Gastritis

Classification

By definition, gastritis is an inflammatory disease of the stom­ach. Many patients with clinical signs of vomiting or upper GI problems are thought to have some type of mucosal injury; however, as infiltration of the gastric mucosa with inflamma­tory cells is either not diagnosed or minimal, it might be there­fore more accurate to use the term gastropathy for these cases.

The Sydney classification system is the most commonly used scheme for the classification of gastritis in human medicine.¹ Unfortunately, a similar system is, as yet, not available in vet­erinary medicine. Gastritis is commonly grouped into acute or chronic, based on the duration of the clinical signs and not on histological parameters. If inflammation is deep, a peptic ulcer may ensue.

4.4.1.1 Acute gastritis

Although many conditions have been found to cause acute gastritis, the most common ones are dietary hypersensitivity and dietary indiscretion.² Acute gastritis does not have any age predilection and can occur in any dog or cat. It is most often a result of ingestion of inappropriate food (i.e., spoiled or toxic food stuff) or foreign material (e.g., rocks, bones, wood, or weeds). Other possible causes are drugs (e.g., NSAIDs, corti­costeroids), chemicals (e.g., fertilizer, herbicide), or heavy met­als (e.g., lead, zinc). Several infectious causes also can cause gastritis, such as viral (e.g., parvovirosis, distemper, infectious hepatitis) or parasitic organisms (e.g., Physaloptera spp., Ollula- nus spp.). In human medicine, the discovery of bacterial gastri­tis due to Helicobacter pylori infection has revolutionized the field of gastroenterology.³ In contrast, in veterinary medicine it is still not clear if Helicobacter spp. is indeed pathogenic, or merely a commensal organism, rarely resulting in vomiting in some patients.⁴ Most often, only a tentative diagnosis can be reached based on signalment, history, clinical signs, and physi­cal examination findings.

Treatment of acute gastritis

Initially, dietary restriction by withholding food for 12­24 hours is all that is needed. Depending on the severity of the clinical signs (i.e., dehydration, continuous vomiting), the ani­mal will also need to be treated with intravenous crystalloids (e.g., lactated Ringer’s solution) but no water is given orally. Because most affected animals are hypokalemic, potassium of­ten needs to be supplemented based on the actual serum po­tassium concentration (see Table 5.3).Water can be introduced 24 hours after vomiting has ceased. If the animal tolerates oral water, a bland commercial or home-cooked diet (e.g., white fish or chicken and rice, cottage cheese), given in small amounts multiple times during the day, is indicated. The animal’s regu­lar food can be slowly reintroduced over a 3- to 5-day period after vomiting has ceased.

In some patients, symptomatic treatment with antiemetics is necessary to stop the vomiting. Because antiemetic therapy is based on the neurotransmitter-receptor interactions, it is im­portant to understand these mechanisms (Figure 4.5). Several neurotransmitters and receptors have been identified in the chemoreceptor trigger zone (CRTZ), including receptors that bind dopamine (D₂-dopaminergic), neurokinin₁ (NK₁), nor­epinephrine (α₂-adrenergic), 5-hydroxytryptamine (5-HT₃- serotonergic), acetylcholine (M₁-cholinergic), histamine (H₁. and H₂-histaminergic), or enkephalins (ENKμ-enkephaliner- gic). In contrast, the only receptors shown to be present in the vomoting center so far are NK₁, 5-hydroxytryptamine₃ and α₂-adrenergic receptors. The α₂-adrenergic receptors in the

Figure 4.5:

Schematic drawing of the emetic pathways and their receptors.

emetic center and in the CRTZ may be antagonized by α₂ antagonists (e.g., yohimbine, atipamezole) or by mixed α₁∕α₂ antagonists (e.g., prochlorperazine, chlorpromazine). In the vestibular apparatus, muscarinic M₁ receptors and acetylcho­line have been demonstrated to be present, and therefore mixed M₁∕M₂ antagonists (e.g., atropine, scopolamine) and pure M₁ antagonists, such as pirenzepine, may inhibit motion sickness in dogs and cats. Many receptors are found in the gastrointestinal tract, but the NK₁, 5-HT3 receptors are likely to play the most important role in the initiation of vomiting. Cytotoxic agents cause the release of 5-HT from enterochro­maffin cells in the gastrointestinal tract, which then activate the 5-HT₃ receptors on afferent vagal fibers. Thus, vomiting induced by the activation of 5-HT₃ receptors can be com­pletely abolished by treating the patient with a 5-HT₃ antago­nist, such as dolasetron, ondansetron, granisetron, or tropiset- ron. Another antagonist of 5-HT3 receptors is metoclopramide, but only at high concentrations. Recently, the administration of substance P has been found to result in emesis by binding to the NK₁ receptor. NK₁-receptor antagonists block central and peripheral vomiting both in dogs and ferrets.⁵

Several antiemetic drugs are directed at the neurotransmitter­receptor system just described (Table 4.1).

are classified as α₂-adrenergic, D₂-dopaminergic, NK₁, H₁-his- taminergic, H₂-histaminergic, M₁-muscarinic-cholinergic, 5-HT3-serotonergic, and 5-HT₄-serotonergic. Some of these drugs have several mechanisms of action as an antiemetic agent. For example, the phenothiazines (e.g., prochlorperazine, chlorpromazine) are antagonists of α₁- and α₂-adrenergic, D₂-dopaminergic, H₁- and H₂-histaminergic, and muscarinic- cholinergic receptors. Phenothiazines are very potent but should be avoided in dehydrated or hypotensive animals with­out first resuscitating the patient with intravenous fluid ad­ministration. Also, these drugs are contraindicated in animals with a known seizure history. Metoclopramide blocks recep­tors in the CRTZ, increases the threshold in the emetic center, and also has an effect on the viscera. Metoclopramide increases the lower esophageal sphincter tone, decreases the pyloric sphincter tone, and increases the frequency and amplitude of gastric and duodenal contractions. All these functions com­bined make metoclopramide useful for controlling vomition that is due to nonspecific gastritis or gastric motility disorders. The prokinetic activity of metoclopramide seems to be lim­ited to the liquid phase of gastric emptying as a study showed no effect on the gastric emptying rate of digestible solids.⁶ Metoclopramide can be given orally, intravenously, or as a constant rate infusion.

Table 4.1: Antiemetic medications. This table shows a comprehensive summary of antiemetic medications with their commonly recommended dosages.

IM = muscular administration; IV = intravenous administration; PO = oral administration; SC = subcutaneous administration

Figure 4.6:

Lymphoplasmacytic gastritis.

Figure 4.7:

Eosinophilic gastritis. This figure shows a histopathological image of the gastric mucosa of a 13-year-old male cat with inappetence and weight loss. Note the abundant presence of eosinophils throughout this section of gastric mucosa. His­tological diagnosis: eosinophilic gastritis. (HE staining, 120x; image courtesy of Dr. Thomas Bilzer, University of Dusseldorf, Germany.)

A new NK₁-receptor antagonist, maropitant, will soon be­come available and licensed for dogs. In various licensing stud­ies, maropitant has been highly effective in abolishing vomit­ing induced through peripheral emetogenic stimuli, such as cisplatin administration or central emetogenic stimuli, such as apomorphine.⁷ Even travel-sickness-induced vomiting was successfully suppressed by the administration of maropitant.

4.3.3.1 Chronic gastritis

The pathogenesis of chronic gastritis in dogs and cats is not fully understood. In some cases, a cause, such as parasitism or a metabolic disorder (e.g., uremia, hepatopathy), can be identi­fied. Several dog breeds are at risk for chronic gastritis, includ­ing the Basenji, the Drentse Patrijshond, and the Norwegian Lundehund.⁸ In most cases, however, chronic gastritis is idio­pathic and an immune-mediated condition is hypothesized to be responsible for the inflammatory infiltrate in the gastric mu­cosa. Experimentally, chronic gastritis in dogs can be induced by mucosal irritants, systemic administration of gastric juice, or prenatal thymectomy;⁹ however, each of these experimental models disturbs oral tolerance.

Clinical signs in dogs and cats with chronic gastritis are charac­terized by chronic persistent or intermittent vomiting of varia­ble frequency and character. Because inflammation impairs gas­tric motility and delays gastric emptying, animals with chronic gastritis may retain food in the stomach for long periods of time. A definitive diagnosis of chronic gastritis requires a mucosal bi­opsy. The gastritis can then be classified based on the histopatho­logical findings as lymphoplasmacytic gastritis, eosinophilic gas­tritis, hypertrophic gastritis, or atrophic gastritis.

4.3.3.1.1 Lymphoplasmacytic gastritis

Most patients with chronic gastritis have some infiltration of the gastric mucosa with lymphocytes and/or plasma cells (Figure 4.6). This form of gastritis is often part of the more diffuse IBD complex and has likely a similar etiopathogenesis. Abnormal or increased food antigens, intestinal bacterial anti­gens, or both together and /or an abnormal or overwhelmed tolerance of the host might play an integral part. There are no typical clinical, laboratory, or diagnostic imaging findings in dogs and cats with gastritis. Since no uniform criteria to eval­uate gastric biopsies exist so far, there must be good commu­nication between the clinician and pathologist to ensure that neither over- nor under-interpretation of the biopsy specimen occurs. Severe lymphoplasmacytic infiltration is often difficult to distinguish from gastric lymphoma, especially when the bi­opsy specimens are small.

b

Figure 4.8:

Electron microscopic views of Helicobacter spp. a: This picture shows a scanning electron microscopic view of Helicobacter felis from an experimentally infected mouse. Please note the typical three periplasmic filaments and the spiral shape. H. felis measures 4-6 μm in length and approximately 0.5 μm in thickness. (Image courtesy of Dr. M. Stoffel, Bern, Switzerland). b: Scanning electron microscopic image of H. bizzozeroniifrom an experimentally infected mouse. While the most common type of H. bizzozeroniilack the periplasmic fibers, some show a filament running along the groove of the spirals. (Image courtesy of Dr. M. Stoffel, Bern, Switzerland.)

4.4.1.2.2 Eosinophilic gastritis

Eosinophilic gastritis is an uncommon disorder of unknown etiology that is characterized by diffuse eosinophilic infiltra­tion of the distal portion of the stomach (Figure 4.7) and is also often associated with eosinophilic infiltration of the small bowel or colon. Gastric infiltration is usually restricted to the mucosa but in some patients may extend into the muscularis and even the serosa. Mucosal involvement causes enlargement of the rugal folds. The diseased mucosa may become ulcerated, which leads to bleeding or leakage of plasma proteins into the gastric lumen. Peripheral eosinophilia is a common finding, but its severity can vary markedly. Some pets also have a his­tory of either urticaria or vomiting that may be associated with the ingestion of a specific diet.

4.4.1.2.3 Hypertrophic gastritis

Chronic hypertrophic gastritis is a rare disorder that appears either as diffuse, generalized mucosal hypertrophy or, more frequently, as a localized hypertrophy of the antral mucosa that may cause intermittent or chronic pyloric obstruction. Causa­tive factors that may lead to gastric mucosal hypertrophy in­clude chronic inflammation, foreign bodies, or long-term use of proton pump inhibitors. Hypergastrinemia can also have a trophic effect on the mucosa, as seen in chronic renal disease, chronic gastric distension, gastrin-secreting tumors (gastri­noma), and idiopathic hypertrophy of antral G cells. Boxers and Basenjis have a predilection for the diffuse form of hyper­trophic gastritis. In contrast, the localized form has a predilec­tion for miniature and toy dog breeds (e.g., Lhasa Apso, Mal­tese, Pekingese, and Shih Tzu). The hypertrophic mucosa is inflamed and causes delayed emptying, chronic vomiting, ano­rexia, and lethargy.

4.4.1.2.4 Atrophic gastritis

Atrophic gastritis is a rare disorder in which the gastric mucosa atrophies and loses its secretory functions. Atrophic gastritis has been reported in the Norwegian Lundehund. The cause is unknown, but the condition occurs mainly in older dogs and may be mediated through the immune system. Atrophic gas­tritis may also be a sequel to chronic reflux gastritis in dogs. The predominant complaint is chronic intermittent vomiting. Mucosal degeneration is thought to result in achlorhydria, which may predispose to bacterial overgrowth in the proximal small intestine. This can lead to malabsorption, chronic di­arrhea, and /or loss of body weight and condition.

4.4.1.2.5 Helicobacter infection

Helicobacter spp. are gram-negative, microaerophilic, curved to spiral-shaped, motile bacteria. Their main location is the stom­ach, however, they can also be found in the intestine and the liver.^11-13 To date, over 30 organisms with typical characteris­tics of Helicobacter spp. have been described, with new species being published constantly. Most gastric Helicobacter-like or­ganisms (GHLO) found in dogs and cats are large spiral organ­isms (0.5 ? 5-10 μm) that cannot be distinguished by light microscopy. To date H. felis, H. bizzozeronii, H. salomonis, Flex- ispira rappini, H. bilis, and “H. heilmannii” have all been re­ported to have been present in the stomach of dogs,^14-16 while H. felis, H. pametensis, H. pylori, H. bizzozeronii, H. salomonis, and “H. heilmannii” have been reported to be present in the stomach of cats (Figures 4.8 a and b). ^13,15,17,18 Mixed infections with two or more Helicobacter spp. appear to be common in dogs and cats.^15,16

Several studies showed a high prevalence of GHLO in cats and dogs (Table 4.2) with up to 100% infection rate amongst labo­ratory animals, 50-100% amongst healthy pets, and 41-100% among vomiting pets. Housing conditions and age appear to play an important role with pets living in shelters or colonies having a higher prevalence, while young animals may be less often colonized than adults, but this is controversial.^14,17

The mode of transmission of Helicobacter spp. is still unclear. Fecal-oral transmission is hypothesized by some, since H. pylori can be cultured from cat feces. Oral-oral transmission is hy­pothesized by others, because H. pylori can be found in the saliva of infected humans. Also, the spouses of infected indi­viduals also were shown to have a higher prevalence.

In human patients, there is extensive evidence implicating H. pylori in the pathogenesis of chronic superficial gastritis. Eradication of H. pylori by use of antimicrobial therapy may cure gastritis and the titer of anti-H. pylori antibodies decreases with time. A plethora of reports have shown many putative mechanisms by which H.pylori alters gastric physiology;¹⁹ e.g., through the induction of gastric inflammation (by secretion of IL-8, platelet activating factor, urease, etc.), through the dis­ruption of the gastric mucosal barrier (by disrupting phos­pholipases, secreting vacuolating cytotoxins, inducing apopto­sis, etc.), or through altering the gastric-secretory axis (by decreasing somatostatin release, inducing hypergastrinemia, diminishing the responsiveness of parietal cells, etc.). Infection with Helicobacter spp. also predisposes humans to the develop­ment of gastric cancer.

In pets with naturally acquired Helicobacter colonization, how­ever, the pathogenic role of this organism is still highly de­bated. Obvious clinical signs of infection are absent in the majority of infected cats and dogs, and few studies have inves­tigated the cellular and immunological consequences of infec­tion. In dogs, a mild gastritis with infiltration of the gastric mucosa involving lymphocytes and plasma cells was most commonly found,^4,14 but no correlation between the his­topathological changes and the occurrence of GHLOs as well as a clear pathologic role due to enlarged canaliculi and py- knotic parietal cells has been reported. In some cats, normal gastric mucosa was found in several GHLO-colonized ani­mals, while others reported mild chronic gastritis irrespective of GHLO colonization.^17,20,21 In dogs with naturally acquired Helicobacter spp. infection, a variety of secretory function tests, such as unstimulated gastric pH, fasting, post-prandial and bombesin-stimulated plasma gastrin concentrations as well as

Table 4.2: Prevalence of gastric Helicobacter-like organisms in cats and dogs

pentagastrin-stimulated maximal acid output and titratable acidity, were similar when compared to a SPF, Helicobacter-free control group.²²

There are only a few studies on experimental infection of dogs and cats with Helicobacter spp. While experimentally infected gnotobiotic dogs showed chronic gastritis and an increase in fasting gastric pH in some, there was no relationship between H.felis infection and gastric inflammation in SPF dogs after six months in others.²³ The gastric secretory axis, assessed by fast­ing and meal-stimulated plasma gastrin concentration, mu­cosal gastrin and somatostatin immunoreactivity, fasting gastric pH and pentagastrin-stimulated gastric acid secretion func­tioned similarly in both the infected and uninfected SPF dogs.²³ Conventional puppies infected with H. pylori showed some clinical signs shortly after inoculation and the gastric mucosa initially demonstrated acute gastritis changing to chronic gastritis with time. In another investigation, SPF, Heli­cobacter-free cats were studied before and for one year after inoculation with H.felis.²⁴ Uninfected cats were used as con­trols. Lymphoid follicular hyperplasia, atrophy, and fibrosis were observed primarily in the pylorus of the infected cats.

Seroconversion of experimentally infected dogs and cats was observed in all of these studies. H.felis- and H. pylori-infected gnotobiotic dogs showed a fairly rapid and uniform serocon­version 3 weeks after infection, while H. felis-infected SPF dogs showed a more gradual and variable seroconversion over a six-month period after infection.²³

Figure 4.9:

Rapid urease test. This figure shows examples of a positive (red) and negative (yellow) rapid urease test that is used for the diagnosis of Helicobacter spp. Rapid urease tests are based on a color change, which is caused by a change in pH that is due to the production of ammonium by urease-producing organisms in a biopsy sample.

Diagnostic tests for GHLO are either invasive (i.e., rapid ure­ase tests, histopathology, touch cytology, culture, polymerase chain reaction of biopsies, or electron microscopy) requiring a biopsy sample or they can also be non-invasive (i.e., urea breath and blood tests, serology, and fecal PCR testing).

Invasive tests for Helicobacter spp.

The rapid urease test (also called CLO test for Campylobacter- like organism test) is based on the production of urease by all gastric Helicobacter spp. A tissue sample is incubated in a broth containing urea and phenol red as a pH indicator. As the ure­ase breaks down urea into ammonia, the pH rises and a color change occurs (Figure 4.9). The results can often be obtained within one to three hours, but may take up to 24 hours.

Histopathology relies on the visualization of Helicobacter or­ganisms in gastric biopsy samples. Special staining such as Warthin-Starry silver, Giemsa, or toluidine blue stain will en­hance the visibility of GHLOs (Figure 4.10). Due to the patchy distribution of the Helicobacter organisms, several biop­sies from the antrum and corpus should be evaluated. Touch cytology stained with Gram’s or Diff Quick stain is a simple, rapid, and sensitive diagnostic test; however, the extent of a concurrent gastritis cannot be evaluated based on cytological evaluation alone (Figure 4.11).

Culture for GHLOs is cumbersome and the least sensitive method for diagnosing these organisms; however, a positive culture is highly specific. Gastric Helicobacter spp. are difficult to isolate in vitro. Polymerase chain reaction (PCR) of DNA extracted from a biopsy specimen permits definitive identifi­cation of the Helicobacter strain present. Electron microscopy can be used to differentiate Helicobacter spp. on the basis of typical morphological criteria. Five cultured canine Helico­bacter spp. could be differentiated based on transmission and scanning electron microscopy (Figures 4.8a and 4.8b).²⁵ Over­all, the rapid urease test, histopathology with special stains, and touch cytology are associated with a high accuracy for diag­nosing a Helicobacter spp. colonization in dogs and cats (Ta­ble 4.3).

Non-invasive tests

The urea breath and blood tests use labeled urea (mostly la­beled with non-radioactive ¹³C). Ingested urea is metabolized in the stomach by bacterial urease to ammonia and the re­leased carbon atoms are absorbed into the systemic circulation

Figure 4.10:

Helicobacter spp. in a Warthin-Starry silver stain of a gastric biopsy. This picture shows a gastric biopsy stained with Warthin-Starry silver stain. This biopsy was taken from a naturally infected cat. Multiple large spiral-shaped organisms can be seen in a gastric pit. The spiral morphology is clearly visible under higher magnifi­cation.

Figure 4.11:

This figure shows multiple Helicobacter spp. organisms in a Gram-stained gastric touch cytology. The proteinaceous background is due to gastric mucous. The enlargements clearly delineate the spiral structure of these bacteria.

and finally exhaled. The exhaled air is collected and the ratio of ¹²CO₂ to ¹³CO₂ is measured.¹⁷-²⁶ Since the urea breath test demonstrates the actual colonization with Helicobacter spp. or­ganisms, it is the preferred non-invasive method to document a successful eradication in both humans and animals.

Serology by ELISA or Western blotting is used extensively in human epidemiological studies and IgG or IgA can be quanti­fied in both serum and gastric fluid. Dogs and cats harbor several Helicobacter spp. but not H. pylori, and thus serum sam­ples of pets cannot be analyzed by commercially available se­rological tests. Amplification of Helicobacter DNA from canine fecal samples has recently been described.¹² With this tech­nique, gastric as well as intestinal Helicobacter DNA could be identified in dogs. Also, the treatment success could be moni­tored non-invasively by this method.

4.3.3.1.2 Parasitic gastritis

Physaloptera spp. are nematodes with an indirect live cycle re­quiring an intermediate host to develop into the infective stage. Suitable intermediate hosts (e.g., cockroaches, field crickets, canal crickets, or flour beetles) ingest the eggs, which have been shed by the definite hosts (e.g., cats, dogs). The first- stage larvae hatch in the intestine of intermediate hosts, mi­grate to the outer layer of the intestine, encyst and molt to second-, and finally, infective third-stage larvae. After the in­termediate hosts are ingested by either paratenic (e.g. frogs, snakes, or mice) or definite hosts, the adults develop and attach to the gastric or duodenal mucosa.²⁷

Table 4.3: Accuracy of various tests for the diagnosis of gastric Helicobacter spp. in dogs and cats

Figure 4.12:

Physaloptera. This figure shows an endoscopic picture of the stomach of a dog with a single Physaloptera specimen. (Image courtesy of Dr. Mike Willard, Texas, USA.)

It is unclear if Physaloptera are always pathogenic and how many stomach worms are required for clinical signs to ensue. Besides histological evidence of gastritis, these parasites can also result in delayed gastric emptying, possibly due to altered electromechanical activity.²⁸ Other clinical signs are chronic or intermittent vomiting, diarrhea, regurgitation, weight loss, melena, and lethargy.²⁷ Diagnosis can be difficult as fecal flota­tion is frequently falsely negative. Speculated reasons for this include that the adults only produce low numbers of eggs, the fact that a single-sex infection produces no eggs at all, or the fact that the specific gravity of the fecal flotation medium is too close to that of the eggs and thus the eggs do not float well.²⁸ Identification of worms in the vomit or endoscopic visualization of stomach worms (1-6 cm in length, stout, cream-colored to white, straight or coiled; Figure 4.12) ap­pears to be most successful in the diagnosis of this parasite.

Ollulanus tricuspis is a common gastric nematode of cats with a prevalence of up to 20% that also occurs rarely in dogs.²⁹ After oral ingestion of third-stage larvae, the complete life cy­cle occurs within the stomach of the host, where the parasite attaches to the gastric mucosa. Infective larvae are vomited up and survive in the environment for up to 15 days, where they can infect another animal. Common clinical signs are inap­petence, intermittent vomiting, and weight loss. Gastric ero­sions, increased mucous production, mucosal hyperplasia, and infiltration with inflammatory cells can be seen histopatho- logically. Diagnosis is best achieved by examining vomited material (possibly induced by the administration of xylazine or metedomidine) or gastric lavage solution. Rarely, parasites can be found in gastric biopsy samples by histopathology. Fecal flotation is rarely diagnostic.

4.3.3.1.3 Treatment of chronic gastritis

If possible, the underlying cause of the gastric inflammation should be managed first (e.g., removal of foreign body, cessa­tion of drug administration). Diagnosis of infestation with a stomach worm (i.e., Physaloptera spp. in dogs and Ollulanus tricuspis in cats) maybe challenging and routine therapy with a broad-spectrum anthelminthic agent that is effective in eradi­cating stomach worms (i.e., in dogs: pyrantel pamoate at 15 mg/kg PO repeated in 2-3 weeks; in cats: fenbendazole at 50 mg/kg PO q 24 h for 3 days) is prudent before recom­mending more expensive diagnostic tests.²⁷ However, most cases of chronic gastritis are idiopathic and treatment of the underlying cause is thus rarely possible. In cases of idiopathic chronic gastritis, rational treatment options include dietary management, immunosuppressive therapy, inhibition or neu­tralization of gastric acid secretion (see 4.4.1.3; Table 4.1; 4.4.1.1).

Dietary management is based on the concept that antigens in the food may be responsible for an exaggerated immune re­sponse of the body. Feeding single novel protein and carbohy­drate sources, to which the animal has not yet been exposed to, is the cornerstone of this treatment concept. Although commercial “hypoallergenic” diets are very useful, on rare oc­casions it is necessary to feed a home-cooked novel protein source (e.g., kangaroo or horse). In most cases, some response should be seen after a 2-week strict dietary trial.

Immunosuppressive drug therapy is indicated in those dogs and cats that do not respond to dietary management alone (e.g., those with lymphoplasmacytic or eosinophilic gastritis). Corticosteroids, in addition to their immunosuppressive and anti-inflammatory properties, have regenerative effects on the gastric parietal cells. The ulcerogenic property of corticoster­oids is of concern only in dogs that are exposed to a marked synergistic ulcerogenic effect (e.g., NSAID administration or hypotension). Initially, prednisone is given at a dose of 1-2 mg/kg PO q 12 h for 5 to 7 days. This dose is then gradually tapered in decremental doses of 50% over a period of several months. Other immunosuppressive drugs, such as azathioprine and cyclophosphamide, have only been used spo­radically in dogs with chronic gastritis and should not be used for this purpose in cats.

4.4.1.3 Gastric ulceration

By definition, an ulcer is an area of damaged gastric mucosa to the level of the lamina muscularis mucosae or deeper; more superficial damage is called erosion. Erosions or ulcers occur when the »aggressive forces« (i.e., acid, pepsin, and /or trauma) are more potent than the Oprotective forces« (i.e., mucosal microcirculation, epithelial turnover, gastric mucus, and prosta­glandins). Epithelial cells have a rapid turnover and need an

abundant blood circulation to ensure the transport of nutri­ents and oxygen and the removal of back-diffused hydrogen ions. The entire gastric surface is replaced every 2 to 3 days. Epithelial cells are produced in the crypts and then migrate towards the gastric lumen, where they are shed. Gastric mucus neck cells produce a viscous gel of glycoprotein (5%) and wa­ter (95%), which adheres to the surface of the mucosa. This mucus protects against mechanical abrasion and acts as a bar­rier against digestive enzymes. In addition, bicarbonate is se­creted actively into this layer. A pH gradient forms from the lumen to the epithelium, which neutralizes gastric acid. Fi­nally, prostaglandins, which are derived from arachidonic acid via the enzyme cyclooxygenase (COX), have a protective role for the gut mucosa. They increase gastric mucus and bicar­bonate secretion, maintain mucosal blood flow by causing vasodilation, and inhibit acid secretion. They may possibly stimulate mucosal cell turnover and migration by acting as an intercellular messenger. Prostaglandin-inhibiting drugs, such as NSAIDs, can counteract all these protective mechanisms and lead to the formation of gastric ulcers.

Peptic ulcers of the gastric and duodenal mucosa are not com­monly seen in dogs or cats, but several underlying mechanisms can lead to the formation of this type of ulcer (Table 4.4). NSAIDs (e.g., aspirin, flunixin, ibuprofen, indomethacin, ke­toprofen, meloxicam, naproxen, phenylbutazone, or piroxi­cam) inhibit the COX-1 enzyme, thereby limiting prostaglan­din production. Even though these drugs have been implicated as a common cause of peptic ulcers in dogs, only a few reports of NSAID-induced peptic ulcers in pets exist.^30,31 Eicosanoids produced by COX-2 are mainly responsible for the inflamma­tory and pain properties of the gastric mucosa, while those produced by COX-1 are mainly responsible for its protective mechanisms. Unspecific COX inhibition increases the ulcero­genic risk dramatically. However, newer NSAIDs are COX-2 specific (e.g., carprofen) and have a lower, although not abol­ished, ulcerogenic effect.³²

Corticosteroids also decrease the production of protective ei­cosanoids. Nevertheless, they are only responsible for peptic ulcers in dogs with concurrent problems, such as severe hypo­tension or if they are also given NSAIDs.³³ Mast cell tumors have long been thought to be responsible for peptic ulcers because of their histamine-containing granules, which can cause hyperacidity in the stomach.³⁴ However, no series of dogs or cats with mast cell tumor and peptic ulceration or even gastritis has been published as of yet. Most dogs with acute intervertebral disk diseases have endoscopic signs of gas­tric erosions, and surgical interventions with or without cor­ticosteroid administration greatly increases the risk for peptic ulcers.³⁵ The gastrointestinal tract is the shock organ of dogs and therefore, hypovolemia, shock, and sepsis are common, but frequently overlooked, causes of gastric ulceration. Thus all critically ill patients should be considered at risk for develop­ing gastric ulcers.³⁶ Gastrinoma (see 9.4.3) arising from the

Figure 4.13:

Large ulcer at the incisura angularis. An 8-year-old male Basset hound presented with a 7-week history of hematemesis. During gastroscopy a peptic ulcer with a hard rim could be seen. Histopathology of the biopsies revealed the cause of this ulcer to be a gastric adenocarcinoma.

Table 4.4: Causes of peptic ulcers in dogs and cats

Drugs

■ NSAIDs

■ Corticosteroids (only when concurrent risk factors are present; e. g., NSAID administration)

Infiltrative Disease

■ Gastric neoplasia

■ Pythiosis in endemic areas

■ Inflammatory bowel disease

Metabolic Disease

■ Hepatopathy

■ Renal failure (common in older cats)

Gastric hyperacidity

■ Gastrinoma

■ Mast cell tumor (rarely causes gastric ulcers)

■ APUDoma

Other Causes

■ Chemical toxins

■ Disseminated intravascular coagulation

■ Foreign objects (might worsen pre-existing gastritis or ulceration)

■ Hypovolemia

■ Pancreatitis

■ Septic shock

■ Stress?

APUDoma = amine precursor uptake and decarboxylation tumors

pancreas can secrete excessive amounts of gastrin and the re­sultant hyperacidity may also cause peptic ulceration.

Large ulcers in the pyloric antral region, often near the in­cisura, are commonly seen in dogs with gastric tumors (Fig­ure 4.13). In a study on cats, 14 of 33 peptic ulcers were due to gastric neoplasia, mostly gastrointestinal lymphoma or gas­tric adenocarcinoma.³¹

4

Clinical signs

Clinical signs of peptic ulceration are poorly defined. Chronic vomiting is probably the most frequent sign, with or without hematemesis. Unlike humans, dogs do not secrete acid con­tinuously and blood in the vomitus does, therefore, not always appear digested. Melena and pale mucous membranes may also be observed if bleeding is severe. Inappetence and ano­rexia are also common. Because of the important pathogenic role of medications, a careful history should include specific questions about any medications the owner may be adminis­tering to the animal.

Any changes in routine blood work are nonspecific. However, routine blood work is used to rule out other causes of vomit­ing. Chronic blood loss may result in anemia that can some­times be non-regenerative and appear typical for iron defi­ciency (i.e., hypochromic, microcytic). Blood biochemistry results may show some electrolyte abnormalities as a conse­quence of profound vomiting.

Minor blood loss from gastric ulceration may not lead to gross melena and a fecal occult blood test may be required to iden­tify such cases. However, some fecal occult blood tests can be affected by red meat in the diet. Fecal occult blood test kits are based on one of two different test principles. Guaiac-based tests contain guaiaconic acid, which when oxidized by hemo­globin leads to the development of a blue quinone. O-toluid- ine-based tests contain tetramethylbenzidine, which when oxidized by hemoglobin also leads to the generation of a blue compound. Both kit types can give positive test results when exposed to red meat or peroxidase-rich foods, such as turnip and cauliflower, present in the diet. However, in one study an o-toluidine-based test was associated with far fewer false pos­itive results due to diet than a guaiac-based test. In another study, the same o-toluidine-based test was also slightly more sensitive than a guaiac-based test at 12 hours after oral admin­istration of hemoglobin. But ideally patients should be fed a meat-free diet for at least 3 days prior to testing.³⁷

Although gastroscopy is by far the best tool to diagnose gastric ulcers, this is often not necessary if the history (i.e., administra­tion of NSAIDs, hematemesis) and clinical findings are in­dicative of gastric ulcers. Diagnosis can also be made based on contrast radiographic studies or exploratory laparotomy. The latter has the disadvantage that the gastric mucosa is not easily evaluated from the exterior of the stomach.

Treatment

The goals of therapy of gastric ulceration are to eliminate clinical signs, complications, and relapses (Table 4.5). To that end, it is vital to avoid ulcerogenic drugs. If the peptic ulcer might be due to decreased mucosal blood flow, the animal should be given sufficient amounts of intravenous fluids. Ant­acids act by neutralizing gastric acid. Calcium carbonate (CaCO₃), sodium bicarbonate (NaHCO₃), magnesium hy­droxide (Mg[OH]₂), or aluminum hydroxide (Al[OH]₃) all contain an H⁺-binding group. The neutralizing reaction with gastric acid produces water and a neutral salt. Antacids are also of benefit in that they bind to bile acids, decrease pepsin activ­ity in the stomach, and stimulate the secretion of endogenous prostaglandins. However, the requirement of frequent dosing and poor palatability make antacids an inconvenient choice for animals.

The cornerstone of peptic ulcer therapy is the reduction of gastric acid secretion as Schwartz' dictum from 1910 “no acid, no ulcer” remains valid today. There are a variety of drugs available and the two most commonly prescribed drug classes in veterinary medicine are histamine₂-receptor antagonists and proton pump inhibitors. H₂-receptor antagonists (H₂-RA) block the secretion of gastric acid by blocking histamine H₂ receptors located on the surface of acid-producing parietal cells within the gastric glands (Figure 4.14). Cimetidine and ranitidine are used equally frequently in veterinary medicine. While ranitidine is 5 to 12 times more potent than cimetidine and has a longer half-life allowing for a decreased frequency of administration, a recent study indicated that ranitidine at the

Table 4.5: Therapeutic agents used for gastric diseases

PO = oral administration; IV = intravenous administration

regular dose (2 mg/kg IV q 12 h) was not different from saline administration in increasing the intragastric pH. In compari­son, famotidine (0.5 mg/kg IV q 2 h) was significantly more effective than saline.³⁸ Another H₂-RA is nizatidine which, together with ranitidine, also possesses prokinetic activity in the stomach. In addition to their blockade of the histamine H₂ receptors of parietal cells, the H₂-RA increase the luminal secretion of bicarbonate and mucus as well as raising mucosal blood flow. These effects may be related to a stimulation of prostaglandin synthesis. In addition, it has been suggested that cimetidine increases in vitro cell-mediated immunity by block­ing the H₂ receptors on T lymphocytes. Cimetidine decreases hepatic perfusion and is recognized as an inhibitor of hepatic P-450 and P-488 enzymes.³⁹ Drugs metabolized by these en­zyme systems may be cleared more slowly and may reach a higher plasma concentration (e.g., cyclosporin) when admin­istered together with cimetidine. Other histamine H₂-receptor antagonists do not show this interaction and may be preferred in animals receiving multiple drugs.

Omeprazole, a substituted benzimidazole, belongs to the class of proton pump inhibitor drugs (PPIs). By blocking the H⁺/ K⁺-APTase enzyme at the luminal membrane of the pa­rietal cell (Figure 4.14), acid secretion is inhibited regardless of the secretagogue (i.e., histamine, gastrin, or acetylcholine). Compared with cimetidine, omeprazole is about 20 times more potent and has a longer duration of action because it accumulates in a pH-dependent manner. Newer PPIs include lansoprazole or pantoprazole, but experience with these newer PPIs in veterinary patients is limited.³⁸

Figure 4.14:

Physiological mechanism of gastric acid secretion. The parietal cell contains recep­tors for gastrin (CCKB), acetylcholine (M₃), and histamine (H₂). In addition, gastrin and acetylcholine can also interact with their receptors on enterochromaffin-like cells (ECL-cells) and release histamine.

Sucralfate is a gastromucosal protectant. It is a basic salt of a sulfate disaccharide with many aluminum hydroxide groups. Sucralfate dissociates after oral ingestion to sucrose octasulfate and aluminum hydroxide, which buffers H⁺. Sucrose octasul­fate reacts in the stomach with hydrochloric acid to form a paste-like complex that has greater affinity for damaged tissue than the normal mucosa. This adhering complex prevents fur­ther damage of the gastric mucosa by pepsin, acid, or bile. Sucralfate may also have some cytoprotective effects, possibly by stimulation of prostaglandin synthesis. Systemic absorption of sucralfate is minimal, and it is extremely well tolerated. Since sucralfate is effective at an acidic to almost a neutral pH, antisecretory drugs can be used concurrently. Other, orally administered drugs, however, should be given 2 hours apart as sucralfate can affect their absorption.³⁹

Finally, misoprostol is a synthetic analog of prostaglandin E₁ (PGE₁). Although orally administered, it has to be absorbed into the circulation to be effective. Its effect is the same as those of endogenous prostaglandins. Although the prophylac­tic effect of misoprostol in dogs receiving corticosteroids or undergoing spinal surgery is debatable, this drug appears to be of little use in dogs that already have a peptic ulcer. Misopros­tol can cause abortion and should be avoided in pregnant animals. Also, women in child-bearing age should use gloves when administering misoprostol to their pet.⁴⁰

Other means of decreasing gastric acid concentration have been developed, but are not yet available for routine use (e.g., gastrin-receptor antagonists, gastrin-releasing peptide receptor antagonists). A class of drugs which might be of future interest is the class of potassium-competitive acid blockers (P-CABs). These drugs block the action of the H⁺-K⁺-ATPase by com­peting with K⁺.⁴¹ Soraprazan and raveprazan are currently un­der investigation, but no information in dogs or cats is yet available.

4.3.4