FUNCTIONAL AND ORGANIC DISEASES OF DIGESTIVE TRACT
Functional diseases of esophagus and stomach in children
Gastroesophageal reflux disease is the most common esophageal disorder in children of all ages. Gastroesophageal reflux (GER) signifies the retrograde movement of gastric contents across the lower esophageal sphincter (LES) into the esophagus. Although occasional episodes of reflux are physiologic, exemplified by the regurgitation of normal infants, the phenomenon becomes pathologic (GERD) in children who have episodes that are more frequent or persistent, and thus produce esophagitis or esophageal symptoms, or in those who have respiratory sequelae.
Pathophysiology.
Factors determining the esophageal manifestations of reflux include the duration of esophageal exposure (a product of the frequency and duration of reflux episodes), the causticity of the refluxate, and the susceptibility of the esophagus to damage. The LES, supported by the crura of the diaphragm at the gastroesophageal junction, together with valvelike functions of the esophagogastric junction anatomy, form the antireflux barrier. In the context of even the normal intra-abdominal pressure augmentations that occur during daily life, the frequency of reflux episodes is increased by insufficient LES tone, by abnormal frequency of LES relaxations (see later), and by hiatal herniation that prevents the LES pressure from being proportionately augmented during abdominal straining. Normal intra-abdominal pressure augmentations may be further exacerbated by straining or respiratory efforts. The duration of reflux episodes is increased by lack of swallowing (during sleep) and by defective esophageal peristalsis. Vicious cycles ensue because chronic esophagitis produces esophageal peristaltic dysfunction (low amplitude waves and propagation disturbances), decreased LES tone, and inflammatory esophageal shortening that induces hiatal herniation, all of them worsening reflux.
Transient LES relaxation (TLESR) is the major primary mechanism allowing reflux to occur. TLESRs occur independent of swallowing, reducing LES pressure to 0–2 mm Hg (above gastric), and last more than 10 s; they appear by the 26 wk of gestation. A vagovagal reflex, composed of afferent mechanoreceptors in the proximal stomach, a brain stem pattern generator, and efferents in the LES, regulates TLESRs. Gastric distention (postprandially, or due to abnormal gastric emptying or air swallowing) is thus the main stimulus for TLESRs. Whether GERD is caused by a higher frequency of TLESRs or by a greater incidence of reflux during TLESRs is debated; both are likely in different individuals. Straining during a TLESR makes reflux more likely, as do positions that place the gastroesophageal junction below the air-fluid interface in the stomach. Other factors influencing gastric pressure-volume dynamics, such as increased movement, straining, obesity, large volume or hyperosmolar meals, and increased respiratory effort (e.g., coughing, wheezing) may have the same effect.
Epidemiology and Natural History.
Infant reflux becomes symptomatic during the first few months of life, peaking at about 4 mo and resolving in most by 12 mo and nearly all by 24 mo. Symptoms in older children tend to be chronic, waxing and waning, but completely resolving io more than half, resembling adult patterns. A genetic predisposition as an autosomal dominant form is located on chromosome 13q14 and chromosome 9.
Clinical Manifestations.
Most of the common clinical manifestations of esophageal disease can signify the presence of GERD. Infantile reflux manifests more often with regurgitation (especially postprandially), signs of esophagitis (irritability, arching, choking, gagging, feeding aversion), and resulting failure to thrive; symptoms resolve spontaneously in the majority by 12 to 24 mo. Older children, in contrast, may have regurgitation during the preschool years; complaints of abdominal and chest pain supervene during later childhood and adolescence. Occasional children present with neck contortions designated Sandifer syndrome. The respiratory (extraesophageal) presentations are also age dependent: GERD in infants may manifest as obstructive apnea or as stridor or lower airway disease in which reflux complicates primary airway disease such as laryngomalacia or bronchopulmonary dysplasia. In contrast, airway manifestations in older children are more frequently related to asthma or to otolaryngologic disease such as laryngitis or sinusitis.
Diagnosis.
For most of the typical GERD presentations, a thorough history and physical examination suffice to reach the diagnosis initially. This initial evaluation aims to identify the pertinent positives in support of GERD and its complications and the negatives that make other diagnoses unlikely. The history may be facilitated and standardized by questionnaires (the Infant Gastroesophageal Reflux Questionnaire, the I-GERD), which also permit quantitative scores to be evaluated for their diagnostic discrimination. Important diagnoses to consider in the evaluation of an infant or a child with chronic vomiting are milk and other food allergies, pyloric stenosis, intestinal obstruction (especially malrotation with intermittent volvulus), nonesophageal inflammatory diseases, infections, inborn errors of metabolism, hydronephrosis, increased intracranial pressure, rumination, and bulimia. Focused diagnostic testing, depending on the presentation and the differential diagnosis, may then supplement the initial examination.
Antacids are the most commonly used antireflux therapy and are readily available over-the-counter. They provide rapid but transient relief of symptoms by acid neutralization. The long-term regular use of antacids cannot be recommended because of side effects of diarrhea (magnesium) and constipation (aluminum) and rare reports of more serious side effects of chronic use.
Histamine-2 receptor antagonists (H2RAs)—cimetidine, famotidine, nizatidine, and ranitidine—are widely used antisecretory agents and act by selective inhibition of histamine receptors on gastric parietal cells. There is a definite benefit of H2RAs in treatment of mild-to-moderate reflux esophagitis. H2RAs are recommended as first-line therapy because of their excellent overall safety profile.
Proton pump inhibitors (PPIs)—omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole—provide the most potent antireflux effect by blocking the hydrogen-potassium ATPase channels of the final common pathway in gastric acid secretion. PPIs are superior to H2RAs in the treatment of severe and erosive esophagitis. Doses of omeprazole for children have been established (0.7–3.3 mg/kg/day), higher than those used in adults on a dose per weight basis.
Prokinetic agents available in the United States include metoclopramide (dopamine-2 and 5HT-3 antagonist), bethanechol (cholinergic agonist), and erythromycin (motilin receptor agonist). Most of these increase LES pressure; some improve gastric emptying or esophageal clearance. None affects the frequency of TLESRs. The available controlled trials have not demonstrated much efficacy for GERD.
Surgery, usually fundoplication, is effective therapy for intractable GERD in children, particularly those with refractory esophagitis or strictures and those at risk for significant morbidity from chronic pulmonary disease. It may be combined with a gastrostomy for feeding or venting. The current availability of potent acid-suppressing medication mandates more rigorous analysis of the relative risks (or costs) and benefits of this relatively irreversible therapy in comparison to long-term pharmacotherapy. Some of the risks of fundoplication include a wrap that is “too tight” (producing dysphagia or gas-bloat) or “too loose” (and thus incompetent). Surgeons may choose to perform a “tight” (360°, Nissen) or “loose” (<360°, Thal, etc.) wrap or to add a gastric drainage procedure (e.g., pyloroplasty) to improve gastric emptying, based on their experience and the patient’s disease. Preoperative accuracy of diagnosis of GERD and the skill of the surgeon are two of the most important predictors of successful outcome.
Complications of GERD
Esophageal: Esophagitis and Sequelae—Stricture, Barrett Esophagus, Adenocarcinoma.
Esophagitis may manifest as irritability, arching, and feeding aversion in infants; chest or epigastric pain in older children; and rarely as hematemesis, anemia, or Sandifer syndrome at any age. Prolonged and severe esophagitis leads to formation of strictures, generally located in the distal esophagus, producing dysphagia, and requiring repeated esophageal dilations and often fundoplication. Long-standing esophagitis predisposes to metaplastic transformation of the normal esophageal squamous epithelium into intestinal columnar epithelium, termed Barrett esophagus, a precursor of esophageal adenocarcinoma. Both Barrett esophagus and adenocarcinoma occur more in white males and in those with increased duration, frequency, and severity of reflux symptoms. This transformation thus increases with age to plateau in the 5th decade; adenocarcinoma is thus rare in childhood. Barrett esophagus warrants periodic surveillance biopsies, aggressive pharmacotherapy, and fundoplication for progressive lesions.
Esophagitis and regurgitation may be severe enough to induce failure to thrive because of caloric deficits. Enteral (nasogastric or nasojejunal, or percutaneous gastric or jejunal) or parenteral feedings are sometimes required to treat such deficits.
Organic diseases of stomach and duodenum in children.
Chronic gastritis, by definition, is a histopathological entity characterized by chronic inflammation of the stomach and duodenum mucosa. Gastritides can be classified based on the underlying etiologic agent (eg, Helicobacter pylori, bile reflux, nonsteroidal anti-inflammatory drugs [NSAIDs], autoimmunity, allergic response) and the histopathological pattern, which may suggest the etiologic agent and clinical course (eg, H pylori–associated multifocal atrophic gastritis). Other classifications are based on the endoscopic appearance of the gastric mucosa (eg, varioliform gastritis). Although minimal inflammation is observed in some gastropathies, such as those associated with NSAID intake, these entities are discussed in this article because they are frequently included in the differential diagnosis.Gastritis is associated with a variety of medications, medical and surgical conditions, physical stresses, social habits, chemicals, and infections. Some of the more common causes of gastritis are these.
Medications
· Aspirin (more than 300 medications contain some form of aspirin)
· Nonsteroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen)
· Steroids (Prednisone is one example)
· Potassium supplements
· Iron tablets
· Cancer chemotherapy medications
· Swallowing poisons or objects
· Corrosives (acid or lye)
· Alcohols of various types
· Swallowed foreign bodies (paper clips or pins)
· Medical and surgical conditions
· Physical stress in the critically ill
· After medical procedures (such as endoscopy, in which a specialist looks into the stomach with a small lighted tube)
· After an operation to remove part of the stomach
· After medical radiation treatment for cancer
· Infections
· Tuberculosis
· Syphilis
· Bacterial infections (H pylori infection is the most common. Many other bacteria—even those that usually cause pneumonia or bladder infections—can cause gastritis.)
· Viral infections, fungal (yeast) infections, parasites, and worms
· Autoimmune diseases
· Pernicious anemias.
Chemical or reactive gastritis is caused by injury of the gastric mucosa by reflux of bile and pancreatic secretions into the stomach, but it can also be caused by exogenous substances, including NSAIDs, acetylsalicylic acid, chemotherapeutic agents, and alcohol. These chemicals cause epithelial damage, erosions, and ulcers that are followed by regenerative hyperplasia, histologically detectable as foveolar hyperplasia and damage to capillaries, with mucosal edema, hemorrhage, and proliferation of smooth muscle in the lamina propria. Inflammation in these lesions caused by chemicals is minimal or lacking; therefore, the term gastropathy or chemical gastropathy is more appropriate to describe these lesions than is the term chemical or reactive gastritis as proposed by the updated Sydney classification of gastritis. Importantly, mixed forms of gastropathy and other types of gastritis, especially H pylori gastritis, may coexist. No single classification of gastritis provides an entirely satisfactory description of all types of gastritis. However, an etiological classification provides a direct target towards which therapy can be directed, and, for this reason, etiological classification is used in this article.
Helicobacter gastritis is a primary infection of the stomach and is the most frequent cause of gastritis. Cases of histologically documented chronic gastritis are diagnosed as chronic gastritis of undetermined etiology or gastritis of undetermined type wheone of the findings reflects any of the described patterns of gastritis and a specific cause cannot be identified.
Pathophysiology:
The pathophysiology of gastritis complicating a systemic disease, such as hepatic cirrhosis, uremia, or another infection, is described in the relevant disease articles. The pathogenesis of the most common forms of gastritis is described as follows.
Classification of the chronic gasroduodenitis
Form
Acute
Chronic
Special:
n Granulomatous
nEosinophilous
Etiology
n Autoimmune
n H. pylori
n Reflux-gastritis
n Reactive
n Idiopathic
Localization
nAntral
n Fundal
nPangastritis
nDuodenitis
Endoscopies disorders
n Superficial
n Erosive
n Hemorrhagic
n Atrophic
n Hyperplastic
Histology
n Superficial
n without atrophy of glands
n with atrophy of glands
n Atrophic
n Intestinal methaplasia
Secretion
n Normal
n Increased
n decreased
Period
n Exacerbation
n Non-full clinical remission
n Full clinical remission
n Clinical, endoscopy morphological remission
nDuodenogastric reflux
n Mild
n Moderate
n Severe
Classification of the peptic ulcer
Localization
· Stomach
· Duodenum
· Clinical and endoscopies stage
· Acute ulcer
· Ulcer epithelization
· Ulcer repairing (healing) with duodenitis (or gastritis)
· Clinical and endoscopies remission
Period
· Exacerbation
· Non-full clinical remission
· Full clinical remission
· Clinical, endoscopy morphological remission
Secretion
· Normal
· Increased
· decreased
Complication
· Bleeding
· Perforation
· Penetration
· Stenosis
· Perivisceritis
Laboratory testing:
Most tests are designed to exclude other causes of your symptoms, leaving gastritis as the only cause of your symptoms. check of your vital signs (pulse, blood pressure)
· The findings of gastritis are “nonspecific.” This means that upper abdominal tenderness just as likely may be caused by gastritis as by an ulcer or an inflamed gallbladder or liver.
· Laboratory testing: Most tests are designed to exclude other causes of symptoms, leaving gastritis as the only cause of your symptoms. No standard panel of laboratory tests can diagnose gastritis. Some doctors will do extensive laboratory testing. Others may do no laboratory testing at all.
· Blood tests (looking mostly for anemia, a low blood count)
· Tests of the liver and kidney functions
· Urinalysis
· Tests of the gallbladder and pancreas
· X-rays
· An ECG (a heart wave tracing)
· Additional testing: The doctor may test your blood for evidence of H pylori infection, thought to be associated with many cases of gastritis.
Specialists: The doctor also may refer you to a gastroenterologist, a specialist in diseases of the stomach, intestines, and colon. The gastroenterologist may in turn recommend an endoscopy.
· Rapid urease test from gastric biopsy tissue; Rapid urease test from gastric biopsy tissue; Bacterial culture of gastric biopsy: This is usually performed in the research setting or to assess antibiotic susceptibility in patients for whom first-line eradication therapy fails.
· Urea breath test with nonradioactive carbon isotope (13C) or with radioactive carbon isotope (14C); Diagnosis of autoimmune gastritis; Antiparietal and anti-IF antibodies in the serum; Achlorhydria, both basal and stimulated, and hypergastrinemia; Low serum cobalamin (vitamin B-12) levels (<100 pg/mL); Possible abnormal result on Schilling test (can be corrected by IF).
Procedures:
· Performing an upper GI endoscopy is essential to establish a diagnosis of gastritis.
· Endoscopic findings in granulomatous gastritis include mucosal nodularity with cobblestoning, multiple aphthous ulcers, linear or serpiginous ulcerations, thickened antral folds, antral narrowing, hypoperistalsis, and duodenal strictures. Extensive gastric involvement may resemble linitisplastica.
· Lymphocytic gastritis at endoscopy shows enlarged folds and aphthoid erosions, with the appearance of small, heaped-up, volcanolike mounds pocked with a central crater. This endoscopic pattern has also been described as varioliform gastritis.
· The endoscopic findings of reflux and chemical gastropathy are those of a gastric mucosa that is red or has red streaks with areas of apparent hemorrhage.
· Diagnosis of H pylori–associated gastritis: The criterion standard method to assess whether H pylori is the underlying cause of gastritis is histological identification of the organism. Histological examination is also used to evaluate the degree and distribution of gastritis. Obtain at least 2 biopsies from the gastric antrum, 2 from the corpus, and 1 from the incisura.
· Special stains to identify H pylori, such as Warthin-Starry, Giemsa, or Genta stain, may be necessary when the organisms are not observed and chronic gastritis is obvious.
· At late stages of infection with extensive atrophic gastritis, the numbers of H pylori organisms are markedly decreased because intestinal metaplasia creates an unfavorable environment for H pylori. In these cases, other tests, such as the urea breath test, and serological evidence of infection may provide evidence for H pylori infection.
Esophagogastroduodenoscopy (EGD) is the procedure of choice for the detection of PUD in the pediatric population.
EGD allows direct visualization of the mucosa, localization of the source of bleeding, and diagnosis of H pylori infection via analysis of biopsy specimens, culturing, or detection of urease activity.
Therapeutic endoscopy for acute bleeding (coagulation of a bleeding ulcer with a heater probe or injection with vasoconstricting agents) is another important indication for EGD.
The gross appearance of an active ulcer seen using EGD is a round or oval punched-out lesion with a smooth white base and surrounding mucosa that is red and edematous.
Consider nasogastric (NG) lavage in a child who is ill and in whom an upper GI
Treatment of H pylori infection in children:
n Diet 1 a (phase of exacerbation)
n To restrict carbohydrates, exclude spices and foods which stimulate gastric secretion
n All foods are in liquid form, boiled, mashed, and warm. Soft foods such as avocados, bananas, potatoes and squash are recommended. Eat frequent small meals 6-7 times a day.
n Diet 1 b, (in the period of remission)
n Moderate protection of stomach and duodenum mucous membrane from hard and spicy food
n This diet permits to include well-cooked millet, white rice, raw goat’s milk, and soured milk products such as yogurt, cottage cheese and kefir. All foods must be in semiliquid form, like puree and warm; food taking 5-6 times daily. Freshly made cabbage, barley wheat and alfalfa juice are useful because they contain chlorophyll, making them potent antiulcer treatments. Avoid fried foods, tea, caffeine, salt, chocolate, alcoholic beverages, strong spices, animal fats of any kind
Treatment of H. pylori
Triple medical regime for 7 days
n De-nol 120-240 mg 3 t/d 30 min to meal
nMetronidazolum 250-500 mg twice a day after meal
nAmoxacillin (flemoxin) 250-500 mg twice a day after meal
Or
De-nol 120-240 mg 3 t/d 30 min to meal
Metronidazolum 250-500 mg twice a day after meal
Clarithromycin 250-500 mg twice a day after meal
Metronidazolum=furazolidone 2 tab. twice a day
II variant of triple medical regime
n De-nol 120-240 mg 3 t/d 30 min to meal
n Amoxacillin (flemoxin) clarithromycin or 250-500 mg twice a day after meal
n Histamine-2 receptor antagonist (ranitidine or famotidine) 1-2 tab. per day or proton pomp inhibiters (omeprozol, lanprazole) 1 tabl./day
Quadra therapy for 7 days
n De-nol 120-240 mg 3 t/d 30 min to meal
nAmoxacillin (flemoxin) clarithromycin or 250-500 mg twice a day after meal
n Clarithromycin 250-500 mg twice a day after meal
nMetronidazolum 250-500 mg twice a day after meal
Peptic ulcer disease.
History:
· In children in whom PUD is suspected, include the following in the history:
· Review of past illnesses and chronic medical conditions
· Family history of ulcer disease or GI tract conditions (eg, Crohn disease)
· Character, location, frequency, duration, severity, and exacerbating (especially meals in children) and alleviating factors of abdominal pain
· Vomiting and description of gastric material
· Bowel habits and description of stool
· Medications (prescribed and over the counter [OTC])
· Prior diagnostic testing and specific GI therapies
· Appetite, diet, and weight changes
· Family and social stressors
· Alcohol ingestion and smoking habits
· Abdominal pain is the most common symptom of childhood PUD.
The pain is usually dull and vague in character and may be poorly localized or localized to the periumbilical or epigastric areas. In preschool-aged children, pain is typically periumbilical and is worse after eating. After age 6 years, the child’s description of pain may be quite similar to the description made by adults. The classic pain of PUD (ie, pain that awakens the child, worsens with food, and is relieved by fasting) is described infrequently, but it helps distinguish GI tract and psychogenic pathology when present. Pain is more likely to be dull and aching rather than sharp and burning, as is described by adults. Frequent exacerbations and remissions of pain extend over weeks to months. The pain is often worsened by food intake, which is the opposite of the adult pattern.
· Vomiting in infants and toddlers may be associated with slow growth. Recurrent vomiting is also noted in preschool-aged and school-aged children.
· GI tract bleeding (eg, melena, hematochezia, hematemesis) may be another presentation in children; however, in infants, particularly in the first month of life, serious underlying illness and stress ulceration present most commonly with acute perforation or hemorrhage.
· GI tract bleeding may lead to iron deficiency anemia (IDA) and may present with more vague complaints of fatigue, headache, dyspnea, or malaise.
· For children with ulcer perforation, the symptoms are consistent with peritonitis and are abrupt in onset.
Physical:
· Include the following with the physical examination:
· General appearance of the child
· Vital signs
· Assessment of perfusion with attention to mental status, heart rate, pulses, and capillary refill
· Assessment of hydration status with attention to mucous membrane (MM) moisture and skin turgor
· Skin and conjunctivae pallor
· Thorough chest examination
· Careful inspection, auscultation, and palpation of the abdomen, also noting liver or spleen enlargement
· Rectal examination and stool blood testing
· Pelvic examination in the sexually active female with pain
· Examination of the testicles and inguinal area
· Hemorrhage accompanies PUD in 15-20% of patients.
· An acute abdomen resulting from GI tract perforation occurs in 5-10% of children with PUD.
Lab Studies:
· A minimum of laboratory studies may be indicated in children with mild symptoms and normal examination findings. The following laboratory data may be needed in children who are unstable, have severe or chronic/recurrent symptoms, or manifest serious complications of PUD.
· Hemoglobin and hematocrit
· To diagnose anemia in the setting of chronic GI tract blood loss
· To determine the severity of anemia in the setting of acute or massive GI tract bleeding
· To guide and monitor transfusion or iron therapy
· Iron studies (serum iron, total iron-binding capacity [TIBC], ferritin, reticulocyte count, peripheral smear) – To determine presence of IDA
· H pylori serology – To detect H pylori infection in children who have not been previously diagnosed or treated
· Prothrombin time (PT) and activated partial thromboplastin time (aPTT) – To identify coagulopathy in patients with sepsis, multiple injuries, or massive GI tract bleeding, or in those at risk for diffuse intravascular coagulation (DIC)
§ Type and cross-match blood – For transfusion in patients in whom the condition is unstable or the illness is critical
§ Electrolyte, BUN, and creatinine levels – For assessment in patients with volume depletion or who require fluid resuscitation
§ Arterial blood gas – To assess degree of acidosis in the patient with systemic illness, respiratory failure, or severe hypovolemia or in patients with severe burns or trauma
§ Urinalysis – To assess hydration status and to screen for infection or stone
§ WBC count and differential – To detect peripheral eosinophilia in children with eosinophilic gastritis
§ Serum gastrin and gastrin-releasing peptide levels – To exclude Zollinger-Ellison syndrome in patients with refractory ulcers
§ Examine and perform guaiac testing on the stool to confirm GI tract bleeding. Melena is usually the result of an upper GI tract bleed, although blood from a duodenal ulcer that quickly transits the intestinal tract may be visible as red or maroon blood in the stool.
Procedures:
Esophagogastroduodenoscopy
Esophagogastroduodenoscopy (EGD) is the procedure of choice for the detection of PUD in the pediatric population.
o EGD allows direct visualization of the mucosa, localization of the source of bleeding, and diagnosis of H pylori infection via analysis of biopsy specimens, culturing, or detection of urease activity.
o Therapeutic endoscopy for acute bleeding (coagulation of a bleeding ulcer with a heater probe or injection with vasoconstricting agents) is another important indication for EGD.
o The gross appearance of an active ulcer seen using EGD is a round or oval punched-out lesion with a smooth white base and surrounding mucosa that is red and edematous.
· Consider nasogastric (NG) lavage in a child who is ill and in whom an upper GI tract hemorrhage is suspected, as evidenced by hematemesis or melena.
Medical Care:
Diet:
Recommend abstinence from all caffeine and alcohol.
In hospitalized children, milk feedings have been found to raise the gastric pH level and to prevent GI tract bleeding.
Activity:
Allow common sense to dictate appropriate activity restrictions in children with chronic symptoms.
Include cessation of smoking in recommendations
Medications used in patients with PUD reduce gastric acidity and serve to eradicate H pylori infection. Drug Category: Histamine H2-receptor antagonists — Receptors for histamine are located on the acid-producing parietal cells. Blocking histamine action suppresses gastric acid secretion. Drug Category: Antacids — Neutralize gastric acid and may be of benefit in children with PUD. Medication compliance may be a problem because of the requirement for frequent dosing. Proton pump inhibitor — A much more potent acid inhibitor than H2-receptor antagonists, this class of drugs blocks gastric acid secretion at the proton pump (ie, hydrogen/potassium adenosine triphosphatase [H+/K+- ATPase] of the gastric parietal cell), which is the final common pathway of secretion. Recommended as a part of the drug regimen for symptomatic H pylori infection. Proton pump inhibition alone does not eradicate H pylori infection, but it does have bacteriostatic activity against H pylori. Antibiotics, macrolide — In the eradication of H pylori infection, multidrug regimens have been studied. All regimens contain 1-2 antimicrobials and agents that neutralize acid or have inhibitory effects on acid secretion.
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