Peptic Ulcer Disease. Epidemiology. Pathogenesis. Helicobacter pylori Infection

Peptic Ulcer Disease Epidemiology The estimated prevalence of PUD ranges from 5% to 15% in Western populations, with a lifetime incidence of almost 10...
Author: Roy Tyler
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Peptic Ulcer Disease Epidemiology The estimated prevalence of PUD ranges from 5% to 15% in Western populations, with a lifetime incidence of almost 10%.[6] Although the incidence and hospitalization rate for PUD have been decreasing since the 1980s, it remains one of the most prevalent and costly GI diseases. Medical costs associated with PUD are an estimated $5.65 billion annually. An estimated 15,000 operations are performed each year on patients hospitalized with PUD. Significant progress has been made over the past 2 decades, with total admissions for PUD decreasing by almost 30%. Admissions for complications of ulcer disease have also been decreasing, which has led to a significant decrease in ulcer-related mortality, from 3.9% in 1993 to 2.7% in 2006.[7] Although overall mortality remains low, this still represents over 4000 deaths caused by PUD each year. The role of surgery in the treatment of ulcer disease has also decreased, primarily caused by a marked decline in elective surgical therapy for chronic disease because the percentage of patients who require emergent surgery for complicated disease has remained constant, at 7% of hospitalized patients.[7] This represents over 11,000 surgical procedures annually. Much of this decline in ulcer incidence and the need for hospitalization has stemmed from increased knowledge of ulcer pathogenesis. Specifically, the role of H. pylori has been defined and the risks of chronic NSAID use have been better elucidated. An increase in H. pylori eradication will hopefully result in a decrease of not just elective surgical procedures, but also a decline in complications and mortality from emergent complications.

Pathogenesis Peptic ulcers are caused by increased aggressive factors, decreased defensive factors, or both.[8] This in turn leads to mucosal damage and subsequent ulceration. Protective (or defensive) factors include mucosal bicarbonate secretion, mucus production, blood flow, growth factors, cell renewal, and endogenous prostaglandins. Damaging (or aggressive) factors include hydrochloric acid secretion, pepsins, ethanol ingestion, smoking, duodenal reflux of bile, ischemia, NSAIDs, hypoxia and, most notably, H. pylori infection.

Helicobacter pylori Infection It is now believed that 90% of duodenal ulcers and approximately 75% of gastric ulcers are associated with H. pylori infection. When this organism is eradicated as part of ulcer treatment, ulcer recurrence is extremely rare. H. pylori is a spiral or helical gram-negative rod with four to six flagella that resides in gastric-type epithelium within or beneath the mucus layer. This location protects the bacteria from acid and antibiotics. Its shape and flagella aid its movement through the mucus layer and it produces enzymes that help it adapt to this hostile environment. Most notably, it is a potent producer of urease, which is capable of splitting urea into ammonia and bicarbonate, creating an alkaline microenvironment in the setting of an acidic gastric milieu. The secretion of this enzyme, however, facilitates detection of the organism. H. pylori is microaerophilic and can only live in gastric epithelium. Thus, it can also be found in heterotopic gastric mucosa in the proximal esophagus, Barrett's esophagus, gastric metaplasia in the duodenum, within a Meckel's diverticulum, and heterotopic gastric mucosa in the rectum. The mechanisms responsible for H. pylori–induced GI injury remain to be fully elucidated, but three potential mechanisms have been proposed: 1 Production of toxic products that cause local tissue injury. Locally produced toxic mediators include breakdown products from urease activity (e.g., ammonia), cytotoxins, a mucinase that degrades mucus and glycoproteins, phospholipases that damage epithelial cells and mucus cells, and platelet-activating factor, which is known to cause mucosal injury and thrombosis in the microcirculation. 2 Induction of a local mucosal immune response. H. pylori can also cause a local inflammatory reaction in the

gastric mucosa, attracting neutrophils and monocytes, which then produce a number of proinflammatory cytokines and reactive oxygen metabolites. 3

Increased gastrin levels with a resultant increase in acid secretion. In patients with H. pylori infection, basal and stimulated gastrin levels are significantly increased, presumably secondary to a reduction in antral D cells because of infection with H. pylori. However, the association of acid secretion with H. pylori is not as straightforward. Although H. pylori–positive healthy volunteers had a small increase or no increase in acid secretion as compared with H. pylori–negative volunteers, H. pylori–infected patients with duodenal ulcers did have a marked increase in acid secretion.[9]

Peptic ulcers are also strongly associated with antral gastritis. Studies done before the H. pylori era have demonstrated that almost all peptic ulcer patients have histologic evidence of antral gastritis. It was later found that the only patients with gastric ulcers and no gastritis were those ingesting aspirin. It is now recognized that most cases of histologic gastritis are caused by H. pylori infection. Even 25% of patients with an NSAID-associated ulcer have evidence of a histologic antral gastritis, as opposed to 95% of those with non–NSAID-associated ulcers. In most cases, the infection tends to be confined initially to the antrum and results in antral inflammation. Other evidence supporting a causal role for H. pylori in histologic gastritis comes from two separate volunteer physicians who ingested inocula of H. pylori after first confirming normal gross and microscopic gastric mucosa. Both developed gastric H. pylori infection. Acute inflammation was observed histologically on days 5 and 10. By 2 weeks, it had been replaced by chronic inflammation with evidence of a mononuclear cell infiltration. These two reports provide documentation that H. pylori can cause histologic gastritis. However, histologic gastritis does not necessarily equate with symptoms of dyspepsia. H. pylori infection usually occurs in childhood, and spontaneous remission is rare. There is an inverse relationship between infection and socioeconomic status. The reasons for this remain poorly understood but seem to be the result of factors such as sanitary conditions, familial clustering, and crowding. This likely explains why developing countries have a comparatively higher rate of H. pylori infection, especially in children. A number of studies have demonstrated what appears to be a steady linear increase in the acquisition of H. pylori infection with age, especially in the United States and northern European nations. In the United States, H. pylori prevalence also varies among racial and ethnic groups. H. pylori infection is associated with a number of common upper GI disorders, but most infected individuals are asymptomatic. Normal U.S. blood donors have an overall prevalence of about 20% to 55%. H. pylori infection is almost always present in the setting of active chronic gastritis and is present in most duodenal (>90%) and gastric (60% to 90%) ulcer patients. Noninfected gastric ulcer patients tend to be NSAID users. There is weaker association with nonulcer dyspepsia. In addition, most gastric cancer patients have current or past H. pylori infection. Although the association between H. pylori and cancer is strong, no causal relationship has been proven. H. pylori–induced chronic gastritis and intestinal metaplasia, however, are thought to play a role. There is also a strong association between +lymphoma and H. pylori infection. Regression of these lymphomas has been demonstrated after eradication of the organism. Limited data are available to estimate the lifetime risk of PUD in patients with H. pylori infection. In a longitudinal study from Australia with a mean evaluation period of 18 years, 15% of H. pylori–positive subjects developed verified duodenal ulcer as compared with 3% of seronegative individuals. In a 10-year study of asymptomatic gastritis patients, 11% of patients with histologic gastritis developed PUD over a 10-year period, compared with only 1% of those without gastritis. Another factor implicating a causative role for H. pylori and ulcer formation is that eradication of H. pylori dramatically reduces ulcer recurrence. Many prospective trials have shown that patients with H. pylori infection and non-NSAID ulcer disease who have documented eradication of the organism almost never (200 pg/mL), and values higher than 1000 pg/mL are diagnostic. In patients with equivocal gastrin levels, the most sensitive diagnostic test is the secretin stimulated gastrin level. Serum gastrin samples are measured before and after IV secretin (2 U/kg) administration at 5-minute intervals for 30 minutes. An increase in the serum gastrin level of greater than 200 pg/mL above basal levels is specific for gastrinoma versus other causes of hypergastrinemia, which do not demonstrate this response. After diagnosis of gastrinoma, acid suppression therapy is initiated, preferably with a PPI. Medical management is indicated preoperatively and for patients with metastatic or unresectable gastrinoma. Localized gastrinoma should be resected.

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