Gastroenterology Hepatology

Peptic ulcer disease

How can I be sure that the patient has peptic ulcer disease?

Presenting symptoms of peptic ulcer disease

Peptic ulcer disease (PUD) typically presents with intermittent episodes of nonradiating epigastric abdominal pain (dyspepsia), which is often described as dull or "gnawing." Unfortunately, the pain associated with PUD is mimicked by other common disorders, including biliary colic, pancreatitis, non-ulcer dyspepsia, and gastric/pancreatic malignancy, making clinical features alone insufficient to confirm a diagnosis of PUD. Cardiac ischemia, especially in the inferior myocardium, may present with epigastic pain that is similar to PUD. Nocturnal pain and pain relief with antacids have also been linked to PUD, but these features are also seen with gastroesophageal reflux disease (GERD) and other disorders. Classically, response to food intake has been used to predict the location of an ulcer, with duodenal ulcer pain improving after a meal and gastric ulcer worsening, but these features do not distinguish ulcer location with any degree of certainty. Physical examination is also not diagnostic; patients with PUD may have epigastric tenderness, but this finding is neither sensitive nor specific. Given the lack of clear diagnostic features, the presence of epigastric pain in the proper clinical setting (nonsteroidal anti-inflammatory drug use, high community prevalence of Helicobacter pylori infection) should spur the performance of more definitive diagnostic testing for PUD or the initiation of empiric therapy.

Symptoms of complicated peptic ulcer disease

Although epigastric pain is the cardinal symptom of ulcer, other symptoms may occur when PUD becomes complicated. Melena or hematemesis, indicative of upper gastrointestinal (GI) hemorrhage, is a common finding in a bleeding peptic ulcer, and a slowly bleeding ulcer may present with iron deficiency anemia and/or guaiac positive stools. Pyloric channel or, occasionally, duodenal ulcers may cause gastric outlet obstruction, with patients presenting with early satiety, episodic nausea and vomiting, and, possibly, weight loss, all of which may mimic malignancy. In cases of ulcer perforation, patients typically present with an acute abdomen and signs and symptoms of peritonitis.

A tabular or chart listing of features and signs and symptoms

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How can I confirm the diagnosis?

Evaluation of the patient with dyspepsia

When PUD is suspected, the physician must decide whether to treat the patient empirically or to pursue a definitive diagnosis. A definitive diagnosis for dyspepsia should be pursued if the patient manifests any "alarm features" that may portend the presence of malignancy; these include age above 45 years, weight loss, overt GI bleeding or occult GI blood loss, anemia, dysphagia, recurrent vomiting, or a family history of GI cancer. Moreover, the presence of severe pain may warrant a more thorough evaluation.

If a patient with dyspepsia does not manifest any of these worrisome features, then current guidelines recommend a strategy known as "test-and-treat." In this schema, the patient is tested for Helicobacter pylori (H. pylori) infection, and if positive, the infection is treated (see below). If symptoms resolve, no further evaluation is generally needed.

Persistent symptoms after treatment implies that H. pylori-associated PUD was not necessarily the cause of the patient's dyspepsia, and it is recommended at this point that additional diagnostic testing be performed. This strategy, while effective, is not without risk. The majority of patients with dyspepsia (75-85%) do not have a peptic ulcer, and because only approximately 10% of patients with H. pylori infection develop ulcer disease, the presence of the organism does not provide definite evidence that the patient's symptoms are due to infection.

Non-ulcer dyspepsia itself may be due to numerous other disease entities in addition to H. pylori infection, including functional disorders, and H. pylori treatment does not reliably improve symptoms. Thus, many patients with H. pylori infection will be treated but will have no symptomatic improvement. Moreover, the widespread use of antibiotics in patients with dyspepsia will undoubtedly increase resistance of H. pylori and other pathogens to current antibiotic therapies.

An alternative approach to a patient with dyspepsia and no alarm symptoms is to treat empirically with antisecretory therapy for 4 to 8 weeks. If symptoms do not improve, further diagnostic evaluation would then be recommended. However, if the patient responds to therapy, he or she can then be evaluated for H. pylori infection and requestioned regarding nonsteroidal anti-inflammatory drug (NSAID) use. If symptoms recur after the discontinuation of therapy and treatment of ulcer risk factors, the patient may have atypical GERD, which will require long-term antisecretory therapy.

Making a definitive diagnosis of PUD

If the diagnosis of PUD is to be made definitively, imaging of the stomach and duodenum is necessary. Although barium upper GI series may demonstrate an ulcer, the most definitive diagnostic test is upper endoscopy (esophagogastroduodenoscopy, or EGD), which allows visualization of an ulcer, as well as biopsy, if indicated.

When a duodenal ulcer is found at endoscopy, the ulcer itself does not need to be biopsied, as the risk of malignancy is extremely low. However, biopsies should typically be obtained from the gastric antrum (and at times the proximal stomach) to look for H. pylori infection, a common cause of PUD. Gastric ulcers, in contrast, carry a small but significant risk of malignancy, and cytology and biopsies of the ulcer itself is recommended. Typically, the ulcer and surrounding area are sampled for cytology, and a minimum of six biopsy specimens should be obtained from the edge of the ulcer crater.

What other diseases, conditions, or complications should I look for in patients with peptic ulcer disease?

Risk factors for PUD

The major risk factors for peptic ulcer include the use of NSAIDS and infection with H. pylori. Less commonly, peptic ulcer may be a manifestation of the Zollinger-Ellison Syndrome (ZES) due to a gastrin-secreting tumor. Although most individuals with ZES present with symptoms similar to "ordinary" peptic ulcer, the diagnosis should be suspected in patients with peptic ulcer (especially multiple duodenal ulcers), accompanied by chronic diarrhea and/or severe GERD, and in patients with manifestations of the MEN-1 syndrome.

Gastric ulcer may be associated with adenocarcinoma, signet ring carcinoma, leiomyosarcoma, lymphoma, and other neoplasms. Rarer causes of gastric ulcer include Crohn's disease (which manifests in the stomach or duodenum in <5% of cases), sarcoidosis, eosinophilic gastritis, fungal infections, secondary syphilis, and tuberculosis. The risk of an infectious etiology for gastric ulcer is significantly increased in immunocompromised patients (HIV, post-transplant).

Complications of PUD

The most common complication of PUD is upper GI hemorrhage; other complications include perforation and gastric outlet obstruction, both of which are far less prevalent than hemorrhage.

If perforation is suspected (in a patient with severe diffuse abdominal pain and peritoneal signs on exam), evidence of pneumoperitoneum should be sought with an upright chest or abdominal X-rays; if these are negative and suspicion is still high, a CT scan can demonstrate small amounts of free air in the peritoneum. A gastrograffin UGI radiograph can also demonstrate perforation, but this test is rarely used at present.

If gastric outlet obstruction is suspected (in a patient with nausea, vomiting, and abdominal distension), an abdominal radiograph or CT may demonstrate a dilated stomach, and the latter may also show peripyloric thickening or inflammatory changes.

During endoscopy, obstruction may be diagnosed by the presence of a dilated stomach with retained food or liquid and a pyloric or duodenal ulcer with edema and inflammation-causing luminal narrowing.

List of complications of PUD

– Upper gastrointestinal hemorrhage

– Gastric outlet obstruction

– Gastric or duodenal perforation

What is the right therapy for the patient with peptic ulcer disease?

Treatment of uncomplicated peptic ulcer disease consists of antisecretory therapy to reduce gastric acidity and promote healing, combined with a removal of the inciting factor(s) responsible for promoting ulcer formation (most commonly, NSAID use and/or H. pylori infection).

Treatment options for PUD

– Antisecretory therapy

H2-receptor antagonists

Proton Pump Inhibitors

– Gastroprotective therapies (second-line agents)

Sucralfate

Misoprostol

– Treatment of H. pylori infection

– Avoidance of NSAIDs

What is the most effective initial therapy?

First-line therapy for PUD

Antisecretory therapy for the treatment of PUD includes H2-receptor antagonists (H2RA) and proton pump inhibitors (PPIs). Both classes of medication are approximately 80% to 90% effective at healing peptic ulcers, although PPIs heal ulcers more rapidly and more effectively. Hence, they are considered the antisecretory drugs of choice for treating peptic ulcers.

The administration of a PPI taken before breakfast represents the optimal medical regimen for treating PUD. It is recommended that duodenal ulcers receive 4 to 8 weeks of antisecretory therapy, while gastric ulcers should be treated for 8 to 12 weeks. Recommended daily doses are as follows: omeprazole 20 mg, pantoprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, esomeprazole 40 mg before breakfast.

Alternative therapies for healing peptic ulcer disease

For the very rare patient who cannot tolerate H2RA or PPI therapy, another option for healing peptic ulcer disease is sucralfate at a dose of 1 gram taken 4 times daily, 30 minutes before meals and at bedtime. This medication does not inhibit acid secretion, but it serves to improve gastric mucosal defense by several proposed mechanisms, including the formation of a gel layer over the ulcer, preventing further damage by acid and pepsin.

Prostaglandin analogues, such as misoprostol (200 mg 4 times daily) are also effective at healing ulcers, but the high incidence of diarrhea and their abortifacient properties, as side effects, make this a less useful therapy for PUD.

Additional measures to prevent ulcer recurrence

Prevention of ulcer recurrence

Healing of a peptic ulcer with antisecretory therapy is essential; however, it is equally important to address the factors responsible for the development of the ulcer because recurrence after healing is extremely common (50-80% annual risk).

All patients with PUD should be tested for H. pylori infection, as eradication of infection markedly reduces ulcer recurrence. Acceptable tests for diagnosis of H. pylori include serum antibody testing, urea breath testing, and stool antigen testing. Additionally, when an ulcer is diagnosed during endoscopy, biopsies of the gastric mucosa should be obtained and tested for the presence of H. pylori, either by direct pathologic examination or by using a rapid urease test.

When H. pylori infection is confirmed, therapy aimed at eradication consists of two antibiotics and a PPI for 10 to 14 days. Commonly used regimens are listed below. Note that the choice of amoxicillin versus metronidazole should be made after considering the rate of metronidazole resistance in the community (in addition to any patient allergies).

FDA-approved regimens to treat H. pylori infection

– PPI (omeprazole 20 mg, lansoprazole 30 mg, esomeprazole 40 mg, rabeprazole 20 mg)

– Clarithromycin 500 mg

– Amoxicillin 1 g

All medication to be given twice daily before breakfast and dinner.

– PPI (omeprazole 20 mg, lansoprazole 30 mg, esomeprazole 40 mg, rabeprazole 20 mg)

– Clarithromycin 500 mg

– Metronidazole 500 mg

All medication to be given twice daily before breakfast and dinner.

– Bismuth subsalicylate 525 mg

– Metronidazole 250 mg

– Tetracycline 500 mg

All medication given 4 times daily, in addition to either ranitidine 150mg twice daily or standard dose PPI twice daily.

The other common cause of PUD is the use of NSAIDs, including aspirin. Fifteen to twenty percent of chronic NSAID users develop PUD, and the relative risk of ulcer complications with NSAID use is nearly 4.0, whereas the risk associated with regular aspirin use (including low-dose) is approximately 2 to 4 (times normal). Several risk factors for PUD in NSAID users have been identified. If NSAID therapy can be discontinued, it is recommended that the patient do so to prevent ulcer recurrence.

If NSAID therapy is essential, concomitant antisecretory therapy should be administered, typically with a daily dose of PPI; the use of PPIs rather than H2RAs is based on studies demonstrating far superior healing and symptom control with PPIs in patients with NSAID-induced ulcers. Alternatively, the prostaglandin analogue misoprostol may be used in an effort to improve mucosal protection.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What if therapy fails to heal PUD?

If appropriate antisecretory therapy fails to heal a peptic ulcer, the first step should be determination of compliance with the medical regimen. In particular, PPI therapy is most effective when taken before the first meal of the day, since H+, K+-ATPase (proton pumps) in the stomach need to be activated before PPIs can effectively inhibit gastric acid secretion. Thus, taking a PPI at bedtime or several hours before or after eating will be much less effective and may lead to inadequate healing. If therapy is appropriate, refractory peptic ulcer requires further work-up.

The possibility of Zollinger-Ellison syndrome (ZES) should be considered, and a fasting gastrin level (off PPI therapy ideally for 10-14 days) should be obtained. An elevated fasting serum gastrin level should raise suspicion for the possibility of gastrinoma, with a level above 1000 pg/mL diagnostic for ZES. However, because the most common cause of hypergastrinemia is achlorhydria, it is imperative that a determination be made that the patient does indeed secrete gastric acid. If the fasting serum gastrin level is elevated but not diagnostic, provocative testing using the secretin injection test should be performed after achlorhydria is excluded.

The diagnosis of ZES should prompt further investigation for tumor localization with somatostatin receptor scintigraphy (octreotide scanning) the initial test of choice. If a gastric ulcer is not healing, it is necessary to rule out malignancy with cytology and extensive biopsies of the lesion. These tests will also enable the detection of the "nonpeptic" causes of ulcer (infection, granulomatous diseases, etc.) described earlier.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

Common side effects of PUD therapy

H2RAs are generally very safe and well tolerated, and with the exception of cimetidine, the drugs in this class have minimal interactions with other medications.

PPIs are also generally safe and well tolerated, but uncommon side effects include headache, diarrhea, and nausea. Since PPI therapy for PUD is usually time-limited, longer-term effects on bone density and risk of infection are not seen.

Because of possible interactions with clopidogrel (discussed below), the use of an H2RA in place of a PPI may be preferred for the initial treatment of PUD.

Long-term effects of maintenance antisecretory therapy to prevent PUD recurrence

If a patient is to be on maintenance PPI therapy (in the setting of continued NSAID use), possible long-term side effects of PPI therapy should be considered.

Recent studies have reported an interaction between PPIs and clopidogrel, a commonly used antiplatelet agent, with three trials showing an increased risk of adverse cardiovascular events in patients taking dual therapy. However, five other studies failed to show this association. A prospective randomized, controlled trial showed no difference in adverse events, but this study was terminated before reaching the predicted sample size. It should be noted that all these studies showed a significant decrease in GI bleeding when PPI therapy was used with antiplatelet therapy. Clearly, the risk-benefit ratio must be balanced for each patient when deciding whether to add PPI therapy to a patient's regimen.

PPI therapy has also been associated with an increased risk of osteoporotic fractures, but studies assessing the risk of this complication have likewise been conflicting. It appears that PPIs do increase the possibility of fracture in patients with other risk factors, but not in all patients.

A modest increased risk for both community-acquired and hospital-acquired pneumonia has been reported in patients on long-term PPI therapy, and a moderately increased risk of Clostridium difficile infection has been demonstrated as well. Conversely, there is little evidence that PPI use is associated with clinically relevant iron or vitamin B12 deficiency.

Given these possible adverse outcomes, the use of long-term PPI therapy should not constitute an "automatic" response to dyspepsia or abdominal complaints; rather, careful consideration weighing the risks and benefits by physicians and patients together should guide the use of these medications.

Listing of these, including any guidelines for monitoring side effects.

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How should I monitor the patient with peptic ulcer disease?

Monitoring the patient after treatment of PUD

As discussed above, peptic ulcer healing is readily achieved using antisecretory therapy, and the eradication of H. pylori and prophylaxis against NSAID-induced ulcers reduces ulcer recurrence.

Duodenal ulcers do not require monitoring after therapy if symptoms resolve completely, as the risk of malignancy is extremely low. Gastric ulcers, however, are associated with a small but significant risk of harboring malignancy, and a repeat endoscopy is recommended 8 to 12 weeks after therapy to assess ulcer healing. If the ulcer has healed completely, no further monitoring is needed. However, if the ulcer persists, it needs to be biopsied aggressively to exclude the possibility of underlying adenocarcinoma.

Successful treatment of H. pylori is generally seen in 80% to 90% of cases, and in patients with uncomplicated ulcer disease, retesting for H. pylori to confirm eradication is not recommended. However, in cases of complicated ulcer disease (i.e., hemorrhage, perforation, obstruction), confirmation of eradication is indicated. Serologic testing is not accurate for this purpose, as antibody titers may remain elevated after eradication. Urea breath testing and stool antigen testing are recommended as the tests of choice to confirm successful treatment. In cases where a second endoscopy is performed, gastric biopsy may also be useful in confirming H. pylori eradication, although breath tests are superior because of the possibility of sampling error associated with the use of the former.

What's the evidence?

Wolfe, MM, Sachs, G.. "Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome". Gastroenterology. vol. 118. 2000. pp. S9-S31.

(A classic reference summarizing the clinical studies of acid suppression in acid-peptic diseases.)

Wolfe, MM, Lichtenstein, DR, Singh, G.. "Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs". N Engl J Med. vol. 340. 1999. pp. 1888-99.

(A comprehensive review of the pathophysiology and therapy of NSAID-related gastrointestinal disorders.)

Berna, MJ, Hoffman, KM, Serrano, J. "Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the NIH and comparison with 2229 cases from the literature". Medicine (Baltimore). vol. 85. 2006. pp. 331-64.

(The largest series of patients with Zollinger-Ellison Syndrome, confirming the role of serum gastrin levels in making the diagnosis.)

Wolfe, MM.. "Diagnosis and management of Zollinger-Ellison syndrome". Prac Gastroenterol. vol. 26. 2002. pp. 15-32.

(A comprehensive review of Zollinger-Ellison Syndrome, outlining the pathophysiology, diagnosis, and therapy of this disorder.)

Gibril, F, Reynolds, JC, Doppman, JL. "Somatostain receptor scintigraphy; its sensitivity compared with that of other Imaging methods in detecting primary and metastatic gastrinomas". Ann Intern Med. vol. 125. 1996. pp. 26-34.

(Review of the utility of somatostatin scintigraphy in the diagnosis of gastrinoma.)

Goldman, JA, Blanton, WP, Hay, DW, Wolfe, MM.. "False-positive secretin stimulation test for gastrinoma associated with the use of proton pump inhibitor therapy". Clin Gastroenterol Hepatol. vol. 7. 2009. pp. 600-2.

Madanick, RD.. "Proton pump inhibitor side effects and drug interactions: much ado about nothing?". Cleve Clin J Med. vol. 78. 2011. pp. 39-49.

(An excellent review of the potential adverse effects of long-term PPI use.)
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