9 Feb 2015
Andy Durham
Job Title
What have we learned, and what is there left to learn, about gastric ulceration? Perhaps the predictable answer is it’s not as simple as first thought.
Initial clinical and experimental studies of gastric ulcers in horses placed significant emphasis on disease of the squamous mucosa. This may have been partly due to the high prevalence of this disease in racehorses, where both research interest and funds are always higher. It may also have been due to the relative ease of examination of this part of the stomach in comparison to the subjacent glandular mucosa. Consequently, a good understanding of the pathophysiology, as well as effective treatment and management, of squamous mucosal disease has developed, which has left gastric glandular disease somewhat trailing in its wake.
Gastric ulceration is a disease of high prevalence in performance horses and low-forage, high-cereal diets have long been recognised in association with increased prevalence of gastric ulcers in racehorses (Hammond et al, 1986). The upper squamous mucosa and lower glandular mucosa of the equine stomach have markedly different properties relevant to the interaction of diet and exercise.
Consistent with evolutionary development as a “continual browser” or “trickle feeder”, the equine stomach secretes hydrochloric acid (HCl) almost continually, leading to normal prolonged exposure of glandular mucosa to acid. Unsurprisingly, development of a strong prostaglandin-dependent antacid defence can be demonstrated in this area of the stomach in contrast to minimal intrinsic defence in the squamous mucosa. Instead, the squamous mucosa largely relies on protection by bicarbonate-rich, saliva-soaked ingesta to protect against acid contact.
Consequently, low-forage intake, especially when combined with gastric fluid agitation by fast exercise, inevitably contributes to squamous mucosal ulceration typical of racehorses. Forage filling the stomach serves to limit mixing and movement of acidic fluid in the stomach and also incurs a considerably increased secretion of salivary buffer than a cereal diet. Additionally, high-cereal diets may stimulate a more prolonged gastrin secretory response (Smyth et al, 1989), further increasing the corrosive properties of gastric fluid.
The harmful effect of HCl may be compounded by the presence of volatile fatty acids (VFAs) in the gastric fluid, such as acetic, propionic, butyric, valeric and isovaleric acids, which arise from bacterial fermentation of food (especially starches) in the stomach. Furthermore, high-starch meals tend to reduce gastric emptying rates and, therefore, further promote fermentative production of VFAs. Most VFAs will be primarily in their non-ionised form in low pH gastric fluid. Diffusion of VFAs across squamous mucosal cell membranes is facilitated by their non-ionised status, and subsequent dissociation of their hydrogen ion within the nearly neutral pH of the cytosol may cause harmful intracellular acidification and cell death (Nadeau et al, 2003).
Thus, gastric squamous mucosal disease has made good sense in terms of the understanding of the pathophysiology of the disease and how this translates to effective treatment and prevention. If squamous mucosal disease occurs simply from acid contact with a mucosa with negligible intrinsic defence, then predictable healing should occur following acid neutralisation and, indeed, consistently high healing rates are reported following omeprazole therapy.
Increased forage access – in terms of quantity, quality and duration – also helps prevent squamous mucosal disease. The combination of fast work and an empty stomach, which might make some superficial sense in anthropomorphic terms, is to be avoided in equine athletes. It is common for racehorses to be exercised when the stomach is relatively free of food content. This practice is partly based on the analogy human athletes feel uncomfortable if running with a full stomach, but it does inevitably promote agitation, movement and splashing of acidic fluid in the stomach during exercise, especially if dietary management has promoted fluid gastric content. Although human athletes suffer a high incidence of gastric symptoms during endurance exercise, the contact of low pH fluid with the equine squamous mucosa is likely to be even more poorly defended than that in the human stomach. Given the relative small size of the equine stomach it is unlikely equines experience the same sensation of fullness as humans would after a meal and the benefit of prevention of acid splashing by a pre-exercise forage feed is significant (Lorenzo-Figueras and Merritt, 2002).
Training significantly increases serum gastrin levels in response to feeding in horses (Furr et al, 1994) and may be a contributor to exercise-induced gastric acidity and ulceration. Alfalfa feeding may offer an additional protective effect in comparison to grass hays (Nadeau et al, 2000). The reasons behind this are speculative, but might involve higher protein content leading to buffering of gastric fluid and reducing mucosal uptake of VFAs, or perhaps another mechanism related to higher calcium content.
Thus, it seems we have squamous mucosal disease fairly well worked out; however, it would never be right to think there is no more to learn and, undoubtedly, questions remain in some atypical cases with squamous ulcers in the absence of obvious risk factors (for example, le Jeune et al, 2006) or in the few that appear quite resistant to antacid therapy.
Gastric glandular disease appears to be a markedly different disorder and is very commonly encountered, especially in populations other than racehorses, and undoubtedly poses greater therapeutic challenges. Glandular disease clearly cannot be created by simple acid contact as this part of the stomach has evolved in almost continuously low pH and is consequently well adapted to this acidic environment. Although some horses may suffer coexisting squamous and glandular ulcers, it is common to see one without the other, also suggesting different causation/risk factors. Many horses with quite severe glandular disease are good eaters with continual access to a high-forage, low-starch diet, and perform relatively little fast work (Figure 1).
Although anatomically adjacent, the squamous and glandular mucosae have little else in common with markedly contrasting histologic structure, physiology and function. Consequently, squamous and glandular gastric disease should perhaps be thought of just as distinctly as we regard dermatitis versus colitis. Furthermore, even the lesions tend to differ, with simple epithelial removal typifying squamous disease (Figure 2), whereas more superficial erosion and inflammatory/ haemorrhagic lesions are seen most commonly in the glandular area (Figure 3).
It might make sense that antagonism of prostaglandins could predispose to glandular disease given its importance in coordinating defence of this area. NSAID-induced gastric ulceration does occur primarily, but not exclusively, in the prostaglandin-dependent gastric glandular mucosa (Monreal et al, 2004). However, there appears to be little evidence NSAID therapy at commonly used doses is a significant cause of gastric ulceration in horses (Hammond et al, 1986; Murray et al, 1996). Endogenous glucocorticoids associated with stress could also potentially harm PG-mediated defence of the glandular mucosa, although experimental studies looking into stress factors have generally failed to control for other important associated risk factors such as dietary intake patterns (McClure et al, 1999, 2005).
Perhaps glandular disease seen in foals might be more likely to be stress-related given its more extensive nature compared to adult glandular disease, although that remains to be established. Glandular disease in adult horses is rarely seen outside of the peri-pyloric area, and anatomic and physiologic idiosyncrasies of this location might be the key to establishing causation – for example, bile acid reflux from the duodenum is likely to impact primarily the peripyloric area and, as described for VFAs, bile acids in their non-ionised form in the low pH gastric fluid may diffuse into mucosal cells leading to cell death and necrosis (Murray, 1999) although this is not a theory supported by all studies (Widenhouse et al, 2002).
Dietary oils have been proposed as a means of defending against gastric ulceration. Possible beneficial mechanisms of action might include provision of substrate for prostaglandin synthesis (likely to primarily aid gastric glandular mucosal defence) or possibly by binding free bile acids in the gastric fluid. However, studies have not consistently found dietary oils to reduce gastric ulcers in horses (Cargile et al, 2004; Frank et al, 2005).
Gastritis is a well-recognised consequence of prolonged exercise in humans and dogs (Simons and Kennedy 2004; Davis et al, 2006) and has been mainly attributed to decreased gastrointestinal perfusion, a key element of glandular mucosal defence (Murray, 1999). Involvement of bacteria in glandular ulceration might be supported by the frequent identification of organisms in the ulcer bed of glandular lesions; however, given the tremendous bacterial populations residing in the equine stomach it would hardly be surprising to find mucosal injuries become colonised as a secondary event.
Thus, perhaps what we have learned in the past 30 years is how squamous mucosal ulcers are an occupational hazard of performance horses, given their traditional diets and exercise programmes. We also know they can be treated effectively with omeprazole and prevented by reasonable modifications of diet and exercise without impairing the intended usefulness of most horses. On the other hand, we have learned little about gastric glandular disease other than how to recognise and diagnose the condition. Treatment choices are less clear and treatment responses are slow and sometimes easy to confuse with placebo. Gastric glandular disease is clearly the disease we need to understand better.
Figure 1. Multiple deep peri-pyloric glandular ulcers found in a field-living cob subject to occasional exercise. No apparent risk factors have been identified.
Figure 3. Typical nodular inflammatory lesion with some diphtheresis and minor haemorrhage adjacent to the pylorus.
