Excessive acid secretion

[What causes excessive acid production)

 

Diminished mucosal defenses

Most gastric ulcers are believed to be related to impaired mucosal defenses, because the acid and pepsin secretory capacity of some affected patients is normal or even below normal.

The risk factors (NSAID ingestion, smoking, alcohol use, psychologic stress, H pylori infection) that have been associated with gastric ulcer probably act by diminishing one or more mucosal defense mechanisms.( What are these???)

Motility defects

Motility defects have been proposed to contribute to development of gastric ulcer in at least three ways: (1) by a tendency of duodenal contents to reflux back through an incompetent pyloric sphincter (bile acids in the duodenal reflux material act as an irritant and may be an important contributor to a diminished mucosal barrier against acid and pepsin); (2) by delayed emptying of gastric contents, including reflux material, into the duodenum; and (3) by delayed gastric emptying and hence food retention, resulting in increased gastrin secretion and gastric acid production. It is not known whether these motility defects are a cause or a consequence of gastric ulcer formation.

Mucosal ischemia

Mucosal ischemia may also play a role in the development of a gastric ulcer.

H pylori infection

H pylori can cause acid-peptic disease by multiple mechanisms, including altered signal transduction, resulting in increased inflammation, increased acid secretion, and diminished mucosal defenses. It may also affect apoptosis in the GI tract. Despite the high rate of association of inflammation with H pylori infection, the important role of other factors is indicated by the fact that only about 15% of H pylori–infected individuals ever develop a clinically significant ulcer. These other factors (both genetic and environmental, such as cigarette smoking) must account for the individual variations and are pathophysiologically important. Nevertheless, the role of H pylori is of particular clinical importance because, of patients who do develop acid-peptic disease, almost all have H pylori infection. Furthermore, treatment that does not eradicate H pylori is associated with rapid recurrence of acid-peptic disease in most patients. Recent studies have also associated different strains of H pylori with different forms and degrees of acid-peptic disease and implicated H pylori infection in the development of GI tract cancers. Cornerstones of therapy for this patient include discontinuation of ibuprofen, proton pump inhibitors to decrease acid production, and antibiotics to treat the H pylori infection.

H pylori generally causes mucosal injury and ulcer complications through inflammation and cytokines. Despite a vigorous systemic and mucosal humoral response, antibody production does not lead to eradication of the infection.

H pylori is a highly heterogeneous bacterium. A combination of microbial and host factors determines the outcome of H pylori infection. The virulence of the organism, host genetics, and environmental factors affect the distribution and severity of gastric inflammation and level of acid secretion.

Several H pylori virulence factors have been associated with gastric atrophy, intestinal metaplasia, and risk of disease. For example, the presence of H pylorivirulence factors that affect the induction of proinflammatory cytokine release or adhesion to the epithelial cell partly explain geographic differences in the incidence of gastric cancer. Several of these bacterial virulence factors include the Cag pathogenicity island (cagPAI), the vacuolating cytotoxin (VacA), and the blood group antigen-binding adhesin (BabA) and are associated with a more severe clinical outcome. Other virulence factors include H pylori neutrophil-activating protein and cell-wall polysaccharide. H pylori that express the cytotoxin-associated gene A (CagA-positive strains) reportedly represent virulent strains having greater interactions with humans. Several genes in a genomic fragment that make up a cagPAI encode components of a type IV secretion island that translocates CagA in host cells and affects cell growth and cytokine production. CagA is a highly antigenic protein that is associated with a prominent inflammatory response by eliciting interleukin-8 production. H pylori strains that also express active forms of VacA or the outer membrane proteins BabA and OipA are similarly associated with a higher risk of diseases than are strains that lack these factors.

H pylori is a spiral gram-negative urease-producing bacterium that can be found in the mucus coating the gastric mucosa or between the mucus layer and gastric epithelium. Multiple factors enable the bacterium to live in the hostile stomach acid environment, including its ability to produce urease, which helps alkalinize the surrounding pH. H pyloriinfection is most commonly acquired in childhood and results in a chronic active gastritis that is usually lifelong without specific treatment. Risk factors for acquiring H pylori include low socioeconomic status, household crowding, and country of origin. The prevalence of H pylori varies among different countries and is significantly higher in developing than in industrialized countries. The majority of infected persons remain asymptomatic, but approximately 10–15% develop peptic ulcer disease during their lifetime. In addition to causing chronic gastritis and peptic ulcers, H pylori has been associated with the development of gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In 1994, the International Agency for Research on Cancer classified H pylori as a group 1 carcinogen and a definite cause of gastric cancer in humans.

Infection with H pylori increases the risk of peptic ulcers and GI bleeding from threefold to sevenfold. Depending on the population, H pylori is present in up to 70–90% of patients with duodenal ulcers and up to 30–60% of gastric ulcers. Multiple clinical studies show that H pylori eradication reduces ulcer recurrence to less than 10% as compared with recurrences of 70% with acid suppression alone. 

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NSAIDS

Prostaglandins (NSAIDs) are known to increase mucosal blood flow as well as bicarbonate and mucus secretion and to stimulate mucosal cell repair and renewal. Thus, their deficiency, resulting from NSAID ingestion or other insults, predisposes to gastritis and gastric ulcer.

, nonsteroidal anti-inflammatory drugs (NSAIDs), and aspirin use are the most common causes.

 

Other medications (eg, potassium chloride, use of steroids, bisphosphonates, sirolimus, mycophenolate mofetil, fluorouracil)

[Neoplasia

Acid hypersecretory disorders (eg, Zollinger-Ellison syndrome)

Hyperparathyroidism

Crohn disease

Sarcoidosis

Myeloproliferative disorder

Systemic mastocytosis

Other rare infections (eg, cytomegalovirus, herpes simplex, tuberculosis)

Critically ill patients with severe burns, head injury, physical trauma, or multiple organ failure]

 

Cigarette smoking also promotes the development of ulcers and may interact with H pyloriand NSAIDs to increase mucosal injury. Smoking also impairs ulcer healing and increases ulcer recurrence. Several studies suggest that alcohol use and diet do not appear to increase ulcer formation, whereas emotional stress may predispose some individuals to ulcers. Critically ill patients with severe burns, physical trauma, or multiple organ failure also have an increased risk of developing gastroduodenal ulcers and associated complications. There is also an association of peptic ulcers with medical conditions such as chronic obstructive lung disease and chronic renal failure, but the mechanisms are unclear. A genetic susceptibility has been reported but is thought to stem mainly from intrafamilial infection with H pylori. Recent studies now suggest that an increasing proportion of ulcers are idiopathic, as they are not related to H pylori, NSAIDs, aspirin, acid hypersecretion, or any other known cause. In a pooled analysis of six clinical trials, for example, 27% of duodenal ulcers had no etiologic cause identified. In other studies, the proportion of idiopathic ulcers that is H pylori–negative and NSAID-negative without any other detectable causes ranges from 20% to 44%. Patients who develop bleeding from H pylori–negative and non-NSAID idiopathic ulcers have also been shown to have a nearly fourfold increased risk of recurrent GI bleeding and higher mortality as compared to patients with bleeding from H pylori–associated ulcers. These idiopathic ulcers appear to be more common in older people with comorbid conditions and have a high rate of relapse.

 

 

Suppression of gastric acid secretion using pharmacologic agents heals ulcers and reduces future complications. Only a few patients have an underlying acid hypersecretory state causing ulcers. For example, fewer than 1% of patients with duodenal ulcers have a gastrin-secreting tumor causing profound acid secretion as part of the Zollinger-Ellison syndrome. Approximately 3–5% of gastric ulcers represent malignancy including adenocarcinoma, lymphoma, or metastatic lesions. Other infections and conditions that increase ulcer formation include cytomegalovirus or herpes simplex (especially among immunosuppressed patients), tuberculosis, Crohn disease, the use of other non-NSAID medications, hyperparathyroidism, sarcoidosis, myeloproliferative disorder, and systemic mastocytosis.

 

 

 

 

 

 

 

The pathogenesis of peptic ulcers is multifactorial and arises from an imbalance of protective and harmful factors.

PUD results when excessive (gastric acid, pepsin) overwhelm “defensive” factors involved in mucosal resistance (gastric mucus, bicarbonate, microcirculation, prostaglandins, mucosal “barrier”)+++++++++++++++++++++++++++

 

In 1984 Marshall and Warren reported that a curved bacillus, initially named Campylobacter pyloridis and subsequently classified as H pylori, was linked to ulcers.

Multiple studies have since shown that eradication of H pylori significantly reduces the rate of ulcer recurrence.

Another major risk factor for peptic ulcers is the use of NSAIDs and aspirin. These medications generally exert their therapeutic and toxic effects by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which, in turn, impair mucosal protection and promote ulcers. The treatment of ulcer patients has been revolutionized since the development of the acid-suppressive medications such as the histamine-2 (H2)-receptor blockers and proton pump inhibitors (PPIs), the synthetic prostaglandin misoprostol, and the selective COX-2 inhibitors.

Only a small fraction of ulcers are associated with neoplasia or caused by acid hypersecretory states such as Zollinger-Ellison syndrome and other rare disorders.

 

A peptic ulcer is a defect in the gastric or duodenal mucosa that extends through the muscularis mucosa into the deeper layers of the wall and usually > 5 mm in diameter. In contrast, erosions are small and superficial mucosal lesions

It may also occur in esophagus, pyloric channel, duodenal loop, jejunum, and Meckel’s diverticulum.

 

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A systematic review of the literature on the epidemiology of peptic ulcer disease estimated an annual incidence ranging from 0.10% to 0.19% for physician-diagnosed peptic ulcers and from 0.03% to 0.17% for peptic ulcers diagnosed during hospitalization. In the United States, over 4 million individuals are affected by peptic ulcers, and approximately 15,000 die from ulcer complications each year. Over two-thirds of ulcer patients develop the disease between the ages of 25 and 64 years. The lifetime prevalence of peptic ulcers is 12% in men and 10% in women. The impact of peptic ulcer disease on US health care costs is substantial, with direct and indirect costs totaling over an estimated $10 billion per year. In addition, peptic ulcer complications adversely affect functional status and quality of life.

 

 

Drugs used in acid-peptic disease reduce intragastric acidity by manipulating systems controlling acid secretion, promote mucosal defense or, in the case of peptic ulcers, eradicate the bacterium Helicobacter pylori, which is detectable in over 80% of patients with duodenal ulcers.

1. Reduce the amount of acid made by the stomach

a. H2 Blockers

  • nizatidine (Axid)
  • famotidine (Pepcid, Pepcid AC)
  • cimetidine (Tagamet, Tagamet HB)
  • ranitidine (Zantac)

H2 blockers reduce the amount of acid made by your stomach.

b. Proton Pump Inhibitors for 10 to 14 days,

 

 


Schematic model of physiologic control of hydrogen ion (acid) secretion by the gastric parietal cells, which are stimulated by gastrin (acting on gastrin/CCK-B receptors), acetylcholine (ACh; M3 receptor), and histamine (H2 receptor).

Acid is secreted across the parietal cell canalicular membrane by the H+/K+ ATPase proton pump into the gastric lumen. The gastrin that is secreted by antral G cells in response to intraluminal dietary peptides acts directly on parietal cells and also stimulates release of histamine from enterochromaffin-like (ECL) cells. The vagus nerve stimulates postganglionic neurons of the enteric nervous system to release ACh, which acts on parietal and ECL cells. In the antrum, release of gastrin-releasing peptide (GRP) from postganglionic neurons directly increases gastrin release, whereas release of ACh indirectly increases gastrin secretion by inhibiting release of somatostatin from antral D cells. The increase in intraluminal H+ concentration causes D cells to release somatostatin and thereby inhibit gastrin release from G cells. CCK, cholecystokinin; R, receptor. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology,12th ed. McGraw-Hill, 2012: Fig. 62–1.)

Image not available.

 

 

 

 

Eradication of H. pylori,

  • Eradication o fH. pylori, involving the use of at least two antibiotics

Gastric ulcer biopsy or documentation of complete healing is necessary to exclude gastric malignancy

 

Management of Upper GI Bleeding

Patients with significant upper GI bleeding who are suspected of having an ulcer should be started on an intravenous PPI followed by prompt endoscopy. A restrictive transfusion strategy is also generally recommended for all patients with acute upper GI bleeding. A hemoglobin threshold for transfusion of 7 g/dL has been shown to significantly decrease further bleeding and adverse events, as well as improve survival.

The administration of an intravenous PPI prior to endoscopy downstages the ulcer lesion and decreases the need for hemostasis therapy as compared to placebo but does not improve the rates of rebleeding, surgery, and mortality.

A meta-analysis has shown that the use of intravenous PPI therapy after endoscopic hemostasis does decrease rebleeding, need for repeat endoscopic therapy, and surgery.

Intravenous therapy also reduced mortality in Asian trials and in high-risk patients with active bleeding or a nonbleeding visible vessel. Intravenous PPI therapy should be maintained for the first 72 hours since most rebleeding occurs during this time.

Other meta-analyses of randomized studies also suggest that intermittent or twice-daily dosing of an intravenous PPI does not appear to be inferior to a high-dose continuous infusion.

The additional use of a promotility agent such as erythromycin ormetoclopramide prior to endoscopy should be considered in patients suspected of having a substantial amount of blood in the upper GI tract. This potentially improves the examination during upper endoscopy.1

 

Endoscopic hemostasis is recommended for high-risk ulcers, based on their endoscopic appearance and likelihood of further bleeding. High-risk ulcers that should be treated include those that are actively spurting or oozing blood, those that have a nonbleeding visible vessel, or those that have an adherent clot. Hemostasis can be performed through a combination of coagulation of bleeding sites (thermocoagulation therapy), placement of hemoclips (mechanical therapy), and injection of epinephrine, alcohol, or a sclerosant (injection therapy). Thermocoagulation or clip placement, either alone or with epinephrineinjection, has been shown to be effective, but epinephrine injection alone is not recommended. Second-look endoscopy may be useful in selected patients but is also not routinely recommended. Nonhealing gastric ulcers should be biopsied or closely followed to exclude underlying neoplasia.

 

 

 

 

 

 

Perforation

1. Initial management includes insertion of a nasogastric tube,

2. Intravenous volume replacement,

3. Intravenous proton pump inhibitor (PPI),

startwith an 80 mg loading dose and 8 mg per hour of the PPI; however, lower doses and twice daily bolus dosing may be equally effective, as noted above. (See 'Acid suppressive therapy' above.)

and broad spectrum antibiotics. A decision is then made about whether the patient requires surgery. (See 'Operative versus nonoperative management' below.)

 

Antibiotics — The antibiotic regimen for a patient with a perforated ulcer should cover enteric gram negative rods, anaerobes, and mouth flora. The antimicrobial susceptibility patterns for gram negative rods such as Escherichia coli have changed, with increasing resistance to antibiotics. Thus, knowledge of local and regional susceptibility patterns for Enterobacteriaceae is essential in selecting empiric therapy [80-82]. 

Reasonable choices for initial empiric antibiotic therapy in the setting of perforated ulcer include a combination beta lactam/beta lactamase inhibitor (such as ampicillin-sulbactam, ticarcillin-clavulanic acid, or piperacillin-tazobactam), or a combination of a third-generation cephalosporin and metronidazole. In areas where the local prevalence of extended spectrum beta-lactamase (ESBL) producing organisms and pathogenic E. coli is common, empiric monotherapy with a carbapenem such as ertapenem, imipenem, or meropenem is appropriate. (See "Pathogenic Escherichia coli" and "Extended-spectrum beta-lactamases".)

The importance of administering an appropriate initial empiric antibiotic regimen was illustrated in a review of 425 patients who required surgery for community-acquired secondary peritonitis, including patients with perforated peptic ulcers [83]. In 13 percent of patients, the initial antibiotic regimen was inappropriate, defined as not covering all bacteria subsequently isolated or not covering both aerobic and anaerobic organisms in the absence of culture results. Resolution of the infection after primary surgery was significantly less likely with an inappropriate regimen (53 versus 79 percent) and failure to achieve clinical success was associated with a six-day prolongation in hospitalization (20 versus 14 days).

Operative versus nonoperative management — A major decision when treating patients with ulcer perforation is whether and when to operate. After resuscitation, emergent operation and closure with a piece of omentum is the standard of care for patients with an acute perforation and a rigid abdomen with free intraperitoneal air. If the patient is stable or improving, especially if spontaneous sealing of the perforation has been demonstrated, nonoperative management with close monitoring is a reasonable option.

With any free perforation, regardless of the presence or size of the leak, if the patient's status is deteriorating, urgent surgery is indicated. Prolonged efforts to establish a diagnosis or pursue nonoperative care despite worsening status can be counterproductive, since a needed operation will be delayed. In addition, surgery is indicated in circumstances where the cause of an acute abdomen has not been established or the patient's status cannot be closely monitored. (See "Surgical management of peptic ulcer disease", section on 'Perforated peptic ulcer'.)

 

●The efficacy of initial conservative therapy with a nasogastric tube, antibiotics, and H2 blockers was compared with immediate laparoscopic surgical repair in a randomized trial of 83 patients with a perforated peptic ulcer [84]. Surgery was required in 11 of 40 patients (28 percent) in the conservative therapy group because of failure to improve clinically after 12 hours. The other 29 patients in the conservative therapy arm were successfully managed without surgery. The two groups did not differ significantly in terms of morbidity or mortality. However, the hospital stay was 35 percent longer in the group treated conservatively. Also, patients over 70 years old were less likely to respond to conservative treatment. The authors concluded that an initial period of nonoperative treatment with careful observation was safe in patients under age 70 years.

 

●A prospective study of 82 patients with perforated peptic ulcers treated patients with nasogastric suction and intravenous H2 receptor antagonists [85]. If patients did not show clinical improvement after 24 hours, surgery was performed. With this approach, surgery was avoided in 44 patients (54 percent). Factors associated with surgery included the size of the pneumoperitoneum, abdominal distension, heart rate >94 beats per minute, pain on digital rectal examination, and age >59 years. Overall mortality in the study was 1 percent.

 

Data also suggest that if spontaneous sealing occurs, patients do well without surgery. A study of 152 patients whose perforations sealed spontaneously found re-leakage in only two patients, comparing favorably with postoperative re-leak rates [77]. The probability of sealing with nonoperative care and intravenous PPIs or H2 receptor antagonists has not been studied; however, over 50 percent of patients with perforated duodenal ulcers have sealed spontaneously when first examined.

Some patients require nonoperative management because severe comorbid illnesses preclude surgery [86,87]. In a retrospective series of 30 high-risk patients treated nonoperatively, 11 patients were treated with H2 receptor antagonists (prior to 1996) and 19 were treated with omeprazole 40 mg daily (1996 and later) [86]. Mortality was 64 percent in the early period and 11 percent in the later period. Hypotension upon presentation was a major risk factor for a poor outcome. These data raise the hypothesis that PPI treatment promotes sealing of perforations. However, a low mortality rate (3.5 percent) was also seen in a series of 84 high-risk patients treated with percutaneous drainage and H2 receptor antagonists [87].

Nonoperative management may also be considered for patients with delayed presentations. If the patient has a persistent leak across the perforation, surgery may be indicated, but can be complicated by peritoneal contamination. Other options in this setting include nonoperative care with percutaneous peritoneal drainage, especially for patients who are not good surgical candidates [87].

Patients with perforated ulcers should have an upper endoscopy to look for evidence of malignancy, to biopsy for H. pylori, and to assess for ulcer healing. To allow the perforation to heal, we suggest waiting at least two weeks prior to performing an upper endoscopy. If the procedure does not need to be done urgently, we prefer to wait six to eight weeks to allow for ulcer healing. At that time, biopsies can be obtained to look for infection with H. pylori and to rule out malignancy (particularly in the case of a nonhealing gastric ulcer). (See "Peptic ulcer disease: Management", section on 'Endoscopy after initial therapy'.)

Surgical approach — For patients who require surgery for a perforated ulcer, the surgical approach depends upon the location of the ulcer. This topic is discussed in detail elsewhere. (See "Surgical management of peptic ulcer disease", section on 'General principles of ulcer surgery'.)

 

Management of Perforation

 

 

Perforation

GI bleeding, obstruction, penetration, and perforation.

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A 23-year-old man has been treated with cimetidine (Tagamet) for 6 months. 
What is the mechanism of action of this drug?
A-Adds a protective membrane to gastric mucosa
B-Blocks the secretion of hydrochloric acid
C-Neutralizes gastric acidity
D-Stimulates H2 receptors

Answer

The correct answer is B

Cimetidine blocks H2 receptor so, it blocks the secretion of hydrochloric acid. It is H2 receptor antagonist.

 

Which of the following is an appropriate test of cure for H. pylori?

The correct answer is A.

 The only test listed that will adequately test for cure of H. pylori after treatment is the stool antigen test. This test looks for the actual presence of H. pylori excreted in the stool, not the antibodies produced in response to the bacteria or the function of the bacteria. Remember that only 57% of patients are antibody-negative to H. pylori a year after successful treatment. Thus, antibody titers cannot document eradication. The CLO and breath tests mentioned are functional tests for the presence of H. pylori. The CLO test is done on biopsy specimens and documents the presence of urea splitting. The same is true for the breath urea test, which is performed on breath samples. In both of these tests, urea is ingested. If H. pylori is present, increased CO2 is generated that can be measured in the blood or breath. 

 

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