Acute hemorrhagic erosive gastropathy and reactive gastropathy

INTRODUCTION — Injury to the gastric mucosa leads to epithelial cell damage and regeneration. Epithelial cell damage and reactive regeneration without associated inflammation is defined as "gastropathy" [1,2]. In contrast, the term gastritis is used to denote inflammation associated with gastric mucosal injury. A practical etiology-based framework for the classification of gastropathy and gastritis is presented [1]. (See "Gastritis: Etiology and diagnosis".)

This topic review will discuss acute hemorrhagic and erosive gastropathy and reactive gastropathy. The classification and diagnosis of gastritis, and the causes of acute and chronic gastritis are presented separately. (See "Gastritis: Etiology and diagnosis" and "Acute and chronic gastritis due to Helicobacter pylori" and "Metaplastic (chronic) atrophic gastritis".)

ACUTE HEMORRHAGIC EROSIVE GASTROPATHY

Etiology — Acute hemorrhagic erosive gastropathy is characterized by hemorrhagic and erosive lesions that develop shortly after exposure of the gastric mucosa to injurious substances or after a substantial reduction in mucosal blood flow (ischemic gastropathy).

Gastric and duodenal ulceroinflammatory lesions occurring during severe damage to the central nervous system (Cushing's ulcers) are often considered in this group, although some authorities consider them to be clinically and pathogenetically distinct [3,4]. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".)

Drugs/toxins — The most frequent injurious agents include:

●Alcohol – Alcohol exerts a direct toxic effect on gastric epithelium. In addition, it impairs gastric motility, leading to delayed gastric emptying and consequent prolonged mucosal contact time, further exacerbating the toxic injury [5]. Injury is dose-dependent and usually requires a gastric alcohol concentration of >10 percent [6].

●Medications

•Nonsteroidal anti-inflammatory drugs (NSAIDs) – Damage can include acute hemorrhagic gastropathy, erosions, reactive gastropathy, ulcers, and perforation. Proton pump inhibitors (PPIs) have been used to mitigate gastrointestinal toxicity; however, there have been reports suggesting that PPIs can exacerbate NSAID-induced enteropathy, particularly within the small intestine [7]. (See "NSAIDs (including aspirin): Treatment and secondary prevention of gastroduodenal toxicity".)

•Iron pills – The consumption of large amounts of oral iron may lead to gastric mucosal necrosis, erosions, and ulcers. Brown pigment may be seen overlying the damaged epithelium [8].

•Oral sodium phosphate preparations – Oral sodium phosphate preparations, used for colonoscopy bowel preparation, are associated with acute hemorrhagic gastropathy [9]. (See "Bowel preparation before colonoscopy in adults", section on 'Sodium phosphate preparations'.)

•Cancer chemotherapy – Damage to gastric mucosa in patients undergoing cancer chemotherapy is multifactorial and includes direct mucosal injury by the medication(s), vomiting-induced mucosal injury, and cancer-mediated or chemotherapy-induced immunosuppression (with opportunistic gastric infections). Hepatic arterial infusion of chemotherapy agents can produce alarming regenerative cellular atypia, easily confused with carcinoma [10].

Ischemia — Cocaine can cause ischemic gastropathy by intense vasoconstriction with subsequent ischemia due to activation of alpha-adrenergic receptors in the mesentery [11]. Other causes of ischemic injury include hypovolemia, sepsis, trauma, and mucosal prolapse.

Pathogenesis — As a result of the acute mucosal injury, the normal protective barrier (which includes secreted mucins, bicarbonate, and the epithelium itself) is disrupted. This permits acid and other luminal substances (eg, pepsin and bile acids) to penetrate into the lamina propria, where they cause injury to the vasculature, stimulate nerves, and cause the release of histamine and other inflammatory mediators [12,13]. The mucosal injury increases significantly during the reperfusion that follows ischemia due to the production of toxic oxygen-free radicals by infiltrating neutrophils [14].

An additional pathogenetic factor in NSAID-induced acute hemorrhagic and erosive gastropathy is the inhibition of mucosal prostaglandin production. Prostaglandins protect against acute mucosal injury due to injurious substances by several mechanisms, including stimulation of mucus and bicarbonate secretion and increased vascular permeability, resulting in perivascular edema that dilutes and delays toxic agents reaching subepithelial capillaries [15,16]. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)

Clinical features — Acute gastropathies often present with abdominal discomfort/pain, heartburn, nausea, vomiting, and hematemesis. Bleeding may be delayed until three to seven days following the stressful event and can range from occult blood to massive hemorrhage. Gastropathy (often referred to as gastritis) is commonly identified at the time of endoscopy, but such gastropathies rarely lead to significant upper gastrointestinal bleeding in the absence of other factors such as anticoagulation, coagulopathy or concurrent gastric/duodenal ulcers. (See "Causes of upper gastrointestinal bleeding in adults", section on 'Gastritis/gastropathy and duodenitis/duodenopathy' and "Approach to acute upper gastrointestinal bleeding in adults".)

Endoscopy and pathology

Gastric erosions — Acute hemorrhagic erosive gastropathy appears as multiple petechial hemorrhages and small red or black erosions on endoscopy [17,18]. Stress-related lesions (including Curling's ulcers) usually appear in the fundus near the gastroesophageal junction and spread distally, but remain confined to the fundus and body [18]. In contrast, gastropathy due to NSAIDs and alcohol ingestion involves the entire stomach from the start, although it may be most evident in the antrum [18]. The erosions in NSAID and alcohol-induced hemorrhagic gastropathy are usually smaller and more rapidly reversible than those seen in ischemic gastropathy [18].

Erosions may have only subtle histological features because mucosal restitution and repair are rapid. In many cases, an attenuated, regenerative-appearing epithelium provides the only evidence for their occurrence [4]. Inflammation is usually slight (consisting of no more than a few neutrophils) or absent.

Gastric/duodenal ulcers — Acute hemorrhagic erosive gastropathy may be associated with the development of acute gastric and duodenal ulcers. Acute stress ulceration is most likely to occur in relation to shock-induced hemodynamic instability. Ulcers are usually multiple, shallow, 0.5 to 2.0 cm in diameter, and almost exclusively located in the corpus and fundus [3,4,18,19].

The pathologic appearance of the ulcers depends upon their age. Ulcers initially appear necrotic, while older ulcers often demonstrate inflammation, granulation tissue, and epithelial cell regeneration. Ulcers of various ages can usually be found in the same patient [19].

Gastric (or duodenal) ulcers developing in the setting of acute hemorrhagic gastropathy may be associated with significant bleeding if they extend below the muscularis mucosae into deeper layers where large vessels are located [3,4,19]. Bleeding is more common from gastric than duodenal ulcers.

Management and prevention — Management of acute hemorrhagic erosive gastropathy is based on the cause and the clinical presentation. Treatment includes removing the causative agent and employing a limited course of acid suppression with a PPI. Bleeding is typically self-limited. Additional measures that may be required include withholding anticoagulants when they may be contributing (if possible), and, if bleeding is severe, endoscopic therapy with modalities such as argon plasma coagulation. (See "Causes of upper gastrointestinal bleeding in adults", section on 'Gastritis/gastropathy and duodenitis/duodenopathy'.)

A variety of measures may also be effective for prevention of acute hemorrhagic gastropathy in high-risk patients. Examples include antisecretory agents (PPIs or H2 receptor antagonists) to prevent stress ulceration in the intensive care unit and for those undergoing cancer chemotherapy. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".)

REACTIVE GASTROPATHY — Reactive gastropathy is usually caused by long-term exposure of the gastric mucosa to substances capable of injuring the gastric mucosa (medications, ethanol, bile reflux), or by mucosal ischemia or vascular congestion. Reactive gastropathy is characterized by a paucity of inflammation, variable degrees of foveolar hyperplasia, mucosal edema, proliferation of smooth muscle fibers in the lamina propria, and vascular dilation and congestion.

Etiology — These changes were first recognized in severe bile reflux gastropathy [20], and have subsequently been observed in biopsy specimens from patients with chronic nonsteroidal anti-inflammatory drug (NSAID)-related mucosal injury [21]. Alendronate, which can cause acute gastropathy [22], can also cause reactive gastropathy.

Chronic NSAID use — The pathogenetic connection between the acute hemorrhagic erosive gastropathy discussed above and the chronic reactive gastropathy associated with NSAIDs is not well understood. Continued, regular administration of NSAIDs in humans and experimental animals can lead to a reduction in visible hemorrhages and erosions as a result of mucosal adaptation [23-27]. However, many patients who take these drugs for prolonged periods continue to have ulceroinflammatory lesions with mucosal hemorrhages and erosions or, in approximately 15 percent of patients, gastric or duodenal ulceration [28,29]. This outcome has been referred to as "failed adaptation" [30]. H. pylori infection is known to exacerbate severe gastric mucosal injury in chronic NSAID users, possibly due to impairment of this adaptation process [31]. The chronic, poorly healing erosions and ulcers that often accompany NSAID-induced reactive gastropathy are usually associated with suppressed epithelial cell regeneration, which can be detected in biopsies obtained from the edge of ulcers [32,33]. The presence of scarring in the muscularis mucosae and submucosa in gastric resection specimens from NSAID users is also consistent with repeated episodes of erosion, ulceration, and repair. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity".)

Bile reflux gastropathy — Bile reflux gastropathy typically results from the entry of bile into the stomach because of an operative stoma, an incompetent pyloric sphincter, or abnormal duodenal motility [34]. The degree of gastric injury reflects the amount of exposure to bile salts. Patients who have a gastroenterostomy, for example, demonstrate the greatest degree of foveolar hyperplasia near the stoma, with decreasing changes proximally [20,35,36]. Bile salt concentration in gastric juice correlates with the severity of foveolar hyperplasia in these patients.

The effect of bile salts on the gastric mucosa is comparable to that seen after chronic NSAID use [34]. Bile salts also appear to be a risk factor for the development of metaplastic (chronic) atrophic gastritis in the antrum [37]. Animal studies have demonstrated that bile salts and the phospholipid lysolecithin cause gastric mucosal injury [38,39]. Their degree of toxicity is influenced by a number of variables, including the type of bile salt, the presence or absence of deconjugation of bile salts by bacteria in the intestine or stomach, the gastric pH, and the presence of pancreatic enzymes. Pancreatic enzymes in particular enhance injury from bile salts, in part because they can catalyze formation of lysolecithin from lecithin. (See "Metaplastic (chronic) atrophic gastritis".)

Lysolecithin and bile salts break down the gastric mucosal barrier [40], leading to back-diffusion of hydrogen ions and mucosal injury [38,39]. Concomitant infection by H. pylori can increase inflammation [41,42]. Cytoprotection from bile-induced injury by prostaglandins has been demonstrated in animal studies [43].

Other causes — Other oral agents known to be injurious to gastric mucosa and likely causing reactive gastropathy with chronic use include potassium and iron supplements [44-47].

Convincing evidence that smoking or alcohol causes reactive gastropathy are lacking [5,21,23,48-50]. Exposure of the gastric mucosa to alcohol is associated with acute hemorrhagic and erosive gastropathy (see 'Drugs/toxins' above) and chronic alcoholism correlates with presence of hemorrhagic and erosive lesions, [51-53]. Investigations directed at correlating alcohol consumption and chronic reactive gastropathy are difficult to conduct because of numerous confounding variables, including the presence of other potential causes of gastric injury such as NSAID use, H. pylori infection, and perhaps smoking. The types of alcoholic beverages consumed also may be important because of variations in alcohol concentration as well as important differences in content between distilled and fermented alcohols [5].

Clinical features — Symptoms in patients with chronic bile acid reflux gastropathy and other forms of reactive gastropathy are variable, ranging from histologic changes only without symptoms to abdominal pain, bilious vomiting, and weight loss [54].

Diagnosis — The diagnosis of reactive gastropathy is usually established on biopsy specimens from patients undergoing upper endoscopy for evaluation of upper abdominal symptoms.

Endoscopy and histopathology — Although there are no endoscopic findings that are diagnostic, mucosal changes are usually limited to hyperemia, and are confined to the antrum or gastroenterostomy sites.

Reactive gastropathy is characterized by a paucity of inflammation, variable degrees of foveolar hyperplasia, mucosal edema, proliferation of smooth muscle fibers in the lamina propria, and vascular dilation and congestion [20]. Foveolar hyperplasia is characterized by lengthening of the foveolae, with individual cells having reduced height and depletion of intracellular mucin. The glands may take on a tortuous, corkscrew appearance in severe cases, as is commonly seen in biopsy specimens taken near gastroenterostomy stomas (in which gastropathy is usually due to bile reflux). Foveolar hyperplasia is part of a spectrum of hyperplastic changes that are found near gastroenterostomies; others include discrete polypoid lesions (ie, polypoid hypertrophic gastritis or gastritis cystica polyposa) [35]. Foveolar hyperplasia can regress after bile is diverted from the gastroenterostomies [55]. These changes were first recognized in severe bile reflux gastropathy [20], and have subsequently been observed in biopsy specimens from patients with chronic NSAID-related mucosal injury [21]. Alendronate, which can cause acute gastropathy [22], can also cause reactive gastropathy.

Determining the etiology — Whereas a potential cause of reactive gastropathy may be elicited based on initial history, it is often difficult to establish with certainty that a particular agent has caused gastropathy [23,56,57]. In patients with surgically altered anatomy, reactive gastropathy can be attributed to bile reflux gastropathy in the absence of other causes. In contrast, gastropathy in patients with non-operated stomachs should not be attributed to exposure to bile without evidence of duodenogastric reflux. Duodenogastric reflux can be demonstrated by visualization of bile in the stomach during endoscopy, bile salt analysis in gastric juice, or radionuclide scanning [34,42,58,59].

Management — Treatment includes removing the causative agent. In patients with symptomatic chronic bile acid reflux gastropathy, surgery to divert bile from refluxing into the stomach (usually a Roux-en-Y revision), has been associated with improvement in symptoms in 50 to 90 percent of patients in several case series [54,60-62]. Improvement is less likely in patients with delayed gastric emptying [60].

While a number of medical treatments have been evaluated, there are limited data to support their use:

●Ursodeoxycholic acid (ursodiol) – In one small placebo-controlled crossover trial that included 12 patients with symptomatic bile reflux gastropathy, ursodeoxycholic acid for 1 month decreased pain and improved nausea and vomiting, but did not improve endoscopic appearance or histology [63]. A subsequent non-randomized trial suggested that ursodiol is superior to a proton pump inhibitor in these patients [64].

●Sucralfate – Sucralfate improved histologic features but not symptoms in a randomized controlled trial that included 23 patients with symptoms of bile reflux gastropathy following Billroth I, Billroth II, or vagotomy and pyloroplasty [65].

●Other – Prostaglandin E2 was ineffective in improving endoscopic features or symptoms in a double-blind crossover trial of bile reflux gastropathy [66]. Cholestyramine combined with alginates (to improve contact time in the gastric remnant) was also ineffective on symptoms or histology in a placebo-controlled trial that included 32 patients [67].

SUMMARY AND RECOMMENDATIONS

●Injury to the gastric mucosa leads to epithelial cell damage and regeneration. Epithelial cell damage and regeneration without associated inflammation is defined as "gastropathy." (See 'Introduction' above.)

●Acute hemorrhagic erosive gastropathy is characterized by hemorrhagic and erosive lesions that develop shortly after exposure of the gastric mucosa to injurious substances or after a substantial reduction in mucosal blood flow. The most frequent injurious agents include drugs (eg, nonsteroidal anti-inflammatory drugs and alcohol), hypovolemia, and chronic congestion. (See 'Etiology' above.)

●Acute hemorrhagic and erosive gastropathy appears as multiple petechial hemorrhages and small red or black erosions on endoscopy. Erosions may have only subtle histological features because mucosal restitution and repair are rapid. In many cases, an attenuated regenerative appearing epithelium provides the only evidence for their occurrence. Inflammation is usually minimal or absent. (See 'Endoscopy and pathology' above.)

●Patients with acute hemorrhagic erosive gastropathy may present as abdominal discomfort, pain, heartburn, nausea, vomiting, and hematemesis. Bleeding may be seen three to seven days following the stressful event and can range from occult blood to massive hemorrhage. Gastropathy (often referred to as gastritis) is commonly identified at the time of endoscopy, but rarely lead to significant upper gastrointestinal bleeding in the absence of other factors such as anticoagulation or a coagulopathy or concurrent gastric/duodenal ulcers. (See 'Clinical features' above.)

●Management of acute hemorrhagic erosive gastropathy is based on the cause and the clinical presentation. Treatment includes removing the causative agent and a limited course of acid suppression with a proton pump inhibitor. Bleeding from gastropathy is typically self-limited. Additional measures that may be required include withholding anticoagulants when they may be contributing (if possible), and, if bleeding is severe, endoscopic therapy with modalities such as argon plasma coagulation. (See 'Management and prevention' above.)

●Reactive gastropathy is usually caused by long-term exposure to substances capable of injuring the gastric mucosa (medications, ethanol, bile), or by mucosal ischemia or vascular congestion. (See 'Etiology' above.)

●Symptoms in patients with chronic bile reflux gastropathy and other forms of reactive gastropathy are variable. Patients may be asymptomatic or have symptoms of abdominal pain, bilious vomiting, and weight loss. (See 'Clinical features' above.)

●The diagnosis of reactive gastropathy is usually established on biopsy specimens from patients undergoing upper endoscopy for evaluation of upper abdominal symptoms. Reactive gastropathy is characterized by a paucity of inflammation, variable degrees of foveolar hyperplasia, mucosal edema, proliferation of smooth muscle fibers in the lamina propria, and vascular dilation and congestion.

(See 'Endoscopy and histopathology' above.)

●The presumed offending agent should be eliminated in patients with reactive gastropathy, if possible. In symptomatic patients with bile reflux gastropathy, surgery diverting bile from refluxing into the stomach is the definitive treatment. (See 'Management' above.)