3. Etiopathogenesis

H. pylori infection and nonsteroidal anti-inflammatory drugs (NSAIDs) account for majority of the cases of PUD. More than 90% of duodenal ulcers and >70% of gastric ulcers are H. pylori positive [8]. A prospective study from Turkey found that H. pylori infection alone was responsible for PUD in 75% of cases, both H. pylori infection and NSAIDs in 50% of cases and NSAIDs alone in 10% of cases [9]. A Japanese study showed that the long-term use of low-dose aspirin could cause PUD in 6.2% of cases. The risk is increased in diabetic patients and in patients taking anticoagulants [9]. Both NSAIDs and aspirin inhibit the cyclooxygenase pathway and decrease the production of prostaglandin which is responsible for cytoprotection of gastric mucosa by stimulating mucus and bicarbonate secretion and increasing mucosal blood flow [10]. The chance of developing NSAID-induced PUD increases in the presence of certain risk factors which include age more than 65, heart disease, past history of PUD, and co-administration of corticosteroid, antiplatelets, and anticoagulants [11]. All NSAIDs can cause gastrointestinal injuries which include inflammation, erosions, ulcerations, and bleeding. The relative risk varies: the highest risk is associated with piroxicam and ketorolac; high risk with indomethacin and naproxen; intermediate risk with meloxicam, diclofenac, and ketoprofen; and low risk with ibuprofen and celecoxib [12]. About 11% of the US population take NSAIDs on a regular basis. 15–30% of them have PUD on endoscopy although clinical upper gastrointestinal events can occur in 1.5–4.5% of patients taking NSAIDs [13].

H. pylori virulence factors are important in the pathogenesis of PUD. Cytotoxinassociated gene A (Cag A), vacuolating cytotoxin A (Vac A), and induced by contact with epithelium antigen (ice A) are associated with PUD. After entering the stomach, H. pylori utilizes its urease enzyme to neutralize the gastric acidity. H. pylori then moves toward the gastric epithelium where it binds to the gastric epithelial cell receptors by its adhesion molecule [14]. Cag A is a strong immunogenic protein and measures the virulence of H. pylori infection. Cag A gene increases production of IL-8 and activates nuclear factor-kB [15], and ice A increases mucosal IL-8 expression. Gastric epithelial layer then activates its innate immunity and neutrophils leading to gastritis and peptic ulcer formation. Vac A toxin is a pore-forming toxin, and it not only stimulates vacuole formation in gastric epithelial cells, parietal cells, T cells, and other immune cells but also helps H. pylori in colonizing the stomach [16].

How H. pylori can cause duodenal ulcer while residing in the gastric mucus layer? In H. pylori gastritis, the cytokine tumor necrosis factor inhibits somatostatin cells (D cells) in the antral mucosa. As a result, gastrin secretion becomes uninhibited, leading to hypergastrinemia, hyperacidity, and duodenal ulcer formation [17]. Another study suggests that gastric metaplasia and H. pylori colonization in the duodenal bulb could play a critically important role in the pathogenesis of duodenal

#### Peptic Ulcer Disease DOI: http://dx.doi.org/10.5772/intechopen.86652

of infection can be as high as 90% [6]. Systematic review of the literature from developed countries estimated that the global incidence and prevalence of

tion [7].

3. Etiopathogenesis

Digestive System - Recent Advances

patients taking NSAIDs [13].

in colonizing the stomach [16].

4

physician-diagnosed PUD were 0.10–0.19% and 0.12–1.50%, respectively. But the incidence and prevalence of PUD have decreased with the universal use of acid suppressant therapy and decrease in prevalence of Helicobacter pylori infection due to improved socioeconomic status and eradication of H. pylori infection after detec-

H. pylori infection and nonsteroidal anti-inflammatory drugs (NSAIDs) account for majority of the cases of PUD. More than 90% of duodenal ulcers and >70% of gastric ulcers are H. pylori positive [8]. A prospective study from Turkey found that H. pylori infection alone was responsible for PUD in 75% of cases, both H. pylori infection and NSAIDs in 50% of cases and NSAIDs alone in 10% of cases [9]. A Japanese study showed that the long-term use of low-dose aspirin could cause PUD in 6.2% of cases. The risk is increased in diabetic patients and in patients taking anticoagulants [9]. Both NSAIDs and aspirin inhibit the cyclooxygenase pathway

and decrease the production of prostaglandin which is responsible for

cytoprotection of gastric mucosa by stimulating mucus and bicarbonate secretion and increasing mucosal blood flow [10]. The chance of developing NSAID-induced PUD increases in the presence of certain risk factors which include age more than 65, heart disease, past history of PUD, and co-administration of corticosteroid, antiplatelets, and anticoagulants [11]. All NSAIDs can cause gastrointestinal injuries which include inflammation, erosions, ulcerations, and bleeding. The relative risk varies: the highest risk is associated with piroxicam and ketorolac; high risk with indomethacin and naproxen; intermediate risk with meloxicam, diclofenac, and ketoprofen; and low risk with ibuprofen and celecoxib [12]. About 11% of the US population take NSAIDs on a regular basis. 15–30% of them have PUD on endoscopy although clinical upper gastrointestinal events can occur in 1.5–4.5% of

H. pylori virulence factors are important in the pathogenesis of PUD. Cytotoxin-

How H. pylori can cause duodenal ulcer while residing in the gastric mucus layer? In H. pylori gastritis, the cytokine tumor necrosis factor inhibits somatostatin cells (D cells) in the antral mucosa. As a result, gastrin secretion becomes uninhibited, leading to hypergastrinemia, hyperacidity, and duodenal ulcer formation [17]. Another study suggests that gastric metaplasia and H. pylori colonization in the duodenal bulb could play a critically important role in the pathogenesis of duodenal

associated gene A (Cag A), vacuolating cytotoxin A (Vac A), and induced by contact with epithelium antigen (ice A) are associated with PUD. After entering the stomach, H. pylori utilizes its urease enzyme to neutralize the gastric acidity. H. pylori then moves toward the gastric epithelium where it binds to the gastric epithelial cell receptors by its adhesion molecule [14]. Cag A is a strong immunogenic protein and measures the virulence of H. pylori infection. Cag A gene increases production of IL-8 and activates nuclear factor-kB [15], and ice A increases mucosal IL-8 expression. Gastric epithelial layer then activates its innate immunity and neutrophils leading to gastritis and peptic ulcer formation. Vac A toxin is a pore-forming toxin, and it not only stimulates vacuole formation in gastric epithelial cells, parietal cells, T cells, and other immune cells but also helps H. pylori ulcer [18]. The gastric metaplasia becomes inflamed by H. pylori infection which disrupts mucosal regeneration leading to duodenal ulcer formation [19].

There are certain unusual causes of PUD which we come across now and then in our clinical practice.

Gastrinoma or Zollinger-Ellison syndrome may present as multiple gastric and duodenal ulcers and accounts for 0.1% or more cases of PUD [20]. Other hormone (histamine)-mediated PUD include systemic mastocytosis, polycythemia vera, and basophilia in myeloproliferative diseases [21].

Besides NSAIDs and low-dose aspirin, few other medications can cause PUD. These include clopidogrel (in combination with NSAIDs), corticosteroids (in combination with NSAIDs), bisphosphonates, potassium chloride, spironolactone, sirolimus, mycophenolate mofetil, hepatic artery infusion of 5-fluorouracil, and selective serotonin reuptake inhibitors [22].

PUD can be due to another helicobacter infection called Helicobacter heilmannii [23]. Gastrointestinal ulcerations due to cytomegalovirus, herpes simplex virus, gastric and duodenal tuberculosis, and syphilis can mimic PUD.

Certain infiltrative diseases like Crohn's disease and sarcoidosis can present like PUD [24].

Family history is an independent risk factor for the development of PUD [25]. Blood group O individuals have higher susceptibility of getting H. pylori infection [26] and are 35–40% more prone to develop duodenal ulcer than people with other blood groups [27]. Salivary secretory status of A, B, and H antigens was also found to be significant. Nonsecretor phenotypes of ABH antigens are more susceptible to develop H. pylori infection and duodenal ulcer [28]. Genetic influence on the formation of PUD is modest, and it is independent of the genetic susceptibility of acquiring H. pylori infection [29]. Other risk factors for the development of PUD include smoking and psychological stress [30].

When we think about the pathogenesis of PUD, we must consider two factors:


PU occurs when there is an imbalance between these factors.

#### 3.1 Clinical features

Patients with PUD may be symptomatic or asymptomatic. Symptomatic patients generally present with dyspepsia, i.e., upper abdominal pain or discomfort. Most of the time, the pain is felt in the epigastric region, but sometimes it can be in the right upper quadrant or left upper quadrant of the abdomen. The pain is burning, gnawing, or dull aching in nature and generally non-radiating but rarely can radiate to the back in the case of posterior penetrating ulcer. Patients with gastric ulcer may feel pain shortly after taking food, but in the case of duodenal ulcer, pain is generally felt 2–3 h after taking meal, or sometimes patients wake up at night with epigastric pain. Duodenal ulcer pain is generally relieved after taking antacids or food which has minimal effect on relieving gastric ulcer pain [31]. Sometimes patients may feel gas and bloating sensation in the abdomen and sometimes may

experience nausea and vomiting. About 30% of elderly patients with PUD may remain asymptomatic [32]. This is also common in patients taking NSAIDs. Silent PU generally presents with gastrointestinal bleeding [33].

Physical examination can be entirely normal except epigastric tenderness.

### 3.2 Diagnosis and evaluation

A thorough history and physical examination is necessary to evaluate the patient. In each case, we should look for alarm features which include [34]:

1. Evidence of overt or occult gastrointestinal bleeding: hematemesis, melena, anemia, heme-positive stool

alternative non-endoscopic strategies can be considered in the absence of alarm

1. H. pylori test and treat: In a population where the prevalence of H. pylori

Stool for H. pylori antigen and urea breath tests are most accurate not only for identification of active H. pylori infection but also for confirmation of eradication of infection. Serology for H. pylori antibody is less reliable and cannot be used for

2. Empiric acid suppression therapy: In a population where the prevalence of H. pylori infection is 10% or less, empiric PPI therapy is most cost-effective. In case of PPI failure, test-and-treat strategy should be applied as mentioned

Physicians should make decision between test-and-treat strategy and empiric PPI therapy for 4–6 weeks in the absence of alarm features. EGD should be considered in the presence of alarm features. The American College of Gastroenterology (ACG)

Risk factors for the development of PUD should be evaluated. Patients should be advised to avoid NSAID intake, stop smoking, and limit drinking of alcohol. If the patient is H. pylori positive, it should be treated, and eradication of infection should be confirmed ≥4 weeks after completion of therapy [37]. There are different

and Canadian Association of Gastroenterology (CAG) suggest that patients ≥60 years of age presenting with dyspepsia should undergo upper endoscopy to

infection exceeds 20%, patients should get tested for H. pylori infection and, if positive, should be treated by anti-H. pylori therapy [36, 37]. If H. pylori test is negative or patients still remain symptomatic after anti-H. pylori therapy, they should be given a 4–6 week course of proton pump inhibitor (PPI) therapy. If PPI therapy fails, patients should be reassured, diagnosis should be reassessed, and EGD should be considered. If patients respond to anti-H. pylori treatment or PPI therapy, they can be managed without further investigation [38].

features:

Figure 2. Gastric ulcers.

Peptic Ulcer Disease

DOI: http://dx.doi.org/10.5772/intechopen.86652

confirmation of cure.

above [39].

4. Management

7

4.1 Uncomplicated PUD

exclude any organic cause [40].


Diagnostic tests should include complete blood count, esophagogastroduodenoscopy (EGD), or upper gastrointestinal (UGI) series and tests for detection H. pylori infection. EGD is preferred over UGI series as it has much higher diagnostic yield and mucosal biopsy can be taken. Endoscopic views of clean-based duodenal ulcer and gastric ulcer are shown in Figures 1 and 2. During endoscopy, the location, size, depth, and any sign or stigmata of bleeding can be evaluated, and gastric biopsy from antrum, body, and incisura can be taken to detect H. pylori infection [35]. Although endoscopic evaluation is the gold standard of diagnosis of PUD, it is not cost-effective to perform EGD in all suspected cases of PUD. The

Figure 1. Duodenal ulcer.

experience nausea and vomiting. About 30% of elderly patients with PUD may remain asymptomatic [32]. This is also common in patients taking NSAIDs. Silent

Physical examination can be entirely normal except epigastric tenderness.

A thorough history and physical examination is necessary to evaluate the patient. In each case, we should look for alarm features which include [34]:

1. Evidence of overt or occult gastrointestinal bleeding: hematemesis, melena,

PU generally presents with gastrointestinal bleeding [33].

4.Left supraclavicular lymphadenopathy (Virchow's nodes)

7. Symptom of obstruction: persistent vomiting

8.Malignancy: anorexia, unintended weight loss

6. Symptom of impending perforation: severe persistent epigastric pain

Diagnostic tests should include complete blood count, esophagogastroduodenoscopy (EGD), or upper gastrointestinal (UGI) series and tests for detection H. pylori infection. EGD is preferred over UGI series as it has much higher diagnostic yield and mucosal biopsy can be taken. Endoscopic views of clean-based duodenal ulcer and gastric ulcer are shown in Figures 1 and 2. During endoscopy, the location, size, depth, and any sign or stigmata of bleeding can be evaluated, and gastric biopsy from antrum, body, and incisura can be taken to detect H. pylori infection [35]. Although endoscopic evaluation is the gold standard of diagnosis of PUD, it is not cost-effective to perform EGD in all suspected cases of PUD. The

3.2 Diagnosis and evaluation

Digestive System - Recent Advances

2. Iron deficiency anemia

5. Palpable abdominal mass

3. Dysphagia

9. Age: >55 years

Figure 1. Duodenal ulcer.

6

anemia, heme-positive stool

alternative non-endoscopic strategies can be considered in the absence of alarm features:

1. H. pylori test and treat: In a population where the prevalence of H. pylori infection exceeds 20%, patients should get tested for H. pylori infection and, if positive, should be treated by anti-H. pylori therapy [36, 37]. If H. pylori test is negative or patients still remain symptomatic after anti-H. pylori therapy, they should be given a 4–6 week course of proton pump inhibitor (PPI) therapy. If PPI therapy fails, patients should be reassured, diagnosis should be reassessed, and EGD should be considered. If patients respond to anti-H. pylori treatment or PPI therapy, they can be managed without further investigation [38].

Stool for H. pylori antigen and urea breath tests are most accurate not only for identification of active H. pylori infection but also for confirmation of eradication of infection. Serology for H. pylori antibody is less reliable and cannot be used for confirmation of cure.

2. Empiric acid suppression therapy: In a population where the prevalence of H. pylori infection is 10% or less, empiric PPI therapy is most cost-effective. In case of PPI failure, test-and-treat strategy should be applied as mentioned above [39].

Physicians should make decision between test-and-treat strategy and empiric PPI therapy for 4–6 weeks in the absence of alarm features. EGD should be considered in the presence of alarm features. The American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) suggest that patients ≥60 years of age presenting with dyspepsia should undergo upper endoscopy to exclude any organic cause [40].
