Francisco C. Ramirez, MD
What are the major factors that disrupt gastric mucosal resistance resulting in ulcer development?
Nonsteroidal anti-inflammatory drugs (NSAIDs), Helicobacter pylori, diminished mucosal bicarbonate secretion, cigarette smoking, and gastric acid hypersecretion.
What are the four most common causes of ulcer disease?
H. pylori, NSAIDs, idiopathic, and hypersecretory states. About 50%–60% of H. pylori-negative ulcers are caused by aspirin or NSAID use, while about 10%–15% are idiopathic. It has been estimated that about 20% of peptic ulcers have false-negative H. pylori results.
What is the main mechanism responsible for mucosal damage in patients taking NSAIDs?
Inhibition of prostaglandin synthesis.
What percent of NSAID users develop asymptomatic peptic ulcer disease (PUD) or gastropathy?
20% in the first year.
Who is more likely to develop an asymptomatic ulcer?
The elderly and those taking NSAIDs.
What percent of NSAID users develop symptomatic PUD or complicated PUD?
What are risk factors for developing NSAID-induced GI complications?
History of PUD or complication of PUD (most important), age older than 60, high-dose NSAIDs, concomitant use of corticosteroids, concomitant use of anticoagulants, and concurrent H. pylori infection.
True/False: Smoking is a risk factor for the development of NSAID-related ulcers.
False. H. pylori-associated ulcers but not NSAID-induced ulcers are exacerbated by smoking.
What is the annual incidence rate of PUD in H. pylori-infected individuals?
What is the lifetime prevalence of clinical PUD in the general population and in the H. pylori-infected population?
10% and 20%, respectively.
Which part of the stomach is predominantly involved in H. pylori-associated duodenal ulcer?
Antrum (antral-predominant gastritis). In contrast, the body of the stomach is predominantly affected in H. pylori-associated gastric ulcer (corpus-predominant gastritis).
True/False: The presence of H. pylori in the corpus of the stomach is associated with a lower gastric pH and a higher incidence of gastroesophageal reflux disease.
False. Diffuse gastritis with H. pylori in this location is typically associated with an increase in gastric pH and may serve as a protective mechanism against reflux. In this situation, the eradication of H. pylori may result in a decrease in gastric pH and an increase in gastroesophageal reflux symptoms in susceptible individuals.
True/False: The presence of pain and its relationship to meals does not accurately distinguish between gastric and duodenal ulcer patients.
True. Nevertheless, as a reminder of the “classic” clinical presentations: Pain related to duodenal ulcers occurs about 2–5 hours after a meal and between 11 pm and 2 am (circadian acid stimulation is maximal), whereas pain related to a gastric ulcer occurs immediately after a meal.
Which hypersecretory states may manifest with PUD?
Hypergastrinemia-related: Zollinger–Ellison syndrome, antral cell hyperplasia, and retained antrum syndrome. Nonhypergastrinemia-related: Systemic mastocytosis (increased histamine).
Describe the nature of the relationship between H. pylori and NSAIDs in the pathogenesis of PUD (and bleeding ulcer).
Describe the nature of the relationship between low-dose aspirin and cyclo-oxygenase (COX)-2 inhibitors in the pathogenesis of PUD.
Synergistic. There is an increased risk of complications when taken concomitantly compared to when taking either drug alone.
True/False: In a patient at high risk of PUD who needs to begin long-term NSAID therapy, the best strategy regarding H. pylori is to test and treat (if present) before initiation of the NSAID.
True/False: In the patient with active PUD who has H. pylori infection and requires continuing long-term NSAID use, the best strategy for managing this patient is to treat the H. pylori and consider prophylactic antisecretory therapy.
True/False: Endoscopically, an ulcer is differentiated from erosion by size alone.
False. Depth is the primary feature differentiating the two. Histologically, an ulcer is defined by penetration of the muscularis mucosa.
Describe instances when testing for H. pylori should be considered.
Active PUD, documented history of PUD, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, family history of gastric cancer, following resection of gastric adenocarcinoma, and uninvestigated dyspepsia in those <55 years of age and without “alarm” features. More controversial indications include naïve NSAID users, iron deficiency anemia, and idiopathic thrombocytopenic purpura (ITP).
Describe the nonendoscopic tests used for the diagnosis of active H. pylori infection and their sensitivities and specificities.
In-office antibody test (sensitivity: 88%–94%; specificity: 74%–88%)
ELISA on serum (sensitivity 86%–94%; specificity: 78%–95%)
Stool antigen (sensitivity 94%; specificity: 92%)
13C or 14C Urea breath test (sensitivity: 90%–96%; specificity: 88%–98%)
Describe the endoscopic tests (requiring gastric biopsy) used for the diagnosis of active H. pylori infection and their sensitivities and specificities.
Rapid urease test (sensitivity: 88%–95%; specificity: 95%–100%)
Histology (sensitivity: 93%–96%; specificity: 95%–100%)
Culture (sensitivity: 80%–98%; specificity: 100%)
What precautions should be taken to avoid false-negative results when testing for H. pylori?
Testing should be performed at least 4 weeks after stopping antibiotics, bismuth, and antisecretory medications.
What is the duodenal ulcer recurrence rate after H. pylori eradication?
Less than 10% (versus 65%–95% of those who remain infected).
True/False: The re-infection rate after successful treatment of H. pylori in adults is about 5% per year.
False. The re-infection rate is <2% per year.
When is confirmation of eradication after H. pylori treatment recommended?
Most guidelines now recommend that eradication be documented in all patients. Previously, this recommendation was limited to those with complicated PUD or those with persistent or recurrent symptoms following treatment.
Which tests are useful to confirm eradication?
Urea breath test, stool antigen, or gastric biopsy. In contrast, serologic antibody tests should not be used to confirm eradication as titers decrease slowly and may remain positive in approximately 40% of those successfully treated even after 18 months.
What are the four main complications of PUD?
Bleeding: 50–170/100,000 (as many as 30% of patients with PUD at some point in their lifetime)
Perforation: 1–10/100,000 (<5%)
Gastric outlet obstruction (rare)
In what locations of the stomach and duodenum are ulcers more likely to bleed?
Ulcers located high on the lesser curve of the stomach or on the posterior inferior wall of the duodenal bulb are more likely to bleed.
Name two high-risk ulcer stigmata at endoscopy that require endoscopic hemostasis and high-dose continuous infusion of a proton pump inhibitor (PPI).
Actively bleeding vessel and nonbleeding visible vessel.
True/False: Young age is a risk factor for ulcer bleeding-related death.
False. Older age and failure to control bleeding endoscopically are risk factors for death within 48 hours of attempted endoscopic treatment.
True/False: The incidence of duodenal ulcer has declined over the past 30 years.
True. This decline is only partially explained by the introduction of potent antisecretory agents as it predated their availability. It may be partly explained by a decrease in smoking or possibly by an increase in antibiotic use.
In patients with symptoms and endoscopically-documented PUD, what percent is present with upper gastrointestinal bleeding (UGIB)?
Approximately 30% (often as the initial symptom).
What is the major effect of administering high-dose PPI therapy prior to endoscopy in the patient presenting with UGIB?
The effect seems to primarily be in the down-staging of endoscopic stigmata rather than modifying actual outcomes.
The presence of an ulcer or ulcers in the distal duodenum or other atypical locations should raise suspicion for which conditions?
Crohn’s disease, ischemia, and Zollinger–Ellison syndrome.
What characteristics should prompt extra awareness on the risk for gastric cancer in the patient with a gastric ulcer?
Absence of H. pylori or NSAID use, large (>2 cm) size, and patient from an endemic area of gastric cancer (eg, Central America and East Asia).
What is required to be present in the duodenum for H. pylori to cause duodenal ulcer?
Gastric metaplasia. Hyperacidity from colonization of the gastric antrum causes gastric metaplasia of the duodenum which can in turn become colonized with the organism and lead to inflammation and ulceration.
What is a unique and striking characteristic of the H. pylori organism?
Production of urease (breath test and rapid urease testing on tissue are based on this characteristic).
Name two H. pylori genotypes associated with increased morbidity in patients with PUD (ie, associated with increased virulence).
vacA-positive (vacuolating cytotoxin) and cagA-positive (cytotoxin-associated gene A).
Name the two main risk factors associated with clinically significant bleeding from stress-related mucosal disease (SRMD).
Mechanical ventilation for >48 hours (OR: 15.6) and the presence of coagulopathy (OR: 4.3).
True/False: Mortality in patients with SRMD and bleeding is high and usually relates to the underlying condition.
Prophylaxis for SRMD-related bleeding is indicated in which circumstances?
Severe trauma, burns involving >1/3 body surface area, major intracranial disease, severe illness requiring mechanical ventilation >48 hours, and the presence of coagulopathy.
True/False: Prophylaxis for SRMD is associated with decreased risk of bleeding.
True. The risk of bleeding, but not mortality, is reduced.
What medications have been shown to have benefit in SRMD prophylaxis?
Histamine receptor antagonists type 2, PPIs, and sucralfate.
What are the two most important factors determining the speed of healing of a duodenal ulcer with antisecretory medications?
Duration of time that the gastric pH is >3.0 and the number of weeks of treatment.
True/False: Multiple endocrine neoplasia type 2 (MEN type 2) is associated with gastrinoma.
False. About 20%–25% of patients with a gastrinoma have MEN type 1 (tumors of pancreas, parathyroid, and pituitary or “3 P’s”).
True/False: A duodenal bulbar ulcer is the most common type of ulcer associated with gastrinoma.
Describe three clinical situations where a gastrinoma should be considered in the differential diagnosis.
1. Presence of multiple duodenal ulcers and esophagitis refractory to medical therapy.
2. Presence of duodenal ulcer(s) and diarrhea (malabsorption due to acid overload and inactivation of pancreatic enzymes).
3. Presence of duodenal ulcer(s) and hypercalcemia (hyperparathyroidism related to MEN type 1).
True/False: A secretin stimulation test is the screening test of choice in the evaluation of a gastrinoma?
False. Serum gastrin level is the screening test of choice. A level >1000 pg/ml strongly suggests gastrinoma.
What test should be considered when the serum gastrin is markedly elevated but below 1000 and achlorhydria has been ruled out?
Secretin stimulation test. A positive test is an increase of at least 200 pg/ml over baseline gastrin level. This test can be done in the presence of PPI use.
True/False: Gastrinoma is the most common cause of hypergastrinemia.
False. Achlorhydria, usually in the setting of atrophic gastritis, is the most common cause of achlorhydria.
How can antral G-cell hyperplasia be differentiated from a gastrinoma?
Like gastrinoma, it is associated with hypergastrinemia and the development of duodenal ulcers. However, it can be differentiated from a gastrinoma on the basis of a negative secretin test.
• • • SUGGESTED READINGS • • •
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Yeomans, ND. The ulcer sleuths: the search for the causes of peptic ulcers. J Gastroenterol Hepatol. 2011;26(Suppl 1):35-41.
Arora G, Singh G, Triadafilopoulus G. Proton pump inhibitors for gastroduodenal damage related to nonsteroidal anti-inflammatory drugs or aspirin: twelve important questions for clinical practice. Clin Gastroenterol Hepatol. 2009;7:725-735.
Barkun A, Leontiadis G. Systematic review of the symptom burden, quality of life impairment and costs associated with peptic ulcer disease. Am J Med. 2010;123:358-366.
Gralnek IM, Barkun AN, Bardou M. Management of acute bleeding from a peptic ulcer. N Engl J Med. 2008;359:928-937.
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McColl KEL. Helicobacter pylori-negative non-steroidal anti-inflammatory drug negative-ulcer. Gastroenterol Clin N Am. 2009;38: 353-361.
Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med. 2010;38:2222-2228.
Barkun AN, Bardou M, Kulpers EJ, et al. International Consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2010;152:101-113.