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W1816495575 abstract "The term Equine Gastric Ulcer Syndrome (EGUS) was first used in 1999 to describe gastric ulceration in the horse.1 However, as discussed by Merritt,2 the terminology is commonly misused. The committee reinforces the importance of distinguishing between diseases of the squamous and glandular mucosa because, as discussed in this statement, important differences exist between the two. In human medicine, the term peptic ulcer disease (PUD) is used as an umbrella term to describe erosive and ulcerative diseases of the stomach and it is recognized that a large number of individual diseases are present under the term.3 Furthermore, while some different diseases might share similarities in pathophysiology and treatment regimens, it is recognized in human medicine that the direct extrapolation of either from one specific disease (such as NSAID-associated ulceration) to another (such as Helicobacter pylori associated ulceration) is inappropriate.3 The committee recognizes that the terminology for EGUS requires clarification and proposes that the nomenclature be: Equine Gastric Ulcer Syndrome (EGUS) as a general all encompassing term to describe erosive and ulcerative diseases of the stomach consistent with the use of the term PUD in man; Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD) as terms that more specifically describe the affected region anatomically. Within ESGD, both primary and secondary disease is recognized. Primary ESGD, the more common of the 2 forms, occurs in animals with an otherwise normal gastrointestinal tract. In contrast, secondary ESGD occurs in animals with delayed gastric outflow secondary to an underlying abnormality such as pyloric stenosis.4 The pathophysiology of EGGD remains to be elucidated and as such further subclassification of lesion type is not possible at this time. Instead, the committee recommends the use of descriptive terminology with a clear distinction of the anatomical region affected (cardia, fundus, antrum, or pylorus as shown in Figure 2) and the gross appearance of the lesion. The committee emphasizes that the affected region of the stomach should be clearly identified when communicating research and clinical findings. A summary of the proposed terminology is depicted in Figure 1. Recommendation: Expansion of the existing EGUS terminology to specifically identify squamous and glandular disease as ESGD and EGGD, respectively, as shown in Figure 1. The prevalence of gastric ulceration varies with breed, use, level of training, as well as between ESGD and EGGD. The highest prevalence of ESGD occurs in Thoroughbred racehorses with 37% of untrained horses affected, increasing to 80–100% within 2–3 months of race training.5-7 Standardbred racehorses have a similar overall ESGD prevalence of 44% that rises up to 87% in training,8-10 while 17–58% show/sport horses and 37–59% of pleasure horses are affected.11-15 Endurance horses have an ESGD prevalence of 48% during the out of competition period that rises to 66–93% during the competitive period, with lesions most prevalent in elite horses.16, 17 Horses that are rarely competed and predominantly used in their home environment have the lowest ESGD prevalence of 11%.18 The prevalence of EGGD is less well understood. Australian Thoroughbred racehorses have reported prevalences of between 47%6 and 65%.19 In endurance horses, the prevalence is 16% outside of the competition period and 27–33% while competing.16, 17 A retrospective study in the United Kingdom found EGGD in 54% of 191 leisure horses and in 64% of 493 sport horses.20 Comparably, 57% of horses used for a variety of purposes were reported to have EGGD in 2 separate studies.14, 21 The majority of EGGD lesions in all of the above studies were found within the pyloric antrum. A postmortem study of 3,715 horses over 72 years found significant associations between the presence of ulceration and breed (Thoroughbred and Standardbred breeds were more likely to have ulcers than cold-blooded horses) and sex (a higher prevalence was reported in stallions than mares and geldings).22 In contrast, 2 large cross-sectional studies of Thoroughbred racehorses documented no significant effect of age or sex on the likelihood of having ESGD.7, 23 Similarly, a large study in Standardbreds found no association between the presence of ESGD and age; however, there was an association between increasing age and worsening ulcer severity, the relative risk for which was greatest in geldings.8 In a retrospective study of 684 sport and leisure horses in the United Kingdom, no effect of age, sex or month of presentation was found on prevalence of ESGD or EGGD. However, a significant association was found between the Thoroughbred breed and the presence of ESGD in horses of any age.20 Together, these findings suggest that other factors such as intensity or duration of exercise outweigh any potential age or sex effect, but that a breed effect might be present with Thoroughbreds predisposed to ESGD. There are few large scale epidemiologic studies that investigated other risk factors for EGUS. Of those available, significant associations have been shown between ESGD and individual trainers, a metropolitan yard location (horses trained in urban areas were 3.9 × more likely to have gastric ulcers), a lack of direct contact with other horses, solid barriers instead of rails, and talk rather than music radio in the barn.23 Straw feeding and a lack of access to water in the paddock have been associated with an increased risk of EGUS in general.24 Further large scale work is required to better understand the epidemiologic factors which influence disease development, particularly EGGD which is largely unstudied at this point in time. Pasture turnout is considered to reduce the risk of EGUS although evidence supporting this belief if cnflicting. Horses with access to some turnout were less likely to have ESGD, and this risk was even lower if they were turned out with other horses in one study of Thoroughbred racehorses in training.23 Conversely no effect of quality of pasture, or time at pasture (stabled, stable and pasture, pastured) was shown on ESGD prevalence in another study of Thoroughbred racehorses.25 In addition, there were no differences observed on intragastric pH in horses fed ad libitum grass hay and grain twice a day (1 kg/100 kg/d) when they were housed in a grass paddock, in a stall on their own or in a stall with an adjacent companion, suggesting that pasture turnout on its own might not affect gastric pH per se.26 Similarly, free access to fibrous feed or frequent forage feeding is widely considered to reduce the risk of gastric ulceration although strong evidence supporting this belief if also lacking. Feeding alfalfa hay and grain results in higher gastric pH and less peptic injury to the gastric squamous mucosa than feeding brome grass hay or coastal Bermuda hay with no grain.27, 28 Furthermore, in a study evaluating the influence of a high fiber diet versus an iso-energetic low fiber diet both the number and severity of ESGD lesions was greater in the high fiber diet group.29 Together, these findings suggest that that the impact of forage feeding in the absence of other risk factor reduction might not be as great as previously believed. There is an increased likelihood of ESGD (severity score ≥2/5) when straw is the only forage provided24 suggesting that forage type might also be important. An increased time between forage meals (>6 hours between meals), compared with more frequent forage feeding (<6 hours between meals) increases the likelihood of ESGD.24 A more consistent effect is observed with increased starch/grain intake and this been associated with an increased risk of ESGD in animals working at various levels of intensity in a number of studies. There is a marked increase in ulceration when nonexercising animals are stabled and fed grain at 1% of BW, 1 hour before hay is fed.30 Similarly, exceeding 2 g/kg BW of starch intake per day is associated with an approximately 2-fold increase in the likelihood of ESGD grade ≥2/5.24 ESGD developed in all horses within 14 days of their removal from pasture, stabling (fed 6 kg concentrate feed/day) and entering a simulated training regimen.31 Intermittent access to water increases the risk of EGUS as it has been shown that horses without access to water in their paddock are more than 2.5 times more likely to have EGUS ≥ 2/5 than horses with constant access to water.24 This was the case for both ESGD or EGUS in all parts of the stomach. Fasting is a well described as a risk factor for ESGD and intermittent starvation causes and increases the severity of ESGD.32 Using this effect, an experimental model has been developed to produce ESGD; however, it is the opinion of the committee that the model's ability to replicate the multifactorial nature of clinical disease is limited. Recommendation: Given that the fasting model appears to poorly reflect the multifactorial nature of gastric disease the committee believes that its use as an experimental model is not justified. Instead, the committee recommends that trials investigating therapeutic or prophylactic efficacy should focus on naturally occurring disease. In the formative years of equine gastric ulcer research, the prevalence and severity of ESGD in horses with clinical signs (poor appetite, poor bodily condition, and abdominal discomfort) was demonstrated to be significantly greater than in horses without clinical signs.11 Gastric ulcers have been loosely associated with a range of clinical signs in adult horses, despite a paucity of strong epidemiological evidence to support these associations. Reported clinical signs include poor appetite or ‘picky eating’,7, 11, 33, 34 poor body condition, or weight loss,9, 11, 33 chronic diarrhea,11, 33 poor coat condition,7 bruxism,35 behavioral changes (including an aggressive or nervous disposition),12, 33, 36 acute or recurrent colic7, 11, 33, 37-39, and poor performance.7, 10, 33, 40, 41 There is some evidence to suggest that gastric ulcers are associated with an increased incidence of colic and, in particular, recurrent postprandial abdominal discomfort.7, 11, 22, 37, 39 Gastric ulcers were reported in 83% of horses with recurrent colic in one study of which 28% had colic attributable to gastric ulceration as documented by a response to acid suppressive treatment.37 There is an association between signs of colic and ESGD with 3.5% of horses with ESGD exhibiting colic over the preceding month.7 Forty-nine percent of horses presenting with acute colic had ESGD in another study and horses that were surgically managed had a lower incidence of ESGD than horses that had been medically managed.38 The reason for this is unclear, but might be because medically treated horses are generally fasted for longer periods of time, placing them at an increased risk of ESGD.4, 32 Alternatively, the presence of ESGD might predispose horses to altered gastrointestinal motility and subsequent medical colic. Several authors have reported an association between inappetence or ‘fussy’ eating and gastric ulceration.7, 11, 34 Signs of reduced appetite in horses with gastric ulcers can vary from mild to severe, and consequently might go unrecognized. Owners often refer to decreased appetite as “fussy” eating, without actually considering it a clinical sign of gastric ulceration.14 Poor body condition is associated with a high prevalence of gastric ulcers in racehorses in active training.9 Poor coat condition is usually listed as a vague clinical sign of gastric ulceration. In a cross-sectional study in Thoroughbred horses, a statistical association between gastric ulceration and rough hair coat was identified.7 In contrast, other studies have failed to identify an association between poor hair coat and EGUS.9, 42 Diarrhea has been reported as a clinical sign of gastric ulceration in adult horses.11 However, there is no evidence of a cause-and-effect relationship; and furthermore, it is anatomically and physiologically implausible, except in the situation where gastric ulceration is part of a wider disease process. It is a common perception that horses demonstrating stereotypic or altered behavior are more likely to have ulcers.11, 33 Reported behavioral changes include nervousness, aggression, and self mutilation.43 Show horses with a nervous disposition are more likely to have ESGD than are quiet or behaviorally normal horses.12 In contrast, no effect of nervousness has been shown in racehorses, and in fact in this population, aggression might have an effect in limiting ESGD.23 There is an association between crib-biting and ESGD, although the mechanism is unclear.36 The potential for EGUS to cause poor performance is of particular importance, yet, surprisingly, to date few studies have investigated the potential relationship between poor performance and the presence of EGUS. Any one of the aforementioned clinical signs can potentially have an indirect effect on performance, for example, through reduced appetite or interruption in training, but the question remains whether gastric ulcers themselves, in the absence of other clinical signs, have an effect on performance. The mechanism by which gastric ulceration might affect performance has not been established, but it has been proposed that reduced performance might arise as a direct consequence of gastric pain.44 Ulcers and erosions in the squamous region of the stomach are similar to the lesions causing heart burn or gastroesophageal reflux disease (GERD) which is common among elite human athletes, with 58% of athletes complaining of upper gastrointestinal pain during exercise that is proportional to increasing exercise intensity.45 Furthermore, human runners with frequent GERD have a significantly decreased time to exhaustion compared to runners without reflux.46 To date, there are only a few published studies that have attempted to examine an association between the presence of ulcers and performance in racehorses. Some used trainer expectation as a surrogate measure of performance while others used objective physiologic responses to incremental treadmill exercise testing. There is a significant association between the presence of ESGD and decreased performance in Thoroughbred racehorses; with poor performance associated with the presence of gastric ulcers, independent of their severity or the number of ulcers.7 Similarly, there is a significant association between the presence of ESGD and performance below expectations in Standardbred racehorses.10 A small case series reported 4 Thoroughbred racehorses that presented with poor performance and gastric ulceration as the only abnormal finding, where improved performance after treatment with omeprazole was observed.41 The effect of ESGD, induced by intermittent feed deprivation, upon physiologic responses to incremental treadmill exercise testing has been examined. Half of the study population was treated with omeprazole (4 mg/kg PO q24h) and half received no treatment. Significantly reduced time to fatigue, significantly lower increase in maximal specific oxygen uptake and stride length were found in untreated horses, when compared to treated animals. The reason for these differences is not clear but the authors postulated that increased abdominal pain could be affecting stride length and ventilation.47 Comment: The committee concludes that a wide range of clinical signs might be present in individual cases of EGUS with varying degrees of reduced appetite and poor body condition the most prevalent at a population level. Although inconsistent, effects on behavior (including stereotypical behaviors) are not uncommon. Likewise, it is recognized that EGUS might result in poor performance; however, given the numerous factors that potentially contribute to poor performance other causes need to be considered. Differences in clinical signs between ESGD versus EGGD are unknown but warrant investigation. Recommendation: Although a wide variety of clinical signs might be present in individual cases of EGUS, they are nonspecific and are poorly associated with the presence of EGUS. The committee therefore does not support the practice of diagnosing EGUS based on ‘characteristic’ clinical signs and recommends that EGUS be confirmed by performing gastroscopy as discussed below. The committee considers that gastroscopy is the only reliable antemortem method for definitively identifying gastric ulceration. The technique has been described elsewhere.48 When performing gastroscopy, it is essential to examine the entire stomach, including the pylorus and proximal duodenum, as lesions in these regions are easily missed. There is no relationship between the presence of ESGD and EGGD6, 14, 49; as such the presence or absence of one cannot be used as predictor for the presence or absence of the other. There are currently no reliable hematological or biomechanical markers available to aid in diagnosis of gastric ulceration. A sucrose permeability test has shown promise for noninvasive detection of gastric ulcers,50, 51 but to date, the diagnostic accuracy of the test has not been reported in clinical cases. Contrary to initial reports, there is no association between the presence of gastric ulcers and the detection of either fecal albumin or hemoglobin.52, 53 Empiric treatment is common where gastroscopy is not available. The committee believes that, given the potential costs of treatment and the importance of distinguishing ESGD from EGGD, the initiation of treatment without prior gastroscopy is not recommended. It is noted that if empirical treatment is attempted and the horse fails to respond to treatment gastroscopy remains indicated to definitively rule out gastric disease as some animals do not appear to show resolution of clinical signs until complete healing of lesions has occurred. Once identified on gastroscopy, assessment of the severity of lesions is most commonly achieved by assigning a grade that describes the mucosal appearance at different anatomic sites. A variety of different systems have been published for the horse, with scales ranging from 0–354 to 0–105 described. A separate 2-part system that describes lesion number and severity has also been proposed.55 In 1999 the Equine Gastric Ulcer Council proposed a 0–4 grading system designed to assign severity based upon lesion depth, size and number1 and recommended that the system should be adopted for both clinical and research use. Despite widespread use, few of the scoring systems have been validated for intra-, or inter-, observer repeatability. When performed for a system describing number and severity, significant interobserver variability was found for the number of squamous lesions.55 Subsequently, this system was compared with necropsy examination and it was found that it underestimated the number of squamous lesions present, while a simplified 0–3 practitioner scale did not.56 A further study recommended that the 0–4 Equine Gastric Ulcer Council system be adopted as the standard EGUS scoring system because of its ease of use, and the repeatability and correlation of grades between examiners.57 Despite this validation, and the original recommendations of the EGUS council, many researchers continue to report their own systems. This lack of uniformity restricts comparison between studies, and hampers the assessment of clinical cases by different endoscopists. Recommendation: The committee recommends that the existing Equine Gastric Ulcer Council 0–4 scoring system (shown in Table 1) be used for ESGD. There is minimal data on the validity of grading glandular lesions. The clinical relevance of the different manifestations of glandular disease are yet to be well evaluated although there is variation in the histologic appearance of glandular lesions, that can also be appreciated endoscopically.58, 59 Lesions can differ in their epithelial appearance (hyperemic, hemorrhagic, fibrinosuppurative, ulcerated) and in their mucosal contour (depressed, flat, raised). Furthermore, separate evaluation of the epithelial and mucosal appearance is important in developing a better appreciation of glandular healing, as epithelial restitution might not lead to the normal mucosal appearance that typifies squamous healing. Last, it appears that subjective visual assessment of severity and the histopathological appearance of the epithelium and mucosa might correlate poorly.58 Considering this; at present, it is not recommended that these different appearances be reflected in a hierarchical grading system such as that used for ESGD. Recommendation: Until better defined, the use of a hierarchical grading system for EGGD is not recommended. In the absence of a grading system, terminology describing the presence/absence, anatomical location, distribution, and appearance of lesions as outlined in Figure 1 should be used. The main challenge facing the endoscopist is assigning clinical, rather than just endoscopic, importance to individual lesions. It has been suggested that there is a correlation between the severity of gastric ulceration and the severity of clinical signs35, 39, 48 and it is intuitive to believe that more severe lesions are more likely to result in clinically important disease. The use of hierarchical systems further implies more severe disease with higher grades. However, this relationship might not be linear or temporally consistent and there is currently a paucity of information in the literature demonstrating a direct cause-and-effect relationship between clinical signs and the presence, severity, or location of gastric ulcers in adult horses. Furthermore, we know that many horses with EGUS will not demonstrate clinical signs, and are considered to have ‘silent’ or non-clinical gastric ulceration.14, 25, 33 Whether these horses are truly without clinical signs, or simply subclinical, warrants consideration as there is improved behavior after treatment in some patients.33 Furthermore, it has been assumed that a loss of mucosal integrity is required for clinical importance. However, in humans hyperemia of the glandular mucosa is considered to reflect acidification of the mucosal surface that, in turn, results in activation of the sensory nerves and pain.60 Whether a similar effect is present in the horse is not known but anecdotally it appears that some horses with hyperkeratosis or hyperemia alone respond to treatment, suggesting that such an effect might be present in a subset of the population. In contrast, some horses with endoscopically severe disease do not have clinical signs and fail to change in response to treatment. Comment: There is little evidence to support the notion that lesion grade (as assessed visually) correlates with clinical signs. Considering this the committee advises that the assessment of clinical relevance should not be made on endoscopic appearance alone. Instead the clinician should assess the relevance of an individual's lesions in light of the horse's recent usage, its history and presenting clinical signs. Future research on EGUS should focus on reporting both clinical and endoscopic outcomes. A variety of management factors contribute to the development of ESGD. All of these factors share the common trait that they increase the exposure of the squamous mucosa to acid. In vitro experiments clearly show that squamous mucosal cells are susceptible to hydrochloric acid (HCl) and volatile fatty acid (VFA) injury in a pH, dose and time dependent manner.61 Damage of the outer cell barrier is induced by HCl, later followed by diffusion into the squamous cells of the stratum spinosum ultimately resulting in ulceration.62 Byproducts of bacterial fermentation of sugars in concentrate diets not only like VFAs and lactic acid, but also bile acids, have been shown to act synergistically with HCL.4, 62 There is a well-described relationship between exposure of squamous mucosa to acidic content and training. Excessive exposure of the squamous mucosa results from the acidic gastric contents being pushed up by the increased intra-abdominal pressure associated with gaits faster than a walk.63 Consistent with this racehorses have an increase in prevalence, lesion severity and number of lesion sites within the squamous mucosa significantly associated with increasing intensity of long-duration training.5, 64, 65 The severity of ESGD in high level endurance horses is directly related to the distance of the ride.17 In contrast, the pathophysiology of EGGD is poorly understood. The glandular mucosa differs fundamentally from the squamous mucosa in that under normal physiological conditions it is exposed to highly acidic gastric contents with the pH in the ventral portion of the stomach relatively stable at between 1 and 3.66 As such, whereas ESGD results from exposure of mucosa unaccustomed to acidity, EGGD is believed to result from a breakdown of the normal defense mechanisms that protect the mucosa from acidic gastric contents. The factors that contribute to breakdown of this protective layer are yet to be elucidated in the horse, but in humans Helicobacter pylori and NSAIDs are the predominant causes of gastric ulceration.3 As such, research in the horse has focused primarily on these 2 mechanisms. To date there remains conflict in the literature as to the role of bacteria in EGGD. Both gastric-adapted bacteria and opportunistic pathogens might play a role in squamous ulceration67 but whether the situation is similar in the glandular mucosa is unknown. Furthermore, although such bacteria are present in ESGD their role appears to be secondary as the response to acid suppression alone is good. Helicobacter-like organisms have been identified in horses affected with EGGD in some studies,68-70 whereas other studies have failed to identify such organisms.21, 58 The potential for NSAIDs to cause EGGD under clinical conditions is equally controversial. An ulcerogenic capacity has been demonstrated for flunixin, phenylbutazone, and ketoprofen at doses 50% higher than typically recommended,71 while at clinical doses phenylbutazone and suxibuzone do not induce gastric ulceration when administered for 15 days.72 As previously stated, high prevalences of EGGD have been observed in many populations with disease rates disproportionate to the number of animals likely to receive NSAIDs under such conditions. Comment: Based on the current knowledge evidence for bacteria as a direct, causative agent is lacking. Similarly, although NSAIDs have the potential to cause EGGD in individual animals they are unlikely to be an important contributor to the prevalence of disease at the population level. Similar to human medicine where a large number of different diseases with separate pathophysiologies result in PUD,3 it is likely that multiple different mechanisms contribute to the development of EGGD in the horse. The mantra “no acid, no ulcer’ acid suppression is considered a cornerstone of gastric ulcer management in humans, regardless of the inciting cause.3 Consistent with this, it is the committee's opinion that appropriate acid suppressor treatment is indicated in the management of both ESGD, for which its efficacy is well documented, and EGGD, regardless of the failure to identify an underlying cause as of yet. Proton pump inhibitors and H2-receptor antagonists are the most commonly used classes of drugs in the horse. Proton pumps inhibitors, of which omeprazole is the best studied in the horse, irreversibly impair the H+, K+ ATPase (proton) pump that secretes HCl with new pumps needing to be made before acid production resumes.73 In contrast, H2-receptor antagonists work via competitively blocking the H2 receptor on the parietal cell and their efficacy is dependent on maintaining plasma concentrations of the drug. Omeprazole is superior to ranitidine in the treatment of naturally occurring disease74 and, in the opinion of the committee, omeprazole remains the drug of choice for treatment of EGUS. A variety of factors including the formulation used, dose and duration of treatment influence the expected outcome of treatment. The recent expiration of the GastroGard1 patent is expected to result in an influx of different formulations onto the market and discussion of the method of protection used to protect the omeprazole in different formulations is warranted. Omeprazole is acid labile and it is generally regarded that some form of protection is necessary to prevent degradation of the drug within the acidic environment of the stomach.66 GastroGard1 and its true generic equivalents utilize a buffered paste formulation to achieve this protection.66 Other formulations utilize enteric coated granules suspended within a paste to achieve the same objective.19 To date, little work has been done on the relative pharmacokinetics of different formulations of omeprazole. A study directly comparing the bioavailability of 4 formulations (2 enteric coated granule formulations and 2 buffered formulations) to GastroGard1 as a reference standard did not find statistically significant differences in bioavailability.75 Similarly, a, clinical study found no significant difference in the bioavailability of an enteric coated granule formulation (Gastrozol2;) when compared with the reference buffered formulation (GastroGard1).76 In contrast, an enteric coated omeprazole formulation (Gastrozol2) has been shown to have approximately twice the bioavailability of a compounded paste formulation of plain, unprotected omeprazole.77 These findings are interesting in light of outcome of recent clinical studies. In a direct comparison between formulations, no difference in endoscopic outcome was observed despite the enteric coated granule formulation (Gastrozol2) being used at 1 mg/kg PO once daily versus 4 mg/kg PO once daily for the buffered formu" @default.
W1816495575 created "2016-06-24" @default.
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W1816495575 date "2015-09-01" @default.
W1816495575 modified "2023-10-03" @default.
W1816495575 title "European College of Equine Internal Medicine Consensus Statement-Equine Gastric Ulcer Syndrome in Adult Horses" @default.
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