Ulcer disease: diagnosis, treatment .

Other peptic ulcers of stomach and duodenum

 

I.                  Ulcer disease: etiology of peptic ulcer disease, diagnosis, pathogenesis.

Gastric and duodenal ulcers usually cannot be differentiated based on history alone, although some findings may be suggestive Epigastric pain is the most common symptom of both gastric and duodenal ulcers. It is characterized by a gnawing or burning sensation and occurs after mealsclassically, shortly after meals with gastric ulcer and 2-3 hours afterward with duodenal ulcer.

In uncomplicated peptic ulcer disease (PUD), the clinical findings are few and nonspecific. Alarm features" that warrant prompt gastroenterology referral include bleeding, anemia, early satiety, unexplained weight loss, progressive dysphagia or odynophagia, recurrent vomiting, and family history of GI cancer. Patients with perforated PUD usually present with a sudden onset of severe, sharp abdominal pain. In most patients with uncomplicated PUD, routine laboratory tests usually are not helpful; instead, documentation of PUD depends on radiographic and endoscopic confirmation. Testing for H pylori infection is essential in all patients with peptic ulcers. Rapid urease tests are considered the endoscopic diagnostic test of choice. Of noninvasive tests, fecal antigen testing is more accurate than antibody testing and is less expensive than urea breath tests. A fasting serum gastrin level should be obtained in certain cases to screen for Zollinger-Ellison syndrome.

Upper GI endoscopy is the preferred diagnostic test in the evaluation of patients with suspected PUD. Endoscopy provides an opportunity to visualize the ulcer, to determine the presence and degree of active bleeding, and to attempt hemostasis by direct measures, if required. Perform endoscopy early in patients older than 45-50 years and in patients with associated so-called alarm features.

Most patients with PUD are treated successfully with cure of H pylori infection and/or avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs), along with the appropriate use of antisecretory therapy. In the United States, the recommended primary therapy for H pylori infection is proton pump inhibitor (PPI)based triple therapy. These regimens result in a cure of infection and ulcer healing in approximately 85-90% of cases. Ulcers can recur in the absence of successful H pylori eradication.

In patients with NSAID-associated peptic ulcers, discontinuation of NSAIDs is paramount, if it is clinically feasible. For patients who must continue with their NSAIDs, proton pump inhibitor (PPI) maintenance is recommended to prevent recurrences even after eradication of H pylori Prophylactic regimens that have been shown to dramatically reduce the risk of NSAID-induced gastric and duodenal ulcers include the use of a prostaglandin analog or a PPI. Maintenance therapy with antisecretory medications for 1 year is indicated in high-risk patients.

The indications for urgent surgery include failure to achieve hemostasis endoscopically, recurrent bleeding despite endoscopic attempts at achieving hemostasis (many advocate surgery after 2 failed endoscopic attempts), and perforation.

Patients with gastric ulcers are also at risk of developing gastric malignancy.

Because many surgical procedures for peptic ulcer disease (PUD) entail some type of vagotomy, a discussion concerning the vagal innervation of the abdominal viscera is appropriate. The left (anterior) and the right (posterior) branches of the vagus nerve descend along either side of the distal esophagus. As they enter the lower thoracic cavity, they can communicate with each other through several cross-branches that comprise the esophageal plexus. However, below this plexus, the 2 vagal trunks again become separate and distinct before the anterior trunk branches to form the hepatic, pyloric, and anterior gastric (also termed the anterior nerve of Latarjet) branches. The posterior trunk branches to form the posterior gastric branch (also termed the posterior nerve of Latarjet) and the celiac branch.

The parietal cell mass of the stomach is segmentally innervated by the terminal branches from each of the anterior and posterior gastric branches. These terminal branches are divided during a highly selective vagotomy. The gallbladder is innervated from efferent branches of the hepatic division of the anterior trunk. Consequently, transection of the anterior vagus trunk (performed during truncal vagotomy) can result in a dilated gallbladder with inhibited contractility and subsequent cholelithiasis. The celiac branch of the posterior vagus innervates the entire midgut (with the exception of the gallbladder). Thus, division of the posterior trunk during truncal vagotomy may contribute to postoperative ileus.

Pathophysiology

Peptic ulcers are defects in the gastric or duodenal mucosa that extend through the muscularis mucosa. The epithelial cells of the stomach and duodenum secrete mucus in response to irritation of the epithelial lining and as a result of cholinergic stimulation. The superficial portion of the gastric and duodenal mucosa exists in the form of a gel layer, which is impermeable to acid and pepsin. Other gastric and duodenal cells secrete bicarbonate, which aids in buffering acid that lies near the mucosa. Prostaglandins of the E type (PGE) have an important protective role, because PGE increases the production of both bicarbonate and the mucous layer.

In the event of acid and pepsin entering the epithelial cells, additional mechanisms are in place to reduce injury. Within the epithelial cells, ion pumps in the basolateral cell membrane help to regulate intracellular pH by removing excess hydrogen ions. Through the process of restitution, healthy cells migrate to the site of injury. Mucosal blood flow removes acid that diffuses through the injured mucosa and provides bicarbonate to the surface epithelial cells.

Under normal conditions, a physiologic balance exists between gastric acid secretion and gastroduodenal mucosal defense. Mucosal injury and, thus, peptic ulcer occur when the balance between the aggressive factors and the defensive mechanisms is disrupted. Aggressive factors, such as NSAIDs, H pylori infection, alcohol, bile salts, acid, and pepsin, can alter the mucosal defense by allowing back diffusion of hydrogen ions and subsequent epithelial cell injury. The defensive mechanisms include tight intercellular junctions, mucus, mucosal blood flow, cellular restitution, and epithelial renewal.

The gram-negative spirochete H pylori was first linked to gastritis in 1983. Since then, further study of H pylori has revealed that it is a major part of the triad, which includes acid and pepsin, that contributes to primary peptic ulcer disease. The unique microbiologic characteristics of this organism, such as urease production, allows it to alkalinize its microenvironment and survive for years in the hostile acidic environment of the stomach, where it causes mucosal inflammation and, in some individuals, worsens the severity of peptic ulcer disease.

When H pylori colonizes the gastric mucosa, inflammation usually results. The causal association between H pylori gastritis and duodenal ulceration is now well established in the adult and pediatric literature. In patients infected with H pylori, high levels of gastrin and pepsinogen and reduced levels of somatostatin have been measured. In infected patients, exposure of the duodenum to acid is increased. Virulence factors produced by H pylori, including urease, catalase, vacuolating cytotoxin, and lipopolysaccharide, are well described.

Most patients with duodenal ulcers have impaired duodenal bicarbonate secretion, which has also proven to be caused by H pylori because its eradication reverses the defect. The combination of increased gastric acid secretion and reduced duodenal bicarbonate secretion lowers the pH in the duodenum, which promotes the development of gastric metaplasia (ie, the presence of gastric epithelium in the first portion of the duodenum). H pylori infection in areas of gastric metaplasia induces duodenitis and enhances the susceptibility to acid injury, thereby predisposing to duodenal ulcers. Duodenal colonization by H pylori was found to be a highly significant predictor of subsequent development of duodenal ulcers in one study that followed 181 patients with endoscopy-negative, nonulcer dyspepsia.

PEPTIC ULCER DISEASE -

An excoriated segment of the GI mucosa, typically in the stomach (gastric ulcer) or first few centimeters of the duodenum (duodenal ulcer), which penetrates through the muscularis mucosae.

Ulcers may range in size from several millimeters to several centimeters. Ulcers are delineated from erosions by the depth of penetration; erosions are more superficial and do not involve the muscularis mucosae.

Because understanding of the central role of H. pylori, in the pathogenesis of acid-peptic disease is growing, diagnosis and treatment of peptic ulcer have changed dramatically.

Comparing Duodenal
and Gastric Ulcers

 

 

H. pylori bacteria can cause peptic ulcerssores on the lining of the stomach or duodenum.

Peptic ulcers are defects in the gastric or duodenal mucosa that extend through the muscularis mucosa. The epithelial cells of the stomach and duodenum secrete mucus in response to irritation of the epithelial lining and as a result of cholinergic stimulation. The superficial portion of the gastric and duodenal mucosa exists in the form of a gel layer, which is impermeable to acid and pepsin. Other gastric and duodenal cells secrete bicarbonate, which aids in buffering acid that lies near the mucosa. Prostaglandins of the E type (PGE) have an important protective role, because PGE increases the production of both bicarbonate and the mucous layer.

In the event of acid and pepsin entering the epithelial cells, additional mechanisms are in place to reduce injury. Within the epithelial cells, ion pumps in the basolateral cell membrane help to regulate intracellular pH by removing excess hydrogen ions. Through the process of restitution, healthy cells migrate to the site of injury. Mucosal blood flow removes acid that diffuses through the injured mucosa and provides bicarbonate to the surface epithelial cells.

Under normal conditions, a physiologic balance exists between gastric acid secretion and gastroduodenal mucosal defense. Mucosal injury and, thus, peptic ulcer occur when the balance between the aggressive factors and the defensive mechanisms is disrupted. Aggressive factors, such as NSAIDs, H pylori infection, alcohol, bile salts, acid, and pepsin, can alter the mucosal defense by allowing back diffusion of hydrogen ions and subsequent epithelial cell injury. The defensive mechanisms include tight intercellular junctions, mucus, mucosal blood flow, cellular restitution, and epithelial renewal.

The gram-negative spirochete H pylori was first linked to gastritis in 1983. Since then, further study of H pylori has revealed that it is a major part of the triad, which includes acid and pepsin, that contributes to primary peptic ulcer disease. The unique microbiologic characteristics of this organism, such as urease production, allows it to alkalinize its microenvironment and survive for years in the hostile acidic environment of the stomach, where it causes mucosal inflammation and, in some individuals, worsens the severity of peptic ulcer disease.

When H pylori colonizes the gastric mucosa, inflammation usually results. The causal association between H pylori gastritis and duodenal ulceration is now well established in the adult and pediatric literature. In patients infected with H pylori, high levels of gastrin and pepsinogen and reduced levels of somatostatin have been measured. In infected patients, exposure of the duodenum to acid is increased. Virulence factors produced by H pylori, including urease, catalase, vacuolating cytotoxin, and lipopolysaccharide, are well described.

Most patients with duodenal ulcers have impaired duodenal bicarbonate secretion, which has also proven to be caused by H pylori because its eradication reverses the defect. The combination of increased gastric acid secretion and reduced duodenal bicarbonate secretion lowers the pH in the duodenum, which promotes the development of gastric metaplasia (ie, the presence of gastric epithelium in the first portion of the duodenum). H pylori infection in areas of gastric metaplasia induces duodenitis and enhances the susceptibility to acid injury, thereby predisposing to duodenal ulcers. Duodenal colonization by H pylori was found to be a highly significant predictor of subsequent development of duodenal ulcers in one study that followed 181 patients with endoscopy-negative, nonulcer dyspepsia.

Classification:

        Phase of disease:

-       Acute;

-       Uncomplete remission;

-       Remission.

        Course of disease:

-       mild;

-       moderate;

-       severe.

        Localization:

-       stomach;

-       duodenum;

-       stomach + duodenum;

-       gastroeneroanostomosis.

        Association with Helicibacter pylori:

-       H. pylori associated;

-       H. pylori not associated.

        Complications

-       Hemorrhage;

-       Perforation;

-       Penetration;

-       Pyloristenosis;

-       Malignancy.

Example of diagnosis: Peptic ulcer disease, acute phase, mild course, active ulcer of duodenum, H. pylori associated.

 

Epidemiology

In the United States, PUD affects approximately 4.5 million people annually. Approximately 10% of the US population has evidence of a duodenal ulcer at some time. Of those infected with H pylori, the lifetime prevalence is approximately 20%. Only about 10% of young persons have H pylori infection; the proportion of people with the infection increases steadily with age.

Overall, the incidence of duodenal ulcers has been decreasing over the past 3-4 decades. Although the rate of simple gastric ulcer is in decline, the incidence of complicated gastric ulcer and hospitalization has remained stable, partly due to the concomitant use of aspirin in an aging population. The hospitalization rate for PUD is approximately 30 patients per 100,000 cases.

The incidence of DU rose steadily until the 1960s but since then has rapidly declined. Peak incidence occurs in the third to fifth decades and is more common in patients with blood group O, particularly those who are non-secretors of the O-related H antigen in mucous glycoprotein. Chronic lung disease, cirrhosis and renal failure are associated with duodenal ulcer but H. pylori infection is the commonest association and epidemiological changes in the incidence of DU disease largely reflect the changes in the epidemiology of H. pylori.

Etiology and Pathogenesis

Although the traditional theories regarding the pathogenesis of peptic ulcers focus on acid hypersecretion, this finding is not universal, and it is now known that hypersecretion is not the primary mechanism by which most ulceration occurs. It appears that certain factors, namely H. pylori and NSAIDs, disrupt the normal mucosal defense and repair, making the mucosa more susceptible to the attack of acid.

The mechanisms by which H. pylori causes mucosal injury are not entirely clear, but several theories have been proposed. Urease produced by the organism catalyzes urea to ammonia. The ammonia, while enabling the organism to survive in the acidic environment of the stomach, may erode the mucous barrier, leading to epithelial damage. Cytotoxins produced by H. pylori have also been implicated in host epithelial damage. Mucolytic enzymes (eg, bacterial protease, lipase) appear to be involved in degradation of the mucous layer, making the epithelium more susceptible to acid damage.

 

 

Proposed mechanism by which H. pylori can result in gastric ulcer/cancer or duodenal ulcer

 

Lastly, cytokines produced in response to inflammation may play a role in mucosal damage and subsequent ulcerogenesis.

American physicians write more than 90 million prescriptions for NSAIDs each year for more than 20 million Americans. In addition, there are more than 200 NSAID-containing products available over the counter, making this one of the most frequently used classes of drugs. NSAIDs inhibit prostaglandin synthesis, and affect the production of gastric acid, bicarbonate and glutathione as well as the integrity of the gastric mucosal barrier, creating an imbalance that may lead to ulcer formation. Symptomatic ulcers occur in approximately one percent of patients taking nonsalicylate NSAIDs after three to six months of chronic use, and in two to four percent after one year, leading to more than 100,000 hospitalizations and 15,000 deaths annually.,, Benign gastric ulcers are more frequently NSAID-associated than are duodenal ulcers. There does not seem to be an increased risk of ulceration in H. pylori-infected patients taking NSAIDs, although this has recently been debated.

Dyspepsia is not predictive of NSAID gastropathy among patients taking these medications. Oddly, symptoms and pathology are not correlated. In addition, many patients who present with complicated ulcer disease have no antecedent symptoms. Gastroesophageal damage is seen on endoscopy in 20 to 40 percent of patients taking chronic NSAIDs, and the point prevalence of asymptomatic gastric ulcers is 15 to 30 percent. This is in marked contrast to the two to four percent of NSAID-users with symptomatic ulcer disease and the clinical significance of such "endoscopic ulcers" is unknown.

NSAIDs likely promote mucosal inflammation and ulcer formation through both topical and systemic effects. Because NSAIDs are weak acids and non-ionized at gastric pH, they diffuse freely across the mucous barrier into gastric epithelial cells, where H+ ions are liberated, leading to cellular damage. Systemic effects appear to be mediated through their ability to inhibit cyclooxygenase activity and thereby prostaglandin production. By inhibiting prostaglandin production, NSAIDs induce several changes in the gastric microenvironment (eg, reduced gastric blood flow, reduced mucus and HCO3 secretion, decreased cell repair and replication), leading to breakdown of mucosal defense mechanisms.

 

 

 

 

 


 

 

Lifestyle factors

Evidence that tobacco use is a risk factor for duodenal ulcers is not conclusive. Support for a pathogenic role for smoking comes from the finding that smoking may accelerate gastric emptying and decrease pancreatic bicarbonate production. However, studies have produced contradictory findings. In one prospective study of more than 47,000 men with duodenal ulcers, smoking did not emerge as a risk factor. However, smoking in the setting of H pylori infection may increase the risk of relapse of PUD. Smoking is harmful to the gastroduodenal mucosa, and H pylori infiltration is denser in the gastric antrum of smokers.

Ethanol is known to cause gastric mucosal irritation and nonspecific gastritis. Evidence that consumption of alcohol is a risk factor for duodenal ulcer is inconclusive. A prospective study of more than 47,000 men with duodenal ulcer did not find an association between alcohol intake and duodenal ulcer.

Little evidence suggests that caffeine intake is associated with an increased risk of duodenal ulcers.

Severe physiologic stress

Stressful conditions that may cause PUD include burns, CNS trauma, surgery, and severe medical illness. Serious systemic illness, sepsis, hypotension, respiratory failure, and multiple traumatic injuries increase the risk for secondary (stress) ulceration.

Cushing ulcers are associated with a brain tumor or injury and typically are single, deep ulcers that are prone to perforation. They are associated with high gastric acid output and are located in the duodenum or stomach. Extensive burns are associated with Curling ulcers.

Stress ulceration and upper-GI hemorrhage are complications that are increasingly encountered in critically ill children in the intensive care setting. Severe illness and a decreased gastric pH are related to an increased risk of gastric ulceration and hemorrhage.

Hypersecretory states(uncommon)

The following are among hypersecretory states that may, uncommonly, cause PUD:

  • Gastrinoma (Zollinger-Ellison syndrome) or multiple endocrine neoplasia type I (MEN-I)
  • Antral G cell hyperplasia
  • Systemic mastocytosis
  • Basophilic leukemias
  • Cystic fibrosis
  • Short bowel syndrome
  • Hyperparathyroidism

Physiological Factors

In up to one third of patients with duodenal ulcers, basal acid output (BAO) and maximal acid output (MAO) are increased. In one study, increased BAO was associated with an odds ratio [OR] of up to 3.5, and increased MAO was associated with an OR of up to 7 for the development of duodenal ulcers. Individuals at especially high risk are those with a BAO greater than 15 mEq/h. The increased BAO may reflect the fact that in a significant proportion of patients with duodenal ulcers, the parietal cell mass is increased to nearly twice that of the reference range.

In addition to the increased gastric and duodenal acidity observed in some patients with duodenal ulcers, accelerated gastric emptying is often present. This acceleration leads to a high acid load delivered to the first part of the duodenum, where 95% of all duodenal ulcers are located. Acidification of the duodenum leads to gastric metaplasia, which indicates replacement of duodenal villous cells with cells that share morphologic and secretory characteristics of gastric epithelium. Gastric metaplasia may create an environment that is well suited to colonization by H pylori.

Genetics

More than 20% of patients have a family history of duodenal ulcers, compared with only 5-10% in the control groups. In addition, weak associations have been observed between duodenal ulcers and blood type O. Furthermore, patients who do not secrete ABO antigens in their saliva and gastric juices are known to be at higher risk. The reason for these apparent genetic associations is unclear.

A rare genetic association exists between familial hyperpepsinogenemia type I (a genetic phenotype leading to enhanced secretion of pepsin) and duodenal ulcers. However, H pylori can increase pepsin secretion, and a retrospective analysis of the sera of one family studied before the discovery of H pylori revealed that their high pepsin levels were more likely related to H pylori infection.

Annitional etiologic factors

Any of the following may be associated with PUD:

         Hepatic cirrhosis

         Chronic obstructive pulmonary disease

         Allergic gastritis and eosinophilic gastritis

         Cytomegalovirus infection

         Uremic gastropathy

         Henoch-Schönlein gastritis

         Corrosive gastropathy

         Celiac disease

         Bile gastropathy

         Autoimmune disease

         Crohn disease

         Other granulomatous gastritides (eg, sacroidosis,tuberculosis)

         Phlegmonous gastritis and emphysematous gastritis

         Other infections, including Epstein-Barr virus, HIV, Helicobacter heilmannii, herpes simplex, and anisakiasis

         Chemotherapeutic agents, such as 5-fluorouracil (5-FU), methotrexate (MTX), and cyclophosphamide

         Local radiation resulting in mucosal damage, which may lead to the development of duodenal ulcers

         Use of crack cocaine, which causes localized vasoconstriction, resulting in reduced blood flow and possibly leading to mucosal damage

Zollinger-Ellison syndrome (ZES) is caused by a nonbeta islet cell, gastrin-secreting tumor of the pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal mucosal ulceration. ZES may occur sporadically or as part of an autosomal dominant familial syndrome called multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually located in the duodenum, the pancreas, and abdominal lymph nodes, but ectopic locations have also been described (eg, heart, ovary, gall bladder, liver, kidney).

The symptoms of ZES are secondary to hypergastrinemia, which causes hypertrophy of the gastric mucosa, leading to increased numbers of parietal cells and increased maximal acid output. Gastrin by itself also stimulates acid secretion, resulting in increased basal acid secretion. The large quantity of acid produced leads to gastrointestinal mucosal ulceration. It also leads to diarrhea and malabsorption. Malabsorption in ZES usually is multifactorial, being caused by direct mucosal damage by acid, inactivation of pancreatic enzymes, and precipitation of bile salts. ZES is sporadic in 75% of patients, while in the other 25% it is associated with MEN 1, an autosomal dominant condition characterized by hyperparathyroidism, pancreatic endocrine tumors, and pituitary tumors.

 

A high index of clinical awareness is needed to make a diagnosis of ZES.

  • Abdominal pain is the most common symptom, present in 75% of patients. Typically, it is located in the upper abdomen and mimics that of peptic ulcer disease. This symptom is reported more frequently by men and patients with the sporadic form of ZES.
  • Of patients with ZES, 73% have diarrhea, and this is the most common symptom in patients who have MEN 1/ZES and in female patients.
  • The combination of diarrhea and abdominal pain is present in more than half the patients.
  • Heartburn is the third most common symptom, and this symptom mimics gastroesophageal reflux disease (GERD).
  • Other symptoms include nausea, vomiting, gastrointestinal bleeding, and weight loss. Gastrointestinal bleeding frequently is due to ulceration in the duodenum and is the presenting symptom in 25% of patients.
  • In patients in whom MEN 1/ZES is suspected, a history indicative of nephrolithiasis, hypercalcemia, and pituitary disorders should be sought. A family history of nephrolithiasis, hyperparathyroidism, and gastrinoma also may be present.

The findings of the physical examination may be normal.

  • Patients may be pale if presenting with gastrointestinal bleeding.
  • Jaundice may occur if the tumor compresses the common bile duct, although this presentation is very rare.
  • Epigastric tenderness may be present.
  • Dental erosions may be noted if symptoms consistent with GERD are present.
  • The presence of hepatomegaly suggests liver metastasis.

 

The goals of treatment are medical control of gastric acid hypersecretion and surgical resection of the tumor.

  • If the patient is acutely ill, immediate control of gastric acid hypersecretion can be achieved with intravenous proton pump inhibitors. Previously, this was accomplished with histamine 2 (H2) receptor blockers. Intravenous pantoprazole was approved recently by the US Food and Drug Administration. Proton pump inhibitors are superior to H2 blockers for the control of gastric acid hypersecretion.
  • Patients who are candidates for surgical resection should be referred for resection of the tumor.
  • For patients with metastatic disease, chemotherapy, interferon, and octreotide may be helpful. The response to these agents in most studies has been low. Liver transplantation for hepatic metastasis also has been reported. For patients with a single confined liver metastatic lesion, surgical resection may be attempted.

 

  • All patients with sporadic ZES without hepatic metastases or medical contraindications to surgery are advised to undergo surgical resection of the tumor because this decreases the risk of developing liver metastases, which can decrease the survival of these patients.
  • The role and timing of surgical resection in patients with MEN 1 is less clear. An attempt at surgical resection has been recommended if the tumor is larger than 2.5 cm. Cure is rarely achieved by surgical resection in patients with MEN 1; however, it may reduce the risk of subsequent metastatic disease.
  • In a single-institution retrospective study with a median follow-up of 18 years from a diagnosis of ZES, Mortellaro et al examined the long-term outcomes in 12 patients with MEN 1 and ZES from 1970 to the present. The pancreas (n = 10), duodenum (n = 4), lymph nodes (n = 3), and liver (n = 1) were the most commonly identified gastrinoma sites. A total of 15 celiotomies were performed, and surgeries included 4 each of distal pancreatectomies and acid-reducing procedures, 3 each of enucleation of pancreatic gastrinoma and duodenal resection, 1 pancreaticoduodenectomy, 7 noted as otherThere was 1 each of a patient with transient (3 y) biochemical postsurgical cure and liver metastasis of gastrinoma (but no deaths from metastatic gastrinoma). Deaths included causes such as respiratory arrest (n = 1), possibly due to aspiration or pulmonary embolus, and nondisease related (n = 3). At last follow-up, 7 patients were alive. The investigators observed patients with MEN 1 and ZES rarely achieve biochemical cures with surgery; however, extended surgical resection was not only not needed in resection of localized gastrinomas, but it was also associated with excellent long-term outcomes.
  • Because this is a rare tumor, surgical resection should be attempted only at centers with personnel experienced in treating patients with ZES.

 

Endoscopic changes

Zollinger-Ellison syndrome

 

On nonenhanced CT scans, a small hypoattenuating nodule may be seen in the duodenum or pancreas. Gastrinomas may occasionally be calcified. They are usually transiently hyperattenuating during arterial phase contrast-enhanced CT scans.

Liver metastases may be seen; these are usually hypervascular and are best seen on arterial phase scanning. For contrast-enhanced CTs of Zollinger-Ellison syndrome, see the images below.

CT scans help to detect 38-75% (with a mean of 50%) of extrahepatic gastrinomas, while 42-76% of hepatic metastasis are seen on CT scans. The detection rate is higher for gastrinomas located in the pancreas or for larger tumor sizes (30% for 1- to 3-cm tumors compared to greater than 95% for tumors larger than 3 cm). CT scans have a specificity of 95%, a positive predictive value of 96%, and a negative predictive value of 54%. For gastrinomas that have metastasized to the liver, CT scans of the abdomen have a sensitivity of 54%, a specificity of 98%, a positive predictive value of 96%, and a negative predictive value of 54%.

Smaller tumors are frequently missed on CT scans.

 

CT scan of the abdomen with contrast enhancement, arterial-phase image. Note the brightly enhancing mass in the wall of the duodenum medially (arrow).

 

CT scan of the abdomen with contrast enhancement, portal venous phase image. Note the significantly decreased enhancement of the mass in the wall of the duodenum medially

Symptoms and Signs

Symptoms depend on ulcer location and patient age; many patients, particularly the elderly, have few or even no symptoms. Pain is the most common symptom; it is often localized to the epigastrium and relieved by food or antacids.

Localization of pain

 

The pain is described as burning, gnawing, or hunger. The course is usually chronic and recurrent. Only about half of patients present with the characteristic pattern of symptoms.

Symptoms of gastric ulcer often do not follow a consistent pattern (eg, eating sometimes exacerbates rather than relieves pain). This is especially true for pyloric channel ulcers, which are often associated with symptoms of obstruction (eg, bloating, nausea, vomiting) caused by edema and scarring.

In duodenal ulcer, pain tends to be consistent. Pain is absent when the patient awakens but appears in midmorning; it is relieved by food but recurs 2 to 3 h after a meal. Pain that awakens a patient at night is common and is highly suggestive of duodenal ulcer.

Epigastric pain is the most common symptom of both gastric and duodenal ulcers. It is characterized by a gnawing or burning sensation and occurs after mealsclassically, shortly after meals with gastric ulcer and 2-3 hours afterward with duodenal ulcer. Food or antacids relieve the pain of duodenal ulcers but provide minimal relief of gastric ulcer pain.

Duodenal ulcer pain often awakens the patient at night. About 50-80% of patients with duodenal ulcers experience nightly pain, as opposed to only 30-40% of patients with gastric ulcers and 20-40% of patients with nonulcer dyspepsia (NUD). Pain typically follows a daily pattern specific to the patient. Pain with radiation to the back is suggestive of a posterior penetrating gastric ulcer complicated by pancreatitis.

Patients who develop gastric outlet obstruction as a result of a chronic, untreated duodenal ulcer usually report a history of fullness and bloating associated with nausea and emesis that occurs several hours after food intake. A common misconception is that adults with gastric outlet obstruction present with nausea and emesis immediately after a meal.

Other possible manifestations include the following:

  • Dyspepsia, including belching, bloating, distention, and fatty food intolerance
  • Heartburn
  • Chest discomfort
  • Hematemesis or melena resulting from gastrointestinal bleeding. Melena may be intermittent over several days or multiple episodes in a single day.
  • Rarely, a briskly bleeding ulcer can present as hematochezia.
  • Symptoms consistent with anemia (eg, fatigue, dyspnea) may be present
  • Sudden onset of symptoms may indicate perforation.
  • NSAID-induced gastritis or ulcers may be silent, especially in elderly patients.
  • Only 20-25% of patients with symptoms suggestive of peptic ulceration are found on investigation to have a peptic ulcer.

Alarm features that warrant prompt gastroenterology referral include the following:

  • Bleeding or anemia
  • Early satiety
  • Unexplained weight loss
  • Progressive dysphagia or odynophagia
  • Recurrent vomiting
  • Family history of GI cancer
  • duodenal sites are 4x as common as gastric sites

 

Diagnosis

Diagnosis of peptic ulcer is suggested largely by history and is confirmed by the studies described below. Stomach cancer may present with similar manifestations and must be excluded, especially in patients who are older, have lost weight, or report particularly severe or refractory symptoms. Endoscopy, cytology, and multiple biopsies are reliable means of distinguishing malignant from benign gastric ulcers. The incidence of malignant duodenal ulcer is extremely low, so biopsies are generally not warranted. Gastrin-secreting malignancy and Zollinger-Ellison syndrome should be considered in a patient who presents with a severe ulcer diathesis, especially when ulcers are multiple and noted in atypical locations (eg, postbulbar).

Helicobacter pylori testing

Testing for H pylori infection is essential in all patients with peptic ulcers.

Endoscopic or invasive tests for H pylori include a rapid urease test, histopathology, and culture. Rapid urease tests are considered the endoscopic diagnostic test of choice. The presence of H pylori in gastric mucosal biopsy specimens is detected by testing for the bacterial product urease. Fecal antigen testing identifies active H pylori infection by detecting the presence of H pylori antigens in stools. This test is more accurate than antibody testing and is less expensive than urea breath tests.

Three kits (ie, CLOtest, Hp-fast, Pyloritek) are commercially available for H pylori testing, and each contains a combination of a urea substrate and a pH sensitive indicator. One or more gastric biopsy specimens are placed in the rapid urease test kit. If H pylori is present, bacterial urease converts urea to ammonia, which changes the pH, resulting in a color change.

Urea breath tests detect active H pylori infection by testing for the enzymatic activity of bacterial urease. In the presence of urease produced by H pylori, labeled carbon dioxide (heavy isotope, carbon-13, or radioactive isotope, carbon-14) is produced in the stomach, absorbed into the bloodstream, diffused into the lungs, and exhaled.

Obtain histopathology, often considered the criterion standard to establish a diagnosis of H pylori infection , if the rapid urease test result is negative and a high suspicion for H pylori persists (presence of a duodenal ulcer).

Antibodies (immunoglobulin G [IgG]) to H pylori can be measured in serum, plasma, or whole blood. Results with whole blood tests obtained from finger sticks are less reliable.

The gold standard test for diagnosis of H. pylori is endoscopy with biopsy and histology. The urease dye test (CLO test) performed with endoscopy requires a biopsy but may provide the diagnosis more rapidly than histologic examination. Culture is the least sensitive of the direct techniques because H. pylori is extremely difficult to culture. Serology is simple and inexpensive, but is not specific for active infection. The urease breath test is both sensitive and specific for active infection, although antimicrobial drugs can temporarily cause false negative results and the test must be used at least four weeks after treatment is completed. The breath test is the best post-treatment test for eradication and would be recommended for everyone if it were readily available and less expensive. Unfortunately, none of the companies that perform it accept Medicaid, and only patients with Medicare and commercial insurance have access. Other patients require a second endoscopy and biopsy in order to prove H. pylori eradication.

Upper GI endoscopy is the preferred diagnostic test in the evaluation of patients with suspected PUD. It is highly sensitive for the diagnosis of gastric and duodenal ulcers, allows for biopsies and cytologic brushings in the setting of a gastric ulcer to differentiate a benign ulcer from a malignant lesion, and allows for the detection of H pylori infection with antral biopsies for a rapid urease test and/or histopathology in patients with PUD.

Gastric ulcer (lesser curvature) with punched-out ulcer base with whitish exudate.

More than 95% of duodenal ulcers are found in the first part of the duodenum; most are less than 1 cm in diameter. Duodenal ulcers are characterized by the presence of a well-demarcated break in the mucosa that may extend into the muscularis propria of the duodenum

Gastric cancer with ulcerated mass.

 

At endoscopy, gastric ulcers appear as discrete mucosal lesions with a punched-out smooth ulcer base, which often is filled with whitish fibrinoid exudate. Ulcers tend to be solitary and well circumscribed and usually are 0.5-2.5 cm in diameter. Most gastric ulcers tend to occur at the junction of the fundus and antrum, along the lesser curvature. Benign ulcers tend to have a smooth, regular, rounded edge with a flat smooth base and surrounding mucosa that shows radiating folds. Malignant ulcers usually have irregular heaped-up or overhanging margins. The ulcerated mass often protrudes into the lumen, and the folds surrounding the ulcer crater are often nodular and irregular.

Duodenal ulcer in a 35-year-old woman who presented with tarry stools and a hemoglobin level of 75 g/L.

 

TABLE 1: Sensitivity and specificity of diagnostic tests for H. pylori

Diagnostic Test

Sensitivity

Specificity

Serology

88-99%

86-95%

Urea Breath Test*

90-97%

90-100%

Endoscopy with Culture

77-92%

~100%

with Histology

93-99%

95-99%

with Urease Test

89-98%

93-98%

Fiberoptic endoscopy is a powerful tool for the diagnosis and management of peptic ulcer disease.

Clinical guidelines have been established to aid the evaluation of patients with dyspepsia, and these should be applied to patients with suspected peptic ulcer disease. If there are any alarm features (i.e., red flags that suggest upper GI cancer, such as weight loss, bleeding, anaemia, vomiting, early satiety, or dysphagia, or if the patient develops dyspeptic symptoms over the age of 55 years), prompt endoscopy is indicated. It is the gold standard diagnostic test for peptic ulcer disease and upper GI tract neoplasms.

Endoscopy is widely available and is more sensitive and specific for peptic ulcer disease than barium radiography. Additionally, it enables biopsy (for diagnosing malignancy and for H pylori detection). Barium radiography should be reserved for patients who are unable or unwilling to undergo endoscopy, and it is not routinely recommended.

In the absence of alarm features, endoscopy is often unnecessary and is only indicated if symptoms persist after treatment.

 

 

 

ENDOSCOPY

 

 

2

 

Gastric ulcer (posterior wall)

2

Gastric ulcer (angle of stomach)

 

3,89

Duodenal ulcer (anterior wall of duodenal bulb)

 

3,102

Duodenal ulcer (posterior wall of duodenal bulb)

 

3,99

Duodenal ulcer (middle part, anterior wall, 9-12 mm)

 

3,106

Duodenal ulcer

 

http://studio.helicobacter.com/images/du_gu_1.jpg

 

 

 

An alternative diagnostic study is double-contrast barium x-ray.

 

Upper GI series in which double
contrast (barium and air) is used, showing rounded
collection of barium in an ulcer (arrow) in the duodenal
bulb of a patient presenting with dyspepsia
(uncomplicated duodenal ulcer)

 

Although endoscopy and x-ray have similar sensitivities for detecting ulcer, endoscopy is becoming the diagnostic modality of choice. Endoscopy more reliably detects esophagitis and esophageal ulcers as well as ulcers located on the posterior wall of the stomach and at sites of surgical anastomosis. Conversely, some 10% of duodenal bulb and postbulbar ulcers may be missed endoscopically, sometimes leading to follow-up with a barium study if the clinical suspicion is high. Endoscopy also allows for biopsy or cytologic brushing of gastric and esophageal lesions to distinguish between simple ulceration and ulcerating stomach cancer. Endoscopy can also be ued to definitively diagnose H. pylori infection.

 

Barium studies of the proximal gastrointestinal tract are still commonly used as a first test for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast study providing detection rates as high as 90%. Sensitivity for detection is decreased in small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated crater, most often seen in the bulb. A GU may represent benign or malignant disease. Typically, a benign GU also appears as a discrete crater with radiating mucosal folds originating from the ulcer margin. Ulcers >3 cm in size or those associated with a mass are more often malignant. Unfortunately, up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery. Radiographic studies that show a GU must be followed by endoscopy and biopsy.

Endoscopy provides the most sensitive and specific approach for examining the upper gastrointestinal tract. In addition to permitting direct visualization of the mucosa, endoscopy facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori. Endoscopic examination is particularly helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities, or to determine if an ulcer is a source of blood loss.

 

 

Barium examination of the stomach and duodenum reveals an ulcer, 1 cm in diameter (arrow), in the duodenal bulb with radiating folds.

 

 

Peptic ulcer disease, duodenal, Fig.1

 

Peptic ulcer disease, duodenal, Fig.2

 

 

 

Diagnostic tests for H. Pylori

 

Non-invasive:

Invasive

 

-Serology

-Urea breath test

 

-Rapid urease test

-Histology

-Cytology

-Culture

 

 

 

Urea breath test with I3C

An urea breath test, sometimes called a carbon urea breath test, is used to detect a bacteria known as (H. pylori). The test is used to find the bacteria in the stomach. Helicobacter pylori can cause a helicobacter pylori infection, gastric or peptic ulcers and gastritis. Individuals with these conditions or suspected to have one of these conditions may undergo this type of test. In most cases, urea breath testing lasts around 30 minutes and is performed on an outpatient basis.

Some people with small traces of helicobacter pylori bacteria may show no outward symptoms. For others, the bacteria can cause serious complications. If the bacteria spreads into the stomach and portions of the small intestines known as the duodenum, an infection can occur. The bacteria may also cause an erosion or ulcer to form in these areas. Certain gastric cancers and inflammation of the lining of the stomach may also be caused by helicobacter pylori bacteria.

During a helicobacter pylori urea breath test, samples will be taken to analyze the breath for carbon dioxide . Urea, a schemical waste , is turned into carbon dioxide by helicobacter pylori bacteria. The test will usually begin by having the patient exhale into a specialized bag. Next, he or she may be given a carbon isotope-containing capsule or solution to swallow. Another breath sample will be obtained and examined for a significant increase in carbon dioxide, which will denote the presence of helicobacter pylori.

Rapid urease activity test

*    H. pylori produces urease that is required for gastric colonization by H. pylori and that may protect it from the effects of gastric acid.

*    This urease producing activity of the organism is utilized for diagnosis by placing the biopsy specimen in urea and assessing ammonia release that changes the color of the solution.

Urease Test

Urease broth is a differential medium that tests the ability of an organism to produce an exoenzyme, called urease, that hydrolyzes urea to ammonia and carbon dioxide.  The broth contains two pH buffers, urea, a very small amount of nutrients for the bacteria, and the pH indicator phenol red.  Phenol red turns yellow in an acidic environment and fuchsia in an alkaline environment.  If the urea in the broth is degraded and ammonia is produced, an alkaline environment is created, and the media turns pink.

Many enterics can hydrolyze urea; however, only a few can degrade urea rapidly.  These are known as rapid urease-positive organisms.  Members of the genus Proteus are included among these organisms.

Urea broth is formulated to test for rapid urease-positive organisms.  The restrictive amount of nutrients coupled with the use of pH buffers prevent all but rapid urease-positive organisms from producing enough ammonia to turn the phenol red pink.

Important:
In our lab, we only use the urease broth, not the agar.

Proteus mirabilis is rapid urease positive as evidenced by the pink color of the media.

Escherichia coli on the right is negative.

 

Urease broth can be used to differentiate members of the genus Proteus (as well as those of Morganella and Providencia, but we dont use those in our lab) from other enterics.

Screening method

For the more commonly used screening methods based on the detection of specific anti-helicobacter antibodies Ig classes A i G in serum, capillary blood subjects. The most studied following serological methods:

1. Enzymatic analysis.

2. Rapid tests based on immunoprecipitation or immunocytochemistry using as test material capillary blood of patients with color enhancement of the reaction products.

 

H. pylori. Electron microphoto.

 

Ulcer disease: complications, differential diagnosis

Complications

Hemorrhage: Hemorrhage is the most common complication of peptic ulcer disease. Symptoms include hematemesis (vomiting of fresh blood or "coffee ground" material); passage of bloody or black tarry stools (hematochezia and melena, respectively); and weakness, orthostasis, syncope, thirst, and sweating caused by blood loss.

If bleeding from an ulcer persists or recurs, several treatment choices exist. Endoscopy may be performed and the bleeding site coagulated by electrocautery, heater probe coagulation, or laser or by injection of alcohol, sclerosant, or epinephrine. Bleeding may recur, even after coagulation. Angiographic embolization of branch vessels supplying the bleeding site may stop the bleeding.

After an ulcer is diagnosed and bleeding is controlled endoscopically, the patient should be given acid suppression with I/V H2 blockers and nothing by mouth. Once the patient's condition has stabilized with no evidence of rebleeding, an oral diet can be resumed, antisecretory therapy (H2 blockers or proton pump inhibitors) given orally, and anti-H. pylori therapy initiated if needed.

Emergency surgery is usually indicated when pulse rate, BP, and Hct indicate continued deterioration in the patient's condition despite treatment and transfusions; more than six transfusions in 24 h have been needed to maintain a stable pulse and BP; or bleeding stops but recurs enough to require multiple transfusions.

 

Penetration (confined perforation): A peptic ulcer may penetrate the wall of the stomach or duodenum and enter the adjacent confined space (lesser sac) or organ (eg, pancreas, liver). Adhesions prevent leakage into the free peritoneal cavity. Pain may be intense, persistent, referred to sites other than the abdomen (usually the back when caused by penetration of a posterior duodenal ulcer into the pancreas), and modified by body position. Radiographic evaluation with contrast study or CT is usually needed to confirm the diagnosis. When medical therapy does not produce healing, surgery is required.

 

Free perforation: Free perforation usually presents as an acute abdomen. Ulcers that perforate the peritoneal cavity are usually located in the anterior wall of the duodenum or, less commonly, in the stomach. The patient experiences sudden, intense, steady epigastric pain that spreads rapidly throughout the abdomen, often becoming prominent in the right lower quadrant and at times referred to one or both shoulders. The patient usually lies still because even deep breathing can worsen the pain. Palpation of the abdomen is painful, rebound tenderness is prominent, abdominal muscles are rigid (boardlike), and bowel sounds are diminished or absent. Symptoms may be less striking in the elderly, the moribund, and those receiving corticosteroids or immunosuppressants.

Diagnosis is confirmed if an upright or a lateral decubitus x-ray of the abdomen shows free air under the diaphragm or in the peritoneal cavity, but the diagnosis is not excluded if no air is seen.

 

 

Perforation. Diagnosis is confirmed if an upright or a lateral decubitus x-ray of the abdomen shows free air under the diaphragm or in the peritoneal cavity, but the diagnosis is not excluded if no air is seen.

 

Pain and abdominal rigidity may partially subside, and the patient's condition appears to improve several hours after onset. However, peritonitis with a temperature elevation may develop, and the patient's condition seriously deteriorates. Shock may ensue, heralded by increased pulse rate and decreased BP and urine output.

 

 

 

 

 

 

 

 Two types of perforation of the stomach and duodenum have been observed. Free perforation occurs when duodenal or gastric contents spill into the abdominal cavity with peritoneal contamination by gastric, pancreatic and biliary juices. Clinically this produces an acute abdomen, which is easily diagnosed. Contained perforation occurs when the ulcer produces a full-thickness hole in the duodenum or stomach, but the omentum or other adjacent organs prevent peritoneal contamination.

Perforations are most likely in elderly patients on chronic NSAID therapy, and are more common in gastric than in duodenal ulcers. Initial symptoms of perforated duodenal or gastric ulcers include severe abdominal pain, worse in the epigastrium, often accompanied by nausea and vomiting. Typically the patient is acutely and severely ill. History and physical exam suggest a diagnosis of perforation. The finding of free air on either an upright or decubitus abdominal radiograph is noted in approximately 70% of cases (Figure ).    
  

 

An upper GI series with gastrografin will confirm the clinical impression of perforation if an x-ray is negative. Perforation is a contraindication for endoscopy because air insufflation may exacerbate spillage of gastric contents or disrupt a sealed perforation.

Urgent surgical therapy is recommended in patients with uncontained, free perforated ulcers, because spontaneous sealing is rare. In addition, gastric adenocarcinoma cannot be ruled out and there is a greater potential for bacterial colonization. Aggressive surgical intervention helps to decrease the high mortality associated with perforating gastric ulcers.

 

Gastric outlet obstruction: This may be caused by scarring, spasm, or inflammation associated with an ulcer. Symptoms include recurrent large volume vomiting, occurring more frequently at the end of the day and often as late as 6 h after the last meal. Persistent bloating or fullness after eating and loss of appetite also suggest gastric outlet obstruction. Prolonged vomiting may cause weight loss, dehydration, and alkalosis.

If the patient's history suggests obstruction, physical examination, gastric aspiration, or x-rays may provide objective evidence of retention. A succussion splash heard > 6 h after a meal or aspiration of fluid or food residue > 200 mL after an overnight fast suggests gastric retention. If gastric aspiration shows marked retention, the stomach should be emptied and endoscopy or x-rays performed to determine the site, cause, and degree of obstruction.

Edema or spasm from an active pyloric channel ulcer is treated with gastric decompression and acid suppression (eg, I/V H2 blockers). Dehydration and electrolyte imbalances from protracted vomiting or continued nasogastric suctioning should be vigorously sought and corrected. Prokinetic agents are not indicated. Generally, obstruction resolves within 2 to 5 days of treatment. Prolonged obstruction may be caused by peptic scarring and may respond to endoscopic pyloric balloon dilation. Surgery is necessary to relieve obstruction in selected cases.

Patients with gastric outlet obstruction usually have a history of nausea, vomiting, and epigastric pain or fullness. Laboratory findings may show anemia, low serum albumin, and hyperkalemic alkalosis. Radiological exam is usually diagnostic, showing a large gastric shadow with an air/fluid level (Figure). An upper GI series yields valuable information by showing marked delay in gastric emptying and a large atonic stomach. Endoscopy is the best test for evaluating gastric outlet obstruction after decompression of the stomach for 1224 hours. 

 

 

Stomach cancer: H. pylori is associated with intestinal-type adenocarcinoma of the gastric body and antrum but not cancer of the gastric cardia. Infected persons are three to six times more likely to develop stomach cancer. Gastric lymphomas and mucosa-associated lymphoid tissue (MALT) lymphomas have also been linked to this infection.

 

 

2

 

GASTRIC CANCER (endoscopy)

2

Gastric ulcer (posterior wall)

 

 

GASTRIC CARCINOMA mortality and morbidity. Though a marked reductionhas been observed in the incidence of gastric carcinoma in North America and Western Europe in the last 50 years, 5-year survival rates are less than 20%, as most patients present late and are unsuitable for curative, radical surgery. Gastritumors are seen in the images below.

 

 

 

Polypoid carcinoma of the body of the stomach.

 

 

Infiltrating carcinoma involving the greater curve of the stomach

 

Gastric adenocarcinomas are divided into 2 types. Type 1 adenocarcinomas are intestinal tumors and have well-formed glandular structures. This form of gastric carcinoma is more likely to involve the distal stomach and occur in patients with atrophic gastritis (seen in the image below). It has a strong environmental association.

A type 2 adenocarcinoma is a diffuse type with poorly cohesive cells, which tendtinfiltrate the gastric wall. Tumors of this type may involve any part of the stomach,especially the cardia; they have a worse prognosis than type 1 tumors.

 

23

 

GASTRIC CANCER (roentgenogram)

 

MALT lymphomas are malignant mono-clonally restricted B-cell lymphoid populations caused by H. pylori. This condition is frequently associated with superficial gastric ulcer and discovered incidentally on biop sies of the ulcer edge and surrounding mucosa. Eradication of H. pylori can cure some cases of MALT lymphoma. Therefore, it is appropriate to treat a localized MALT lymphoma with anti-H. pylori therapy, document bacterial cure, and closely monitor for tumor progression before proceeding with chemotherapy or radical surgery. There are no data to suggest that eradicating H. pylori prevents progression of gastritis to more common cancers or lymphomas of the stomach. Therefore, there is no scientific reason to diagnose and treat H. pylori to prevent malignant complications, especially because stomach cancer is relatively uncommon in the USA.

Recurrence: The 1-yr relapse rate for gastric and duodenal ulcers is > 60% after cessation of traditional antiulcer therapy. Long-term treatment with H2 blockers or proton pump inhibitors reduces the risk of recurrence proportionally to the amount of acid suppression achieved. The rate of ulcer recurrence is considerably lower after anti-H. pylori therapy (< 10%).

The most common reason for recurrent peptic ulcer is unsuccessful eradication of H. pylori. In a patient with recurrent disease, possible persistent infection should be investigated. If infection is documented, a second course of anti-H. pylori therapy is warranted.

Other factors that may affect recurrence include NSAID use and smoking. Patients taking NSAIDs who have developed a peptic ulcer are candidates for long-term therapy with misoprostol or an antisecretory agent (eg, H2 blockers, proton pump inhibitors). Less commonly, a gastrinoma (Zollinger-El-lison syndrome) may be the cause of refractory or recurrent peptic disease.

 

Differential Diagnosis

Presentation

Diagnosis

Suspected uncomplicatedulcer

Nonulcer dyspepsia, gastroesophageal reflux,biliary colic, pancreatic disease, angina pectoris, gastric cancer

Bleeding ulcer

Varices, Mallory-Weiss tear, esophagitis, vascular lesion (angiodysplasia)

Perforated ulcer

Appendicitis, pancreatitis, cholecystitis,

spontaneous bacterial peritonitis, bowel

ischemia or infarction, diverticulitis

Penetrating ulcer

Pancreatitis, muscle strain, herniated vertebral disk, ureteral stone

 

III. Ulcer disease: treatment

Treatment of gastric and duodenal ulcers had previously focused on neutralizing or decreasing gastric acidity. However, attention has shifted toward eradication of H. pylori. Antibiotic treatment should therefore be considered in all H. pylori-infected patients with acute ulcers and in those who have had a gastric or duodenal ulcer diagnosed in the past by endoscopy or barium x-ray, even if they are asymptomatic or receiving long-term acid suppression therapy. This is particularly important in patients with a past history of complications (eg, bleeding, perforation), because H. pylori, eradication can prevent future complications.

Antibiotic therapy for H. pylori is evolving. Single agents should not be used because no single antibiotic can predictably cure most H. pylori infections. Initially, bismuth-based triple therapy was recommended. This approach is being challenged by simpler dual drug regimens, which include the use of acid-blocking drugs. Regardless of which therapy is used, antibiotic resistance, physician counseling, and patient compliance determine its success.

H2 blockers have a role in the treatment of peptic ulcer disease but are no longer primary therapy when used alone; they are frequently used as antisecretory drugs in an anti-H. pylori regimen. With differing potencies and half-lives, each drug (cimetidine, ranitidine, famotidine, and nizatidine) is a competitive inhibitor of histamine at the H2 receptor. Histamine plays an important role in vagal and gastrin-stimulated acid secretion, thereby making H2 blockers effective suppressors of basal gastric acid output and acid output stimulated by food, the vagus nerve, and gastrin. Gastric juice volume is proportionately reduced. Histamine-mediated pepsin secretion is also decreased.

H2 blockers are well absorbed from the GI tract, with 37 to 90% bioavailability. Onset of action is 30 to 60 min after ingestion, and effects peak at 1 to 2 h. I/V administration produces a more rapid onset of action. Duration of action is proportional to dose and ranges from 6 to 20 h. Several hepatic metabolites, inactive or less active than the parent compound, are produced, but much unchanged drug is eliminated via the kidney, requiring dose adjustment for renal function. Hemodialysis removes H2 blockers, and redosing is necessary after dialysis. Doses often should be reduced in the elderly.

Cimetidine has minor antiadrenergic effects expressed as reversible gynecomastia and, less commonly, impotence in a few patients on high doses for prolonged periods (eg, hypersecretors). Mental status changes, diarrhea, rash, drug fever, myalgias, thrombocytopenia, and sinus bradycardia and hypotension after rapid I/V administration have been reported with all H2 blockers, generally in < 1% of treated patients but more commonly in the elderly.

Cimetidine and, to a lesser extent, other H2 blockers interact with the P-450 microsomal enzyme system and may delay metabolism of other drugs eliminated through this system (eg, phenytoin, warfarin, theophylline, diazepam, lidocaine).

Proton pump inhibitors are potent inhibitors of the proton (acid) pump (ie, the enzyme H+,K+-ATPase), located in the apical secretory membrane of the parietal cell. Proton pump inhibitors can completely inhibit acid secretion and have a long duration of action.

Proton pump inhibitors are key components of many anti-H. pylori regimens. In active duodenal or gastric ulcers, omeprazole 20 mg/day orally or lansoprazole 30 mg/day orally is usually continued for 2 wk after completion of antibiotic therapy to ensure complete healing of the ulcer. Proton pump inhibitors are more effective than H2 blockers in healing NSAID-associated gastric and duodenal ulcers when the NSAID must be continued.

Although it was originally surmised that long-term proton pump inhibitor therapy could predispose to the formation of stomach cancer, this does not appear to be the case. Likewise, although patients infected with H. pylori taking proton pump inhibitors develop gastric atrophy, this does not appear to lead to metaplasia or increased risk of gastric adenocarcinoma. Prolonged suppression of gastric acid raises theoretical but undocumented concerns of bacterial overgrowth, susceptibility to enteric infection, and vitamin B12 malabsorption.

Certain prostaglandins (especially misoprostol) can inhibit acid secretion and enhance mucosal defense. The role of synthetic prostaglandin derivatives in the management of peptic ulcer disease is predominantly in the area of N SAID-induced mucosal injury. Patients at high risk for NSAID-in-duced ulcers (ie, the elderly, those with a past history of ulcer or ulcer complication, those also taking corticosteroids) are candidates for misoprostol 200 μg orally 4 times a day along with their NSAID. Common side effects of misoprostol are abdominal cramping and diarrhea, which occur in 30% of patients. Misoprostol is a powerful abortifacient and is absolutely contraindicated in women of childbearing age who are not using contraception.

Sucralfate is a sucrose-aluminum complex that promotes ulcer healing. It has no effect on acid output or gastrin secretion. Its suspected mechanisms of action include inhibition of pepsin-substrate interaction, stimulation of mucosal prostaglandin production, and binding of bile salts. Sucralfate also appears to have trophic effects on the ulcerated mucosa, possibly by binding growth factors and concentrating them at the ulcer site. In the acid milieu of the stomach, sucralfate dissociates and forms a barrier over the ulcer base, protecting it from acid, pepsin, and bile salts.

Systemic absorption of sucralfate is negligible. Constipation occurs in 3 to 5% of patients. Sulcrafate may bind to other medications, interfering with their absorption.

Antacids give symptomatic relief, promote ulcer healing, and reduce recurrence. They are relatively inexpensive but must be taken five to seven times per day. The optimal antacid regimen for ulcer healing appears to be 16 to 30 mL of liquid or 2 to 4 tablets 1 and 3 h after each meal and at bedtime. The total daily dosage of antacids should provide 200 to 400 mEq neutralizing capacity.

In general, there are two types: (1) Absorbable antacids (eg, sodium bicarbonate), which provide rapid, complete neutralization, may occasionally be taken short-term for intermittent symptomatic relief. However, because they are absorbed, continuous use may cause alkalosis or milk-alkali syndrome. (2) Nonabsorbable antacids (relatively insoluble salts of weak bases) are preferred because of fewer systemic side effects. They interact with hydrochloric acid to form poorly absorbed salts, thereby increasing gastric pH. Pepsin activity diminishes as gastric pHl rises to > 4.0, and pepsin may be adsorbed by some antacids. Antacids may interfere with the absorption of other drugs (eg, tetracycline, digoxin, iron).

Aluminum hydroxide is a relatively safe, commonly used antacid. With chronic use, phosphate depletion may rarely develop as a result of binding of phosphate by aluminum in the GI tract. The risk of phosphate depletion increases in alcoholics, malnourished patients, and patients with renal disease, including those receiving hemodialysis. Aluminum hydroxide causes constipation.

Magnesium hydroxide is a more effective antacid than aluminum but may cause diarrhea. To limit diarrhea, many proprietary antacids contain both magnesium and aluminum hydroxides; some contain aluminum hydroxide and magnesium trisilicate. The latter tends to have less neutralizing potency. Because small amounts of magnesium are absorbed, magnesium preparations should be used with caution in patients with renal disease.

 

Pharmacological Management of Ulcer Disease

Table of Contents

Drug Treatment

Other GI Drugs 

 

Anti-H. pylori therapy (Maastricht Consensus):

Triple therapy

*                Amoxycillin 1000mg twice daily +

*                Clarithromycin 500mg twice daily +

*                Proton pump inhibitor

(Lansoprazole 30mg twice daily)

Quadruple therapy

*    Tetracycline 500mg 4 times daily +

*    Metronidazole 400mg 4 times daily +

*    De-nol 120mg 4 times daily +

*    Proton pump inhibitor

(Lansoprazole 30mg twice daily)

The goal of therapy for peptic ulcer disease is to relieve symptoms, heal craters, prevent recurrences, and prevent complications. Medical therapy should include treatment with drugs, and attempt to accomplish the following: 1) reduce gastric acidity by mechanisms that inhibit or neutralize acid secretion, 2) coat ulcer craters to prevent acid and pepsin from penetrating to the ulcer base, 3) provide a prostaglandin analog, 4) remove environmental factors such as NSAIDs and smoking, and 5) reduce emotional stress (in a subset of patients).

Antacids neutralize gastric acid and are more effective than placebo in healing gastric and duodenal ulcers. However, antacids have to be taken in relatively large doses 1 and 3 hours after meals and at bedtime, and may cause side effects. The major side effect of magnesium-containing antacids is diarrhea caused by magnesium hydroxide.   

Figure. Mechanism of acid production in the gastrin parietal cell.

H2-receptor antagonists reduce gastric acid production by blocking the H2 receptor on the parietal cell (Figure 16). Examples of available H2 blockers used to treat gastric and duodenal ulcers include cimetidine, ranitidine, famotidine and nizatidine. This group of compounds effectively decreases acid secretion. H2-receptor antagonists are relatively safe. The choice of drug should be dictated by cost, dosing schedule, convenience, and possible drug interactions.

The family of drugs known as as PP inhibitors, or PPIs, inactivates the parietal cell hydrogen-potassium ATPase located on the lumenal surface. ATPase acts as a PPI and constitutes the final common pathway in the secretion of hydrogen ions. This class of medicines is now considered the gold standard in medical therapy of peptic ulcer disease. Examples of available PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Increasing the PPI dose can reduce acid secretion to the point of achlorhydria (unachievable by H2 blockade). Thus, the PP inhibitors are the primary treatment when gastric hypersecretion is resistant to other therapies. Proton pump inhibitors have been shown to prevent NSAID-associated gastroduodenal ulcers, and to provide a safe and effective form of therapy. Furthermore, studies have shown that PPIs are more effective than H2-receptor antagonists at treating all types of peptic ulcer disease.   

 

Sucralfate is the aluminum salt of a sulfated disaccharide. The drug forms a barrier or coating over the ulcer crater, stimulates prostaglandin synthesis, and binds to noxious agents such as bile salts. Although the exact mechanism of action is unclear, it appears sucralfates stimulate prostaglandins, which promote improved mucosal integrity and enhance epithelialregeneration . Because it requires multiple doses per day, patients are less likely to follow a sucralfate regimen even though it has been shown to be as effective as an H2 blocker in healing both duodenal and gastric ulcers. Sucralfate is not absorbed systemically, and its only remarkable side effect is constipation.

Misoprostol is prostaglandin a E1 analog that increases mucosal resistance and inhibits acid secretion to a minor degree. Misoprostol has been advocated for prophylaxis of NSAID-induced mucosal injury. The drug has significant side effects, primarily mild to moderate diarrhea, and is too costly to be used by most patients on long-term NSAIDs.

The suppression of gastric acid production promotes the healing of peptic ulcers. Unfortunately, if acid suppression therapy is not maintained, peptic ulcers regularly recur. Since the long-term cure of peptic ulcers accompanies the eradication of H. pylori, all ulcers associated with this infection should be treated with the aim of infection eradication. Although H. pylori is sensitive to a variety of antibiotics in vitro , its habitat beneath the gastric mucosa makes it difficult to treat. The original treatment gold standard was 2 weeks of triple therapy, including bismuth, tetracycline or amoxicillin, and metronidazole. Where compliance with this regimen can be assured, H. pylori cure rate is 9095% or more; however, 20% of these cases develop side effects.

Newer simpler regimens have been developed and H. pylori treatment recommendations are still evolving. Today, the current gold standard of therapy is a triple combination of drugs that includes a PPI (e.g. omeprazole or lansoprazole) plus amoxicillin and a newer antibiotic, clarithromycin. All three medicines are to be taken twice per day for 7-14 days (preferably 14 days). Alternative drugs may be offered to those patients with certain allergies or medication intolerances. Physicians should always offer patients with peptic ulcer disease and confirmed H. pylori infection the option of curative therapy.

Gastric ulcers should be re-evaluated by multiple endoscopic biopsies and cytology to rule out gastric carcinoma if they have not healed after 8 weeks of conventional medical therapy. If no malignancy is seen on biopcy, aggressive treatment should be instituted for 6 weeks to eradicate H. pylori and to suppress acid with full doses of a PP inhibitor. A gastric ulcer that does not heal after this second aggressive course of medical therapy may suggest underlying malignancy, even with negative repeat biopsies. Non-healing gastric ulcers should be resected surgically. 

 

 

 

Possible reasons for failure of H pylori eradication

 

Adjunctive treatment: There is no evidence that changing a diet speeds ulcer healing or prevents recurrence. Thus, many physicians recommend eliminating only foods that cause distress (eg, fruit juice, spicy and fatty foods). Milk, which had been a mainstay of therapy, does not aid ulcer healing and actually promotes gastric acid secretion. Although there are no definitive data linking moderate amounts of alcohol to delayed ulcer healing, alcohol is a strong promoter of acid secretion, so ulcer patients are commonly advised to restrict alcohol consumption to dilute and small amounts. Smoking is a risk factor for the development of ulcers and their complications and appears to impair ulcer healing and increase the incidence of recurrence. The risk of recurrence and degree of healing inhibition correlate with the number of cigarettes smoked per day.

Surgery: With current drug therapy, the number of patients requiring surgery has declined significantly. Indications (see Complications, above) include perforation, obstruction that does not respond to medical therapy, uncontrolled or recurrent bleeding, suspected malignant gastric ulcer, and symptoms refractory to medical management.

Acute perforation usually requires immediate surgery. The longer the delay, the poorer the prognosis. When surgery is contraindicated, alternatives are continuous nasogastric suction (preferably in an ICU) and broad-spectrum antibiotics.

The incidence and type of postsurgical symptoms vary with the type of operation. Resective surgical procedures include antrectomy, hemigastrectomy, partial gastrectomy, and subtotal gastrectomy (ie, resection of from 30 to 90% of the distal stomach with a gastroduodenostomy-Billrothl or gastrojejunostomy-Billroth II), with or without vagotomy. After resective surgery, as many as 30% of patients have significant symptoms, including weight loss, maldigestion, anemia, dumping syndrome, reactive hypoglycemia, bilious vomiting, mechanical problems, and ulcer recurrence.

Weight loss is common after subtotal gastrectomy; the patient may limit food intake because of early satiety (because the residual gastric pouch is small) or to prevent dumping syndrome and other postprandial syndromes. With a small gastric pouch, distention or discomfort may follow a meal of even moderate size; patients should be encouraged to eat smaller and more frequent meals. Maldigestion and steatorrhea caused by pancreatobiliary bypass, especially with Billroth anastomosis, may contribute to weight loss. Anemia is common (usually from iron deficiency, but occasionally from B12 deficiency caused by loss of intrinsic factor or bacterial overgrowth), and osteomalacia may occur. M vitamin B12 supplementation is recommended for all patients with total gastrectomy, but it may also be given to patients with subtotal gastrectomy if deficiency is suspected.

A dumping syndrome may follow gastric surgical procedures, particularly resections. Weakness, dizziness, sweating, nausea, vomiting, and palpitation occur soon after eating, especially hyperosmolar foods. This phenomenon is referred to as early dumping, the cause of which remains obscure but likely involves autonomic reflexes, intravascular volume contraction, and release of vasoactive peptides from the small intestine. Dietary modifications, with smaller, more frequent meals and decreased carbohydrate intake, usually help. Another form of the syndrome, reactive hypoglycemia or late dumping, results from rapid emptying of carbohydrate from the gastric pouch. Early high peaks in blood glucose stimulate excess release of insulin, which leads to symptomatic hypoglycemia several hours after the meal. A high-protein, low-carbohydrate diet and adequate caloric intake (in frequent small feedings) are recommended.

Mechanical problems, including gastrc-paresis and bezoar formation, may occur secondary to a decrease in phase gastric motor contractions, which are altered after antrectomy and vagotomy. Diarrhea is especially common after vagotomy, even without a resection (pyloroplasty). A more recently recommended operation for duodenal ulcer is the highly selective, or parietal cell, vagotomy (which is limited to afferents at the corpus and spares antral innervation, thereby obviating the need for drainage), which has a very low mortality and avoids the morbidity associated with resection and traditional vagotomy.

Postsurgical ulcer recurrence rates are 5 to 12 % after highly selective vagotomy and 2 to 5% after resective surgery. Recurrent ulcers are diagnosed by endoscopy and generally respond to medical therapy with either proton pump inhibitors or H2 blockers. For recurrent ulcers, the completeness of vagotomy should be tested by gastric analysis, H. pylori treated if present, and the Zollinger-Ellison syndrome ruled out by serum gastrin studies.

 

 

 

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