Granulomatous Gastritis in Sarcoidosis and Crohn’s Disease

Granulomata detected in the gastric mucosa of a patient with established sarcoidosis or Crohn’s disease can be assumed to be part of the systemic process, and no further investigation is required. Because the finding of gastric mucosal granulomata may precede the discovery of the disease in other organs, the careful interpretation of gastric biopsy findings together with appropriate suggestions for further tests may lead to the prompt diagnosis of a condition that could otherwise remain obscure for a long time.

In sarcoidosis, involvement of the gastrointestinal tract is found occasionally at autopsy, but only rarely has it clinical importance. However, severe gastric disease with outlet obstruction or bleeding has been reported. Endoscopic findings may include nodularity, polypoid changes, erosions, ulcers, and segmental, usually distal, rigidity resembling linitisplastica. These gross changes reflect the presence of numerous mucosal granulomata and severe fibrosis.

Studies have challenged the perception that gastric involvement is rare in Crohn’s disease, and they found a prevalence of gastric granulomata of approximately 10% to 15% and a prevalence of “focally enhanced” H.pylori–negative active gastritis of between 30% and 70%. In these patients, focal gastritis was almost twice as frequent in the corpus as in the antrum, and epithelioid granulomata were twice as prevalent in the antrum.

Isolated Granulomatous Gastritis

Isolated granulomatous gastritis is a “holding category,” applied as a temporary diagnostic label to cases of granulomatous gastric inflammation for which no cause has yet been determined. Support for this approach derives from studies showing that most gastric granulomata are an expression of either concurrent or incipient Crohn’s disease or systemic sarcoidosis. Even after careful evaluation, some gastric granulomata will remain unexplained. These lesions are usually asymptomatic, there is no information on their natural history or evolution, and, therefore, no treatment can be recommended.

Chemical (reactive) gastropathy

An association between the presence of bile in the stomach and gastric mucosal damage ( duodenogastric reflux) was first postulated by William Beaumont in 1859, and several subsequent clinical observations led to the development of surgical techniques to prevent or minimize the regurgitation of duodenal contents into the stomach. In 1983, Dewar, Dixon, and Johnston systematically described the histopathological changes associated with bile reflux in the stomachs of patients who had undergone gastrectomy as well as patients with duodenal or gastric ulcer. The original term bile reflux was later replaced by chemical gastritis, to include the recently discovered NSAID-induced changes in the gastric mucosa. The terms reactive gastritis, type C gastritis, and chemical gastropathy have also been used. Chemical gastropathy is now defined as the constellation of endoscopic and histological changes caused by chemical injury to the gastric mucosa. This is an implicit admission that this diagnosis can be made only when converging clinical and histopathological evidence is present. Radiation gastritis, which results from a physical agent rather than a chemical one.

Clinical Manifestations

Three categories of patients may exhibit the endoscopic and histological changes of chemical gastropathy: patients with alkaline reflux after partial gastrectomy, patients with duodenogastric bile reflux as part of a poorly understood dysmotility syndrome, and patients who take NSAIDs.

Postgastrectomy alkaline reflux may present with a syndrome characterized by burning midepigastric pain unresponsive to antacids and aggravated by eating and recumbency. Bilious vomiting, anemia, and weight loss may occur. Endoscopic confirmation of bile reflux and documentation of the characteristic histopathological findings support the diagnosis, and corrective surgery (e.g., creation of a 40- to 50-cm Roux-en-Y gastrojejunostomy) is successful in about half of all cases.

Duodenogastric bile reflux secondary to gastroduodenaldysmotility or to cholecystectomy is a controversial condition, rarely considered in the differential diagnosis of dyspepsia in patients with an intact stomach. Thus, the frequency of endoscopic or histological changes of chemical gastropathy in these patients is unknown.

Millions of persons take daily doses of NSAIDs for indefinite periods, in many cases for life, to control pain caused by osteoarthritis, rheumatoid arthritis, or other chronic conditions. Unknown numbers of these NSAID users experience epigastric pain; approximately 10% per year develop erosions or ulcers, and 1% to 2% per year have a major gastric bleeding episode. Reactive gastropathy has been documented histopathologically in 10% to 45% of long-term users of NSAIDs, but no relationship could be established between the appearance of the mucosa and dyspeptic symptoms.

Pathogenesis

Duodenogastric reflux (with alkaline pancreaticoduodenal secretions as well as acids, bile salts, and lysolecithin) disrupts the mucous barrier and directly damages the gastric surface epithelium. This combined injury leads to accelerated exfoliation of surface epithelial cells and a histamine-mediated vascular response that manifests as edema and hyperemia. Persistent epithelial damage may lead to the release of other proinflam­matory agents, such as platelet-derived growth factor, which among its many actions stimulates smooth muscle and, later on, fibroblastic proliferation. Epithelial injury after exposure to NSAIDs appears to be mediated by reduced prostaglandin synthesis. Prostaglandins are important cytoprotective agents in the gastric mucosa and exert their effects by maintaining mucosal blood flow, by increasing secretion of mucus and bicarbonate ions, and by augmenting epithelial defense against cytotoxic injury. Thus, NSAID-inflicted injury can be partially prevented by simultaneous administration of prostaglandin analogs such as misoprostol and by suppression of gastric acid production with proton pump inhibitors. Newer selective cyclooxygenase 2 inhibitors (inhibitors, second-generation NSAIDs, or selective NSAIDs) are reportedly better tolerated by the gastric mucosa. Whether the initial encouraging results will hold true when these drugs become widely used, remains to be evaluated.

Endoscopic Appearance

In patients who have undergone a Billroth II gastrectomy, the gastric mucosa at the anastomotic site may have a polypoid appearance with congestion, edema, and friability. Superficial erosions may be present in more proximal areas of the gastric stump, but they are not specific, because they can be caused by a variety of injuries. In patients with nonoperated stomachs and possible duodenogastric bile reflux, the mucosa may exhibit congestion, edema, and erosions. In long-term NSAID users, the mucosa may be normal or may show congestion, erosions, or ulcers.

Histopathology

Although some histological features are more frequently found in regular NSAID users, the histopathological diagnosis of chemical gastropathy remains a challenging problem. The histopathological changes that have been associated with reactive gastropathy include evidence of epithelial regeneration, foveolar hyperplasia, edema of the lamina propria, and expansion of the smooth muscle fibers into the upper third of the mucosa, an area in which they are not normally found. Both the specificity and the predictive value of these features are low because of several potential confounding factors. Surreptitious use of NSAIDs, other substances in the diet (e.g., alcohol, spices, salt) that may cause similar mucosal changes, and clinically silent bile reflux can rarely be excluded; furthermore, the difficulty of obtaining a perfect control population cannot be overemphasized. H.pylori infection induces some of the features traditionally considered characteristic of chemical gastropathy: mucosal hyperemia and edema, superficial erosions, foveolar hyperplasia, and regenerative changes. Therefore, the pathologist can suspect chemical gastropathy and communicate this suspicion to the clinician, but a firm histopathological diagnosis can be made only when supportive clinical data are available and H.pylori infection is absent.

Partial Gastrectomy and Carcinoma

The polypoid appearance of the distal portions of the gastric stump in patients who have undergone gastrectomy has been referred to as gastritis cysticapolyposa. Several studies, mostly conducted in Europe and Asia, have reported a high prevalence of low-grade dysplasia in these polypoid areas, as well as an increased incidence of gastric adenocarcinoma 2 to 3 decades after gastrectomy. The implications of these findings, potentially important because of the suggestion that patients who undergo partial gastrectomy may need endoscopic surveillance, seem less urgent in the present era, when partial gastrectomy for peptic ulcer disease has become an exceedingly rare operation.