Peptic Ulcer- Definition, Epidemiology, Etiology and Pathophysiology!

 PEPTIC ULCER

Definition:

"The term Peptic Ulcer describes a condition in which there is a discontinuity in the entire thickness of the gastric or duodenal mucosa, that persists as a result of acid and pepsin in the gastric juice."

• Esophageal ulceration due to acid reflux, is generally classified under GERD.
• Peptic ulcer disease often presents to clinicians as dyspepsia. However, not all patients with dyspepsia have peptic ulcer disease. "Dyspepsia" is defined as persistent or recurrent pain or discomfort centered in the upper abdomen. 
• The most common causes of dyspepsia include:

1. non-ulcer or functional dyspepsia
2. GERD
3. Peptic ulcer

Epidemiology:

• The incidence of duodenal ulcer is now declining, which follows the decline H.Pylori infection.
• However, hospital admission rates for gastro-intestinal bleeding associated with gastric and duodenal ulcers are rising. This is probably a consequence of increased prescription for low-dose aspirin, NSAIDs, Antiplatelets, anti-coagulants and selective serotonin reuptake inhibitors (SSRI).
• Over a decade, there has been an increase in the idiopathic (unknown cause) peptic ulcer disease in patients who test negative for H.pylori and who do not take Aspirin or NSAIDs.

Etiology of Peptic Ulcers:

Two major causes of Peptic Ulcers are H.PYLORI or NSAID induced ulcers.

Less common causes are associated with massive hypersecretion of acid which occurs in the rare gastrinoma (Zollinger-Ellison syndrome).

1.H.PYLORI:

• Helicobacter pylori is a gram negative spiral microaerophilic bacterium found primarily in the gastric antrum of the human stomach. The bacterium is located in the antrum and the acid-secreting microenvironment of the corpus of the stomach is less hospitable to the bacterium.
• Infection by H.pylori, a spiral bacterium of the stomach remains an important epidemiological factor in causing peptic ulcer. Most H.pylori infections are acquired by oral-oral and oral-fecal transmissions.
• Risk Factors:The most important risk factors include low social class, over-crowding and home environment during childhood such as bed sharing. Transmission may occur within a family, a fact demonstrated by the finding that family members, especially spouses may have the same strain of H.pylori.
• 95%of the duodenal ulcers and 85% of the gastric ulcers are associated with H.pylori.
• The contribution of H.pylori infection to the risk of ulcers in the NSAIDs users is not clear but there appears to be an additive effect.
• The risk of peptic ulcer in long-term NSAID users is greater in those who test positive for H.pylori and eradication of H.pylori in these patients prior to commencing NSAID treatment has shown to reduce the risk of H.pylori NSAID associated peptic ulcer.
• Pathophysiology: The underlying pathophysiology associated with H.pylori infection involves the production of cytoxin-associated gene A (CagA) proteins and vacuolating cytotoxins such in H.pylori infection, Such as Vac-A (which activates the inflammatory cascade). Cag A status and one genotype of the Vac-A gene are also predictors of ulcerogenic capacity of strain.
• In addition, a number of enzymes produced by H.pylori may also be involved in causing tissue damage and include Urease, Hemolysins, Neuraminidase and Fucosidase.
• Gastrin is the main hormone involved in stimulating gastric-acid secretion and gastrin homeostasis is also altered the hyperacidity in duodenal ulcer may result from H.pylori induced hypergastrinemia.
• The elevation of gastrin may be a consequence of bacterially mediated decrease of antral D cells that secrete somatostatin, thus losing the inhibitory modulation of somatostatinon gastrin; or direct stimulation of gastrin cells by cytokines liberated during the inflammatory process. 
• Long standing hypergastrinemia leads to an increased parietal cells mass.
• High acid content in the proximal duodenum leads to metaplastic gastric-type mucosa, which provides a niche for H.pylori infection followed by inflammation and ulcer formation.   

2.NSAIDs:

• Three causes of mucosal damage are caused by NSAIDS. These include;

1. superficial erosions and hemorrhages
2. Silent ulcers detected at endoscopy
3. Ulcers causing clinical symptoms and complications

• Weak NSAIDs such as Acetylsalicylic acid are concentrated from the acidic gastric juice into mucosal cells and may produce acute superficial erosions via inhibition of COX and by mediating the adherence of leucocytes to mucosal endothelial cells.
• All NSAIDs have the ability to inhibit COX. The presence of NSAID-induced ulcers do not correlate with abdominal pain and NSAIDs themselves often mask ulcer pain.
• Approximately 20% of patients taking NSAIDs experience symptoms of Dyspepsia.
• Patients taking NSAIDs have a 4-fold increase in risk of ulcer complications compared with non-users.
• The risk of ulcer bleeding in low-dose aspirin users is 2 to 3 fold and there may be differences in risk factors.

Risk Factors for NSAID ulcers mainly include:

• Age greater than 65 years 
• Previous peptic ulceration/bleeding
• High dose of NSAID or more than one NSAID (including Aspirin)
• Short-term history of NSAID (use less than 1 month)
• Concomitant corticosteroid or anticoagulant use
• Cardiovascular health

Selective Cyclo-oxygenase-2 Inhibitors:

• COX-1 stimulates synthesis of homeostatic prostaglandins while COX-2 is predominantly induced in response to the inflammation.
• Selective COX-2 inhibitors tend not to reduce the mucosal production of protective prostaglandins to the same extent as NSAIDs COX-2 inhibitors are therefore considered to be safer than the non-selective NSAIDs in patients at high risk of developing gastro-intestinal mucosal damage.
• Although studies have confirmed the reduction of endoscopic and symptomatic ulcers, an increase in Cardiovascular risk including heart attack and stroke, has resulted in the withdrawal of some COX-2 inhibitors from the market.

Nitric Oxide-Releasing NSAIDs:

• NO-releasing NSAIDs are being investigated to see if the gastric mucosa protection associated with nitric oxide prevents ulceration when prostaglandins are inhibited by NSAIDs.
• Nitric oxide is coupled to the NSAID via an ester, resulting in prolonged release of nitric oxide.
• Animal studies suggest that NO-releasing agents such as Naproxcinod have the minimum cardiovascular and gastrointestinal toxicity.