Equine Gastric Ulcers

Equine gastric ulcer syndrome (EGUS): Separating Fact from Fiction

Benjamin R Buchanan, DVM, DACVIM, DACVECC

Specialist Equine Internal Medicine

Specialist Equine Critical Care

Equine gastric ulcer syndrome (EGUS) is common in performance horses. Depending on the environment up to 90% of horses can be affected. All age and breeds are susceptible and current therapeutic strategies focus on modalities to raise stomach pH. Currently only one approved pharmaceutical agent for the treatment of EGUS exists (Gastrogard^TM Merial). Management strategies are also important in preventing and treating the condition.

The term gastric ulcer most commonly refers to ulceration of the non-glandular mucosa of the equine stomach. EGUS typically includes gastric non-glandular, gastric glandular and esophageal ulcerations.

The equine stomach is unique in anatomy with the proximal third of the stomach lined with squamous epithelium, and the distal 2/3 lined with glandular mucosa responsible for the secretion of pepsinogen and hydrochloric acid. The esophagus is a tube of smooth muscle with non-glandular mucosa connecting the oropharynx to the cardia of the stomach. Smooth muscle in the distal esophagus functions as a “sphincter” or “valve” preventing reflux of acid. Acid induced injury of the esophagus occurs when this sphincter allows acid exposure of the distal esophageal mucosa.

The glandular mucosa is very important in activation and secretion of hormones critical to digestion. The glandular stomach has two types of glandular cells: gastric and pyloric glands. The gastric gland is made up of mucus producing cells, chief cells, and parietal cells. The chief cells produce pepsinogen. The parietal cells produce hydrochloric acid and intrinsic factor. The pyloric glands produce predominately mucus and gastrin.

               

The gastric gland is under the influence of both neural and hormonal signals. Acetylcholine release by the nervous system stimulates the production of both types of glandular cells directly. During digestion gastrin cells release gastrin which stimulates the enterochromaffin cells to produce histamine. Histamine has a direct and profound effect on the gastric gland to release HCl.

Discussion about the development of gastric ulcers focuses on protective and aggressive factors, which are different in the different areas of the GI tract.

PROTECTIVE FACTORS

Protective factors in the glandular mucosa include mucus production, bicarbonate production, and epithelial restitution. The typical pH of this area is 2-3. Because of the constant acid exposure, the glandular mucosa has many anatomical features which protect it from acid injury. Bicarbonate rich mucus production creates an alkaline barrier at the luminal surface. What acid diffuses through this barrier is absorbed quickly buffered and transported away from the stomach by an extensive capillary network. The mucus production and blood flow is regulated by production of prostaglandins.

The protective factors of the esophagus and nonglandular gastric mucosa are limited when compared to the glandular mucosa. There is no buffering capacity from bicarbonate or mucus secretion. Epithelial restitution to repair ulcerated tissue is the primary protective mechanism of the non-glandular mucosa. Buffering of acid in the non glandular area of the stomach is accomplished by salivary bicarbonate and consumption of hay and grass. The typical pH of this area is 5-6.

AGGRESSIVE FACTORS

Aggressive factors for all of the gastric mucosa include exposure to hydrochloric acid, exposure to volatile fatty acids (VFA), pepsin conversion from pepsinogen, and exposure to duodenal reflux of bile. Of these factors the most significant are hydrochloric and VFA exposure. Acid exposure develops during exercise when increased abdominal pressure decreases stomach volume and exposes more of the non glandular tissue to low pH gastric fluid. Frequent exercise of performance horses may be one reason for the increased incidence of nonglandular ulcers found in this group. Exercise may decrease in gastric blood flow and increase serum gastrin which stimulates acid production.

Intermittent feeding or reduced voluntary intake leads to increased acid exposure. When continuous grazing is an option the gastric pH stays elevated (>4) for most of the day. When feed is withheld, gastric pH drops rapidly. Intermittent feeding is one model for creating gastric ulcers and barn management which does not provide hay continuously increases the risk for gastric ulceration. Transportation and stall confinement are the two most common methods of involuntary fasting.

Bacterial fermentation of carbohydrates in the stomach leads to production of volatile fatty acids. These VFAs typically have a pKa of around 4. This means that at pH above 4 they are dissociated and do not penetrate the mucosa. At a pH close to 4 these acids become partially dissociated and lipophillic, and at lower pH they are undissociated, highly lipophillic and able to penetrate the mucosa. Once inside the cell where the pH is elevated they dissociate and alter the intracellular function leading to submucosal swelling and cell death. When combined with an acidic stomach environment the damage is more severe than exposure to hydrochloric acid alone. Lactic acid has not been shown to be synergistic with hydrochloric acid in non glandular ulcer pathogenesis.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is often implicated as a major cause of gastric ulceration. They inhibit prostaglandin production which is important for regulation of glandular blood flow and protection of the glandular mucosa. The role of NSAIDs in non-glandular ulcer development is probably overstated as the mucosal blood flow is not a major protective mechanism.

Aggressive factors in the glandular mucosa include all those listed for the non-glandular stomach. Additionally, local bacterial infections have been theorized but never proven to be involved in chronic non-responsive ulcerations of this area. Because the protective mechanisms depend on prostaglandins, the use of NSAIDs (which inhibit prostaglandin production) will cause ulcers in this region.

CLINICAL SIGNS

Clinical signs of EGUS are numerous and often vague. Common clinical signs include refusing grain, partial anorexia, recurring colic, poor performance, and stretching often to urinate. Other symptoms reported to occur secondary to ulcers includes acute colic, excessive recumbency, poor body condition, attitude changes, inadequate energy, and chronic diarrhea.

DIAGNOSIS

Several options are available in diagnosing gastric ulcers. Gastroscopy with a 3 meter endoscope following a 12-24 hour fast allows visualization of the esophagus, non-glandular mucosa, glandular mucosa, and proximal duodenum. Partial gastroscopy can be accomplished with an endoscope of 2.5 meters in most horses. Specialized 3 meter videoendoscopy systems are becoming increasingly common and affordable and are necessary to adequately visualize the pylorus and duodenum.

A newer technique for diagnosing damage to the gastric mucosa is a sucrose absorption test. After sucrose is emptied into the proximal portion of the small intestine, it is rapidly hydrolyzed to its monosaccharide units by the brush border enzyme sucrase-isomaltase; this occurs even in the face of severe small intestinal disease. Any absorption of the intact sugar is thought to occur through defects in the gastric mucosa. The sugar is concentrated in the urine, and increasing concentration is thought to be an indication of ulcer severity. Two techniques have been described. For the original test, the bladder is drained, a dose of table sugar is administered orally, and urine collected two hours later. Recently the test has been modified to a single blood sample 30 to 90 minutes after NG administration of sucrose.

When finances or availability preclude the use of a gastrocope to diagnose ulcers, a tentative diagnosis can be made based on clinical signs, ruling out other diseases, and response to therapy. Clinical signs related to gastric ulcers should abate in 3-4 days after appropriate treatment. However, gastroscopy is often helpful in predicting the length of treatment.

               

TREATMENT

Drug therapy to treat EGUS can be divided into two categories: those that alter gastric pH, and those that alter other factors. To date the only therapy that has achieved positive results in clinical and experimental research are drugs that alter the gastric pH. Such drugs include proton pump inhibitors, histamine type 2 receptor antagonist, and antacids. A Google search netted 30+ pages, and a quick search of the AAEP and ECN list serves found one discussion on ulcer treatment each month for the last two years. However, only therapies that have been published in peer reviewed literature will be discussed here.

               

Proton pump inhibitors prevent the exchange of potassium for hydrogen in the lumen of the gastric gland. Omeprazole is a proton pump inhibitor, and is the standard of care for treating gastric ulcers in the horse. Merial has formulated a paste into 4 gram tubes; Gastrogard^TM. Orally administered Gastrogard^TM at 4 mg/kg will maintain gastric pH >4 for 18-24 hours. Because this is a FDA approved product currently under patent protection, there is no “generic” formulation and compounded formulations are illegal.

               

Additionally omeprazole is not an easy product to force into a solution or paste unless it is dissolved in an acid medium. Using an acid medium for a vehicle shortens the shelf life of omeprazole, which may be the reason for the frequent failures of these products in treatment. Also worth noting is that omeprazole begins to turn dark and/or purple as it loses its potency.

An intravenous form of omeprazole has not been FDA approved for use in horses, but can be legally purchased for administration to horses that are unable to consume products orally. While often cited as being prohibitively expensive, it affordable from certain compounding pharmacies. Recently this product was shown to be effective at suppressing acid production at a dose of 0.5 mg/kg intravenously once daily.

The histamine type 2 (H2) receptor antagonists competitively inhibit the effect of histamine on the gastric glands.  Because the horse has constant acid secretion, the effect of these drugs is dependent on appropriate doses, frequent administration and maintenance of therapeutic levels. A recent study found that 96% of horses in race training on H2 receptor antagonists had evidence of gastric ulcers, most likely due to inappropriate dosing. Ranitidine is the most frequently studied H2 receptor antagonist in horses. At a dose of 6.6 mg/kg PO every 8 hours, it will effectively prevent ulcers in a feed fast model and will inhibit acid secretion. Lower and less frequent doses are not effective. Cimetidine has also been used in horses. Very little research has been done with cimetidine and it does not appear to be effective.

Oral antacids are effective at increasing gastric pH. However, they must be given in large doses and frequently. In a study comparing aluminum hydroxide/magnesium hydroxide and bismuth subsalicylate, only a dose of 30 g of aluminum hydroxide/ 15 g of magnesium hydroxide resulted in a significant increase in gastric pH over baseline or control values. Mean pH was 5.2 +/- 0.62 and 4.59 +/- 0.48 for post treatment hours 1 and 2, respectively.  Each 5 ml of Extra Strength Maalox contains 400 mg magnesium hydroxide, 306 mg aluminum hydroxide and 40 mg simethicone. This means a horse would need almost 100 ml to raise gastric pH for two hours.

Many agents are purchased for the treatment of gastric ulcers that are not acid inhibitors. Many are based on human physiology which target the more uncommon ulcers of the glandular mucosa. Use of dietary rice bran oil had no protective effect on the development of non glandular ulcers in a feed fast model. Corn oil on the other hand, did have a potential protective benefit on the glandular mucosa.

Despite their popularity no other published reference could be found for the multitude of products pushed on clients for treating gastric ulcers.

PREVENTION

There has also been discussion recently on the prevention of gastric ulcers. Because the development of non-glandular ulcers requires constant acid exposure, intermittent inhibition of acid secretion may be preventative. While a 1 mg/kg dose of oral omeprazole may not inhibit acid secretion for 24 hours, when targeted for times of day when there is a high risk of low pH, it may be beneficial in preventing ulcer development. For example giving a 1 mg/kg dose at night when the horse is stalled or not grazing my help horses that do not have turnout or free choice hay all day long. Merial is currently marketing Ulcergard^TM which contains the same amount of omeprazole per tube as gastrogard but is dosed at 1 mg/kg instead of 4 mg/kg.

Another target strategy is to start performance horses on a 4 mg/kg dose of gastrogard a day or two before they ship to a competition and maintain them on gastrogard for the duration of the competition. This will protect the horse from ulcers as it adapts to a new environment and feeding schedule. Prescribing Gastrogard or Ulcergard based on a horse’s risk, may ease some of the financial concerns of the owner. (Table 1)

While the use of drugs is often on everyone’s treatment plan for gastric ulcers, diet and management are also important factors to consider. Addition of alfalfa to the diet has been shown to reduce the number of gastric ulcers seen on endoscopy. Additionally, in vitro, addition of calcium improved recovery of tissue exposed to HCl and volatile fatty acids.

Equine gastric ulcer syndrome is a common problem in performance horses. Understanding the pathophysiology is important in developing rationale treatment and management plans.

TABLE 1 Prevention strategies based on horse’s risk for EGUS

Level of Risk	Husbandry	Diet	Therapy for Prevention
Intense / Race training	Stall confinement	Free choice grass hay and alfalfa. Fed prior to grain.	1-2 mg/kg of Omeprazole PO in evenings
Moderate / Show training	Some pasture turnout	Free choice grass hay and alfalfa when stalled. Fed prior to grain	1 mg/kg of Omeprazole PO in evenings. Alternatively treat with 4 mg/kg Omeprazole PO beginning 3 days before stressful event and continuing for duration of event.
Minimal / Pleasure horse	Complete pasture maintenance	Maintained on pasture	Teat with 4 mg/kg Omeprazole PO beginning 3 days before stressful event and continuing for duration of event.