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| | ==Pathophysiology== | | ==Pathophysiology== |
| − | The cause of EGUS is multifactorial (Jonssen 2006) Differences in the aetiology of ulcers in different locations of the stomach. (Luthersson et al 2009)
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| − | Hydrochloric, lactic acid and volatile fatty acids
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| − | Hydrochloric acid (HCl) and a sustained gastric pH<4.0 are probably the most important cause of gastric ulcers. Recently, other acids (volatile fatty acids [VFAs], lactic acid and bile acids) have been shown to act synergistically with HCl to cause changes in nonglandular mucosal bioelectric properties, which are the first indication of acid injury. VFAs and lactic acid are byproducts of bacterial fermentation of sugars in concentrate diets.
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| − | Ulcers are most prevalent in the nonglandular mucosa because this area lacks resistance to acid injury. HCl induces injury in this region by damaging the outer cell barrier, followed later by diffusion into the squamous cells of the stratum spinosum resulting in inhibition of cellular sodium transport, cell swelling and eventual ulceration (Argenzio and Eismann 1987; Nadeau et al. 2003a,b).
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| − | Whereas, VFAs (acetic, propionic, butyric and valeric acids), because of their lipid solubility, induce damage by rapidly diffusing into the squamous mucosal cells of the stratum spinosum layer and immediately inhibit sodium transport which results in cell swelling and ulceration. Squamous mucosal cells are susceptible to HCl and VFA injury in pH, dose and time dependent manner (Andrews et al. 2006).
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| − | Lactic acid has a similar chemical structure to VFAs. But lactic acid (pH 1.5 and 40 mmol/l) exposed to the nonglandular mucosa increased tissue permeability, as indicated by increased transepithelial conductance (Andrews et al. 2008).
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| − | Furthermore, HCl and VFAs have been shown to cause disruption in bioelectric properties and barrier function of the NG mucosa of horses in an in vitro Ussing chamber system (Widenhouse et al. 2002; Nadeau et al. 2003a,b; Andrews et al. 2006). The proposed mechanism by which VFAs cause acid injury is as follows: at low pH (≤4.0), VFAs remain undisassociated (nonionic) and are highly lipid soluble. By penetrating the NG mucosal cells and acidifying cellular contents they disrupt cellular sodium transport, leading to cell swelling, cell death and ulceration (Argenzio and Eisemann 1996; Nadeau
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| − | et al. 2003a,b).
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| − | Lactic acid (LA), commonly found in the stomach of horses after eating, has a chemical structure and low pKa (3.8) similar to acetic acid, but LA is stronger. In previous studies, LA concentrations in the stomach were high (Wolter and Chaabouni 1979; Al Jassim 2006), compared to other regions of the digestive tract. Stomach LA is probably produced by resident acid-tolerant bacteria, such as Lactobacillus and Streptococcus spp., which have been found in abundance in the equine stomach (Al Jassim
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| − | et al. 2005; Varloud et al. 2007). Also, a recent study showed a3-fold increase in post prandial L-/D-lactate concentration (Varloud et al. 2007). Therefore, LA exposure to NG mucosa of horses in an acidic environment would be expected to cause similar acid injury to that caused by other VFAs.
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| − | Lactic acid, produced in the stomach of horses fed a high-grain diet, does not significantly alter sodium transport or permeability in equine NG mucosal tissue. Lactic acid may require a longer exposure time or may need the presence of other VFAs in HCl to cause gastric ulcers.(Andrews 2008)
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| − | Helicobacter spp. and other bacteria
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| − | Recently a new enterohepatic Helicobacter species, Helicobacter equorum, was isolated from faecal samples of 2 clinically healthy horses (Fox 2002). Also, Helicobacter equorum DNA was demonstrated in the faeces of 2/7 (28.6%) foals aged <1 month and 40/59 (67.8%) foals aged 1–6 months (Moyaert et al. 2009). Furthermore, Helicobacterlike DNA was detected in the stomachs of 10 Thoroughbred horses in Venezuela (Contreras et al. 2007). Furthermore, 10/11 of the horses infected with Helicobacter had either gastric ulcers or gastritis or both pathologies. However, 39% of the horses in that study did not have gastric lesions, so multiple causes are likely.
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| − | Bacteria, including E. coli, were cultured from the stomach of horses (Al Jassim et al. 2006). Bacterial colonisation of gastric ulcers in the stomach of horses may delay ulcer healing and in this case treatment with antibiotics may be indicated.(Nadeau 2009)
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| − | The pathophysiology of gastric ulcer formation involves an imbalance between aggressive (HCl, pepsin) and defensive factors. In the nonglandular region, intercellular tight junctions and intracellular buffering systems act as barriers, while the glandular region is protected by a 200 μmol/l thick mucus layer into which bicarbonate ions are secreted (Murray 1992b). Adequate mucosal blood flow and mucus secretion is maintained by appropriate prostaglandin release (Morrissey et al. 2008). Epidermal growth factor has also been found to contribute to the healthy maintenance and repair of equine gastric squamous epithelium (Jeffrey et al. 2001). Any disruption in the chain of these events may act to promote damage and ulceration.
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| − | (Martineau 2009)
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| − | Major intrinsic factors promoting ulcer formation include HCl, bile acids, pepsin, HCl is predominant. Intrinsic factors protect against ulcers: mucus-bicarbonate layer, maintenance of adequate mucosal blood flow, mucosal PG E2 and EGF production, gastrodudodenal motility. Serum Abs vs H.pylori are common in post-suckling foals and their dams (32) Other extrinsic ulcerogenic factors that may be important in horses include: NSAIDs, stress, changes in diet, GI disorders, esp those resulting in delayed gastric emptying (1).
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| − | Pathophysiology of squamous mucosal ulceration appears similar to gastrooesophageal relfuc disease (GERD) in human beings and ulceration of non-glandular mucosa in pigs. XS acid exposure is predmoninant mechanism but details unclear (34). HCl is secreted by parietal cells in gastric glands via H+K+-ATPase) pump on luminal side. Horses secrete acid continuously and measured pH from equine gastric contents is variable from less than 2 to greater than 6, depending on dietary state (fed vs fasted) (35,36). A protocol of repeated 24h periods of fasting and feeding(37) results in prolonged gastric acidity (pH <2) and because concurrent ranitdine reduces lesion severity, it supports the role of acid exposure in pathogenesis.
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| − | Predominant stimuli to HCl secretion are gastrin, histamine and Ach via vagus nerve (1). Gastrin is released by G cells within gastric mucosa, histamine by mast cells and ECL cells in gastric gland. Histamine binds to type 2 receptors on parietal cell membrane causing an increase in cAMP resulting in phosphorylation of enzymes that activate proton pump. Gastrin and Ach can act via calcium-mediated (Sanchez)
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| − | gastric acidity of a horse or foal is very high between periods of eating or nursing. Ulcers in the squamous mucosa result from increased exposure to hydrochloric acid, which can be secondary to prolonged periods of not eating or nursing, intensive exercise, or delayed gastric emptying. (Merck)
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| − | Am J Vet Res. 2010 May;71(5):592-6.
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| − | Expression of cyclooxygenase isoforms in ulcerated tissues of the nonglandular portion of the stomach in horses.
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| − | Rodrigues NL, Doré M, Doucet MY.
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| − | Increased expression of COX-2 in gastric ulcers of the squamous portion of the stomach in horses suggested a role for this enzyme in gastric ulcer healing.
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| − | Anatomy
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| − | Equine gastric ulcers occur in the squamous portion of the stomach in 75-80% of cases.
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| − | The squamous epithelium, which covers approximately one third of the stomach wall (Fig 21) and the oesophagus, is a relatively simple structure that consists of a tightly bound cornified superficial layer of cells that serves as a protective barrier. The squamous portion of the stomach lining has no absorptive or secretory function, leaving it more vulnerable to peptic injury.
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| − | The more complex glandular portion of the stomach contains mucus-secreting cells and gastric glands
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| − | (Fig 221, all of which respond to various stimuli and provide secretions that have a specific function. The gastric glands contain six predominant cell types (Table 3).
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| − | Physiology
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| − | The parietal cell secretes H+ via H+/K+ ATPase proton pump (Fig 19) located on its apical membrane. The K+ used by this proton pump and the C1- that combines with the H+ are secreted through the same apical membrane via ion-specific channels. The resultant HCl moves up through the gastric gland and into the gastric lumen, lowering the pH of the gastric contents. Acid and the enzyme pepsin exert peptic influences on digestion. The stomach has a number of protective mechanisms that prevent acid and peptic activity from causing inappropriate mucosal destruction.
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| − | Glandular mucosal defence mechanisms
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| − | Two important substances involved in gastric glandular mucosal protection are epidermal growth factors (EGFs) and prostaglandin E2 (PGE2). Epidermal growth factors are found in salivary gland secretions and promote DNA synthesis and proliferation of gastric mucosal cells. They also play a role in prostaglandin synthesis. The PGEz promotes numerous protective functions within the gastric mucosa which include:
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| − | Suppression of HC1 secretion
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| − | Mucus secretion
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| − | Bicarbonate secretion
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| − | Epithelial restitution mechanisms (maintain tight junctions)
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| − | Adequate mucosal blood supply.
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| − | Mucus, secreted by specialised mucous neck cells, is a viscous, hydrophobic glycoproteinaceous gel that adheres to the mucosa and resists acid and pepsin contact. The gel also acts as a lubricant that minimises mechanical damage by gastric contents.
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| − | Bicarbonate secretion by gastric mucosal cells is triggered by a response to luminal acid concentrations, mechanical irritation, and by release of endogenous prostaglandins. Bicarbonate trapped in the mucous barrier adhering to the stomach wall forms a pH gradient that allows a physiological pH at the mucosal surface and a pH similar to that of stomach acid at the luminal surface.
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| − | Prostaglandins have an important role in gastric mucosal protection, although their precise mechanism is vague. Prostaglandins inhibit acid secretion, promote mucosal blood flow (vasodilate), increase mucus and bicarbonate secretions, and support mucosal cell repair.
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| − | Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or the administration of prostaglandin antibodies results in ulcer formation in various species, including horses. This effect can be blunted by administering exogenous prostaglandins.
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| − | Epithelial cell restitution is another important mechanism in the maintenance of gastric mucosal integrity. Epithelial cells act as a protective covering, counter shear forces that induce damage, and provide rapid restoration of damaged protective barriers. In the case of the gastric mucosa, epithelial injury induces a migration of adjacent cells to replace damaged cells. This occurs within minutes without need of new cell proliferation. Shear forces, induced by mixing of ingested material raking against the mucosal wall, cause cell damage that is normally countered by the process of epithelial restoration.
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| − | An abundant mucosal blood supply is required to provide the mucosa with the oxygen and nutrients necessary to produce the mucus-bicarbonate layer and to support the rapid turnover of epithelial cells. An adequate blood supply is also required to remove acid that has diffused through the mucous layer to the mucosa. Alterations in blood flow (i.e., shock, microvascular thrombosis) are highly correlated with mucosal erosions and gastric ulcers in man. Epidermal growth factors are found in salivary gland secretions and promote DNA synthesis and proliferation of gastric mucosal cells. They also play a role in prostaglandin synthesis and inhibit the parietal gland secretions of hydrochloric acid.
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| − | Squamous mucosal defence mechanisms
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| − | Many discussions surrounding equine squamous disease are extrapolated from human oesophageal disease and data from other species. In these species, the initial response of squamous tissues exposed to acid is to thicken.
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| − | Cell-to-cell junctions are closely adhered (‘tight junctions’), which ensures a weak acid barrier. Buffering also is a component of the squamous tissue defence scheme, but unlike the glandular portion, there is no external mucus-bicarbonate layer. Rather, squamous tissues buffer internally (within the cell) and use leucotrienes for defence. By contrast, glandular tissue relies on prostaglandins for adequate mucosal protection.
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| − | In summary, the squamous tissues of the stomach have a limited number of defence mechanisms that centre around acid repulsion and intracellular buffering. Once the acid penetrates these defences, it builds up within the cell layers and necrosis (cell death) leads to ulcer formation.
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| − | Gastric acidity and secretion
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| − | The horse secretes acid in a continuously variable pattern, such that acid secretion occurs in the absence of ingestion of feed. The mean pH of gastric fluid in horses withheld from feed for several hours has consistently been found to be 2.0 or less. However, periodic fluctuations, in which the pH reaches 6-7 for 5 to 15 min, are commonly seen. Whereas acid output reflects the magnitude of hydrochloric acid secretion, gastric acidity is determined by the pH of gastric secretions and/or contents.
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| − | The distinction between gastric acid output and pH is relevant, since administration of antisecretory medications may significantly decrease acid output but have minimal effect on gastric fluid pH in horses until the output becomes very small.
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| − | Few studies on the effect of feeding on gastric physiology have been performed in horses. Serum gastrin increase after feeding was more profound when grain was fed compared with feeding only hay. Horses with free access to hay had greater mean 24 h gastric pH than did horses withheld from feed for 24 h (3.4 * 0.9 vs. 1.9 * 0.5).
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| − | These latter results support the continuous acid secretion of the equine stomach and the buffering capacity of feed and bicarbonate-rich salivary secretions that are stimulated by feeding. In foals, milk has been demonstrated to have a marked buffering effect.
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| − | Extrapolating from other species, causes of glandular ulcer formation would include:
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| − | Bile reflux into the stomach
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| − | Hypotensiod shock (resulting in the diminution of mucosal blood flow)
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| − | Increased sympathetic tone (leading to a decrease in mucosal blood flow)
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| − | Severe disease states such as uraemia, infections, coagulopathies and conditions that result in the impairment of blood flow
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| − | Neurological imbalance, resulting in impairment of gastric motility (results in the accumulation of acids)
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| − | Micro-organisms
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| − | .(EGUC)
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| − | It has been proposed that the disease in a high performance horse is directly linked to unnatural feeding, exercise and management regimes that result in either increased acidity of gastric contents or increased exposure of vulnerable areas of the stomach to acid contents (Murray and Eichorn 1996; Berschneider et al. 1999;Nadeau et al. 2000; Lorenzo-Figueras et al. 2002; Bell et al. 2007).
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| − | For horses kept in a more natural environment with continuous grass feeding, as some of these were, the aetiology of disease is more puzzling.(Martineau 2009)
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| − | We conclude that combinations of bile salts and acid are more injurious to the stratified squamous gastric mucosa of the equine than acid alone. Concentrations of bile salts and acid sufficient to alter the electrolyte transport function of this mucosa can be found in the gastric contents of horses deprived of feed for as little as 14 h.(Berschneider 1999)
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| − | In the horse, the junction of the glandular and squamous epithelia is at the margo plicatus, analagous to the gastro-oesophageal junction in man. Therefore, gastric ulceration seen in the equine patient more closely resembles oesophagitis and oesophageal ulceration seen in man (Collier and Stoneham 1997). Severe training regimes may cause diversion of blood flow to muscle, decreasing mucosal blood flow leading to a fall in mucosal resistance.(Collier 1999)
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| − | Horses secrete gastric acid continuously, even when they are not eating (Campbell-Thompson and Merritt 1987).
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| − | Grains contain less buffering material than hay and also contribute an acid load to the system (Roby et al. 1987).
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| − | There also appears to be an effect of exercise on the stomach that is independent of feeding, as horses fed the same diet before and during training had higher gastrin levels during training (Furr et al. 1994). Whether this is a stress response or some other physiological effect is unknown, but it suggests that exercise itself may be a predisposing factor in the development of gastric ulcers.
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| − | Stress has been thought to contribute to gastric ulcers or at least to epigastric distress in man and severe stress, associated with illness, may cause ulcers in man and in foals, but only in the glandular portion of the stomach (Furr et al. 1992). (Orsini)
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| − | Foal sites of ulceration:
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| − | Healthy foals: squamous mucosa, margo plicatus, greater curvature, squamous epithelial desquamation
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| − | Sick foals: margo plicatus, lesser curvature and cardia, glandular mucosa, pylorus and duodenum
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| − | NOT associated with ''Helicobacter pylori'' and not typically associated with ''Gasterophilus''
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| − | Foals: hx, cx, gastric reflux, +/- occult blood in faeces,
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| − | Foals - lesions mainly in glandular epithelium
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| − | Adults - margo plicatus and squamous epithelium
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| | ==Risk Factors== | | ==Risk Factors== |