A 54-year-old man complains of recurrent burning epigastric pain. He has been experiencing this problem for about six weeks and, during the past two weeks, the pain has often awakened him during the night. The pain lessens after meals but gets worse if he fasts for several hours. He has not been experiencing nausea or vomiting. His vital signs are: T = 37.1 C, P = 90, R = 18, BP = 135/85 mm Hg. The physical examination is unremarkable except for some slight epigastric tenderness. When asked about his family's medical history, the patient indicates that his mother and one of his two siblings have had recurring symptoms similar to those he is experiencing now.

Question 1.1: What is your preliminary diagnosis?

The symptoms are suggestive of peptic ulcer disease (PUD), which encompasses both gastric ulcers (GUs) and duodenal ulcers (DUs). This case most likely involves a DU. Abdominal pain is common to many gastrointestinal disorders, including PUD, but has poor predictive value for the presence of DU or GU. Nevertheless, one should always carry out a careful history and physical examination when dealing with a patient who may have PUD. Epigastric pain may manifest as a burning or gnawing discomfort, or as an ill-defined, aching sensation that resembles hunger pain. The typical pain pattern in DU occurs 90 min to 3 h after a meal and is often relieved by antacids or food. Pain that awakens the patient from sleep is the most discriminating symptom, with two-thirds of DU patients describing this complaint. In contrast, discomfort in GU patients may actually be precipitated by food. Also, nausea and weight loss are more common in GU patients.

The physical exam is often unremarkable with PUD. Epigastric tenderness is the most frequent finding. Although not seen in the present case, additional symptoms may be indicative of complications associated with peptic ulcers. Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation, as does a severely tender, boardlike abdomen. Pain that worsens with meals, nausea, and vomiting of undigested food suggests gastric outlet obstruction, as does the presence of a succussion splash (indicative of retained fluid in the stomach). Tarry stools or coffee ground emesis indicate bleeding. Tachycardia and orthostasis suggest dehydration secondary to vomiting or active gastrointestinal blood loss.

Question 1.2: What tests should you perform?

A comprehensive history and physical examination are required to eliminate other possible diagnoses, which include gastroesophagal reflux disease (GERD), cholelithiasis syndrome, pancreatitis, gastritis, non-ulcer dyspepsia, neoplasm (gastric carcinoma, lymphoma, etc.), angina pectoris, dissecting aneurysm, high small bowel obstruction, early appendicitis, etc.

Diagnostic modalities include endoscopy or UGI series. Endoscopy is invasive and more expensive, but is preferred for several reasons: (1) highest accuracy (90-95%, compared to 70-80% for UGI barium studies), (2) ability to identify superficial or very small lesions, (3) necessity for full diagnosis of GUs), (4) biopsy of suspicious looking ulcers, (5) electrocautery of bleeding ulcers, and (6) biopsy for detection of possible microbial causative agent.

Question 1.3: What is the causative agent and how can it be detected?

DUs and GUs may be caused by damage induced by use of non-steroid anti-inflammatory drugs (NSAIDs). However, the majority of cases are associated with infection by Helicobacter pylori, the only microbe associated with PUD. Methods for detection of H. pylori infections include:

* Urea breath test: This test documents active infection. The patient ingests a small amount of urea labeled with carbon-13 or carbon-14. If urease is present (produced by H. pylori), urea is hydrolyzed and the patient exhales labeled CO2 that is collected and measured. This test is more expensive and less readily available than serologic testing.

* Serologic testing for antibodies: This test is easy and inexpensive, but the presence of antibodies may only demonstrate a previous (as opposed to a current) infection. Antibodies to H. pylori can remain elevated for months to years after infection has cleared.

* Histologic evaluation of endoscopic biopsy samples: This is currently the gold standard for accurate diagnosis of H. pylori infection.

* Stool antigen test: This approach is as accurate as the urea breath test for follow-up evaluation of patients treated for H. pylori infection.

Question 1.4: What are the key virulence factors of the causative agent?

H. pylori is a Gram-negative microaerophilic rod found most often in the deeper portions of the mucous gel coating the gastric mucosa or between the mucous layer and the gastric epithelium. It may attach to gastric epithelium but, under normal circumstances, it does not appear to invade cells. It is S-shaped and contains multiple sheathed flagella.

H. pylori can facilitate gastric residence, induce mucosal injury, and avoid host defenses. A specific region of its genome, the pathogenicity island, encodes virulence factors Cag A (cytotoxin associated gene protein) and pic B (induces cytokine production). Vac A (vacuolating cytotoxin) also contributes to pathogenicity but is not encoded within the pathogenicity island. These virulence factors, along with other bacterial constituents, can cause mucosal damage. Urease, which allows H. pylori to live in the acidic stomach, generates NH3, which can damage epithelial cells. The bacteria produce surface factors that are chemotactic for neutrophils and monocytes, which, in turn, contribute to epithelial cell injury. H. pylori secretes proteases and phospholipases that break down the glycoprotein lipid complex of the mucous gel, thus reducing the efficacy of this first line of mucosal defense. The bacterium expresses adhesins, which facilitate attachment of its cells to gastric epithelial cells. Although lipopolysaccharide (LPS) of Gram-negative bacteria often plays an important role in the infection, H. pylori LPS has low immunologic activity compared to that of other organisms. It may promote a smoldering chronic inflammation.

The host responds to H. pylori infection by mounting an inflammatory response, which contributes to gastric epithelial cell damage without providing immunity against infection. The neutrophil response is strong both in acute and chronic infections. A number of cytokines are released in response to H. pylori infection, including proinflammatory cytokines such as tumor necrosis factor (TNF), interleukins (IL-1, IL-6), and interferon (IFN)

Question 1.5: Is the causative agent associated with other diseases?

H. pylori infection is virtually always associated with a chronic active gastritis, but only 10-15% of infected individuals develop frank peptic ulceration. The basis for this difference is unknown. The bacterium is also involved in the development of gastric mucosal-associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma. The particular end result of H. pylori infection (gastritis, PUD, gastric MALT lymphoma, gastric cancer) is determined by a complex interplay between bacterial factors (e.g., different strains produce different virulence factors) and host factors (e.g., the intensity of the inflammatory response).

It is not clear how H. pylori, which lives in the stomach, causes ulcers in the duodenum. A possible explanation is that gastric metaplasia in the duodenum of DU patients permits H. pylori to bind to it and produce local injury secondary to the host response. Another hypothesis is that H. pylori antral infection could lead to increased acid production, increased duodenal acid, and mucosal injury. H. pylori infection has also been associated with decreased production of bicarbonate by the duodenal mucosa. Data supporting and contradicting each of these interesting theories have been presented, so the actual mechanism by which H. pylori infection of the stomach leads to duodenal ulceration remains to be established.