Gastric ulcers are erosions of the gastric mucosa which may involve also the deeper layers, such as the submucosa and muscularis, and may then be the cause of perforations of the gastric serosa with subsequent peritonitis.
AETIOLOGY
Gastric ulcers are the consequence of a direct mucosal insult caused by acid and pepsin, whenever the gastric mucosa is not capable of adequately protecting itself and of substituting its damaged cells. Ulcerations may also be the result of a direct trauma; in this case the pathophysiology is however mechanical in nature. From the histopathological and microanatomical viewpoint, if the insult is mild and superficial it normally causes only haemorrhage and erosions, while real ulcers are present only when the damage involves at least the muscolaris mucosae and eventually also the deeper layers.
The prevalence of gastric ulcers in the dog and cat is not known and compared with the frequency of the same disorder in humans it is to be considered as a rare event. It is however likely that many patients presenting with vomiting and haematemesis and which respond to symptomatic medical therapy may in fact present gastric ulcers.
The stomach is endowed with protective mechanisms such as mucosal microcirculation, epithelial turnover, gastric mucous and prostaglandins, mechanism which may be summarized with the concept of gastric mucosal barrier. The epithelial turnover is extremely rapid (in 2 or 3 days the entire surface of the gastric mucosa is substituted), however the process requires an abundant microcirculation in order to assure the transport of nutritional substances and of oxygen as well as the removal of hydrogen ions. Gastric mucous is instead a viscous gel, consisting of glycoproteins (5%) and water (95%), which firmly adheres to the mucosa thus ensuring its physical protection from digestive enzymes. In addition, the active secretion of bicarbonate further contributes to the formation of a pH gradient on the mucosal cellular surface, which is capable of neutralizing gastric juices. Prostaglandins, which derive from arachidonic acid, play a fundamental role in terms of active protection as they increase the secretion of bicarbonate and mucous, they maintain the local blood flow inducing vasodilation and they inhibit acid secretion. Whichever factor that may interfere with the physiological functioning of the mucosal barrier may contribute to the formation of mucosal erosions or ulcerations.
Ulcers are defined as peptic when the exposure to gastric juices and to pepsin causes mucosal damage. This type of ulcer is associated with numerous causes, among which drug exposure (NSAIDS, corticosteroids), metabolic disorders (liver diseases, renal failure), infiltrative diseases (tumours, IBD), gastric hyperacidity (gastrinoma, APUDoma, rarely mastocytoma), chemical substances, CID, foreign bodies, hypovolaemia, pancreatitis and septic shock.
Exposure to NSAIDS causes mucosal damage especially when combined with the administration of steroids. NSAIDS block the action of prostaglandins by means of COX (cyclooxygenase)-1 and COX-2 inhibiting mechanisms. The inhibition of COX-1 causes a reduction in the secretion of bicarbonate, the formation of mucous and local vascular effects. In addition, NSAIDS also have a direct toxic activity on the gastric mucosa (mitochondrial damage). Eicosanoids produced by COX-2 are responsible for the inflammatory and painful reactions of the gastric mucosa, while those produced by COX-1 are fundamentally responsible for protective mechanisms. All the commonly used NSAIDS, independently from their COX-2 specificity, may cause gastric lesions, however real ulcers are rarely observed. If this action is combined with that of corticosteroids the presence of erosions and ulcerations is more likely.1
Cortecosteroids decrease the production of protective eicosanoids and consequently hinder the growth of gastric mucosa cells, the production of mucous and the secretion of prostaglandins, while they instead increase acid secretion. Steroids, if used with ionotherapy, are rarely the cause of ulcers, unless if used at very high dosages or in combination with risk factors such as severe hypotension or the administration of NSAIDS. If used in combination with NSAIDS, even at an anti-inflammatory dose, corticosteroids can be ulcerogenic, as they potentiate their effect. Dexamethasone is the drug with apparently the highest ulcerogenic effect.
One of the main risk factors for the formation of peptic ulcers is the reduction of local blood flow caused by hypotension. This condition is mostly present in the course of shock,sepsis and hypovolaemia. In general, all critical patients should be considered at risk for the development of gastric ulcerations, as in the presence of a state of shock the GI tract is the apparatus that suffers most from hypotension and sepsis. Prolonged hypotension in the course of anaesthesia for surgical interventions may also be the cause of ulcers. Furthermore, an article2 reports that 19 out of 25 patients with an acute, vertebral disc disease present endoscopic lesions compatible with gastric erosions and that surgery, with or without the administration of corticosteroids, increases the risk considerably.
Gastrinoma, although a rare disease, may be the cause of severe gastric and duodenal ulcerations, in view of the secretion of gastrin and the consequent hyperacidity. Other, less important risk factors include infiltrative gastrointestinal diseases, renal or liver diseases, congestive heart failure and gastric outflow obstruction. Furthermore, in the dog, gastric adenocarcinoma usually presents itself in the form of ulcers with raised margins, mainly localized at the level of the angular notch and of the distal third of the stomach.
In the cat, gastric ulcers are a rare condition; in one retrospective study3 ulcerations of neoplastic origin were reported in 14 cats out of 33 (mostly lymphoma and adenocarcinoma).
CLINICAL SIGNS
The clinical signs may be nonspecific: chronic vomiting is perhaps the most relevant manifestation, associated or not with haematemesis. The blood present in the vomit often appears digested, although fresh blood may also be present as the dog’s stomach - differently than in humans - does not continuously secrete acid. In the presence of relevant blood loss melena and anaemia may also be present. Inappetence, anorexia and abdominal pain may be variably present.
DIAGNOSIS
In the course of gastric ulcers laboratory examinations may result normal. When alterations are present these are in any case nonspecific. Chronic blood loss may cause anaemia, which is typically non regenerative and caused by iron deficiency, and hence mycrocitic and hypochromic. When the vomiting is very intense electrolytic alterations may also be present. Whenever blood loss is suspected, in the absence of macroscopic melena, a faecal occult blood test can be done. Two types of tests are available: tests containing guaiaconic acid (oxidized by haemoglobin it develops a blue quinone) and the o-toluidine test (which contains tetramethylbenzidine which, when oxidized, causes the formation of a blue compound). This latter assay has proven to be more sensitive and with an inferior number of false positive results. In any case all these tests may be altered by the presence of red meat in the diet, consequently all patients must follow a meatless diet for at least 3 days before being tested.
In some cases, especially in the presence of ulcers which are either perforated or associated with a primary disease, leukocytosis may be present, with or without a left shift. Abdominal x-rays (Fig. 1), which are part of the general work-up of the patient and should always be carried out in the presence of vomiting, are very often normal as the radiographic appearance of ulcers is nonspecific. The use of a contrast medium may allow the identification of filling defects and eventually of a perforation. Should perforation be suspected, an iodinated contrast medium is recommended. The contrast medium examination also usually results in nonspecific findings, which are hence to be confirmed with ultrasonography or endoscopy. Ultrasonography may identify gastric areas with parietal oedema associated with a reduction in motility and the presence of an intraluminal fluid pattern. An ulcerous crater interrupting the superficial portion of the wall may be identifiable, associated with the presence of hyperechoic foci with reverberation artefacts caused by the presence of gas and clots on the bottom of the lesion. In the presence of perforation ultrasonography may show signs referable to a focal peritonits.
Endoscopy (Figs. 2, 3 and 4), which allows the direct visualization, localization and biopsying of the ulcer, is the most sensitive diagnostic technique. In the presence of ulcers having a known cause and of surely benign nature, such as in the case of drug-induced ulcers, endoscopy is not necessary and should in fact be avoided; endoscopy requires total anaesthesia and the hypotension associated with the anaesthesia might worsen the clinical condition. In all other cases, if an ulcer is found during endoscopy bioptic samples should be collected, especially on the margins of the lesion, trying to avoid the necrotic centre. Duodenal exploration and sampling is also recommended, especially when diffuse, gastric erosions are present. In the presence of gastrinoma the gastric and duodenal mucosa is characterized by the presence of diffuse haemorrhagic suffusions, oedema, erosions and ulcerations and can be easily perforated, especially at duodenal level.
THERAPY
Goal of ulcer treatment is the elimination of the predisposing or causal factors. Depending on the clinical conditions of the patient it is at the same time recommendable to start an adequate symptomatic therapy for the reduction of gastric secretion and an adequate supportive therapy. Should the cause of the ulcer be linked to a condition of hypotension, and hence to a reduction in the mucosal blood flow, the administration of intravenous fluid therapy is necessary. In the presence of blood loss, and hence of haematemesis or melena, a blood transfusion is possible, preferably first typing the blood group of the patient.
The mainstay of ulcer treatment is to reduce gastric acid secretion. The more commonly used drugs are histamine H2-receptor antagonists and proton-pump inhibitors. H2 receptor antagonists (H2RAs) act via a competitive inhibition of receptors located on parietal cells. Drugs belonging to this pharmacological class are cimetidine, ranitidine, famotidine and nizatidine. Only the first two are registered for use in the dog and ranitidine is 5-10 times more powerful than cimetidine. Apart from inhibiting gastric secretion, these drugs also favour the luminal secretion of bicarbonate and mucous, they increase the mucosal blood flow and induce antroduodenal peristaltic activity. A recent study has however shown that ranitidine (2 mg/kg IV q12h) does not cause any increase in gastric pH compared to the administration of saline solution; in the same study famotidine (0,5 mg/kg IV q12h) has instead shown a greater activity compared to saline solution.4 A rather common opinion is that in the course of ulcers H2RAs are less effective than PPIs, however no specific data on this topic has been published to date.
Proton-pump inhibitors (PPIs) inhibit the H+/K+-ATPase enzyme on the luminal membrane of the parietal cell, thus blocking any acid secretion independently from the neurogenic stimulus (gastrin-histamine-acetylcholine). PPIs are more powerful than H2 antagonists and they have a longer duration of action. In humans, therapeutic efficacy is achieved within 3-5 days with complete reduction of acid secretion. In the dog this time lapse does not seem necessary; omeprazole and pantoprazole are in fact effective in a couple of days. All PPIs available on the market (omeprazole, lansoprazole, esomeprazole, pantoprazole and rabeprazole) are equally effective and safe and in the dog the short-term adverse events are minimal. In humans, in the long term the use of proton-pump inhibitors has been associated with the onset of hypertrophic gastropathy and hyperplasia of parietal cells, as these are overstimulated by a basic pH. It is in addition imaginable that the prolonged absence of an acid pH may favour the flow of toxic or infectious agents into the duodenum, which would otherwise be inhibited by the gastric environment. For this reason, in humans, enteric bacterial overgrowth has been correlated with the administration of pump inhibitors.
Misoprostol, a synthetic prostaglandin analogue, is indicated in the prevention of peptic ulcers caused by the administration of NSAIDs. It is not instead indicated in the treatment of NSAID- associated ulcers, as its capacity of reducing gastric acid secretion is minimal compared to PPIs and H2RAs. The use of these drugs should be avoided in pregnant animals.
Whenever the presence of an ulcer is confirmed, the mucosa must be protected with the administration of sucralfate. This is a sulphate disaccharide basic salt with numerous aluminium hydroxide groups; following oral ingestion it dissociates into sucrose 8-sulphate and aluminium hydroxide, which buffers hydrogen ions. Sucralfate not only acts as a physical barrier against acids and pepsin, but it also stimulates the secretion of endogenous prostaglandins, thus having a cytoprotective activity. Systemic absorption is minimal and well tolerated. Sucralfate is active with an acid and a neutral pH and it can hence be used in association with antisecretory drugs. Sucralfate may however interfere with the absorption of other drugs and hence it is to be administered at least two hours apart from other drugs.
The administration of antibiotics is recommended in the presence of gastric ulcers with an underlying risk of perforation and peritonitis. Although the association between ulcers and the presence of Helicobacter has not been documented, should the ulcer be massively contaminated by this microorganism its eradication is recommended.
Should vomiting be present, this must be controlled with the use of antiemetic drugs; the suggested drugs are NK1 inhibitors (maropitant), metoclopramide or ondansetron.
References
- Lascelles BDX et al: Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002-2003). JAVMA 227: 1112, 2005
- Neiger R, Gaschen F, Jaggy A. Gastric mucosal lesions in dogs with acute intervertebral disc disease: characterization and effects of omeprazole or misoprostol J Vet Intern Med. 2000 Jan-Feb;14(1):33-6
- Liptak JM, Hunt GB, Barrs VR, Foster SF, Tisdall PL, O'Brien CR, Malik R. Gastroduodenal ulceration in cats: eight cases and a review of the literature. J Feline Med Surg. 2002 Mar;4(1):27-42. Review
- Bersenas AME et al: Effects of ranitidine, famotidine, pantoprazole and omeprazole on intragastric pH in dogs. AJVR, 66:425, 2005