This discussion was extracted from the broader article discussing colic (also on this web site) by Dr. Terry Gerros. We chose to highlight this topic because it has particular value and application to miniature horses in general and foals in particular. In addition to what Dr. Gerros describes in detail here, we have read numerous other publications that state ulcers are more prevalent in horses than most people recognize and can be a real source of problems. Horses are prone to stress whether it be from travel, illness, medication, the show and training environment, moving to new surroundings, changes in feed and the list goes on. Horse owners need to be aware of the tendency toward ulcers and the debilitating effect they can have. The article that follows is very detailed as well as being technical but provides a great source of information on this important subject. Although this article discusses primarily foals, it applies equally to all horses particularly those in stressful situations.
Terry C. Gerros, DVM, MS, Diplomate, ACVIM
Ulcers are defects in the gastrointestinal mucosa that penetrate the muscularis mucosa. This distinguishes them from superficial erosions that do not extend through the muscularis mucosa. In humans, the term peptic ulcer indicates ulcers which occur in the stomach, pylorus, or duodenal bulb but also can develop in the esophagus and the postbulbar duodenum.
There have been various hypotheses offered to explain the cause of gastroduodenal ulceration in foals, few have been proven. In general, ulcers occur when luminal aggressive factors overcome opposing mucosal defenses. There are four clinical syndromes of gastroduodenal ulcers which have been recognized: asymptomatic erosions and ulcers, symptomatic ulcers, perforating ulcers, and ulcer-associated gastric or duodenal obstructions.
Diagnosis is based on clinical findings, contrast radiography, fiber-optic gastroscopy, and most recently determination of serum pepsinogen levels. Treatment has traditionally been with antisecretory drugs, cytoprotective agents, and antacids.
In addition to the mucus-secreting cells that line the surface of the stomach, the stomach mucosa has two different types of tubular glands: the oxyntic or gastric glands and the pyloric glands. The gastric glands contain chief (peptic) cells, parietal (oxyntic) cells, and mucous neck cells, which secrete pepsinogen, hydrochloric acid, and mucus, respectively. The pyloric glands primarily release mucus, for protection of the pyloric mucosa, pepsinogen, and the hormone gastrin (produced from gastrin (G) cells).
Three endogenous chemicals (acetylcholine, gastrin, and histamine) stimulate gastric acid and pepsinogen secretion. Acetylcholine, a neural transmitter, is released by vagal efferent neurons. Vagal stimulation of acid secretion occurs in response to sight, smell, taste of food, or chewing and swallowing. Local neurons within the wall of the stomach also release AcH and are activated when the stomach is distended. Gastrin is a hormone responsible for acid secretion. Protein in food is the most potent stimulant of gastrin release, but vagal stimulation, calcium, other cations such as magnesium or aluminum, circulating catecholamines, bombesin-like immunoreactive substances or alkalinization of the antrum also release gastrin.
Secretion of gastrin is inhibited by a gastric pH less than 2.5, by somatostatin, and by certain prostaglandins. Histamine stimulates acid secretion via a paracrine mechanism. Mastlike cells that contain histamine are located in the lamina propria of the stomach in close proximity to parietal cells. When histamine is liberated from mast cells, it diffuses through intercellular spaces to reach parietal cells. Gastrin or AcH or both may release histamine from mast cells. AcH, gastrin, and histamine are believed to act on receptors on parietal cell membranes to cause acid secretion.
Mechanisms within the parietal cell that leads to acid secretion are not well defined. It is believed that cAMP is important in the mediation of histamine-stimulated acid secretion, while Ca++ entry into parietal cells is believed to play a role in AcH-stimulated secretion. A hydrogen/potassium adenosine triphosphatase (ATPase) enzyme is located on the luminal surface of parietal cells. This enzyme serves as a proton pump, which is the final step in secretion of hydrogen ions.
In fasted horses, there is a continuously variable gastric fluid secretion that is not stimulated by offered food. Under normal feeding conditions, the stomach is never completely empty. Gastric emptying begins very soon after a horse starts to eat. When feeding stops, the contractions cease and the stomach retains its contents; the contents undergo a degree of digestion and reach a critical size for removal. The gastric fundus is responsible for storage of food. The body of the stomach serves as a mixing vat, and the antrum is involved with propulsion of the chyme to the duodenum. Equine gastric acid and pepsin are secreted continuously during fasting conditions, and gastric fluid was produced at approximately 1 liter/hour, having a pH of approximately 2.0. Since acid and pepsin are necessary for ulcerogenesis, inhibition of acid production or increasing mucosal protection are two avenues to prevent mucosal damage. Pepsin output generally follows acid output, and since acid is required to activate transformation of pepsinogen to pepsin, inhibition of acid also accomplishes reduction in pepsin proteolysis.
**MAINTENANCE OF NORMAL MUCOSAL INTEGRITY**
Defense mechanisms which protect the gastric and duodenal mucosa from damage by acid, pepsin, bile, and pancreatic enzymes include mucus, bicarbonate, mucosal blood flow, and cell renewal. Endogenous prostaglandins currently are the most likely candidates as mediators to control these defense mechanisms.
Mucus. This secretory product is a gel that forms a thin, protective coat over superficial mucosal cells. Mucus has several functions:(1) to protect underlying cells from mechanical forces of digestion; (2) to lubricate the mucosa, assisting movement of food over mucosal surfaces; (3) to retain water within the mucus gel and thereby provide an aqueous environment for underlying cells; and (4) to form an unstirred layer impeding, but not blocking, diffusion of hydrogen ions from the lumen to the apical membrane of epithelial cells.
Bicarbonate. A bicarbonate-rich fluid is secreted by surface epithelial cells in the stomach and duodenum. Although some bicarbonate reaches the lumen, much of the secreted bicarbonate remains below or within the mucus layer. Thus, the, mucosal surface is in contact within fluid that contains a high pH relative to the lumen of the stomach. Under normal conditions, hydrogen ions are neutralized by bicarbonate (producing CO2 and H2O) as they diffuse through the mucus gel layer. A pH gradient is thus established between the lumen and surface epithelial cells.
Mucosal Blood Flow. The rich blood supply of the stomach and duodenum is important in maintaining normal mucosal integrity. Gastric and duodenal mucosae are supplied by extensive mucosal capillaries that traverse the glandular area of the stomach and duodenum. Beneath the muscularis mucosa, an extensive system of submucosal arteries and a submucous plexus of arteries and veins regulate the blood supply to surface epithelial cells.
Cell Renewal. Normal cell renewal is also an important factor in maintaining mucosal integrity. Cells are constantly dying and are being replaced by new cells. In order for this system to function normally, there must be a balance between cell loss and cell renewal. Disruption of this steady state may lead to mucosal damage.
Endogenous Prostaglandins. Prostaglandins of the E, F, and I types are found in the gastric and duodenal mucosa. When administered exogenously, PG’s stimulate secretion of mucus and bicarbonate and increase mucosal blood flow. PG’s may also have a trophic effect on the mucosa. Duodenal mucosal PG’s appear to stimulate basal duodenal bicarbonate secretion and its response to luminal acid. Exogenously administered PG’s protect the mucosa against a variety of noxious agents, including bile acids, NSAID’s, ethanol, and boiling water, this is termed cytoprotection. Based on the properties of exogenous PG’s, it is presumed that endogenous PG’s have a similar effect.
Many factors predisposing to GDU in foals have been incriminated but few have been proven. Presently, NSAID’s have been the only documented cause of GDU in foals. Such environmental stresses as very hot weather, overcrowding, and excessive handling have been associated with GDU. Dietary factors are also believed to play a role. It has been suggested that alfalfa hay and sweet feed rations presented to mares give rise to plant steroids and toxins in the milk, which probably have an irritating effect on the foals’ gastric mucosa.
A high-protein, high fiber diet thus can act as a buffer against gastric acidity. Occasionally, rotavirus, Salmonella spp. or Candida infection is found in association with ulceration in foals.
The pathophysiology of gastroduodenal ulceration in foals has not yet been determined but it is presumed to be comparable to that in other animals and humans. The presence or absence of an ulcer is determined by the delicate interplay between gastric acid secretion and mucosal resistance. Ulceration is produced when the aggressive effects of acid-pepsin dominate over the protective effects of gastric or duodenal mucosal resistance. A disruption of the normal mucosal/mucus protective barrier and the epithelial barrier by breakage of the connecting intercellular bridges thus promotes the back diffusion of hydrogen ions into the mucosa. This mechanism results in cellular injury and allows an increase of acid secretion by activating histamine release from nearby mast cells. The small blood vessels are simultaneously damaged, resulting in mucosal hemorrhage, local thrombosis/ischemia, superficial ulceration, and finally ulceration.
**CLINICAL PICTURE AND SYNDROME**
Based on clinical, post mortem, and surgical findings, four clinical syndromes can be defined for foals with gastroduodenal ulcers.
These occur most often in the non-glandular portion of the stomach along the margo plicatus in foals <30 days of age. These lesions are frequently associated with desquamation of the squamous epithelium. Desquamation may occur with or without ulceration. The lesions are usually singular and non-perforating. There may be hemorrhage associated with the lesion. In the majority of foals these lesions apparently resolve without treatment and without causing a clinical problem. If clinical signs do occur, diarrhea and poor appetite are most frequently observed.
These occur in foals one day to about four months old. They may heal spontaneously or develop into more life-threatening complications. Abdominal pain may be manifest by restlessness, rolling and lying in dorsal recumbency. Excessive salivation and bruxism are also common signs present in these foals and presumably reflect reflux of gastric juice into the esophagus and mouth. The tongue may also be coated with a white to grey plaque signifying dehydration or chemical irritation. Affected foals may retch upon passage of a NG tube. Some affected foals may be sensitive to palpation over the paracostal regions or near the xiphoid. Other non-specific signs include mild depression, periodic tachycardia and tachypnea, decreased borborygmi, inconsistent reflux of gastric fluid following NG intubation and diarrhea. Foals that present with the classic signs of GDU, which include bruxism, dorsal recumbency, salivation, interrupted nursing, and/or colic, almost invariably have lesions in the glandular mucosa of the stomach and/or duodenum.
These almost always result in diffuse peritonitis and mortality that approaches 100%. The lesions apparently are most common in the nonglanular stomach. Small perforations may heal spontaneously by adhesions, although abscessation can occur later at these sites. These foals exhibit profound depression, signs of cardiovascular collapse (extreme tachycardia and injected, toxic mucus membranes), tachypnea, and varying degrees of peritoneal pain. Disease progression is rapid and the foal usually dies within several hours despite attempts at surgical correction and intensive care.
Ulcer-associated gastric or duodenal obstruction (stricture)
This arises from healing ulcers that produce cardiac, antral, pyloric, or proximal duodenal strictures. Strictures involving the proximal duodenum appear to be more common than those involving the stomach. Segmental ulcerative duodenitis, rather than a discrete duodenal, ulcer, occurs near the entrance of the bile duct in some foals. Other foals develop extensive diffuse thickening of the duodenum and proximal jejunum. Foals with interference of pyloric outflow or duodenal flow exhibit signs of active ulceration except that gastro-esophageal reflux is more consistent and pronounced. All the classic signs of ulceration are present. “Tongue sucking” may also be observed. Aspiration pneumonia may occur in these foals because of the volume of gastric reflux.
Foals with ulcer-associated obstruction are usually three to five months old, and may present with dehydration, hypochloremia and moderate acidosis. Less consistent electrolyte disturbances include hyponatremia and hypocalcemia. Prognosis is grave without surgical intervention.
Detection of a pyloric stricture via gastroscopy is highly subjective, and since it is near impossible to pass an endoscope into the duodenum, duodenal strictures are almost impossible to see. Contrast radiography demonstrates a flaccid esophagus filled with fluid that does not reach the stomach. If no contrast material fills the small intestine within 90 minutes of administration and there is an absence of distension of the small intestine, then duodenal stricture is likely. Differentiating a pyloric from a duodenal stricture based on pH of refluxed fluid is not reliable.
The goals in treating GDU in foals are to eliminate clinical signs, promote ulcer healing, and prevent ulcer recurrence and complications. Antiulcer therapy should be instituted on the basis of clinical signs and endoscopic examination. A minimum of two weeks is recommended; some ulcers take longer to heal. Healing should be based upon endoscopic evaluation. In the case of strictures, gastrojejunostomy can correct gastric outflow obstruction and allow duodenal lesions to heal.
Suppression of acid secretion is important in treating gastric and duodenal ulcers in humans. Suppression in the range of 55-60% during a 24 hour period apparently is effective. Higher doses of drugs that suppress acid secretion to a greater degree do not increase the therapeutic benefit. Although there is no evidence that foals with GDU secrete excess acid, there is a clinical impression that acid suppression in such patients is beneficial.
**Agents Which Neutralize Gastric Acids**
Antacids. Antacids reduce gastric acidity by neutralizing secreted gastric acid. The ulcer-healing effects of antacids may also result from their inactivation of pepsin and bile acids. They also improve mucosal defenses by the enhanced synthesis of endogenous prostaglandins.
The common antacids include magnesium hydroxide, aluminum hydroxide, and calcium carbonate. Variations in the chemical formulation account for differences in neutralizing capacity, rapidity of action, and side effects. Most formulations are mixtures of MgOH and AlOH. This combination optimizes the extent and rate of acid neutralization. Magnesium salts and calcium carbonate have a short but rapid neutralizing effect; aluminum hydroxide has a slow rate of acid neutralization that persists longer. There are commercially available mixtures which attempt to maximize antacid-neutralizing properties and to minimize the undesirable effects of each component. Magnesium/aluminum-containing antacids are preferred because of their increased neutralizing capacity, duration of action, and reduced side effects. The most common side effects of antacids are diarrhea and constipation. Magnesium salts produce a dose-related osmotic diarrhea. The frequency of diarrhea is 60-70% when more than 1,000 mEq of antacid is used/day, as compared with <20% for low doses (<300 mEq/day), in man. Constipation tends to occur with large doses of aluminum or calcium salts. Gastrointestinal side effects can be minimized by alternating magnesium/aluminum with aluminum-containing antacids.
All aluminum-containing antacids (except AlP04) form insoluble salts with dietary phosphorous and thereby reduce phosphorous absorption. If taken in high doses for long periods, hypophosphatemia may result and require supplementation. On the other hand, it may be beneficial to renal failure patients with hyperphosphatemia.
Acid rebound, a sustained hypersecretion of gastric acid, can occur after an antacid has emptied from the stomach. Only calcium-containing antacids have been reported to have this effect. The specific mechanism of action is not known but may be related to hypercalcemia and gastrin release. These drugs can also alter the absorption and/or excretion of many drugs when administered concomitantly. The magnitude of the drug interaction may depend on the antacid dose and the type of antacid salt (AlOH vs MgOH). Mechanisms by which antacids effect other drugs include elevation of gastric pH leading to a change in drug dissolution, absorption of drugs, complexation of drugs, and a change in urinary pH that either increases or decreases renal excretion of drugs. Most drug interactions can be avoided by separating administration by 1-2 hours. When administered on an empty stomach their effectiveness lasts only 20 to 40 minutes because of rapid gastric emptying, but when administered following a meal they buffer gastric acid for at least 3 hours. Although they have been used in human medicine for years, there have been few studies to suggest that neutralization of gastric acid effectively promotes or speeds healing of gastric ulceration. The administration of a given quantity of antacid in large infrequent doses is less likely to provide sustained buffering than a more frequent administration of the antacid in smaller doses. The key to success of using antacids for GDU in foals may be frequent administration. Use of antacids has been disappointing, possibly because of stress caused by handling the foal during frequent administration. Antacids are available in several dosage forms and in various potencies.
Histamine H2-receptor antagonists. H2 receptors mediate the action of histamine on gastric parietal cells, heart, uterus, and T lymphocytes and are blocked by H2 antagonists. Inhibition of gastric acid secretion is believed to be through the reduction of intracellular cyclic AMP. The H2 receptor is the dominant receptor for stimulation of acid secretion. This fact is demonstrated by studies in which H2-receptor antagonists are potent inhibitors of cholinergic- and gastrin- stimulated acid secretion while antimuscarinic or gastrin-blocking drugs only partially suppress histamine-stimulated secretion. Presently there are four available for use in the United States, cimetidine, ranitidine, famotidine, and nizatidine. None are approved for use in the horse.
Cimetidine and ranitidine are the most frequently used drugs of this class in equine medicine. The compounds are, however, structurally dissimilar, cimetidine having an imidazole ring and ranitidine a furan ring. This chemical difference probably accounts for some, if not all the important clinical differences. The most important distinction to be made among the H2 blockers is the inhibitory effect of cimetidine on the hepatic cytochrome P450 mixed-function oxidase (MFO) system. The result of this MFO inhibition is a reduction in hepatic clearance, leading to an increased serum concentration of many drugs, including warafin, theophylline, phenytoin, benzodiazepines, lidocaine, and propranolol. Ranitidine binds to the cytochrome P450 enzymes with less affinity and minimally affects drug metabolism. Other side effects include central nervous system toxicity, antiandrogenic effects (impotence, gynecomastia, and breast tenderness), and bone marrow suppression. Ranitidine is not antiandrogenic. Clinical and research experiences have demonstrated that a minimum dosage of 4.4 mg/kg of both cimetidine and ranitidine must be given. Cimetidine should be given 4-6 times daily and ranitidine 2-3 times daily to be effective. It has even been recommended to give cimetidine at 8.8 mg/kg. Medications should be given for 10-21 days. Lower dosages, from 1.1 to 2.2 mg/kg, have been effective in alleviating clinical signs of gastric ulcers, but endoscopic examination has revealed that significant ulceration was present.
Omeprazole, a substituted benzimidazole, inhibits gastric acid secretion be suppressing the activity of hydrogen-potassium-ATPase. This enzyme causes secretion of hydrogen ions into the gastric lumen and is referred to as the proton pump of the parietal cells. Omeprazole blocks the final common step in the pathway of gastric acid secretion. Omeprazole inhibits basal secretion as well as histamine-, gastrin-, and pentagastrin-stimulated secretion of gastric acid. Binding to the H-K-ATPase may explain the prolonged inhibition of acid secretion despite a relatively short half-life. Intravenously administered at 0.5 mg/kg has caused a significant drop in basal free gastric acid content and a concomitant increase in gastric pH (for 7 hours) in the horse. It was temporarily suspended from clinical investigation because of cancer formation in rats, but is presently being used in Zollinger-Ellison syndrome in humans without the side effect.
**Sucralfate** is a complex molecule that consists of a combination of sucrose octasulfate and aluminum hydroxide. Systemic absorption is minimal. The beneficial effects are through local action on the mucosa. The mode of action is multifactorial. In the acid secretion of the stomach, sucralfate dissociates to aluminum hydroxide ions and sucrose octasulfate. Sucrose octasulfate polymerizes to a viscous substance that adheres to the mucosa, protects against back diffusion of hydrogen ions, and promotes ulcer healing. Because of electrostatic charges, sucralfate preferentially adheres to ulcerated tissue. It also inactivates pepsin and absorbs bile acids. The agent is cytoprotective in that it enhances mucosal defense mechanisms by increasing the synthesis of prostaglandins, mucus, and bicarbonate. The common dosage in foals varies from 2-4 grams three to four times daily. The most common side effect is constipation caused by the aluminum hydroxide. Although it may adsorb other drugs that are orally administered, clinical significant drug interactions have not been reported.
Misoprostol is a synthetic prostaglandin E1 analog. It is extensively absorbed, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and, unlike the parent compound, is detectable in plasma. The alpha side chain undergoes beta oxidation and the beta side chain undergoes omega oxidation followed by reduction of the ketone to give PGF analogs. It is rapidly absorbed after oral administration. It does not effect the MFO enzyme systems in animals. It has both antisecretory and mucosal protective properties (increased bicarbonate and mucus). Diarrhea and abdominal pain are the most commonly reported side effects. It may cause abortion. Misoprostol, when administered orally at 0.5 mcg/kg, produced about 80-99% reduction of basal free acid contents for an 8 hour period monitored. It has been reported that the oral administration of 16,16-dimethyl PGE2 ester analogue at 5.0 mcg/kg was effective in preventing GI ulcers induced by a toxic dose of phenylbutazone. In man 3 mcg/kg of misoprostol was as potent as 3 mg/kg of cimetidine. In contrast to a study done in horses which found 0.5 mcg/kg as effective as 8.8.mg/kg of cimetidine when given orally.
**Bismuth subsalicylate** may help speed ulcer healing. It forms insoluble complexes with glycoproteins and mucopolysaccharides of the ulcerated gastric mucosa. Covering the ulcer, they shield the tissue from the irritating gastric juices. Not routinely used 100-200g P.O. appears to have some beneficial effect.
Metoclopramide has a direct stimulatory effect on the upper GI tract and lower esophageal sphincter, thereby decreasing gastric reflux into the esophagus. Intravenous administration of 0.25 mg/kg/hour has been used to increase gastric motility to restore propulsive intestinal motility. May be used in cases of stricture.