Peptic Ulcer Diseases Part 2

Imaging studies

Although ulcer disease can be suggested by history, physical examination, and laboratory studies, none of these has sufficient specificity to confirm the diagnosis. Ulcers are diagnosed endo-scopically, radiologically, or surgically. Once an ulcer is diagnosed, additional studies can help in determining the cause of the ulcer (e.g., H. pylori infection, NSAID use, gastrinoma, or cancer masquerading as benign ulcer).

Endoscopy

Endoscopy is the most accurate way to diagnose a peptic ulcer [see Figure 3]. Most patients require local anesthesia of the pharynx and conscious sedation with an intravenous agent such as midazolam. The advantages of endoscopy are its nearly 100% specificity (rare false positives), greater than 90% sensitivity, portability (i.e., it can be performed in the intensive care unit, emergency department, or operating room), and ability to obtain tissue samples to help determine the etiology of the ulcer. The disadvantages of endoscopy are its cost and its potential for serious side effects. The most serious complications of en-doscopy are respiratory depression and perforation of the GI tract. When a bleeding or obstructing ulcer is suspected, the stomach should be intubated and emptied with a large-bore tube before endoscopy to decrease the possibility of bronchopul-monary aspiration of gastric contents and to facilitate endoscop-ic visualization of mucosal lesions. Endoscopy is contraindicat-ed in cases of suspected ulcer perforation.

Radiology

Despite having a lower sensitivity and specificity than en-doscopy, an upper GI series using barium and air (double contrast) may be favored by primary care physicians and patients over referral for endoscopy for suspected uncomplicated ulcer. An upper GI series offers lower cost, wider availability, and fewer complications [see Figure 3]. However, for troublesome and undiagnosed dyspepsia, an upper GI series may be superfluous, because a normal result will often necessitate endoscopy (endoscopy is more sensitive than radiography) and because an upper GI series showing a gastric ulcer will also necessitate en-doscopy for biopsy of the ulcer to exclude gastric malignancy. In many patients, only a finding of a duodenal bulbar ulcer on an upper GI series will preclude endoscopy [see Figure 4].

Plain films of the abdomen, abdominal sonography, and computed tomographic scans may be helpful in patients presenting with suspected complicated ulcers, particularly perforated or obstructing ulcers. Upright chest x-rays of a patient with a perforated ulcer may show free intraperitoneal air [see Figure 4b], typically beneath the right hemidiaphragm. When plain films are negative or equivocal, pneumoperitoneum may be diagnosed by abdominal sonography or CT scan. Such studies should be performed only if the diagnosis of perforation is unclear; if physical signs of peritonitis are obvious, the patient should be referred to a surgeon. Patients with gastric outlet obstruction may have an enlarged stomach with old food debris visible on plain film of the abdomen, upper GI series, abdominal sonography, or CT scan.

Surgical diagnosis

Certain patients will not have ulcers diagnosed until surgery is performed. Such patients include those presenting with an acute abdomen, in whom the diagnosis of perforated ulcer is made at exploratory laparotomy; those presenting with copious upper GI bleeding, in whom it is difficult for the endoscopist to visualize and treat the ulcer; and those with an obstructing ulcer who have a pinpoint pylorus or a duodenal stricture that prevents passage of the endoscope beyond the stenosis.

Tests to Establish the Etiology of the Ulcer

Endoscopic tests

The endoscopist can take a biopsy sample of the stomach of an ulcer patient to determine whether H. pylori organisms are present [see Figure 5]. H. pylori organisms contain abundant amounts of urease, which splits urea into carbon dioxide and ammonia. If the biopsy sample is placed on a urea-containing medium that also contains a pH-sensitive dye, a change in color indicates that ammonia is being produced. This so-called rapid urease test has a high sensitivity and specificity (> 90%) for H. pylori. If the rapid urease test is negative, a separate biopsy specimen should be sent to a pathology laboratory in formalin for histology. H. pylori can be detected with routine hematoxylin and eosin stains [see Figure 5] or, if necessary, by special stains. Moreover, the presence of diffuse, active, chronic gastritis is highly suggestive of H. pylori infection, and its absence excludes H. pylori infection.

Another useful endoscopic procedure is to obtain multiple biopsies from the edges and the base of the ulcer to exclude malignancy. This is routinely done in cases of gastric ulcer because 2% to 4% of benign-appearing gastric ulcers are in actuality an ulcer within a malignancy, usually an adenocarcinoma. Duodenal ulcers need not be biopsied unless the ulcer is located in a mass distal to the duodenal bulb.

Endoscopy may also demonstrate a neuroendocrine tumor, compatible with a gastrinoma on special stains. Such a tumor is usually located in the proximal duodenum.

In an ulcer patient with a negative rapid urease test and no H. pylori-related gastritis or gastric malignancy on histology, further history regarding NSAID use should be obtained from the patient or the patient’s family. Many patients with NSAID-relat-ed ulcers have erosions, subepithelial hemorrhages, or both, which clue the endoscopist to the possibility of occult or surreptitious NSAID use; these lesions may occur with or without gastric or duodenal ulcers.7

Serologic tests

A number of serum antibody tests for H. pylori are available that have a greater than 90% sensitivity and specificity if the patient has not yet received therapy for H. pylori.17 In patients with active ulcers diagnosed by radiology or surgery in whom gastric tissue is not available, H. pylori serology can confirm infection with high accuracy [see Figure 3].

In ulcer patients with no evidence of H. pylori infection or NSAID use, the fasting serum gastrin concentration should be measured [see Figure 3] to screen for gastrinoma (Zollinger-Elli-son syndrome). If the serum gastrin concentration is greater than 1,000 pg/ml in a patient with duodenal ulcer, the diagnosis of gastrinoma is confirmed. A modest elevation in fasting serum gastrin concentration (> 150 pg/ml but < 1,000 pg/ml) is suggestive of gastrinoma, but a provocative test should be performed using intravenous secretin (2 IU/kg as a bolus).18 A rise in serum gastrin concentration of more than 200 pg/ml after se-cretin administration has a greater than 90% sensitivity and specificity for gastrinoma. Because achlorhydria can produce marked hypergastrinemia as a result of the loss of negative feedback of gastric acid on gastrin release, basal acid output or pH should be measured to confirm that the stomach secretes acid in ulcer patients with fasting hypergastrinemia. The combination of achlorhydria, hypergastrinemia, and duodenal ulcer is exceedingly rare, whereas the combination of achlorhydria, hyper-gastrinemia, and gastric ulcer is sometimes encountered and should suggest gastric adenocarcinoma or NSAID use. A fasting gastric pH measurement will almost invariably distinguish gas-trinoma (pH 1 to 2) from achlorhydria (pH 6 to 8), unless the pa- tient has received a potent acid antisecretory agent before pH measurement.

Figure 5 Gastric biopsy samples stained with hematoxylin and eosin demonstrating (a) chronic active gastritis with a few H. pylori organisms faintly seen in the lumen of a gland and (b) chronic active gastritis with H. pylori organisms more abundant.

Table 1 Differential Diagnosis of Peptic Ulcer Disease

Presentation	Diagnosis
Suspected uncomplicated ulcer	Nonulcer dyspepsia, gastroesophageal reflux, biliary colic, pancreatic disease, angina pec-toris, gastric cancer
Bleeding ulcer	Varices, Mallory-Weiss tear, esophagitis, vascular lesion (arteriovenous malformation, Dieulafoy lesion, angiodysplasia)
Perforated ulcer	Appendicitis, pancreatitis, cholecystitis, spontaneous bacterial peritonitis, bowel ischemia or infarction, diverticulitis
Penetrating ulcer	Pancreatitis, muscle strain, herniated vertebral disk, ureteral stone
Fistulizing ulcer	Gallstones, GI malignancy, Crohn disease, intra-abdominal abscess

Measurement of serum thromboxane B2 (platelet COX-1 activity) has been used in research laboratories to demonstrate occult or surreptitious NSAID use.19 However, this assay is not widely available.

Breath tests

A noninvasive method for detecting H. pylori in the stomach, the urea breath test, begins with oral ingestion of urea that has been labeled with carbon-13 (13C) or carbon-14 (14C). If H. pylori, with its abundant urease, is present in the stomach, the labeled urea will be rapidly converted to 13CO2 or 14CO2, which can be detected in breath samples collected during the first 30 to 60 minutes after urea ingestion. Sensitivity and specificity of the breath test are comparable to those of serology.16 In a patient for whom there is no clinical indication for endoscopy, a urea breath test is an alternative to serology for documenting H. pylori infection [see Figure 3]. However, because proton pump inhibitors can suppress H. pylori without eradicating it, use of these drugs should be avoided for 2 weeks before the urea breath test is administered, to minimize false negative results.

Because serology is quicker, it is preferred to breath testing for initial diagnosis. Breath testing is more useful than serology in diagnosing failure of eradication of H. pylori or reinfection in patients who were previously treated for H. pylori infection, because the serology will usually remain positive for several months even after successful treatment.20

Fecal antigen test

Stool testing for H. pylori antigen compares favorably with urea breath tests.21 Like breath testing, stool testing can distinguish current infection (antigen present in stool) from past infection (antigen not present in stool).

Differential Diagnosis

The most common disorder confused with uncomplicated peptic ulcer is nonulcer dyspepsia; the most serious GI disorder confused with uncomplicated peptic ulcer is gastric cancer [see 12:VIPancreatic, Gastric, and Other Gastrointestinal Cancers].

Nonulcer, or functional, dyspepsia is a symptom complex similar to that experienced by patients with peptic ulcers. However, no ulcers or other lesions are visible on endoscopy. Nonul-cer dyspepsia is a heterogeneous, poorly understood group of disorders. H. pylori gastritis probably causes dyspepsia in a few of these patients, and many physicians treat all dyspeptic patients who are infected with H. pylori. The cost-effectiveness of this approach has not been established, however; studies show that eradication of H. pylori is unlikely to relieve symptoms of nonulcer dyspepsia.22-24 Many patients with nonulcer dyspepsia appear to suffer from a dysmotility of the upper GI tract that is akin to irritable bowel syndrome of the lower GI tract. Such individuals may complain of abdominal fullness, postprandial bloating, early satiety, and nausea, all suggestive of delayed gastric emptying. In some of these patients, gastric prokinetic agents such as domperidone or metoclopramide may help relieve symptoms.

Complicated ulcers may be confused with a variety of disorders. These include both intra-abdominal and musculoskeletal processes [see Table 1].

Treatment

The goals of ulcer therapy are rapid relief of symptoms; healing the ulcer; preventing ulcer recurrences; and reducing ulcer-related complications, morbidity (including the need for endo-scopic therapy or surgery), and mortality. The general strategy in a patient with an ulcer should be to treat complications aggressively if present; to determine the etiology of the ulcer; to discontinue NSAID use if possible; to eradicate H. pylori infection if present or strongly suspected, even if other risk factors (e.g., NSAID use) are also present; and to use acid antisecretory therapy to heal the ulcer if H. pylori infection is not present. Smoking cessation should be encouraged. If duodenal ulcer is diagnosed by endoscopy, rapid urease testing of endoscopically obtained gastric biopsy samples, with or without histologic examination, should reliably establish the presence or absence of H. pylori. If duodenal ulcer is diagnosed by x-ray, then a serolog-ic, urea breath, or fecal antigen test to diagnose H. pylori infection is recommended before treating the patient for H. pylori.

Treatment of uncomplicated duodenal ulcers

H. pylori-Related Duodenal Ulcer

Duodenal ulcer associated with H. pylori infection should be treated with antimicrobial therapy because successful therapy is associated with markedly reduced ulcer recurrences [see Figure 6]4,5 Antimicrobial therapy is usually empirical rather than based on results of culture and in vitro antimicrobial sensitivity testing. No single antimicrobial agent has an acceptably high success rate against H. pylori. Combinations of antimicrobial agents are required, and some regimens that have been approved by the Food and Drug Administration can be recommended [see Table 2].

H. pylori has adapted to the acidic stomach, and potent acid antisecretory agents facilitate eradication of H. pylori by antimicrobial agents. Bismuth compounds, like proton pump inhibitors, suppress the growth of H. pylori but usually do not by themselves eradicate it from the stomach. For this reason, they are frequently employed together with antibiotics.

Antimicrobial agents with activity against H. pylori include metronidazole, tetracycline, amoxicillin, and clarithromycin. Most popular are 10- to 14-day regimens, although 7-day courses may be effective and are especially favored in Europe. A 2-week course of a three-drug regimen that includes a proton pump inhibitor, clarithromycin, and amoxicillin has a success rate approaching 90%. The major causes of treatment failure are poor compliance with the regimen and clarithromycin resistance; the latter occurs in around 10% of current strains and is increasing with more macrolide use in the population. Metronidazole resistance occurs in 30% to 40% of strains. However, unlike resistance to clarithromycin, which is usually absolute, resistance to metronidazole is relative and can be overcome in some patients.

Figure 6 Approach to treatment and follow-up of a patient with an uncomplicated duodenal or gastric ulcer.

If a patient carefully complies with one of the clarithromycin-based regimens yet the treatment fails, clarithromycin resistance is likely. In such cases, the retreatment regimen should not include clarithromycin. Most physicians choose a regimen consisting of metronidazole, tetracycline, bismuth (e.g., Pepto Bismol), and a proton pump inhibitor or H2 receptor blocker. Because of the frequency of metronidazole resistance, other antimicrobials with activity against H. pylori are being used more often.25-28 These agents include azithromycin, the quinolones norfloxacin and levofloxacin, and rifabutin [see Table 3]. In one study, a 7-day rescue treatment for persistent H. pylori infection using the proton pump inhibitor rabeprazole plus rifabutin and levo-floxacin had a 95% success rate, as did a four-drug regimen consisting of rabeprazole, bismuth subcitrate, metronidazole, and tetracycline.29

It may also be possible to predict resistance to clarithromycin or to metronidazole by taking a careful history to look for prior exposure to these drugs. Such a history might help the physician choose a first-line regimen that will be more likely to be successful.

Side effects of H. pylori-directed therapy are not uncommon but are generally mild. Physicians should be aware of potential drug-drug interactions if the patient is receiving other medications. If the patient has an active, symptomatic ulcer, an antise-cretory drug should be continued at a reduced (standard) dosage for 2 to 5 weeks after completion of antimicrobial agents.

After a patient has completed a course of ulcer therapy for an H. pylori-related uncomplicated duodenal ulcer, it is acceptable to follow the patient clinically without confirming eradication, because most compliant patients will be successfully cured of their H. pylori infection [see Figure 6]. A patient with an H. pylori-related duodenal ulcer that does not recur symptomatically within 2 years after antimicrobial therapy is probably cured. Serology has often reverted to negative by this time.20

Table 2 Selected Clarithromycin-Based Regimens to Eradicate Helicobacter pylori

Esomeprazole, amoxicillin, clarithromycin (EAC)

Esomeprazole, 40 mg b.i.d. for 10 days; then 40 mg q.d. for 18 days if an active ulcer is present

Amoxicillin, 1 g b.i.d. for 10 days

Clarithromycin, 500 mg b.i.d. or t.i.d. for 10 days

Lansoprazole, amoxicillin, clarithromycin (LAC)

Lansoprazole, 30 mg b.i.d. for 10-14 days; then 15 mg q.d. for 14-18 days if an active ulcer is present

Amoxicillin, 1 g b.i.d. for 10-14 days Clarithromycin, 500 mg b.i.d. for 10-14 days

Omeprazole, amoxicillin, clarithromycin (OAC)

Omeprazole, 20 mg b.i.d. for 10 days; then 20 mg q.d. for

18 days if an active ulcer is present

Amoxicillin, 1 g b.i.d. for 10-14 days

Clarithromycin, 500 mg b.i.d. for 10 days

Rabeprazole, amoxicillin, clarithromycin (RAC)

Rabeprazole, 20 mg b.i.d. for 7 days; then 20 mg q.d. for 21 days if an active ulcer is present Amoxicillin, 1 g b.i.d. for 7 days

Clarithromycin, 500 mg b.i.d. for 7 days

Table 3 Additional Antimicrobial Agents with Activity against Helicobacter pylori

Agent*	Dosage	Comments
Azithromycin	500 mg q.d.	Combined with either amoxicillin or metronidazole, plus a proton pump inhibitor, for 3-7 days
Norfloxacin	400 mg b.i.d.	Combined with a proton pump inhibitor for 14 days
Levofloxacin	500 mg q.d.	Combined with either amoxicillin or metronidazole, plus a proton pump inhibitor, for 7 days
Rifabutin	300 mg q.d.	Combined with amoxicillin and a proton pump inhibitor for 7-10 days

Those in whom recurrent ulcer symptoms develop during the first 2 years after therapy should be assessed either by en-doscopy (for ulcer recurrence and for H. pylori persistence or reinfection) or by a urea breath test or fecal antigen test. The most common cause of recurrent ulceration in patients treated for H. pylori-related duodenal ulcer is failure to eradicate the organism. Retreatment of these patients is indicated [see Treatment of Intractable Duodenal Ulcers or Gastric Ulcers, below]. Rarer causes of duodenal ulcer recurrence include an acid hypersecre-tory state (e.g., Zollinger-Ellison syndrome), NSAID use, and reinfection with H. pylori.

H. pylori-Negative Duodenal Ulcer

In a duodenal ulcer patient who is H. pylori negative, the physician should consider NSAID use and gastrinoma (Zollinger-Ellison syndrome).30 Patients with duodenal ulcer who are taking NSAIDs should discontinue the NSAID, if possible. At the same time, an acid antisecretory drug should be administered for 4 to 8 weeks [see Table 4]. The anticipated healing rate with this regimen is 85% to 95%.

Table 4 FDA-Approved Antisecretory Drugs for Active Peptic Ulcer Disease*

Class	Drugs	Dosage	Drug Interactionst
H receptor blockers1	Cimetidine	800 mg h.s. or 400 mg b.i.d.	Warfarin, theophylline, phenytoin, benzodiazepines, itraconazole, ketoconazole, atazanavir, cefpodoxime, cefditoren, gefitinib, memantine, metformin, and many others
	Ranitidine	300 mg h.s. or 150 mg b.i.d.	Warfarin, atazanavir, itraconazole, ketoconazole, cefpodoxime, cefditoren, enoxacin, gefitinib, memantine, metformin, tolazoline
	Nizatidine	300 mg h.s. or 150 mg b.i.d.	Atazanavir, itraconazole, ketoconazole, cefpodoxime, cefditoren
	Famotidine	40 mg h.s. or 20 mg b.i.d.	Atazanavir, itraconazole, ketoconazole, cefpodoxime, cefditoren
Proton pump inhibitors6	Omeprazole	20 mg q.d., a.c.	Benzodiazepines, ampicillin, atazanavir, digoxin, iron, itracona-zole, ketoconazole, voriconazole, methotrexate, tacrolimus
	Lansoprazole	15 mg q.d., a.c.	Ampicillin, atazanavir, digoxin, iron, itraconazole, ketoconazole
	Esomeprazole	40 mg q.d., a.c.	Atazanavir, digoxin, iron, ketoconazole
	Rabeprazole	20 mg q.d., a.c.	Warfarin, ampicillin, atazanavir, digoxin, iron, itraconazole, ketoconazole
	Pantoprazole	40 mg q.d., a.c.	Ampicillin, atazanavir, iron, itraconazole, ketoconazole

*Patients with gastrinoma (Zollinger-Ellison syndrome) will usually require much higher dosages of antisecretory drugs than listed here.

^Use for 4-8 wk in the treatment of duodenal ulcer and 6-12 wk in the treatment of gastric ulcer. Duodenal ulcers that do not heal by 8 wk and gastric ulcers that do not heal by 12 wk are considered intractable. Dosage of H2 receptor blockers should be reduced in patients with renal failure.

tMicromedex Health Care Services. Most of these drug interactions are minor and not clinically relevant; nevertheless, caution is advised.

Table 5 Treatment and Prevention of Peptic Ulcers

Type of Ulcer	Treatment	Prevention	Comments
Helicobacter pylori-related ulcers	Antibiotics [see Tables 2 and 3] ± antisecretory agents [see Table 4]	None needed if H. pylori eradicated	Highly cost-effective; document healing in gastric ulcer; document H. pylori eradication in complicated duodenal or gastric ulcer and in intractable duodenal or gastric ulcer
NSAID-related ulcers	Antisecretory agents (proton pump inhibitors have greater efficacy than H2 receptor blockers) [see Table 4] Discontinue NSAID use, if possible	Misoprostol (600-800 ^g/day) or proton pump inhibitor (e.g., omeprazole, 20-40 mg q.d., or lansoprazole, 15-30 mg q.d.) along with an NSAID	Diarrhea may limit compliance in patients treated with misoprostol; avoid misoprostol during pregnancy (abortifacient); proton pump inhibitors are not yet approved by the FDA for prevention of NSAID-related ulcers
Ulcers associated with Zollinger-Ellison syndrome and other hypersecretory states	High-dose proton pump inhibitor	Proton pump inhibitor, adjusted to keep basal acid output < 5-10 mEq/hr	Consider exploratory laparotomy (guided by abdominal imaging studies) to remove easily resectable gastrinomas, if feasible; consider MEN I syndrome (present in 20%-30% of cases)21
Idiopathic ulcers	H2 receptor blocker or proton pump inhibitor	Nocturnal H2 receptor blocker or A.M. proton pump inhibitor	Parietal cell vagotomy for intractable duodenal ulcer and antrectomy for intractable gastric ulcer
Stress ulcers (ICU)	I.V. H2 receptor blocker or proton pump inhibitor (e.g., pantoprazole) ?Angiography ?Surgery	I.V. H2 receptor blocker or proton pump inhibitor; intragastric sucralfate; or intragastric antacid	Maintain pH above 4 with H2 receptor blocker, proton pump inhibitor or antacid; continuous I.V. infusion is superior to I.V. boluses of antise-cretory drug
Cameron ulcers (linear gastric erosions in a hiatal hernia)	Iron salts; packed red cell transfusions; endoscopic hemostasis ?Angiography ?Surgery	Hiatal hernia repair, laparoscop-ic or open	Roles of H2 receptor blockers and proton pump inhibitors are unproved

MEN I—multiple endocrine neoplasia type

NSAID—nonsteroidal anti-inflammatory drug

Patients with duodenal ulcer as part of the Zollinger-Ellison syndrome should be managed initially with a high dose of a proton pump inhibitor, followed by a maintenance dose guided by gastric acid measurements. If there is no evidence of hepatic metastasis on abdominal CT scan, then exploratory laparotomy for gastrinoma resection, with or without parietal cell vagotomy, is warranted.31 Radionuclide scintigraphy with octreotide, an analogue of somatostatin, is a highly sensitive and specific pre-operative test for detecting and staging gastrinoma, as is endo-scopic ultrasonography.

The vast majority of duodenal ulcers, regardless of cause, heal after 8 weeks of antisecretory therapy with a proton pump inhibitor or an H2 receptor blocker. Antacids are often prescribed as needed to relieve ulcer symptoms.

In rare cases of idiopathic duodenal ulcer, it is prudent that, after the ulcer has been healed by an acid antisecretory agent, the patient be placed on a maintenance dose of an H2 receptor blocker given at bedtime to reduce ulcer recurrences. Proton pump inhibitors are also effective in preventing duodenal ulcer recurrences. It is not necessary to confirm duodenal ulcer healing by endoscopy or x-ray before reducing the antisecretory drug dose to a maintenance level.