiple diagnostic tests. Stress management, tailoring of diet to avoid symptom-inducing foods, and attention to psychologic factors that may contribute to dyspepsia are important components of therapy. Pharmacologic agents are used with caution because placebo response rates are high and symptoms may recur over time; if a medication proves ineffective, the patient should switch to another agent, since “stacking” of medications is ineffective and costly.

[edit] REFERENCES

[edit] ADDITIONAL READINGS

• MJ Blaser, J Parsonnet: Parasitism by the “slow” bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J Clin Invest 1994; 94:4.
• W DeBoer, W Driessen, A Jansz, G Tytgat: Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet 1995; 345:817.
• M Feldman, ME Burton: Histamine₂-receptor antagonists: standard therapy for acid-peptic diseases. N Engl J Med 1990; 323:1672.
• L-E Hansson, O Nyren, AW Hsing,et al.: The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996; 335:242.
• CJ Hawkey, JA Karrasch, L Szczepanski,et al.: Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998; 338:727.
• D Jaspersen, T Koerner, W Schorr,et al.: Helicobacter pylori eradication reduces the rate of rebleeding in ulcer hemorrhage. Gastrointest Endosc. Ann Intern Med 1995; 41:5.
• DR Lichtenstein, S Syngal, MM Wolfe: Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract: the double-edged sword. Arthritis Rheum 1995; 38:5.
• NIH Consensus Conference: Helicobacter pylori in peptic ulcer disease. JAMA 1994; 272:65.
• JJ Ofman, J Etchason, S Fullerton,et al.: Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997; 126:280.
• J Parsonnet: Helicobacter pylori in the stomach: a paradox unmasked. N Engl J Med 1996; 335:278.
• JB Raskin, RH White, JE Jackson,et al.: Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug–induced gastric and duodenal ulcers: a comparison of three regimens. Ann Intern Med 1995; 123:344.
• T Rokkas, A Karameris, A Mavrogeorgis,et al.: Eradication of Helicobacter pylori reduces the possibility of rebleeding in peptic ulcer disease. Gastrointest Endosc 1995; 41:1.
• FE Silverstein, DY Graham, JR Senior,et al.: Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123:241.
• NJ Talley, MD Silverstein, L Agreus,et al.: AGA technical review: evaluation of dyspepsia. Gastroenterology 1998; 114:582.
• JJ Vicari, RM Peek, GW Falk,et al.: The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998; 115:50.
• JL Wallace: Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 1997; 112:1000.
• Wolfe MM Therapy of digestive disorders: a companion to Sleisenger and Fordtran's Gastrointestinal diseases. Philadelphia: Saunders; 2000:
• Wolfe MM Gastrointestinal pharmacotherapy. Philadelphia: Saunders; 1993:
• MM Wolfe, AH Soll: The physiology of gastric acid secretion. N Engl J Med 1988; 319:1707.
• MM Wolfe, DR Lichtenstein, G Singh: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999; 340:1888.
• ND Yeomans, Z Tulassay, L Juhasz,et al.: A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1998; 338:719.