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Equine Gastric Ulcer Syndrome: An Update on Current Knowledge

April 2023
Animals 13(7):1261

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Massey University

Equine Gastric Ulcer Syndrome (EGUS) is a term that has been used since 1999, initially being used to describe all gastric mucosal disease in horses. Since this time, the identification of two distinct main disease entities of the equine gastric mucosa have been described under the umbrella of EGUS; these are Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD). In 2015 the European College of Equine Internal Medicine (ECEIM) released a consensus statement defining these disease entities. This document highlighted the lack of evidence surrounding EGGD compared to ESGD, and identified knowledge gaps for further research to be directed. Subsequently, many studies on EGGD have been published, especially on pathophysiology, diagnosis, and treatment. This article updates current knowledge on both ESGD and EGGD as understanding has evolved since the last large-scale review.

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Citation: Vokes, J.; Lovett, A.; Sykes,

B. Equine Gastric Ulcer Syndrome:

An Update on Current Knowledge.

Animals 2023,13, 1261. https://

doi.org/10.3390/ani13071261

Academic Editors: Carlos Eduardo

Medina-Torres and Francisco Javier

Mendoza

Received: 16 February 2023

Revised: 14 March 2023

Accepted: 29 March 2023

Published: 5 April 2023

Licensee MDPI, Basel, Switzerland.

This article is an open access article

distributed under the terms and

conditions of the Creative Commons

Attribution (CC BY) license (https://

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4.0/).

animals

Review

Equine Gastric Ulcer Syndrome: An Update on Current Knowledge

Jessica Vokes * , Amy Lovett and Benjamin Sykes

Equine Veterinary Clinic, School of Veterinary Sciences, Massey University, Palmerston North 4474, New Zealand

*Correspondence: j.vokes@massey.ac.nz

Simple Summary:

The term Equine Gastric Ulcer Syndrome has been used to describe mucosal

diseases of the equine stomach since the 1990s. More recently, speciﬁc nomenclature has been

used to differentiate diseases affecting the squamous and glandular mucosa, as the diseases of

these anatomic regions vary widely. Over the past 20 years, a large amount of research has been

performed to understand both diseases and their management. Signiﬁcant progress has been made

in their pathophysiology, treatment, and prevention. This review aims to look at previously and

recently published literature to deﬁne these diseases, as well as their prevalence, diagnosis, and

long-term management.

Abstract:

Equine Gastric Ulcer Syndrome (EGUS) is a term that has been used since 1999, initially

being used to describe all gastric mucosal disease in horses. Since this time, the identiﬁcation of

two distinct main disease entities of the equine gastric mucosa have been described under the

umbrella of EGUS; these are Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric

Disease (EGGD). In 2015 the European College of Equine Internal Medicine (ECEIM) released a

consensus statement deﬁning these disease entities. This document highlighted the lack of evidence

surrounding EGGD compared to ESGD, and identiﬁed knowledge gaps for further research to be

directed. Subsequently, many studies on EGGD have been published, especially on pathophysiology,

diagnosis, and treatment. This article updates current knowledge on both ESGD and EGGD as

understanding has evolved since the last large-scale review.

Keywords:

Equine Squamous Gastric Disease; Equine Glandular Gastric Disease; horse; stomach;

omeprazole; misoprostol; sucralfate

1. Terminology

Equine Squamous Gastric Disease (ESGD) describes lesions involving the squamous

mucosa encompassing the margo plicatus, greater and lesser curvatures and the dorsal

squamous fundus [

]. This can then be further classiﬁed into primary or secondary based

on the known pathophysiology of disease. Primary ESGD occurs in an otherwise healthy

gastrointestinal tract and is the most common form of this disease. Secondary ESGD is

due to delayed gastric outﬂow as sequela to other diseases, such as pyloric stenosis, severe

EGGD or inﬂammatory bowel disease (IBD) [1–4].

Equine Glandular Gastric Disease (EGGD) describes lesions of the glandular mucosa

involving the cardia, ventral glandular fundus, antrum, pylorus and proximal duode-

num [

]. The pylorus or antrum, often referred to as the ‘pyloric antrum’ appears to

be the most frequently affected region of the glandular mucosa, as described by several

gastroscopic studies [5–8].

2. Prevalence

The prevalence of ESGD and EGGD has been reported extensively elsewhere [

–

Prevalences for ESGD vary by group sampled and exercise program. Prevalences of 37–52%,

38–56% and 48% in Thoroughbred, Standardbred and endurance racehorses, respectively,

Animals 2023,13, 1261. https://doi.org/10.3390/ani13071261 https://www.mdpi.com/journal/animals

Animals 2023,13, 1261 2 of 25

while out of training have been reported. These increase up to 100%, 72–88% and 57–93%

respectively when these same populations are in training [

–

]. The prevalence ranges

greatly in other populations of horses, including 11% in university teaching horses [

55–68%

of adult horses at Thoroughbred stud-farms [

], 79% in Western pleasure

horses [

] and 51% in Italian donkeys [

]. More recently, the prevalence of ESGD at

post-mortem has been described as 61% in feral horses in the UK [

] and 64% of equids in

a safari park [

]. It is worth noting that many of the prevalence studies were performed

some time ago, and therefore may not be entirely relevant to current management practices.

The prevalence of EGGD is less well documented and more variable between pop-

ulations. Reports include 25–65% in Thoroughbred racehorses [

], 47% in a mixed

population of Standardbred and Thoroughbred racehorses [

], 16–33% in endurance

horses [

], 72% in Canadian showjumpers [

], 69% in Canadian polo ponies [

], 59%

in American Quarter Horses [

], 6% in Brasileiro de Hipismo military horses [

], 15% in

Italian horses [

] and 3% in Italian donkeys [

]. An abattoir survey in the UK found a

prevalence of 71% in domesticated horses compared to 30% in feral horses [26].

3. Risk Factors

Since the 2015 ECEIM consensus statement, few large-scale epidemiological studies

have been performed to investigate populations at risk of EGUS. Of the studies that

have been performed, many have been of limited sample size, leading to an increased

risk of both type one and type two errors [

]. Therefore, results from single studies

should be considered with caution and the literature looked at collectively. On this basis,

several conclusions have been drawn about the risks of ESGD and EGGD for certain

signalments such as breed and sex, but less so for others, such as age. The Thoroughbred

and Standardbred breeds are associated with an increased risk of ESGD [

] although

whether these are true breed predilections or simply reﬂective of exposure to management

risk factors is unclear. Similarly, limited evidence suggests that the Warmblood breed is

associated with an increased risk of EGGD; however, this is described in countries with

limited breed variety [

] and is likely multifactorial. A small amount of evidence

ﬁnds ponies at a reduced risk of EGUS when ESGD and EGGD are not differentiated [

There is conﬂicting evidence of the effect of sex on EGUS, with many studies ﬁnding

geldings to be at higher risk than mares [

] meanwhile others ﬁnding no

effect

[12,13,29,38–41]

. Within the adult population, age does not appear to be a signiﬁcant

risk factor for either ESGD or EGGD when other factors, such as exercise, are accounted

for [8,18,28,30].

Investigation of ESGD and EGGD risk by management factors has been described

in several publications. One recent study found a number of factors protective against

undifferentiated gastric disease, including open front stabling year-round, feeding hay from

a hay net (vs. unspeciﬁed), keeping retired horses as companions, and using omeprazole

therapy during periods of stress [

]. A small sample of American Quarter Horses found

city dwelling and use in performance disciplines to increase the risk of undifferentiated

gastric disease [

]. Interestingly, this study also found the classiﬁcation of horses as ‘friend’,

referring to the use solely as a pet, as a risk for disease and found increasing time spent in

contact with humans to be associated with higher ulcer grade [9].

A large-scale investigation of Thoroughbred racehorses in Australia found individual

trainer, metropolitan yard location, lack of contact with other horses, solid partitions and

playing talk radio to all increase the risk of ESGD [

]. Other risk factors speciﬁc for

ESGD include being owned for a shorter period [

], an increased time in work, travel-

ling

[28,30,40]

, current training [

] or recent racing [

]. Interestingly, Standardbred

trotters are at a higher risk of ESGD when directly compared to Standardbred pacers [

although it is unknown if the difference in gaits, or other management factors contribute to

this ﬁnding.

Crib biting is associated with an increased risk of ESGD, as are other stereotyp-

ies [

]. The relationship between these factors is not well studied; however, it is

Animals 2023,13, 1261 3 of 25

proposed that horses with ESGD display stereotypies subsequently to their disease [

Alternatively, it has been proposed that crib biting mimics the effects of exercise increasing

the duration of acid exposure to the squamous mucosa. Thoroughbred racehorses that

display aggression towards humans have been demonstrated to have a reduced risk of

ESGD [

]. Factors found to be protective against ESGD in polo ponies include housing in

a paddock and non-steroidal anti-inﬂammatory drug (NSAID) use [30].

Risk factors speciﬁcally for EGGD are less well documented. Exercising

≥

5 days

per week, racing below expectation, and trainer are risk factors for EGGD in Thorough-

bred racehorses [

]. Increased days in work and actively competing are risk factors in

Warmblood showjumpers [

]. Housing in single pens has also been associated with an

increased risk of EGGD [

]. Although not statistically signiﬁcant, an increased number of

caretakers and riders showed a tendency towards an increased risk of EGGD in a mixed

Finnish population [

]. The prevalence of EGGD doubles in endurance horses during

the competition season, when compared to the inter-season period [

]. Collectively with

the increased prevalence observed in domesticated horses, when compared with feral

horses [

], this suggests that intensive management plays a role in increased EGGD risk,

although via different mechanisms than for ESGD. Time in work did not affect EGGD risk in

Thoroughbred racehorses [

] but increased years of experience reduces the risk of EGGD

in Canadian polo ponies [

] and show jumpers [

]. This suggests an element of adaptation,

management changes over time, or that the selection of healthy horses might occur.

The nutritional risk factors associated with ESGD have remained consistent since

2015. Speciﬁc risk factors include lower hay provision and consumption, lower meal

number per day and higher grain and starch feeding [

]. Horses that had

access to some pasture turnout were less likely to have ESGD, with horses turned out

with other horses having a further decreased risk, in one study [

]. Conversely, pasture

turnout was not found to be protective against ESGD in other populations [

]. Pasture

provision likely plays a multifactorial role in disease pathophysiology that will be discussed

later. Oral hypertonic electrolyte administration increases lesion number and severity of

ESGD [48].

Most studies have failed to ﬁnd a relationship between nutritional risk factors and

EGGD [

]. A study following foals through weaning found the feeding of molasses-

coated alfalfa chaff to increase the incidence of pyloric lesions when compared with hay [

Similarly, a recent study found alfalfa feeding to be a risk factor for EGGD [

]. The

signiﬁcance of these ﬁndings is unclear at this point in time and the authors caution against

overinterpreting the ﬁndings pending further studies.

4. Clinical Signs

Many clinical signs have been ascribed to gastric mucosal disease over the years,

but surprisingly few studies have investigated these on a large scale. Proposed clini-

cal signs, discussed below, include colic [

–

], weight loss or poor body condi-

tion [

], poor coat condition [

], reduced appetite [

], diar-

rhea [

], bruxism [

], ﬂehmen response [

], behavioral changes [

] and

poor performance [

–

]. In interpreting the above, it is important to

distinguish between ESGD and EGGD as the majority of literature is weighted towards

ESGD, and a recent study found no associations between owner-reported clinical signs

and EGGD [

]. Similarly, there is other evidence to show that horses with gastric disease

can show no signs at all [

–

] and some horses with signs do not display

improvement of these signs with the resolution of gastric disease [56].

4.1. Colic

There is evidence to suggest an increased incidence of colic and post-prandial dis-

comfort exists in horses with both ESGD [

] and EGGD [

–

Supporting this, many cases show a positive response to acid suppressive therapy on

follow-up, both in the literature [53,62], and anecdotally.

Animals 2023,13, 1261 4 of 25

4.2. Inappetence and Weight Loss

Reports linking ‘picky’ eating, change in appetite or inappetence and EGUS exist

in the literature [

–

]. Supporting this, a relationship between gastric disease

and low body condition was found in Standardbred racehorses mostly diagnosed with

ESGD [

] and horses with severe EGGD [

]. However, other studies failed to demonstrate

a relationship between either ESGD or EGGD and poor body condition [

]. Interestingly,

a small study in Thoroughbreds found horses with EGGD ate faster than controls [23].

It warrants note that not all cases of ESGD are primary. In cases of ESGD occurring

secondary to diseases of delayed gastric emptying, such as pyloric stenosis, severe EGGD

or IBD [

], it might be the primary disease process, not ESGD, that has greater

inﬂuence on body condition. Association between gastritis and more distal small intestinal

inﬂammation, suggestive of IBD [

], might explain a relationship between EGGD and

weight loss.

4.3. Poor Coat Quality

An early cross-sectional study identiﬁed an association between a rough hair coat

and gastric disease [

] but several studies have failed to demonstrate this relationship

since [

]. The signiﬁcance of poor coat quality or rough hair coat is questionable in

its relationship with EGUS.

4.4. Diarrhea

In early gastric disease research, diarrhea was reported as a clinical sign in adults [

]

and a more recent study found a reported increase in free fecal water to be associated with

EGGD [

] supporting this ﬁnding. Other than these examples, diarrhea has not been

reported as a clinical sign of gastric disease.

4.5. Behavior

Changes in behavior are often attributed to gastric disease in practice, although reports

in the literature supporting this are variable [

]. A cross-sectional study of

50 show horses identiﬁed that horses with nervous behavior more likely to have ESGD [

Multiple studies have shown a relationship between ESGD and crib biting [

] or

other stereotypies [28,40].

One of the common behaviors attributed to gastric disease by owners is ‘girthiness’,

i.e., signs of pain and negative behavior during girthing [

]; however, studies have

failed to show a relationship between girthing behavior and ESGD or EGGD [35,63,70].

It is hypothesized that stress plays a role in the pathophysiology of EGGD [

], and

if so, this might have an association with behavior. Supporting this, horses with EGGD

have increased cortisol responses to novel stimuli [

] and exogenous adrenocorticotropic

hormone (ACTH) stimulation [

], as well as higher fecal cortisol metabolites after

exposure to novel stimuli [

]. The relationship between stress and ESGD is less well-

deﬁned; one study showed an inverse correlation between hair cortisol and ESGD grade,

suggesting that long-term stress is associated with ESGD [73].

These non-speciﬁc behavioral complaints are likely to have a complex, multifactorial

relationship with ESGD and EGGD, where these downstream effects of pain and stress

response are closely intertwined. The authors propose that gastric pain in horses could play

a role in the development of stereotypical, undesired or anticipatory behaviors, and that

these behaviors might continue beyond the course of disease. It is also possible that some

horses are ‘predisposed’ to both gastric disease and behavioral anomalies concurrently.

As there is little evidence proving causation in this area, certain conclusions cannot be

made at this stage. Moreover, the behaviors attributed to ESGD and EGGD are not speciﬁc

for gastric disease, thus, other gastrointestinal diseases, such as sand enteropathy [

]

or IBD [

], and non-gastrointestinal (e.g., musculoskeletal) diseases should remain as

differentials [36,68,69].

Animals 2023,13, 1261 5 of 25

4.6. Poor Performance

Owner-reported poor performance is often reported as a clinical sign of ESGD [

EGGD [

] or both [

]. Poor performance is one of the most common reported

signs

[56,57]

, despite its lack of speciﬁcity for gastric disease. Racing below expectation

was a risk factor for EGGD in another study [

]. The mechanism of this effect is cur-

rently unknown, although might be due to gastric pain limiting stride-length and oxygen

consumption in racehorses [

] or reducing behavioral compliance in other disciplines.

Conversely, other studies failed to demonstrate this effect [

], possibly due to the wide

scope of interpretation of performance level.

5. Pathophysiology

5.1. Equine Squamous Gastric Disease

The understanding of primary ESGD pathophysiology has not changed signiﬁcantly

in the years since the ECEIM consensus [

]. Management factors that increase the acid

exposure of the squamous mucosa predispose to the development of ESGD [

]. The suscep-

tibility of the squamous mucosa to hydrochloric acid and volatile fatty acids is pH, time and

dose dependent [

]. Following initial damage by the acid, diffusion into the stratum

spinosum causes ulceration [

]. By-products of bacterial fermentation of carbohydrates,

such as lactic acid and volatile fatty acids, perpetuate the damage caused by hydrochloric

acid, when fed in large volumes that are unlikely to be seen clinically

[3,77]

. It should

be remembered that pasture can be a signiﬁcant source of Non-Structural Carbohydrates

(NSCs) [78].

The effect of pasture in the pathophysiology of ESGD is likely multifactorial, which

might explain the variability of study results with some showing pasture turnout as

protective [

] and others ﬁnding no effect [

]. Measurement of intragastric pH in

horses fed hay and grain found no effect of pasture turnout in one study [

]. Speciﬁc

factors in the relationship between ESGD and pasture are not deﬁned in equids at this

time. Likely factors include the NSC content, ﬁber quantity and ﬁber composition of the

pasture provided. The importance of ﬁber in the pathogenesis of ESGD is likely two-fold;

by increasing the saliva produced by chewing, which has a buffering effect on stomach acid,

and its ability to create a ‘roughage ball’ in the stomach to limit acid splashing. Therefore, it

follows that not all ﬁber will have the same effect, with ﬁber size likely being an important

factor, as it is in creating a ruminal mat and increasing time masticating in cattle [

]. Other

effects of diet on the microbiota of the stomach, and its relationship to disease are not

yet fully understood. It is also possible that other factors associated with pasture turnout

are associated with risk reduction, such as increased socialization [

], display of natural

behaviors and stress reduction.

Exercise increases the exposure of the squamous mucosa to acid due to increased

abdominal pressure and stomach contraction [

]. In ﬁtting with this, prevalence and ESGD

score is associated with the intensity of long-duration exercise in Thoroughbreds [

]

and distance of ride in endurance horses [13].

Secondary ESGD can occur due to delayed gastric outﬂow from other diseases, includ-

ing pyloric stenosis and severe EGGD [

–

]. The possibility of severe EGGD causing delay

in gastric emptying, and subsequently ESGD, has been proposed by several authors in

recent years [

]. Diagnosis of delayed gastric emptying is difﬁcult in horses [

], which

makes conﬁrmation of this hypothesis scant despite its theoretical validity [84].

5.2. Equine Glandular Gastric Disease

Conversely, the pathophysiology of EGGD remains poorly understood. It has been

hypothesized that the damage to the glandular mucosa in cases of EGGD is due to a loss of

normal defense mechanisms to physiologic acid [

]. In humans, this is most often caused

by infection with Helicobacter pylori and NSAID use [

]. In horses, there is evidence to

suggest that EGGD is a form of gastritis, identiﬁed by histopathology [

–

]. One

study even showed a correlation between histopathological gastric glandular inﬂammation

Animals 2023,13, 1261 6 of 25

to duodenal inﬂammation, including lymphoplasmacytic inﬂammation and eosinophilic

inﬁltrate, but not to more distal segments of the GI tract [

]. This evidence of EGGD as a

form of gastritis is supported by evidence of immune upregulation in EGGD, demonstrated

by altered protein composition of serum and saliva of horses with EGGD compared to

controls [

]. Further work is needed to deepen the understanding of inﬂammation in

EGGD pathophysiology.

5.3. Non-Steroidal Anti-inﬂammatory Drugs

Research into NSAIDs as a common cause of ESGD or EGGD at the population level is

lacking. Furthermore, several population-based studies have failed to ﬁnd NSAID use as-

sociated with increased risk of EGGD [

]. At an experimental level, multiple studies

have shown the ulcerogenic capacity of NSAIDs at high doses in horses [

–

]. Most

of these studies, however, use NSAID doses in excess of what is typically recommended

for clinical use [

]. The ability for fed-fasted NSAID models to cause both ESGD and

EGGD at normal therapeutic doses has also been demonstrated [

]. These models

are worth considering when assessing the risk of EGUS in hospitalized horses that often

undergo periods of fasting with concurrent NSAID administration. A study investigating

phenylbutazone given at 4.4 mg/kg daily for 10 days showed an increased risk of EGGD

compared to ﬁrocoxib at 0.1 mg/kg daily, which was itself increased compared to the

control [

]. Conversely, another study looking at label dosing of phenylbutazone and

suxibuzone for up to 15 days failed to cause increased risk of EGGD [

100

]. The mechanism

of NSAID-associated EGGD is not fully understood at this time, with prostaglandin con-

centrations in the stomach and glandular mucosa not changing when NSAID-associated

disease was induced in a single study [

]. The authors believe that the ability for NSAIDs

to cause EGGD is over-estimated in the clinical setting and that the use of high-dose NSAID

models for induction of EGGD for treatment trials is not justiﬁed; instead, these trials

should focus on naturally occurring disease.

5.4. Helicobacter spp.

Helicobacter species have been implicated in gastric and duodenal ulceration in humans

since the 1980s [

101

]. Helicobacter-like species have been identiﬁed in the stomachs of horses

with EGUS; however, studies fail to associate these bacteria with gastric disease

[102–107]

Other studies have failed to detect Helicobacter-like species from horses with gastric dis-

ease [

108

–

111

]. As such, the authors believe that at present there is no evidence to support

that Helicobacter species play a role in EGGD pathogenesis.

5.5. Microbiota

Recent research has shown that horses with unclassiﬁed gastric disease have lower

gastric and fecal microbial diversity compared to healthy controls [

112

]. One study looking

at microbial communities from gastric ﬂuid and mucosal biopsies found differences in the

microbiome between horses with gross EGGD and controls [

102

]. Another study comparing

diseased and non-diseased areas of glandular mucosa within horses showed signiﬁcant

differences in Firmicutes and Proteobacteria [

111

]. Stomach bacterial diversity was shown

to cluster by bedding type, water access and feeding frequency in one study [

108

], and by

management involving stabling compared to pasture turnout in another [

109

]. A recent

study showed glandular mucosal microbiota to differ with multiple management factors

including offering hay, type of hay, provisions of ‘sweet feed’, turnout and stalling [

113

]. In

humans, an increase in the Firmicutes phylum, speciﬁcally the Streptococcus genus, is associ-

ated with non-H. pylori, non-NSAID associated gastritis [

]. Increasingly, the relationship

between microbiota and EGGD pathophysiology appears to be relevant, although unclear,

and the deﬁnition of a ‘healthy’ microbiota is not established at this time. Importantly, al-

though microbial differences exist between diseased and non-diseased animals, the authors

do not believe that this supports the use of antimicrobials for the treatment of EGGD at this

Animals 2023,13, 1261 7 of 25

point in time. Consistent with this, one study showed no improvement in gastric disease

with an oral antimicrobial in combination with omeprazole [114].

5.6. Management

Increased days of work per week is a risk factor for EGGD in both Thoroughbred

racehorse and Warmblood showjumper populations [

]. The prevalence of EGGD

doubles in endurance horses during the competition season [

]. These ﬁndings suggest

that exercise plays a role in the pathophysiology of disease. A proposed hypothesis for this

is the disruption of normal blood ﬂow to the stomach during exercise, with exercise acting

as a physiological stressor for the glandular mucosa [115].

Several studies have found an association between trainers and EGGD risk [

The reason for this is unclear.

One proposed mechanism is through environmental stressors with the domestication

and management of horses potentially playing a role in the pathophysiology of disease [

The ﬁndings of pet horses being at increased risk of disease, as well as increased time

spent with humans associated with increased ulcer grade in one study [

] support this

theory and ﬁt with the higher prevalence of EGGD in domesticated horses compared to a

feral population seen in another [

]. Horses diagnosed with EGGD have higher cortisol

responses to novel stimuli [

] and exogenous ACTH [

], as well as higher fecal cortisol

metabolites after exposure to novel stimuli [

], further supporting a role for behavioral

stress in the pathogenesis of disease.

6. Diagnosis

Gastroscopy is consistent and reliable in the diagnosis of squamous disease [

116

However, there are growing concerns regarding the signiﬁcance of gross glandular lesions

to their presenting complaints [

] and histological ﬁndings [

]. Gastroscopy has been

shown to have moderate inter- and intra-individual agreement for ESGD [

116

], but con-

siderable variability for descriptors of EGGD [

116

–

118

]. Further, there is also increasing

evidence of the lack of association between gross glandular lesions and histological evi-

dence of inﬂammation [

]. Therefore, the use of gastroscopy alone to determine clinical

signiﬁcance of lesions should be avoided, especially with regards to EGGD. Instead, other

factors, such as owner or trainer reported complaints and clinical signs and response to

therapy, should be considered alongside gastroscopy to assess the potential relevance of

gross mucosal changes.

The use of histopathology to assess disease, especially of the glandular mucosa, is

becoming increasingly described [

119

120

]. One study directly comparing gross

EGGD to histopathological disease showed poor correlation, with 71% of grossly normal

stomachs having mild gastritis, and all EGGD lesions demonstrating various degrees of

gastritis histologically, regardless of gross severity [

]. Another study demonstrated both

glandular gastric lymphoplasmacytic inﬂammation and eosinophilic inﬁltrate in a relatively

small sample population [

]. The comparison of biopsy techniques feasible via endoscopy

to full thickness samples post-mortem found the ‘double bite’ technique to yield the best

samples for assessment [

]. Larger samples for histopathology are described using a snare

when lesions are sufﬁciently raised, such as glandular polyps (Figure 1) [121].

Alternative means of diagnosis aside from gastroscopy are appealing. The use of

fecal occult blood testing for ESGD and EGGD was ﬁrst described over a decade and

a half ago, initially showing average performance in diagnostic ability [

122

]. Further

independent studies have been performed, indicating that fecal occult blood testing is

unreliable for the diagnosis of EGUS [

123

–

125

]. Similarly, studies show that hematology

and biochemistry or inﬂammatory markers, such as serum amyloid A (SAA), have little

clinical use in the diagnosis of, or screening for either ESGD or EGGD [126,127]. Research

into novel serum and salivary testing for detecting ESGD and EGGD has been undertaken

with some differences demonstrated between diseased and control populations, although a

Animals 2023,13, 1261 8 of 25

large degree of overlap exists between populations [

126

128

129

]. The clinical utility

of these tests is very limited at this point in time.

Animals 2023, 13, x 8 of 27

the best samples for assessment [88]. Larger samples for histopathology are described us-

ing a snare when lesions are sufficiently raised, such as glandular polyps (Figure 1) [121].

Figure 1. An adenomatous polyp in the pyloric region.

Alternative means of diagnosis aside from gastroscopy are appealing. The use of fecal

occult blood testing for ESGD and EGGD was first described over a decade and a half ago,

initially showing average performance in diagnostic ability [122]. Further independent

studies have been performed, indicating that fecal occult blood testing is unreliable for

the diagnosis of EGUS [123–125]. Similarly, studies show that hematology and biochem-

istry or inflammatory markers, such as serum amyloid A (SAA), have little clinical use in

the diagnosis of, or screening for either ESGD or EGGD [126,127]. Research into novel

serum and salivary testing for detecting ESGD and EGGD has been undertaken with some

differences demonstrated between diseased and control populations, although a large de-

gree of overlap exists between populations [50,89,126,128,129]. The clinical utility of these

tests is very limited at this point in time.

Initial investigation into sucrose permeability testing in a feed deprivation model of

disease found a correlation of urinary sucrose with ESGD with 83% sensitivity and 90%

specificity [130]. Further research into sucrose permeability testing by serial blood sam-

pling initially showed a difference between moderate or marked ESGD compared to the

baseline [131]. The same author then applied sucrose permeability testing to weanling

foals with gastric disease, finding a sensitivity of 81–97% with a poor specificity [132]. In

contrast, the same protocol in a wider sample of adults showed poor sensitivity and spec-

ificity for the detection of ESGD or EGGD compared to healthy controls [6]. Another

showed no association of sucrose permeability testing with ESGD or EGGD [133].

7. Grading

The continued use of the 0–4 scale described by the EGUS council [134] for the de-

scription of ESGD remains an effective way to classify and monitor disease and allows

easy assessment of large populations and comparison between studies. Anecdotally, the

authors note that some horses with grade 1/4 ESGD and clinical signs respond to therapy,

while other horses with grade 4/4 disease show no change in clinical signs with treatment.

Therefore, the usefulness of a numerical scale can be limited when applied at the individ-

ual patient level and the authors propose that it might be more appropriate to consider

disease on a dichotomous present or absent basis, consistent with the ECEIM consensus

statement recommendations [1].

Grading lesions of the squamous mucosa as described by Sykes et al [1], adapted

from Andrews et al [134]:

Figure 1. An adenomatous polyp in the pyloric region.

Initial investigation into sucrose permeability testing in a feed deprivation model

of disease found a correlation of urinary sucrose with ESGD with 83% sensitivity and

90% speciﬁcity [

130

]. Further research into sucrose permeability testing by serial blood

sampling initially showed a difference between moderate or marked ESGD compared to

the baseline [

131

]. The same author then applied sucrose permeability testing to weanling

foals with gastric disease, ﬁnding a sensitivity of 81–97% with a poor speciﬁcity [

132

In contrast, the same protocol in a wider sample of adults showed poor sensitivity and

speciﬁcity for the detection of ESGD or EGGD compared to healthy controls [

]. Another

showed no association of sucrose permeability testing with ESGD or EGGD [133].

7. Grading

The continued use of the 0–4 scale described by the EGUS council [

134

] for the de-

scription of ESGD remains an effective way to classify and monitor disease and allows

easy assessment of large populations and comparison between studies. Anecdotally, the

authors note that some horses with grade 1/4 ESGD and clinical signs respond to therapy,

while other horses with grade 4/4 disease show no change in clinical signs with treatment.

Therefore, the usefulness of a numerical scale can be limited when applied at the individual

patient level and the authors propose that it might be more appropriate to consider disease

on a dichotomous present or absent basis, consistent with the ECEIM consensus statement

recommendations [1].

Grading lesions of the squamous mucosa as described by Sykes et al. [

], adapted

from Andrews et al. [134]:

1. Grade 0 Epithelium intact, no appearance of hyperkeratosis

2. Grade 1 Mucosa intact, areas of hyperkeratosis

3. Grade 2 Small, single or multifocal lesions (Figure 2)

4. Grade 3 Large single or extensive superﬁcial lesions

5. Grade 4 Extensive lesions with areas of deep lesions

For EGGD, the recommendation at this time remains not to assign a grade to these

lesions, but instead, that lesions be described by anatomical location, distribution, severity

and appearance [

]. Appearance is described as hyperemic/hemorrhagic (Figures 2and 3),

erosive/ulcerated or ﬁbrinosuppurative, and by contour; depressed, ﬂat or raised [

]. The

existence of glandular gastric polyps is also considered as a form of EGGD [120,121].

Animals 2023,13, 1261 9 of 25

Animals 2023, 13, x 9 of 27

1. Grade 0 Epithelium intact, no appearance of hyperkeratosis

2. Grade 1 Mucosa intact, areas of hyperkeratosis

3. Grade 2 Small, single or multifocal lesions (figure 2)

4. Grade 3 Large single or extensive superficial lesions

5. Grade 4 Extensive lesions with areas of deep lesions

For EGGD, the recommendation at this time remains not to assign a grade to these

lesions, but instead, that lesions be described by anatomical location, distribution, severity

and appearance [1]. Appearance is described as hyperemic/hemorrhagic (Figures 2 and

3), erosive/ulcerated or fibrinosuppurative, and by contour; depressed, flat or raised [1].

The existence of glandular gastric polyps is also considered as a form of EGGD [120,121].

Figure 2. Multifocal, hyperemic lesions of the lesser curvature; grade 2/4 ESGD lesions.

Figure 3. Multiple, linear, flat, hemorrhagic lesions of the pyloric mucosa.

8. Treatment

The pathophysiology of ESGD is sufficiently well understood and studied to support

acid-suppression therapy as the basis of pharmaceutical therapy [1]. Conversely, the treat-

ment of EGGD is not as well understood. Without fully understanding the pathophysiol-

ogy of EGGD, it is difficult to create treatment recommendations based on the primary

Figure 2. Multifocal, hyperemic lesions of the lesser curvature; grade 2/4 ESGD lesions.

Animals 2023, 13, x 9 of 27

1. Grade 0 Epithelium intact, no appearance of hyperkeratosis

2. Grade 1 Mucosa intact, areas of hyperkeratosis

3. Grade 2 Small, single or multifocal lesions (figure 2)

4. Grade 3 Large single or extensive superficial lesions

5. Grade 4 Extensive lesions with areas of deep lesions

For EGGD, the recommendation at this time remains not to assign a grade to these

lesions, but instead, that lesions be described by anatomical location, distribution, severity

and appearance [1]. Appearance is described as hyperemic/hemorrhagic (Figures 2 and

3), erosive/ulcerated or fibrinosuppurative, and by contour; depressed, flat or raised [1].

The existence of glandular gastric polyps is also considered as a form of EGGD [120,121].

Figure 2. Multifocal, hyperemic lesions of the lesser curvature; grade 2/4 ESGD lesions.

Figure 3. Multiple, linear, flat, hemorrhagic lesions of the pyloric mucosa.

8. Treatment

The pathophysiology of ESGD is sufficiently well understood and studied to support

acid-suppression therapy as the basis of pharmaceutical therapy [1]. Conversely, the treat-

ment of EGGD is not as well understood. Without fully understanding the pathophysiol-

ogy of EGGD, it is difficult to create treatment recommendations based on the primary

Figure 3. Multiple, linear, ﬂat, hemorrhagic lesions of the pyloric mucosa.

8. Treatment

The pathophysiology of ESGD is sufﬁciently well understood and studied to support

acid-suppression therapy as the basis of pharmaceutical therapy [

]. Conversely, the treat-

ment of EGGD is not as well understood. Without fully understanding the pathophysiology

of EGGD, it is difﬁcult to create treatment recommendations based on the primary cause.

There is a body of evidence showing that acid-suppression therapy, in combination with

mucosal protection, is efﬁcacious in the treatment of EGGD, albeit with less success when

compared to the treatment of ESGD [29,123,135,136].

Healing rates for oral omeprazole monotherapy range from 67–100% for ESGD

[135,137]

and up to 100% using long-acting injectable omeprazole [

138

] over a 2–4 week period.

Treatment for ESGD remains as previously recommended [

] with proton pump inhibitors

(PPIs), such as omeprazole, as the cornerstone of therapy and other agents, such as H2

pump blockers, used if resolution is not seen.

In contrast to ESGD, oral omeprazole monotherapy has lower rates of EGGD healing,

at 14–25% [

135

138

]. However, up to 93% EGGD healing has been reported for a long-

acting injectable formulation [

]. It has long been recognized that, no matter the

cause of EGGD, reducing the acidity of the stomach can allow for healing of the glandular

mucosa [

]. The efﬁcacy of treatment for EGGD with oral omeprazole is improved by

adjunctive mucosal protection such as oral sucralfate [70].

Animals 2023,13, 1261 10 of 25

8.1. Omeprazole

The main changes to acid suppression therapy in recent years is the licensing of more

omeprazole formulations for horses. Different formulations of omeprazole paste have

differing pharmacokinetic proﬁles, and thus, different dosing recommendations [

]. Lit-

erature on the relative pharmacokinetics of different formulations of oral omeprazole in

horses is growing. A study comparing the pharmacokinetics between ﬁve oral omeprazole

concentrations found a buffered formulation and two enteric coated granule formulations

to have no differences to the reference enteric coated granule formulation [

138

]. Another

study directly compared the pharmacokinetics and pharmacodynamics of an enteric coated

granule-in-paste formulation with a buffered formulation at 4mg/kg and found no dif-

ferences [

139

]. In contrast, an enteric coated formulation was found to have a 26% higher

bioavailability in a further study [140].

The importance of minor variations in bioavailability are unclear in the clinical setting

but care should be taken in extrapolating the results of one formulation to another. In-

stead, the authors propose that clinical endpoints are likely a better marker for comparing

potential differences between formulations. A clinical study in Thoroughbred racehorses

found enteric coated omeprazole granules-in-paste formulation at 1, 2 and 4 mg/kg per os

(PO—orally) semel in die (SID—once a day) to not differ in their improvement and healing

rates for both ESGD and EGGD [

]. This is in contrast to an earlier study that found dosing

of a buffered formulation of omeprazole at 4 mg/kg PO SID to be superior to a 1.6 mg/kg

PO SID dose in ESGD, but not EGGD, healing [

135

]. These ﬁndings support the use of

formulations at their registered dose, regardless of formulation type, as the registration

process typically accounts for the interaction between variations in dose and bioavailability

between formulations.

Oral omeprazole has superior bioavailability when fed to fasted animals [

141

]. It is

also a pro-drug that is absorbed into systemic circulation and requires activation in response

to feeding before reversibly binding and inhibiting proton pumps in the stomach [

142

As such, it is preferred that omeprazole is given after a period of fasting and prior to a

meal

[29,115,135,143]

. Due to the normal circadian rhythm of feed intake in horses, remov-

ing feed to enforce an overnight fast has minimal effect on gastric pH [

144

]. Therefore, it is

recommended to give omeprazole early in the morning after a period of overnight fasting,

a minimum of 30 min before the re-introduction of feed (see Figures 4and 5) [20,115].

Animals 2023, 13, x 11 of 27

Figure 4. Proposed timing of omeprazole administration and feeding.

Figure 5. Proposed timing of omeprazole and sucralfate administration and feeding.

Given the role of exercise-associated gastric contraction and acid splash in the path-

ophysiology of ESGD [81], as well as the duration of acid suppression not spanning a full

24 hours [143,145], it is logical that timing the omeprazole treatment pre-exercise would

be superior for the healing of ESGD lesions [29]. A single study comparing treatment tim-

ing found a trend for the timing of feeding to affect the outcome; however, this was not

statistically significant, likely due to an inadequate population size [135]. Considering

this, the effect of omeprazole timing should not be dismissed at this time and the authors

recommend administering omeprazole followed by a small feed prior to exercise to opti-

mize acid suppression at the time of peak injury to the squamous mucosa.

Earlier investigations into long-acting intramuscular omeprazole at 7-day intervals

for 2 weeks found the resolution of 52–100% and 54–75% of ESGD and EGGD, respectively

[5,146]. A further 2 weeks of treatment increased resolution rates to 86% and 58% of ESGD

and EGGD, respectively [146]. Two small parallel retrospective studies comparing 4

mg/kg IM long-acting injectable omeprazole weekly to conventional oral omeprazole

found the injectable formulation to be non-inferior for the treatment of ESGD and EGGD

[57]. A recent study showed superior results using a compounded, long-acting intramus-

cular formulation (currently available in Australia, the UK and Canada) at 5-day intervals

compared to 7-day intervals, with 97% and 93% resolution of ESGD and EGGD, respec-

tively, over 4 treatments [66]. In contrast, a study comparing the compounded formulation

of long-acting injectable omeprazole available in the Unites States, given weekly, found

no difference to conventional oral omeprazole treatment [147]. This formulation is also

responsible for a higher rate of injection site reactions at 8% after the first injection, in-

creasing to 48% at the 4th injection [147], compared to 1.2–6.5% over the treatment course

for the Australian/UK/Canadian formulation [56,57,66,146].

The duration of acid-suppressive therapy should also be considered. Evidence sup-

ports that 3 weeks of treatment is sufficient for ESGD treatment [137] and that if healing

has not occurred in that time, then the benefit of prolonged treatment is unclear. Similarly,

recent reports suggest that 3–4 weeks of treatment might be sufficient for EGGD if ade-

quate acid suppression can be achieved [66].

8.2. Sucralfate

Sucralfate is a complex polyammonium hydroxide salt that adheres to the glandular

mucosa. Proposed benefits of this treatment, additional to acting as a physical barrier to

acid diffusion, includes the stimulation of mucus secretion, inhibition of pepsin and bile-

acid release, prevention of fibroblast degradation, stimulation of growth factors and in-

creased production of prostaglandin E [115]. With the uncertain and likely complicated

pathophysiology of EGGD, the addition of a mucosal protectant to acid suppression ther-

apy for this disease is logical, consistent with the current Consensus Statement recommen-

dations [1]. Supporting this, a combined omeprazole and sucralfate therapy for the treat-

ment of EGGD is superior to omeprazole alone [148]. The recommended dose is currently