What Causes Peptic Ulcers?

A peptic ulcer is not a condition with a single cause, but involves several interrelated factors which affect the health and integrity of the gastric and duodenal mucosa.

The male preponderance of peptic ulceration is a well-known fact. Apart from gender, genetic factors and heredity may also have a role to play in its causation.

Some of these factors have to do with gastric acid production, while others involve pepsinogen secretion and activation, and still others deal with repair of the gastric and duodenal mucosa, to keep it in good shape against the constant action of peptic enzymes and hydrochloric acid.

It is well known that both acid and pepsin need to be present for a peptic ulcer to form, whether in the stomach or in the duodenum. However, these agents are present in all normal individuals, so that their mere presence is obviously not the sole condition for a peptic ulcer to form.

Mean normal acid levels are not exceeded in many gastric peptic ulcers, thus pointing to a failure of mucosal repair as the primary reason behind the evolution of an ulcer.

In other words, there is a lack of balance between the protective and ulcerogenic factors.

Protective factors include:

• The secretion of mucus and bicarbonates to form a buffer against acid-peptic digestion
• The release of locally protective prostaglandins
• The speed at which cells regenerate
• The adequacy of blood flow in the mucosal plexus.

Ulcer-producing factors are:

• The attack by gastric acid and pepsin
• Local inflammation
• Gastric metaplasia
• Colonization by Helicobacter pylori
• Bile salts with their mucus-dispersing effects
• Drugs such as salicylates which reduce prostaglandin secretion
• Other irritants such as alcohol

The causes of ulcers have been studied under three broad classes, namely:

• Those which are due to the presence of the infectious agent Helicobacter pylori (H. pylori)
• Those which are NSAID-associated
• Those which are H. pylori negative and un-associated with NSAID use, as with Zollinger-Ellison syndrome, Cushing’s ulcer, or following radiation to the upper abdomen.

Helicobacter pylori and peptic ulceration

A common factor in peptic ulcer causation is the presence of the infectious agent Helicobacter pylori.

This bacterium causes an inflammatory reaction locally, involving the release of neutrophil-derived lysosomal enzymes, leukotrienes and reactive oxygen species, all of which lower the level of local mucosal defense. The pro-inflammatory cytokines interfere with normal repair, and this allows the ulcer to linger and establish itself.

In addition, the powerful ammonia-producing activity of H. pylori means that the local alkaline effect of ammonia around the colonies prevents the antral D cells from sensing the actual level of gastric acid, instead pushing up the secretion of gastrin and somatostatin. This creates a feedback loop which keeps the acid level high while preventing inhibition of the acid-secreting cells.

Infection with H. pylori is especially important in duodenal ulcers, where the acid and pepsin levels are often somewhat higher than the mean levels. The mucosa often shows inflammation, which becomes chronic, resulting in cellular changes including gastric metaplasia. This metaplastic tissue is an essential for H. pylori colonization, which in turn repeats the cycle of inflammation-mucosal attack-ulceration, due to the failure of repair.

The factors that determine which of the large group of people infected by H. pylori (over 50% of the global population) will eventually develop a peptic ulcer (less than 5-10%) include:

• The presence of cellular changes in response to chronic inflammation.
• The presence of gastritis, which brings about changes in the regulation of acid and gastrin secretion.
• The occurrence of gastric metaplasia in the duodenum.
• The interaction between the bacterium and the mucosal defences.
• The immune reaction to colonization.
• The type of strain of the pathogen, some being more ulcerogenic than others.
• Genetic patterns of acid secretion, sensitivity of acid-secreting cells to hormonal and nervous stimulation.

Acid-peptic reflux and ulceration

The presence of reflux of the duodenal contents into the stomach (duodenogastric reflux), and atrophic gastritis, are both associated with peptic ulceration of the body of the stomach, or type 1 ulcers, supporting the etiological role of poor gastric mucosal protection.

NSAIDs and gastric ulceration

Another important factor in this process is the presence of irritant substances in the stomach, notably non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, aspirin or ibuprofen. Their mechanism of action is by inhibition of prostaglandin synthesis, which is, however, a vital part of mucosal repair.

Both cyclo-oxygenase-1 (COX 1) and COX-2 inhibitors are associated with gastric ulceration, especially COX-2 inhibitors. There are various mechanisms of disrupted mucosal protection via NSAIDs, namely:

• Neutrophil adhesion which leads to the release of reactive oxygen species, damage to cellular membranes, release of proteases and impairment of capillary flow.
• Inhibition of nitric oxide (NO) and hydrogen sulphide (H2S), which are important in protecting the structural and functional integrity of the mucosa. Both of them inhibit neutrophil adhesion, increase the secretion of mucus, and the capillary blood flow in the mucosal vessels. Suppression of these leads to breakdown of the mucosal barrier.

Summary

Poor mucosal repair and protection due to H. pylori infection, or NSAID use, or functional impairment of bicarbonate ion release.

Hyperacidity of the duodenum, an inherited trait seen to be due to excessive numbers of parietal and chief cells, resulting in hypersecretion of gastric acid, in approximately 50% of patients.

Hyperacidity of the duodenum with normal acid secretion, due to excessive stimulation of parietal and chief cells by vagal impulses, or gastrins, or else because the cells are hypersensitive to stimulation. At the same time, it is essential that there is associated failure of negative feedback on gastrin secretion, leading to inappropriately high levels of gastrin.

Reduced secretion of bicarbonate ions is found to be a functional abnormality of the duodenal mucosa, which contributes to the formation of the ulcer. This is the most common etiology of type 3 ulcers, or prepyloric ulcers.