GASTRO-OESOPHAGEAL REFLUX DISEASE

GASTRIC DYSPEPSIA

CHRONIC GASTRITIS

I. Gastro-oesophageal reflux disease (etiology, diagnosis, differential diagnosis, complications, treatment)

Gastro-oesophageal reflux disease (GORD) is the most common cause of indigestion, affecting up to 30% of the general population. GORD develops when gastric or duodenal contents flow back into the oesophagus. Oesophageal reflux is only considered a pathological condition when it causes undesirable symptoms.

Gastroesophageal reflux is a normal physiologic phenomenon experienced intermittently by most people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury

A study by Richter and a Gallup Organization National Survey estimated that 25-40% of healthy adult Americans experience symptomatic GERD, most commonly manifested clinically by pyrosis (heartburn), at least once a month. Furthermore, approximately 7-10% of the adult population in the United States experiences such symptoms on a daily basis

In most persons with GERD, endogenous defense mechanisms either limit the amount of noxious material that is introduced into the esophagus or rapidly clear the material from the esophagus so that symptoms and esophageal mucosal irritation are minimized. Examples of the defense mechanisms include actions of the lower esophageal sphincter (LES) and normal esophageal motility. When the defense mechanisms are defective or become overwhelmed so that the esophagus is bathed in acid or bile and acid-containing fluid for prolonged periods, GERD can be said to exist.

Patients with GERD can exhibit various symptoms, both typical and atypical. Typical symptoms include heartburn, regurgitation, and dysphagia. Atypical symptoms include noncardiac chest pain, asthma, pneumonia, hoarseness, and aspiration. Patients typically have numerous daily episodes of symptomatic reflux, including pyrosis, water brash or sour taste in the mouth, nighttime coughing or aspiration, pneumonia or pneumonitis, bronchospasm, and laryngitis and voice changes, including hoarseness. In addition, objective evidence of esophageal damage can be seen on esophagogastroduodenoscopy as manifested by the incremental grades of esophagitis discussed below.

The anatomy of the esophagus, stomach, and esophagogastric junction is critical in the understanding of the pathogenesis of reflux.

The esophagus is divided into 3 parts: cervical, thoracic, and abdominal. The body of the esophagus is made up of inner circular and outer longitudinal muscular layers. The proximal third of the esophagus is striated muscle, which transitions to smooth muscle in the distal two thirds. The proximal esophagus contains the upper esophageal sphincter (UES), which comprises the cricopharyngeus and thyropharyngeus muscles.

The distal thoracic esophagus is located to the left side of midline. As the thoracic esophagus enters the abdomen through the esophageal hiatus in the diaphragm, it becomes the abdominal esophagus. The hiatus is formed by the right crus of the diaphragm, which forms a sling around the esophagus with the right and left pillars, so that the esophagus narrows when the diaphragm contracts. The actual contribution the diaphragm provides in maintaining an adequate length of intra-abdominal esophagus is not clearly understood; however, careful identification and approximation of the pillars during surgical treatment is crucial for preventing recurrence of reflux disease.

At this level, the phrenoesophageal ligament or membrane (see the image below), which is the reflection of the subdiaphragmatic fascia onto the transversalis fascia of the anterior abdominal wall, also encircles the esophagus. A prominent fat pad located on the anterior surface of the esophagus marks the lower limit of the phrenoesophageal ligament, which corresponds to the esophagogastric junction. This junction lies in the abdomen and forms the angle of His. The acute angle and the length of abdominal esophagus both contribute to the normal closure of the esophagus when intragastric and intra-abdominal pressures are high.

Relationship of the phrenoesophageal ligament to the diaphragm and esophagus.

The lower esophageal sphincter—or, more accurately, the distal esophageal high-pressure zone (HPZ)—is the distal most segment of the esophagus (3-5 cm in adults) and can be anywhere from 2-5 cm in length. Maintenance of an adequate intra-abdominal HPZ is crucial in preventing GERD. This HPZ does not correspond to any visible anatomic structure. It is a zone created by a complex architecture of smooth muscle fibers, and it is typically identified during manometry.

Usually, GERD is caused by a malfunction of one or more of these anatomic features. Proper surgical treatment requires complete preoperative and intraoperative evaluation and correction of all defective features.

Bllod supply of esophagus and stomach

The blood supply of the esophagus is segmental. The inferior thyroid artery supplies the cervical esophagus. Branches of the bronchial arteries and branches directly off of the aorta supply the proximal and distal thoracic esophagus, respectively. Finally, branches of the left gastric and inferior phrenic artery supply the abdominal esophagus. A relatively constant branch connects the left gastric and inferior phrenic arteries, called the Belsey artery.

Arterial blood supply and lymphatic drainage of the esophagus.

The blood supply of the stomach is rich, with overlap among the vessels. The lesser curve is supplied by the left and right gastric arteries, branches of the celiac trunk and proper hepatic artery, respectively. The greater curve is supplied by the right gastroepiploic artery arising from the gastroduodenal artery and the left gastroepiploic artery and the short gastric arteries originating from the splenic artery. This excellent collateral blood supply of the stomach allows the surgeon to ligate much of the arterial supply (ie, the short gastric arteries during fundoplication) without risk of ischemia

Pathophysiology

Schematically, the esophagus, lower esophageal sphincter (LES), and stomach can be envisioned as a simple plumbing circuit as described by Stein and coworkers. The esophagus functions as an antegrade pump, the LES as a valve, and the stomach as a reservoir. The abnormalities that contribute to GERD can stem from any component of the system. Poor esophageal motility decreases clearance of acidic material. A dysfunctional LES allows reflux of large amounts of gastric juice. Delayed gastric emptying can increase volume and pressure in the reservoir until the valve mechanism is defeated, leading to GERD. From a medical or surgical standpoint, it is extremely important to identify which of these components is defective so that effective therapy can be applied.

Esophageal defense mechanism

Esophageal defense mechanisms can be broken down into 2 categories (ie, esophageal clearance and mucosal resistance). Proper esophageal clearance is an extremely important factor in preventing mucosal injury. Esophageal clearance must be able to neutralize the acid refluxed through the lower esophageal sphincter. (Mechanical clearance is achieved with esophageal peristalsis; chemical clearance is achieved with saliva.) Normal clearance limits the amount of time the esophagus is exposed to refluxed acid or bile and gastric acid mixtures. Abnormal peristalsis can cause inefficient and delayed acid clearance.

Whether peristaltic dysfunction is secondary to esophageal exposure to acids or a primary defect is not understood clearly. In a review by Kahrilas et al, peristaltic dysfunction was progressively more common in patients with greater degrees of esophagitis. Abnormal peristalsis was identified in 25% of patients with mild esophagitis and 48% of patients with severe esophagitis.

Buttar and associates described the importance of esophageal mucosal resistance as a protective mechanism. They classified the factors into pre-epithelial, epithelial, and postepithelial defenses. When the defenses fail, esophagitis and other complications of reflux disease arise.

Dysfunction of the lower esophageal sphincter

The lower esophageal sphincter (LES) is defined by manometry as a zone of elevated intraluminal pressure at the esophagogastric junction. For proper LES function, this junction must be located in the abdomen so that the diaphragmatic crura can assist the action of the LES, thus functioning as an extrinsic sphincter. In addition, the LES must have a normal length and pressure and a normal number of episodes of transient relaxation (relaxation in the absence of swallowing).

LES dysfunction occurs via one of several mechanisms: transient relaxation of the LES (most common mechanism), permanent LES relaxation, and transient increase of intra-abdominal pressure that overcomes the LES pressure.

Delayed gastric emptying

The postulated mechanism by which delayed gastric emptying may cause GERD is an increase in gastric contents resulting in increased intragastric pressure and, ultimately, increased pressure against the lower esophageal sphincter. This pressure eventually defeats the LES and leads to reflux. However, objective studies have produced conflicting data regarding the role of delayed gastric emptying in the pathogenesis of GERD.

Hiatus hernia

When discussing mechanisms for GERD, the issue of hiatal hernia must be addressed. Hiatal hernias can be encountered frequently in patients with reflux disease; however, it has been well proven that not all patients with hiatal hernias have symptomatic reflux.

Buttar and coworkers state that a hiatal hernia may contribute to reflux via a variety of mechanisms.The lower esophageal sphincter may migrate proximally into the chest and lose its abdominal high-pressure zone (HPZ), or the length of the HPZ may decrease. The diaphragmatic hiatus may be widened by a large hernia, which impairs the ability of the crura to function as an external sphincter. Finally, gastric contents may be trapped in the hernial sac and reflux proximally into the esophagus during relaxation of the LES. Reduction of the hernias and crural closure is key to restoring an adequate intra-abdominal length of esophagus and recreating the HPZ.

Epidemiology

Western dietary habits have made GERD a common disease. Richter and associates reported that 25-40% of Americans experience symptomatic GERD at some point. Approximately 7-10% of Americans experience symptoms of GERD on a daily basis. Because many individuals control symptoms with over-the-counter (OTC) medications and without consulting a medical professional, the actual number of individuals with GERD is probably higher.

No sexual predilection exists: GERD is as common in men as in women. However, the male-to-female incidence ratio for esophagitis is 2:1-3:1. The male-to-female incidence ratio for Barrett esophagus is 10:1. White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations.

GERD occurs in all age groups. The prevalence of GERD increases in people older than 40 years.

The risk factors for reflux include:

· Alcohol (possibly)

· Hiatal hernia (a condition in which part of the stomach moves above the diaphragm, which is the muscle that separates the chest and abdominal cavities)

· Obesity

· Pregnancy

· Smoking

Heartburn and gastroesophageal reflux can be brought on or made worse by pregnancy and many different medications. Such drugs include:

· Anticholinergics (e.g., for seasickness)

· Beta-blockers for high blood pressure or heart disease

· Bronchodilators for asthma

· Calcium channel blockers for high blood pressure

· Progestin for abnormal menstrual bleeding or birth control

· Sedatives for insomnia or anxiety

· Tricyclic antidepressants

If you suspect that one of your medications may be causing heartburn, talk to your doctor. Never change or stop a medication you take regularly without talking to your doctor.

Classification of GERD

(According to unified clinical and statistical classification of diseases of the digestive system (HCD of Ukraine, 2004)

-Endoscopic "-" GERD (without esophagitis)

-Endoscopic "+" GERD (with esophagitis)

Clinical forms of GERD

Nonerosive GERD (is defined as those who have typical reflux symptoms without evidence of erosive changes in their lower esophageal mucosa; observed in approximately 60% of patients with GERD);

Erosive GERD (erosive changes of esophageal epithelium in varying degree, found in 37% of patients);

Grade A - one or more mucosal breaks < 5 mm in maximal length

Grade B - one or more mucosal breaks > 5mm, but without continuity across mucosal folds

Grade C - mucosal breaks continuous between > 2 mucosal folds, but involving less than 75% of the esophageal circumference

Grade D - mucosal breaks involving more than 75% of esophageal circumference

Complications of GERD (Barrett's esophagus, peptic esophageal ulcer, stricture, bleeding) (defined in 3% of patients).

Clinical features of GERD

Gastroesophageal reflux disease (GERD) is associated with a set of typical (esophageal) symptoms, including heartburn, regurgitation, and dysphagia. (However, a diagnosis of GERD based on the presence of typical symptoms is correct in only 70% of patients.) In addition to these typical symptoms, abnormal reflux can cause atypical (extraesophageal) symptoms, such as coughing, chest pain, and wheezing.

The American College of Gastroenterology (ACG) published updated guidelines for the diagnosis and treatment of GERD in 2005. According to the guidelines, for patients with symptoms and history consistent with uncomplicated GERD, the diagnosis of GERD may be assumed and empirical therapy begun. Patients who show signs of GERD complications or other illness or who do not respond to therapy should be considered for further diagnostic testing.

A history of nausea, vomiting, or regurgitation should alert the physician to evaluate for delayed gastric emptying.

Patients with GERD may also experience significant complications associated with the disease, such as esophagitis, stricture, and Barrett esophagus. Approximately 50% of patients with gastric reflux develop esophagitis.

The most common symptoms of oesophageal reflux are dyspepsia, heartburn

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and regurgitation, which can be provoked by bending, straining or lying down. Waterbrash, which is salivation due to reflex salivary gland stimulation as acid enters the gullet, is often present. A history of weight gain is common.

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Other less common symptoms include dysphagia (difficulty swallowing), odynophagia (pain on swallowing), and symptoms of anaemia. A small number of patients present with atypical chest pain, which may be severe, can mimic angina and is probably due to reflux-induced oesophageal spasm.

Belching air, food, sour, bitter, regurgitation occurs because of retrograde reflux of gastric content into the esophagus and mouth (more than 50% of patients);

Chest pain. Less frequently observed arises from spasm of the esophagus in response to acid-peptic aggression. Localization and irradiation are similar to symptoms in angina. In these patients, excluding cardiac etiology is important prior to labeling the pain as noncardiac chest pain secondary to GERD.

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Pathophysiology of GERD

Mandatory studies include upper GI endoscopy and manometry. Endoscopy can help confirm the diagnosis of reflux by demonstrating complications of reflux (esophagitis, strictures, Barrett esophagus) and can help in evaluating the anatomy (eg, hiatal hernia, masses, strictures). Manometry helps surgical planning by determining the lower esophageal sphincter (LES) pressure and identifying any esophageal motility disorders. Esophageal amplitudes and propagation of esophageal swallows are also evaluated.

Optional studies include 24-hour pH probe test and upper GI series. Use of 24-hour pH testing helps confirm the diagnosis in patients in whom the history is not clear, atypical symptoms dominate the clinical picture, or endoscopy shows no complications of reflux disease. Upper GI series can be ordered to further delineate the anatomy. Hiatal hernias can be evaluated (size) and reflux can be demonstrated. In addition, gastric emptying can be evaluated to a limited. If a question exists regarding inadequate gastric emptying or if the patient has a history of nausea and vomiting, a nuclear medicine gastric emptying study can be obtained.

At the authors' institution, endoscopy, manometry, and 24-hour pH studies are obtained routinely. Upper GI series and nuclear medicine gastric emptying studies are ordered only if clinically indicated. Currently, no role exists for CT, MRI, or ultrasonography in the routine evaluation of patients with reflux disease.

Occasional episodes of GORD are common in health, particularly after eating. Gastro-oesophageal reflux disease develops when the oesophageal mucosa is exposed to gastric contents for prolonged periods of time, resulting in symptoms and, in a small proportion of cases, this leads to oesophagitis.

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Normally, prevention of acid damage is achieved by a combination of physiological barriers. The LOS is a 3-4 cm long collection of smooth muscle fibres which maintains a resting tone of 10-30mmHg pressure.

Oesophageal manometry studies.

There is also extrinsic pressure exerted from the crura of the diaphragm at the same point and the angle of His (the angle of entry of the oesophagus into the stomach) which both help retain acid within the stomach. Periods of LOS relaxation occur in all individuals and allow transient reflux of acid into the oesophagus. This initiates a distal oesophageal peristaltic wave which progressively clears the acid. Swallowed saliva is alkaline and also helps neutralise oesophageal acid.

Mechanism of protection of oesophagus from acid reflux

Abnormalities of the lower oesophageal sphincter related to GORD

In health the lower oesophageal sphincter is tonically contracted, relaxing only during swallowing. Some patients with GORD have reduced lower oesophageal sphincter tone, permitting reflux when intra-abdominal pressure rises. In others basal sphincter tone is normal but reflux occurs in response to frequent episodes of inappropriate sphincter relaxation.

Hiatus hernia

A hiatal hernia occurs when part of the stomach protrudes through the diaphragm and into the thoracic cavity. Such hernias are extremely common in older people and more common in women than in men. A hiatus hernia causes reflux because the pressure gradient between the abdominal and thoracic cavities, which normally pinches the hiatus, is lost. In addition the oblique angle between the cardia and oesophagus disappears. Many patients who have large hiatus hernias develop reflux symptoms, but the relationship between the presence of a hernia and symptoms is poor. Hiatus hernias are very common in individuals who have no symptoms, and some symptomatic patients have only a very small or no hernia.

Important features of a hiatus hernia include:

• Occur in 30% of the population over the age of 50 years.

• Often asymptomatic.

• Heartburn and regurgitation can occur.

• Gastric volumes may complicate large hernias.

The role of gastric contents in GORD

Gastric acid is the most important oesophageal irritant and there is a close relationship between acid exposure time and symptoms. Alkaline reflux, due to bile reflux following gastric surgery, is of uncertain importance.

Increased intra-abdominal pressure

Pregnancy and obesity are established predisposing causes. Weight loss commonly improves symptoms and patients should be encouraged to avoid tight-fitting garments.

Dietary and environmental factors

Dietary fat, chocolate, alcohol and beverages such as tea and coffee relax the lower oesophageal sphincter and may provoke symptoms.

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There is little evidence to incriminate smoking or non-steroidal anti-inflammatory drugs (NSAIDs) as causes of gastro-oesophageal reflux disease.

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Delayed oesophageal clearance

Defective oesophageal peristaltic activity can be seen in patients who have GORD. Poor oesophageal clearance leads to increased exposure to acid from the stomach.

Complications of GORD

Oesophagitis

Reflux oesophagitis is a chronic inflammatory process mediated by gastric acid and pepsin from the stomach as well as bile from the duodenum, which can result in ulceration of the mucosa and secondary fibrosis in the muscular wall. A range of endoscopic findings, from mild redness to severe bleeding ulceration with stricture formation, is recognised. There is a poor correlation between symptoms and histological and endoscopic findings. A normal endoscopy and normal oesophageal histology are perfectly compatible with significant gastro-oesophageal reflux disease.

An endoscopic view of a normal oesophagus

Other causes of oesophagitis: infectious diseases. Viruses, bacteria, fungi and mycobacterium can all cause oesophageal infection. The most common of these are candida. Oesophageal candidiasis occurs in debilitated patients and those taking broad-spectrum antibiotics or cytotoxic drugs. It is a particular problem in AIDS patients, who are also susceptible to a spectrum of oesophageal infections. Oesophageal candidiasis rarely develops in patients who do not have an underlying disease such as diabetes, immune deficiency or malignancy. The main symptoms of oesophageal candidiasis are dysphagia and odynophagia. Severe infection of the gullet can destroy oesophageal innervation, causing abnormal motility.

Endoscopic view of mild oesophagitis.

Reflux oesophagitis.

Peptic esophagitis. A rapid urease test (RUT) is p

Peptic esophagitis. A rapid urease test (RUT) is performed on the esophageal biopsy sample. The result is positive for esophagitis.

Esophagitis may be diagnosed using endoscopy, although it cannot always be appreciated on endoscopy. As many as 50% of symptomatic patients with GERD demonstrate no evidence of esophagitis on endoscopy. Still, documentation of this complication is important in diagnosing GERD. Degrees of esophagitis are described by the Savary-Miller classification as follows.

Grade I – Erythema
Grade II – Linear nonconfluent erosions
Grade III – Circular confluent erosions
Grade IV – Stricture or Barrett esophagus.

Reflux esophagitis is demonstrated on barium esophagram.

Reflux oesophagitis.

Corrosives

Accidental or suicidal ingestion of highly alkaline or acidic substances may result in injury to the oesophagus. The most common symptom is odynophagia, but patients may also complain of dysphagia and chest pain. Ingestion of caustic compounds is followed by painful burns of the mouth and pharynx and by extensive erosive oesophagitis. At the time of presentation, management is conservative, based upon analgesia and nutritional support. Vomiting should be avoided and endoscopy should not be done at this stage because of the high risk of oesophageal perforation. Following the acute phase, a barium swallow and X-ray examination is performed to demonstrate the extent of stricture formation. Endoscopic dilation is usually necessary, although it is difficult and hazardous because strictures are often long, tortuous and easily perforated.

Strictures are advanced forms of esophagitis and are caused by circumferential fibrosis due to chronic deep injury. Strictures can result in dysphagia and a short esophagus. Gastroesophageal reflux strictures typically occur in the mid-to-distal esophagus and can be visualized on upper GI tract studies and endoscopy. Presence of a stricture with a history of reflux can also help diagnose GERD. Patients present with dysphagia to solid meals and vomiting of nondigested foods.

As a rule, the presence of any esophageal stricture is an indication that the patient needs surgical consultation and treatment (usually surgical fundoplication). When patients present with dysphagia, barium esophagography is indicated to evaluate for possible stricture formation. In these cases, especially when associated with food impaction, eosinophilic esophagitis must be ruled out prior to attempting any mechanical dilatation of the narrowed esophageal region.

Esophageal stricture

Barrett’s oesophagus

Barrett’s oesophagus is defined as epithelial metaplasia in which the normal squamous epithelium of the oesophagus is replaced by one or more of the following types of columnar epithelium: a specialised columnar epithelium, a junctional type of epithelium; and/or a gastric type of epithelium. Barrett’s oesophagus is thought to be a consequence of chronic gastro-oesophageal reflux.

Diagnosis of Barrett’s oesophagus is made by endoscopic visualisation of the oesophageal mucosa, supported by examination of tissue biopsies. Barrett’s oesophagus is recognised endoscopically as confluent areas or fingers of pink, gastric-like mucosa extending from the cardia of the stomach into the oesophagus. The prevalence of adenocarcinoma in patients with Barrett’s oesophagus is reported to be in the region of 30 to 50 times that of the general population (Clark et al. 2000). Consequently patients discovered to have Barrett’s changes during endoscopy are considered for endoscopic surveillance programmes. Patients with moderate dysplasia should undergo repeated biopsies at 6 to 12-monthly intervals. Patients found to have severe dysplasia usually have associated cancer and are usually referred for oesophageal surgery.

In Barrett esophagus, columnar epithelium extends proximal to the gastroesophageal junction (the imaginary line at which the esophagus ends and the stomach begins, which corresponds to the most proximal extent of the gastric folds).

Histology. Barrett’s oesophagus

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Endoscopy. Barrett’s oesophagus

Management of patients with Barrett esophagus.

Anaemia

Iron deficiency anaemia occurs as a consequence of chronic, insiduous blood loss and can result from longstanding oesophagitis.

Benign oesophageal stricture

Esophageal stricture

Treatment of strictures may involve the use of weighted bougies, pneumatic balloon dilators or graduated plastic Savary-Gillard dilators. Subsequent treatment usually involves long-term therapy with a proton pump inhibitor drug (i.e. omeprazole or lansoprazole) which should be prescribed to reduce the risk of recurrent oesophagitis and stricture formation. The patient should be advised to chew food thoroughly and it is also important to ensure that dentition is adequate.

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Balloon dilation of a benign oesophageal stricture.

Investigations for GORD

Investigation is advisable if patients present in middle or late age, if symptoms are atypical or if a complication is suspected. Endoscopy is the investigation of choice. This is done to exclude other upper gastrointestinal diseases that can mimic gastro-oesophageal reflux, and to identify complications. A normal endoscopy in a patient with compatible symptoms should not preclude treatment for gastro-oesophageal reflux disease. When, despite endoscopy, the diagnosis is unclear or if surgical intervention is under consideration, 24-hour pH monitoring is indicated. This involves tethering a slim catheter with a terminal radiotelemetry pHsensitive probe above the gastro-oesophageal junction. The intraluminal pH is recorded whilst the patient undergoes normal activities, and episodes of pain are noted and related to pH. A pH of less than 4 for more than 4% of the study time is diagnostic of reflux disease.

Gastroesophageal reflux may be classified into 3 categories as follows:

Physiologic (or functional) gastroesophageal reflux: These patients have no underlying predisposing factors or conditions; growth and development are normal; and pharmacologic treatment is typically not necessary, though it may be needed to relieve symptoms if lifestyle changes are unsuccessful.
Pathologic gastroesophageal reflux or GERD: Patients frequently experience complications noted above, requiring careful evaluation and treatment
Secondary gastroesophageal reflux: This refers to a case in which an underlying condition may predispose to gastroesophageal reflux, with examples including asthma (a condition that may also be, in part, caused by or exacerbated by reflux) and gastric outlet obstruction

The diagnosis of GERD in patients with atypical symptoms can be difficult. When patients present with atypical complaints, the diagnosis of GERD must be kept in mind. Patients with recurrent aspiration can have asthma, history of pneumonias, and progressive pulmonary fibrosis. Additionally, hoarseness can be present due to chronic laryngeal irritation. Chest pain is another presenting symptom that can be difficult to evaluate. In these patients, excluding cardiac etiology is important prior to labeling the pain as noncardiac chest pain secondary to GERD.

The clinical presentation of GERD in pregnant women is similar to that for the general population. Heartburn and regurgitation are the cardinal symptoms. The diagnostic evaluation consists of a thorough history and physical examination.

Management of GORD

The first-line nursing of patients with GORD should relate to behaviour modification and nurses should encourage the following recommendations:

• weight loss

• avoidance of tight-fitting garments

• avoidance of dietary items which the patient finds worsens symptoms

• elevation of the bed-head in those who experience nocturnal symptoms

• avoidance of late meals

• cessation of smoking

Antacids, which are said to produce a protective mucosal ‘raft’ over the oesophageal mucosa, are taken with considerable symptomatic benefit by most patients. H2 receptor antagonist drugs, which reduce gastric acid secretion, help symptoms without healing oesophagitis. They are well tolerated and the timing of medication and dosage should be tailored to individual need. Proton pump inhibitors are the treatment of choice for severe symptoms and for complicated reflux disease. These drugs irreversibly inhibit the proton pump, reducing the transport of hydrogen (H) ions out of parietal cells. Symptoms almost invariably resolve and oesophagitis heals in the majority of patients. Recurrence of symptoms is almost inevitable when therapy is stopped, and some patients require lifelong treatment. Patients who fail to respond to medical therapy, those who are unwilling to take long-term proton pump inhibitors and those whose major symptom is severe regurgitation are considered for anti-reflux surgery.

Nissen fundoplication.

Evidence-based guidelines for the management of GORD have been published by the Scottish Intercollegiate Guidelines Network (SIGN) (2003) and the British Society of Gastroenterology (BSG) (2002).

II. Gastric dyspepsia (etiology, diagnosis, differential diagnosis, complications, treatment)

NON-ULCER DYSPEPSIA

It is not unusual for there to be confusion when a diagnosis is based on symptoms alone. This is undoubtedly the case with non-ulcer dyspepsia (NUD), but it is an essential diagnostic group because it represents up to 40% of patients who present with 'persistent or recurrent pain or discomfort that is centred in the upper abdomen or epigastrium' (dyspepsia), and in whom upper GI endoscopy and radiology are normal. Symptoms can be subdivided into:

• Ulcer-like dyspepsia

Epigastric pain relieved by food, often occurring at night

• Dysmotility-like dyspepsia

Upper abdominal discomfort, worse after meals, accompanied with bloating, early satiety and nausea

• Reflux-like dyspepsia

Upper abdominal pain with associated reflux symptoms. This classification has not proved helpful in tailoring therapy, except for reflux-like symptoms which might be better treated as for GORD. The pathology responsible for causing the symptoms of NUD has focused on two main areas:

1. gastric dysmotility

2. Helicobacter pylori-related gastritis.

During fasting, the stomach exhibits migrating motor complexes (MMCs) along with the rest of the GI tract and post-prandially shows relaxation of the gastric fundus to accommodate the food bolus. The antrum has high amplitude contractions to reduce particle size and the pylorus has phasic contractions to allow slow emptying of the stomach. There may be decreased compliance of the gastric fundus in NUD patients but this does not correlate well with symptoms, particularly nausea and early satiety, nor does it predict a good outcome with treatment using promotility agents.

H. pylori-related gastritis has come under close scrutiny in patients with NUD. There appears to be no benefit accrued by eradicating H. pylori in patients with NUD. Gastric acid hypersecretion does not cause NUD as basal and peak acid output is similar in both patients and controls.

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

Diagnostic tests for H. pylori and their estimated costs.

MANAGEMENT

After the diagnosis of NUD, subsequent further investigation should be avoided as it implies diagnostic uncertainty and may worsen therapeutic outcome. Minimum treatment required should be adopted with simple antacids. More intractable cases may be treated with H2 receptor antagonists or PPIs for 4-6 weeks and then discontinued and reserved for symptom recurrence. Promotility agents may be beneficial and are best taken shortly before meals. Evidence supporting the usefulness of H. pylori eradication in NUD patients is lacking but as peptic ulcer disease is periodic, it is possible that patients were in remission at the time of endoscopy. Consequently, it may be appropriate to offer H. pylori eradication therapy in patients showing relevant symptoms.

Approach to a patient with new and undiagnosed ulcerlike symptoms refractory to a trial of antisecretory therapy with an H2 receptor blocker or a proton pump inhibitor at customary doses or a patient with recurrent ulcerlike symptoms when the antisecretory therapy is stopped.

GASTRITIS

Definition

Gastritis means inflammation of the gastric mucosa. It is caused by irritants, such as gastric acid, bile reflux, medications or toxins. Gastritis is often associated with an impairment of natural protective mechanisms. It can be classified according to its inflammatory pattern as acute (erosive, haemorrhagic gastritis) or chronic (non-erosive gastritis).

Acute gastritis

This may involve the gastric body and antrum of the stomach and is often erosive and haemorrhagic. The response of the gastric mucosa to trauma is similar to that in other tissues with the release of an array of physiologically active substances. Erythema and oedema are predominant features.

Causes of acute gastritis

Acute gastritis often produces no symptoms but may cause dyspepsia, anorexia, nausea or vomiting, haematemesis or melaena. Many cases resolve quickly and do not merit investigation; in others endoscopy and biopsy may be necessary to exclude peptic ulcer, cancer or bleeding. Treatment should be directed to the underlying cause. Acute gastritis almost always responds to conservative therapy with oral antacids.

Chronic gastritis

Chronic gastritis is common in adults and may be associated with a number of conditions including gastric ulcers and Helicobacter pylori (HP). It usually involves the gastric body and antrum of the stomach. Most patients are asymptomatic and do not require any treatment. At present there is no indication for widespread use of HP eradication therapy in patients with chronic gastritis but without evidence of peptic ulcer disease.

Chronic gastritis can be classified as:

· Type A (autoimmune)

· Type B (bacterial infection)

· Type C (reflux gastritis)

Type A: autoimmune chronic gastritis (ACG)

Atrophic gastritis is a condition of chronic inflammation and atrophy (tissue destruction) affecting the stomach's mucosal lining. Over time, atrophic gastritis leads to a loss of the gastric glandular and chief cells, a subsequent breakdown of the mucosal lining, and an eventual replacement of the mucosa by intestinal and fibrous tissue.

Atrophic gastritis has two causes: 1) an autoimmune process targeting parietal cells or intrinsic factor and 2) environmental causes such as persistent infection with Helicobacter pylori bacteria or dietary factors. Recent evidence suggests that Helicobacter pylori can trigger the development of autoimmune atrophic gastritis through a process of molecular mimicry in which the bacterial organisms take on the appearance of parietal cells.

However, these two types of gastritis are distinct, with each disorder causing different tissue changes when biopsy samples are examined. In autoimmune gastritis tissue destruction is restricted to the gastric corpus and fundus, whereas infectious gastritis is a multifocal process with more extensive involvement of the strictures related to the gastric corpus and fundus. Atrophic gastritis associated with Helicobacter pylori is also less likely to cause symptoms and more likely to lead to the development of stomach cancer.

In autoimmune atrophic gastritis, autoantbodies cause destruction of the parietal cell mass that makes up the gastric mucosa. The autoimmune response causes an infiltration of white blood cells and the release of chemical cytokines that accelerate the disease process. Ultimately, the autoimmune response impairs the mucosal cells' ability to produce hydrochloric acid, digestive enzymes such as pepsin, and intrinsic factor, a substance needed for the absorption of vitamin B12.

Signs and Symptoms

Deficiencies of intrinsic factor lead to vitamin B12 deficiency and a condition of pernicious anemia. Deficiencies of hydrochloric acid (hypochlorhydria) induce the production of G (Gastrin producing) cells. Increased proliferation of G cells causes excess gastrin production, which in turn increases the risk for development of gastric polyps and gastric adenocarcinoma (stomach cancer).

Early in the course of the disease, symptoms rarely occur although mild symptoms of indigestion may be present. Autoimmune atrophic gastritis is the most frequent cause of pernicious anemia in temperate climates. The risk of gastric adenocarcinoma is reported to be at least 2.9 times higher in patients with pernicious anemia than in the general population. Patients with pernicious anemia are also at increased risk for esophageal squamous-cell carcinomas.

Autoimmune atrophic gastritis typically causes symptoms related to vitamin B12 (cobalmin) deficiency, including anemia, gastrointestinal symptoms, and neurologic symptoms including dementia. Megaloblastic anemia may develop, and rarely platelet deficiency (thrombocytopenia) may occur. Symptoms of anemia include weakness, light-headedness, vertigo, tinnitus, palpitations, angina and symptoms of congestive heart failure. Other symptoms include sore tongue, weight loss, irritability, mild jaundice, and heart enlargement.

ACG involves the body of the stomach but does not affect the antral region and results from autoimmune activity against parietal cells. The histological features are diffuse chronic inflammation, atrophy and loss of fundi glands, intestinal metaplasia and sometimes hyperplasia of enterochromaffin-like (ECL) cells. In some patients the degree of gastric atrophy is severe and loss of intrinsic factor secretion leads to pernicious anaemia. The gastritis itself is usually asymptomatic but some patients have evidence of other organ-specific autoimmunity, particularly thyroid disease. There is a fourfold increase in the risk of gastric cancer development.

Type B: bacterial infection

H pylori is a gram-negative rod that has the ability to colonize and infect the stomach. The bacteria survive within the mucous layer that covers the gastric surface epithelium and the upper portions of the gastric foveolae. The infection is usually acquired during childhood. Once the organism has been acquired, has passed through the mucous layer, and has become established at the luminal surface of the stomach, an intense inflammatory response of the underlying tissue develops.

The presence of H pylori is associated with tissue damage and the histologic finding of both an active and a chronic gastritis. The host response to H pylori and bacterial products is composed of T and B lymphocytes, denoting chronic gastritis, followed by infiltration of the lamina propria and gastric epithelium by polymorphonuclear leukocytes (PMNs) that eventually phagocytize the bacteria. The presence of PMNs in the gastric mucosa is diagnostic of active gastritis.

Interaction of H pylori with the surface mucosa results in the release of interleukin (IL)-8, which leads to recruitment of PMNs and may begin the entire inflammatory process. Gastric epithelial cells express class II molecules, which may increase the inflammatory response by presenting H pylori antigens, leading to further cytokine release and more inflammation. High levels of cytokines, particularly tumor necrosis factor-α (TNF-α) and multiple interleukins (eg, IL-6, IL-8, IL-10), are detected in the gastric mucosa of patients with H pylori gastritis.

Leukotriene levels are also quite elevated, especially the level of leukotriene B4, which is synthesized by host neutrophils and is cytotoxic to gastric epithelium. This inflammatory response leads to functional changes in the stomach, depending on the areas of the stomach involved. When inflammation affects the gastric corpus, parietal cells are inhibited, leading to reduced acid secretion. Continued inflammation results in loss of parietal cells, and the reduction in acid secretion becomes permanent.

Antral inflammation alters the interplay between gastrin and somatostatin secretion, affecting G cells (gastrin-secreting cells) and D cells (somatostatin-secreting cells), respectively. Specifically, gastrin secretion is abnormal in individuals who are infected with H pylori, with an exaggerated meal-stimulated release of gastrin being the most prominent abnormality.

When the infection is cured, neutrophil infiltration of the tissue quickly resolves, with slower resolution of the chronic inflammatory cells. Paralleling the slow resolution of the monocytic infiltrates, meal-stimulated gastrin secretion returns to normal.

Various strains of H pylori exhibit differences in virulence factors, and these differences influence the clinical outcome of H pylori infection. People infected with H pylori strains that secrete the vacuolating toxin A (vacA) are more likely to develop peptic ulcers than people infected with strains that do not secrete this toxin.

Another set of virulence factors is encoded by the H pylori pathogenicity island (PAI). The PAI contains the sequence for several genes and encodes the CAGA gene. Strains that produce CagA protein (CagA⁺) are associated with a greater risk of development of gastric carcinoma and peptic ulcers. However, infection with CagA^- strains also predisposes the person to these diseases.

H pylori- associated chronic gastritis progresses according to the following 2 main topographic patterns, which have different clinical consequences:

Antral predominant gastritis – This is characterized by inflammation and is mostly limited to the antrum; individuals with peptic ulcers usually demonstrate this pattern
Multifocal atrophic gastritis – This is characterized by involvement of the corpus and gastric antrum with progressive development of gastric atrophy (loss of the gastric glands) and partial replacement of gastric glands by an intestinal-type epithelium (intestinal metaplasia); individuals who develop gastric carcinoma and gastric ulcers usually demonstrate this pattern

An increased duodenal acid load may precipitate and wash out bile salts, which normally inhibit the growth of H pylori. Progressive damage to the duodenum promotes gastric foveolar metaplasia, resulting in sites for H pylori growth and more inflammation. This cycle renders the duodenal bulb increasingly unable to neutralize acid entering from the stomach until changes in bulb structure and function are sufficient for an ulcer to develop. H pylori can survive in areas of gastric metaplasia in the duodenum, contributing to the development of peptic ulcers.

MALT lymphomas may develop in association with chronic gastritis secondary to H pylori infection. The healthy stomach lacks organized lymphoid tissue, but after infection with H pylori, lymphoid tissue is universally present. Acquisition of gastric lymphoid tissue is thought to be due to persistent antigen stimulation from byproducts of chronic infection with H pylori.

The continuous presence of H pylori results in the persistence of MALT in the gastric mucosa, which eventually may progress to form low- and high-grade MALT lymphomas. MALT lymphomas are monoclonal proliferations of neoplastic B cells that have the ability to infiltrate gastric glands. Gastric MALT lymphomas typically are low-grade T-cell–dependent B-cell lymphomas, and the antigenic stimulus of gastric MALT lymphomas is thought to be H pylori.

Another complication of H pylori gastritis is the development of gastric carcinomas, especially in individuals who develop extensive atrophy and intestinal metaplasia of the gastric mucosa. Although the relationship between H pylori and gastritis is constant, only a small proportion of individuals infected with H pylori develop gastric cancer. The incidence of gastric cancer usually parallels the incidence of H pylori infection in countries with a high incidence of gastric cancer and is consistent with H pylori being the cause of the precursor lesion, chronic atrophic gastritis.

Persistence of the organisms and associated inflammation during long-standing infection is likely to permit the accumulation of mutations in the gastric epithelial cells’ genome, leading to an increased risk of malignant transformation and progression to adenocarcinoma. Studies have provided evidence of the accumulation of mutations in the gastric epithelium secondary to oxidative DNA damage associated with chronic inflammatory byproducts and secondary to deficiency of DNA repair induced by chronic bacterial infection.

Although the role of H pylori in peptic ulcer disease is well established, the clinical role of the infection in nonulcer dyspepsia remains highly controversial. H pylori eradication may be beneficial for symptom relief in a small proportion of patients, but routine H pylori testing and treatment in nonulcer dyspepsia are not currently widely accepted. Therefore, H pylori eradication strategies in patients with nonulcer dyspepsia must be considered on a patient-by-patient basis.

Type C: reflux gastritis

Reflux gastritis is caused by the regurgitation of duodenal contents into the stomach through the pylorus. It may be present with dyspepsia and bilious vomiting.

Chronic gastritis is identified histologically by an inflammatory cell infiltrate consisting primarily of lymphocytes and plasma cells, with very scant neutrophil involvement. Distribution of the inflammation may be patchy, initially involving superficial and glandular portions of the gastric mucosa. This picture may progress to more severe glandular destruction, with atrophy and metaplasia. Chronic gastritis has been classified according to histologic characteristics. These include superficial atrophic changes and gastric atrophy.

The early phase of chronic gastritis is superficial gastritis. The inflammatory changes are limited to the lamina propria of the surface mucosa, with edema and cellular infiltrates separating intact gastric glands. Additional findings may include decreased mucus in the mucous cells and decreased mitotic figures in the glandular cells. The next stage is atrophic gastritis. The inflammatory infiltrate extends deeper into the mucosa, with progressive distortion and destruction of the glands. The final stage of chronic gastritis is gastric atrophy. Glandular structures are lost; there is a paucity of inflammatory infiltrates. Endoscopically the mucosa may be substantially thin, permitting clear visualization of the underlying blood vessels. Gastric glands may undergo morphologic transformation in chronic gastritis. Intestinal metaplasia denotes the conversion of gastric glands to a small intestinal phenotype with small-bowel mucosal glands containing goblet cells. The metaplastic changes may vary in distribution from patchy to fairly extensive gastric involvement. Intestinal metaplasia is an important predisposing factor for gastric cancer.

Lymphocytic gastritis

This is a type of chronic gastritis with dense infiltration of the surface and foveolar epithelium by T lymphocytes and associated chronic infiltrates in the lamina propria. Because of similar histopathology relative to celiac disease, lymphocytic gastritis has been proposed to result from intraluminal antigens. High anti–H.pylori antibody titers have been found in patients with lymphocytic gastritis, and, in limited studies, the inflammation disappeared after H pylori eradication. However, many patients with lymphocytic gastritis are serologically negative for H pylori. A number of cases may develop secondary to intolerance to gluten and drugs such as ticlopidine.

Picture 1 - Lymphocytic Gastritis

Eosinophilic gastritis

Large numbers of eosinophils may be observed with parasitic infections such as those caused by Eustoma rotundatum and anisakiasis. Eosinophilic gastritis can be part of the spectrum of eosinophilic caused by Eustoma rotundatum and anisakiasis. Although the gastric antrum is commonly affected, this condition can affect any segment of the GI tract and can be segmental. Patients frequently have peripheral blood eosinophilia. In some cases, especially in children, eosinophilic gastroenteritis can result from food allergy, usually to milk or soy protein. Eosinophilic gastroenteritis can also be found in some patients with connective tissue disorders, including scleroderma, polymyositis, and dermatomyositis

Picture 2 - Eosinophilic Gastritis

Radiation gastritis

Small doses of radiation (up to 1500 R) cause reversible mucosal damage, whereas higher radiation doses cause irreversible damage with atrophy and ischemic-related ulceration. Reversible changes consist of degenerative changes in epithelial cells and nonspecific chronic inflammatory infiltrate in the lamina propria. Higher amounts of radiation cause permanent mucosal damage, with atrophy of fundic glands, mucosal erosions, and capillary hemorrhage. Associated submucosal endarteritis results in mucosal ischemia and secondary ulcer development.

Ischemic gastritis

Ischemic gastritis is believed to result from atherosclerotic thrombi arising from the celiac and superior mesenteric arteries.

Chronic gastritis is also classified according to the predominant site of involvement. Type A refers to the body-predominant form (autoimmune) and type B is the central-predominant form (H. pylori-related). This classification is artificial in view of the difficulty in distinguishing these two entities. The term AB gastritis has been used to refer to a mixed antral/body picture

Type A Gastritis

The less common of the two forms involves primarily the fundus and body, with antral sparing. Traditionally, this form of gastritis has been associated with pernicious anemia in the presence of circulating antibodies against parietal cells and intrinsic factor; thus it is also called autoimmune gastritis. H. pylori infection can lead to a similar distribution of gastritis. The characteristics of an autoimmune picture are not always present.

Antibodies to parietal cells have been detected in >90% of patients with pernicious anemia and in up to 50% of patients with type A gastritis. Anti-parietal cell antibodies are cytotoxic for gastric mucous cells. The parietal cell antibody is directed against H+,K+-ATPase. T cells are also implicated in the injury pattern of this form of gastritis.

Parietal cell antibodies and atrophic gastritis are observed in family members of patients with pernicious anemia. These antibodies are observed in up to 20% of individuals over age 60 and in ~20% of patients with vitiligo and Addison's disease. About half of patients with pernicious anemia have antibodies to thyroid antigens, and about 30% of patients with thyroid disease have circulating anti-parietal cell antibodies. Anti-intrinsic factor antibodies are more specific than parietal cell antibodies for type A gastritis, being present in ~40% of patients with pernicious anemia. Another parameter consistent with this form of gastritis being autoimmune in origin is the higher incidence of specific familial histocompatibility haplotypes such as HLA-B8 and -DR3.

The parietal cell-containing gastric gland is preferentially targeted in this form of gastritis, and achlorhydria results. Parietal cells are the source of intrinsic factor, lack of which will lead to vitamin B12 deficiency and its sequelae (megaloblastic anemia, neurologic dysfunction).

Gastric acid plays an important role in feedback inhibition of gastrin release from G cells. Achlorhydria, coupled with relative sparing of the antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin levels can be markedly elevated (>500 pg/mL) in patients with pernicious anemia. ECL cell hyperplasia with frank development of gastric carcinoid tumors may result from gastrin trophic effects. The role of gastrin in carcinoid development is confirmed by the observation that antrectomy leads to regression of these lesions. Hypergastrinemia and achlorhydria may also be seen in non-pernicious anemia-associated type A gastritis.

Type B gastritis

Type B, or antral-predominant, gastritis is the more common form of chronic gastritis. H. pylori infection is the cause of this entity. Although described as "antral-predominant," this is likely a misnomer in view of studies documenting the progression of the inflammatory process towards the body and fundus of infected individuals. The conversion to a pan-gastritis is time-dependent-estimated to require 15 to 20 years. This form of gastritis increases with age, being present in up to 100% of people over age 70. Histology improves after H. pylori eradication. The number of H. pylori organisms decreases dramatically with progression to gastric atrophy, and the degree of inflammation correlates with the level of these organisms. Early on, with antral-predominant findings, the quantity of H. pylori is highest and a dense chronic inflammatory infiltrate of the lamina propria is noted accompanied by epithelial cell infiltration with polymorphonuclear leukocytes.

Multifocal atrophic gastritis, gastric atrophy with subsequent metaplasia, has been observed in chronic H. pylori-induced gastritis. This may ultimately lead to development of gastric adenocarcinoma. H. pylori infection is now considered an independent risk factor for gastric cancer. Worldwide epidemiologic studies have documented a higher incidence of H. pylori infection in patients with adenocarcinoma of the stomach as compared to control subjects. Seropositivity for H. pylori is associated with a three- to sixfold increased risk of gastric cancer. This risk may be as high as ninefold after adjusting for the inaccuracy of serologic testing in the elderly. The mechanism by which H. pylori infection leads to cancer is unknown. However, eradication of H. pylori as a general preventative measure for gastric cancer is not recommended.

Infection with H. pylori is also associated with development of a low grade B cell lymphoma, gastric MALT lymphoma. The chronic T cell stimulation caused by the infection leads to production of cytokines that promote the B cell tumor. Tumor growth remains dependent upon the presence of H. pylori in that its eradication is often associated with complete regression of the tumor. The tumor may take more than a year to regress after treating the infection. Such patients should be followed by EUS every 2 to 3 months. If the tumor is stable or decreasing in size, no other therapy is necessary. If the tumor grows, it may have become a high-grade B cell lymphoma. When the tumor becomes a high-grade aggressive lymphoma histologically, it loses responsiveness to H. pylori eradication.

Gastric biopsy samples stained with hematoxylin and eosin demonstrating (a) chronic active gastritis with a few H. pylori organisms faintly seen in the lumen of a gland and (b) chronic active gastritis with H. pylori organisms more abundant.

Picture 3.Endoscopic picture chronic gastritis.

Gastric glands may undergo morphologic transformation in chronic gastritis. Intestinal metaplasia denotes the conversion of gastric glands to a small intestinal phenotype with small-bowel mucosal glands containing goblet cells. The metaplastic changes may vary in distribution from patchy to fairly extensive gastric involvement. Intestinal metaplasia is an important predisposing factor for gastric cancer.

Picture 4. Endoscopic picture gastric cancer.

Type A Gastritis. The less common of the two forms involves primarily the fundus and body, with antral sparing. Traditionally, this form of gastritis has been associated with pernicious anemia in the presence of circulating antibodies against parietal cells and intrinsic factor; thus it is also called autoimmune gastritis. H. pylori infection can lead to a similar distribution of gastritis. The characteristics of an autoimmune picture are not always present.

Type B gastritis. Type B, or antral-predominant, gastritis is the more common form of chronic gastritis. H. pylori infection is the cause of this entity. Although described as "antral-predominant," this is likely a misnomer in view of studies documenting the progression of the inflammatory process towards the body and fundus of infected individuals. The conversion to a pan-gastritis is time-dependent-estimated to require 15 to 20 years. This form of gastritis increases with age, being present in up to 100% of people over age 70. Histology improves after H. pylori eradication. The number of H. pylori organisms decreases dramatically with progression to gastric atrophy, and the degree of inflammation correlates with the level of these organisms. Early on, with antral-predominant findings, the quantity of H. pylori is highest and a dense chronic inflammatory infiltrate of the lamina propria is noted accompanied by epithelial cell infiltration with polymorphonuclear leukocytes.

Treatment of the gastritis.

Treatment in chronic gastritis is aimed at the sequelae and not the underlying inflammation. Patients with pernicious anemia will require parenteral vitamin B12 supplementation on a long-term basis. Eradication of H. pylori is not routinely recommended unless PUD or a low-grade MALT lymphoma is present.

Miscellaneous Forms of Gastritis. Lymphocytic gastritis is characterized histologically by intense infiltration of the surface epithelium with lymphocytes. The infiltrative process is primarily in the body of the stomach and consists of mature T cells and plasmacytes. The etiology of this form of chronic gastritis is unknown. It has been described in patients with celiac sprue, but whether there is a common factor associating these two entities is unknown. No specific symptoms suggest lymphocytic gastritis. A subgroup of patients has thickened folds noted on endoscopy. These folds are often capped by small nodules that contain a central depression or erosion; this form of the disease is called varioliform gastritis. H. pylori probably plays no significant role in lymphocytic gastritis. Therapy with glucocorticoids or sodium cromoglycate has obtained unclear results.

Marked eosinophilic infiltration involving any layer of the stomach (mucosa, muscularis propria, and serosa) is characteristic of eosinophilic gastritis. Affected individuals will often have circulating eosinophilia with clinical manifestation of systemic allergy. Involvement may range from isolated gastric disease to diffuse eosinophilic gastroenteritis. Antral involvement predominates, with prominent edematous folds being observed on endoscopy. These prominent antral folds can lead to outlet obstruction. Patients can present with epigastric discomfort, nausea, and vomiting. Treatment with glucocorticoids has been successful.

Several systemic disorders may be associated with granulomatous gastritis. Gastric involvement has been observed in Crohn's disease. Involvement may range from granulomatous infiltrates noted only on gastric biopsies to frank ulceration and stricture formation. Gastric Crohn's disease usually occurs in the presence of small-intestinal disease. Several rare infectious processes can lead to granulomatous gastritis, including histoplasmosis, candidiasis, syphilis, and tuberculosis. Other unusual causes of this form of gastritis include sarcoidosis, idiopathic granulomatous gastritis, and eosinophilic granulomas involving the stomach. Establishing the specific etiologic agent in this form of gastritis can be difficult, at times requiring repeat endoscopy with biopsy and cytology. Occasionally, a surgically obtained full-thickness biopsy of the stomach may be required to exclude malignancy.

Antibiotic treatment should therefore be considered in all H. pylori-infected patients with chronic H. pylori-induced gastritis

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 chronic H. pylori-induced gastritis 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 H. pylori-induced gastritis, 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 H. pylori-induced gastritis.

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.

Anti-H. pylori therapy (Maastricht Consensus):