Updated: 03/17/08 03:45 PM
HOME HEAL EDUCATE RESEARCH DIRECTORY OUTREACH


Authors: C.E. Rubin and D.R. Saunders
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I. Chronic Disruptions of Gastric Mucosa

Mucosal defenses against acid & pepsin: Why doesn't the upper gut digest itself? Peptic ulceration is believed to result from the confrontation between luminal aggression and mucosal defense. The prevalence of peptic ulcer disease in our society is estimated to be 1%. Among habitual users of aspirin-like compounds, prevalence is 10-20% for gastric ulcer, and 2-5% for duodenal ulcer. Some of the important factors in mucosal defense may be:

Bicarb secreted from mucosa.
  1. The mucus-bicarbonate barrier. Both fundal and antral mucosa secrete alkaline bicarbonate and mucus. These two substances impede acid and pepsin digestion of the gastric mucosa. Prostaglandins and nitric oxide (NO) seem to have an important local role in mucosal defense. Their synthesis is increased in response to injurious stimuli. Prostaglandins and NO enhance mucus production and bicarbonate secretion by gastroduodenal mucosa. Anti-inflammatory drugs depress mucus, and prostaglandin production.
Bile, pancreatic juice, and mucus.
  1. Neutralizing secretions of the upper gut include bile and pancreatic juice as well as mucus and bicarbonate secreted from Brunner's glands in the duodenum
Epithelial resistance to “backdiffusion” of H+.
  1. Resistance of the gastric epithelium and mucus barrier to acid. It is thought that the gastric epithelium provides an effective barrier to the absorption of secreted H+. Substances such as aspirin, bile salts, and bacterial products damage the gastric epithelium so that appreciable "backdiffusion" of H+ can occur. It is theorized that the gastric absorption of secreted H+ can lead to mucosal destruction: peptic digestion of the injured tissue may lead to ulceration. The evidence to support these concepts is inconclusive.
Rapid epithelial renewal
  1. Rapid renewal of the surface epithelium. This is normally accelerated after injury, but it may be depressed by tobacco.
1. Helicobacter pylori

Chronic gastritis Helicobacter pylori are curved, microaerophilic, highly motile gram negative bacteria which have a predilection for the mucous layer overlying antral or fundal gastric mucosa. They are rarely seen to be invading the underlying epithelium by light-microscopy. A smoldering inflammation of the underlying mucosa afflicts the antrum predominantly and is lifelong unless treated. Over time, atrophy of pyloric glands, and replacement of antral epithelium with intestinal goblet cells can occur. Infection is thought to occur early in life through oral-oral, or fecal-oral transmission. Prevalence of infection with H. pylori is higher in impoverished, crowded people and increases with age. In our society, 60% of octogenarians may be infected. Obviously, factors other than infection with H. pylori determine duodenal ulcer disease which, fortunately, does not afflict 60% of such venerable people. Proposed virulence factors include:

H. Pylori virulence factors
  1. Spiral motility which allows burrowing into the mucous layer where the neutral pH allows optimal growth.


  2. Abundant production of urease hydrolyzes urea to ammonia and CO2. The ammonia can neutralize HC1, thereby protecting H. pylori from acid-peptic digestion, and it can injure mucosal cells. In addition, H. pylori elaborates mucinase and catalase. The urease enzyme is the basis for several tests for H. pylori, including the urea breath test, and is the antigen upon which serology is based.


  3. Adhesins allow the bacilli to attach the superficial gastric epithelium.


  4. Some strains produce cytotoxins (CagA, VacA) which are associated with more mucosal inflammation.
NSAIDs NSAIDs can cause local injury, but they also depress prostaglandin and NO synthesis by gastric and duodenal mucosa, which, in turn, adversely affects the mucus-bicarbonate barrier, mucosal blood flow, and epithelial proliferation. NO is an important down-regulator of neutrophil adherence and activation.

Oxygen-derived free radicals and proteases from activated neutrophils contribute to tissue injury. In humans, prostaglandins are synthesized by at least two cyclooxygenases, COX-1 and COX-2. Constitutively expressed COX-1 is responsible for the production of prostanoids that regulate such functions as platelet aggregation and gastric mucosal protection. COX-2 is induced in many tissues by cytokines so that COX-2 mediates synthesis of prostanoids generated in inflammation and pain.

Most NSAIDs inhibit both COX-1 and COX-2. Selective COX-2 inhibitors such as celecoxib can relieve arthritis pain possibly with a reduced risk of gastrointestinal toxicity.

2. Classification of Chronic Peptic Ulcer Disease

H. pylori
  1. Infection with H. pylori is associated with 80% of duodenal ulcers and with 75% of gastric ulcers.


  2. NSAIDS are associated with 25% of gastric ulcers and 5% of duodenal ulcers.
Acidic aggression
  1. Overwhelming acid-peptic aggression. In gastrinoma, the pH in the proximal small intestine may be < 2, resulting in ulceration. Ingesting NSAIDs potentiates acid aggression.
a. Gastric Ulcer:

Histology can help differentiate NSAIDS from H. pylori The usual gastric ulcer patient tends to secrete normal or subnormal amounts of gastric acid so that pathogenetic mechanisms focus on decreased resistance of gastric mucosa to acid and pepsin. Patients colonized with H. pylori have mucosal inflammation surrounding the ulcer, and they typically have gastritis of the fundus, and body of the stomach as well as the antrum. If the surrounding mucosa is uninflamed, then NSAID-induced ulceration is almost certain. Rarely, a gastric ulcer is due to gastric carcinoma.

b. Duodenal Ulcer:

Pathogenesis Patients with duodenal ulcer tend to secrete normal or elevated amounts of gastric acid. The ulcer is usually located in the first portion of the duodenum (duodenal bulb). The increased capacity of duodenal ulcer patients to secrete HC1 relates to an increased number of parietal cells in the fundal gland area and an increased drive to secrete acid.

About 80% of patients with duodenal ulcers have antral gastritis due to H. pylori. Antral infection with H. pylori can increase fundal secretion of acid by decreasing antral release of somatostatin. Patients whose antrum is infected with H. pylori have an enhanced release of gastrin after a meal when they are compared with uninfected controls. After the infection is cured, the meal-stimulated gastrin release returns to normal.

c. Pathology of Peptic Ulcer:

Characteristics:






Healing: 		A chronic peptic ulcer has much fibrous tissue and cellular infiltration in its floor and at its margins. The ulcer base and several cm around its circumference may be relatively avascular. At endoscopy a benign peptic ulcer appears as a round or oval depressed area with a grey base, and with an edematous surrounding border of mucosa. The radiologists usually see a bulge of barium extending outside the profile of the barium-filled stomach. During healing, granulation tissue grows up from the base of the ulcer and is covered by epithelium growing in from the margins of the ulcer. This healing process is slower than that of an acute ulcer and considerable scarring occurs. Newly formed mucosa which grows over relatively avascular granulation tissue is liable to break down more easily and form a recurrent ulcer.

d. Complications of Peptic Ulcer:










Guaiac test is insensitive, and non-specific
  1. Hemorrhage:

    An ulcer may erode into a blood vessel. Blood in the stomach is rapidly modified by gastric acid to become brown and granular ("coffee grounds"). Hematemesis (vomiting blood) may be coffee grounds or bright red. Blood passing through the intestine can be altered by colonic bacteria to produce a "tarry" stool (melena). Invisible or "occult" blood in stool may be detected by the guaiac test which is based on the presence of a hemoglobin peroxidase. This test is performed by smearing a small bit of stool on guaiac-impregnated paper. Two drops of H2O2 are then placed upon the specimen. Immediate development of a dark blue color is a strong positive. Slow reactions or the development of a green color are considered negative. Bismuth, or iron-containing compounds can cause black guaiac-negative stool. Myoglobin in red meat, and peroxidases in fruits can result in guaiac-positive stools.


Perforate into peritoneal cavity: Chemical
Peritonitis
→ Bacterial Peritonitis.
  1. Perforation:

    When ulcers of the anterior surface of the duodenum or stomach perforate, gastric contents may be spilled into the peritoneal cavity. Chemical peritonitis is followed in approximately 12 hours by bacterial peritonitis, and death may ensue unless the surgeon intervenes promptly. Why is the peritonitis initially chemical? How does it become bacterial? Posterior ulcers may erode into branches of the gastroduodenal artery, with resultant hemorrhage. In posterior perforation gastric contents may be localized to the lesser omental sac.


  2. Obstruction:

    Obstruction of the gastric outlet may result from chronic peptic ulceration and scarring near the pylorus.
e. Clinical Aspects of Peptic Ulcer Disease:

Usually the most prominent symptom is periodic epigastric pain which occurs 2-3 hours after eating or at nighttime and which is relieved by food or alkali. The diagnosis is confirmed by X-ray using barium or by endoscopy.

f. Medical Treatment of Benign Gastric
and Duodenal Ulcer:

Need pepsin + acid to get an ulcer. A peptic ulcer cannot occur unless the chemical conditions for peptic digestion of the mucosa exist. Pepsin is different from most luminal digestive enzymes because it is optimally active near pH 2 rather than close to neutrality. Hence, the dictum "no acid - no ulcer." Some measures that have been purported to reduce gastric acid include:



Measures to ↓ acid are mentioned below:

“Bland” diets do not hasten healing.







Coffee & wine are stimulants of acid secretion.

Mg(OH)2 & CaCO3 are most effective antacids





Side effects:





Antacid do help healing DU
  1. Diet:

    The strictly “bland” diets of yesteryear, such as hourly milk or cream do not increase the healing rate of peptic ulcers. It makes reasonable sense to deny coffee and wine, especially when the stomach is empty because these two chemicals are stimulants of gastric acid secretion. There is evidence that smoking is not good for ulcers as it stimulates acid secretion. There is no evidence that buffering gastric juices with several small meals/day hastens healing.


  2. Antacids:

    Most single doses of antacid are effective for only about 30 minutes although antacids administered one hour after a meal empty more slowly from the stomach and may reduce gastric acid for 2 - 3 hours. Antacids vary in their neutralizing capacity: Mg(OH)2 and CaCO3 in tablet or in liquid form are far more effective than Al(OH)3. Al(OH)3 can be almost inert as a tablet and its liquid preparations vary in their neutralizing capacity. Mg++ produces diarrhea. A1(OH)3 may cause constipation. CaCO3, in sufficient doses, can lead to hypercalcemia which increases gastric acid secretion by enhancing gastrin release, and by increasing Ca++ medicated parietal cell secretion. The usual single dosage of an emulsion of magnesium-aluminum hydroxide mixture is 15-30 cc and of calcium carbonate magnesium mixtures is 0.5-1.0 g. There is evidence that antacids increase the rate of healing of duodenal ulcers.



Anticholinergics are not very helpful
  1. Anticholinergics:

    These drugs, of which atropine is the prototype, inhibit the actions of acetylcholine on structures innervated by postganglionic cholinergic nerves. A "medical" vagotomy cannot be achieved in patients because the high doses required induce side-effects such as blurring of vision, dry mouth, urinary retention and mental confusion. For this reason, anticholinergics are not commonly used clinically for ulcer healing.



80% of DU patients healed in 6 weeks with H2- blockers, but 90% recur in one year
  1. Histamine H2 Receptor Antagonists:

    Histamine H2 receptor antagonists are inactive analogues of histamine. H1 receptor sites (stimulation of contraction of smooth muscle in bronchi and in gut) are blocked by conventional antihistamines such as mepyramine. H2 receptor sites regulate acid secretion, atrial contraction, and uterine contraction. Prospective controlled trials have shown H2-blockers are effective in treatment of duodenal ulcer and of gastric ulcer and in preventing ulcer recurrence.



PPIs
block K+/H+ pump
  1. Proton-Pump Inhibitors (PPI):

    Substituted benzimidazoles, such as omeprazole, rabeprazole, pantoprazole, and lansoprazole, are long-acting inhibitors of gastric acid secretion because they inhibit proton pumps irreversibly. PPIs are weak bases which must be protected from gastric acid when they are ingested. From the blood, they partition into the acidic milieu of the parietal cell canaliculae where their sulfhydryl groups can bind to cystein(s) in the H+/K+ pumps. They are very useful in gastric and duodenal ulcer, in Z.E. syndrome, and reflux esophagitis.


Thought to coat base of ulcer & protect from digestion.

May ↑ prostaglandin synthesis.
No side effects.
  1. Sucralfate:

    Sucralfate is a polysulfated sucrose which is not absorbed. It is thought to coat the base of an ulcer, and thereby to protect the ulcer from acid-peptic digestion. Sucralfate may improve mucosal defense by enhancing production of prostaglandins by gastroduodenal mucosa. Sucralfate must be taken twice a day before meals. It is a useful agent because it has no important side effects except constipation.


“No H. pylori → no ulcer”









Serum IgG Ab can be used to diagnose H.pylori infection
  1. H. pylori:

    Ridding a patient of H. pylori cures most cases of gastric or duodenal ulcer disease. The strongest evidence that infection with H. pylori is important in duodenal ulcer disease comes from clinical trials which revealed that duodenal ulcer recurs much less frequently (10% vs. 90% of patients in one year) if H. pylori is eradicated with antibiotics; recurrent ulcers were associated with continued infection. Gastric ulcers, and duodenal ulcers, can be cured with antibiotics without H2-blockers if H. Pylori is eradicated. Several treatment regimens for H. pylori exist. The most commonly used is a proton pump inhibitor, clarithromycin, and amoxicillin. A recent NIH panel concluded that patients with gastric or duodenal ulcers should be offered combined therapy (antibiotics plus acid-inhibitors) unless the ulcers were associated with NSAIDs, and there was no evidence of infection with H.pylori (such as serum IgG antibody).
g. Surgical Treatment of Peptic Ulcer:

Elective surgery for peptic ulcer disease is rarely necessary, and it should not be considered until patients have stopped smoking, discontinued NSAIDS, and been treated successfully for H. pylori infection.

Surgical therapy may be desirable or necessary during urgent laparotomy for a complication of peptic ulcer disease.

Vagotomy as treatment of peptic ulcer. The most common form of surgical denervation for treatment of peptic ulcer disease is truncal vagotomy in which both right and left vagal trunks are cut proximal to hepatic and celiac branches. "Selective" vagotomy involves cutting the vagi distal to hepatic and celiac branches. The celiac branch is distributed to the pancreas, entire small bowel, and large bowel up to the mid-transverse colon. A third type of vagotomy involves cutting all of the small gastric branches except the terminal distal branches of the anterior and posterior nerves; in this "highly selective" vagotomy the fundus and body of the stomach are denervated but the motor supply to the antrum is intact.



Figure 8



Heineke – Mikuliez Pyloroplasty
Figure 9		 Gastroenterostomy
Figure 10

Because complete gastric vagotomy impairs gastric emptying of solids, some form of gastric drainage is necessary such as a pyloroplasty (enlarges the pyloric canal), or a gastroenterostomy (Figures 9, 10). Highly selective vagotomy seeks to preserve vagal innervation of the antrum, and pylorus (and the rest of the gastrointestinal tract), so gastric emptying should be unimpaired.



Figure 11

Subtotal gastrectomy Resection of approximately three-quarters of the stomach is called a subtotal gastrectomy. This involves all of the antrum and some of the fundal gland area. Variations among operations are concerned with how intestinal continuity is restored (Figure 11).



Antrectomy and vagotomy is an operation which seeks to abolish both the gastric and cephalic phases of gastric secretion. It is very effective in reducing acid secretion.

Surgical treatment does not always cure the disorder. The usual surgical treatments for peptic ulcer frequently, but not invariably, cure the disease. Unfortunately, these operations may cause bothersome (30%) or disabling (10%) symptoms. The mechanisms of most symptoms (i.e., surgical side-effects) include: abnormal gastric emptying, duodenogastric reflux, and disabling diarrhea secondary to vagotomy.


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