Chapter 409. Inflammatory Disorders of the Stomach

The terms acid peptic diseases, peptic diseases, or acid-related disorders are used synonymously to describe conditions that involve gastric acid and pepsin in their pathogenesis; they refer to a number of disorders including esophagitis, gastritis, peptic ulcer disease, and duodenitis. Gastritis is a condition diagnosed histologically, not clinically or radiologically.1-5 It is characterized by the presence of inflammatory cells and is often found to be present in biopsies taken from gastric mucosa that appears normal at endoscopy. Some forms of chronic, severe gastritis may destroy mucosal elements, resulting in atrophic gastritis and intestinal metaplasia, which in some forms may be preneoplastic. Although gastritis and ulcer disease may occur as stand-alone entities, they are often part of a continuum of disease.2,3,6 A special case is that of Helicobacter pylori, an important cause of gastritis and peptic ulcer disease discussed separately.

Gastropathy refers to those entities in which inflammation is not a prominent feature, although there is often epithelial damage and regeneration, and perhaps vascular abnormalities. Gastropathies often have a typical endoscopic appearance (eg, portal hypertensive gastropathy, prolapse gastropathy) but are not usually associated with biopsy evidence of inflammatory infiltrate.

Epidemiology

Peptic ulcer and gastritis are uncommon in infants and young children. Peptic disorders are far less prevalent in the pediatric age group overall than in adults, accounting for probably no more than 10% to 20% of children seeking medical attention for abdominal pain even in a subspecialty gastrointestinal (GI) outpatient clinic setting.7 In adults, there has been a profound decline in the frequency of uncomplicated peptic ulcer disease. In contrast, there has been a relative increase in complicated disease which may be due to increasing use of nonsteroidal anti-inflammatory drugs (NSAIDs) and an aging population.

A number of factors are alleged to cause or predispose to peptic ulcer disease.8Helicobacter pylori and NSAIDs are recognized as the major causes of peptic ulcer disease in adults. Familial clustering is most commonly due to H pylori but in non–H pylori peptic ulcer disease there may be a genetic disposition for peptic ulcer disease, as suggested by studies on concordant twins. Certain HLA subtypes, or carriers of certain blood group antigens, also appear to be at increased risk. A strong association exists between chronic pulmonary disease in adults and peptic ulceration that may be related to cigarette smoking. Cigarette smoking predisposes to ulcer formation and complications, probably by inhibiting prostaglandin synthesis and thereby compromising preepithelial or mucosal integrity. Peptic ulcer disease is associated with hepatic cirrhosis and chronic renal disease. There is no evidence that any dietary factors contribute to peptic ulcer disease, although spicy foods may cause dyspepsia in some individuals. Coffee, tea, and cola are potent acid secretagogs, but no link to peptic ulceration has been established. Decaffeinated coffee is as potent a secretagog as caffeinated coffee. Emotional stress alone, without the contribution of H pylori and NSAIDs, is unlikely to cause ulceration. However, even modern studies have suggested that emotional distress may be a contributing factor to the occurrence of peptic ulcer complications; for example, after an earthquake in Kobe, Japan, in the 1990s, the incidence of bleeding gastric ulcers increased.Emotional stress may well play a role in genetically susceptible individuals.

In the early part of the 20th century, psychologic stress and diet were regarded as the key pathogenetic factors for peptic ulceration. Patients with peptic ulcers were hospitalized for bedrest and prescribed unpalatable “bland diets.” In the 1950s, attention was focused on the major pathogenetic role of gastric acid, and buffering of acid with antacids, or with continuous milk feeds, was in vogue. When Dragsted introduced surgical acid reduction with vagotomy, such was the unpleasantness of the “bland” or “alkali diet” that even surgery appeared an attractive option. Even though surgery was attended by high failure rates and significant morbidity, it remained a mainstay of therapy for recalcitrant or recurrent ulcer disease.

The advent of the H2-receptor antagonist cimetidine in the 1970s began the era of acid suppression, replacing buffering. In the 1980s, the introduction of proton pump inhibitors (PPIs) allowed for more potent acid suppression and better ulcer healing rates. However, studies showed that some 90% of healed ulcers relapsed within a year if treatment with acid-suppressing agents was discontinued. Therefore, until the late 20th century, peptic ulcer disease was regarded as a chronic relapsing, largely incurable, disorder. By the mid to late 1980s, it came to be recognized that most primary duodenal ulcers were associated with gastric infection by a bacterium, Helicobacter pylori, the eradication of which resulted in cure of ulcer disease in most cases. Despite the skepticism with which the bacterial etiology was initially greeted, once it had been embraced, virtually all chronic duodenal ulcers were considered to be H pylori related.

However, more recently, it has been recognized that approximately 20% to 40% of chronic duodenal ulcers are not related to H pylori, or to NSAIDs, or to other identifiable causes. This changing incidence reflects the success of medical treatment of peptic ulcer disease with either H pylori eradication or PPIs, acid-reducing operations are now almost never performed for peptic ulcer disease.

Pathophysiology

The stomach secretes water, acid, bicarbonate, other electrolytes (K+, Cl, Na+), enzymes that are active at low pH (pepsin from chief cells and lipase from gastric body epithelium), and intrinsic factor from parietal cells and mucins.8,9 The enzyme H+,K+ ATPase, ie, the “proton pump,” drives this active, energy-requiring process.

In full-term newborn humans, acidification of gastric contents (pH < 4) occurs immediately after birth. Basal acid output increases over the first month regardless of gestational age at birth, and by 24 weeks of life reaches the adult maximal acid output level is reached.10-13 Even healthy preterm infants of 24 weeks’ gestation are able to acidify the stomach from the first day of life, but factors such as feeding and stress may influence the normal progression of acid production with time.12,14

Peptic disease results from an imbalance of the gastric mucosal aggressive and protective mechanisms shown in Figure 409-1. The “mucus-bicarbonate barrier” is a viscous mechanical and chemical barrier, of the consistency of axle grease. Secretion of bicarbonate into the unstirred mucous gel layer results in a pH of 7 at the epithelial cell surface, the gradient falling to pH 2 at the luminal mucus–gel surface. This pH gradient protects the epithelial cells from gastric acid and from pepsin, which as it diffuses slowly through the gel, is deactivated when the pH reaches 5 or more. Bicarbonate ions are primarily produced and secreted by the surface epithelial cells. Uninterrupted mucosal blood flow is also essential for maintaining surface epithelial cell integrity and, therefore, adequate mucus and bicarbonate production.

The net effect of a disruption in any of the gastric mucosal protective mechanisms—be it due to ischemic cell damage, non-steroidal anti-inflammatory drug (NSAID)-induced prostaglandin inhibition, or H pylori–associated mucus and bicarbonate impairment—will be to permit acid–pepsin diffusion and damage to the underlying mucosa.

Clinical Features

Patients with gastritis or gastropathies may or may not have symptoms, and when symptoms occur, they are seldom specific. The classically reported symptoms of peptic ulcer disease include gnawing or burning epigastric pain that occurs 2 to 3 hours after meals and is relieved by antacids. This presentation is uncommon in children. True epigastric pain is relatively uncommon in children and always requires investigation, as does upper gastrointestinal (GI) bleeding with or without pain. A temporal relationship of pain with meals occurs in only about half of children with peptic ulcer disease.15-17 Peptic disorders may also present with symptoms of nausea, vomiting, and weight loss. Symptoms of H pylori ulcer disease, non–H pylori ulcer disease, and the various gastritides and gastropathies overlap with those of hepatobiliary disease, pancreatitis, and with functional disorders such as nonulcer dyspepsia or functional heartburn. A detailed approach to history taking and differential diagnosis in childhood abdominal pain is described in Chapter 384. In children presenting with abdominal pain, blood loss, anemia, or upper GI lesions at endoscopy, it is particularly important to actively solicit a history of use of over-the-counter NSAIDs, as parents and children often fail to mention nonprescription drugs in the medication history. The most common causes of abdominal pain in children are constipation and irritable bowel syndrome, and although these conditions usually present with nonepigastric pain, difficulties may arise when the child is unclear about the nature and location of the pain—which is not infrequently the case.7,18

On physical examination, epigastric tenderness is an unreliable sign of peptic disease because other disorders may cause similar findings. Referred pain to the back may suggest a perforated ulcer. GI bleeding may occur with longstanding antecedent epigastric pain or other symptoms, but painless bleeding may be the only manifestation of ulcer disease. In fact, of children with endoscopically proven duodenal ulcers, up to 25% of children have a “silent” presentation; about 25% present with bleeding and antecedent pain, and the rest present only with abdominal pain or recurrent vomiting.19,20 Iron deficiency anemia may be a consequence of H pylori gastritis, even in the absence of pain or ulcer disease.21 Peripheral edema from hypoalbuminemia suggests a diagnosis of Menetriere disease. Rarely, a succession splash may suggest a gastric outlet obstruction.

In infants and toddlers, and children who are neurologically impaired, symptoms are even less specific and may include only unexplained crying, arching, or grimacing. These symptoms are nonspecific and may be due to a variety of causes, which include constipation, “infant colic,”22 sensitivity to cow or soy milk protein, infection, exposure to tobacco smoke, social neglect, and gastroesophageal reflux disease.23,24

A positive family history of peptic ulcer disease may support a clinical suspicion of peptic disease. However many individuals have been told they have “an ulcer” or “gastritis” on the basis of a clinical impression, or a questionable barium study, without an accurate diagnosis having been made. More often than not, this makes the family history of questionable relevance, unless it can be verified by an endoscopy report.

Diagnostic Evaluation

The diagnostic approach to peptic disorders depends upon the diagnostic presentation. Those patients with upper gastrointestinal (GI) bleeding are best evaluated as described in Chapter 387. Upper endoscopy provides a definitive diagnosis and may allow therapeutic interventions in the case of an ulcer. In most children, the symptoms of peptic disease are less specific so a decision regarding the need for further evaluation depends upon the frequency and intensity of the symptoms, as well as how disruptive the symptoms are to the child’s normal daily activities. Patients with nonspecific symptoms with suspected peptic disease are often treated empirically with antacids, histamine-2-antagonists (H2RAs) blockers, or proton pump inhibitors (PPIs). Those who have significant symptom relief or repeated response to these therapies most likely have some form of acid peptic disease, but a response to empiric therapy does not provide a specific diagnosis or guide treatment. For symptoms that are chronic or relapsing, an upper GI endoscopy with biopsy is required to help differentiate between the varying causes of symptoms, preferably while off acid-suppressing therapy for at least 1 to 2 weeks.2,3,4,5

Specific diagnostic testing is available for H pylori, but this testing does not distinguish between H pylori infection and H pylori disease (see discussion below). Initiation of treatment based upon these tests alone is not recommended.25-28 Upper GI contrast studies (“upper GI series” or “barium study”) have no role in the diagnosis of gastritis or uncomplicated peptic ulcer disease because findings are frequently falsely positive or falsely negative for gastric mucosal disorders, including ulcers.20,29,30 Findings, such as “poor filling of the duodenal cap,” “irritability of the duodenum,” or “duodenitis” are nonspecific. Rarely, radiology identifies an ulcer crater, but because radiography cannot distinguish between causes of ulceration, endoscopy with biopsies is still necessary to determine the underlying cause of ulceration and whether the findings are relevant to the child’s symptoms. However, upper GI contrast studies are helpful with some symptom presentations to exclude malrotation, or other anatomic abnormalities such as ulcer-related complications including antral or pyloric outlet narrowing, or perforation.

Endoscopy and biopsy allow categorization of entities as erosive and hemorrhagic or nonerosive. This helps to narrow the diagnostic possibilities as shown in Table 409-1, but because most gastritis and ulcer disease are part of a continuum of response to injury, the endoscopic findings of any mucosal abnormality including erosions or ulcer (Fig. 409-2 and eFig. 409.1) do not delineate a cause of the lesion. For example, although Crohn disease and cytomegalovirus gastritis are most often nonerosive, they often progress to erosions and ulcers. H pylori gastritis is classified as nonerosive, because it most often presents with normal or nodular mucosa, with abnormalities seen only on histologic examination, but it can cause erosions or ulcers in the stomach and duodenum.

Following demonstration of an ulcer diagnostic classification as either primary peptic ulcer disease or secondary disease is useful (Table 409-2).25-28 The most common cause of primary ulcers is H pylori. Although categorization is based on etiology, primary peptic ulcers are usually chronic, with fibrinopurulent debris overlying active inflammatory infiltrate, granulation tissue, and fibrosis.31 In contrast, secondary peptic ulcers are usually acute in onset, often induced by physiologic stress or drug ingestion, and usually are not fibrotic. Primary peptic ulcers are more often duodenal, whereas secondary ulcers are more often gastric. Secondary ulcers are those occurring in the presence of systemic underlying disease, whereas in primary ulcer disease this is usually not present. Primary peptic disease is uncommon below the age of 8 years or so, whether H pylori related or not.19,20,25,26,28 Secondary ulcer disease occurs at all ages, depending on the cause of the underlying gastritis.

Delineation of a specific or most likely diagnosis requires a careful review of the biopsy in the context of the clinical scenario.5 Specific diagnostic entities are discussed below. Biopsy interpretation is often only descriptive, and semiquantitative. The types of cell present and their distribution in the mucosa is described. “Acute” or “active” refers to the presence of neutrophils, “chronic” refers to the presence of round cells (lymphocytes, monocytes, plasma cells), and “chronic active” refers to a combination of a chronic process with some neutrophils present. There are no precise definitions for chronic gastric inflammation because the “normal” number of mononuclear “allowable” is unknown32-34 Although adult “normal” or asymptomatic volunteers sometimes undergo endoscopy and biopsy as a baseline for studies, their histology even in “health” may reflect many variables, such as normal aging, smoking, intake of alcohol, NSAIDs, and so forth. These findings cannot be extrapolated to children, who should have “virgin” mucosa, unaffected by aging or toxins, unless a recent infection, including a systemic viral infection has occurred. In addition to the types of cells and lymphoid collections, descriptive terminology also includes the extent or depth of inflammation in the mucosa (superficial, deep, or pan-mucosal) and distribution (diffuse or focal). These terms can be combined to provide an overall description, for instance, “chronic active, pan-mucosal.”19

Differential Diagnosis

Helicobacter Pylori–Associated Gastritis and Ulcer

Gastric infection with H pylori is one of the most common causes of gastritis and peptic ulcer disease. H pylori organisms are spiral-shaped gram-negative, urease-producing bacteria that are highly motile because of multiple unipolar flagella. H pylori colonizes the mucus layer of the stomach, adjacent to the gastric mucosa. The prevalence of gastric infection with H pylori varies between countries and socioeconomic groups, but even where it is common, children are considerably less susceptible to peptic ulcers and other sequelae than adults. Improved sanitation and socioeconomic status decrease childhood H pylori acquisition rates.35 In most individuals, it is “silent” or asymptomatic and most often unassociated with complications. However, antral-predominant gastritis causes high-output gastric acid secretion,8,9,36-38 and it has a lifetime incidence of 10% to 15% of development of duodenal ulcer disease.39,40

In its acute phase, H pylori causes an acute, active (neutrophilic) gastritis, antral-predominant. The acute infection is accompanied by symptoms and increased acid hypersecretion for a week or so, then by hypochlorhydria,41,42 lasting for 6 weeks or so, after which serum gastrin levels and acid secretion are elevated, or occasionally normal. This fluctuation probably has to do with the areas of stomach infected, but the commonest residuum, at least when ulcer disease is present, is acid hypersecretion.38 If the organism is not eradicated, in most cases, the gastritis becomes chronic and active. Virtually all individuals infected with H pylori have some gastritis, but there are considerable individual and geographic variations in intensity and distribution of inflammation and in the disease associations. Two typical distribution patterns of infection in the stomach are observed with different pathophysiology. The first is an antral-predominant gastritis associated with increased gastric acid production. Individuals with this pattern of distribution are prone to peptic ulcer disease (PUD). This has been postulated to be due to the organism secreting ammonia resulting in a local increase in mucosal pH which in turn increases gastrin secretion. However, the mechanisms by which H pylori–associated gastritis causes ulceration in the duodenum remain unclear.43 The second distribution pattern of H pylori infection is a pan-predominant gastritis or corpus-predominant gastritis with decreased gastric acid production which are more prone to developing gastric atrophy (intestinal metaplasia and possibly gastric adenocarcinoma). The most prevalent pattern of gastritis in children19 in the Western world is an antral-predominant gastritis, with little or no involvement of the body (corpus) of the stomach.

Primary gastritis per se (ie, without ulcer disease), even though otherwise silent, causes iron-deficiency anemia in some children.21H pylori is a cofactor in the development of the very rare gastric B-cell lymphoma arising from mucosa-associated lymphoid tissue, or MALT, that is rare in childhood but has been described in children aged 11 to 16 years, with subsequent cure after H pylori eradication in some.6

Diagnosis

As a general principle, diagnostic tests for H pylori should be employed judiciously and be reserved for those children who are most likely to derive measurable benefit such as those who reasonably may be suspected to have peptic ulcer disease. H pylori infection in developed countries is low, and, in the absence of peptic ulceration, H pylori is only rarely a cause of symptoms.44 A positive urea breath test merely indicates that H pylori infection is present, not that it is the cause of symptoms; it is neither diagnostic of specific gastroduodenal pathology nor rules out other diagnoses. Abdominal pain in children is more commonly due to causes other than H pylori; therefore, testing for H pylori in all children presenting with abdominal pain is not indicated. Expert consensus groups have recommended that in children presenting with abdominal pain, the goal of diagnostic testing should be to determine the cause of the pain, not the presence of H pylori.25-28

In contrast, in adults, guidelines recommend the use of H pylori testing (urea breath tests or stool antigen tests) of adults with persistent dyspepsia, followed by treatment of those with positive tests.45

Antibody tests utilizing whole blood, serum, or saliva are not recommended in children for clinical use. Antibody tests are of low sensitivity and specificity—they may remain positive for years after eradication or resolution of infection; therefore, a positive test does not necessarily mean that active infection is present at the time of testing. The urea breath test (UBT) is sensitive and specific for the presence of active infection. Monoclonal stool antigen tests are less accurate for the presence of H pylori,46,47 and there is insufficient evidence to recommend fecal antigen testing in children.25-28

Endoscopy with biopsies provides the most accurate approach for definitive diagnosis of upper gastrointestinal mucosal diseases, including H pylori–associated disorders. Although H pylori gastritis may be present at endoscopy, it may not be the cause of presenting symptoms if ulcer disease is not present.25-28 Marked nodularity (see Fig. 409-3 and eFig. 409.2) is present in the antrum of patients in approximately 50% of children with H pylori gastritis without peptic ulcer disease, and in virtually all those with H pylori gastritis with peptic ulcer disease.19 Peptic ulcers that are H pylori related look the same endoscopically as H pylori–negative ulcers—the presence of H pylori gastritis makes the distinction.

Treatment

If active H pylori infection is present in a symptomatic patient, it is considered prudent to eradicate the organism. These recommendations are largely based upon the belief that treatment will potentially decrease the risk of gastric cancer. Eradication of H pylori is best acheived with a combination of 3 drugs.25-28 Examples of such regimens are a PPI approved for use in children, plus amoxicillin plus clarithromycin; or, PPI plus amoxicillin plus metronidazole; or PPI plus clarithromycin plus metronidazole. The medications are all given as twice-daily doses for 2 weeks; compliance is key to success of eradication. Elimination of H pylori is followed closely by the disappearance of neutrophils, which may be completely absent within 1 week of treatment. The chronic inflammation and the lymphoid hyperplasia subside more slowly, often taking longer than 1 year.19,48-50 Confirmation of eradication of H pylori with a UBT is recommended.25-28

Eradication of H pylori infection results in ulcer cure, with very low rates of ulcer recurrence. Potential sequelae of persistent H pylori infection include atrophic gastritis and intestinal metaplasia with a risk for gastric cancer (see atrophic gastrititis below).

Other Infectious Gastritides

Helicobacter Heilmanii

This organism, previously Gastrospirillum hominis, is probably transmitted from cats and dogs51,52 and may cause chronic active gastritis similar to that of H pylori, but with less severe inflammation, which is focal and usually restricted to the antrum. A definite association between H heilmanii infection and ulcer disease has not been established.

Anisakiasis

Acute gastric anisakiasis occurs frequently in Japan and in areas of high consumption of raw fish. Gastric symptoms may occur within 3 hours of ingestion and in sensitized people systemic allergic symptoms may arise within 5 hours. Peripheral leukocytosis and eosinophilia may also occur. Endoscopy shows one or more worms protruding into the lumen a couple of millimeters off the gastric mucosa, surrounded by a ring of intense erythema, mucosal swelling, and sometimes gastric erosions. The worms can be in the antrum or body but tend to favor the greater curvature of the stomach. Early endoscopy is diagnostic and therapeutic, allowing for removal of worms and relief of symptoms.

Other Gastric Infections

Several gastric infections have been described in immune-suppressed, sick, or malnourished individuals, including newborns with some infections (see Chapter 391). These include cytomegalovirus (CMV)53, herpes simplex, candidiasis, histoplasmosis, mucormycosis Mycoplasma pneumoniae, Mycobacterium tuberculosis, syphilis, Epstein–Barr virus, herpes zoster varicella virus, ascaris lumbricoides, strongyloides stercoralis. Influenza A is a rare cause of bleeding from hemorrhagic gastropathy in children and is sometimes fatal.54 CMV infection tends to occur in the gastric fundus and body, and may cause wall thickening, ulceration, hemorrhage, and perforation.55 Histologic findings include acute and chronic inflammation with edema, necrosis, and cytomegalic inclusion bodies in epithelial and endothelial cells, as well as in ulcer bases and mucosa adjacent to ulcers.

Helicobacter Pylori–Negative Gastritis and Ulcer

The exact prevalence of H pylori–negative duodenal and gastric ulceration is unclear, ranging from 1.7% to 48% in both the adult and the pediatric population.6 Some adult studies report a prevalence of H pylori–negative duodenal and gastric ulceration as low as 1.7% and 3.2%, respectively,56 whereas others report H pylori–negative duodenal ulcer disease rates of 8% to 12%,57,58 up to 48%.59 The few data in children indicate a prevalence of up to 29%.58,60,61 In children with H pylori–negative duodenal ulcer disease, the gastric antrum is normal at endoscopy and histologically; this is in contrast to the findings in H pylori–associated ulcer disease. That there are widely differing prevalences of H pylori–negative ulcer disease likely reflects different degrees of thoroughness of exclusion of H pylori infection, as well as truly changing prevalences of H pylori infection within communities as eradication treatments are used. H pylori–negative ulcer disease can be diagnosed only when H pylori infection has been reliably excluded (use of more than one test) and in the absence of recent antibiotic or bismuth ingestion (partial treatment of H pylori). NSAID ingestion and other conditions that cause ulcer disease, such as Crohn disease, Zollinger–Ellison syndrome, and G-cell hyperplasia, also must be excluded.

Atrophic Gastritis and Intestinal Metaplasia

Atrophic gastritis, also known as “gastric atrophy,” describes a loss of normal gland components or the presence of intestinal metaplasia. It is considered to be a preneoplastic lesion when a certain type of intestinal metaplasia develops in the atrophic mucosa.62-64 Atrophic gastritis of the stomach is a patchy lesion and may be missed by sampling error if tissue from multiple sites is not obtained. There is relatively little information on atrophic gastritis in children. When it does occur, it generally does so in the presence of H pylori, after the age of 10 years, with intestinal metaplasia very infrequently present.65,66-69 As the degree of atrophy progresses, the presence of active H pylori infection decreases, owing to the loss of H pylori–friendly, acid-secreting, superficial gastric mucosa, and newly present intestinal metaplasia that does not harbor H pylori. The supervention of hypochlorhydria is also somewhat hostile to H pylori colonization, because in the absence of acid, other organisms can proliferate and offer competition for H pylori. The acid–H pylori relationship and the mechanisms of development of atrophy have been well described elsewhere.36 Although H pylori infection is far and away the most important cause of atrophic gastritis worldwide, atrophy may result from any severe, chronic mucosal injury to the gastric mucosa in disorders such as in severe chronic varioliform gastritis and in autoimmune disease (scleroderma) with gastrointestinal tract involvement, including in children.1

MéNéTrièR Disease

Ménétrièr disease is a rare condition characterized by giant gastric folds, excess mucus secretion, decreased acid secretion, and hypoproteinemia due to the selective loss of serum proteins across the gastric mucosa. Although this condition is reported from the neonatal period onwards, the mean age of onset in children is 4.7 years.70 In children, it may follow a viral prodrome. Presentation includes epigastric pain, anorexia, vomiting, edema, hypoproteinemia, and raised IgE levels in some.71 Fecal alpha-1-antitrypsin levels are often elevated as in other protein-losing enteropathies. In children, it is generally a benign self-resolving disorder that may be associated with acute cytomegalovirus (CMV) infection.71,72 In adults, Ménétrièr disease is a more severe disease that is an acquired premalignant disorder. It may even present with malignancy. The diagnosis of Ménétrièr disease is made by endoscopy and biopsy. The differential diagnosis includes consideration of other disorders associated with large gastric folds including lymphoma, infections such as H pylori, CMV and anisakiasis, granulomatous gastritides, eosinophilic and allergic gastritis, and other rare disorders such as plasmacytoma and systemic lupus erythematosus. Some “thick fold” diseases may require full-thickness gastric biopsy, but Menetrier disease does not. Dramatic resolution of many manifestations in adults has been reported with the use of anti-EGFR antibody. Ganciclovir may be beneficial in children.73

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Aspirin, and Other Drugs

There are few data on the frequency of adverse gastrointestinal (GI) effects of NSAIDs in children, but they do occur.74,75,76,77-81 Though the conventional wisdom is that short-term use of NSAIDs for fever control is safe, a recent case series suggests otherwise.81 As in adults, erosions and ulcers due to NSAIDs may be single or multiple; the gastric antrum tends to be involved more than the body, but any or all regions of the stomach may be involved. In young children, ulceration of the incisura presenting with upper GI bleeding is a typical NSAID lesion, and bleeding may occur after just 1 or 2 doses of drug, or with more chronic use. NSAIDs can result in mucosal damage, ranging from histologic changes alone to frank ulceration; patients may be asymptomatic or suffer life-threatening ulcer bleeding or perforation. Many patients have gastric erosions when starting on NSAIDs, but often are asymptomatic and the erosions often heal spontaneously82—the phenomenon of “gastric adaptation.” Although enteric-coated (“buffered”) aspirin may cause fewer symptoms, enteric-coating of aspirin does not prevent complications.83

Risk factors for gastrointestinal complications of NSAIDs include a history of ulcer (complicated or uncomplicated), drug dose, comcomitant use of aspirin and another NSAID, use of a corticosteroid, use of an anticoagulant, and, possibly, H pylori infection.84 Current evidence suggests that eradication of H pylori is indicated before instituting high-dose or long-term NSAID therapy. PPIs and misoprostol are effective in preventing morbidity; the adverse effects (abdominal cramps, diarrhea) of misoprostol limit its use. At present there are no data on effectiveness of PPI for prophylaxis of children receiving NSAIDs.

Erosive or hemorrhagic gastropathies have also been described with valproic acid, dexamethasone, chemotherapeutic agents, alcohol, potassium chloride, iron, long-term fluoride ingestion, and cysteamine.6

Gastric Acid Hypersecretory States

Zollinger-Ellison syndrome, G-cell hyperplasia, and systemic mastocytosis are extremely rare in children.85-87 Zollinger-Ellison syndrome is caused by gastrin-secreting tumors called gastrinomas, which produce a baseline fasting hypergastrinemia (> 125 pg/mL).4 It should be noted that plasma gastrin levels well in excess of 100 pg/mL are often seen in patients receiving PPIs.88 Zollinger-Ellison syndrome may occur in association with multiple endocrine neoplasia type 1 (MEN1) or as a sporadic form. Hyperparathyroidism, hypercalcemia, and renal stones are found in patients with Zollinger-Ellison syndrome and MEN1.4,89,90

Systemic mastocytosis is a condition in which mast cells accumulate in skin, bone, bone marrow, liver, spleen, and GI tract. Mast cell products such as histamine and cytokines produce a variety of effects, including gastric hypersecretion, that may be associated with symptoms of nausea, vomiting, abdominal pain, peptic ulceration, diarrhea, and malabsorption.91-94 Management with acid suppression is usually effective.94

Other conditions associated with gastric acid hypersecretion include short bowel syndrome, hyperparathyroidism, and cystic fibrosis. Peptic ulcer disease is reported in children and adults with short bowel syndrome, but the exact mechanism remains unclear.95-97 Treatment with PPIs can be helpful; they may have to be given intravenously in severe refractory peptic ulcer disease associated with short bowel syndrome.95 Peptic ulceration, usually duodenal, can occur in patients with primary hyperparathyroidism as a result of hypercalcemia-induced gastric acid hypersecretion.98 Cysteamine, used for treatment of cystinosis is a potent secretagog, causing hypergastrinemia and gastric acid hypersecretion.6

Stress Gastropathy

Physiologic stressors such as shock, metabolic acidosis, hypoxemia, bacterial sepsis, head injury, burns, major surgery, or multiple organ failure reduce gastric blood flow with subsequent mucosal ischemia. This impairs the mucosal defensive barrier, increasing the risk of acid causing mucosal damage, even though hypersecretion is seen only in cases of sepsis and central nervous system trauma. Further risk factors for hemorrhage include gastric hypersecretion, mechanical ventilation, and use of corticosteroids. Stress lesions usually occur within 24 hours of the onset of critical illness and result in overt upper GI hemorrhage. The erosions are typically asymptomatic, multiple, superficial, and tend not to perforate.

Most neonatal gastropathies are due to physiologic stress, including prematurity, hypoxemia, prolonged ventilatory support, sepsis, and acid–base imbalance. Hemorrhagic gastropathy has been reported in otherwise healthy full-term infants presenting with severe upper gastrointestinal hemorrhage,99 and also in one patient as antenatal hemorrhage,100 most cases of hemorrhagic gastropathy are reported in sick neonates in the intensive care unit.

Traumatic Gastropathy

Forceful retching or vomiting may cause tears either above or below the gastroesophageal junction (Mallory-Weiss tears) or may produce typical subepithelial hemorrhages in the fundus and proximal body of the stomach (prolapse gastropathy101) from “knuckling” or trapping of the proximal stomach into the distal esophagus. Although both prolapse gastropathy and tears tend to resolve quickly, they can result in significant blood loss. Generally, bleeding ceases spontaneously as vomiting resolves, but occasionally bleeding from a Mallory-Weiss tear may be severe enough to warrant endoscopic therapy. By a similar mechanism of trauma, linear erosions may occur in the herniated gastric mucosa of patients with a large hiatal hernia, resulting in chronic blood loss anemia.102 Gastric erosions may also result from trauma secondary to long-term nasogastric tube placement. Aggressive continuous suction through nasogastric or gastrostomy tubes, especially in children who are receiving anticoagulants, can cause severe subepithelial hemorrhage and bleeding. Ingestion of foreign bodies, gastrostomy feeding devices, and endoscopic procedures such as diathermy103 are also common causes of subepithelial hemorrhage, erosion, and ulcer.

Portal Hypertensive Gastropathy

This congestive gastropathy is common in children with both cirrhotic and noncirrhotic portal hypertension104 but is not related to the severity of underlying liver disease, the size of esophageal varices, the presence of hypersplenism, or a previous history of bleeding and variceal sclerotherapy. Although hemorrhage from portal hypertensive gastropathy is not usually catastrophic, bleeding may occur and result in severe blood loss and anemia. In adults, congestive gastropathy is more frequently associated with large gastroesophageal varices than with esophageal varices alone, and sclerotherapy of esophageal varices may exacerbate portal hypertensive gastropathy and gastric varices. Diagnosis is made by endoscopy alone. Biopsy is not required and is potentially dangerous.

Gastritis Associated with Autoimmune Diseases

Gastritis with and without atrophy has been seen in children with autoimmune thyroiditis and nongoitrous juvenile hypothyroidism, some with achlorhydria and gastric parietal cell antibodies.105 Autoimmune atrophic gastritis has also been described in 15% of adults with vitiligo.106 Conversely, hypertrophic gastropathy has been associated with systemic lupus erythematosus.107 In children and adults with connective tissue diseases, a mast cell gastritis and a combination mast cell and eosinophilic gastritis have been described.108

Graft versus host disease (GVHD) is discussed further in Chapter 133. Acute GVHD may involve the stomach with biopsy findings consisting of crypt epithelial cell apoptosis and drop-out.109 Chronic GVHD rarely involves the stomach.

The classic adult form of pernicious anemia, associated with body-predominant atrophic gastritis, occurs rarely in children. Patients have antibodies against parietal cell components, including the proton pump, intrinsic factor, and pepsinogen.106 The typical finding at endoscopy is thin rugae of the gastric body, sometimes with blood vessels visible through the mucosa. Histologic examination shows severe atrophic fundic gland gastritis with absence of parietal cells. It is associated with endocrinopathies such as autoimmune thyroid disease and diabetes mellitus, vitiligo, selective IgA deficiency, abnormal cellular immunity, chronic candidiasis, and collagen vascular disease.110 Adenocarcinoma of the stomach occurs as a complication. Although gastric adenocarcinoma is rare in children, it does occur,111 and endoscopic surveillance of pernicious anemia is indicated. Other causes of vitamin B12 deficiency are discussed in Chapter 188.

GI bleeding in patients with systemic sclerosis and CREST syndrome has been reported and is most often due to mucosal telangectasia, although peptic ulcers and erosive gastritis have also been described.112 In a large group of children with insulin-dependent diabetes mellitus, 7% had upper GI symptoms for which endoscopy was performed113; half had evidence of erosions and ulcers.

In celiac disease (see Chapter 408) gastroscopy is usually normal, but if biopsies are taken, a lymphocytic gastritis is often detected as characterized by the intraepithelial location of the lymphocytic infiltrate.114-116 Rarely, bleeding from gastric or duodenal ulcers may occur in celiac disease.117

Inflammatory Bowel Disease and Other Granulomatous Gastridities

Crohn disease is the most common cause of granulomatous disease of the stomach.5 Although gastroduodenal involvement is relatively common, Crohn disease is rarely isolated to the stomach and usually also involves more distal intestinal disease.118 If disease is isolated to the upper GI tract, particularly in younger children, other conditions such as chronic granulomatous disease of childhood should be considered and excluded.

Chronic granulomatous disease (CGD) is a rare inherited immune deficiency disorder discussed in Chapter 188. Gastric involvement typically presents with a narrowed, poorly mobile antrum on contrast radiography53,119 and a swollen, pale lusterless anral mucosa. Histologic findings include focal, chronic active inflammation in the antrum, with granulomata or multinuclear giant cells. The pathognomonic lipochrome-pigmented histiocytes may be absent in gastric biopsies but are often evident on biopsies from the lower gastrointestinal tract.5

Other rare granulomatous gastritides include reaction to foreign bodies, tuberculosis, histoplasmosis, histiocytosis X, sarcoidosis, Wegener disease, and idiopathic isolated granulomatous gastritis, a rare condition of a chronic granulomatous reaction limited to the stomach, and a diagnosis of exclusion.

Other Gastritides and Gastropathies

Allergic and eosinophilic gastroenteropathies are discussed in detail in Chapter 411. Henoch-Schönlein purpura (HSP) (see Chapter 472) can involve the stomach with endoscopic findings that include erythematous or hemorrhagic mucosa, mucosal edema, with erosions or ulcers.120 Corrosive injury causes mucosal damage. The ingestion of strong acids and alkalis usually results in damage to the esophagus but may involve the stomach. When gastric injury occurs, the prepyloric area is particularly vulnerable,121,122 probably because of pylorospasm and pooling of secretions. Endoscopic findings range from mild friability and erythema to necrosis, ulcers, exudates, hemorrhage, and gastric outlet obstruction with perforation rarely occurring. Chronic cicatrization is relatively infrequent and may take several months to become apparent, hence the need for serial imaging or evaluation. Iron poisoning, especially with ferrous sulfate, is common in children in some areas of the world and may cause a corrosive gastropathy with stricture.123 Therapeutic administration of oral ferrous sulfate can cause mild endoscopic abnormalities in the stomach; these are of uncertain clinical significance.124

Exercise-induced gastropathy or gastritis occurs in long-distance runners, usually presenting with blood loss anemia, with or without upper GI symptoms. Symptoms often occur postexercise and include abdominal cramps or epigastric pain, nausea, gastroesophageal reflux, and vomiting.125-127

Long-term or high-dose PPI therapy often causes a characteristic hyperplasia of parietal cells, with a thickened parietal cell zone, and lingular pseudohypertrophy of individual parietal cells. Endoscopic evidence of polyps or nodules may occur in children. The changes are benign and often resolve with cessation of PPI therapy.

In acute renal failure, gastropathy may be due to physiologic stress rather than renal failure. When GI bleeding occurs in acute renal failure, it is associated with erosions or ulcers in 71% of cases in adults and with an increased risk of death and duration of hospital stay; additional factors that predispose to bleeding are use of corticosteroids and concurrent disease such as liver cirrhosis.128

Duodenogastric reflux causing bile gastropathy was common in patients who had undergone gastric resection surgery for peptic ulcer disease. Other than for cancer or rare indications like hypersecretory syndromes not responsive to acid suppression, these operations are largely obsolete even in adults these days, making this disorder uncommon. The mere finding of bile in the stomach at endoscopy is common and unlikely to be of any significance.

Chronic varioliform gastritis is a subacute, inflammatory gastric mucosal disease characterized by swollen congested rugae and disseminated mucosal erosions which is exceedingly rare in childhood.1

Complications and Treatment

Principles of management are given here, with treatments specific to less common forms of gastritis given under each type of gastritis. The approach to H pylori is a special case and is addressed separately in the section above.

Gastric acid and pepsin are major factors in the final pathway leading to mucosal damage. Therefore, acid-suppressing or buffering therapy is often important in the management of gastritis and of peptic ulcer disease, but not always. Proton pump inhibitors (PPIs) are generally recommended treatment of acid peptic disorders, and as part of H pylori eradication therapy. The length of therapy depends upon the etiology and severity of the disease, but initial PPI therapy usually should not exceed 2 months. H2-receptor antagonists (eg, ranitidine, cimetidine, famotidine) are also commonly used in children. However, they are of lower efficacy than PPIs, and their major drawback is the tolerance that develops, often within a few weeks.129,130 Antacids may relieve occasional dyspepsia, but they are not useful for treatment of significant disease. Chronic use of acid suppression therapies (proton pump inhibitors or H2-receptor antagonists) may increase rates of community-acquired pneumonia in adults and children, Clostridium difficile infection in adults, bacterial gastroenteritis in adults, gastroenteritis in children, candidemia and necrotizing enterocolitis in preterms, and vitamin B12 deficiency in adults over 65 years.131-137

Sucralfate is a complex of aluminum and sulfated sucrose that has very little acid-neutralizing ability. It is occasionally used for children with large areas of oozing from the stomach, or in children where duodenogastric reflux is thought to be a cause of symptoms. In children with renal failure, aluminum may be inadequately excreted; therefore, aluminum levels should be monitored closely, or, better yet, sucralfate use should be avoided.

When appropriate, specific treatment of the underlying cause of the mucosal injury should be administered. For example, the key management strategy for stress-induced gastritis is treatment of the underlying acidosis, hypoxemia, or sepsis. Traumatic gastropathy requires supportive therapy as well as attention to the underlying cause of forceful emesis. Crohn disease or eosinophilic gastritis is treated with immune modulation.

Diet plays little role in the prevention or treatment of acid peptic disease. In some patients, it may be useful to exclude beverages causing increased acid secretion, such as tea, coffee, and cola. Bland diets are not of any proven benefit in the treatment of peptic ulcers and serve only to diminish quality of life. There is no need specifically to exclude spicy foods from the diet, unless the patient complains that these cause symptoms; the same principle applies to other foods.

The major complications of gastritides are bleeding, which is either diffuse or in the case of peptic ulcer disease may be focal and severe; perforation that sometimes penetrates into an adjacent organ (eg, pancreas); and distortion of the antrum or pylorus or duodenum, which results in varying degrees of gastric outlet obstruction.138 Other complications such as hypoalbuminemia or B12 deficiency are observed in specific disorders as discussed above.

Bleeding is treated with endoscopic therapy or surgery as discussed in Chapter 387. Treatment of scarring and distortion of the gastric outlet may require endoscopic dilation139 or, rarely, surgery.