Pathology of Reactive Gastropathy

Reactive gastropathy refers to the constellation of endoscopic and histologic findings caused by chemical injury to the gastric mucosa. ^[1] The histologic picture is characterized by foveolar hyperplasia with edema, interfoveolar smooth muscle fibers, erosions, and congestion of superficial capillaries in the lamina propria in the absence of significant inflammation (see an example in the image below). ^[2]

These features were originally described in biopsy specimens obtained from patients who had undergone gastric surgery and were felt to be specific for bile reflux. ^{[3, 4, 5]} It has since become apparent, however, that the constellation of histologic features seen in reactive gastropathy is a nonspecific response to chemical injury of the gastric mucosa. ^{[6, 7, 8]}

Reactive gastropathy has also been referred to as chemical gastropathy, reflux gastritis, and type C gastritis. ^[6] The term "chemical gastropathy" was recommended by the Updated Sydney System, ^[1] because it indicates an underlying chemical injury that is not associated with infection. ^[9]

Go to Peptic Ulcer Disease for complete information on this topic.

The common underlying causes of reactive gastropathy include chronic bile reflux and long-term intake of nonsteroidal anti-inflammatory drugs (NSAIDs). Bile reflux usually occurs in patients who have undergone a Billroth II partial gastrectomy; it is also recognized to occur in intact stomachs in individuals with alcohol abuse, cigarette smoking, chronic respiratory disease, or duodenal ulcer, other medications (proton pump inhibitors [PPIs], iron, kayexalate, colchicine, antineoplastics, and corticosteroids), and even in healthy subjects. ^{[9, 10, 11, 12]}

The duodenogastric reflux results in disruption of the protective mucus barrier and direct injury to the gastric mucosa, causing backflow of hydrogen ions and epithelial damage. ^[2] The various bile acid species differ in their capacity to cause injury to the gastric mucosa. ^[5] The secondary (deoxycholic and lithocholic) and deconjugated bile acids are more injurious to the gastric mucosa than the primary (colic and chenodeoxycholic) and conjugated bile acids.

In situations of upper gastrointestinal (GI) stasis, as is seen after gastric surgery, bacterial overgrowth occurs within the proximal small intestine. This increase in intraluminal bacteria leads to subsequent generation of relatively increased concentrations of deconjugated and secondary bile acids within the refluxate. The increased concentration of the more toxic forms of bile acid, coupled with the decreased gastric emptying time of the refluxed bile, results in gastric mucosal injury and subsequent reactive gastropathy (chemical gastropathy).

The predominant mechanism of NSAID-induced gastric injury involves decreased synthesis of mucosal prostaglandins. ^{[13, 14]} Prostaglandins are derived from arachidonic acid via the cyclooxygenase (COX) pathway. Thus, inhibition of COX by NSAIDs reduces prostaglandin synthesis, thereby diminishing mucosal blood flow and decreasing mucus and bicarbonate secretion.

Furthermore, NSAIDs, being weak organic acids, can freely diffuse into the gastric epithelium. As a result of the neutral pH within the surface epithelial cells, the NSAID compound dissociates into its ionized form, contributing to direct cell injury. ^[15]

Although it is known that NSAIDs that selectively inhibit COX-2 cause significantly fewer GI complications than nonselective COX inhibitors do, it is still unclear whether administration of selective inhibitors results in less severe reactive gastropathy (chemical gastropathy). ^[16] However, most of these COX-2 inhibitors have been withdrawn from the market or have had their indications drastically limited in view of their potential serious cardiovascular side effects. ^[17]

The epithelial injury results in excessive exfoliation of the surface epithelial cells, which gives rise to a reactive foveolar hyperplasia. ^[3] The accompanying histamine-mediated vascular response leads to edema and hyperemia. Persistent epithelial damage may result in the release of platelet-derived growth factor (PDGF), which stimulates smooth muscle proliferation, followed by fibroblastic proliferation. ^[2]

The mucosal changes seen in reactive gastropathy are usually most prominent in the antrum and prepyloric region. When associated with bile reflux secondary to partial gastrectomy, the lesions develop near the surgical stoma, ^[18] but the more proximal oxyntic mucosa may also be affected.

To date, no specific genetic predisposing factors for the development of reactive gastropathy have been identified.

Reactive gastropathy is the second most common pathologic diagnosis rendered on gastric biopsies, after Helicobacter pylori gastritis (H pylori-associated active gastritis is discussed in a separate pathology article); the prevalence is significantly more common in women and increases steadily with age. ^{[16, 19, 20]}

This condition was originally described in patients who had undergone partial gastrectomy—most frequently, Billroth II gastric reconstruction. It has also been observed after Billroth I gastric reconstruction, truncal vagotomy, and pyloroplasty ^[4] and occasionally after cholecystectomy and ampullary sphincterotomy. ^{[21, 22, 23]}

At present, reactive gastropathy is usually encountered in the clinical setting of chronic nonsteroidal anti-inflammatory drug (NSAID) use. The reported prevalence of reactive gastropathy among patients taking daily NSAIDs for at least 1 month ranges from 30% to 40%. ^{[6, 8, 24, 25]}

Overall, the most common clinical presentations for reactive gastropathy include gastroesophageal reflex syndrome, epigastric pain, dyspepsia, and dysphagia. ^[20]  (See Pathophysiology and Etiology.)

Patients with reactive gastropathy secondary to bile reflux typically have an enterogastric anastomosis and most commonly present with continuous burning midepigastric pain that is often exacerbated by food and recumbency. Nausea, bilious vomiting, and other dyspeptic symptoms may also be present. ^[26] Although the findings are not specific, several authors claim that weight loss and a hypochromic microcytic anemia are also associated features. ^[5]

The most common complaint associated with NSAID-induced reactive gastropathy is mild dyspepsia. Chronic consumption of these drugs, however, can lead to the development of erosions and ulcers, increasing the risk for complications such as obstruction, perforation, and bleeding. ^[15]

Portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) should be considered in the differential diagnosis. Vascular gastropathy refers to a group of disorders characterized by alterations in the gastric mucosal blood vessels in the setting of little or no inflammation, including portal hypertensive gastropathy and GAVE. The presence of fibrin thrombi in the mucosal capillaries is a characteristic feature of GAVE rather than of reactive gastropathy. This finding, along with its distinctive endoscopic appearance ("watermelon stomach"), aids in the differentiation of GAVE from other similar-appearing entities.

Also consider H pylori-associated gastritis in the differential diagnosis of reactive gastropathy.

The endoscopic findings of reactive gastropathy are mostly nonspecific. The mucosa may be normal or may exhibit erythema, congestion, edema, or erosions. ^[9] In cases with bile reflux, bile might be seen in the gastric lumen. ^[27]

Mucosal changes in reactive gastropathy are readily appreciated by comparison with normal gastric mucosa (see the image below).

Reactive gastropathy is characterized by prominent foveolar hyperplasia with elongation and tortuosity of the gastric pits that gives these structures a corkscrew appearance. The surface may appear villiform. The foveolar cells show regenerative changes with mucin depletion, nuclear hyperchromasia, and increased mitoses.

Superficial erosions may be observed. There is smooth muscle hyperplasia in the lamina propria with edema and congestion of superficial capillaries. There is a paucity of both acute and chronic inflammatory cells. However, in the presence of erosions, superficial neutrophils may be seen. Occasionally, focal intestinal metaplasia may be present. Special stains for H pylori are negative.

Reactive gastropathy may range from mild to severe and, as noted (see Pathophysiology and Etiology), may involve the oxyntic mucosa as well as the antral mucosa (see the images below).

The microscopic features of reactive gastropathy were well characterized by Dixon et al in their original description of reflux gastritis as a distinct histopathologic entity. ^[3]

In this study, a score ranging from 0 (normal or absent) to 3 (severe) was assigned to each of the following histologic features: (1) foveolar hyperplasia, (2) edema and smooth muscle fibers in the lamina propria, and (3) vasodilatation and congestion of the lamina propria. Two other features, (4) acute and (5) chronic inflammatory cells, were graded separately; scores for each ranged from 0 (severe increase) to 3 (absence of inflammatory cells), for a combined score of 0 to 6. The cumulative reflux gastritis score therefore ranged from 0 to 15.

Patients who had undergone gastric surgery were found to have a statistically significant increase in reflux gastritis score, gastric pH, and gastric bile acid concentration. Scores of 10 or higher were found to be highly characteristic of reactive gastropathy (chemical gastropathy). ^[3]

A prospective multicenter study by Wolf et al developed a new score with visual analog scales. The study concluded that foveolar hyperplasia, smooth muscle fibers, and vasodilatation and congestion as key histologic parameters for the diagnosis of reactive gastropathy. ^[28]

Mucin expression is reported to be altered in reactive gastropathy in comparison with normal gastric mucosa as well as H pylori gastritis. A patchy or complete loss of the membrane mucin MUC1 was observed in 67% of cases. ^[29] Aberrant expression of the secreted mucins was also demonstrated. MUC5AC was seen in pyloric glands in 81% of cases, and MUC6 was seen in the upper foveolar epithelium in 14% of cases.

These alterations in mucin expression were shown in cases of both nonsteroidal anti-inflammatory drug (NSAID)-associated and bile reflux–associated reactive gastropathy (chemical gastropathy). Additionally, these changes are dissimilar to those seen in H pylori gastritis, reflecting the mechanistic differences between these gastropathies. ^[29]

Reactive gastropathy is also characterized by differences in cytoskeletal structure and cell cycle kinetics, as compared with normal gastric mucosa and H pylori gastritis. Such changes have been studied in terms of immunohistochemical expression of CK7, CK8, CK18, CK19, CK20, and Ki-67.

In reactive gastropathy (chemical gastropathy), the distribution of CK8, CK18, and CK19 was normally distributed but increased in intensity. The localization of CK7 and CK20 staining was modified, with extension toward the deep foveolar region. In contrast to H pylori gastritis, the surface epithelium lacked Ki67 expression and a downward elongation of the proliferative zone was noted. ^[30]

Patients with reactive gastropathy are less likely to have normal mucosa in other parts of the gastrointestinal tract. Some of the lesions that have been reported in association with reactive gastropathy include reflux esophagitis, Barrett esophagus, lymphocytic esophagitis, duodenal peptic disease, and duodenal intraepithelial lymphocytosis. ^[20]

The finding of reactive gastropathy indicates the presence of an offending agent, usually nonsteroidal anti-inflammatory drugs (NSAIDs) or reflux of bile acid-containing duodenal contents into the stomach. The management of this condition may include discontinuance of NSAID use along with administration of proton pump inhibitors (PPIs) and prostaglandin analogues.

Stump carcinoma has been reported in postgastrectomy stomachs. Bile reflux is thought to play a key role in the development of dysplasia and carcinoma in the gastric remnant. ^[31] In fact, some studies have reported improvement of preneoplastic changes after diversion of the enteric reflux. ^[32] Regular endoscopic surveillance starting 10 to 15 years after surgery is recommended.

With the advent of highly effective medical treatment for H pylori infection, there has been a decline in such surgical procedures, paralleled by a reduction in the incidence of stump carcinoma. ^[2]

Despite the occasional development of stump carcinomas in postgastrectomy stomachs, reactive gastropathy is not a major risk factor for gastric carcinoma.