The gastric mucosal barrier is a complex defense mechanism, protecting the normal mucosa from the harsh chemical environment of the gastric luminal contents. Gastric luminal peptides and gastric distention provide strong stimulation for gastric acid production. In response to stimulation, parietal cell H+/K+-ATPase and KCl transporters become incorporated into the parietal cell canalicular membrane. Hydrogen ions are released into the gastric lumen from parietal cells upon stimulation in exchange for potassium, resulting in a very acidic environment.
The gastric mucosal barrier protects the gastric epithelium from the highly acidic luminal contents. Tight junctions seal the cellular layers of the gastric mucosa, ensuring that the luminal contents do not leak into or around these cells. A thick, bicarbonate-rich mucous layer covers the epithelial surface. The small amount of gastric acid that diffuses into epithelial cells is quickly cleared by the high blood flow to this area. This high blood flow also supports cellular metabolism and rapid renewal of injured cells. Local production of prostaglandins E2 and I2 help maintain the GI mucosal blood flow and integrity, increase mucous and bicarbonate secretion, decrease acid secretion, and stimulate epithelial cell turnover.
In the normal GI tract, the potential disruptive properties of the luminal contents are balanced by the defense mechanisms of the GI mucosal barrier. However, many drugs and diseases have the potential to upset the balance between the harsh luminal contents and the GI protective barrier. GI ulceration primarily targets the stomach and/or duodenum.
A defect in the normal GI mucosal barrier leads to a self-perpetuating cycle of further mucosal damage. Injury to this barrier allows hydrochloric acid, bile acids, and proteolytic enzymes to degrade the epithelial cells, disrupt lipid membranes, and induce inflammation and apoptosis. Back diffusion of luminal contents through the tight junctions leads to inflammation and hemorrhage of the GI cells, with further acid secretion mediated by inflammatory cells and their products. Mast cell degranulation occurs, causing histamine release that perpetuates further gastric acid secretion. The inflammatory environment also causes decreased blood flow, resulting in ischemia, decreased ability for cellular repair, and reduced secretion of mucus and cytoprotective prostaglandins. Mucosal ulceration can result, exposing the submucosa or deeper layers of the GI tissue to the harsh chemical luminal contents.
The incidence of GI ulceration in dogs and cats is unknown but it appears to be more common in dogs. NSAID administration, neoplasia, and hepatic disease are the most common reported causes of gastroduodenal ulceration or perforation in dogs. NSAIDs can cause direct topical damage to the GI mucosa, and inhibition of cyclooxygenase (COX)-1 decreases production of protective prostaglandins. The use of COX-2-specific NSAIDs is thought to decrease GI ulceration, but ulceration and perforation can still occur with use of these medications.
Primary GI neoplasia such as lymphoma, adenocarcinoma, leiomyoma, and leiomyosarcoma can result in ulceration due to local effects of the tumor. Additionally, paraneoplastic syndromes secondary to mast cell tumors and gastrinomas (Zollinger-Ellison syndrome) have been associated with increased gastric hydrochloric acid production and subsequent ulceration in dogs.
Various hepatic diseases (eg, acute hepatic injury, intrahepatic portosystemic shunt) are associated with gastroduodenal ulceration, but the mechanism of disease is not known. Possible causes include increased gastric acid secretion and alterations in mucosal blood flow, potentially leading to ulcer formation.
Other causes of ulceration in dogs include major trauma, spinal disease, renal disease, hypoadrenocorticism, GI inflammation such as inflammatory bowel disease or presence of a traumatic foreign body, systemic inflammation such as pancreatitis and sepsis, and extreme exercise such as sled dog racing.
Corticosteroid therapy is a controversial cause of GI ulceration. Combining NSAID and corticosteroid therapy will increase risk of GI ulceration and is contraindicated. Neoplasia (eg, lymphoma, adenocarcinoma) is the most common cause of feline GI ulceration, but the etiology is often not known.
Most patients with GI ulceration have nonspecific clinical signs, including vomiting, anorexia, abdominal pain, and weight loss. Signs of hematemesis and melena are variable. Cats with GI ulceration rarely show specific signs such as melena or hematemesis. Animals with severe ulceration and/or GI perforation may present with signs of pain, weakness, pallor, and shock. Clinical signs consistent with sepsis can be present in cases of perforated ulcer. Clinical signs of a causative factor may be seen. Some dogs and cats with GI ulceration do not show any clinical signs.
A minimum database (CBC, serum biochemistry profile, and urinalysis) can help differentiate primary GI disease from non-GI disease and can identify metabolic derangements resulting from GI disease. Additional testing, such as liver function tests or an ACTH stimulation test, may be warranted depending on the clinical picture and minimum database results.
Common laboratory abnormalities in dogs and cats with GI ulceration
Abdominal radiographs generally do not help to diagnose nonperforating GI ulceration but can help rule out GI obstruction, intussusceptions, and peritonitis. Abdominal ultrasound can reveal mural lesions, presence of mass or ulceration, and can identify non-GI lesions. Peritoneal fluid and/or gas can be detected radiographically or via ultrasonography in cases of perforating GI ulceration.
GI endoscopy allows visualization of the esophagus, stomach, duodenum, and colon and allows for identification of mucosal lesions and ulcers. Endoscopy also allows for lesion fine-needle aspirates or biopsy collection, although full-thickness surgical biopsies may be required to identify infiltrative disease and tumors. Ulcerated areas should be biopsied only on the periphery to help avoid the potential complication of perforation. Capsule endoscopy is a noninvasive option to help visualize GI mucosal lesions (see image).
Primary treatment of GI ulceration is directed at the underlying cause. Supportive care may be required to correct metabolic derangements and can include fluid therapy. Medication directed at the ulcer itself reduces gastric acidity, prevents further destruction of GI mucosa, and promotes ulcer healing. Optimal duration of antiulcerative therapy is not well described but is likely 4-6 weeks based on recommendations in people.
Gastric acid production is stimulated by histamine (most potent), gastrin, and acetylcholine. Drugs that decrease acid secretion help protect damaged GI mucosa.
Histamine-2 receptor antagonists (eg, cimetidine, famotidine) decrease acid production by blocking H2 receptors on parietal cells, and some agents also act as prokinetics (eg, ranitidine). Tachyphylaxis has been reported with short-term continuous use in dogs and cats. Famotidine (0.5-1 mg/kg PO, SC, or IV twice daily) has been shown to be more potent in reducing gastric pH than other H2 blockers but is inferior to proton pump inhibitors.
Proton pump inhibitors (eg, omeprazole 1 mg/kg, PO, twice daily or pantoprazole 1 mg/kg, IV, twice daily) offer more complete inhibition of gastric acid secretion by binding to and inhibiting the H+/K+-ATPase pumps of the parietal cell in an acidic environment. Proton pump inhibitors are superior to H2 blockers in treatment of ulcers. There is no benefit to combination therapy with an H2 blocker plus a proton pump inhibitor, and this combination may decrease the efficacy of the proton pump inhibitor.
Rebound hyperacidity is likely upon stopping a long treatment of either H2 blockers or proton pump inhibitors; gradual tapering (eg, weekly decrease of 50%) should be performed when discontinuing proton pump administration in patients receiving therapy for a month or longer. There are several documented drug interactions with proton pump inhibitors in humans, and these should be considered in veterinary species. Prophylactic use of H2 blockers or proton pump inhibitors to prevent GI ulceration is controversial, although benefits have been observed in certain populations (eg, racing sled dogs). Antacids have a short half-life, and there is scarce evidence that they provide benefit in veterinary patients with GI ulceration, so their utility is limited.
The cytoprotective agent sucralfate (dogs: 0.5–1 g, PO, 2–3 times daily; cats: 0.25 g, PO, 2–3 times daily) is comprised of aluminum hydroxide and sucrose. Its protective actions include binding to areas of eroded or ulcerated GI mucosa, cytoprotection, stimulating mucus and bicarbonate secretion, binding to pepsin, and reducing apoptosis. Because this drug inhibits absorption, it should be given 1–2 hours separately from food or other drugs. There is no evidence supporting the benefit of sucralfate therapy in treatment of GI ulceration in dogs or cats. The prostaglandin E2 analogue, misoprostol, has cytoprotective and acid inhibiting properties. The benefits of misoprostol for treatment of GI ulceration secondary to high-dose aspirin use has been reported in dogs; evidence for its use in treatment of NSAID or corticosteroid-associated ulcer formation is sparse.
Prophylactic use of antibiotics can be considered in cases of major GI mucosal barrier disruption or shock or in other cases when clinicopathologic signs (ie, fever, hematochezia, leukopenia, neutrophilia) suggest that bacterial translocation is of concern. Surgery is needed to treat perforated GI ulceration or in some cases for which medical management fails to resolve the ulcerated lesion.
The prognosis for canine GI ulceration depends on multiple factors, including reversibility of underlying cause(s), severity of ulceration, and rapidity of diagnosis and therapy. Prognosis is favorable in cases in which the underlying cause can be treated or removed, when ulceration is mild, and when the condition is rapidly diagnosed and treated appropriately. Ulceration associated with severe or end-stage conditions such as hepatic insufficiency is difficult to control. Perforated ulcers and peritonitis require more aggressive therapy and can be associated with poorer prognoses. Dogs and cats undergoing surgery due to GI perforation have approximately a 60% mortality rate.
Feline GI ulceration is often related to neoplasia, and intensive care is frequently required due to the high prevalence of marked hemorrhage in these cases. The prognosis associated with these cases is poor. In cats with GI ulceration secondary to a non-neoplastic disease, the clinical nature of these cases is less severe, and overall prognosis is good.