The stomach plays a key initial role in digestion through its mixing actions, and through the secretion of gastric acid and pepsin, which are important for the activation of key digestive enzymes.
The stomach plays a key initial role in digestion through its mixing actions, and through the secretion of gastric acid and pepsin, which are important for the activation of key digestive enzymes. The gastric epithelium is remarkably resistant to the deleterious effects of low pH because of the presence of a number of protective elements that prevent acid-induced injury. However, if gastric acid secretion increases to the point that the protective forces are overwhelmed, and/or there is a breakdown or loss in these protective forces, a gastric ulcer can develop.
Secretion of gastric acid is under control of central and peripheral neurological and hormonal stimuli. Peripherally, the important mediators of gastric acid secretion are acetylcholine, gastrin and histamine. Gastrin is released from G cells in the antral mucosa, and histamine is secreted by enterochromaffin cells in the gastric glands. Gastrin and acetylcholine stimulate the release of histamine from enterochromaffin cells, and the histamine in turn stimulates acid secretion when it binds to H2 receptors on the parietal cells of the gastric glands. The final step in the secretion of gastric acid is the mobilization of a proton pump to the apical surface of the parietal cell so that the pump can exchange a K+ ion for a H+ ion to be secreted into the lumen of the gastric gland. The intragastric pH can become as low as 2, an extremely acidic environment.
The principle protective forces of the gastric mucosa are an adequate blood flow, a mucus/bicarbonate layer, and epithelial cells that are capable of rapidly spreading to cover defects in the mucosa. Locally synthesized prostaglandins, primarily PGE2, support many of these protective forces. Mucosal blood flow is maintained by adequate concentrations of PGE2. The anatomy of the mucosal capillary bed promotes delivery of an HCO3 - ion, generated during the production of acid, to the capillaries underlying the surface epithelium where they can be available to neutralize any protons that have diffused back to the epithelial surface. Secretion of mucus is also promoted by PGE2. The mucus layer itself has within it a pH gradient, with the highest (most basic) pH situated at the epithelial surface. The gastric epithelial cells are capable of altering their shape to become flatter and more spread out to quickly cover any superficial epithelial layer defects, a process known as restitution. Gastric epithelial cells can also, under the right stimuli (growth factors, cytokines, inflammatory mediators), undergo rapid proliferation to fill larger breaches like ulcers in the epithelial barrier.
Gastric ulcers develop when there is an excess of harmful substances, primarily acid and pepsin, or there is a breakdown in a local protective force, or both. Most causes of ulcers in dogs and cats reflect one or both of these pathophysiological processes. Diseases that are known to increase secretion of gastric acid production often do so as a consequence of increases in gastrin or histamine. Examples of the former include renal failure (acute or chronic), and gastrinomas. Mast cell tumors predispose to gastric ulcers as a consequence of increased circulating concentrations of histamine. Studies of dogs with mast cell tumors have documented increased blood histamine concentrations as compared to normal dogs. A recent study of gastric ulcers in cats found systemic mast cell tumors the most common cause of ulcers in that study population.
Gastric ulcers also develop when there are deficiencies in protective forces. Alterations in mucosal blood flow are a common risk factor for the development of gastric ulcers, and can result from many different processes. Administration of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids decrease local prostaglandin production thereby reducing mucosal blood flow, limiting the epithelium's capacity to protect itself from the injurious effects of acid. Recent investigations in other species on the effects of NSAIDs have suggested that this class of drugs can also impair ulcer healing through inhibition of angiogenesis (necessary for granulation tissue formation in the ulcer bed) and epithelial proliferation. Hypovolemia, shock, vascular thrombosis, or other processes that interrupt gastric blood flow (e.g. gastric dilatation/volvulus) also can cause mucosal ulceration. Other diseases associated with ulcers can disrupt normal mucosal architecture, and likely also alter blood flow; examples include gastric neoplasms and inflammatory stomach diseases. Malignant gastric epithelial cells would not be expected to behave like normal epithelial cells thus potentially compromising the process of epithelial restitution, further enhancing the risk of ulcer development. For some of the diseases that are associated with ulcers, for example liver disease and hypoadrenocorticism in dogs, the mechanisms contributing to ulcer formation are not well-characterized, but are still likely to involve aberrations in mucosal protective functions; abnormalities in mucosal blood flow could easily be envisioned with either.
A common clinical sign of gastric ulcers in dogs and cats is vomiting, which may or may not have blood in it. Blood in the vomitus can appear fresh, or digested to create the classic "coffee grounds" appearance. It must be pointed out that the appearance of fresh or digested blood in vomitus does not definitively indicate that an ulcer is the source of blood as blood emanating from the nasal cavity, nasopharynx or esophagus could be swallowed and vomited. Clients may report seeing melena if there has been large-scale bleeding, but not seeing melena doesn't exclude the possibility of gastrointestinal bleeding. As just suggested, the presence of melena also does not specifically indicate bleeding of gastrointestinal origin.
Other clinical signs associated with gastric ulcers include anorexia, weight loss, increased salivation, and abdominal pain. Clinical signs attributed to underlying disease (e.g. polyuria/polydipsia with renal failure or hepatic disease) may be present in addition to those that are more directly referable to the presence of the ulcer. It is also very important to understand that there may be no overt clinical signs directly suggestive of gastric ulcers, likely making the incidence of gastric ulceration in dogs and cats underestimated.
There are no physical examination findings that specifically denote the presence of an ulcer. Mucous membrane pallor may be seen if bleeding has been severe, and the presence of cutaneous masses, or enlargement of draining lymph nodes, in animals with other features suggestive of ulcers should prompt at least needle cytology to exclude a mast cell tumor as the primary cause of an ulcer. Abdominal pain in some animals could be a reflection of peritonitis from a perforation, or near perforation. There may be overt evidence of melena on a rectal examination, but again, a normal appearing stool does not exclude the presence of an ulcer. If ulcers are associated with other systemic disease such as hypoadrenocorticism or hepatic disease, there may be physical examination abnormalities consistent with those diseases (e.g. bradycardia with hypoadrenocorticism, icterus and abdominal effusion in patients with liver disease).
There are no pathognomonic clinical pathology abnormalities seen in patients with gastric ulcers, but several that can be highly suggestive in a patient with other supportive historical and physical examination findings. Anemia, which can be regenerative or non-regenerative, will be seen in some animals. Defining an anemia as regenerative by the presence of reticulocytosis narrows the differential list to either hemorrhage or hemolytic disease, so obtaining reticulocyte counts can be very helpful in raising suspicion of GI tract bleeding and ulcers in some patients. Some patients may have microcytosis and hypochromasia (neither will be evident on reports that do not give indices, or if there has been no examination of a blood smear), with or without anemia, suggestive of iron deficiency if there has been chronic gastric bleeding. Inflammatory leukograms are possible reflecting the inflammation that often accompanies ulcers. Platelet numbers are usually normal, but can vary depending on the underlying cause of ulcers; chronic ulcers may be associated with thrombocytosis.
Serum biochemistry abnormalities will be variable and sometimes reflect the underlying cause and severity of the gastric ulcer. Increases in liver enzyme activity and abnormalities in the indirect indicators of hepatic function (decreases in one or more of albumin, cholesterol, BUN and glucose) may be seen in patients with ulcers attributed to liver disease; cholestatic liver diseases may be accompanied by hypercholesterolemia. Albumin and globulin concentrations may be decreased as a consequence of intraluminal bleeding, and in some patients, an increase in BUN without an increase in creatinine may be seen with large-scale gastric hemorrhage. Results of a urinalysis don't overtly suggest the presence of an ulcer, but could be important to rule out urinary tract causes of, or contributions to, anemia or hypoalbuminemia; results of a urinalysis could also suggest the presence of liver disease (e.g. low urine specific gravity and biurate crystals). Patients with suspected, or confirmed, gastric ulcers without any other identified risk factor may be candidates for measurement of fasting serum gastrin concentrations to rule out gastrinomas.
Patients with gastric ulcers can have chronic, low-grade blood loss that is not overtly apparent by the character of the stool. For patients that do not have overt signs of gastrointestinal bleeding, but for which bleeding is suspected as a cause of anemia or microcytosis, a fecal occult blood test can help confirm the intestinal tract as a site of blood loss. Substantial amounts of blood in the proximal intestinal tract are needed to produce melena, so normal stools do not at all exclude gastrointestinal hemorrhage in the suspect patient as noted above.
The initial suspicion of gastric ulcers is usually aroused by the presence of compatible clinical signs and laboratory abnormalities, particularly in a patient that has an identifiable risk factor in the history (e.g. NSAID or glucocorticoid administration) or laboratory data base (liver disease or renal failure). However, few patients actually have a definitive diagnosis established, but are instead empirically treated.
Definitive diagnosis of gastric ulcers is made by visualization of the ulcer, usually by endoscopic examination, or during gastrotomy. An advantage to endoscopic or surgical diagnosis is the potential for biopsy of tissue in and around the ulcer to examine for primary gastric diseases, especially neoplasia, when other risk factors for gastric ulcers do not exist. Strongly supportive findings for ulcers can be generated from contrast radiography or abdominal ultrasonography. Filling defects, gastric wall thickening, and prolonged retention of contrast material in the stomach are features that can be seen in some, but not all, patients with gastric ulcers during contrast radiography. Ultrasonographic findings supportive of gastric ulcers include gastric wall thickening, which is often focal, the detection of a mucosal crater that may have tiny bubbles within it, disruption of the normal layering of the gastric wall, and gastric hypomotility. Several of these ultrasonographic findings can be seen with other gastric diseases (e.g. gastric neoplasia) and aren't specific for gastric ulcers.
Key to treatment of gastric ulcers is identification and elimination, whenever possible, of underlying diseases or risk factors. In the majority of patients, treatment will also entail administration of drugs that reduce gastric acid secretion, and that provide mucosal protection in the face of an ulcer. The most commonly used class of drugs to reduce acid secretion is the H2 receptor blocker which includes famotidine, ranitidine and cimetidine; the author tends to avoid use of cimetidine because of its greater potential for altering metabolism of other drugs. Proton pump inhibitors such as omeprazole are also appropriate for treatment of gastric ulcers, but have been more favored for patients with difficult to treat ulcers or with difficult to treat primary causes (e.g. some gastrinomas). Administration of synthetic PGE2 analogs such as misoprostol can also be of benefit, particularly for patients with NSAID-induced ulcers. Sucralfate is an appropriate medication to give to patients with confirmed, or suspected ulcers. In an acid environment, sucralfate attains a gel-like consistency that fosters drug binding to ulcer beds protecting them from additional acid-injury. Sucralfate can also promote local production of prostaglandins and enhance the protective properties of mucus. Coupled with the fact that sucralfate carries a low risk of drug-induced side effects (occasional constipation), it is recommended for virtually all ulcer patients. One does need to be aware that sucralfate can interfere with the absorption of other drugs.
Drugs commonly used in the treatment of gastric ulcers
Patients with life-threatening hemorrhage, or medically intractable ulcers, are candidates for surgical resection of ulcers. Excised tissue should be submitted for histopathological examination to exclude gastric neoplasia as a primary cause of the ulcer.
For patients with unavoidable risk factors, administration of PGE2 analogs can be helpful in reducing the risk of developing gastric ulcers. Several studies in dogs document the protective benefits of misoprostol administration to prevent NSAID-induced ulcers. H2 blockers are commonly given to patients with mast cell tumors, renal failure or hepatic disease to prevent gastric ulcers. Because cimetidine can alter the metabolism of other drugs, and usually requires administration every 8 hours, the author favors other H2 blockers for patients with liver disease, or that are receiving other drugs.
Prevention of glucocorticoid-induced ulcers remains problematic in small animal practice. While it seems common to administer H2 blockers to patients receiving high-doses glucocorticoids, H2 blockers have not been proven to prevent the development of gastric ulcers in dogs or cats.
The prognosis for patients with gastric ulcers varies with the underlying etiology. The prognosis is good for patients that have correctable underlying risk factors or diseases (e.g. drug-induced ulcers, hypoadrenocorticism), but can be poor if the underlying disease cannot be reversed (e.g. chronic renal failure or unresectable neoplasia).
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